Download Welcome to EUROGIN 2003

Welcome to EUROGIN 2003
As promised, we are gathered here to focus on the latest developments and findings in the
prevention, diagnosis and treatment of cervical cancer and human papilloma virus (HPV)
infection. This multi-faceted challenge has once again reunited our growing family of
researchers and physicians from around the world to review and analyse what has been
achieved to date, to determine what remains to be done, and to identify key areas for further
research in a spirit of commitment, friendship and solidarity.
Eighteen years ago, an idea was born to bring together HPV experts and concerned physicians
to assess current knowledge in the field, exchange experiences, and find solutions to the
questions which arise in clinical practice. After much work and a lot of dedication and
support, EUROGIN has become a multi-disciplinary organisation with an international scope.
Today, 1 200 attendees from 70 countries have gathered here to share and increase their
knowledge and skills iin order to relay the message about the latest developments in
preventive measures and to optimise patient care and management. I would also like to point
out that 15 000 visitors have accessed the EUROGIN website over the last 9 months; this is a
clear illustration of the importance of our collaborative effort to provide evidence-based and
timely information not only for doctors but also to respond to patient demand to learn about
prevention or to find out more about their illness or condition.
As participants have come to expect, EUROGIN 2003 covers a multitude of themes ranging
from the latest research discoveries through to clinical application and the role of innovative
technology in providing new diagnostic and treatment options for the prevention and control
of cervical cancer. Highlights of this year's programme include the use of HPV DNA
detection technology in primary screening, recent improvements in PAP smear screening,
office-based probes which allow real-time detection of cervical neoplasia, probes for mitosisassociated proteins and other molecular tests to detect HPV-related lesions. Even the holy
grail of preventing disease caused by HPV may become a reality through HPV vaccination,
and immune modulators and new topical cytostatic formulations hold the promise of
noninvasive interventions to treat our patients. The numerous seminars, scientific sessions,
symposia, plenary sessions, training courses, workshops, and poster presentations have been
designed to allow maximum interaction with leading authorities and experts on a very diverse
range of topics. I am sure that over the next four days, everybody here will find plenty of food
for thought in this structured concentration of knowledge, and benefit from the rich exchange
with old and new friends.
At the same time, we must not lose sight of the fact that among women in low-resource
settings, mortality due to genital tract cancer remains alarmingly high. EUROGIN's ongoing
efforts to facilitate knowledge sharing and technology transfer through international cooperation with regional centres in Latin America, Eastern Europe, Asia and Australia. is
helping to bridge the gap between developed and developing countries. A growing network of
investigators are working together to find better, easier, and cheaper ways to screen, treat and
improve outcome in women in developing regions, and a truly international exchange will
remain a priority for EUROGIN.
On behalf of the Organising Committee, I would like to express my gratitude to all the people
who have worked so hard to make this meeting such a special and relevant event for all
participants. Special thanks go to Daniel Dargent and Alexander Meisels, the Congress
Presidents, the Educational and Scientific Committee for putting together such an exciting
programme, the French and Quebec Ministeries of Health for sponsoring the French sessions
on prevention in womens' health, and the teams at EUROGIN and VBCE for their invaluable
behind-the-scenes assistance. We also thank all the attendees, speakers and sponsors who
ensure the education of both patients and practitioners by taking an active role as healthcare
partners in the field.
We trust that the social programme will allow you to taste the many cultural and culinary
treats that Paris has to offer.
Best regards
Joseph Monsonego
Chairman of the Scientific Committee
Disclaimer
This publication contains the abstracts submitted for the Eurogin 2003 Congress, held in
Paris, from April 13th to 16th, 2003.
More than 600 abstracts were received and reviewed. For uniformity, all abstracts have been
formatted electronically. Occasionally, symbols in electronically submitted abstracts may
have been lost or changed in the re-formatting process. Please advice the Congress staff of
substantive errors that distort the data or change the meaning.
The Abstracts have been organized to reflect the Scientific Program. The first section contains
summaries provided by the invited speakers presenting in the Concurrent Sessions and
Plenaries ; they are followed by the Free Communication abstracts, and the posters, which
are grouped thematically. Please refer to the Final Program for an explanation of the coding
system used. The code shown with each poster abstract is also the number that will appear on
the poster board. These codes are also used ast he reference in the Author and Co-Author
Index.
Publication of these abstracts does not necessarily mean that the information, data, results
and conclusions presented are endorsed by EUROGIN or by the Organizing Committee or the
Scientific Committee of the EUROGIN 2003 Congress.
T
his volume covers the outstanding research developments in Human Papillomavirus
Infection and Cervical Neoplasia Prevention presented during the Eurogin 2003
International Congress on the Global Challenge of Cervical Cancer Prevention, held
in Paris on April 13-16 2003. The programme of the congress was devised to
provide valuable information to delegates, thanks to the participation of internationally
renowned specialists.
During the conference, emphasis was put on the importance of intregating basic and clinical
research into cervical cancer screening and prevention and on the need for international
collaboration and epidemiological studies.
The strateggering pace of new technology has enabled investigators in both academia and
industry to develop innovative approaches to solving many of the problems that have
bedevilled gynecologists and pathologists for years. HPV DNA detection technology has
improved by orders of magnitude and may be useful for primary screening : computers can
screen Paps better than cytotechnologists ; probes that can be used in the office promise real
time cervical neoplasia detection opportunities ; Pap smears using fluid-based systems have
significantly improved sensitivity ; and probes for mitosis-associated proteins and other
molecular tests are being evaluated for potential use in detecting HPV related lesions. Even
the holy grail of of prevention rather than treatment of HPV caused diseases may become a
reality through HPV vaccination. At the same time , new treatment modalities are being
evaluated and are likely to lead to new management algorithms. Immune modulators and new
topical cytostatic formulations may make medical rather than ablative or excisional
procedures a reality.
While this fantastic technology is being pursued in the developed countries, women in low
resource settings continue to die from genital tract cancers at an alarming rate. The problems
relating to money, infrastructure, competing needs, an political indifference frequently seem
insurmountable. But investigators in a dozen countries are systematically exploring better,
easier, and less expensive ways to screen underserved women for cervical neoplasia and to
treat their disease when it is detected. These studies mesh well with advances in service
delivery, and they may all come together in the near future to provide at least partial solutions
to what was thought to be intractable problems.
We trust that the latest technological and pharmaceutical advances presented in the scientific
programme will enable participants to identify current-day problems and provide them with
the opportunity of developing a practical policy.
The international and multidisciplinary participation of delegates was a particularly
stimulating feature. We would like to extend grateful thanks to the contributors and exhibitors
for their generous support as well as to the organizing committee for their devoted efforts and
to Monduzzi Editions for publishing these proceedings.
Joseph Monsonego
Chairman of the Scientific Committee
ORAL SESSIONS
OC: OPENING SESSION
Sunday April 13 - 2003, 19:00 – 20:00
Welcome J. MONSONEGO (FRANCE)
Keynote address : THE STORY OF HUMAN PAPILLOMAVIRUS INFECTION : EMERGENCE,
ACCOMPLISHMENTS AND TRIUMPH
A. MEISELS (CANADA) OC-01
T. COX (USA) OC-02
D. DARGENT (FRANCE)
J.T. SCHILLER (USA) OC-03
Sexually Transmitted Infections (STIs) in the 21st
Century: the Global Picture
Sunday April 13 - 2003
SS1: EMERGING ISSUES OF NON VIRAL STI : CONTEXT, RISK AND SOLUTIONS
• GONORRHEA-CHLAMYDIAE, NEW THOUGHTS ON OLD DISEASES R. PEELING (SWITZERLAND),
SS1-01
• RECENT ADVANCES ON SYPHILIS INFECTION N. DUPIN (FRANCE)
• COMPLICATIONS AND MANAGEMENT OF CHRONIC DISEASES : ADDRESSING THE ISSUES P. JUDLIN
(FRANCE), SS1-03
SS2: NEW DIAGNOSTIC METHODS OF STIs
• MOLECULARBIOLOGICAL METHODS FOR CHLAMYDIAL AND GONOCOCCAL DIAGNOSIS A. STARY
(AUSTRIA), SS2-01
• THE ROLE OF LIQUID-BASED CYTOLOGY IN SEXUALLY TRANSMITTED INFECTIONS E. SHEETS (USA),
SS2-02
• CURRENT ISSUES IN DIAGNOSTIC TESTING OF STIs R. PEELING (SWITZERLAND), SS2-03
• APPLICATIONS OF THE UTILITY CHANNEL CONCEPT FOR THE ESTABLISHMENT OF NEW TARGETS D.
GOLLIN (USA), SS2-04
• RAPID TESTS FOR STIs: PROMISES AND FUTURE CHALLENGES R. PEELING (SWITZERLAND), SS2-05a
• ACCESSIBILITY, AFFORDABILITY AND IMPACT OF POINT OF CARE DIAGNOSTICS FOR STIS IN RESOURCE
POOR COUNTRIES S. HAWKES (UK), SS2-05b
SS3: VIRAL STI: UPDATE, PERSPECTIVES AND EMERGING ISSUES
• HERPEX SIMPLEX, THE SILENT EPIDEMIC M. STEBEN (CANADA), SS3-01
• HUMAN PAPILLOMAVIRUS AS AN STI: WHAT TO UNDERSTAND OF THIS COMPLEX INFECTION J. PALEFSKY
(USA), SS3-02
• HIV MANAGEMENT ISSUES IN WOMEN D. MONEY (USA), SS3-03
• HEPATITIS B AND HEPATITIS C S. GARLAND (AUSTRALIA), SS3-05
• PERSPECTIVES OF TREATMENT S. TYRING (USA)
SS4: PREVENTION & MANAGEMENT OF STI CURRENT STRATEGIES, PROTOCOLS &
GUIDELINES: AN INTERNATIONAL FORUM
• PREVENTION OF STIS, HOW EFFECTIVE CAN YOU BE: THE WHO PERSPECTIVE R. PEELING
(SWITZERLAND)
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• EUROPEAN MANAGEMENT GUIDELINES FOR NON VIRAL STIS J.M. BOHBOT (FRANCE)
• THE CDC PROTOCOLS FOR MANAGEMENT OF VIRAL STIS (EXCLUDING HPV) S. ARAL (USA)
• CONSENSUS CONFERENCE: MANAGEMENT OF EXTERNAL GENITAL WARTS A. FERENCZY (CANADA),
SS4-04
• CONCLUSION : BUILDING STIS CONTROL PROGRAM
Training Courses
Sunday April 13 – 2003
TC1-1: COLPOSCOPY COURSE: 1 - DIAGNOSIS OF CIN
• EDUCATIONAL LECTURE H. JONES (USA)
• COLPOSCOPY OF THE NORMAL CERVIX A. SINGER (UK)
• COLPOSCOPY OF THE ABNORMAL CERVIX (CIN AND HPV INFECTIONS) AND NEW NOMENCLATURE P.
WALKER (UK), TC1-1-03
• GRADING COLPOSCOPIC FEATURES S. DEXEUS (SPAIN)
• COLPOSCOPY OF GLANDULAR LESIONS J. JORDAN (UK)
TC1-2: COLPOSCOPY COURSE: 2 - TREATMENT OF CIN
• HOW TO TREAT ? W. PRENDIVILLE (IRELAND)
• TREATMENT OF CIN: RESULTS, COMPLICATIONS AND FOLLOW-UP D. LUESLEY (UK), TC1-2-02
TC1-3: COLPOSCOPY COURSE: 3 - INTERACTIVE COURSE VIDEO MASTER CLASS
AND CASE STUDIES (TOUCH PAD)
M. ROY (CANADA), J.L. LEROY (FRANCE), D. LUESLEY (UK), A. FERENCZY (CANADA), F. BOSELLI
(ITALY), A. PERINO (ITALY), J.C. BOULANGER (FRANCE), J.L. MERGUI (FRANCE), T.J.M. HELMERHORST
(THE, NETHERLANDS) D. PEREIRA DA SILVA, (PORTUGAL) J.M. MOUTINHO (PORTUGAL), M. MENTON
(GERMANY), E. DIAKOMANOLIS (GREECE), S. TATTI (ARGENTINA), P. NAUD (BRAZIL), S. DEXEUS
(SPAIN), A. BAR-AM (ISRAEL), J. JORDAN (UK), R. TESTA (ARGENTINA), P. WALKER (UK), G. DE PALO
(ITALY), M. PERONI (ITALY), H. JONES (USA), B. BLANC (FRANCE), P. HILLEMANNS (GERMANY)
TC2: CYTOPATHOLOGY COURSE
• CYTOPATHOLOGY TERMINOLOGY 2003 E. WILKINSON (USA), TC2-01
• CONVERSION TO LIQUID-BASED GYNECOLOGIC CYTOLOGY, A USA PERSPECTIVE M. AUSTIN (USA),
TC2-03
• COMPUTER-ASSISTED AUTOMATION D. WILBUR (USA), TC2-04
• PROLIFERATION AND DIFFERENTIATION MARKERS E. Mc GOOGAN (UK)
• MOLECULAR TECHNIQUES FOR CYTODIAGNOSIS J. LINDER (USA), TC2-07
• INTERACTIVE CASE STUDIES with the contribution of experts: R. ASHFAQ (USA), R. DACHEZ (FRANCE), S.
LABBE (FRANCE), N. FROMENT (FRANCE), R. MARTY (FRANCE), L. ZERAT (FRANCE), J. LINDER (USA), O.
REAL (PORTUGAL), A. MEISELS (CANADA), J.C. HAMMOU (FRANCE), D. WILBUR (USA), T. DARRAGH (USA)
TC3-1: VULVAR DISEASES COURSE
• EDUCATIONAL LECTURE R.W. JONES (NEW ZEALAND)
• THE VULVA: FROM NORMAL TO DISEASES M. MOYAL-BARRACCO (FRANCE)
• VULVODYNIA J. BORNSTEIN (ISRAEL), TC3-1-03
• LICHEN SCLEROSUS AND SQUAMOUS CELL HYPERPLASIA S. NEILL (UK), TC3-1-04
• LICHEN EROSIVE OF THE VULVA M. PELISSE (FRANCE)
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• VULVAR EROSIONS AND ULCERATIONS M. FAURE (FRANCE), TC3-1-06
• VIN: DIAGNOSTIC AND TREATMENT M. SIDERI (ITALY), TC3-1-07
• PAGET'S DISEASE B. PANIEL (FRANCE)
• PSYCHOSOMATIC EVALUATION OF VULVAR PAIN M. STEBEN (CANADA), TC3-1-09
TC3-2: VULVAR DISEASES COURSE
• VULVAR DISEASES COURSES: INTERACTIVE CASE STUDIES L. MICHELETTI (ITALY), TC3-2-01
with the contribution of experts: M. VAN BEURDEN (THE NETHERLANDS), M. FAURE (FRANCE), M. PELISSE
(FRANCE), R.W. JONES (NEW ZEALAND), M. SIDERI (ITALY), M. MOYAL-BARRACCO (FRANCE),
C. RENAUD-VILMER (FRANCE)
TC4-1: OFFICE GYNAECOLOGICAL PROCEDURES. TRICKS OF THE TRADE:
1 - LOWER GENITAL TRACT
• DIGITAL COLPOSCOPY S.C. QUEK (INDONESIA), TC4-1-01
• ENDOCERVICAL CURETTAGE (ECC) VERSUS ENDOCERVICAL BRUSHING A.FERENCZY (CANADA),
TC4-1-02
• INDICATIONS AND MODALITIES OF CO2 LASER A.SINGER (UK)
• LLETZ, SWETZ W.PRENDIVILLE (IRELAND)
• VARILOOP J.L. MERGUI (FRANCE)
• CRYOTHERAPY FOR CERVICAL INTRAEPITHELIAL NEOPLASIA A. FERENCZY (CANADA), TC4-1-06
• TREATMENT OF VAGINAL DISEASE E. PARASKEVAIDIS (GREECE)
• DUO-BRUSH: A NEW DEVICE FOR CONVENTIONAL AND LIQUID BASED PAP-TEST SAMPLING D. BARRES,
C. SAVET (FRANCE), TC4-1-08
TC4-2: OFFICE GYNAECOLOGICAL PROCEDURES: OLD AND NEW:
2 - BREAST
• DUCTAL LAVAGE AND THE MANAGEMENT OF WOMEN AT HIGH RISK FOR BREAST CANCER VOGEL,
TC4-2-01
TC4-3: OFFICE GYNAECOLOGICAL PROCEDURES: OLD AND NEW:
3 - ENDOMETRIUM
• HYSTEROSONOGRAPHY VERSUS HYSTEROSCOPY N. PERROT (FRANCE)
• 3D ULTRASOUND VERSUS 2D VAGINAL SCANNING FOR UTERINE DISEASES F. BONILLA-MUSOLES
(SPAIN)
• ADNEXAL DISEASES : SUSPICIOUS SIGNS J.N. BUY (FRANCE)
• MANAGEMENT OF POST-MENOPAUSAL BLEEDING L. BOUBLI (FRANCE)
• HYSTEROSCOPIC TREATMENT OF SYNECHIAS J. HAMOU (FRANCE)
• OFFICE HYSTEROSCOPY : IS IT POSSIBLE DURING CONSULTATION ? J.L. MERGUI (FRANCE)
• PIPELLE® MARK II : A NEW DEVICE FOR COMBINED CYTOLOGY AND HISTOLOGY TESTING OF THE
ENDOMETRIUM E. CORNIER (FRANCE), TC4-3-07
• THE FIRST OESTRO-PROGESTIN COMBINATION IN 24 J.L. MERGUI (FRANCE)
•
Monday April 14 – 2003
TC5: ADVANCED COURSE ON SEXUALLY TRANSMITTED INFECTIONS (STI)
• MST RÉÉMERGENTES: GONOCOCCIE ET SYPHILIS A. BERREBI (FRANCE), TC5-01
• INFECTIONS ET GROSSESSE J.P. STAHL (FRANCE)
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• CONSEILS DE PRÉVENTION POUR LES COUPLES SÉRODIFFÉRENTS A. BERREBI (FRANCE), TC5-04
• DIAGNOSTIC RAPIDE DES INFECTIONS GÉNITALES. ACTUALITÉS ET PERSPECTIVES. LE POINT DE VUE DU
BIOLOGISTE ET DU CLINICIEN J.E. MALKIN (FRANCE), J. CROIZE (FRANCE)
Seminars
Sunday April 13 - 2003
SEM1-1: HPV IN CLINICAL PRATICE I: ROLE OF HPV TESTING FOR MANAGING
PATIENTS WITH ABNORMAL PAP • Session supported by DIGENE
• VACCINATION AGAINST ONCOGENIC VIRUSES: LESSONS FROM THE HEPATITIS B VACCINES A.GOUDEAU
(FRANCE)
• EPIDEMIOLOGICAL EVIDENCE AND RATIONALE FOR HPV TESTING E. FRANCO (CANADA), SEM1-1-01
• NOVEL MARKERS FOR RISK STRATIFICATION OF HPV POSITIVE WOMEN A. LORINCZ (USA), SEM1-1-02
• REVUE OF CURRENT PRACTICE T. COX (USA)
• MANAGEMENT AS A RESULT OF THE ALTS TRIAL AND BETHESDA PROTOCOLS T. COX (USA), SEM1-1-04
• HPV AS A TEST OF CURE T. WRIGHT (USA), SEM1-1-05
• HUMAN PAPILLOMAVIRUS TYPES AND VARIANTS IN HIV SEROPOSITIVE AND SERONEGATIVE SOUTHERN
ITALIAN WOMEN R. PICCOLI (ITALY)
• THE EFFECT OF HPV INFECTION ON THE QUALITY OF SPERM M. RINTALA (FINLAND)
• A COMPREHENSIVE ANALYSIS OF HIGH-RISK HPV INVOLVEMENT IN ADENOCARCINOMA AND
ADENOCARCINOMA IN SITU OF THE CERVIX P.J.F. SNIJDERS (THE NETHERLANDS)
SEM1-2: HPV IN CLINICAL PRACTICE II: HPV TESTING IN PRIMARY SCREENING, AN
INTERNATIONAL EXPERIENCE
1 - DEVELOPED WORLD
• UNITED KINGDOM: THE HART STUDY UPDATE J. CUZICK (UK) SEM1-2-07
• FRANCE C. CLAVEL (FRANCE)
• GERMANY K.U. PETRY (GERMANY)
• NETHERLANDS C. MEIJER (THE NETHERLANDS)
• CANADA S. RATNAM (CANADA), SEM1-2-05
• PORTLAND: STUDY UPDATE A. LORINCZ (USA), SEM1-2-06
SEM1-3: HPV IN CLINICAL PRACTICE II: HPV TESTING IN PRIMARY SCREENING, AN
INTERNATIONAL EXPERIENCE
2 - DEVELOPING COUNTRIES
• SOUTH AFRICA L. DENNY (SOUTH AFRICA), SEM1-3-01
• INDIA R. SANKARANARAYANAN, SEM1-3-02
• CHINA J.L. BELINSON (USA), SEM1-3-03
• CONCLUSIONS T. COX (USA), C. MEIJER (THE NETHERLANDS)
SEM2-1: EMERGING ISSUES IN CERVICAL CANCER SCREENING:
1 - DEVELOPED COUNTRIES
• EPIDEMIOLOGY OF CERVIX CANCER IN DEVELOPED COUNTRIES. EVOLUTION SINCE THE INTRODUCTION
OF THE PAP TEST M. PARKIN (FRANCE), SEM2-1-01
• ORGANISED SCREENING PROGRAMMES FOR CERVICAL CANCER: EXPERIENCE IN FINLAND M. HAKAMA
(FINLAND), SEM2-1-02
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• VOLUNTARY SCREENING PROGRAMMES FOR CERVICAL CANCER: EXPERIENCE IN FRANCE
R. ANCELLE-PARK (FRANCE), H. SANCHO GARNIER (FRANCE)
• ECONOMICS: EFFECTIVENESS, COST-EFFECTIVENESS AND LIMITING FACTORS D. HABBEMA
(NETHERLANDS), SEM2-1-03
• CERVICAL SCREENING: THE CHALLENGE FOR THE FUTURE J. PATNICK (UK), SEM2-1-04
• CHALLENGE FOR THE FUTURE J. PATNICK (UK)
SEM2-2: EMERGING ISSUES IN CERVICAL CANCER SCREENING:
2 - DEVELOPING COUNTRIES With the Contribution of Alliance for Cervical Cancer Prevention (ACCP)
• PROGRAMME OF ALLIANCE FOR CERVICAL CANCER PREVENTION (ACCP) P. BLUMENTHAL (USA)
• CERVICAL CYTOLOGY. DOES IT WORK? L. DENNY (SOUTH AFRICA), SEM2-2-02
• HPV DNA TESTING T. WRIGHT (USA), SEM2-2-03
• VIA R. SANKARANARAYANAN (FRANCE), SEM2-2-04
• REAL TIME SCREENING METHODS A. SINGER (UK), SEM2-2-05
• SCREENING TESTS RELEVANT TO DEVELOPING COUNTRIES T. WRIGHT (USA), SEM2-2-06
• THE ALLIANCE FOR CERVICAL CANCER PREVENTION: 2003 STATUS J. SHERRIS (USA), SEM2-2-07
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Plenary Sessions
Monday April 14 - 2003
PS1: PREVENTING AND CONTROLLING CERVICAL CANCER, AN INTERNATIONAL
COMMITTMENT:
1 - INTEGRATING EVIDENCE-BASED-MEDICINE INTO THE PRACTICE
• CERVICAL CANCER CONTROL, FROM PAST TO PRESENT TO FUTURE, TRIBUTE TO F. MONTZ A. SINGER
(UK)
• THE CAUSAL ASSOCIATION BETWEEN HPV AND CERVICAL CANCER X. BOSCH (SPAIN), PS1-02
• MOLECULAR EVIDENCE OF HPV CARCINOGENESIS A. LORINCZ (USA), PS1-03
• CERVICAL CANCER SCREENING, FACING THE REALITY IN THE WORLD M. PARKIN (FRANCE),
PS1-04
• NEW SCREENING METHODS, CHALLENGING THE SUCCESS R. RICHART (USA)
• MANAGING THE ABNORMAL PAP: CURRENT PRACTICE PROTOCOLS T. COX (USA), PS1-06
PS2: PREVENTING AND CONTROLLING CERVICAL CANCER, AN INTERNATIONAL
COMMITTMENT:
2 - THE PATIENT, A WISE CONSUMER
• WOMEN AGAINST CERVICAL CANCER L. ALEXANDER (USA), PS2-01
PS3: PREVENTING AND CONTROLLING CERVICAL CANCER: AN INTERNATIONAL
COMMITTMENT:
3 - THE ROLE OF DECISION MAKERS AND INSTITUTIONS
• IMPACT OF HEALTH ECONOMIES E.R. MYERS (USA)
• THE CONSENSUS CONFERENCES L. ALEXANDER (USA), PS3-02
• ROLE OF INTERNATIONAL ORGANISATIONS AND NGOS A. MILLER (GERMANY), PS3-03
PS4: MODERN AND FUTURE PRACTICE ISSUES: I - CLINICAL PRACTICE ISSUES:
ACCREDITATION, CERTIFICATION, QUALITY SCIENCE EVALUATION PROGRAMS
• THE RATIONALE FOR ACCREDITATION, CERTIFICATION & QUALITY SCIENCE EVALUATION PROGRAMS
H.W. LAWSON (USA), PS4-01
• FORMULATING GUIDELINES IN COLPOSCOPY H.C KITCHENER (UK), PS4-02
• COLPOSCOPY - WHO SHOULD PRACTICE? H.C KITCHENER (UK), PS4-03
• ACCREDITATION, CERTIFICATION, QUALITY SCIENCE EVALUATION PROGRAMS K. ALLEN, PS4-4a
• CLINICAL PRACTICE ISSUES A. MEISELS (CANADA), PS4-4b
• QUALITY SCIENCE EVALUATION PROGRAMS H.W. LAWSON (USA), PS4-5a
• EVALUATION AND PERFORMANCE MONITORING IN THE NATIONAL HEALTH SERVICE CERVICAL
SCREENING PROGRAMME (NHSCSP) J. RIMMER (UK), PS4-5b
PS5: MODERN AND FUTURE PRACTICE ISSUES II: INNOVATION IN HIGH
PERFORMANCE COMMUNICATION SYSTEMS
• INNOVATION IN HIGH PERFORMANCE COMMUNICATIONS SYSTEMS L. ALEXANDER (USA), PS5-00
• TELECOLPOSCOPY I.J. ETHERINGTON (USA), PS5-01
• HEALTH ON THE NET C. BOYER (SWITZERLAND)
• STEPS TOWARD RELIABLE ONLINE CONSUMER HEALTH INFORMATION C. BOYER (SWITZERLAND),
PS5-03
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PS6-1: MANAGEMENT PROTOCOLES OF CERVICAL NEOPLASIA
PART 1: DISCUSSION ON IDEAL PROTOCOLS
• 2001 BETHESDA SYSTEM T. WRIGHT (USA), PS6-1-01
• ASCUS T. WRIGHT (USA), PS6-1-02
• MANAGEMENT OF WOMEN WITH LSIL CYTOLOGY E. WILKINSON (USA), PS6-1-03
• H. SIL/ADC T. COX (USA)
• EARLY INVASION E. DIAKOMANOLIS (GREECE)
PS6-2: MANAGEMENT PROTOCOLES OF CERVICAL NEOPLASIA
PART 2: THE PRACTICALITY OF MANAGEMENT PROTOCOLS WORLDWIDE: AN
INTERNATIONAL FORUM
• INTERNATIONAL FEDERATION OF COLPOSCOPY AND CERVICAL PATHOLOGY – IFCCP S. DEXEUS
(SPAIN)
• EUROPEAN FEDEATION OF COLPOSCOPY - EFC J. JORDAN (UK)
• AMERICAN SOCIETY OF COLPOSCOPY AND CERVICAL H. JONES (USA)
PS7: CONCLUSION: CERVICAL CANCER CONTROL, PRIORITIES AND NEW
DIRECTIONS - INTERNATIONAL CHARTER
• HPV C. MEIJER (THE NETHERLANDS), T. COX (USA)
• EPIDEMIOLOGY X. BOSCH (SPAIN) PS7-2a, E. FRANCO (CANADA) PS7-2b
• CYTOPATOLOGY E. MC GOOGAN (UK), J. LINDER (USA)
• COLPOSCOPY/MANAGEMENT A. SINGER (UK), J. MONSONEGO (FRANCE)
• SCREENING T. WRIGHT (USA), R. SANKARANARAYANAN (FRANCE)
• VACCINES J.T. SCHILLER (USA), P. COURSAGET (FRANCE), I FRAZER (AUSTRALIA)
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Scientific Sessions
April 15-16 - 2003
SS5: NEW DEVELOPMENTS ON HPV TESTING METHODS
• UPDATE ON TARGET AMPLIFICATION-BASED HPV TESTS C. MEIJER (THE NETHERLANDS)
• NEW DEVELOPMENTS ON HPV TESTING METHODS T. IFTNER (GERMANY), SS5-02
• DETECTION OF HIGH-RISK HUMAN PAPILLOMAVIRUS USING A PROTOTYPE AMPLICOR MWP ASSAY J.
KORNEGAY (USA), SS5-03
• HPV DETECTION AND GENOTYPING BY BROAD-SPECTRUM SFP10 CPR AND REVERSE HYBRIDIZATION ON
A LINE PROBE ASSAY W.G.V. QUINT (THE NETHERLANDS), SS5-04
• P16INK4A: A POSSIBLE MARKER FOR DIAGNOSIS OF CERVICAL PRE-CANCER - AN ALTERNATIVE TO HPV
TESTING? K. BISGAARD (DENMARK), SS5-06
• HIGH LEVEL EXPRESSION OF HPV-16 E7 ONCOPROTEIN IN CERVICAL BIOPSIES REVEALED BY
IMMUNOHISTOCHEMISTRY: A NEW METHOD FOR CERVICAL CANCER SCREENING P. JANSEN-DUERR
(AUSTRIA), SS5-07
• PROSPECTS FOR ENHANCED SIGNAL AMPLIFICATION-BASED HPV TESTS A. LORINCZ (USA), SS5-08
SS6: HPV TESTING: RECENT CLINICAL APPLICATIONS
• PERSISTENT HPV INFECTION: ROLE OF HPV DNA TESTING A. FERENCZY (CANADA), SS6-01
• CLINICAL ROLE OF VIRAL LOAD J. CUZICK (UK), SS6-02
• SCREENING BY SELF SAMPLING FOR HPV DNA P. HILLEMANNS (GERMANY), SS6-03
• RATIONALE FOR MODULATION OF CYTOLOGIC SCREENING INTERVALS BASED ON HPV TESTING IN
WOMEN 30+ YEARS OF AGE W. KINNEY (USA), SS6-04
• HPV TESTING CAN REDUCE THE NUMBER OF FOLLOW-UP VISITS IN WOMEN TREATED FOR CERVICAL
INTRAEPITHELIAL NEOPLASIA GRADE 3 G.D. ZIELINSKI (THE NETHERLANDS), SS6-05
• VALUE OF HUMAN PAPILLOMAVIRUS TESTING AFTER CONIZATION FOR HIGH GRADE SQUAMOUS
INTRAEPITHELIAL LESION P. COLLINET (FRANCE), SS6-06
• CORRELATION OF VIRAL INTEGRATION AND VIRAL LOAD AMONG HPV 16 INFECTED WOMEN
S. SYRJANEN (FINLAND), SS6-07
• EPIDEMIOLOGY OF HPV INFECTION IN PICARDY AND VIRAL LOAD J.C. BOULANGER (FRANCE), SS6-08
• EVALUATION OF UNIVERSAL COLLECTION MEDIUM (UCM)® FOR THE DETECTION OF HUMAN
PAPILLOMAVIRUS (HPV), NEISSERIA GONORRHOEAE (NG) AND CHLAMYDIA TRACHOMATIS BY THE
HYBRID CAPTURE II® (HC II) AS A MOLECULAR TEST G. DORES (BRESIL), SS6-09
• A CROSS SECTIONAL STUDY OF PHYSICIAN AND PATIENT COLLECTED CERVICAL MATERIAL FOR
CYTOLOGY AND HPV TESTING F. GARCIA (USA), SS6-10
SS7: CYTOPATHOLOGY, TRENDS AND FUTURE APPLICATIONS
• INTRODUCTION R. RICHART (USA)
• LIQUID-BASED CYTOLOGY SYSTEMS E. MC GOOGAN (UK)
• THIN-PREP IMAGING SYSTEM J. LINDER (USA), SS7-03
• TRI-PATH IMAGING SYSTEM D. WILBUR (USA)
SS8: REAL TIME SCREENING METHODS: CURRENT AND EMERGING
TECHNOLOGIES
• THE VALUE OF REAL TIME SCREENING METHODS A. SINGER (UK), SS8-01
• OPTOELECTRONIC METHODS IN PRIMARY AND SECONDARY SCREENING S.C. QUEK (INDONESIA), SS8-02
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• IN VIVO MICROSCOPIC IMAGING OF CERVIX BY FIBER OPTIC CONFOCAL MICROSCOPY A. MILBOURNE
(USA), SS8-03
• CERVICAL SPECTROSCOPY AS AN ADJUNCT TO COLPOSCOPY L. ALEXANDER (USA), SS8-04
• CERVICAL FULL-FIELD FLUORESCENCE IMAGING FOR HIGH SIL A. FERENCZY (CANADA)
• VIA /VIAM L. DENNY (SOUTH AFRICA)
• SINGLE VISIT APPROACH TO CERVICAL CANCER PREVENTION: SAFETY AND ACCEPTABILITY IN RURAL
THAILAND P. BLUMENTHAL (USA), SS8-07
SS9: SCREENING FOR ANAL NEOPLASIA IN WOMEN: CHALLENGES AND
OPPORTUNITES
• EPIDEMIOLOGY AND PATHOGENESIS OF AIN IN WOMEN J. PALEFSKY (USA), SS9-01
• WOMEN AND AIN, THE PERSPECTIVES OF THE GYNECOLOGIST I. HEARD (FRANCE), SS9-02
• DIAGNOSTIC METHODS FOR AIN T. DARRAGH (USA), SS9-03
• CONVENTIONAL SURGICAL TREATMENT AND IRC TREATMENT OF AIN P. GODEBERGE (FRANCE), SS9-04
• IMIQUIMOD AND THERAPEUTIC VACCINE APPROACHES TO AIN S. TYRING (USA)
• THE RESEARCH AGENDA FOR THE NEXT DECADE J. PALEFSKY (USA)
SS10: HPV EPIDEMIOLOGY, RECENT PROGRESS
• NEW DIRECTIONS IN HPV EPIDEMIOLOGY E. FRANCO (CANADA), SS10-01
• HORMONES AND OTHER RISK FACTORS FOR CERVICAL CANCER X. BOSCH (SPAIN), SS10-02
• UPDATE ON MEN'S ROLE X. BOSCH (SPAIN), X. CASTELLSAGUE (SPAIN) SS10-03
• NATURAL HISTORY STUDIES N. SCHLECHT (CANADA), SS10-04
• OTHER STDS ISSUES J.H.F. SMITH (UK), SS10-05
• ADVANCES AND PERSPECTIVES IN HPV VACCINES S. FRANCESCHI (FRANCE), SS10-06
• HPV TRANSMISSION IN FAMILIES S. SYRJANEN (FINLAND), SS10-07
SS10a: EUROPEAN CERVICAL CANCER CONSORTIUM
• EDUCATION PROJECT P. DAVIES (UK)
• MODELLING PROJECT T. IFTNER (GERMANY)
• CERVICAL CANCER SCREENING IN EUROPE: DATA ON SEVEN/EIGHT YEARS OF FOLLOW-UP IN DENMARK
S. KRUGER-KJAER (DENMARK), SS10A-03
• HPV TESTING IN PRIMARY SCREENING WITH HYBRID CAPTURE: AN EXPERIENCE OF 5 YEARS IN A
FRENCH POPULATION C. CLAVEL (FRANCE), SS10A-04
• PRIMARY SCREENING FOR HUMAN PAPILLOMAVIRUS INFECTION J. DILLNER (SWEDEN), SS10A-05
• THE MISCAN MODEL: EXPERIENCE FROM THE DANISH TRIALS T. COOL (NETHERLANDS), SS10A-06
SS11: ADVANCED TOPICS ON HPV IMMUNOLOGY
• IMMUNOBIOLOGY OF HPV INFECTIONS M. STANLEY (UK), SS11-01
• T CELL RESPONSES AND ANTIGEN PROCESSING IN CERVICAL CANCER S. MAN (UK), SS11-02
• RELATIVE IMMUNOGENICITIES OF HPV16 ANTIGENS IN WOMEN WITH DIFFERENT DEGREES OF CERVICAL
DYSPLASIA J. STEELE (UK), SS11-03
• THE ANTIBODY RESPONSE IN HUMAN PAPILLOMAVIRUS INFECTIONS J. DILLNER (SWEDEN), SS11-04
• HLA F. BREITBURD (FRANCE)
• IMMUNOTHERAPY OF HPV INFECTION S. TYRING (USA)
• CLINICAL ASPECTS OF IMMUNOLOGY A.B. MOCICKI (USA), SS11-8a
EUROGIN 2003
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• CLINICIAN PANEL: TRANSLATING IMMUNOLOGY INTO THE PRACTICE I. BOURGAULT-VILADA (FRANCE),
SS11-8b
SS12: ANOGENITAL NEOPLASIA IN HIV POSITIVE MEN AND WOMEN
• EPIDEMIOLOGY AND PATHOGENESIS OF HPV AND CIN IN HIV-POSITIVE WOMEN I. HEARD (FRANCE),
SS12-01
• DIAGNOSTIC WORKUP IN HIV POSITIVE WOMEN T. WRIGHT (USA)
• EFFECT OF HAART ON CIN D. MONEY (USA), SS12-03
• LONG TERM EFFECT OF HIGLY ACTIVE ANTIRETROVIRAL THERAPY ON HPV INFECTION AND RELATED
LESIONS IN HIV POSITIVE WOMEN F. LILLO (ITALY), SS12-04
• ROLE OF MUCOSAL IMMUNITY IN THE NATURAL HISTORY OF HPV INFECTION IN HIV INFECTED AND NON
INFECTED WOMEN: PRELIMINARY REPORT H. CASOLATI (ITALY), SS12-05
• TREATMENT OF ANOGENITAL NEOPLASIA IN WOMEN M. ROY (CANADA)
• EPIDEMIOLOGY AND PATHOGENESIS OF AIN IN MEN J. PALEFSKY (USA), SS12-08
SS13: COLPOSCOPY, IMPROVING THE PRACTICE
• EVALUATION OF THE A.T.Z. : ACCURACY OF COLPOSCOPY H. JONES (USA)
• ADJUNCT TEST TO COLPOSCOPY: THE ROLE OF HPV DNA TESTING A. FERENCZY (CANADA), SS13-03
• TECHNOLOGY ASSESSMENT OF FLOURESCENCE AND REFLECTANCE SPECTROSCOPY A MILBOURNE
(USA), SS13-05
• EXPLORING THE CHARACTERISTICS OF A COLPOSCOPY SCORING SYSTEM B. STRANDER (SWEDEN),
SS13-07
• AN AUDIT ON THE FOLLOWUP AFTER THE TREATMENT AFTER CIN P. RAMANATHAN (UK), SS13-08
• IMPLEMENTATION OF FAST TRACK REFERRAL FOR COLPOSCOPIC EXAMINATION V. KAUL (UK), SS13-09
• A POPULATION-BASED STUDY OF COLPOSCOPIC FINDINGS AMONG WOMEN WITH HPV DNA
PERSISTENCE K. ELFGREN (SWEDEN), SS13-10
SS14: PROGRESS IN COLPOSCOPY
• QUALITY STANDARDS IN COLPOSCOPY H.C KITCHENER (UK), SS14-01
• MEDICAL EDUCATION AND COLPOSCOPY TRAINING IN COLPOSCOPY C. REDMAN (UK)
• THE PATIENT'S PERSPECTIVE T. FREEMAN-WANG (UK)
• INVASIVE CERVICAL CANCER: ANALYSIS FROM THE UK NATIONAL SCREENING PROGRAMME
P. WALKER (UK), SS14-04
• MANAGEMENT OF CIN IN PREGNANCY J.J. BALDAUF (FRANCE)
• COLPOSCOPIC FINDINGS AND HPV TYPES D. STEFANON (ITALY)
• MODELLING COLPOSCOPY SERVICES IN THE UK: IMPLICATIONS OF THE PROPOSED GUIDELINE CHANGE
WITH RESPECT TO A SINGLE MILDLY DYSKARYOTIC SMEAR R. HADWIN (UK), SS14-07
• IMPLEMENTING DIGITAL COLPOSCOPY: HOSPITAL NETWORKING AND TELECOLPOSCOPY N. PISAL (UK),
SS14-08
SS15: NEW TECHNOLOGIES, NEW TREATMENTS: APPLICATIONS AND ADVANCED TOPICS
• MULTISPECTRAL DIGITAL COLPOSCOPY FOR THE DETECTION OF CERVICAL NEOPLASIA A MILBOURNE
(USA), SS15-02
• OPTICAL DETECTION OF HIGH-GRADE CERVICAL NEOPLASIA IN VIVO IN 30 SECONDS W.K. HUH (USA),
SS15-04
• ABSTRACT: MULTIMODAL SPECTROSCOPIC IMAGING OF THE HUMAN UTERINE CERVIX FOR TRIAGE OF
PATIENTS WITH INDETERMINATE CERVICAL CYTOLOGY L. TWIGGS (USA), SS15-05
• DIAGNOSTIC EFFICACY OF OPTICAL COHERENCE TOMOGRAPHY FOR PREINVASIVE AND INVASIVE
CANCER OF THE CERVIX AND VULVA J.L. BELINSON (USA), SS15-07
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• DETECTION OF CERVICAL NEOPLASIA USING NON-INVASIVE FIBRE-OPTIC CONFOCAL MICROSCOPY W.
MAC LAREN (AUSTRALIA), SS15-08
• CERVICAL FULL-FIELD FLUORESCENCE IMAGING FOR HIGH-GRADE CIN A. FERENCZY (CANADA),
SS15-06
• A RANDOMIZED PLACEBO-CONTROLLED STUDY OF ZYC101A FOR THE TREATMENT OF HIGH GRADE
INTRAEPITHELIAL NEOPLASIA K.U. PETRY (GERMANY), SS15-09
• A MULTICENTRE STUDY OF A PRIME-BOOST VACCINATION STRATEGY IN WOMEN WITH ANOGENITAL
INTRAEPITHELIAL NEOPLASIA. A. TRISTRAM (UK), SS15-10
• APPLICATION OF IMIQUIMOD BY SUPPOSITORIES (ANAL TAMPONS) EFFICIENTLY PREVENTS
RECURRENCES AFTER ABLATION OF ANAL CANAL CONDYLOMA M. KASPARI (GERMANY), SS15-11
• PHASE 1-2 STUDY OF CIDOFOVIR GIVEN INTRALESIONALY IN CERVICAL INTRAEPITHELIAL NEOPLASIA
GRADE 2 OR 3 C. VAN PACHTERBEKE (BELGIQUE), SS15-12
SS16: CURRENT METHODS FOR SCREENING AND DIAGNOSIS
• OPTICAL DETECTION OF CERVICAL NEOPLASIA: EFFECT OF BIOLOGICAL AND PROCEDURAL VARIABLES
R.M. CESTERO (U.S.A.), SS16-01
• TRUSCAN CERVICAL SCREENING SYSTEM: A PRELIMINARY EXPERIENCE G. DE PALO (ITALY)
• DIGITAL CERVICOGRAPHY A. STAFL (USA), SS16-03
• PERFORMANCE OF THE ACETIC ACID TEST WHEN USED IN FIELD CONDITIONS AS A SCREENING TEST
FOR CERVICAL CANCER P. CLAEYS (BELGIUM), SS16-04
• USE OF P16INK4A AS A DIAGNOSTIC MARKER IN CERVICAL DYSPLASIA AND CERVICAL CANCER, BASIC
ASPECTS AND CLINICAL APPLICATIONS M. VON KNEBEL DOEBERITZ (GERMANY), SS16-05
• CYTOLOGICAL AND HISTOLOGICAL DETECTION OF P16 IN CERVICAL PRECANCEROUS LESIONS J.
HARIRI (DENMARK), SS16-06
• INITIAL RESULTS FROM WESTERN AUSTRALIA OF HPV REFLEX TESTING USING PCR F. FROST
(AUSTRALIA), SS16-07
• SWISS HPV PRIMARY SCREENING TRIAL: COMPARING CANCER PRECURSOR DETECTION SENSITIVITY
AND SPECIFICITY OF LIQUID-BASED CYTOLOGY AND HYBRID CAPTURE II IN 15 000 WOMEN G. BIGRAS
(SWITZERLAND), SS16-08
SS17: IMPACT OF HEALTH ECONOMICS ON CERVICAL CANCER PREVENTION
• IMPACT OF HEALTH ECONOMICS ON CERVICAL CANCER PREVENTION D. JENKINS (USA), SS17-00
• EVALUATING THE EVIDENCE FOR NEW TECHNOLOGY IN CERVICAL CANCER PREVENTION D. JENKINS
(USA), SS17-01
• MEASURING COSTS D. WHYNES (UK), SS17-02
• IMPACT OF HEALTH ECONOMICS ON CERVICAL CANCER PREVENTION: MEASURING OUTCOMES D.
HARPER (USA), SS17-03
• PUTTING IT TOGETHER: SCREENING E.R. MYERS (USA), SS17-04
• COMBINING PRIMARY AND SECONDARY PREVENTION: POTENTIAL HEALTH AND ECONOMIC IMPACT OF
ADDING A HUMAN PAPILLOMAVIRUS VACCINE TO SCREENING PROGRAMS S. KULASINGAM (USA),
SS17-05
• EXAMINING THE ECONOMIC BURDEN OF GENITAL WARTS: LESSONS FROM THE FIELD R. INSINGA (USA),
SS17-06
SS18: WOMEN'S ADVOCACY SESSION
• WOMEN'S ADVOCACY SESSION L. ALEXANDER (USA), SS18-00
• THE U.S.HPV AND CERVICAL CANCER PREVENTION CAMPAIGN : WOMEN'S ADVOCACY AND EDUCATION
IN ACTION K. CARLSON (USA)
• WOMEN AND CERVICAL CANCER PREVENTION : THE CAPE TOWN EXPERIENCE AND LESSONS L. DENNY
(SOUTH AFRICA)
• HPV INDUCED CERVICAL CANCER: PROVIDING ANSWERS TO PATIENT QUESTIONS T. COX (USA), SS18-04
EUROGIN 2003
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• "LIGUE CONTRE LE CANCER" ACTIONS FOR WOMEN'S PREVENTION ON BREAST CANCER SCREENING
P. MOUROUGA (FRANCE), SS18-05
SS18a: CERVICAL CANCER CONTROL IN LATIN AMERICA
• BASICS GOVERNAMENTAL ACTIONS TO CERVICAL CANCER CONTROL L.C. THULER (BRAZIL)
• METHODS OF VALIDATION ON CERVICAL CANCER CONTROL S. TATTI (ARGENTINA)
• IMPLEMENTATION OF CERVICAL CANCER SCREENING IN LATIN AMERICA AND THE CARIBBEAN: IS IT
FEASIBLE? S. ROBLES (USA), SS18A-03
• COMPARING PAP SMEAR CYTOLOGY, AIDED VISUAL INSPECTION (VIA), SCREENING COLPOSCOPY,
CERVICOGRAPHY AND HPV TESTING BY HCII (NORMAL AND SELF-SAMPLING) AS OPTIONAL SCREENING
TOOLS IN LATIN AMERICA. EXPERIENCE FROM THE LAMS STUDY K. SYRJANEN (ITALY), SS18A-04
SS19: PUBLIC HEALTH ISSUES IN THE PERSPECTIVE OF HPV PROPHYLACTIC
VACCINES Session supported by MERCK VACCINE DIVISION
• EFFICACY PARAMETERS AND CLINICAL ENDPOINTS REQUIRED FOR HPV VACCINATION PROGRAMS E.S.
OLSSON (SWEDEN)
• TRANSMISSION MODELS AND HERD IMMUNITY EFFECTS FOR HPV DISEASE J. HUGHES (USA)
• POTENTIAL COST-EFFECTIVENESS OF VARIOUS PREVENTION E.R. MYERS (USA), SS19-04
SS20: ADVANCES AND PERSPECTIVES IN HPV VACCINES. Educational Grant
supplied by AVENTIS -PASTEUR MSD
• GEOGRAPHIC VARIATION IN HPV INFECTION S. FRANCESCHI (FRANCE), SS20-01
• A RANDOMISED PLACEBO CONTROLLED TRIAL OF IMMUNOTHERAPY FOR CIN I. FRAZER (AUSTRALIA),
SS20-02
• PROPHYLACTIC HPV VACCINE DEVELOPMENT J.T. SCHILLER (USA), SS20-03
• EFFICACY OF AN E7 RECOMBINANT THERAPEUTIC VACCINE J.M. BALLOUL (FRANCE)
• DEVELOPMENT OF AN ADJUVANTED HUMAN PAPILLOMAVIRUS TYPE 16/18 L1 VIRUS LIKE PARTICLE
VACCINE G. DUBIN (USA), SS20-05
• STATUS OF PROPHYLACTIC VACCINES AGAINST CERVICAL CANCER K. JANSEN (USA), SS20-06
• HPV 16 L1E7 CHIMERIC VIRUS-LIKE PARTICLE VACCINE L. GISSMANN (GERMANY), SS20-07
• NEUTRALIZING AND CROSS-NEUTRALIZING ANTIBODIES INDUCED BY L1 AND L1+L2 VIRUS-LIKE
PARTICLES P. COURSAGET(FRANCE), SS20-08
SS21: PRESENT STANDARDS FOR MANAGEMENT OF ABNORMAL PAP/CIN
• CHALLENGING WITH MANAGEMENT OF GLANDULAR LESIONS L. TWIGGS (USA)
• ROLE OF HPV TESTING FOR MANAGING WOMEN WITH ABNORMAL PAP SMEARS: LSIL, HSIL AND AGC W.
KINNEY (USA), SS21-02
• THE IMPACT OF LARGE LOOP EXCISION (LLETZ) ON TREATMENT OF CIN H.C KITCHENER (UK), SS21-03
• IS DESTRUCTIVE TREATMENT OF CIN OBSOLETE ? OUR EXPERIENCE WITH LASER AND CRYOSURGERY
F.B. GUIJON (CANADA), SS21-04
• HOW DO THE SCREENING TOOLS WORK IN EMERGING COUNTRIES S. TATTI (ARGENTINA)
• GUIDELINES FOR MANAGEMENT OF WOMEN WITH CERVICAL CYTOLOGICAL ABNORMALITES J.L. LEROY
(FRANCE), SS21-06
SS22: MANAGEMENT OF ABNORMAL PAP/CIN: CURRENT ISSUES
• DIAGNOSIS OF INTRAEPITHELIAL LESIONS OF THE CERVIX:WICH IS THE GOLD STANDARD? X. CORTESBORDOY (SPAIN), SS22-01
• MANAGEMENT OF NORMAL COLPOSCOPY AFTER AN ABNORMAL SMEAR J.J. BALDAUF (FRANCE)
EUROGIN 2003
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• HOW TO MANAGE PATIENTS FOLLOWING INVOLVED MARGINS CONIZATION A. AGOSTINI (FRANCE),
SS22-03
• ASSESSMENT OF VAGINAL VAULT AFTER HYSTERECTOMY M. PERONI (ITALY), SS22-04
• CONSERVATIVE TREATMENT OF PRECANCEROUS AND EARLY INVASIVE LESIONS IN MENOPAUSAL
WOMEN C. ZANARDI (ITALY), SS22-05
• THE CLININAL AND ECONOMIC BENEFIC OF HPV LOAD ASSESSMENT IN THE FOLLOW-UP AND
MANAGEMENT OF WOMEN POST-CONE BIOPSY DUE TO HIGH GRADE CERVICAL INTRAEPITHELIAL
NEOPLASIA B. ALMOG (ISRAEL), SS22-06
• SINGLE CELL DNA ANEUPLOIDY IS ASSOCIATED WITH ONCOGENIC HPV INFECTION IN ASCUS AND SIL R.
BOLLMANN (GERMANY), SS22-07
SS23: UPDATE AND BREAKTHROUGHS IN CERVICAL CANCER SCREENING
• IMPLEMENTATION OF SCREENING PROGRAMMES A. MILLER (GERMANY), SS23-01
• RENEWING OF THE ORGANIZED SCREENING PROGRAMME FOR CERVICAL CANCER IN FINLAND, A
RANDOMISED EXPERIENCE M. HAKAMA (FINLAND), SS23-02
• TESTING OPTIONAL SCREENING TOOLS FOR CERVICAL CANCER IN THE NEW INDEPENDENT STATES
(NIS) OF THE FORMER SOVIET UNION K. SYRJANEN (ITALY), SS23-03
• SHANXI PROVINCE CERVICAL CANCER SCREENING STUDY II: SELF-SAMPLING FOR HPV COMPARED TO
DIRECT SAMPLING FOR HPV AND LIQUID BASED CERVICAL CYTOLOGY J.L. BELINSON (USA), SS23-04
• DEVELOPING COUNTRIES : SCREEN AND TREAT T. WRIGHT (USA)
• WHEN TO START SCREENING? A.B. MOCICKI (USA), SS23-06
• ESTIMATES OF LIFETIME RISK OF CERVICAL CANCER USING DATA FROM WOMEN WITH MULTIPLE
NEGATIVE PAP TESTS IN A LARGE PRE-PAID HEALTH PLAN. S. KULASINGAM (USA), SS23-07
• CERVICAL CANCER WITHIN 3 YEARS OF CERVICAL CYTOLOGY G.F. SAWAYA (USA)
• PAP TEST HISTORY IN WOMEN WITH INVASIVE CERVICAL CANCER : THE INSTITUT GUSTAVE ROUSSY
EXPERIENCE S. CAMATTE (FRANCE)
• INTERVENTION TO INCREASE ATTENDANCE AT SCREENING FOR CERVICAL CANCER. A LARGE
POPULATION-BASED RANDOISED CONTROLLED TRIAL IN SWEDEN P. SPAREN (SWEDEN), SS23-10
SS24: INNOVATION IN CYTOPATHOLOGY
• INNOVATION IN CYTOPATHOLOGY MEISELS, SS24-01
• IMPROVING DETECTION OF GLANDULAR LESIONS R. ASHFAQ (USA)
• THE ROLE OF FROZEN SECTION EXAMINATION OF CONIZATIONS IN THE MANAGEMENT OF WOMEN WITH
CIN F. BRETELLE (FRANCE)
• HISTOLOGICAL CORRELATION OF CONVENTIONAL AND LIQUID-BASED SMEARS WITH REFERENCE TO
HPV TESTING R. DACHEZ (FRANCE), SS24-04
• DNA-CITOLIQ SYSTEM® (DCS) LIQUID-BASED CYTOLOGY; DIAGNOSTIC PERFORMANCE IN RESIDUAL
CERVICAL SAMPLES G. DORES (BRAZIL), SS24-05
• EVALUATION OF HYPERCHROMATIC GROUPS (HCG) IN CERVICAL SMEARS: EXPERIENCE WITH LIQUID
BASED CYTOLOGY (AUTOCYTE® PREP) SMEARS M. CHIVUKULA (USA), SS24-06
• LIQUID BASED CYTOLOGY AN INNOVATIVE METHOD EIGHT YEARS RESULTS OF EXPERIMENT J.C.
HAMMOU (FRANCE), SS24-07
• A PROSPECTIVE AND RANDOMISED PUBLIC-HEALTH TRIAL ON NEURAL NETWORK ASSISTED
SCREENING FOR CERVICAL CANCER IN FINLAND P. NIEMINEN (FINLAND), SS24-08
• THE FEASIBILITY OF FOKALPOINT IN PRE-SCREENING OF CONVENTIONAL SMEARS AND REDUCTION OF
WORK LOAD J. HARIRI (DENMARK), SS24-09
SS25: HPV AND OTHER STIS INTERACTIONS, NEW TRENDS
• HPV/CHLAMYDIAE INTERACTION J. PAAVONEN (FINLAND)
• HPV/HIV INTERACTION D. MONEY (USA), SS25-02
EUROGIN 2003
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• HPV/HSV INTERACTION J.H.F. SMITH (UK)
• SELF SELECTED SAMPLING FOR DIAGNOSTICS S. GARLAND (AUSTRALIA)
• DIAGNOSIS OF SEXUALLY TRANSMITTED INFECTIONS STI) USING NON INVASIVE SPECIMENS GARLAND,
SS25-04
• REAL TIME PCR QUANTIFICATION OF HPV16 DNA LOAD V. DALSTEIN (FRANCE), SS25-05
• IS PRESERVCYT TRANSPORT MEDIUM SUITABLE FOR CHLAMYDIA TRACHOMATIS DETECTION ? BIANCHI,
SS25-06
• RAPID AND SENSITIVE DETECTION OF HSV DURING PREGNANCY AND BEFORE LABOR BY DFA WITH
MONOCLONAL ANTIBODIES M. ASKIENAZY-ELBHAR (FRANCE), SS25-07
• ASSESSMENT OF THE RISK FACTORS, PATHOGENETIC MECHANISMS AND PROGNOSIS OF HPV
INFECTIONS AND CERVICAL CANCER IN HIV-POSITIVE AND HIV-NEGATIVE WOMEN WITH IMPLICATIONS IN
SCREENING AND MANAGEMENT (HPV-PATHOGENISS STUDY) M. BRANCA (ITALY), SS25-08
• TREATMENT OF GENITAL HERPES WITH RISIQUIMOD S. MAJEWSKI (POLAND)
SS26: GLOBAL APPROACH TO GENITAL WARTS MANAGEMENT
• IMMUNE RESPONSE TO HPV INFECTION S. TYRING (USA)
• RATIONALE OF IMMUNOTHERAPY FOR GENITAL WARTS M. STANLEY (UK), SS26-02
• COMBI-THERAPY FOR EGW'S G. VON KROGH (SWEDEN), SS26-03
• IMMUNOTHERAPY FOR EXTERNAL GENITAL WARTS S. GARLAND (AUSTRALIA), SS26-04
• COST OF WART THERAPIES: A CANADIAN AUDIT A. FERENCZY (CANADA)
• GLOBAL APPROACH TO GENITAL WARTS MANAGEMENT P. LANGLEY (USA), SS26-06
SS27: RECENT PROGRESS ON FERTILITY PRESERVING TREATMENT OF
INFILTRATIVE CERVICAL CANCER Under auspices of European Society of Gynaecological
Oncology (ESGO) & European Academy of Gynaecological Cancer (EAGC)
• INTRODUCTION A. ONNIS (CANADA)
• THE VALUE OF RADIATION THERAPY A. GERBAULET (FRANCE)
• ABDOMINAL RADICAL TRACHELECTOMY P. BOSZE (HUNGARY), SS27-02
• VAGINAL RADICAL TRACHELECTOMY D. QUERLEU (FRANCE), SS27-03
• RADICAL VAGINAL TRACHELECTOMY - RESULTS IN FRANCE D. DARGENT (FRANCE)
• RADICAL VAGINAL TRACHELECTOMY FOR INVASIVE CERVICAL CANCER: THE QUÉBEC EXPERIENCE. M.
ROY (CANADA), SS27-05
• SURGERY : RADICAL VAGINAL TRACHELECTOMY - RESULTS IN UK J.H. SHEPHERD (UK)
• RADICAL VAGINAL TRACHELECTOMY - RESULTS IN THE USA A. BURNETT (USA), SS27-07
• RECENT PROGRESS ON FERTILITY PRESERVING TREATMENT OF INFILTRATIVE CERVICAL CANCER.
CLINICAL APPLICATIONS C. POMEL (FRANCE), SS27-08
• RECENT PROGRESS ON FERTILITY PRESERVING TREATMENT OF INFILTRATIVE CERVICAL
CANCER.CLINICAL APPLICATIONS A. ONNIS (CANADA), SS27-09
• CONCLUSIONS T. MAGGINO (ITALY)
SS28: CURRENT PERSPECTIVES ON VIRAL AND MOLECULAR BIOLOGY
• INTEGRATION OF HUMAN PAPILLOMAVIRUS GENOMES IN ADVANCED CERVICAL DYSPLASIA BASIC
CONCEPTS AND CLINICAL APPLIACATIONS M. VON KNEBEL DOEBERITZ (GERMANY), SS28-01
• CLINICAL SIGNIFICANCE OF GENETIC ALTERATIONS OF CHROMOSOME 3,7,X AND EGFR GENE IN
UTERINE CERVICAL CANCER PROGRESSION G. CORRADO (ITALY), SS28-02
• GENETIC SUSCEPTIBILITY OF ONCOGENIC HUMAN PAPILLOMAVIRUS (HPV) IN CERVICAL CANCER D.
DAT DAO (USA), SS28-03
EUROGIN 2003
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• GENOMIC INSTABILITY AND CHROMOSOMAL ABERRATIONS IN POLYPLOID CELLS OF HIGH-GRADE
SQUAMOUS INTRAEPITHELIAL LESIONS (HSIL) G. MEHES (HUNGARY), SS28-04
• CHROMOSONE 9 POLYSOMY: USE AS AN INTERMEDIATE ENDPOINT BIOMARKER IN INTERIM ANALYSIS
A.T. VLASTOS (SWITZERLAND), SS28-06
• THE DETECTION OF HPV 16 SPECIFIC CD8+ T LYMPHOCYTES IN THE PERIPHERAL BLOOD OF WOMEN
WITH VIN 3 USING AN ELISPOT ASSAY OF INTEFERON GAMMA RELEASE. R. TODD (UK), SS28-07
• RELATIVE DISTRIBUTION OF ONCOGENIC HPV TYPES IN BENIGN AND PRE-MALIGNANT CERVICAL
BIOPSIES. A STUDY WITH HPV DNA SEQUENCE ANALYSIS S. ANDERSSON (SWEDEN), SS28-08
• P16 FREQUENTLY EXPRESSED IN HIGH GRADE SQUAMOUS LESIONS OF THE GENITAL TRACT A. HAN
(USA), SS28-09
• DETECTION OF "HIGH-RISK" ONCOGENIC HPV16 E6 DNA BUT NOT HPV18 DNA IS A FREQUENT FINDING IN
VULVAR LS AND LS-ASSOCIATED SCC S. REGAUER (AUSTRIA), SS28-10
• CYCLIN B1 (CB1) EXPRESSION IN CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN) A.T. VLASTOS
(SWITZERLAND), SS28-11
• THE POTENTIAL OF MIB1 AS A MARKER FOR CERVICAL INTRAEPITHELIAL NEOPLASIA GRADE 3 IN
CERVICAL SCRAPES. R.L.M. BEKKERS (THE NETHERLANDS), SS28-12
SS29: VULVAR DISEASES: THE ESSENTIAL
• THE NATURAL HISTORY OF VULVAL INTRAEPITHELIAL NEOPLASIA (VIN) R.W. JONES (NEW ZEALAND),
SS29-01
• THE ROLE HPV IN VIN. M. VAN BEURDEN (THE NETHERLANDS), SS29-02
• VIN: CONVENTIONAL TREATMENT MODALITIES M. ROY (CANADA), SS29-03
• CHRONIC VESTIBULITIS: NEW DEVELOPMENTS AND UNDERSTANDING L. MICHELETTI (ITALY), SS29-05
• SENTINEL NODE IN VULVAR CANCER M. SIDERI (ITALY), SS29-06
• PLASTIC RECONSTRUCTIVE SURGERY B. PANIEL (FRANCE)
• INCIDENCE OF HPV 16 AND 33 IN PATIENTS WITH MULTICENTRIC LOWER GENITAL TRACT DYSPLASIAS
M. HAMPL (GERMANY), SS29-08
• OVEREXPRESSION OF P53, P16 AND PTEN IN VULVAL INTRAEPITHELIAL NEOPLASIA G. TASKER (UK),
SS29-09
• CLINICAL EFFECTS OF A VACCINE (TA-HPV) IN ANOGENITAL INTRAEPITHELIAL NEOPLASIA. A.
TRISTRAM (UK), SS29-10
SS30: EPIDEMIOLOGY - SCREENING
• HIGH CUMULATIVE PREVALENCE OF HPV IN WOMEN WITH NORMAL CERVICAL CYTOLOGY M. VAN HAM
(THE NETHERLANDS), SS30-01
• HIGH PREVALENCE OF HUMAN PAPILOMAVIRUS TYPE 58 IN MEXICAN WOMEN M. GONZALES-LOSA
(MEXICO), SS30-02
• COMPARATIVE EFFICACY OF VISUAL INSPECTION WITH ACETIC ACID, HPV TESTING AND CONVENTIONAL
CYTOLOGY IN CERVICAL CANCER SCREENING: A RANDOMISED INTERVENTION TRIAL IN MAHARASHTRA
STATE, INDIA S. SHASTRI (INDIA), SS30-03
• SCREENING FOR CERVICAL CANCER PRECURSORS USING VISUAL INSPECTIONS METHODS COMPARED
TO CYTOLOGY IN JAIPUR, INDIA A. SHARMA (INDIA), SS30-04
• COMPARISON OF VISUAL SCREENING METHODS AND CYTOLOGY FOR THE DETECTION OF CERVICAL
CANCER PRECURSORS IN TRIVANDRUN, INDIA T. SOMANATHAN (INDIA), SS30-05
• SCREENING FOR CERVICAL CANCER PRECURSORS USING VISUAL INSPECTION METHODS IN BAMAKO,
MALI A. DOLO (MALI), SS30-06
• SCREENING FOR CERVICAL CANCER PRECURSORS USING VISUAL INSPECTION METHODS IN GUINEA M.
KOULIBALY (GUINEA), SS30-07
• COMPARISON OF VISUAL SCREENING METHODS AND CYTOLOGY IN THE EARLY DETECTION OF
CERVICAL NEOPLASIA IN CALCUTTA, INDIA R. MANDAL (INDIA), SS30-08
EUROGIN 2003
20
• DNACITOLIQ LIQUID-BASED CYTOLOGY SYSTEM VERSUS CONVENTIONAL PAP SMEAR IN A HIGH RISK
POPULATION. ANALYSIS OF 925 SPLIT SAMPLES AND COMPARISON WITH HYBRID CAPTURE II A.
LONGATTO FILHO (BRAZIL), SS30-09
• THE PRESENCE OF CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN) IN ADOLESCENT GIRLS H. VLASTA
(ROMANIA), SS30-10
• ORGANIZATION AND IMPLEMENTATION OF CERVICAL SCREENING PILOT PROGRAM IN COUNTY OF CLUJ,
TRANSILVANIA. O. SUTEU (ROMANIA), SS30-11
• INTERLABORATORY QUALITY CONTROL (QC) OF PAP SMEAR CYTOLOGY AS A PART OF THE
MULTICENTRE TRIAL COMPARING SIX OPTIONAL SCREENING TOOLS IN LATIN AMERICA (THE LAMS
STUDY) M. ERZEN (SLOVENIA), SS30-12
SS31: CARCINOGENESIS, EPIDEMIOLOGY: AN UPDATE
• CARCINOGENESIS J. CUZICK (UK), SS31-00
• NATURAL HISTORY OF HPV INFECTIONS: RECENT DEVELOPMENTS K. SYRJANEN (ITALY), SS31-01
• PROGNOSTIC VALUE OF PERSISTENCE AND LOAD OF HIGH RISK HPV DNA IN THE PROGRESSION TO
CERVICAL HIGH-GRADE LESIONS C. MOUGIN (FRANCE), SS31-02
• DOES TELOMERASE HAVE A ROLE IN HPV INDUCED CARCINOGENESIS? S. SYRJANEN (FINLAND),
SS31-04
• COMPARISON OF HPV TYPE DISTRIBUTION IN HSIL AND CERVICAL CANCER: A METAANALYSIS G.
CLIFFORD (FRANCE), SS31-05
• RELATIONSHIP BETWEEN COEXISTING HIGH-GRADE GLANDULAR AND SQUAMOUS CERVICAL LESIONS
AND HUMAN PAPILLOMAVIRUS INFECTIONS. W. MELCHERS (THE NETHERLANDS), SS31-06
• HUMAN PAPILLOMAVIRUS (HPV) TYPE DISTRIBUTION IN HIV-SEROPOSITIVE AND -SERONEGATIVE
ITALIAN WOMEN R. PICCOLI (ITALY), SS31-07
• HIGH RISK HPV DNA AFFECTS TO PH OF SPERM M. RINTALA (FINLAND), SS31-08
• A COMPREHENSIVE ANALYSIS OF HIGH-RISK HPV INVOLVEMENT IN ADENOCARCINOMA AND
ADENOCARCINOMA IN SITU OF THE CERVIX P.J.F. SNIJDERS (THE NETHERLANDS), SS31-09
SS32: SKIN AND GENITAL CANCER
• P53 CODON 72 POLYMORPHISM IS A RISK FACTOR FOR SKIN CANCERS IN TRANSPLANT RECIPIENTS F.
AUBIN (FRANCE)
• HIGH COPY NUMBER OF HUMAN PAPILLOMAVIRUS TYPE 92 IN TWO CASES OF BASAL CELL CARCINOMA
G. FORSLUND (SWEDEN), SS32-03
• COEXISTENCE OF VIN AND VULVAR CANCER WITH INTRAEPITHELIAL OR INVASIVE CHANGES WITHIN
UTERINE, CERVIX AND VAGINA IN YOUNG WOMEN AS A CLINICAL PROBLEM K. ADAMEK (POLAND),
SS32-04
• TREATMENT PATTERN OF VULVAR CANCER IN ELEDRELY PATIENTS: A POPULATION BASED STUDY V.
BEFFA (SWITZERLAND), SS32-05
• BEHAVIOUR OF MICROINVASIVE (MIC) SQUAMOUS- AND ADENOCARCINOMA OF THE UTERINE CERVIX IN
THE LIGHT OF WORLD LITERATURE AND EXPERIENCE FROM OUR CLINIC M. ERZEN (SLOVENIA), SS32-06
• USING OF FLOW CYTOMETRY PARAMETERS FOR CERVIX CARCINOMA TREATED WITH BRACHYTHERAPY
O. KRAVETZ (RUSSIA), SS32-07
EUROGIN 2003
21
Santé des femmes :
promotion, prévention et
dépistage
• STRATEGIES OF CANCER PREVENTION AT THE GYNECOLOGIST'S CLINIC. CONTRIBUTION TO THE
PROTOCOLS FOR THE ANNUAL VISIT X. BOSCH (SPAIN), SF-01
• IS PREVENTION OF BREAST CANCER POSSIBLE? T. MAUDELONDE (FRANCE), SF-02
• LA CONTRACEPTION ET INTERRUPTIONS DE GROSSESSE COMME DERNIER RECOURS POUR LES
FEMMES, POSITION QUÉBÉCOISE J. BÉRUBÉ (CANADA), SF-03
• CHLAMYDIA TRACHOMATIS ET LUTTE CONTRE L’INFERTILITÉ B. de BARBEYRAC (FRANCE), SF-04
• MUTILATIONS GÉNITALES C. FORTIN (CANADA), SF-05
• DÉPISTAGE DE LA VIOLENCE CONJUGALE ET PROTOCOLE MÉDICO-SOCIAL AUPRÈS DES VICTIMES
D’AGRESSION SEXUELLE L. LANGLOIS (FRANCE), SF-06
• LES ASSOCIATIONS FÉMININES VOUS PARLENT : RÉSEAU QUÉBECOIS D’ACTION POUR LA SANTÉ DES
FEMMES L. LAMONTAGNE (CANADA), SF-07
• NOUVEAUX MODES DE VIE ET CONSEQUENCES SUR LA REPRODUCTION E. SEDBON (FRANCE), SF-08
• SEXUALITE ET QUALITE DE VIE F. PIETTE (FRANCE), SF-09
• NOUVEAUX MODES DE VIE ET CONSEQUENCES SUR LA REPRODUCTION F. PIETTE (FRANCE), SF-10
• FEMMES POUR TOUJOURS N. KREMER (FRANCE), SF-11
• MOUVEMENT FRANÇAIS POUR LE PLANNING FAMILIAL F. LAURENT (FRANCE), SF-12
EUROGIN 2003
22
Free Communications
FC1: HPV TESTING
• HUMAN PAPILLOMAVIRUS AND CERVICAL CANCER: KNOWLEDGE, INFORMATION PROVISION AND
ATTITUDES TO TESTING A. TRISTRAM (UK), FC1-01
• A RANDOMISED TRIAL ON HPV TESTING FOR PRIMARY CERVICAL SCREENING: STUDY DESIGN G.
RONCO (ITALY), FC1-02
• HIGH RISK-HPV AND BORDERLINE AND MILD DYSKARYOSIS IN CERVICAL CANCER SCREENING;
PRELIMINARY RESULTS POBASCAM C. MEIJER (THE NETHERLANDS), FC1-03
• HPV DNA TESTING IN ROUTINE CLINICAL PRACTICE FOR IDENTIFICATION OF UNDERLYING CIN2/3+ IN
WOMEN WITH ASC-US AND AGC PAP SMEARS B. FETTERMAN (USA), FC1-04
• HPV GENOTYPING BY SPF10 PCR LIPA IN COMBINATION WITH COMPLEMENTARY SEQUENCE ANALYSIS
L.J. VAN DOORN (THE NETHERLANDS), FC1-05
• ROUTINE HPV DETECTION BY PCR OR AN AUTOMATED IN SITU HYBRIDIZATION TECHNIQUE - A
COMPARATIVE ANALYSIS AND CLINICAL RELEVANS. S. CAJANDER (SWEDEN), FC1-06
• DETECTION OF HPV AND SUBTYPING OF HPV IN PAP-SPIN MEDIUM COLLECTED CERVICAL CELLS M.
RAMAEL (BELGIUM), FC1-07
• FREQUENT GENITAL SHEDDING OF HUMAN PAPILLOMAVIRUS HARBORING ATYPICAL DISTRIBUTION OF
HIGH-RISK GENOTYPES IN CHILDBEARING-AGED WOMEN LIVING IN LIBREVILLE, GABON A. SIMOHAMED (FRANCE), FC1-08
• HUMAN PAPILLOMAVIRUS AND HERPES SIMPLEX VIRUS TESTING ON SELF-COLLECTED SPECIMENS IN
WOMEN WITH PRIOR NORMAL PAP SMEARS IN BALTIMORE N. KHANNA (USA), FC1-09
• HPV DNA AS A MARKER TO PREDICT RECURRENT CERVICAL DYSPLASIA IN WOMEN POST TREATMENT
J. TAN (AUSTRALIA), FC1-10
• HPV TYPING AND QUANTITATION IN SURGICALLY REMOVED HGSIL, COMPARISON WITH PRE AND POST
SURGICAL CERVICAL BRUSH F. LILLO, FC1-11
FC2: SCREENING AND MANAGEMENT METHODS
• THE VALUE OF ENDOCERVICAL CURETTAGE IN THE EVALUATION OF ABNORMAL PAP SMEARS A.K.
GOODMAN (USA), FC2-01
• THE IMPORTANCE OF THE CELL SAMPLE IN CERVICAL CYTOLOGY-REVISITING THE ENDOCERVICAL
COMPONENT J. GRACE (UK), FC2-02
• WHEN WILL NEW CYTOLOGICAL TECHNOLOGIES FOR CERVICAL CANCER SCREENING BE COSTEFFECTIVE? W. MEERDING (THE NETHERLANDS), FC2-03
• ADJUNCT CERVICAL CANCER SCREENING TESTS: THE ROLE OF PAP SMEAR, VISUAL INSPECTION AND
HYBRID CAPTURE II R. GONTIJO (BRAZIL), FC2-04
• MANAGEMENT OF "ASCUS" IN POSTMENOPAUSAL WOMEN P. CRISTIANI (ITALY), FC2-05
• ATYPICAL GLANDULAR CELLS AND HIGH RISK-TYPES HUMAN PAPILLOMAVIRUS DETECTION BY HYBRID
CAPTURE II S. DERCHAIN (BRAZIL), FC2-06
• COLPOSCOPIC FOLLOW-UP STUDY OF PATIENTS WITH ASCUS/POSSIBLE HIGH GRADE ABNORMALITY
ON PAPANICOLAOU SMEARS R. SKINNER (AUSTRALIA), FC2-07
• REAL TIME DEVICES FOR THE SCREENING AND DIAGNOSIS OF CERVICAL DISEASE C. CHOW (UK),
FC2-08
• DIAGNOSIS OF CERVICAL IMAGES CAPTURED WITH A DIGITAL VIDEO COLPOSCOPY SYSTEM N. PISAL
(UK), FC2-09
• VIDEO COLPOSCOPY IN DIAGNOSIS OF CERVICAL SQUAMOUS INTRAEPITHELIAL LESIONS C. XUEHONG
(CHINA), FC2-10
• LOOP ELECTROSURGICAL EXCISION PROCEDURE (LEEP) OF THE CERVIX - A FIVE YEAR EXPERIENCE E.
FERNANDES (PORTUGAL), FC2-11
EUROGIN 2003
23
• OPTICAL COHERENCE TOMOGRAPHY IN DIAGNOSIS OF CERVICAL NEOPLASIA SHAKHOVA, FC2-12
• EVALUATION OF LOOP ELECTROSURGICAL EXCISION PROCEDURE (LEEP) IN DIAGNOSIS AND
MANAGEMENT OF CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN): A PROSPECTIVE STUDY C. XUEHONG
(CHINA), FC2-13
• IMPROVING HEALTH SYSTEMS TOWARDS EQUALITY-BASED CONTROL OF CERVICAL CANCER IN LATIN
AMERICA P. NAUD (BRAZIL), FC2-14
• LIGHT EMITING DIODES IN LGT DIAGNOSTICS A. VAITKUVIENE (LUTHANIA), FC2-15
FC3: EPIDEMIOLOGY AND NATURAL HISTORY
• TRENDS IN THE INCIDENCE OF INVASIVE CERVICAL CANCER IN US WOMEN UNDER AGE 30 YEARS G.F.
SAWAYA (USA), FC3-01
• ESTIMATING THE NATURAL HISTORY OF CERVICAL CANCER FROM SCREENING DATA P. SPAREN
(SWEDEN), FC3-02
• CERVICAL CANCER SCREENING IN THE NATIONAL BREAST AND CERVICAL CANCER EARLY DETECTION
PROGRAM V. BENARD (FRANCE), FC3-03
• CAN CHANGES IN SEXUAL BEHAVIOUR EXPLAIN THE OBSERVED INCREASE IN CERVICAL CANCER
INCIDENCE IN FINLAND? R. BARNABAS (UK), FC3-04
• MULTIETHNIC COHORT STUDY OF SERUM MICRONUTRIENT M. GOODMAN (USA), FC3-05
• HPV PREVALENCE IN SOUTH OF BRAZIL P. NAUD (BRAZIL), FC3-06
• CERVICAL SCREENING AMONG HIV-INFECTED WOMEN IN ITALY P. PISELLI (ITALY), FC3-07
• IMPACT OF HIV INFECTION ON INVASIVE CERVICAL CANCER IN KENYAN WOMEN P. GICHANGI (KENYA),
FC3-08
• HUMAN PAPILLOMAVIRUS VIRAL LOAD IN PREDICTING DISEASE SEVERITY IN WOMEN SHOWING
ATYPICAL PAP SMEARS L. SARIAN (BRAZIL), FC3-09
• HPV DNA TESTING IN FOLLOW-UP AFTER TREATMENT FOR CIN: A SYSTEMATIC REVIEW OF THE
LITERATURE A. SOTIRIADIS (GREECE), FC3-10
• QUANTITATIVE ANALYSIS OF MORE THAN 1500 CERVICAL DYSPLASTIC BIOSPIES: CORRELATION WITH
PATHOLOGY GRADES AND HPV STATUS M. GUILLAUD (CANADA), FC3-11
• HUMAN PAPILLOMAVIRUS (HPV) TYPE 16 VARIANT DISTRIBUTION IN THE ITALIAN POPULATION M.
TORNESELLO (ITALY), FC3-12
• INCIDENCE AND SURVIVAL RATE OF WOMEN WITH CERVICAL CANCER IN THE LARGER AMSTERDAM
AREA C. MEIJER (THE NETHERLANDS), FC3-13
FC4: SEXUALLY TRANSMITTED DISEASES
• RISK FACTORS FOR HSV2 INFECTION IN INDIVIDUALS WHOSE PARTNERS HAVE GENITAL HERPES J.
PAAVONEN (FINLAND), FC4-01
• LOWER LEVELS OF SEXUAL CONTACT AND HIGHER LEVELS OF CONDOM USE REPORTED DURING
PERIODS OF SYMPTOMATIC GENITAL HERPES S. SEKHIN (RUSSIA), FC4-02
• ONCE DAILY VALACICLOVIR REDUCES TRANSMISSION OF GENITAL HERPES R. PATEL (UK), FC4-03
• INCIDENCE OF GENITAL WARTS AMONG PRIVATELY INSURED PATIENTS IN THE UNITED STATES J.
KOSHIOL (UK), FC4-04
• HPV AND OTHER STDS IN CROATIA G. GRUBISIC (CROATIA), FC4-05
• CERVICAL AND VAGINAL INFECTIONS IN CHILEAN WOMEN: PROBLEMS AND SOLUTIONS E. CASTRO
(CHILI), FC4-06
• THE DEVELOPMENT OF A SELF-LEARNING WEB BASED MODULE ON STI FOR HEALTHCARE
PROFESSIONALS J. MANN (CANADA), FC4-08
• TREPONEMA PALLIDUM - HIV INTERACTION: SINGS AND SYMPTOMS OF VARIOUS FORMS OF
NEUROSYPHILIS IN HIV-INFECTED PATIENTS AND ITS TREATMENT S. POTEKAYEV (RUSSIA), FC4-09
EUROGIN 2003
24
Satellite Symposia
S1: UPDATE ON THE MANAGEMENT OF GENITAL WARTS • 3M PHARMACEUTICALS
SATELLITE SYMPOSIUM
• THE EPIDEMIOLOGY ON HPV INFECTION IN EUROPE X. BOSCH (SPAIN), S1-01
• MODE OF ACTION OF IMIQUIMOD AND ITS POTENTIAL FOR THE TREATMENT OF STI'S M. STANLEY (UK),
S1-02
• ALDARA® IN THE TREATMENT OF GENITAL WARTS S. GARLAND (AUSTRALIA)
• GENITAL WARTS AND PSYCHOLOGICAL ISSUES C. O’MAHONY (UK), S1-04
S2: HPV TESTING IN CONJUNCTION WITH CYTOLOGY FOR PRIMARY SCREENING:
A TOOL FOR GREATER DIAGNOSTIC ACCURACY AND BETTER RISK AND INTERVAL
MANAGEMENT • DIGENE SATELLITE SYMPOSIUM
R. RICHART (USA), C. CLAVEL (FRANCE), J.T. COX (USA), J. CUZICK (UK),
C. MEIJER (THE NETHERLANDS), W. KINNEY (USA)
• THE RATIONALE FOR THE USE OF HPV TESTING IN CONJUNCTION WITH CYTOLOGY
• HPV TESTING AS A PRIMARY SCREENING TEST TO IDENTIFY THOSE AT RISK FOR
DEVELOPING HIGH-GRADE CERVICAL LESIONS
• THE CLINICAL APPLICATION OF THE DNA PAP
• FOLLOW-UP OF HPV POSITIVE/PAP NORMAL PATIENTS
• OPTIMUM SCREENING INTERVAL AND AGE RANGE
S3: THINPREP® IN AN ORGANISED CERVICAL SCREENING PROGRAMME • CYTYC
SYMPOSIUM
• THE USE OF LIQUID-BASED CYTOLOGY IN CERVICAL SCREENING: A META-ANALYSIS P. KLINKHAMER
(THE NETHERLANDS), S3-01
• THE SCANDINAVIAN CERVICAL SCREENING EXPERIENCE W. RYD (SWEDEN), S3-02
• COORDINATING PRIMARY CARE - A VIEW FROM SCOTLAND
S4: HPV - FUTURE TRENDS IN VACCINES • GSK BIOLOGICALS SATELLITE
SYMPOSIUM
• HPV TYPE DISTRIBUTION IN CERVICAL CANCER. WHAT CAN WE ANTICIPATE FOR VACCINE COMPOSITION
X. BOSCH (SPAIN), S4-02
• HPV VACCINES IN DEVELOPMENT: AN OVERVIEW J.T. SCHILLER (USA)
• THE GSK HPV VACCINE: AN UPDATE
S5: ELECTRIC-OPTICAL REAL TIME SCREENING METHODS • POLARTECHNICS
SATELLITE SYMPOSIUM
• RATIONALE FOR REAL TIME SCREENING N. HACKER (AUSTRALIA), S5-01
• SCREENING PRACTICE VARIATIONS AND POTENTIAL ROLE OF REAL TIME SCREENING S. DEXEUS
(SPAIN), S5-02
• TRUSCREEN - REAL TIME TECHNOLOGY K. CANFELL (UK), S5-03
• TRUSCREEN MULTI-CENTRE CLINICAL TRIAL RESULTS A. SINGER (UK), S5-04
• TRUSCREEN EXPERIENCE IN ITALY G. DE PALO (ITALY), S5-05
• CLINICAL MANAGEMENT IMPLICATIONS T. COX (USA), S5-06
EUROGIN 2003
25
S6: NEW ADVANCES IN HPV TESTING • VENTANA MEDICAL SYSTEMS SATELLITE
SYMPOSIUM
• PREDICTING CERVICAL LESIONS: COMPARISON OF ISH HPV AND HC2 HPV N. QURESHI (USA), S6-01
• THE VALUE OF HPV TESTING ON TISSUE SAMPLES S. CAJANDER (SWEDEN)
• THE FUTURE IN THE HPV TESTING: E6/E7, MICROARRAYS AND OTHER BIOMARKERS L. LAYFIELD (USA)
S7: NEW STRATEGIES TO PREVENT GENITAL HERPES TRANSMISSION • GSK
SATELLITE SYMPOSIUM
• DIAGNOSIS AND MANAGEMENT OPTIONS FOR GENITAL HERPES S. MAJEWSKI (POLAND)
• PREVENTING GENITAL HERPES TRANSMISSION R. PATEL (UK)
• TRANSMISSION OF HSV TO NEONATES Z. BROWN (USA)
S8: PRACTICAL ASPECTS OF MOLECULAR DIAGNOSTIC APPLIED TO WOMEN'S
HEALTH • ROCHE MOLECULAR DIAGNOSTICS SATELLITE SYMPOSIUM
• LIQUID CYTOLOGY AND MOLECULAR DIAGNOSTICS APPLICATIONS
• THE ROCHE HPV PROGRAM : FROM SCIENCE TO PRACTICE J. KORNEGAY (USA), K.U. PETRY (GERMANY)
• FUTURE MOLECULAR APPLICATIONS IN WOMEN'S HEALTH
S9: HSV - LOOKING INTO THE FUTURE • GSK BIOLOGICALS SATELLITE SYMPOSIUM
• OPENING BY CHAIRMAN B. BELSCHE (USA)
• SEROPREVALENCE OF HSV-2 AND HSV-1 INFECTIONS IN THE UNITED STATES AND EUROPE J. SMITH
(FRANCE), S9-02
• HSV VACCINES: PROSPECTS AND CHALLENGES L. STANBERRY (USA), S9-03
• THE EPIDEMIOLOGICAL DETERMINANTS OF THE IMPACT OF A GENITAL HERPES VACCINE:
MATHEMATICAL MODEL RESULTS BASED ON THE OBSERVED EFFICACY OF A GENITAL HERPES
VACCINE G. GARNETT (UK), S9-04
• DESIGN OF PHASE III HSV VACCINE EFFICACY STUDY B. BELSCHE (USA)
S10: CURRENT UNDERSTANDINGS OF THE IMMUNE RESPONSE OF HPV INFECTION
OF THE VAGINA/CERVIX • 3M PHARMACEUTICALS SATELLITE SYMPOSIUM
• IMMUNE CELL CHANGES AND CYTOKINE PROFILE INDUCTIONS RELATED TO HPV INFECTION AND
CLEARANCE B. GOSTOUT (USA)
• THE CLINICAL EXPERIENCE/UTILITY OF IMMUNE RESPONSE MODIFIERS WITH VAGINAL AND CERVICAL
DISEASE T. COX (USA), S10-02
S11: IMPLEMENTATION OF NEW TECHNOLOGIES FOR CERVICAL CANCER
SCREENING: LABORATORY FEEDBACK • TRIPATH IMAGING SATELLITE SYMPOSIUM
• LIQUID-BASED CYTOLOGY: OPTIMIZING SAMPLING PROCESS G. BIGRAS (SWITZERLAND), S11-01
• THE TRIPATH FOCALPOINT IMAGING SYSTEM D. WILBUR (USA), S11-02
• COMBINED USES OF NEW TECHNOLOGIES IN PRIMARY SCREENING FOR CERVICAL CANCER
P. VASSILAKOS (SWITZERLAND), S11-03
• IMPLEMENTATION OF LOCATED GUIDED SCREENING IN A EUROPEAN LABORATORY H. NEUMANN
(GERMANY), S11-04
• IMMUNE CHANGES AND CYTOKINE PROFILE INDUCTIONS RELATED TO HPV INFECTION AND CLEARANCE
B. GOSTOUT (USA), S11-05
S12: HPV GENOTYPING : A NEW APPROACH TO DISEASE MANAGEMENT ?
INNOGENETICS SATELLITE SYMPOSIUM
• INTRODUCTION R. RICHART (USA)
EUROGIN 2003
26
• GENERAL ASPECTS OF HPV GENOTYPING W.G.V. QUINT (THE NETHERLANDS)
• EVALUATION OF NOVEL HPV GENOTYPING TESTS T. IFTNER (GERMANY)
• THE USE OF TYPING IN EPIDEMIOLOGYICAL STUDIES OF HPV X. BOSCH (SPAIN)
• TYPING GENITAL TRACT HPV INFECTIONS : AN ESSENTIAL RESEARCH TOOL FOR PROPHYLACTIC HPV
VACCINE DEVELOPMENT B. INNIS (USA)
EUROGIN 2003
27
Leader Meeting
• THE ROLE OF EVIDENCE-BASED MEDICINE IN SCREENING AND PREVENTION OF
CERVICAL CANCER LMN-01
• LIQUID–BASED THIN LAYER CYTOLOGY FOR CERVICAL CANCER SCREENING LMN-02
• REAL TIME SCREENING METHODS AND EMERGING TECHNOLOGIES LMN-03
• HUMAN PAPILLOMAVIRUS TESTING IN PRIMARY SCREENING FOR THE DETECTION OF HIGHGRADE CERVICAL LESIONS: A STUDY OF 9,747 WOMEN LMN-04
• CAN CERVICAL SCREENING BE MADE MORE EFFICIENT BY ADDING A TEST FOR HIGH-RISK HPV?
LMN-05
• NEW SCREENING TECHNIQUES: VISUAL INSPECTION WITH ACETIC ACID (VIA) AND VISUAL
INSPECTION WITH LUGOL’S IODINE (VILI) LMN-06
• EXPERIENCE ON HPV TESTING BY HYBRID CAPTURE II AS AN OPTIONAL SCREENING TOOL OF
WOMEN AT DIFFERENT RISK FOR CERVICAL CANCER IN COUNTRIES OF THE FORMER SOVIET
UNION LMN-07
• BETHESDA SYSTEM 2001 LMN-08
• HPV TESTING FOR TRIAGE OF ABNORMAL PAP SMEARS LMN-09
• THE ROLE OF PROTEIN MARKERS LMN-10
• CONVENTIONAL METHODS OF TREATMENT OF CIN/GIN AND NEW STRATEGIES FOR
DETERMINING CURE LMN-11
• GLANDULAR INTRAEPITHELIAL NEOPLASIA (GIN) / ADENOCARCINOMA IN-SITU (AIS) LMN-12
• PERSPECTIVES OF PATIENT APPLIED THERAPIES FOR CIN: IMMUNOMODULATORS LMN-13
• MX-6: A NOVEL RETINOID-LIKE MOLECULE FOR THE TREATMENT OF CIN LMN-14
• EPIDEMIOLOGY AND PREDICTORS OF HUMAN PAPILLOMAVIRUS INFECTION IN WOMEN IN
PICARDIE, FRANCE LMN-15
• INFORMATION SYSTEMS AND TECHNOLOGY: OPPORTUNITIES AND CHALLENGES LMN-16
• PROPHYLACTIC AND THERAPEUTIC HPV VACCINES: RECENT AND ONGOING STUDIES LMN-17
• IMPACT OF COMMUNICATION ON CERVICAL CANCER SCREENING LMN-18
• INTRODUCTION: THE ROLE OF WOMEN AND OPINION LEADERS LMN-19
• THE ROLE OF PUBLIC OPINION AND DEDICATED PATIENT GROUPS IN THE TREATMENT OF
CANCER LMN-20
• ETHICAL AND LEGAL ISSUES IN ORGANISED CANCER SCREENING. THE IMPACT OF
COMMUNICATION ON CERVICAL CANCER SCREENING LMN-21
• COMPARISON OF POLICIES FOR CERVICAL CANCER SCREENING USING THE PAP SMEAR LMN-22
• COST-EFFECTIVENESS OF HPV TESTING: PRIMARY SCREENING AND ASCUS TRIAGE LMN-23
• COST-EFFECTIVENESS MODEL STUDIES ON LIQUID BASED CYTOLOGY LMN-24
• AUTOMATION TECHNOLOGIES: THE INCREASED IMPORTANCE OF THE ECONOMIC IMPACTS IN
CERVICAL CANCER PREVENTION. LMN-25
• AUTOMATION TECHNOLOGIES: PRIMARY SCREENING FOR CERVICAL CANCER PRECURSORS BY
THE COMBINED USE OF LIQUID BASED CYTOLOGY, COMPUTER-ASSISTED CYTOLOGY AND HPVDNA TESTING LMN-26
• HPV VACCINES: ISSUES IN ESTIMATING THE POTENTIAL EFFECTIVENESS AND COSTEFFECTIVENESS LMN-27
• THE ROLE OF PUBLIC-PRIVATE PARTNERSHIPS LMN-28
• EVALUATION OF CERVICAL CYTOLOGY FOR POLICY MAKERS:
THE AHCPR REPORT LMN-29
• ALTS STUDY RESULTS LMN-30
• THE IMPACT OF INTERNATIONAL HEALTH ORGANIZATIONS. THE UICC PERSPECTIVE. LMN-31
• NON-GOVERNMENTAL ORGANIZATIONS: ALLIANCE FOR CERVICAL CANCER PREVENTION (ACCP)
LMN-32
EUROGIN 2003
28
POSTERS
Viral and molecular biology
BRITO E.
EPSHTEIN A.
MORIN J.
PIENNA SOARES
SAMAMA B.
ZHANG J.
P001
P002
P003, P004
P005
P006
P007
Immunology
CAO XUANLIN
GONCALVES M.
P008
P009, P010
Pathogenesis
DASKALAKIS G.
VENTUROLI
P011
P012
Epidemiology and natural history
ADESINA O.
ANDRAE B.
ANGELIDOU E.
GONTIJO R.
HINKULA M.
KHRYANIN A.
KUNTZ C.
LOPEZ REVILLA R.
MATOS A.
PEROVIC M.
PIROG E.
SEVERINI A.
THEODOSI G.
TSITSISHVILI Z.
VACCARELLA S.
VOLKOV V.
ZUKANOVIAE D.
P013, P014, P015
P016
P017, P018
P019, P020
P021
P022
P023
P024
P025
P026
P027
P028
P029
P030
P031
P032
P033
Terminologies
RUTGERS J.
CULLEN A.
DIVANI S.
GONTIJO R.
GRCE M.
KANBOUR A.
LONGATTO FILHO A.
NASSAR A.
PERRONS C.
RIBACCHI R.
RODRIGUEZ-IGLESIAS M.
SARIAN L.
SELKOV S.
SHIPULINA O.
VASCONCELOS A.
VENTUROLI S.
P048
P049
P050
P051
P052
P053
P054
P055
P056
P057
P058
P059
P060
P061
P062
Liquid based cytology
BOTACINI DAS DORES G.
KANBOUR A.
LONGATTO FILHO A.
MARGARI H.
PANITCHENCO I.
P063, P064
P065
P066
P067, P068
P069
New technologies
BISGAARD K.
CHEUNG T.
RUSSO M.
SLUZHYNSKA O.
P070
P071
P072
P073
STD & HIV infection
DRABEK M.
KOLIEVA G.
KOLIEVA G.
KUBANOV A.
MALINOVA M.
MANN J.
SUEUR J.
P074
P075
P076
P077
P078
P079
P080, P081
P034
Diagnostic procedures
Screening methods
MILANOVA E.
MORIN J.
NASSAR A.
NAUD P.
PIENTONG C.
POTANCOK B.
REPSE-FOKTER A.
ROTELI-MARTINS C.
TISCI S.
P036
P037
P038
P039
P040
P041
P042
P043
P044
HPV testing
BABIC D.
CHOI H.
CIOTTI M.
EUROGIN 2003
P045
P046
P047
DASKALAKIS G.
EKALAKSANANAN T.
GONTIJO R.
KEDZIA W.
MOCIULSCHI R.
NAUMOV J.
TARKKANEN J.
ZLATKOV V.
P082, P083
P084
P085
P086, P090
P087
P088
P089
P091
Colposcopy
HAVRANKOVA A.
KUBANOV A.
LOURENCO C.
STOJOVSKI M.
P092
P093
P094
P095
29
Cervical neoplasia
ANTON M.
BAHEIRAEI A.
DINCA G.
HERNDON M.
IDESTROM M.
KRAVETZ O.
LUKASZUK K.
LYGYRDA N.
NAJDANOVIC-MANDIC V.
NICOLAESCU R.
OSUNA M.
PEPA A.
PROCA D.
RUSSO M.
SINGH A.
SOMOGYI L.
TALVENSAARI-MATTILA A.
TARLEA V.
VELASCO J.
WIDSCHWENDTER A.
ZDRODOWSKA-STEFANOW
Genital warts
P096
P097
P098
P099
P100
P101
P102
P103
P104
P105
P106
P107, P108
P109
P110
P111
P112
P113
P114
P115
P116
P117
BOUDGHENE O.
PERISIC Z.
P121
P122
Conventional therapies
PERRINI G.
RADIC V.
P123
P124
New treatments
KLIMEK M.
SUSKA P.
WALIGORA M.
YANG L.
P125
P126
P127
P128
Vaccines
KULASINGAM S.
P129
Vulvar diseases
PIROG E.
PRILEPSKAYA K.
SARIAN L.
EUROGIN 2003
P118
P119
P120
30
AUTHORS
A
ADESINA P013, P014, P015
ANDRAE P016
ANGELIDOU P017, P018
B
BABIC P045
BAHEIRAEI P097
BARBEYRAC SF-04
BARRES TC4-1-08
BÉRUBÉ SF-03
BIGRAS SS16-08, S11-01
BISGAARD SS5-06, P070
BORNSTEIN TC3-1-03
BOSCH PS1-02, PS7-2a, SS10-02, SF-01, S1-01,
S4-02
BOSZE SS27-02
BOTACINI DAS DORES SS6-09, SS24-05, P063,
P064
BOUDGHENE P120
BOULANGER SS6-08, SS21-06
BOURGAULT VILADA SS11-8b
BOYER PS5-03
BRANCA SS25-08
BRITO P001
BURNETT SS27-07
C
CAJANDER FC1-06
CANFELL S5-03
CAO XUANLIN P008
CASOLATI SS12-05
CASTELLSAGUE SS10-03
CASTRO FC4-06
CESTERO SS16-01
CHEUNG P071
CHIVUKULA SS24-06
CHOI P046
CHOW FC2-08
CIOTTI P047
CLAEYS SS16-04
CLAVEL SS10A-04
CLIFFORD SS31-05
COLLINET SS6-06
COOL SS10A-06
CORRADO SS28-02
CORTES-BORDOY SS22-01
CORNIER TC4-3-07
COURSAGET SS20-08
COX SEM1-1-04, OC-02, PS1-06, S5-06,
SS18-04, S10-02
CRISTIANI FC2-05
CULLEN P048
CUZICK SEM1-2-07, SS6-02, SS31-00
D
DACHEZ SS24-04
DALSTEIN SS25-05
DAO SS28-03
EUROGIN 2003
DARRAGH SS9-03
DASKALAKIS P011, P082, P083
DE PALO S5-05
DENNY SEM1-3-01, SEM2-2-02
DERCHAIN FC2-06
DEXEUS S5-02
DILLNER SS11-04, SS10A-05
DINCA P098
DIVANI P049
DRABEK P074
DUBIN SS20-05
E
EAKER SS23-10
EKALAKSANANAN P084
ELFGREN SS13-10
EPSHTEIN P002
ERZEN SS30-12, SS32-06
ETHERINGTON PS5-01
F
FAURE TC3-1-06
FERENCZY TC4-1-02, TC4-1-06, SS4-04,
SS6-01, SS13-03, SS15-06
FERNANDES FC2-11
FETTERMAN FC1-04
FORSLUND SS32-03
FORTIN SF-05
FRANCESCHI SS10-06, SS20-01
FRANCO SEM1-1-01, PS7-2b, SS10-01
FRAZER SS20-02
FROST SS16-07
G
GARCIA SS6-10
GARLAND SS26-04, SS3-05, SS25-04
GARNETT S9-04
GICHANGI FC3-08
GISSMANN SS20-07
GODEBERGE SS9-04
GOLLIN SS2-04
GONCALVES P009, P010
GONTIJO FC2-04, P019, P020, P050, P085
GONZALES-LOSA SS30-02
GOODMAN A. FC2-01
GOODMAN M. FC3-05
GOSTOUT S11-05
GRACE FC2-02
GRCE P051
GRUBISIC FC4-05
GUIJON SS21-04
GUILLAUD FC3-11
H
HABBEMA SEM2-1-03
HACKER S5-01
HADWIN SS14-07
HAKAMA SEM2-1-02, SS23-02
HAMMOU SS24-07
HAMPL SS29-08
HAN SS28-09
31
HARIRI SS16-06, SS24-09
HARPER SS17-03
HAVRANKOVA P092
HAWKES SS2-05b
HEARD SS9-02, SS12-01
HERNDON P099
HILLEMANNS SS6-03
HINKULA P021
HUH SS15-04
I
IDESTROM P100
IFTNER SS5-02
INSINGA SS17-06
J
JANSEN SS20-06
JANSEN-DUERR SS5-07
JENKINS SS17-00, SS17-01
JONES SS29-01
JUDLIN SS1-03
K
KANBOUR P052, P065
KASPARI SS15-11
KAUL SS13-09
KEDZIA P086, P090
KHANNA FC1-09
KHRYANIN P022
KINNEY SS6-04, SS21-02
KITCHENER PS4-02, PS4-03, SS14-01, SS21-03
KJAER SS10A-03
KLIMEK P124
KLINKHAMER S3-01
KOLIEVA P075, P076
KORNEGAY SS5-03
KOSHIOL FC4-04
KOULIBALY SS30-07
KRAVETZ SS32-07, P101
KREMER SF-11
KRUGER-KJAER SS10A-03
KUBANOV P077, P093
KULASINGAM SS17-05, SS23-07, P129
KUNTZ P023
L
LAMONTAGNE SF-07
LANGLEY SS26-06
LANGLOIS SF-06
LAURENT SF-12
LAWSON PS4-01, PS4-5a
LEROY SS21-06
LILLO SS12-04, FC1-11
LINDER TC2-07, SS7-03, PS4-4a
LONGATTO FILHO SS30-09, P053, P066
LOPEZ REVILLA P024
LORINCZ SEM1-1-02, SEM1-2-06, PS1-03,
SS5-08
LOURENCO P094
LUESLEY TC1-2-02
LUKASZUK P102
LYGYRDA P103
M
MALINOVA P078
EUROGIN 2003
MAN SS11-02
MANDAL SS30-08
MANN J. FC4-08
MARGARI P067, P068
MATOS P025
MAUDELONDE SF-02
MAY-LEVIN SS18-05
MCLAREN SS15-08
MEERDING FC2-03
MEHES SS28-04
MEIJER FC1-03, FC3-13
MEISELS OC-01, PS4-4b, SS24-01
MELCHERS SS31-06
MICHELETTI SS29-05, TC3-2-01
MILANOVA P036
MILBOURNE SS8-03, SS13-05, SS15-02
MILLER PS3-03, SS23-01
MOCICKI SS11-8a, SS23-06
MOCIULSCHI P087
MONEY SS3-03, SS12-03, SS25-02
MONSONEGO WELCOME
MORIN P003, P004, P037
MOUGIN SS31-02
MYERS SS19-04, SS17-04
N
NAJDANOVIC-MANDIC P104
NASSAR P038, P054
NAUD FC2-14, FC3-06, P039
NAUMOV P088
NEILL TC3-1-04
NEUMANN S11-04
NICOLAESCU P105
NIEMINEN SS24-08
O
O’MAHONY S1-04
ONNIS SS27-09
OSUNA P106
P
PAAVONEN FC4-01
PALEFSKY SS3-02, SS9-01, SS12-08
PANITCHENCO P069
PARKIN SEM2-1-01, PS1-04
PATEL FC4-03
PATNICK SEM2-1-04
PEELING SS1-01, SS2-03, SS2-05a
PEPA P107, P108
PERISIC P121
PERONI SS22-04
PEROVIC P026
PERRINI P122
PERRONS P055
PETRY SS15-09
PIETTE SF-09, SF-10
PICCOLI SS31-07
PIENNA SOARES P005
PIENTONG P040
PIROG P027, P117
PISAL SS14-08, FC2-09
PISELLI FC3-07
POMEL SS27-08
POTANCOK P041
POTEKAYEV FC4-09
PRILEPSKAYA P118
32
PROCA P109
Q
QUEK TC4-1-01, SS8-02
QUERLEU SS27-03
QUINT SS5-04
QURESHI S6-01
R
RADIC P124
RAMAEL FC1-07
RAMANATHAN SS13-08
RATNAM SEM1-2-05
REGAUER SS28-10
REPSE-FOKTER P042
RIBACCHI P056
RIMMER PS4-5b
RINTALA SS31-08
ROBLES SS18A-03
RODRIGUEZ-IGLESIAS P057
RONCO FC1-02
ROTELI-MARTINS P043
ROY SS29-03, SS27-05
RUSSO P072
RUTGERS P034
RYD S3-02
S
SANKARANAYANAN SEM1-3-02, SEM2-2-04
SARIAN FC3-09, P058, P119
SAVET TC4-1-08
SAWAYA FC3-01
SCHILLER OC-03, SS20-03
SCHLECHT SS10-04
SEDBON SF-08
SEKHIN FC4-02
SELKOV P059
SEVERINI P028
SHAKHOVA FC2-12
SHARMA SS30-04
SHASTRI SS30-03
SHEETS SS2-02
SHERRIS SEM2-2-07
SHIPULINA P060
SIDERI TC3-1-07, SS29-06
SI-MOHAMED FC1-08
SINGER SEM2-2-05, SS8-01, S5-04
SINGH P110
SKINNER FC2-07
SLUZHYNSKA P073
SMITH J.H.F. SS10-05
SMITH J. S9-02
SNIJDERS SS31-09
SOTIRIADIS FC3-10
SPAREN FC3-02
STAFL SS16-03
STANBERRY S9-03
STANLEY S1-02, SS11-01, SS26-02
STARY SS2-01
STEBEN SS3-01, TC3-1-09
STEELE SS11-03
STOJOVSKI P095
STRANDER SS13-07
SUEUR P080, P081
SUSKA P126
SUTEU SS30-11
EUROGIN 2003
SYRJANEN S. SS10-07, SS6-07, SS31-04
SYRJANEN K. SS18A-04, SS23-03, SS31-01
T
TALVENSAARI-MATTILA P112
TAN FC1-10
TARLEA P113
TARKKANEN P089
TASKER SS29-09
THEODOSI P029
TISCI P044
TODD SS28-07
TORNESELLO FC3-12
TRISTRAM SS15-10, FC1-01, SS29-10
TSITSISHVILI P030
TWIGGS SS15-05
V
VACCARELLA P031
VAITKUVIENE FC2-15
VAN BEURDEN SS29-02
VAN DOORN FC1-05
VAN HAM SS30-01
VASSILAKOS S11-03
VON KROGH SS26-03
VAN PACHTERBEKE SS15-12
VASCONCELOS P061
VELASCO P114
VENTUROLI P012, P062
VLASTA SS30-10
VLASTOS SS28-06, SS28-11, SS32-00
VOGEL TC4-2-01
VOLKOV P032
VON KNEBEL DOEBERITZ SS16-05, SS28-01
W
WALIGORA P127
WALKER TC1-1-03, SS14-04
WHYNES SS17-02
WIDSCHWENDTER P115
WILBUR TC2-04, S11-02
WILKINSON TC2-01, PS6-1-03
WRIGHT SEM1-1-05, SEM2-2-03, SEM2-2-06,
PS3-02, PS6-1-01, PS6-1-02, SS8-04
X
XUEHONG FC2-10, FC2-13
Y
YANG P128
Z
ZANARDI SS22-05
ZDRODOWSKA-STEFANOW P116
ZHANG P007
ZIELINSKI SS6-05
ZLATKOV P091
ZUKANOVIAE P033
33
Abstracts
EUROGIN 2003
34
BACK TO INDEX:
ORAL SESSIONS
POSTERS
AUTHORS
SS1-01
GONORRHEA-CHLAMYDIAE, NEW THOUGHTS ON OLD DISEASES
Peeling Rosanna W.
World Health Organization, Dpt Sexually Transmitted Diseases Diagnostics Initiative (SDI), Geneva,
Switzerland
In recent years, exciting new technologies are being exploited to resolve age-old problems
concerning genital infections caused by Chlamydia trachomatis and Neisseria gonorrhoeae.
Advances in nucleic acid-based amplification diagnostics have already translated into
improvements in patient management and control of these diseases while new knowledge
gleamed from genomics and proteomics continues to fuel hopes of development of effective
vaccines and novel treatment modalities.
Highly sensitive and specific nucleic acid-based amplification tests (NAAT) are commercially
available for the detection of these two infections, either singly or as duplex tests. The
sensitivity of NAATs allows the use of non-invasive specimens such as vaginal swabs and
urine, which can be collected outside of traditional clinic-based settings. Studies have also
shown that tampons and self-collected vaginal swabs can be used in place of providercollected specimens. Real-time polymerase chain reaction assays can now provide
quantitative results in 30 minutes.
While there have been only sporadic reports of treatment failure for C. trachomatis, the
development and spread of antibiotic resistance for N. gonorrhoeae continue to be a major
problem in the management of gonococcal infections. The rapid development of quinolone
resistance within 2-3 years of the introduction of ciprofloxacin in Asia and its spread to many
areas of the world during the 1990s have rendered quinolones ineffective for the treatment of
gonorrhea. The challenge remains for the synthesis of new knowledge of the biology of the
pathogen with drug development expertise to develop novel drugs or drug combinations that
can be used without inducing resistance in this versatile pathogen.
The genome of C. trachomatis has recently been sequenced. Studies of gene and protein
expression at different stages of disease are beginning to yield important new information
regarding the biology of this pathogen and its pathogenesis. Such knowledge will offer
excellent opportunities for the discovery of novel diagnostic and vaccine targets.
EUROGIN 2003
35
BACK TO INDEX:
ORAL SESSIONS
POSTERS
AUTHORS
SS1-03
EMERGING ISSUES OF NON VIRAL STIS : COMPLICATIONS AND
MANAGEMENT OF CHRONIC DISEASES : ADDRESSING THE ISSUE
Judlin Philippe
Maternité Régionale, Faculty of Medicine, Dept Obstetrics & Gynecology, Nancy, France
Most of the complications and chronic diseases resulting from STIs are related to Pelvic
Inflammatory Diseases (PID) and their complications. Gonococcal and C. trachomatis STIs
constitute a major factor of PID. Currently, gonococcal PIDs are relatively rare in European
Union. Most of the cases of PID due to C. trachomatis are asymtomatic - or, when clinical
signs exist, unrecognized - and that explains why too many cases are not adequately treated.
C. trachomatis can trigger immuno-inflammatory reactions in the Fallopian tubes leading to
tubal alterations and pelvic adhesions. Acute complications such as pelvic abscesses and
peritonitis can complicate PIDs. Chronic forms of PID exist, especially in case of C.
trachomatis infection. In the long term, pelvic sequellae due to PID result in many cases of
infertility and of ectopic pregnancies.
Thus, prevention and adequate management of STIs are essential in order to avoid
complications such as PID and pelvic sequellae than can lead to infertility.
EUROGIN 2003
36
BACK TO INDEX:
ORAL SESSIONS
POSTERS
AUTHORS
SS2-01
MOLECULARBIOLOGICAL METHODS FOR CHLAMYDIAL AND
GONOCOCCAL DIAGNOSIS
Stary A.
Outpatients Centre for Infectious Venero-dermatological Infections.Vienna, Austria
Methods using the artificial amplification of nucleic acid are a new advantage in diagnosis of
STDs. Chlamydial diagnosis has rapidly developed during the last decade and the demand for
an ideal diagnostic test system with a sensitivity of about 90% and a specificity of about 99%
is most closely approached by methods using nucleic acid amplification (NAA) assays
Commercially available NAA assays for Chlamydia trachomatis and Neisseria gonorrhoeae
have long been restricted to two commercially available techniques, the Amplicor PCR, a
DNA target amplification assay, and the ligase chain reaction LCR, a DNA probe
amplification assay. The number of NAA assays has increased and their quality has improved
by including an internal control in some of the assays, such as COBAS Amplicor and the
strand displacement amplification (SDA) assay. In addition to DNA amplification, RNA
amplification is used in the new APTIMA Combo 2 assay, which has a target capture method
included in addition to RNA amplification increasing the sensitivity for samples with only
small numbers of RNA. These assays provide laboratories with powerful tools with particular
impact in the detection of genital infections and have been approved by FDA for practical use
for the diagnosis of both, chlamydial as well as gonococcal infections. For practical relevance,
coamplification of Neisseria gonorrhoeae and C. trachomatis from one sample enables
diagnosis of genital infections with these pathogens within few hours.
The high sensitivity of NAA enables the detection of a low number of organisms present in
asymptomatic patients and their contact persons without signs of inflammation. Furthermore,
the detection of nonviable organisms offers the opportunity to detect specific DNA or RNA in
specimens contaminated with microorganisms such as first void urine and introital
vulvovaginal samples with similar sensitivities when compared to cervical and urethral
specimens in both, men and women. It has also been shown that mailed home-obtained urine
or self-taken vulval-introital samples are useful alternative diagnostic procedures. NAA
assays offer therefore screening possibilities especially for asymptomatic individuals
However, it is also important to be aware of the limitations of NAAassays and handling
procedures have to be carefully and continuously monitored for contamination and
reproducibility problems. Furthermore, in contrast to NAA assays, gonococcal culture enables
resistance proof which has been shown to be important in areas with increasing multiple
antibiotic resistance in gonococci.
EUROGIN 2003
37
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ORAL SESSIONS
POSTERS
AUTHORS
SS2-02
THE ROLE OF LIQUID-BASED CYTOLOGY IN SEXUALLY
TRANSMITTED INFECTIONS
Sheets Ellen
Cytyc Corporation
Combining sexually transmitted infections (STIs) screening with cervical cytology increases
the possibility of appropriate testing by using the residual cytology sample from a liquidbased pap (LBP) test. The most relevant STIs for the practicing clinician are Neisseria
gonorrhoeae (NG), Chlamydia trachomatis (CT) and human papillomavirus (HPV).
Essentially all CT/NG screening scenarios for asymptomatic women under age 30 are cost
effective compared to screening only symptomatic women. Such data underscore the serious
outcomes of an untreated CT or NG related pelvic inflammatory infection. HPV infections
will commonly result clinically in the manifestation of Condyloma accuminata or less
frequently, abnormal cervical cytology. It is the focus on cervical cancer screening resulting
in a pap test that appears to distract the clinician and patient away from secondary cervical
sample co-collection for STIs in asymptomatic women.
Given the current DNA based methods for CT/NG/HPV detection, simply preservation of a
representative cellular sample from the cervix should allow for accurate detection thus
eliminating the need for a secondary co-collection sample. Methodology must take into
account the possibility of cross contamination between laboratory samples, which could
potentially occur using any method in any large scale screening project. The clinical
indications for HPV testing will differ by age group and intent. The pros and cons of testing
for these infections out of the LBP will be presented along with recommended testing
protocols.
EUROGIN 2003
38
BACK TO INDEX:
ORAL SESSIONS
POSTERS
AUTHORS
SS2-03
CURRENT ISSUES IN DIAGNOSTIC TESTING OF STIS
Peeling Rosanna W.
World Health Organization, Dpt Sexually Transmitted Diseases Diagnostics Initiative (SDI), Geneva,
Switzerland
Highly sensitive and specific nucleic acid-based amplification tests (NAAT) have largely
replaced culture as the paradigm for the sensitive and specific detection of most bacterial
STIs. The sensitivity of NAATs allows the use of non-invasive specimens such as vaginal
swabs and urine. Studies have shown that tampons as well as self-collected vaginal swabs can
be used in place of provider-collected swabs. NAATs will also improve case detection and
make partner notification more cost-effective. For patients presenting with genital ulcer
disease, urethral or vaginal discharge, the use of multiplex NAAT testing to detect all the
pathogens for the syndrome using a single specimen and a single reaction saves time and
resources. Real-time PCR methods can now provide quantitative results in 30 minutes. A
nucleic acid based assay without amplification for human papillomavirus (HPV) is available.
It is expensive and given the biology of HPV, studies to determine the utility of such tools for
screening and control of HPV are urgently needed. Point-of-care tests are now available for C.
trachomatis, N. gonorrhoeae, T. vaginalis, syphilis, herpes simplex virus, bacterial vaginosis.
It remains to be seen whether they address disease control needs. Some syphilis rapid tests
have performance comparable to laboratory-based tests and can be used in primary care health
settings with minimal training and equipment. With such tools and inexpensive treatment, the
elimination of congenital syphilis in developing countries is no longer an elusive goal.
Despite these major improvements, new diagnostic testing methods have posed a number of
problems. NAATs are costly and require a high level of laboratory expertise. Studies to
determine the cost-effectiveness of utilizing such technologies in various settings are needed.
Inherent in the high sensitivity of these assays is the potential for false positive results due to
contamination unless strict quality control procedures are in place. Substances in the
specimen can inhibit amplification reactions leading to false negative results. Internal controls
to monitor inhibitions should be part of NAATs.The conversion of many laboratories to
antigen or nucleic acid based diagnostics has led to a decrease in number of laboratories with
the capacity and expertise to perform culture and antimicrobial susceptibility testing to
monitor antibiotic resistance. The development and rapid spread of antibiotic resistance for N.
gonorrhoeae continue to be a major problem in the management of gonococcal infections.
Quinolone resistance in Asia emerged within 2-3 years of the introduction of ciprofloxacin in
Asia and its spread to many areas of the world during the 1990s have rendered quinolones
ineffective for the treatment of gonorrhea.
EUROGIN 2003
39
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SS2-04
APPLICATIONS OF THE UTILITY CHANNEL CONCEPT FOR THE
ESTABLISHMENT OF NEW TARGETS
Gollin David
Roche Molecular Diagnostics, Marketing, Pleasanton, CA
Our next generation real-time PCR based diagnostic instrument, the COBAS® TaqMan® 48
analyzer, is capable of running both commercial IVD and in-house developed assays. The inhouse developed assays are run with the "utility channel" function of the analyzer adding
flexibility and convenience to your laboratory processes. This presentation will describe the
system and show preliminary data demonstrating the use of the utility channel in routine assay
development.
EUROGIN 2003
40
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POSTERS
AUTHORS
SS2-05a
RAPID TESTS FOR STIS: PROMISES AND FUTURE CHALLENGES
Peeling Rosanna W.
World Health Organization, Dpt Sexually Transmitted Diseases Diagnostics Initiative (SDI), Geneva,
Switzerland
Simple, rapid, affordable tests are needed for the diagnosis and screening of STIs, especially
for women, as the syndromic approach is neither sensitive nor specific for women with
vaginal discharge. Tests that can be done rapidly at the point of care, resulting in immediate
treatment, are likely to be more effective than those which require samples to be sent to a
distant laboratory since many clinic attenders find it hard to return for results. In addition to
enabling treatment to be given immediately and thus avert long term complications and
interrupting disease transmission, point-of-care tests make it possible to initiate partner
notification with confidence at the first clinic visit.
Many rapid tests are now available for the major STIs but their performance has not been
widely evaluated. Most rapid tests are formatted as antigen or antibody detection tests in the
form of a nitrocellulose strip. The treponemal tests for syphilis are simple (requiring 2-3
steps), can be performed with minimal training and equipment, and the results are available
within 30 minutes. Some can be used with whole blood. A recent evaluation of rapid
treponemal tests by a network of SDI laboratory sites showed that some of these rapid tests
have performance characteristics comparable to laboratory based treponemal tests. Rapid tests
for chlamydia and gonorrhea require specimen processing prior to antigen detection and are
neither simple nor inexpensive. Most of these tests do not have sufficient sensitivity to be
used with non-invasive specimens such as vaginal swabs or urine specimens. A rapid test for
herpes simplex virus type 2 serology is easy to use but is expensive. Rapid tests for bacterial
vaginosis and Trichomonas vaginalis are simple but costly, and their performance has not
been widely evaluated. Clearly rapid tests can be an effective tool for patient management and
disease control. The challenge, in the short term, is to evaluate the performance of these tests
in various settings and determine their cost-effectiveness. In the long term, given the
perceived lack of return for investment for STI test development, advocacy for the application
of novel rapid detection technology to the development of more sensitive yet simple, rapid
and affordable tests for STIs remains a major challenge.
EUROGIN 2003
41
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SS2-05b
ACCESSIBILITY, AFFORDABILITY AND IMPACT OF POINT OF
CARE DIAGNOSTICS FOR STIS IN RESOURCE POOR COUNTRIES
HAWKES Sarah
London School of Hygiene and Tropical Medicine, Clinical Research Unit, London
Sexually transmitted infections (STIs) impose a high burden of disease in resource poor
countries. These infections have significant resource implications for both infected/affected
persons and health care systems seeking to provide care. They are associated with a high
degree of morbidity and complications - including their link to the increased risk of hiv
transmission. Current methods for diagnosis of these infections are either very expensive or
are relatively non-specific and result in high levels of over-treatment, especially in women.
Moreover, diagnosis usually depends on infected people recognising their symptoms and
seeking appropriate care. Given that the majority of stis in women and significant levels of
stis in men are carried asymptomatically, most people with infection do not seek care and will
only be detected and treated through widespread screening programmes. To date, screening
programmes have been beyond the financial reach of most low and middle income countries
as they rely on a functioning health system with laboratory services in place.
Point of care diagnostics which are sensitive and specific enough may offer resource limited
countries the opportunity not only to improve case management for symptomatic individuals
seeking care, but may also enable countries to establish screening programmes. However, this
will be dependent on assuring the accessibility and affordability of these diagnostics.
This talk outlines the burden of disease associated with stis in resource poor countries, and
explores the impact that affordable and effective point of care diagnostics could make on
reducing disease burden and improving quality of care.
EUROGIN 2003
42
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SS3-01
HERPEX SIMPLEX, THE SILENT EPIDEMIC
Steben Marc
Institut national de Santé publique du Québec, Risque biologiques, occupationnels et
environnementaux, Montréal
Genital infection caused by Herpes simplex viruses are on the rise. From a rare condition it is
now recognised as one of the 3 main reasons for consulting about a sexually transmitted
disease. The prevalence rate in adults is around 20%. Most patients are tought to be silent
carriers but they are more frequently with an unrecognised genital infection: because it is selfhealing, with symptoms easily controlled with topical non-specific agents the diagnosis is not
frequently made. It has been shown that 91% of HSV-2 carriers are ignorant of their
conditions while up to 80% have symptoms related to the condition. Control of episodes can
be achieved with oral antiviral in episodic mode for infrequent outbreaks to daily suppressive
therapy for frequent outbreaks. A vaccine for prophylactic immunization is currently under
large scale testing: it has been shown to be 72% effective in HSV-1 and HSV-2 women only.
Therapeutic vaccine are not foreseeablev in a near future but immunomodulator are currently
being testes. Screening with type specific serology is being more and more considered for
discordant couples especially when a pregnancy is considered. Large scale screening is
meeting strong resistance because of inadequate lab infrastructure and lack of professionnals
with counselling experience with seropositivity to HSV-2. Women with HSV-2 infection
should not be offered elective cesarean section but should be screened for presence of signs
and symptoms and selective antiviral prophylaxis could be offered to high risk patients such
as those having acquired HSV-2 during the actual pregnancy or suffering from frequent
recurrences during the pregnancy. Prevention of neonatal herpes could tranlate in 1) the use of
prophylactic antiviral in the infected male especially if the female is seronegative to HSV-2,
2) the use of antiviral in the infected mother, 3) avoidance of oral sex in pregnancy, 4)the
performance of a cesarean section in case where the infection is highly possible (7-10 days
before the onset of labor) and 5) the avoidance of traumatic iatrogeny to the baby. Anxiety is
linked to the number of recurrences, psycho-sexual management is essential.
EUROGIN 2003
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SS3-02
HUMAN PAPILLOMAVIRUS AS AN STI: WHAT TO UNDERSTAND
OF THIS COMPLEX INFECTION
Palefsky Joel
UCSF, Medicine, San Francisco
Human papillomavirus (HPV) infection is the most common viral STI and contributes to the
development of epithelial cancers of the anogenital region as well as other epithelial sites.
Although much progress has been made in the last decade to define the epidemiology of
cervical HPV infection and delineate the mechanisms by which HPV contributes to malignant
transformation, there remains a great deal to be learned. From an epidemiologic standpoint,
more information is needed on the prevalence, incidence and transmissability of penile HPV
infection, a field that may be ready to move forward with the recent description of reliable
HPV sampling techniques on the penis. The epidemiology of anal HPV infection, its
relationship to cervical HPV infection and to HIV infection are not yet fully understood. The
epidemiology of HPV infection in individuals over the age of 60 years is also an emerging
area of investigation. Other areas that require further elucidation include: the role of different
HPV strain variants in disease pathogenesis; further functional characterization of HPV
proteins and their role in malignant transformation and the viral life cycle; understanding the
role of up-regulation or down-regulation of cellular genes and their role in malignant
transformation; determining the nature of the immune response to HPV and its role in
protection against disease; assessment of prophylactic HPV vaccines; development and
assessment of therapeutic HPV vaccines; development of non-immunologic HPV-specific
therapeutic approaches; and development and assessment of rapid, reliable and inexpensive
techniques to detect and treat CIN in developing countries.
EUROGIN 2003
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SS3-03
VIRAL STI:UPDATE, PERSPECTIVES AND EMERGING ISSUES HIV
MANAGEMENT ISSUES IN WOMEN
MONEY Deborah
University of British Columbia, Dept Obstetrics and Gynaecology, Vancouver, Canada
Data will be presented on the main issues in the management of HIV in women. Worldwide,
the primary issue for women is access to diagnosis and care. The majority of HIV worldwide
is acquired through heterosexual transmission and is often in the context of social and sexual
vulnerability. These marginalized situations, make access to treatment challenging even in
settings where HIV therapy is readily available.
Presuming treatment is available, there are unique aspects of care for HIV infected nonpregnant and pregnant women. Evidence for ideal therapy in women is limited, as many of
the treatment trials have had few women enrolled. Important gender differences, include the
feature that women have a lower CD4 cell count for a given level of HIV viral load than men.
Time to response and durability of response to highly active antiretrovirals (HAART) is
similar to men. Higher rates of toxicities are seen for given HAART regimens, possibly
related to higher blood levels. Therapeutic drug monitoring suggests a sex and body weight
relationship to drug levels. Side effects such as lipodystrophy need to be better defined in
women, and the relationship of perceived risk of lipodystrophy and adherence to therapy is
important to understand.
HIV infected women have higher rates of cervical dysplasia than HIV negative women,
associated with high rates of carriage of oncogenic HPV. High rates of genital herpes are also
described, but bacterial STD's are not increased in many studies. Genital shedding of HIV is
related to sexual and vertical transmission. Genital tract viral load is generally correlated with
plasma HIV viral load and usually suppresses with therapy, with some menstrual cycle
variations.
Most HIV infected women are reproductive age, so therapy needs to initiated with a careful
consideration of first trimester teratogenicity of antiretroviral drugs. Efavirenz and delavirdine
should be avoided in women who may become pregnant. Treatment of HIV infection in
pregnancy needs to take into consideration both the status of the women's HIV infection and
need for therapy for her health as well as the need to prevent transmission to the infant while
minimizing on fetal toxicity. Choice and timing of HAART in pregnancy should minimize the
risk of resistance development for the women.
EUROGIN 2003
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SS3-05
HEPATITIS B (HBV) AND HEPATITIS C (HCV)
Garland S.M.
Department of Microbiological Research, Department of Microbiology and Infectious Diseases, Royal
Women’s Hospital, Melbourne, Australia
Hepatitis B (HBV) and C (HCV) viruses can both result in asymptomatic carrier states
(chronic carriers), as well as result in chronic liver disease and ultimately primary
heptocellular carcinoma.
Both are transmitted by blood and/or body fluids: the risk to a healthcare worker from a
needlestick incident of contaminated positive blood being far greater for HBV (HbeAg+ 30%,
HbeAg- 3%) than HCV (1.8%).
Sexual transmission for HBV occurs, although for HCV it is not clearly defined. It probably
happens but very inefficiently, accounting for a minority of cases.
Mother-to-infant transmission of HBV is largely responsible for the pool of chronic cases
worldwide, although this route can be effectively and efficiently interrupted by the newborn
HBV vaccination programme. Neonatal transmission of HCV occurs although at a lower rate
(^5%), unless a mother is co-infected with HCV when it increases threefold.
EUROGIN 2003
46
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SS4-04
CONSENSUS CONFERENCE: MANAGEMENT OF EXTERNAL
GENITAL WARTS
Ferenczy Alex
McGill University and The Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Canada
The primary reason for treating visible EGW's is to provide cure or to induce wart-free
periods. Patients can be assured that EGW's rarely, if ever, become malignant, and physicians
should be prepared to counsel patients with a variety of sexual and psychosocial issues
associated with EGW's. Sex partners should be included in the process of prevention and if
appropriate, diagnosis and treatment, and education about HPV in general, EGW's and other
STD's.
- A given treatment(s) should be discontinued if no response is obtained by four weeks or
only partial response is observed at eight weeks of therapy. Alternate therapies are to be
instituted. Exception to the rule is 5% imiquimod which is associated with a substantial rate of
complete clearance if used up to 16 weeks.
- Treatment strategies should be discussed with the patient and be instituted after obtaining a
mutual (patient-healthcare provider) agreement on the choice(s) of therapy.
- Provider-administered and patient-applied therapies are appropriate either as first-line or
second-line treatments. Their choice depends on volume, distribution, and type of lesion as
well as patient's preference and financial resources.
- Most therapeutic agents or interventions result in an approximately 50 percent wart
clearance, and recurrence rates range from close to 10 percent and 90 percent with an average
of 30 percent. Patients have to be informed about the need for multiple and often combined
therapies and possible adverse effects associated with wart treatments. Overall, approximately
80 percent of patients will clear of their warts within one year, the remaining 20 percent need
multiple therapies on a relatively long-term basis.
- Currently, the most attractive patient-applied therapy uses the immune response modifier
5% imiquimod in the form of topical cream (AldaraTM).
- Clinicians involved in the management of HPV infections including EGW's, are awaiting the
development of both prophylactic and therapeutic HPV-vaccines.
(Ferenczy A. External anogenital
1999;December:1305-1313.)
EUROGIN 2003
warts:
old
and
new
therapies.
J
SOGC
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TC1-1-03
COLPOSCOPY OF THE ABNORMAL CERVIX (CIN AND HPV
INFECTIONS)
Walker Patrick
British Society for Colposcopy and Cervical Pathology
The technique of colposcopy was first described by Hans Hinselmann in the 1920s. The
original colposcopic terminology was first reviewed and a new terminology adopted during
the 2nd World Congress of Cervical Pathology and Colposcopy in Graz, Austria in October
1975. The terminology was reviewed at the 7th World Congress in Rome in 1990 and the
basic colposcopy terminology refined. As the Nomenclature Committee of the International
Federation for Cervical Pathology and Coloposcopy commented in their published article in
1991 ‘no terminology is perfect….no terminology is fixed. It is anticipated that this new
terminology will be modified as new scientific data are generated.
After the 10th World Congress in Colpsocopy in Buenos Aires in 1999 a new nomenclature
committee was established. It was decided that a review of the terminology should
concentrate on the following features: First it should be descriptive to allow colposcopists
throughout the world to be able to describe lesions to each other and to undertake important
collaborative research. Second, nomenclature should be written in such a way that it can guide
a colposcopist in training and aid the established colposocopist during the diagnostic process.
Third, it was believed that the terminology should be pragmatic and that a description of
different types of transformation zone might lead to more rational triage for the most
appropriate treatment for women with abnormal transformation zones.
The nomenclature committee consisted of:
Patrick Walker, United Kingdom, Chairman
Santiago Dexeus, Spain, Past President IFCPC
Giuseppe de Palo, Italy, President IFCPC
Renzo Barasso, France
Michael Campion, Australia
Frank Girardi, Austria
Carlos Jakob, Argentina
Michel Roy, Canada.
Mr Walker will present the details of the new classification and terminology with examples.
The precise text of the new classification and terminology is published in Obstetrics and
Gynecology, Volume 101, Number 1 in January 2003. The copyright for the Journal is with
the American College of Obstetricians & Gynecologists. The Journal is published by Elsevier
Science Incorporated.
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TC1-2-02
TREATMENT OF CIN: RESULTS, COMPLICATIONS AND FOLLOW-UP
Luesley David
University of Birmingham, Gynaecological Oncology, Birmingham
Most series of treated CIN published to date are heterogeneous in that they include those with
high grade and low-grade lesions. Low-grade lesions probably do not pose as great a risk to
the individual as high grade lesions. However, our inability to accurately determine the
natural history and progression of low grade lesions coupled with the understandable anxiety
of the woman herself mean that there is likely to be a continuing need to offer treatment to
some women with low grade disease.
Regardless of grade, treatment methods and principles are the same, that is removal or
destruction of the entire TZ to a depth that safely exceeds the deepest gland clefts. In the vast
majority of published series, success rates for treatment of all grades of CIN range from 9398%. One must be careful to determine what outcome is being presented. A single smear may
have a false negative rate and perhaps the most reliable method would be at repeat biopsy 12
months following treatment. This is obviously impractical and probably unethical. In most
series a reasonable endpoint has been normal colposcopy following treatment in association
with two consecutive negative smears. (6 and 12 months following treatment).
Factors independently associated with failure of treatment include the size of the lesion,
excision status (when recorded) and hosts immune status and HPV status. Although
cryocautery has been associated with a lower success rate than other destructive methods it
has not been possible to show whether this relates to the method or the user.
Excisional methods of treatment are associated with a primary haemorrhage rate in the order
of 1-2% and a similar secondary haemorrhage rate. All treatment methods may result in
anatomical scarring and even stenosis although this is more likely to be associated with the
amount of cervical tissue removed and not the technique used. Stenosis can cause
dysmenorrhoea or amenorrhoea and also lead to difficulties in achieving an adequate
cytological sample for follow up. Pelvic infection has been reported anecdotally after
treatment but no definite cause and effect link has been established.
It seems unlikely from published data that a single treatment will adversely affect fertility or
reproductive performance. Data on multiple treatments are awaited.
All women who have had treated or indeed untreated CIN require heightened surveillance as
they remain at an elevated relative risk for the development of cervical cancer. There is no
universally accepted consensus on how long follow up should be conducted, how frequent or
by what method. The UK NHS CSP are currently recommending that after the treatment of
high grade disease a woman should be tested by cytology (at least) six months following
treatment and then annually for 10 years. Women who have low grade SIL can be discharged
to routine recall much sooner than that and three years has been promoted.
Follow up may be an area where HPV testing can rationalise care. There is a recognised
association between HPV positivity following treatment and persisting (or recurrent CIN). It
is possible that HPV testing 6 months following treatment could be used to triage patients into
a high risk group for more intensive cytological and or colposcopic review, and low risk for
perhaps less frequent cytological review.
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TC2-01
CYTOPATHOLOGY TERMINOLOGY 2003
Wilkinson Edward
University of Florida, Pathology, Gainesville
With the new 2001 Bethesda System changes have been made in terminology, and the criteria
for establishing adequacy of a cervical pap test have been further refined. In the interpretative
section, the classification "within normal limits" has been replaced by "negative for
intraepithelial lesion or malignancy". The classification "benign cellular changes" has been
removed. The classification "ASCUS" has been replaced by "atypical squamous cells",
(ASC). The classification AGUS has been replaced by "atypical glandular cells", (AGC). In
addition the finding of normal endometrial cells in a patient 40 years of age or older has been
placed under a category termed "other", rather than placed under the AGC category. The 2001
Bethesda System with its major changes, as well as corresponding cytopathologic findings,
will be presented.
Reference: Solomon D et al., 2001 Bethesda System. Terminology for Reporting Results of
Cervical Cytology. JAMA, 2002, 287;16:214-9.
EUROGIN 2003
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TC2-03
CONVERSION TO LIQUID-BASED GYNECOLOGIC CYTOLOGY. A
USA PERSPECTIVE
Austin R.Marshall
Coastal pathology Laboratories & Medical University of South Carolina, Pathology, Charleston
Well over half of the current USA Pap test market employs liquid-based cytology (LBC).
Introduction of LBC into the clinical marketplace in the USA has proven complex, with some
initial resistance by clinicians, payers, and laboratories to replacing the time-proven
conventional Pap smear with a new test. Economic factors have played a major role in this
ongoing conversion. Since introduction in 1996, peer-reviewed direct-to-vial studies
comparing several hundreds of thousands of ThinPrep LBC Pap tests with the results of
conventional Pap smears have generally shown increased and usually biopsy-confirmed
detection of LSIL and HSIL by margins ranging from 50% to over 100%. A few intended use
studies have now also suggested that detection of endocervical glandular neoplasms,
increasing in relative and absolute frequency in the USA, are enhanced with ThinPrep. Reflex
Hybrid capture II HPV DNA testing from residual vial fluid, FDA-approved with ThinPrep in
1999,is now the preferred cost-effective method for identifying which women with ASCUS
Pap test results may harbor HSIL and need to undergo colposcopic evaluation. Intended use
direct-to-vial peer-reviewed articles on Surepath LBC Pap tests have also begun to also
appear since late 2000. Reflex HPV DNA testing from residual Surepath vials fluid of
ASCUS cases has been in USA laboratories carrying out self-validation studies. Publication
of an updated USA Bethesda System (TBS2001) has focused new attention on adequacy
criteria for LBC, defining new standards for minimum cellularity. For ThinPrep, preprocessing or reprocessing of bloody specimens using an off-label hemolytic glacial acetic
acid method is fairly widespread in the USA as a method for preventing or reevaluating
hypocellular test slides. Initially developed as a platform for computer-assisted screening,
LBC has been FDA approved since late 2001 for primary screening of Surepath slides with
the Focal Point Slide Profiler and pending approval for location-guided primary screening of
ThinPrep slides with the ThinPrep Imaging System. Modelling studies suggest that
widespread use of more sensitive LBC could improve USA cervix cancer outcomes.
EUROGIN 2003
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TC2-04
COMPUTER-ASSISTED AUTOMATION - SESSION TC2 (8:15AM TO
11:45AM, 13/04/2003)
Wilbur David
Massachusetts General Hospital, Pathology, Boston
Computer-assisted automated screening is currently a reality. The TriPath FocalPoint System
with Location Guided Screening is currently being utilized in countries outside the United
States (in the United States it is currently entering clinical trials). The Cytyc Computerized
Screening System is nearing the completion of United States clinical trial review at this
writing. Each system has the potential to improve the efficiency and accuracy of the screening
process by directing screening personnel to areas on the slide most likely to contain abnormal
cells. In this process they present the technologist with the electronic equivalent of a
"predotted" slide. Review of selected fields of view allows a triage of the slide to either full,
or no further manual review. Data in support of these applications will be presented in the
body of the presentation.
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TC2-07
MOLECULAR TECHNIQUES FOR CYTODIAGNOSIS
LINDER J.
Cytyc Corporation, USA
The Pap test has been a successful cancer-prevention tool because of its simplicity, and the
enormous amount of information that can be obtained from the morphologic review of a
microscope slide.
However, morphology has limitations, principally manifested by uncertainty in the behavior
of some lesions e.g. ASCUS and LSIS; and in intraobserver and interobserver variability
inherent in morphologic review.
A variety of molecular techniques have been explored as possible adjuncts to the microscopic
examination of the Pap. The most extensive literature relates to the testing of the Pap sample
for the presence of certain types of HPV, as an adjunct for the triage of morphologically
indeterminate samples, or for the primary assessment of the cervical sample. The central role
that HPV plays in cervical carcinogenesis speaks to the utility of this testing.
Because HPV infection can alter the ploidy of cells, or the rate of cell proliferation, molecular
markers of increased cell proliferation or ploidy have been examined for their potential utility
in assessing the Pap sample. In addition, a variety of markers of DNA replication or cellular
control, that may be altered in the process of carcinogenesis e.g. keratins, oncogene products,
p16INK4a have been explored for their diagnostic utility.
The ideal markers would allow the prediction of significant cellular alteration that has high
risk for progression to cancer, and allow laboratory personnel to distinguish insignificant
HPV infections from those that pose a risk to patient health.
EUROGIN 2003
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TC3-1-03
VULVODYNIA
Jacob Bornstein M.D., MPA
Associate Professor, Vice President, The International Society for the Study of Vulvovaginal Disease
(ISSVD), Department of Obstetrics and Gynecology, Carmel Medical Center and Rappaport Faculty of
Medicine, Technion-Israel Institute of Technology, Haifa, Israel
A common cause of dyspareunia is vulvar vestibulitis, hyperesthesia of the vestibule. In 2001
the International Society for the Study of Vulvovaginal Disease (ISSVD) introduced a new
terminology, in accordance with the Snowmed classification, for vulvar pain syndromes.
Vestibulitis is now termed: "Provoked, localized vulvar dysesthetic disorder"
An operative procedure called perineoplasty was advocated in 1981 by JD Woodruff for the
treatment of severe vestibulitis. It included vestibulectomy and vaginal advancement and has
been used successfully since then. Non surgical treatments include: Biofeedback pelvic floor
training and low oxalate diet.
Table: Outcome of surgery (Perineoplasty) for vulvar vestibulitis: review of the world
literature (646 reported cases)
Age follow-UP
Outcome
IN YEARS CR PR
CR+PR
NR Total
17-80 0.2-10 371(57%) 103(16%) 104(16%) 68(11%) 646(100%)
CR = Complete response
PR = Partial response
NR = No response
EUROGIN 2003
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TC3-1-04
LICHEN SCLEROSUS AND SQUAMOUS CELL HYPERPLASIA
Neill S.
St Thomas’ Hospital London. St Peters Hospital Chertsey Surrey and Chelsea and Westminster
Hospital London
Lichen sclerosus (LS) is a lymphocyte-mediated dermatosis that has a predilection for the
genital skin and was first described as a variant of lichen planus (LP) at the end of the 19th
century by Hallopeau and Darier . The typical histological findings are of a thinned epidermis
with hyperkeratosis and a band of hyalinized collagen in the upper dermis with the
lymphocytic infiltrate beneath this. There may also be small foci where there is a lichenoid
infiltrate along the dermoepidermal juction The treatment is an ultrapotent topical steroid
which clears symptoms, improves the clinical signs and can reverse the histological findings.
In some cases lichen sclerosus may be associated with epidermal thickening i.e. squamous
cell hyperplasia. These cases are slower to respond to treatment and seem to be more
commonly associated with squamous cell carcinoma.
It is not known why squamous cell hyperplasia occurs with lichen sclerosus but a few of the
cases are probably examples of hypertrophic lichen planus and some may be an overlap
syndrome of lichen sclerosus and lichen planus. In other instances there appears to other
factors in addition to the lichen sclerosus that may be the cause of the hyperplasia. This may
be anoth<er dermatosis e.g. psoriasis. No link with human papilloma virus and lichen
sclerosus has yet been established
It is important to identify the patients with lichen sclerosus and squamous cell hyperplasia as
they require long term follow up as they appear to have a higher risk of developing squamous
cell carcinoma.
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TC3-1-06
VULVAR EROSIONS AND ULCERATIONS
FAURE Michel
Clinique Dermatologique, Hopital Edouard Herriot, Lyon - France
This is a review of clinical conditions presenting with erosions or ulcerations of the vulva.
A. Infections: herpes, syphilis...
B. Inflammatory skin disorders affecting the genitalia:
contact dermatitis, irritant or allergic
lichenoid disorders: lichen sclerosus, lichen planus, lupus
erythematosus
vesicubullous disorders
auto-immune: pemphigoids, pemphigus
toxic: Stevens Johnson syndrome, TEN
genetic: Epidermolysis bullosa, Hailey-Hailey‘s disease and other nonimmune acantholytic disorders
aphtosis, Crohn’s disease
C. Néoplastic disorders: carcinomas, VIN 3, Histiocytosis X, Paget’s disease
D. Others: trauma (obstetrical, surgical, sexual, accidental)
Skin examination for the presence of typical skin lesions, examination of the mouth, anus,
perianal and perineal regions, surgical biopsy for anatomapathological examination and direct
IF, tests for the presence of various circulatins auto-antibodies (auto-immune bullous
diseases) are helpful for the diagnosis.
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TC3-1-07
VIN DIAGNOSIS AND TREATMENT
Sideri Mario
Europena Institute of Oncology, Dpt. Gynecology, Milano
Vulvar intraepithelial neoplasia (VIN) of squamous origin is a preneoplastic lesion of the
female externa genitalia. The occurence of this disease is increasing while the mean age of the
affected patients is dropping. Pruritus and burning are the most common symptoms, but some
patients are asymptomatic. Phisical and colposcopic examination are used for diagnosis and a
biopsy is required for confirmation. Different treatment modalities have been proposed
including cold knife excision and laser therapy. However, the optimal modality has not been
yet established, since relapses often occur and treatment sequelae are associated with wide
excisional therapy. Moreover the natural history of these lesions is still not completely
understood. There are many issues that must be considered in the surgical management of
high grade vulvar intraepithelial neoplasia (VIN 2-3): diagnosis of occult early invasion,
preservation of vulvar morphology, prevention of the development of invasive cancer, and
symptoms relief. Many reports have demonstrated the inability of vulvar colposcopy
(vulvoscopy) to detect early stromal invasion in the vulvar area, and up to 18% of
unrecognized invasion at vulvoscopy was demonstrated. The first aim of surgical
management of VIN is therefore the excision of the entire lesion for diagnostic histological
purposes. The importance of detection of early invasion in the vulvar area is stressed by the
finding of 10% lymph node metastases in patients with depth of invasion as low as 1 to 5 mm
and surgical excision offers the possibility to achieve a correct diagnosis since early invasion
is easily identified. Cosmetic and functional results of surgery are of utmost importance when
approaching the treatment of VIN3, since the age of the affected patients is dropping in some
series almost one third of the patients was less than 40 years old. Recent reports have
questioned the preventive aim of VIN3 therapy on the basis of literature data demonstrating
high recurrence rate after surgical excision. This ia an attractive hypothesis, to follow up
VIN3; however since areas of occult early invasion can be easily missed by vulvoscopy and
targeted biopsies, this alternative can not be considered the standard procedure; the possibility
to follow up young patients with VIN 3 should be adopted with caution, only in center with
high experience in the field. In addition there are no data on the follow up of untreated VIN3
which can support the safety the "wait and see" treatment option, and, until these data are not
available, the standard management of VIN3 is excisional.
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TC3-1-09
PSYCHO-SOMATIC EVALUATION OF VULVAR PAIN
Steben Marc
Institut national de Santé publique du Québec, Risque biologiques, occupationnels et
environnementaux, Montréal
Psycho-somatic evaluation of vulvar pain is of paramount importance in a vulvar pain
practice. Without such evaluation, patients are categorized as difficult, creating a barrier to
proper diagnosis and comprehensive management. Psycho-somatic presenting disease are
easy to diagnose if simple anxiety and depression screening tools are used. The psychosomatic disorders can be primary or secondary. The spectrum of diagnosis frequently seen in
vulvar clinic is 1) the simple and temporary "adaptation problem with anxio-depressive
reaction", 2) the depressive disease spectrum, usually with somatic complaints and 3) the too
frequently forgotten anxiety spectrum ranging from the generalized anxiety disorder to the
post-traumatic stress disorder, the panic disorder , the phobic disorder and the social phobia
disorder. Whether they are primary or secondary proper management should avoid
minimization or banalization. Ignorance of these conditions influences the chronicity of the
pain and exposes the patient to multiple testing usually finishing in invasive testing such as
laparoscopy and even hysterectomy. Psycho-somatic complaints when found are better
managed trough a multidisciplinary team with experience in the domain. Management can
include 1) the use of pharmacologic agents of antidepressants with pain control properties, 2)
the intervention of a psychologist or a psychiatrist with bereavement management experience,
pain control techniques and various psychotherapies, 3) the intervention of a sex therapist to
help direct sex in it's most pleasurable way considering the handicap to sex expression
(individually or in couple) etc. The use of mood altering substance such as marijuana or
alcohol to control pain and/or psycho-somatic symptoms should be evaluated since they
usually potentiate the depressive and anxious disorders. Normalization of psycho-somatic
complaints is very important for these patients. The simple ignorance of psycho-somatic
conditions in patient presenting with chronic vulo-vaginal complaints is a major factor in
patient being unhappy about the attending physician and a source of professionnal
frustration...for the attending physician!
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TC3-2-01
VULVAR DISEASES COURSES: INTERACTIVE CASE STUDIES
Micheletti L., Bogliatto F., Chieppa P., Massobrio M.
Department of Gynaecology and Obstetrics, University of Torino, Italy
Vulvar disorders represent a diverse spectrum of lesions varying from innocuous alterations to
incapacitating diseases which often represent a diagnostic and therapeutic challenge for many
practitioners.
The management of a woman suffering from a vulvar discomfort can be further complicated
either by the fact that women often self-medicate before consulting a physician, taking
medications that may not help their condition but aggravate their symptoms, complicating the
clinical aspect, either by the fact that the three types of physicians, usually dealing with these
women (generalists, dermatologists, and gynaecologists), receive little training in and have
little experience with vulvar problems.
The end result is that women today are receiving far less than optimal care for their vulvar
disorders. This situation is remediable through a standardization and systematization of the
scattered medical knowledge of vulvar disease into the multidisciplinary subspecialty devoted
entirely to the vulva which is termed vulvology. Vulvology provides a point of consolidation
for the much-too-fragmented knowledge regarding embryology, anatomy, and physiology of
the vulva and will surely improve the care of women with vulvar problems.
During the “interactive case studies” section a picture of the clinical aspect of the following
three cases will be presented and discussed.
Case 1: congenital atrophy of the labia minora referred as vulvar lichen sclerosus
Case 2: vulvar psoriasis referred as micotic vulvitis
Case 3: small iperpigmented nodule referred as vulvar melanoma
During the interactive discussion it will be demonstrated that:
• in case 1, an accurate history combined to a specific knowledge regarding anatomy,
physiology, and pathology of the vulva is sufficient to exclude the diagnosis of lichen
sclerosus.
• in case 2, an accurate history combined to a careful inspection of other cutaneous regions
can be sufficient for a skilled vulvologist to pose the diagnosis of vulvar psoriasis, even if a
biopsy could be further helpful.
• in case 3, even a skilled vulvologist, facing an iperpigmented nodule, may always performe
a biopsy to be sure to exclude a malignant melanoma.
(Micheletti L, Preti M, Bogliatto F, Lynch PJ. Vulvology: a proposal for a multidisciplinary
subspecialty. J Reprod Med, 2002;47:715-7)
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TC4-1-01
DIGITAL COLPOSCOPY
Quek, S.C
KK Women's & Children's Hospital, Gynaecologic Oncology Unit, Singapore
Traditional diagnostic colposcopy can be enhanced by the use of digital imaging systems and
associated patient data management technologies. The basic equipment required for a digital
colposcopy system includes a video camera, a computer with frame grabbing facility, and the
appropriate software for image and patient data management. Several integrated systems are
now available on the market. An example is the MediScan system, which allows the capture
of digital video and digital stills. The integrated system software incorporates various
technical features to assist clinical practice. For example, it enables image comparison with
previous colposcopic images obtained from the patient or with images stored in a database as
exemplars of various colposcopic appearances. Annotation of images can be performed
through the use of a digital light pen. In addition, all the image and epidemiological data can
be stored on DVD and retrieved for evaluation.
Variations in image quality between digital systems can be understood in terms of the system
optics, the video camera and the frame grabber. Each of these components has an impact on
the final quality of the image. System optics are largely defined by the quality of the
colposcope in terms of the fidelity of reflected light transmission to the imaging surface of the
camera. However in practice, misalignment of the camera, low illumination levels, poor focus
and excessive surface reflections are the most common causes of low quality images. In
addition, some systems capture images at low resolution or compress the images in order to
save storage space. The choice of camera is critical (1-CCD or 3-CCD). The camera video
signal is transferred to the frame grabber, which is responsible for converting the image into a
digital format. The frame grabber and its associated software play a crucial role in
determining the quality of the final image.
In conclusion, the advent of digital video technology for colposcopy allows the introduction
of a range of tools designed to facilitate diagnosis, increase efficiency, provide a platform for
quality assurance, and improve management of patient records. It is also an invaluable aid in
the teaching of colposcopy.
A series of digital colpophotographs will be presented to demonstrate the use of a digital
colposcopy system.
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TC4-1-02
ENDOCERVICAL CURETTAGE (ECC) VERSUS ENDOCERVICAL
BRUSHING
Ferenczy, A.
McGill University and The Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Canada
In many colposcopic practices, evaluation of the endocervical canal by histology is an integral
part of the initial investigation in women with an abnormal cervical cytology. Arguments
against ECC include patient discomfort, relatively high cost and false-positive and falsenegative results. There has been a trend in recent years to use less painful methods to evaluate
the endocervical canal, i.e. endocervical cytobrushing. However, cellular samples obtained by
endocervical brushing have disadvantages, namely high false-positive rates. This is mainly
due to the difficulty in interpreting endocervical cytology and contamination of the sample
from CIN located at or in the external os. Endocervical brushing used for histologic
evaluation of the endocervical canal may be more appropriate than cytology. We have
evaluated 315 women randomized to have either ECC or endocervical brushing for histology.
Both techniques yielded similar diagnostic performance and patient discomfort. Endocervical
brushing had lower false-positive rates than those reported in the literature for cytologic
analysis. The amount of specimen was scantier by endocervical brushing (7.6%) than by ECC
(2.5%) (p < 0.04). Both techniques are acceptable for evaluating the endocervical canal,
although ECC using metal curettes is the preferred choice for evaluation of the endocervical
canal, when brushing yields scant or no specimen for histologic evaluation.
(Klam S, Arseneau J, Mansour N, Franco E, Ferenczy A. Comparison of endocervical
curettage and endocervical brushing. Obstet Gynecol 2000;96:90-94.)
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TC4-1-06
CRYOTHERAPY FOR CERVICAL INTRAEPITHELIAL NEOPLASIA
Ferenczy Alex
SMBD-Jewish General Hospital, Pathology, Montreal, Quebec
Cryotherapy has been established as an acceptable and effective office therapeutic approach
to CIN. All patients considered for cryotherapy should be evaluated with a satisfactory
colposcopic examination, the squamocolumnar junction should be visible in its entirety, and
the limits of the lesion should be completely seen. A negative endocervical curettage should
be established. Multiple rather than directed biopsies of the disease should provide for
appropriate histologic diagnosis and ruling out the presence of invasive disease. Several
studies indicate that with proper selection of patients, appropriate technique used and careful
follow-up, the success rate is on the order of 90% after a single session of cryotherapy
regardless of grade of lesion matched for size. Experience suggests that with large high-grade
CIN lesions (over 2 cm in diameter or involving more than two quadrants of the cervix),
failure rates after cryotherapy may be relatively high. In these patients, excisional methods
such as LLETZ / LEEP should be considered. Patient compliance and adequate follow-up of
evaluation should be ensured. Follow-up for a minumum of two years with negative cytologic
reports or combining cytology with colposcopy or HPV DNA testing (HC-II) at 6 months
post-cryotherapy effectively reduces the incidence of undetected failure in treatment. The
advantages of cryotherapy include easy to perform technique, safe and less costly outpatient
procedure than other ablative or excisional therapies used for treating CIN, particularly its
low-grade variant. The disadvantages of cryotherapy are vasovagal symptoms during therapy,
copious vaginal discharge in most patients during the two post-treatment weeks and for 50%,
external os stenosis in women aged 45 and over.
(Ferenczy A. Comparison of cryo- and carbon dioxide laser therapy for cervical intraepithelial
neoplasia. Obstet Gynecol 1985;66:793-798.)
(Falcone T, Ferenczy A. Cervical intraepithelial neoplasia and condyloma: An analysis of
diagnostic accuracy of post-treatment follow-up methods. Am J Obstet Gynecol
1986;154:260-264.)
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TC4-1-08
DUO-BRUSH: A NEW DEVICE FOR CONVENTIONAL AND LIQUID
BASED PAP-TEST SAMPLING
BARRÈS Denis, SAVET Christian
Pathologist and cytologist, PARIS
The study was aimed at probing the efficiency of Duo-Brush. We tested it for quality as well
as quantity of cellular material and patient and pactitioner comfort.
Duo-Brush consits in two plastic brushes orientated at right angle. The long one in
prolongation of the handle for endocervical sampling. The short, curved one is for exocervical
sampling. The transforming zone should lie in between.
21 practionners (gynecologists and GP) volunteered for the sampling collection of 1604 paptests read in two pathology laboratory. 52 % were conventional smears and 48 % monolayers.
The samples were graded as optimal, suboptimal or insufficient as regards quantity of cells
for correct cytopathologic procedure. Suboptimal and optimal slides were considered as
“acceptable” for cytopathologic analysis.
Only 1% of samples were unsatisfactory for insufficient cell number, and necessitated a new
sampling procedure.
Among the 99 % globally satisfactory slides, subclassifications for each sampling zone
regarding respectively optimal + suboptimal cell quantity grades were as follows:
- Endocervix: 46% + 44% = 90%
- Transition Zone: 50% + 45% = 95%
- Ectocervix: 80% + 19% = 99%
There was no difference between conventional smears and liquid based technique.
Distribution of diagnoses was the same as observed in other smears or monolayers of the
same laboratory during the same period.
Sixty percent of women and over seventy five percent of practitioners appreciated the device
for its comfort and ease of use. According to practitioners, use of Duo-brush allowed for 40%
of time saving on the whole process.
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TC4-2-01
DUCTAL LAVAGE AND THE MANAGEMENT OF WOMEN AT HIGH
RISK FOR BREAST CANCER
Vogel Victor
Magee-Womens Hospital, Breast Program, Pittsburgh
Ductal lavage is an office-based procedure that can be assimilated easily into clinical practice.
The potential for reducing the risk of breast cancer through selective estrogen receptor
modulators (SERMs), aromatase inhibitors, and surgery has generated interest in the addition
of ductal lavage to traditional breast cancer risk factors. Comprehensive breast cancer risk
management includes a discussion of ductal lavage for improved risk stratification, multiple
options for risk reduction, and surveillance strategies that incorporate investigational imaging
protocols. Exfoliated epithelial cells lie within the ductal-lobular system of the breast. The
presence of atypical ductal cells in nipple aspirate fluid (NAF) is an independent predictor of
breast cancer risk: cytologic atypia discovered in NAF imparts a relative risk of 4.9 for breast
cancer when compared to women who did not yield NAF. In a multicenter study of women at
elevated risk for breast cancer, 84% of participants had fluid-yielding ducts that served as
sites for lavage. Among these women, 23% were found to have atypia (17% mild and 6%
marked atypia), 54% had benign cytology, and two patients (less than 1%) had frankly
malignant cells. Ductal lavage demonstrated a three-fold greater sensitivity in the detection of
atypia compared with NAF. In the multi-center study 29% of women considered lavage more
comfortable than mammography, 20% felt it was comparable, and 51% felt it was less
comfortable than mammography. Current indications for ductal lavage include: 1) Gail model
5-year risk of 1.7% or greater, 2) patients with a prior history of breast cancer, and 3) women
who carry BRCA1/2 mutations. If ductal lavage demonstrates cytologic atypical hyperplasia,
it is reasonable to use the Gail model for quantifying risk, entering a "biopsy that showed
atypical hyperplasia." Risk reduction with tamoxifen will have a larger net benefit in these
women who will be more likely to adopt a drug intervention risk reduction strategy. Cytologic
findings from ductal lavage can provide pertinent information to formulate management
decisions, and the promise of ductal lavage extends to both genomics and proteomics.
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TC4-3-07
PIPELLE® MARK II : A NEW DEVICE FOR COMBINED CYTOLOGY
AND HISTOLOGY TESTING OF THE ENDOMETRIUM
Dr Edgar Cornier
Clinique de la Muette, Paris
Pipelle® sampling is widely used worldwide for uterine cancer screening. It replaces previous
techniques, such as endometrial biopsy and curettage, as well as other methods more costly or
less effective. The Pipelle® curette is used to perform painless suction biopsies on an
outpatient basis. It is the reference instrument for outpatient diagnosis and has been
mentioned in 80 international publications (cf Medline: Endometrial biopsy Pipelle).
The new device, Pipelle® Mark II (Laboratoire C.C.D. Paris France) is fitted with a
polypropylene sheath with a lateral opening at its distal extremity. The tip is ground, using a
patented industrial laser process, to produce a rough surface on 2 centimetres. The rest of the
sheath is graduated. The piston slides inside the sheath up to the narrowing at its proximal
end.
Processing Pipelle® Mark II sampling for analysis: Cut off the rough distal tip and place it in
a solution for cell-suspension based cytology (vial n°1). Eject the contents of the sheath into
10% Neutral Buffered Formalin for histology testing (vial n°2).
With Pipelle® Mark II, the smear collected in the suspension medium can differentiate cells
originating from the cervix, the isthmus, and the endometrium.
In young women, the biopsy of the endometrium provides large quantities of tissue.
In patients treated with HRT, the endometrium is atrophied with markedly less material
collected. Papanicolaou’s smear cannot be used to screen for endometrial cancer, whereas
Pipelle® Mark II is able to collect endometrial tissue, even if it is atrophied.
Cancer screening is essential in patients with menorrhagia.
Endometrial cytology is used to complement the histology analysis provided by Pipelle®
sampling in women with postmenopausal atrophy.
Screening is necessary in women with metrorrhagia, or in young women at high risk.
Pipelle® Mark II sampling is a painless procedure, designed to collect material from the
whole endometrium-uterus for histology and cytology analyses. It is an endometrial screening
and the reading of results is not operator dependent.
Ultrasonography and Pipelle® each have clear-cut roles. These procedures complement each
other within the management strategy of women with metrorrhagia.
Sampling with Pipelle® Mark II is not dangerous and does not carry a risk of cancer cell
dissemination, unlike abrasive curettage or hysteroscopy.
The Pipelle® sensitivity is between 98% and 100% of established invasive cancer cases, and
its specificity could be improved in early or precancerous cases. This is the objective of
Pipelle® Mark II designed for combined cytology and histology testing.
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TC5-01
IST REEMERGENTES: GONOCOCCIE ET SYPHILIS
Berrebia A, Duclusaud A, Castagno R
Fédération de Gynécologie Obstétrique – CHU La Grave - Toulouse
Depuis 20 ans, les infections sexuellement transmissibles (IST) se sont nettement modifiées
avec l'apparition du SIDA au début des années 80, l'augmentation des souches résistantes aux
antibiotiques et la réémergence des "vieilles" IST que sont la gonococcie et la syphilis.
La gonococcie à quasiment disparu des pays occidentaux entre 1986 et 1998. Depuis 1998, un
certain nombre de services cliniques et de réseaux de surveillance signalent une réémergence
de cette IST et une augmentation des souches présentant une sensibilité diminuée à la
pénicilline, aux cyclines et aux quinolones. C'est dans la population des hommes homosexuels
que cette réémergence est la plus nette. Du fait de la fréquence de plus en plus grande de
souches résistantes, le traitement antibiotique des gonococcies fait appel en premier lieu à la
spectinomycine (Trobicine® 2g IM) ou à la ceftriaxome (Rocéphine® 500mg IM).
La syphilis a également pratiquement disparu des pays occidentaux avant même la venue du
SIDA dans les années 80. Depuis 1998, il semble comme pour la gonococcie que cette IST
réapparaisse dans les populations ciblées comme les homosexuels masculins, les patients
infectés par le VIH, les toxicomanes et les individus ayant un comportement sexuel à risque.
Le traitement, en absence d'allergie, repose sur la pénicilline: benzyl-pénicilline
(Extencilline® 2,4 millions d'unités IM) en dose unique ou en deux injections à une semaine
d'intervalle.
La gonococcie et la syphilis sont des infections graves (salpingite et stérilité pour la première,
complications et séquelles sévères pour la seconde). Leur réémergence, depuis les 3-4
dernières années, fait craindre leur diffusion dans la population à faible risque. La vigilance
est donc de mise malgré leur relative rareté par rapport aux quatre grandes IST que sont
l'infection à HPV, l'herpès génital, l'infection à chamydia trachomatis et le SIDA.
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TC5-04
CONSEILS DE PREVENTION POUR LES COUPLES
SERODIFFERENTS
Berrebia A., Duclusaud A., Castagno R.,
Fédération de Gynécologie Obstétrique, CHU La Grave, Toulouse
Les infections nécessitant des conseils de prévention chez les couples sérodifférents sont
celles qui se transmettent par voie sexuelle et pour lesquelles nous ne possédons pas de
traitement permettant l'éradication de l'agent pathogène. C'est le cas, en particulier, des
infections à VIH, HSV, HVB, EBV, CMV et HTLV 1.
Ces infections ne faisant pas l'objet d'un dépistage systématique, une sérodifférence dans un
couple peut être mise en évidence devant une affection symptomatique, lors d'un don de sang,
lors d'un dépistage volontaire, lors de traitements nécessitant un don d'organe, de moelle ou
de cellules sanguines ou avant certaines vaccinations. Dans le cas particulier de la grossesse,
seule la sérologie VIH est systématiquement proposée avant la gestation et au début de celleci. Pour les autres affections, leur recherche peut être motivée par une primo-infection
symptomatique ou une anomalie fœtale (malformations, retard de croissance).
Seule l'infection à VIH est suffisamment grave pour obtenir d'un couple sérodifférent une
protection sexuelle par l'utilisation constante et définitive du préservatif (masculin ou
féminin). Pour les autres infections, il est illusoire d'essayer d'obtenir d'un couple une mesure
préventive aussi radicale sauf dans certaines circonstances limitées dans le temps. C'est le cas
de la grossesse ou des périodes virémiques transitoires. Dans le cas particulier de l'aide
médicale à la procréation, les lois de bioéthiques nous imposent la recherche systématique du
VIH, de l'HVB et de l'HVC. Si le couple est sérodifférent, la prise en charge dépendra du
partenaire infecté. Si la femme est séropositive et l'homme séronégatif, les techniques d'autoinsémination, d'insémination intraconjugale ou de fécondation in vitro (FIV) permettront de
protéger le partenaire. Si l'homme est séropositif et la femme séronégative, les techniques de
traitement du sperme virologiquement testé ou de FIV avec injection intracytoplasmique d'un
spermatozoïde (ICSI) permettront de protéger la partenaire.
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SEM1-1-01
EPIDEMIOLOGY
Franco Eduardo
McGill University, Division of Cancer Epidemiology, Montreal
As a professional community, we are currently living a period of great excitement with the
perspective of making major strides in cervical cancer control. New leads are allowing us to
practice more efficient and tailored screening for the disease and its precursor lesions via
liquid cytology, HPV testing, visual inspection, and other technologies. On the primary
prevention front, prophylactic vaccination with HPV 16 capsid antigens seems to protect
against acquisition of persistent HPV 16 infection and development of high grade precursors.
Having come this far we now must avoid a setback. Public health authorities in middle and
low income countries have closely monitored the debate on new screening technologies.
Between the fear of increased health care costs consequent to the adoption of new screening
tests and the promising results on HPV vaccines it is all too tempting to take a wait-and-see
attitude concerning cervical cancer prevention. This posture could become widespread in
developing countries and lead to decreased funding of cytology quality control, training, and
needs assessment, in the false hope that HPV vaccines will be available soon to reduce the
burden of cervical cancer, thus obviating the need for substantial expenditures modifying or
maintaining screening programs. This scenario will prove disastrous. It behooves us as
scientists concerned with cervical cancer control to place our work in a broader, more useful
public health context where competing priorities come in many varieties and degrees of
urgency. Societal variables should be incorporated in efficacy and cost-effectiveness studies
so that the right lessons will be learned. Producing and sifting through the evidence on the
role of emerging technologies for cervical cancer screening requires complex mobilization of
resources by multi-disciplinary investigations. The most definitive answers to come from
these studies will take at least a decade to be obtained. We need, therefore, to alert
stakeholders that cytology-based programs are not to be relaxed or we risk wiping out the
gains from the past 50 years in cervical cancer prevention.
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SEM1-1-02
NOVEL MARKERS FOR RISK STRATIFICATION OF HPV POSITIVE
WOMEN
Lorincz Attila
Digene Corp, Research, Gaithersburg, Maryland USA
Given the necessary causal relationship of certain HPVs with cervical cancer and the fact that
it takes 8 to 10 years for cancer to develop from an incident infection, there is little risk of
cervical cancer among women who are HPV negative. There has been criticism of HPV
testing for routine screening because most infections do not progress to cancer and there is the
danger of excessive and costly interventions. This fear can be minimized by proper education
of clinicians on appropriate test usage. There are strong arguments for restricting use of HPV
screening to women above the ages (over ~30 years) at which HPV behaves as an STD.
However, even with this age stratification there is a need for additional improvement in HPV
DNA test specificity. The use of novel markers is proposed as a way to stratify HPV positive
women into risk groups. It may be possible to stratify on the basis of E6 and/or E7 expression
levels although direct clinical supporting data are lacking. Some have suggested that novel
protein markers such as p16, MCM5, EGFR, various cyclins etc, may replace the need for
HPV testing. However, these arguments overlook the inability of such tests to identify the atrisk pool, namely those women who are persistently HPV infected without concurrent
cytological abnormalities but who are at risk for high grade disease in coming years. We have
undertaken an investigation of novel protein markers to stratify HPV positive women. We
employed immunocytochemistry to look at issues of test sensitivity and specificity of
individual and of panel protein tests, alone or in combination with HPV DNA testing. Our
preliminary data reveal that none of the markers alone are as sensitive for detection of highgrade cervical lesions as HPV DNA tests and should be used as panels. However, use of the
best panel as a stand-alone test suffers from poor specificity. In contrast use of the panel on
HPV positive women appears to stratify these into groups with adequate sensitivity and
specificity to be considered a potential triage strategy.
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SEM1-1-05
HPV AS A TEST OF CURE
Thomas C., Wright Jr.
Columbia University, New York, USA
HPV DNA testing is now routinely being utilized in a number of clinical situations. These
include use as an adjunct to cervical cytology for primary screening in women over the age of
30 years, determining which patients with ASC-US cervical cytology results require
colposcopy, follow-up of women biopsy-confirmed CIN 1, and as a test of cure in women
who have undergone treatment for CIN 2,3. A number of studies have evaluated the use of
testing for high-risk types of HPV as a method to identify those women who develop
recurrent or persistent CIN after treatment. In general these studies have found that women
who subsequently become HPV DNA negative post-treatment are at very low risk for having
recurrent / persistent CIN. Because of the low risk of having CIN 2,3 in women who become
high-risk HPV DNA negative post-treatment, the recent 2001 Consensus Guidelines for the
Management of Women with Cervical Intraepithelial Neoplasia have recognized HPV DNA
testing as an acceptable modality for the post-treatment follow-up. During this presentation
the data supporting the use of HPV as a "test of cure" and recommendations for its use will be
reviewed.
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SEM1-1-04
MANAGEMENT AS A RESULT OF THE ALTS TRIAL AND
BETHESDA PROTOCOLS
Cox JT
University of California - Santa Barbara, California, USA
The availability of the ASCUS/LSIL Triage Study (ALTS) data and the clear need in the US
for evidenced-based national guidelines for the management of abnormal Paps fostered the
convening of a national consensus conference on the management of women with cervical
cytological abnormalities and cervical cancer precursors in Bethesda, Maryland, on
September 6-8, 2001. The conference was organized and sponsored by the American Society
for Colposcopy and Cervical Pathology (ASCCP) and was attended by representatives from
29 participating professional organizations, federal agencies, and national and international
health organizations. HPV testing was integrated into national guidelines in the initial triage
of women with ASC-US, and in the initial evaluation of some women with LSIL, in the
follow-up of women with ASC-H, HPV positive ASC-US and LSIL not found to have CIN or
cancer at initial colposcopy, and in the expectant management of women with CIN 11.
In the ALTS trial the sensitivity of Hybrid Capture 2 (HC2) (Digene Corp., Gaithersburg,
MD) for CIN 2 or 3 at enrollment was 96%, whereas the sensitivity for the repeat liquid-based
ThinPrep Pap (ThinPrep Pap, Boxsborough, MA) was 85 percent. 2 Additionally, at the
threshold for referral to colposcopy of ≥ASCUS, slightly more women (59 percent) were
referred to colposcopy on the first repeat Pap test than on HPV testing (56 percent).2 Twoyear follow-up documented that a single HPV test at 12 months detected 95% of all the CIN3
not detected at first colposcopy with 55% referred to colposcopy and liquid-based cytology
detected 74% at first repeat and 88% at second repeat, with a total of 63% referred. The
findings indicate that a triage strategy of repeat Pap testing would require two repeat liquidbased Pap tests to equal the sensitivity of a single HC2 for detection of CIN 3+.
The ASCCP consensus guidelines did not recommend HPV testing in the triage of women
with ASC-H (ASC “cannot rule out high-grade”) or of premenopausal women with LSIL
because of the very high rate of HPV positivity and CIN2+ for women with these Pap
interpretations1. 525 of 668 (78.6 percent) women (median age 29) referred with LSIL tested
positive for high-risk HPV types by HC23. Because LSIL is often misclassified in
postmenopausal women and misclassified LSIL is not due to HPV, the ASCCP Guidelines gave
HPV testing at 12 months as one option for management under these circumstances1.
1. Wright TC, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ, for the 2001 ASCCPSponsored Consensus Conference. 2001 consensus guidelines for the management of
women with cervical cytological abnormalities. JAMA. 2002;287:2120.
2. Solomon D, Schiffman MH, Tarone R. Comparison of three management strategies for
patients with atypical squamous cells of undetermined significance: baseline results
from a randomized trial. J Natl Cancer Inst. 2001;93:293-9.
3. The Atypical Squamous cells of Undetermined Significance/Low-Grade Squamous
Intraepithelial Lesions Triage Study (ALTS) Group. Human papillomavirus testing for
triage of women with cytologic evidence of low-grade squamous intraepithelial lesions:
baseline data from a randomized trial. J Natl Cancer Inst. 2000;92:1014.
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SEM1-2-05
ROLE OF HUMAN PAPILLOMAVIRUS (HPV) TESTING IN PRIMARY
CERVICAL CANCER SCREENING: A CANADIAN EXPERIENCE
Ratnam S (1)., Franco E (2). and Ferenczy A (3).
(1) Public Health Laboratory, St. John’s, Newfoundland, Canada; (2) Department of Oncology, and (3)
Department of Pathology, Obstetrics and Gynecology, McGill University, Montréal, Québec
As oncogenic HPV types are the etiologic agents of cervical cancers, HPV testing could
augment the sensitivity and specificity of cytology-based cervical cancer screening. A study
was carried out to determine the role of HPV testing in primary cervical cancer screening. A
total of 2,098 women aged 18 to 64 years were screened utilizing both the Pap and HPV tests.
Hybrid Capture HPV DNA test was used to detect high risk HPV types. Colposcopy/histology
were done in women with abnormal cytology and/or positive HPV results. By cytology, 193
(9.2%) had abnormal Pap smears, of which 92 (4.4%) were squamous intraepithelial lesions
(SIL), and 101 (4.8%) atypical squamous cells of undetermined significance (ASCUS). HPV
test was positive in 227 (10.8%). Of those with SIL, 67.4% had a positive HPV test compared
with 8.2% with ASCUS or negative cytology. Of the 2,098 women, 128 had histology, based
on which the diagnostic indices of cytology and HPV test were determined. In detecting high
grade SIL (HSIL), the sensitivity of cytology (ASCUS or worse) was 53.3% (CI: 36.1-69.8)
versus 90.0% (74.4-96.5) for the HPV test. The specificity, positive predictive value and
negative predictive value of cervical cytology (ASCUS or worse) to detect HSIL were 51.0%,
25.0%, and 78.1%, respectively, and 51.0 %, 36.0%, and 94.3%, respectively, for the HPV
test. The combination HPV/PAP (ASCUS or worse) testing had a sensitivity of 93.3% (85.397.1) for detecting SIL which rose to 100% (88.6-100) for detecting HSIL with a negative
predictive value of 100% (85.1-100). The data indicated the HPV test alone was significantly
more sensitive and as specific as conventional cervical cytology in a primary cervical cancer
screening. The combination HPV/PAP testing can significantly improve primary cervical
cancer screening with a sensitivity of 100% for detecting HSIL. Its very high negative
predictive value has the potential to relegate up to 84% of women to a longer screening
interval. HPV testing alone may also be an attractive alternative to cytology in financially
challenged countries with a high prevalence of cervical cancer.
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SEM1-2-06
PORTLAND STUDY UPDATE
Lorincz Attila
Digene Corp, Research, Gaithersburg, Maryland
Adjunctive HPV DNA screening appears promising because of the demonstrated necessary
causal relationship between HPV and cervical cancer and because a high negative predictive
value of combined HPV DNA plus Pap tests, typically 99.8% to 100%, has been observed.
The Kaiser Portland Oregon study was a 10-year longitudinal investigation of HPV natural
history, Sherman et al (JNCI 2003;95:46) recently described the protocol and key data.
Enrollment occurred from 1989 to 1990 and 20810 women (mean 35.9 years) who provided
valid baseline Pap data were studied. Testing for carcinogenic HPV DNA on archived
baseline cervicovaginal specimens was conducted by HC2 in 2001. HPV data were not used
for clinical follow-up. Questions of interest included: a) the ability of baseline HPV DNA
and/or Pap tests to identify incident CIN 3 or cancer (CIN 3+), and b) the relative risk (RR)
for future CIN 3+ in women with HPV DNA and Pap negative results at baseline as compared
to women with three normal consecutive Paps regardless of HPV status.
Followup was by yearly conventional Pap screening and 171 cases of CIN 3+ were detected
cumulatively over 122 months. In the first 45 months cumulative incidence of CIN 3+ was
4.54% (95% CI = 3.61-5.46%) among women with Paps of ASC or worse, positive HPV
tests, or both, as compared to 0.16% (95% CI = 0.08-0.24%) among women with both tests
negative. Of the 171 women with CIN 3+ 33% had a positive Pap test at baseline, in
comparison 64% were HPV DNA positive, and 69% were positive for either Pap or HPV at
baseline. Of CIN 3+ diagnosed during the first 45 months 86% (95% CI = 80.3-92.6%) were
positive by the combined tests at baseline. The RR for CIN 3+ of women with a negative
baseline Pap and/or HPV DNA test was lower (RR = 0.68, 95% CI = 0.51-0.89) than among
reference women with three consecutive negative Pap tests (RR = 1).
It appears that negative results with combined testing should provide added reassurance for
lengthening the screening interval among low-risk women, while positive results identify a
small sub-group that requires more frequent surveillance.
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SEM1-2-07
MANAGEMENT OF HPV POSITIVE, CYTOLOGY NEGATIVE
WOMEN - RESULTS FROM THE HART STUDY
Cuzick J*, Szarewski A*, Hulman G, Menon U, Kitchener H, Luesley D, McGoogan E, Cubie H,
Terry G, Edwards R*, Brooks C*, Desai M, Gie C, Ho L, Jacobs I, Pickles C, Sasieni P
*Cancer Research UK, London and participating centres
The HART study is a multicentre trial of 11085 women aged 30-60 screened by conventional
cytology and HPV using the high risk Hybrid Capture II test. Thus far 120 women (1.2%)
have been diagnosed with histologically confirmed high grade disease. Overall, HPV testing
was more sensitive (94% vs 78%) than cytology (borderline or higher) for CIN 2+, but
slightly less specific (94% vs. 96%). The positive predictive value (PPV) for HPV was 17%
compared to 22% for borderline or worse cytology or 43% for mild vs worse cytology (where
sensitivity was only 65%). The specificity of HPV testing was improved to 95% and PPV to
20% if a 2RLU cut-off was used without loss of sensitivity. 825 women were either HPV
positive and cytology negative (536), or had borderline cytology with (78) or without (211)
being HPV positive. These women were randomised to be managed by immediate colposcopy
(414) or to receive followup cytology and HPV testing at 6 and 12 months (411). Women in
the later group also received a colposcopy at 12 months to ensure all disease was detected. 32
high grade lesions have been found in this group of which 30 were HPV positive. The two
missed lesions were CIN 2 and occurred among 211 women who had borderline lesions
which were HPV negative, indicating that these women can be safely returned to routine
screening without referral to colposcopy. Overall, there was no difference in high grade
lesions in the two management groups (15 vs 17, 4%), but low grade lesions were reduced
from 85 (21%) in the immediate referral group to 33 (8%) in the watched group, indicating
substantial regression. While HPV was very sensitive in women with borderline or negative
cytology, it was not very specific (PPV = 5%). However, all high grade lesions in the watched
group remained HPV positive on follow-up and about half of HPV positive would become
HPV negative. In women who had two positive tests, at least 6 months apart, the positive
predictive value of HPV positivity on both occasions was 12%.
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SEM1-3-01
HPV DNA TESTING AS A PRIMARY SCREENING TEST
Denny L., Kuhn L., Pollack A., Wright TC.
Most cases of cervical cancer can be prevented through screening. Few, if any, developing
countries have been able to initiate and sustain effective cytologically based screening
programmes and cervical cancer remains the commonest cancer cause of death in women in
these countries. This has led to the search for alternative methods of screening that may prove
more sustainable. One such alternative is HPV DNA testing.
Methods: From 1998 to 1999, 2754 previously unscreened African women, aged 35 – 65
years, were screened using visual inspection of the cervix after the application of 5% acetic
acid, cytology, HPV DNA testing for high risk types using Hybrid Capture II™ and
Cervicography. Women positive on any of the screening tests were referred for on-site
colposcopy and histological sampling
Results:HPV DNA testing identified 20% of women as having a positive test and had a
sensitivity, specificity, PPV and NPV of 81, 82, 18 and 99% respectively. Using a higher
threshold to define a positive HPV DNA test (10 x the positive control), 10% of the
population were found to be positive and the specificity increased to 93%, with a decrease of
sensitivity to 63% The equivalent findings using cytology (LSIL and >), which identified
7.5% of women as having a positive test, were 62, 95, 35 and 98%. Among women who were
HIV positive, the sensitivity of HPV testing increased to 95%, with a drop in specificity to
61%, compared to 79% and 85% respectively in HIV negative women. The commonest types
of HPV found in the total study population were 16, 35, 18, 45 and 58. Were the HPV
‘cocktail’ to be restricted to these types, the sensitivity and specificity of HPV DNA testing
would be 64% and 94% respectively. Highest specificity of HPV testing (98%) would be
achieved by only screening for HPV 16, but the sensitivity would decrease to 31%.
Conclusion: HPV DNA testing has a superior sensitivity to cytology, but a lower specificity.
Specificity however may be altered by either changing the threhold used to define a positive
test or by altering the cocktail of probes used for testing.
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SEM1-3-02
HPV TESTING IN PRIMARY SCREENING, AN INTERNATIONAL
EXPERIENCE: DEVELOPING COUNTRIES-INDIA
Sankaranarayanan R
International Agency for Research on Cancer, Lyon, France
There is considerable interest in the use of molecular techniques to detect carcinogenic HPV
in cervical cells for the early detection of cervical intraepithelial neoplasia (CIN). We use
hybrid capture technology (HCII), a second generation semi-quantative assay, to detect the
presence of any of 13 carcinogenic HPV DNA using signal amplification in our studies in
India. Currently, primary screening with HPV testing is evaluated in 3 cross-sectional studies
(Bombay, Calcutta and Trivandrum) and in a cluster randomised screening intervention trial.
Women aged 30-59 years (15,098) have been screened concurrently with cytology, HPV
testing and visual inspection with acetic acid (VIA) and with Lugol’s iodine (VILI), in 3
cross-sectional studies. All screened women were evaluated with colposcopy, and biopsies
were directed in those with colposcopic abnormalities. The final diagnosis was based on
histology (had biopsies been taken) or colposcopic findings, allowing direct estimation of
sensitivity, specificity and predictive values. Relative light unit/positive control cut off of ³ 1
at an HPV DNA detection threshold of 1.0pg/ml constituted a positive HCII test. The test
positivity rate was 7.1% and the sensitivity of the test to detect CIN2-3 lesions was 59.5%
with a specificity of 93.6%. We observed a much lower sensitivity for HCII compared to
reported results from elsewhere. A randomized intervention trial involving 160,000 women
aged 30-59 years is on-going in Western India to evaluate the efficacy and cost effectiveness
of screening with VIA, cytology, and HPV DNA testing in cervical cancer prevention.
Eligible women in 502 villages under 52 clusters of Osmanabad district in Maharashtra State,
Central India, have been randomized to receive one of the above interventions or to be part of
a 'control' group. Approximately 40,000 women in groups 1-3 will receive VIA, cytology, and
HPV testing, respectively. Women with positive screen tests will be investigated for cervical
precancer/cancer and treated. Women in the control group receive health education on
cervical cancer. The study groups are followed up for cervical cancer incidence and mortality.
On 31 July 2002, a total of 45,986 women had been screened. The detection rates of CIN2
plus diseases in the different arms are as follows; VIA 1.3%; cytology: 1.4%; HPV testing:
1.2%. The detection rates of high-grade cervical precursor lesions are similar with VIA, HPV
testing and cytology screening.
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SEM1-3-03
HPV TESTING FOR PRIMARY SCREENING, AN INTERNATIONAL
EXPERIENCE, FEASIBILITY AND FUTURE TRIAL DESIGN
Belinson JL (1),Qiao YL (2),Pretorius RG (3),Zhang WH (2),Wu LY (2),Tisci SE (4),Fife D (1)
(1) Cleveland clinic foundation,Cleveland,Ohio,USA; (2) The Cancer Institute/Hospital, Chinese
Academy of Medical Sciences,Beijing,China; (3) Kaiser Permanente Fontana, California,Usa; (4)
University Of North Carolina,Chapel Hill,North Carolina,USA.
Objectives: Determine the sensitivity and specificity of various algorithms for primary
screening. Determine the effectiveness and patient acceptance of a variety of techniques and
devices. Design and implement a primary screening program.
Methods: The sensitivity and specificity of various screening algorithms have been
determined by studies in rural Shanxi Province, China, that have included more than 11,000
women. Subjects underwent a self-sample for HPV (by HC-II assay). The self-sample HPV
specimens have been obtained with a dacron swab and a conical-shaped brush (Digene
Cervical SamplerÔ, Digene Corp. Gaithersburg, MD) and transported in STM. Liquid based
cervical cytology has been done using both the Thin Prep system and the Autocyte system.
Direct HPV tests have been transported in the Thin Prep solution (PreservCyt), STM, and
UCM. A new survey instrument has tested patient’s acceptance and the potential barriers to
self-sampling. Multiple cervical biopsies were used as the criterion standard. A new selfsampling device is being developed to take advantage of the information gathered to date.
Results: In our most recent studies the mean age of the subjects was 40.9 years (range 27-51).
4.4% of subjects had ³CIN II. 25.6% of subjects had positive self-sample and 23.7% had
positive direct test for HPV (cut point 1 pg HPV DNA). The sensitivity for detection of ³CIN
II was 87.5% for self-sampling for HPV and 96.8% for the direct test for HPV. Cut point
analysis for the self-test using 1.785pg resulted in a sensitivity and specificity of 85.6% and
80.5% respectively. A secondary screen using cervical cytology can improve the specificity to
91%. Using VIA, as the secondary screen or using a repeat HPV test are additional ways we
are exploring to improve specificity. Patient education is the the greatest hurdle to the
implementation of a self-sampling screening program.
Conclusion: We believe the self-sampling technique appears to be well suited for overcoming
barriers for reaching the highest-risk women. The combination of a new device and technique
for self-sampling may improve the sensitivity of self-sampling, hopefully approaching that of
a direct sample. A large primary screening trial is now ongoing which will explore the risks of
over-treatment and under-treatment when primary HPV screening is combined with VIA and
treatment instituted without histological confirmation.
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SEM2-1-01
EPIDEMIOLOGY OF CERVIX CANCER IN DEVELOPED
COUNTRIES: EVOLUTION SINCE THE INTRODUCTION OF THE
PAP TEST.
D.M. Parkin
International Agency for Research on Cancer, Lyon, France
Organized screening was introduced in 1959 in Norway, and 1960 in Scotland. Programmes
vary greatly between countries, in design (ages and frequency), coverage and level of
organization (presence of excess testing, especially opportunistic). Evaluation has been by
three types of study. Case-control studies are informative about the level and duration of
protection afforded to an individual by a screening test. Cohort studies can measure the
reduction in incidence in groups of women being screened versus those who are not.
Population-level time trends in incidence attempt to infer how much of the observed declines
in rates can be ascribed to screening. The problem, without a control population, is to know
what would have happened in its absence. The consensus overall is that well organized
programmes can achieve quite substantial reductions – 70-80% in Sweden and Finland, for
example.
Challenges in the pre-vaccine future are to reduce redundancy in programmes (opportunistic
tests that are too frequent and at too young ages), to improve the quality of cytology and
triage of trivial lesions (ASCUS), and to contemplate whether testing for HPV might not be
useful.
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SEM2-1-02
SCREENING PROGRAMMES FOR CERVICAL CANCER
HAKAMA Matti,
School of Public Health, University of Tampere, FINLAND
Screening for cervical cancer works in terms of reduction of incidence and mortality. The
success is not uniform, however, but there are highly effective programme to activities with
no tried and tested effect. Screening consists of several components from definition and
identification of the target population, adequate facilities to take the smear, high quality
laboratory, and adequate clinical facility for diagnostic confirmation ant treatment. The most
common reasons for suboptimal programme are probably poor coverage of the proceed from
one phase to another due to failure linking of the components of the programme.
Organized programme has the potential to avoid these obvious deficiences. Organized
programmes have in general resulted in larger effect or smaller cost compared to the
spontaneous or opportunistic ones. In Finland there has operated an organized screening
programme for cervical cancer from 1963 which resulted in about 80% reduction in the
incidence of invasive disease. Practically every Finnish woman is personally invited to
screening from ages 30 to 60 every five years. Such a programme with short age range and
long screening interval combined with centralised laboratory facilities is inexpensive. In fact,
it was estimated that there were savings in the health services due to screening as the
expensive treatment of advanced cancer was radically reduced.
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SEM2-1-03
ECONOMIC CONSIDERATIONS IN CERVICAL CANCER
SCREENING: EFFECTIVENESS, COST-EFFECTIVENESS AND
LIMITING FACTORS.
Habbema Dik
Erasmus University Medical Centre, Public Health, Rotterdam
Economics of cervical cancer screening is an important issue. Cervical cancer screening is not
a major killer. Therefore there is a limited upper bound to the population health gain from
screening. Moreover, in the population there is for each case of cancer a number of cervical
lesions and HPV-infections that will never lead to cancer.
A classical quality controlled Pap-smear based screening program with e.g. a 5 year interval is
very effective in preventing cervical cancer mortality.
If there is lack of success, it will mainly be caused by lack of population coverage. Also, some
cancers at young age and at old age will be missed. But extending a cervical screening
program to very young (<25 year) or very old (>65 year) ages will create more health
problems than it solves.
Cost-effectiveness in cervical cancer screening is only favourable for a limited screening
program, e.g. a Pap-smear every 5 years between ages 30 and 60. A small screening interval,
and opportunistic excess smears out of tune with the proposed schedule will both cause a
disproportional number of false-positives, and will be detrimental to the cost-effectiveness.
In view of these considerations, new developments for cervical cancer screening are
promosing from a public health point of view when, in comparison with the conventional
Pap-smear, they are: cheaper; easier to administer; more specific for progressive disease;
enabling a reduced follow-up of positives; and permitting the screening interval to be
lengthened. Some modern technologies based on the Pap-smear, like liquid based cytology,
have not proven to satisfy these requirements. HPV-testing is a promising biologically sound
new approach. It satisfies many of the conditions for a good screening tool. Its costeffectiveness has as yet to be established.
References:
Van den Akker et. al. (2002) JNCI: 94; 193-204
Van Ballegooijen et al (2000) EUR.J.CA: 36;2177-2188
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SEM2-1-04
CERVICAL SCREENING: THE CHALLENGE FOR THE FUTURE
Patnick Julietta
NHS Cervical Screening Programme, Sheffield
Cervical screening is the oldest established screening programme and its efficacy is well
recognised. The major challenge has always been reaching all women. This is unlikely to
change in the future. Certain women, such as new immigrants or poor women, are hard to
reach for healthcare, including cervical screening. They are also often the very women who
are at highest risk.
New technologies offer new challenges. Liquid Based Cytology is coming into use now and is
used for the majority of screening tests in the United States. While the women may notice
very little change, for the doctor or nurse performing the test there is the challenge of learning
a new technique, and for the cyto-techs, there is the challenge of learning to report a new type
of sample. This is particularly difficult when many years of experience have been gained in
conventional smear taking and reporting.
HPV testing, whether used as a primary screening technique or as triage, offers a major
communications challenge. There is now quite an explicit association for the woman
undergoing the test, between cervical disease and sexual activity, and the possible stigma of a
sexually transmitted infection. While this has always been there to some extent, it has not
been so openly acknowledged.
The major challenge of cervical screening may come with HPV vaccines. This may replace
cervical screening altogether in time. The challenge there may be whether practitioners have
the courage to abandon such a well-established technique if it has become redundant.
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SEM2-2-02
DIRECT VISUAL INSPECTION OF THE CERVIX
Denny Lynette
Direct Visual Inspection of the cervix after the application of 5% acetic acid (DVI) has been
evaluated in a number of studies as an alternative to cytology for cervical cancer screening in
low resource settings.
Methods: Four tests were used to screen 2754 previously unscreened women: DVI with and
without 4.5x magnification and differentiating between all and well-circumscribed acetowhite lesions; testing for high-risk types of HPV DNA using HC II assay™, cervical cytology
and Cervicography™. Women with positive results on any of the screening tests were
referred for colposcopy and histological sampling.
Results: Histologically confirmed cancer was diagnosed in 21 women (0.8%), HSIL in 96
(3.5%) and LSIL in 102 (3.7%). The estimated sensitivity of DVI when performed without
magnification for HSIL was 70%, with an estimated specificity of 79%. Magnification did not
significantly improve sensitivity for HSIL (74% without magnification) but significantly
reduced specificity (&&%). Restricting the definition of a positive DVI test to a well-defined
aceto-white lesion reduced sensitivity and significantly improved specificity. Infection with
T.vaginalis, N.gonorrhoea and C.trachomatis did not alter sensitivity or specificity.
Conclusions: This study confirmed the utility of DVI as a primary screening test however
further prospective randomized trials are necessary to evaluate the impact of this screening
test on cervical cancer prevention.
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SEM2-2-03
HPV DNA TESTING
Thomas C., Wright Jr.
Columbia University, New York, NY
There is considerable interest in using HPV DNA testing as a primary cervical cancer
screening method for developing countries. This is because HPV DNA testing is widely
recognized to be the most sensitive screening method that is currently available, identifies
those women at risk for developing cervical neoplasia in the next several years, requires less
skilled technicians than does cervical cytology, and is considerably less subjective and prone
to day-to-day variation than are the simple visual screening methods such as direct visual
inspection (DVI). In addition, HPV DNA testing offers the additional advantage that it can be
performed on self-collected vaginal specimens. This might allow widespread screening of a
population without requiring speculum examinations. The primary disadvantages of HPV
DNA testing are that a sensitive point-of-care test has yet to be developed, it is relatively
expensive for use in most developing countries, and in many populations testing for high-risk
types of HPV has a relatively low specificity. In this presentation the data obtained from
multiple clinical trials that have evaluated HPV DNA testing as a cervical cancer screening
method will be reviewed and discussed.
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SEM2-2-04
EMERGING ISSUES IN CERVICAL CANCER SCREENING:
DEVELOPING COUNTRIES: VIA
Sankaranarayanan R
International Agency for Research on Cancer, Lyon, France
Visual inspection with acetic acid (VIA) is currently being evaluated as a low-cost alternative
to cervical screening by cytology. It consists of applying 3-5% dilute acetic acid to the cervix
and, if a definite acetowhite area is observed close to the squamocolumnar junction or if the
entire cervix turns dense acetowhite, the test is categorised as positive. The accuracy of VIA
to detect cervical intraepithelial neoplasia grades 2-3 (CIN 2-3) and invasive cancer has been
evaluated in several cross-sectional studies. Results from these studies suggest that it is as
sensitive as good quality cytology but its specificity is lower. VIA has an average sensitivity
around 79% and specificity around 82%. Results, based on 41,000 women in our on-going
cross-sectional studies in India and Africa reveal a sensitivity of 78% and specificity of 85%.
A randomised intervention trial involving 160,000 women is on-going in Western India to
evaluate the efficacy/cost effectiveness of screening with VIA, cytology, and HPV DNA
testing. Eligible women in 502 villages under 52 primary healthcare centre units of
Osmanabad district in Maharashtra State, Central India, have been randomised to receive one
of the above interventions or to be part of a 'control' group. Approximately 40,000 women in
groups 1-3 will receive VIA, cytology, and HPV testing, respectively. Women with positive
screen tests will be investigated for cervical precancer/cancer and treated. Women in the
control group receive health education on cervical cancer. The study groups are followed up
for cervical cancer incidence and mortality. On 31 July 2002, 45 986 women had been
screened. The detection rates of CIN2 plus diseases in the different arms are as follows; VIA
1.3%; cytology: 1.4%; HPV testing: 1.2%. Detection rates of high-grade cervical precursor
lesions are similar to VIA, HPV testing and cytology screening. Another cluster-randomised
trial involving 70,000 women is being run in Dindigul district, South India, to evaluate the
reduction in incidence of cervical cancer with VIA. Findings from on-going controlled trials
will further clarify the role of organised VIA-based screening programmes.
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SEM2-2-05
REAL TIME SCREENING METHODS
Singer, A. (1), Jelinik, C. (2), Dungo, A. (3), Gonzales, G. (4) and Fernando, E. (5)
(1) The Whittington Hospital, London, UK; (2) Polartechnics Limited, Sydney, Australia; and (3)
Philippines General Hospital, (4) University of Santo Tomas Hospital, and (5) San Juan Medical
Centre, Manila, The Philippines.
Implementation of cytological screening programmes in the developing world has proven
problematic. Reaching women in rural areas with limited access to health care facilities is
likely to require alternative approaches to screening. One possibility is to implement mobile
screening units, whereby trained screeners travel to remote regions and examine a large
proportion of the population at each site. However, mobile screening programmes are only
feasible in the context of a screening approach that gives an immediate result - either direct
visual inspection (DVI) or new real time screening technology. Use of these screening
methods opens up the possibility of immediate treatment with cryotherapy or loop excision,
and thereby dispenses with the infrastructure required to organise the tracking and recall of
women for treatment.
The Philippines provides a model for the screening challenge in the developing world, with
the majority of women currently unscreened or underscreened. A study to evaluate the
comparative performance of the TruScreen real time device and DVI in the Philippines
population is currently ongoing. Volunteers are recruited via radio campaigns and examined
at one of three centres in Manila. An estimated 70% of the study participants to date have
never previously been screened.
DVI is performed by staff trained to the Philippines Department of Health guidelines. All
women receive an examination with TruScreen, DVI, and a Pap smear, followed by
colposcopy performed by a consultant gynaecologist, with biopsy as appropriate. The
TruScreen results are encrypted, and the DVI is performed in a session prior to colposcopy,
thus ensuring that the colposcopist is blinded to the results of the screening tests. Preliminary
results will be presented and the implications of these results will be discussed.
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SEM2-2-06
SCREENING TESTS RELEVANT TO DEVELOPING COUNTRIES
Thomas C. Wright, Jr.
Columbia University, New York, NY
Although cervical cancer is one of the leading causes of cancer deaths in women in many
developing countries, for the most part these countries have been unable to implement
effective cytology based cervical cancer prevention programs. There are a number of reasons
why developing countries have been unable to implement cytology based screening. One is
the nature of cervical cytology. Cervical cytology requires highly trained cytotechnicians, a
laboratory infrastructure, and sophisticated tracking, recall, and quality control mechanisms.
In addition, because of its relatively low sensitivity, cervical cytology needs to be repeated at
regular intervals in order to be highly effective. There is now considerable interest in
developing and carefully evaluating alternative screening methods for low resource settings
including simple visual screening methods such as direct visual inspection (DVI) and HPV
DNA. For the poorest, direct visual inspection (DVI) may offer the only viable screening
option. During this presentation data obtained from multiple clinical trials that have evaluated
simple visual screening methods in a variety of countries will be reviewed and discussed.
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SEM2-2-07
THE ALLIANCE FOR CERVICAL CANCER PREVENTION: 2003
STATUS
Sherris Jacqueline
PATH, Reproductive Health Strategic Program, Seattle, USA
Worldwide, cervical cancer kills more than 288,000 women each year and disproportionately
affects the poorest, most vulnerable women. At least 80 percent of cervical cancer deaths
occur in developing countries, with most occurring in the poorest regions - South Asia, subSaharan Africa, and parts of Latin America. In order to address this inequity, the Alliance for
Cervical Cancer Prevention (ACCP) is working to clarify, promote, and implement strategies
for preventing cervical cancer in developing countries.
The ACCCP-made up of EngenderHealth, International Agency for Research on Cancer
(IARC), JHPIEGO Corporation, Pan American Health Organization (PAHO), and Program
for Appropriate Technology in Health (PATH)-has been working worldwide to achieve
ACCP objectives to:
. Assess innovative approaches to screening and treatment;
. Improve service delivery systems;
. Ensure that community perspectives are incorporated into program design, implementation,
and evaluation; and
. Heighten awareness of cervical cancer and effective prevention strategies.
Funded by a generous grant from the Bill & Melinda Gates Foundation, Alliance work has
brought new insights regarding the feasibility and effectiveness of various screening and
treatment approaches - including visual inspection strategies, HPV DNA testing, and
treatment via cryotherapy - and the most effective ways to inform and involve stakeholders in
planning and implementing new cervical cancer prevention programs in developing countries.
Alliance-funded research and demonstration projects currently are underway in Bolivia, El
Salvador, Ghana, India, Kenya, Malawi, Peru, South Africa, and Thailand, among other
countries.
Our task for the coming years is to build on this knowledge base by implementing a range of
activities aimed at demonstrating, promoting, and supporting evidence-based approaches in
countries around the world. This includes clearly demonstrating the effectiveness of specific
screening and treatment protocols and providing a comprehensive set of tools for policy
makers and program managers working to design effective and affordable cervical cancer
prevention programs. The Alliance's collaborative approach to undertaking this challenge
enhances and strengthens our work. Our partnership allows us to synthesize data and
experience from vastly different settings and draw upon a wide range of individual expertise
and experience.
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OC-01
THE STORY OF HUMAN PAPILLOMAVIRUS INFECTION:
EMERGENCE
Meisels A
Dept. Path. Université Laval, Québec, Canada
This is a brief historical review of the cytological recognition of papillomavirus infection up
to the time when its role in the etiology of carcinoma of the cervix began to be recognized. It
includes work by Ayre (1), Papanicoloau (2), Koss (3), and Meisels (4), among others.
(1)Ayre JE: The vaginal smear: "precancer" cell studies using a modified technique. Am J
Obstet Gynecol 58:1205-1219, 1949
(2)Papanicolaou GN: Atlas of Exfoliative Cytology, Cambridge, Mass, Harvard University
Press, 1954
(3)Koss LG, Durfee GR: Unusual patterns of squamous epithelium of the uterine cervix:
Cytologic and pathologic study of koilocytotic atipa. Ann N Y Acad Sci 63:1245-1261, 1956
(4)Meisels A, Fortin C: Condylomatous lesions of the cervix and vagina: I Cytologic patterns.
Acta Cytol 20:505-509, 1976
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OC-02
THE STORY OF HUMAN PAPILLOMAVIRUS INFECTION:
EMERGENCE, ACCOMPLISHMENTS AND TRIUMPH
Cox JT
University of California - Santa Barbara, California, USA
In the US cervical screening with the Pap smear remained essentially unchanged from its
introduction in 1949 until the introduction of liquid-based cytology (ThinPrep Pap,
Boxborough, MA) in 1996. Improved quality of the cytologic preparation, increased
sensitivity for SIL and the ability to “reflex test” the solution for human papillomavirus
(HPV) when the Pap is interpreted as ASC-US has dramatically changed the cervical
screening landscape. The potential for using HPV testing in a clinical manner began with the
association of HPV with cytologic abnormalities by Meisels and Fortin in 1976. Zur Hausen,
Gissman, Lorincz and Syrjanen pioneered in the molecular biology and epidemiology of
HPV, providing imperative insight into the natural history of this virus and, with other
researchers, in the discovery of increasing numbers of HPV types. The first HPV tests were
too cumbersome to be utilized in any but research settings, but in 1988 the first commercial
HPV test (ViraPap) was approved in the US for clinical use. This opened the door to
evaluation of HPV testing in a variety of settings. Succeeding generations of commercially
available HPV tests have proven to have increasing analytic sensitivity, decreasing
misclassification of HPV types and improvement in ease of use in the laboratory. Studies on
triage of women with ASCUS with Hybrid Capture 1 paved the way for the pivotal studies on
use of HC2 by Manos and Kinney in 1999, and the ASCUS/LSIL Triage Study (ALTS) in
2001. Results from the large randomized ALTS trial provided much of the evidence behind
new US national Pap management guidelines that recommend HPV testing in a variety of Pap
management settings. In parallel, Meijer, Walboomers, Nobbenhuis and others in the
Netherlands evaluated long-term type-specific persistence as detected by PCR as a predictor
of risk for the development of high-grade cervical neoplasia, and absence of detectable HPV
as the most sensitive predictor of reassurance that no significant lesion will develop. Building
on these findings, Schneider, Petry, Iftner and others from Germany, Clavel and Birembaut
from France, Cuzick from Great Britain and Wright, Schiffman and Belinson from the US
along with many others have all provided data on HPV testing in the setting of primary
cervical screening that has established molecular testing for HPV as an adjunct to cervical
cytology as an option in routine screening of women over the age of 30, and may eventually
challenge the Pap for primacy.
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OC-03
THE STORY OF HPV INFECTION: EMERGENCE,
ACCOMPLISHMENTS AND TRIUMPHS - A VIROLOGIST'S
PROSPECTIVE
Schiller John
National Institutes of Health, Laboratory of Cellular Oncology, NCI, Bethesda, USA
Over the last century, studies of papillomaviruses have made substantial contributions to
biomedical research and hold great promise of making substantial impact on public health in
this century. In the 1930s, cottontail rabbit papillomavirus (CRPV) was the first tumorinducing virus to be identified. CRPV studies in the 1950s established important principals
concerning the roles of serologic and cell mediate immunity in immunprophylaxis and
immunotherapy of viral disease. However, the inability to propagate PV in cultured cells
limited virologic studies to a few animal model systems. There was a resurgence in PV
studies in the late 1970s, due to the advent of molecular biology. Genetic engineering
permitted the cloning and sequencing of PV genomes and studies of the activities of the
genomes and individual viral genes in cultured cells. In the early 1980s, HPV16, HPV18 were
first cloned and shown to be present in the majority of human cervical cancers. This was soon
followed by the discovery of the selective retention and expression of E6 and E7 in the
cancers and the ability of these two genes to cooperate in the induction of genetic instability
and immortalization in normal human keratinocytes. These results provided biological
plausibility for a causal link between HPV infection and cervical carcinogenesis. This
plausibility was strengthened by the findings that E6 and E7 inactive p53 and pRb, two tumor
suppressor proteins that are often mutated in cancers that are not associated with viral
infections. During the 1980's and 1990's, the regulation of viral gene expression and the
biological and biochemical activities of the viral gene products were largely defined. Based
upon the development of sensitive assays for measuring type specific HPV DNA, prospective
studies of cervical HPV in the 1990s produced consistent results that established HPV
infection as the central cause of cervical neoplasia. Development of reliable HPV DNA assays
also provides an opportunity for a virologic assessment of cervical cancer risk. HPV DNAbased screening is currently receiving considerable attention and could in the future have a
significant impact on cervical cytological screening programs. The 1990s also saw the
development of a number of HPV vaccine candidates, both prophylactic and therapeutic. The
recent reports of clinical trails of virus-like particle prophylactic vaccines have raised hopes
that the infections by the major oncogenic HPV types can be prevented in the next generation
of women.
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PS1-02
THE CAUSAL ASSOCIATION BETWEEN HPV AND CERVICAL
CANCER
F. Xavier Bosch
Institut Català d’Oncologia, Servei d’Epidemiologia i Registre del Càncer, L’Hospitalet de Llobregat, Spain
State-of-the art amplification techniques have unequivocally shown that in adequate
specimens of cervical cancer HPV-DNA can be detected in 90 to 100% of the cases as
compared to a prevalence of some 5-20% from cervical specimens of women identified as
suitable epidemiological controls. Detailed investigations of the few cervical cancer
specimens that appear as HPV DNA negatives in most series has been occasionally conducted
and the results strongly suggest that these are largely false negatives. As a consequence, the
claim has been made that this is the first necessary cause of a human cancer ever identified,
providing a strong rationale for the use of HPV tests in screening programs and for the
development of HPV vaccines.
RISK ESTIMATES FROM IARC'S CASE CONTROL STUDIES:
The pool of IARC studies are large enough to provide, for the first time, type specific risk
estimates for 18 types. The adjusted Odds Ratios for HPV DNA detection (the factor by
which the reference risk of cervical cancer is multiplied if HPV DNA is detected) was OR any
single type = 172.6 (95%CI: 122.2-243.7). Type specific risk estimates were as follows: HPV
16: OR= 435; HPV 18: 248; HPV 45 OR= 198; HPV 31 OR= 124; HPV 33 OR=374; HPV 35
OR=74; HPV51, OR= 67; HPV 52 OR= 200; HPV 58 OR= 115; HPV 59 OR= 419.
According to these results, the types that have to be considered of high risk for cervical cancer
are, at least, 14 types as follows: HPV 16, 18, 45, 31, 52, 33, 58, 35, 59, 51, 56, 39, 73, 82.
The risk for any given high-risk type was not statistically different from the risk reported for
HPV 16. The standard estimates of the attributable fraction AF %, (the proportion of disease
that is related to HPV DNA) derived from these and most other studies range from 90 to 98%.
The practical conclusions from these analyses strongly indicates that, under current evidence,
group testing of clinical specimens for a cocktail of high risk types should be sufficient for
screening and patient management.
RECOMMENDED READING:
1. Bosch FX, Lorincz A, Munoz N, et al. J Clin Pathol 2002;55:244-65.
2. Muñoz N, Bosch FX, de Sanjosé S, et al. N Eng J Med 2003;348(6):518-527.
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PS1-03
MOLECULAR EVIDENCE OF HPV CARCINOGENESIS
Lorincz A
Digene Corporation, Gaithersburg, Maryland, USA
The neoplastic potential of HPV depends on viral type and the nature and timing of host
influences. Variation in HPV carcinogenic potential is governed by the E6 and E7
oncoproteins, secondary to antagonism of key cell-cycle regulatory protein functions
controlled by the p53, Rb, and p21 tumor suppressors. HPV infection of basal stem cells can
lead to persistence. In contrast infection restricted to parabasal cells is more likely to be
transient. In low grade CIN lesions E6/E7 expression is mainly found in differented spinous
cells ,whereas in high grade CIN and cervical carcinomas strong E6/E7 expression is seen in
the proliferating cell compartments. Thus, risk of cancer is related to HPV persistence, which
commonly leads to integration of viral DNA and continuous overexpression of E6 and E7.
The molecular pathways are very complex and extensively interconnected. Key features
include the binding of E7 to the Rb protein, which results in liberation of E2F factors and the
promotion of DNA synthesis. Excess E7 inactivates p21 while the E6 protein can overcome
p53 control pathways important in preventing genetic damage. In the case of major DNA
damage or high levels of viral replication another p53 role is activation of apoptosis. In basal
cells p21 production is actively regulated by p53, however, inactivation of p53 by E6 prevents
accumulation of p21, providing for reduced interference with E7 activities. The extent to
which E7 overcomes Rb and p21 and stimulates basal cells is important to malignant
progression. Thus, in the case of E6 mediated destruction of p53 coupled with E7 stimulation,
the cells continuously replicate and accumulate genetic mutations. An important step in
immortalization of such cells is maintaining telomere length and stability as telomeres
normally shorten with each cell division. E6 can activate telomerase that in combination with
other proteins stabilizes telomeres. These cells can now bypass a mortality checkpoint and
accumulate further mutations that may lead to fully malignant cells.
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PS1-04
CERVICAL CANCER SCREENING. FACING THE REALITY IN THE
WORLD.
D.M. Parkin,
International Agency for Research on Cancer, Lyon, France
About 80% of cervical cancers occurs in the countries of the developing world, where the
disease presents relatively late, and prognosis is much poorer than in Europe or North
America. Screening by cytology has been rather unsuccessful in reducing incidence and
mortality in most of these countries. The reasons are poor quality cytology, low coverage of
at-risk populations, and inadequate follow-up and treatment. It is doubtful if the model of
organized Pap smear screening should be continued to be pressed upon low income countries.
The organizational aspects are exceedingly difficult to implement, and the success achieved
with such a mediocre test in many western countries is probably more the result of the huge
volume of testing (well in excess of programme requirements being carried out), than any
merit of the Pap test.
The simple methods based on visual inspection now undergoing rigourous field testing hold
out more promise in the immediate future. The indications (from simulation modelling) are of
a better cost effectiveness than a Pap test-based programme. Simple tests for HPV or its
oncogenic products may be an alternative or adjunct.
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PS1-06
PS1 MANAGING THE ABNORMAL PAP; CURRENT PRACTICE
PROTOCOLS
Cox JT
University of California - Santa Barbara, California, USA
New US national consensus guidelines for the management of women with abnormal cervical
cytology are widely used throughout the US1. This presentation will cover the management
options for ASC-US, ASC-H, AGC, LSIL and HSIL, and will point out variations in special
circumstances. Post-colposcopy management of women with any of these Pap interpretations,
not outlined in this abstract, will also be discussed.
ASC-US: All 3 management options for women with ASC-US are acceptable; repeat
cytology at 4 to 6 mos. with return to routine screening after 2 normal follow-up Paps or to
colposcopy with any repeat Pap >ASC, immediate colposcopy for all women with ASC-US,
or HPV DNA testing with referral to colposcopy of all women testing positive for high-risk
HPV. If the cytology that generated the ASC-US Pap was liquid-based, or when co-collection
of HPV DNA testing can be done, “reflex” HPV DNA testing is the preferred approach
because the HPV test can be done without the need for a woman to return for a repeat office
visit. Women with ASC-US who are high-risk HPV DNA negative can be followed with
repeat cytology at 12 mos.
ASC-H: The recommended management of women with ASC-H is colposcopy. This is
because of the much higher risk of having CIN 2/3, and of being HPV positive for high-risk
types.
AGC: The initial management of women with atypical glandular cells (AGC), with the one
exception of women with atypical endometrial cells, should initially be by colposcopy and
endocervical sampling. The only exception is women with atypical endometrial cells who
initially require endometrial sampling.
LSIL: All women with LSIL should have colposcopy. Management of LSIL may vary if the
woman is pregnant, postmenopausal or an adolescent. The subsequent management options
depend partially on whether the colposcopy is satisfactory or unsatisfactory.
HSIL: All women with HSIL cytology should have colposcopy. If no lesion is identified after
colposcopy in women with HSIL, when possible, review of the cytology, colposcopy, and
histology should be performed. If a review does not yield a revised interpretation, a diagnostic
excisional procedure is recommended in non-pregnant patients.
Wright TC, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ, for the 2001 ASCCP-Sponsored
Consensus Conference. 2001 consensus guidelines for the management of women with
cervical cytological abnormalities. JAMA. 2002;287:2120.
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PS2-01
WOMEN AGAINST CERVICAL CANCER
Alexander Linda L.
Vice President, Women’s Health Digene Corporation
This session will provide an overview of two international consumer based efforts to address
cervical cancer prevention. Ms. Karen Carlson, Executive Director of the Gynecologic Cancer
Foundation will present an overview of the National Cervical Cancer Prevention Campaign.
The Campaign, based in the United States, is a coalition of women’s advocacy and provider
organizations with an educational mission. The Campaign seeks to reach women patients and
consumers with the latest information about cervical screening. Ms. Peggy Maquire, Director
General of the European Institute of Women’s Health will provide an overview of the
Institute and its focus on creating awareness with cervical cancer prevention in Europe. She
will also discuss the organizational audit that provided an status report on cervical cancer
screening practices in European member states. Dr. Alexander will provide a summary of
women’s advocacy efforts and the importance of mobilizing women and women’s
organizations to address cervical cancer as a priority women’s health issue.
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PS3-02
THE CONSENSUS CONFERENCES
Thomas C. Wright Jr.
Columbia University, New York, NY
In 2001 two large consensus conferences were held in the United States to revise the
terminology utilized for cervical cytological reporting (2001 Bethesda System) and to develop
management guidelines for the management of women with cytological abnormalities and
women with biopsy-confirmed cervical intraepithelial neoplasia (CIN) (2001 Consensus
Guidelines for the Management of Cytological Abnormalities). Both conferences had
representation from a large number of professional societies and government and nongovernment agencies involved in women's health care. Both conferences utilized web-based
discussion boards in order to obtain input from clinicians from around the globe and to obtain
consensus. During this presentation the key areas addressed by the conferences will be
described and some of the most controversial recommendations made by them will be
discussed.
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PS3-03
ROLE OF INTERNATIONAL ORGANISATIONS AND NGOS
Miller A.
International organizations can be instrumental in producing guidelines for controlling
cervical cancer, building upon the expertise within member states. The World Health
Organisation has been prominent in trying to fulfil this role, and will shortly release a report
on Cervical Cancer Screening in Developing countries that carefully evaluated cytology
screening, screening using visual inspection with acetic acid and human papillomavirus DNA
testing. The authors of the report conclude that underlying all programmes, care has to be
taken over organisational considerations that will be instrumental in securing success. These
include high quality of delivered services, adequate compliance with screening and with
treatment recommendations for precursors, coupled with adequate and carefully trained staff.
Cytology screening remains the standard for application in middle-income countries.
However, VIA holds substantial promise, and providing this is confirmed in studies ongoing,
and the difficulties associated with its lower specificity overcome, it may replace cytology in
lower income countries. Tests for HPV DNA also show promise, and may, if further refined,
eventually become the preferred approach, but only if means can be found to avoid the overtreatment of lesions destined to regress. All tests, however, have to be applied within an
organised setting, preferably as a component of a National Cancer Control Programme.
Non-Governmental Organisations (NGOS) can be important facilitators of programmes at the
country level, and in North America particularly, were largely instrumental through public
education in ensuring high compliance with cytology screening. The International Union
Against Cancer (UICC) works closely with WHO in ensuring dissemination of appropriate
guidelines to its member organisations.
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PS4-01
THE RATIONALE FOR ACCREDITATION, CERTIFICATION &
QUALITY SCIENCE EVALUATION PROGRAMS
Lawson Herschel
Centers for Disease Control and Prevention, Division of Cancer Prevention and Control, Atlanta
The establishment of clinical pathways for detecting and evaluating abnormal cervical cancer
screening results is the result of many discrete factors. Included are 1) a demonstrated need
for a particular screening test; 2) the need for standardized collection of screening samples,
and interpretation and reporting of test results; 3) a mechanism for communicating test results
to providers responsible for managing patients in a clear and timely manner; 4) the need for
responsible providers to communicate the findings of the tests to patients in a culturally
competent manner so that informed consent can be the result of an appropriate decisionmaking process; 5) the need for clinical diagnostic tests and treatment procedures that evolve
from the most rigorous scientific methodology and withstand the scrutiny of the scientific
community, and time, and 6) the need for ongoing evaluation of each step to insure that
patients receive the most efficacious and when possible, the most cost-effective clinical
evaluation and treatment. At each step, methods should be established to ensure that processes
and outcomes meet desired goals and objectives. Such evaluation, whether a process of
accreditation, certification, or a means of measuring program outcomes against established
clinical guidelines, is essential to ensure that science and technology are appropriately applied
for the continued health and safety of patients, and so that supplies of providers and devices
are adequate to meet the needs for screening, diagnostic and treatment services. Finally,
evaluation is essential to measure the most vital outcome of the screening process -reduction
in incidence and mortality from the disease as a result of the screening and diagnostic
methods applied — and for measuring the success of programs to recruit women at greatest
risk of cervical cancer — those who have never or rarely been screened.
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PS4-02
FORMULATING GUIDELINES IN COLPOSCOPY
Kitchener Henry Charles
University of Manchester, Academic Unit of Obstetrics & Gynaecology, Manchester
Clinical guidelines are internationally acknowledged to be an important measure in achieving
consistent standards of medical care across various grades of expertise and across national
borders. They are particularly useful in colposcopic practice because of its largely routine,
high volume nature with a relatively small number of scenarios.
Guidelines require to be credible and valid or practitioners will not use them. The key element
of guidelines therefore, is that they are based on robust evidence. In colposcopy the evidence
base varies from randomised trials for certain treatments to essentially professional consensus
for certain scenarios e.g. treatment of CIN should be avoided in pregnancy.
Guidelines should be produced in a manner that is acceptable to practitioners. For example it
will not be acceptable for a single individual to write a set of guidelines based solely on
his/her views, nor is it acceptable for a workshop of experts simply to describe a set of agreed
guidelines. Guidelines need to be linked to the evidence in an explicit manner.
Because of entrenched views or scepticism, even excellent guidelines are not necessarily
translated into practice. There is need to audit the use of guidelines if they are to be widely
used. National societies have a major role to play in developing evidence based guidelines
valid for an individual country's healthcare system and resources, and to develop systems of
ensuring compliance.
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PS4-03
COLPOSCOPY - WHO SHOULD PRACTICE?
Kitchener Henry Charles
University of Manchester, Academic Unit of Obstetrics & Gynaecology, Manchester
The objective of colposcopic examination is to diagnose epithelial abnormalities of the lower
genital tract, the most common example being cervical intraepithelial neoplasia when
preceded by an abnormal cervical smear. Less commonly, vaginal intraepithelial neoplasia
may be present and there is now an increasing incidence of vulval intraepithelial neoplasia.
The appropriate use of the colposcope requires training and experience in order to develop
and maintain diagnostic skills, and colposcopic guided treatment also requires adequate
training.
In some countries, colposcopy is part of the routine examination of the cervix, however in
countries with cervical screening the benefit of colposcopy over naked eye examination of the
cervix seems unclear, unless there is a cytological examination.
Colposcopy may be performed by different types of healthcare professional; gynaecologist,
family practitioner, genitor-urinary physician or nurse practitioner. The common requirement
is training, the structure is essentially similar for all professionals. This training requires
evidence of sufficient knowledge, sufficient number of supervised colposcopy in women with
abnormal cytology and evidence of understanding colposcopic management. Practitioners of
colposcopy require to maintain skills by continuing education and practice.
In the United Kingdom, colposcopists require to be accredited by the BSCCP and the Royal
College of Obstetricians and Gynaecologists. Re accreditation takes place every 3 years based
on evidence of continuing practice and continuing medical education.
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PS4-4a
ACCREDITATION, CERTIFICATION, QUALITY SCIENCE
EVALUATION PROGRAMS
LINDER Jim
Cytyc Corporation, USA
The review of microscope slides by a Cytotechnologist (CytoScreener, Cytologist, other) is an
essential component of the Pap test. Without adequate training of personnel in accredited
programs, and the subsequent certification of personnel by governmental, or professional
organizations, the accuracy of Pap testing cannot be assured.
Unfortunately, because of a variety of factors, there is a shortage of qualified
Cytotechnologists in many countries. For example, in the United States recent surveys by the
American Society of Cytotechnology showed Cytotechnologist job openings were present in
the laboratories of 35.4% of survey participants. Similar data have been found in surveys by
the American Society of Clinical Pathology.
If morphologic Pap testing is to be provided to women, in both developed and developing
countries, there needs to be an adequate workforce of Cytotechnologists. This need may be
met through expansion of training programs, or through the use of computer-aided imaging of
Pap samples that may improve the productivity of laboratory personnel.
Additional practice issues include the migration of molecular-testing into the cytology
laboratory. Cytology personnel may be involved in the performance of molecular testing for
HPV (e.g. PCR or Hybrid Capture II) or in the interpretation of microscopic preparations that
have been stained either by in situ hybridization or immunocytochemical methods.
It is likely that the practice of cytology will change as these technologies are introduced into
the laboratory. The training of cytology personnel will need to adapt to this changing practice
environment.
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PS4-4b
CLINICAL PRACTICE ISSUES
Meisels A,
Dept. Path. Université Laval, Québec, Canada, Diagnostic procedures
Cytopathology is inherently subjective and dependent on accumulated experience.
Practitioners need not only to receive adequate training in specialized schools or programs,
but also have to acquire the necessary experience by examining large numbers of smears from
all sites. Even in the best situations gynecological cytopathology remains a screening tool
fraught with an incompressible rate of errors. Although efforts have to continue to reduce the
rate of errors to a minimum, there is no way to eliminate them completely and clinicians and
the public at large should be made aware of this fact. Gynecologic cytopathology is not a
precise diagnostic tool and should not be judged on the small number of errors but rather on
the life saving achievements of the past half century.
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PS4-5a
QUALITY SCIENCE EVALUATION PROGRAMS
Lawson Herschel
Centers for Disease Control and Prevention, Division of Cancer Prevention and Control, Atlanta
During the past decade, the level of existing scientific evidence about many clinical topics has
become the gold standard against which established and new clinical practice measures are
evaluated. This process provides a basis in which supporting data can be rigorously analyzed
to determine the effectiveness of screening protocols and therapies. The ultimate result is not
only for the protection and benefit of human subjects, but the advancement of quality clinical
trials and other quality studies that show promise for further reducing the burden of disease
processes such as invasive cervical cancer.
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PS4-5b
EVALUATION AND PERFORMANCE MONITORING IN THE
NATIONAL HEALTH SERVICE CERVICAL SCREENING
PROGRAMME (NHSCSP)
Rimmer J & Patnick J
National Health Service Cancer Screening Programmes, Sheffield, England
A national cervical screening programme was established in England in 1988, with the
introduction of computerised call/recall programmes and a National Coordinating Network, to
facilitate the adoption of common standards and working practices.
The responsibility for improving the overall performance of the NHSCSP is now held by the
national office, which develops and reviews national quality standards and issues, monitors
performance and ensures that information is collected to support the evaluation of the
programme. Regional QA centres represented on national QA coordinating groups facilitate
the evaluation and audit of the programme locally.
Standard statistics are collected from all call/recall systems, laboratories and colposcopy
clinics and collated nationally. These enable the performance of all aspects of the programme
to be compared against national standards, including coverage, laboratory reporting profiles
and colposcopy practices. Multidisciplinary QA visits allow regional QA teams to assess local
service arrangements, share good practice and address shortfalls in the service.
Multidisciplinary audit of screening histories in all cases of invasive cervical cancer is also
now performed.
Participation in external quality assessment is mandatory for all staff reporting cervical
cytology and individual performance statistics are generated to monitor the accuracy of
screening. Laboratories are also required to seek accreditation with Clinical Pathology
Accreditation (UK) Ltd.
Since the introduction of the NHSCSP reductions in the incidence and mortality from
invasive cervical cancer have been observed. These achievements are believed to reflect
improvements made to the quality of the screening programme, which are only possible with
continual monitoring, evaluation and improvement of standards.
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PS5-01
TELECOLPOSCOPY
Etherington IJ
A colposcopic diagnosis is made from pattern recognition of cervical changes.
Cervicography, where diagnosis is based on the assessment of an image of the cervix, has
long been used as a method of diagnosis for women with certain cytological abnormalities. It
is a simple extension of this principle to use modern technology to transmit and review
cervical images at a distance. This is telecolposcopy. Still images and video clips can be
captured in a digitised format and transmitted between computers.
A telecolposcopy system requires suitable equipment for image capture and this may vary
according to the clinical situation. Image transmission can be real time or as store-andforward. The choice of transmission will depend on the purpose of the teleconsultation, the
file size to be transmitted and the state of local telecommunications networks. For
sophisticated video transmission a broadband network is essential.
This form of telemedicine can be used in a variety of ways including obtaining rapid second
opinions from other expert colposopists, remote diagnosis for women who reside far from a
colposcopy clinic, monitoring of colposcopy training, secondary screening for women with
minor cytological abnormalities, and use in the developing world where screening strategies
are rudimentary.
Current clinical uses of telecolposcopy include giving access to services for women living in
remote rural areas in the USA1;2. In one study1 teleconsultation was found to be acceptable for
diagnostic accuracy, but determination of colposcopic examination adequacy was impaired.
The authors concluded that telecolposcopy may help reduce barriers to medical access for
women in rural areas. Our own unit has been running a randomised trial of telecolposcopy as
a secondary screen for women with minor smear abnormalities3. Eligible women are screened
by nurses in primary care and the video and still images are reviewed by an expert
colposcopist from our unit. Our pilot data show the technique to be accurate in terms of
diagnosis and we have found the approach to be highly acceptable to women.
Reference List
1. Ferris DG, Macfee MS, Miller JA, Litaker MS, Crawley D, Watson D. The efficacy of
telecolposcopy compared with traditional colposcopy. Obstet.Gynecol. 2002;99:248-54.
2. Harper DM, Moncur MM, Harper WH, Burke GC, Rasmussen CA, Mumford MC. The
technical performance and clinical feasibility of telecolposcopy. Journal of Family
Practice 2000;49:623-27.
3. Etherington IJ. Telecolposcopy - a feasibility study in primary care. J.Telemed.Telecare.
2002;8 Suppl 2:22-24.
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PS5-03
STEPS TOWARD RELIABLE ONLINE CONSUMER HEALTH
INFORMATION
Boyer Celia
The latest developments in information technologies have allowed for the development and
implantation of applications that are having a tremendous repercussion in the healthcare field.
Though information has become essential for the maintenance of health, it can assume
dangerous forms that must be addressed if they are not to cause harm.
The first attempt at ‘truth in labeling’ for online health content was the HONcode (Table 1.),
brainchild of Prof. Jean-Raoul Scherrer of the Geneva University Hospitals. Introduced in
1996, the HONcode sets out eight principles for web publishers which, if followed, give the
webmaster the right to display HON’s ‘seal of approval’. The HONcode makes no attempt to
judge the content of a medical/health web site, however the principles (below) require web
publishers to disclose potential conflicts of interest, to attribute authorship to information
sources and to pledge to apply strict guidelines for the confidential treatment of users’
personal information. A site should not only comply with the HONcode principles but also
demonstrate how each principle is implemented.
The HONcode is a first step toward qualifying information as trustworthy based on the
willingness of publishers to comply with an easy to follow set of ethical standards. How then
are we to address the really difficult issue of the content itself? Peer review of the massive
volume of available documents is not reasonable; automation could be a solution to be used to
perform a validation function.
The Internet favors communication between patient, physician and pharmacist, and has brings
disease sufferers out of isolation and into intense interaction. Consensus, based on trust, will
arise from the good will and efforts of all stakeholders. HON, a neutral body already grouping
thousands of online health information providers, can mediate among all stakeholders and, in
consultation with governments, the EU and UN, is elaborating standards and creating tools to
improve access to the best online health and medical information.
The Internet is not an environment conducive to regulation, but where voluntary participation,
correct behavior and respect can be rewarded. Tools, adapted to the needs of all types of
users, can be made available to increase consumer awareness and create channels for
feedback to the professional and governmental sectors. Conflicts of interest can be avoided
and consumer awareness increased with improved communication.
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Table 1. The Health On the Net Code of Conduct
HONcode: the principles
HONcode thus includes eight principles whose three principal pillars are: identification of the site editors, and
their competencies; citation of references to external sources; and a clear distinction between advertising and
scientific editorials.
The HONcode was initially and simultaneously written in English and French (cf. version below). The
HONcode is currently (as of 29th January, 2003) available in 25 languages: Arabic, Catalan, Czech, Chinese,
Danish, Dutch, English, Finnish, French, German, Greek, Hungarian, Icelandic, Italian, Japanese, Korean,
Malaysian, Norwegian, Polish, Portuguese, Russian, Slovak, Spanish, Swedish and Turkish
[http://www.hon.ch/HONcode/]. Below one will find the English version of the HONcode:
1. Authority
Any medical or health advice provided and hosted on this site will only be given by medically trained
and qualified professionals unless a clear statement is made that a piece of advice offered is from a nonmedically qualified individual or organization
2. Complementarity
The information provided on this site is designed to support, not replace, the relationship that exists
between a patient/site visitor and his/her existing physician.
3. Confidentiality
Confidentiality of data relating to individual patients and visitors to a medical/health Web site,
including their identity, is respected by this Web site. The Web site owners undertake to honour or
exceed the legal requirements of medical/health information privacy that apply in the country and state
where the Web site and mirror sites are located.
4. Attribution
Where appropriate, information contained on this site will be supported by clear references to source
data and, where possible, have specific HTML links to that data. The date when a clinical page was last
modified will be clearly displayed (e.g. at the bottom of the page).
5. Justifiability
Any claims relating to the benefits/performance of a specific treatment, commercial product or service
will be supported by appropriate, balanced evidence in the manner outlined above in Principle 4.
6. Transparency of authorship
The designers of this Web site will seek to provide information in the clearest possible manner and
provide contact addresses for visitors that seek further information or support. The webmaster will
display his/her E-mail address clearly throughout the Web site.
7. Transparency of sponsorship
Support for this Web site will be clearly identified, including the identities of commercial and noncommercial organizations that have contributed funding, services, or material for the site.
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PS6-1-01
2001 BETHESDA SYSTEM
Thomas C. Wright Jr.
Columbia University, New York, NY
The 2001 Bethesda System for the reporting of cervical cytological results is the product of a
year long iterative review process that involved a comprehensive review of the literature,
internet based bulletin boards for discussion and review of draft documents, and a formal
consensus conference held in May 2001 where recommendations were developed before
being placed on the internet for final review by the international community. Specific areas
that are addressed include: specimen adequacy; benign cellular changes and infections;
ASCUS; atypical glandular cells; LSIL and HSIL; HPV triage; endometrial cells; computerassisted diagnoses; recommendations, educational notes and disclaimers. During this
presentation the key areas where changes to the previous terminology were made will be
discussed.
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PS6-1-02
ATYPICAL SQUAMOUS CELLS
Thomas C., Wright Jr
Columbia University, New York, NY
The 2001 Bethesda System subcategories atypical squamous cells (ASC) into two categories:
atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells,
cannot exclude a HSIL (ASC-H). In this presentation the clinical significance of these two
diagnoses will be discussed and management recommendations of the 2001 Consensus
Conference for the Management of Cytological Abnormalities presented.
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PS6-1-03
MANAGEMENT OF WOMEN WITH LSIL CYTOLOGY
Wilkinson Edward J.
University of Florida, Pathology, Gainesville
Management Protocols of Cervical Neoplasia
Part 1 Discussion of Ideal Protocols: LSIL
Evidence based consensus guidelines for the management of women with cervical cytologic
finding of low grade squamous intraepithelial lesion (LSIL) have been developed by the
A.S.C.C.P. The preferred management of women with LSIL is colposcopy. Options are
influenced by whether the colposcopy examination is satisfactory and if a lesion is identified.
If no CIN or cancer is identified on colposcopy or related biopsies, the patient can be returned
for cytology at 6 and 12 months, or HPV testing for high risk HPV types can be performed at
12 months. Cytologic finding interpreted as ASC-US or more severe at 6 or 12 months follow
up are indications for repeat colposcopy with appropriate biopsies. If HPV testing for high
risk types is used, and is positive at 12 months, repeat colposcopy and appropriate biopsies
are recommended. If cytology remains negative at 12 months, or HPV testing for high risk
types is negative at 12 months, the patient can return to routine screening. If the patient is
found to have CIN or cancer on colposcopy at 6 or 12 months then the patient can be
managed according to guidelines for management of high or low grade CIN, or for carcinoma.
In selected post menopausal patients and selected adolescents, follow up without initial
colposcopy using a protocol of follow up with repeat cytology at 6 and 12 months and referral
to colposcopy with a threshold of ASC-US is acceptable. If HPV testing for high risk types is
selected at 12 months and is positive, colposcopy with appropriate biopsies is recommended.
Experience and evidence for such management is limited.
Routine use of cervical excisional or ablation procedures in evaluation of women with LSIL
cytology in the absence of a biopsy that confirms CIN is unacceptable, with good evidence
against a "see and treat" approach for women with LSIL cytology alone.
Wright TC, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 Consensus Guidelines for
the Management of Women with Cervical Cytological Abnormalities. J Lower Genital Tract
Dis 2002;6(2):127-143 also see Wright et al., JAMA 2002;287(16):2120-2129 or
www.ASCCP.org.
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PS7-2a
THE USE OF HPV TYPING IN EPIDEMIOLOGICAL RESEARCH
F. Xavier Bosch
Institut Català d’Oncologia, Servei d’Epidemiologia i Registre del Càncer, L’Hospitalet de Llobregat, Spain
Recent evidence from case control studies of invasive cervical cancer provided, for the first
time, type specific risk estimates for 18 HPV types. These studies are part of the resullta of
the large IARC's coordinated HPV research program which included over 2000 cases in 9
different countries using equivalent protocols and centralized HPV testing research
laboratories. The adjusted Odds Ratios for HPV DNA detection was OR any single type =
172.6 (95%CI: 122.2-243.7). Type specific risk estimates were as follows: HPV 16: OR=
435; HPV 18: 248; HPV 45 OR= 198; HPV 31 OR= 124; HPV 33 OR=374; HPV 35 OR=74;
HPV51, OR= 67; HPV 52 OR= 200; HPV 58 OR= 115; HPV 59 OR= 419. According to
these results, the types that have to be considered of high risk for cervical cancer are, at least,
14 types as follows: HPV 16, 18, 45, 31, 52, 33, 58, 35, 59, 51, 56, 39, 73, 82. The risk for
any given high-risk type was not statistically different from the risk reported for HPV 16. The
standard estimates of the attributable fraction AF %, (the proportion of disease that is related
to HPV DNA) derived from these and most other studies range from 90 to 98%. The practical
conclusions from these analyses strongly indicates that, under current evidence, group testing
of clinical specimens for a cocktail of high risk types should be sufficient for screening and
patient management.
HPV typing is still a requirement under research conditions. These include 1) natural history
studies dealing with concepts of HPV persistency 2) studies of HPV transmission 3)
intervention studies including the use of type specific HPV vaccines. The analysis of HPV
variants of the common HPV types may be a further requirement of these studies.
RECOMENDED READING: Muñoz Bosch et al NEJM 2003
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PS7-2b
EPIDEMIOLOGY
Franco Eduardo
McGill University, Division of Cancer Epidemiology, Montreal
As a professional community, we are currently living a period of great excitement with the
perspective of making major strides in cervical cancer control. New leads are allowing us to
practice more efficient and tailored screening for the disease and its precursor lesions via
liquid cytology, HPV testing, visual inspection, and other technologies. On the primary
prevention front, prophylactic vaccination with HPV 16 capsid antigens seems to protect
against acquisition of persistent HPV 16 infection and development of high grade precursors.
Having come this far we now must avoid a setback. Public health authorities in middle and
low income countries have closely monitored the debate on new screening technologies.
Between the fear of increased health care costs consequent to the adoption of new screening
tests and the promising results on HPV vaccines it is all too tempting to take a wait-and-see
attitude concerning cervical cancer prevention. This posture could become widespread in
developing countries and lead to decreased funding of cytology quality control, training, and
needs assessment, in the false hope that HPV vaccines will be available soon to reduce the
burden of cervical cancer, thus obviating the need for substantial expenditures modifying or
maintaining screening programs. This scenario will prove disastrous. It behooves us as
scientists concerned with cervical cancer control to place our work in a broader, more useful
public health context where competing priorities come in many varieties and degrees of
urgency. Societal variables should be incorporated in efficacy and cost-effectiveness studies
so that the right lessons will be learned. Producing and sifting through the evidence on the
role of emerging technologies for cervical cancer screening requires complex mobilization of
resources by multi-disciplinary investigations. The most definitive answers to come from
these studies will take at least a decade to be obtained. We need, therefore, to alert
stakeholders that cytology-based programs are not to be relaxed or we risk wiping out the
gains from the past 50 years in cervical cancer prevention.
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SS5-02
NEW DEVELOPMENTS ON HPV TESTING METHODS
Iftner Thomas
Experimentelle Virologie
Ideally, an HPV test should allow detection of multiple HPV types, identify individual types
and provide quantitative information about the viral load of each individual type found.
Moreover, it should be easy to perform, highly reproducible, with a high specificity and
sensitivity, amenable for high throughput analysis and automation. Since we do not yet fully
understand the true value of viral load and the biological relevance of the different HPV
types, at present any HPV test used for screening should be able to detect the clinically
relevant high-risk types with a sufficient sensitivity of at least 10.000 genome copies per
sample. In order to be able, however, to detect persistent high risk HPV infections as the
necessary risk factor for cervical cancer, genoytping tests have to be performed. To compare
the performance characteristics of two recently established commercial test systems, we
analyzed 884 cervical samples from a routine screening population pretested by HC2
(Digene) and Pap smear. From patients with a positive HC2 test or Pap smear, or positive in
both cases, that were further examined by colposcopy and if necessary biopsied, histological
diagnosis were also available. All 884 samples were tested with the Roche Amplicor LBA
(line blot assay) and with the HPV DNA Chip from Biomedlab, which are both based on
PCR-amplification of a fragment from the L1 gene, for the presence of 27 or 22 different
HPV types, respectively. In parallel we tested all samples with an in house consensus primer
PCR/sequencing technique as an independent method, that relies on PCR-amplification of a
fragment from the E1 gene. The comparative analysis of these data allows to define clinical
sensitivities and specificities as well as the false negative/positive rate of all HPV test systems
used and to identify differences in the abilities of the two genotyping tests to detect HPV
types in multiple infections.
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SS5-03
DETECTION OF HIGH-RISK HUMAN PAPILLOMAVIRUS USING A
PROTOTYPE AMPLICOR MWP ASSAY.
Geyer L, Lu T,. Aldrich C, Sadorra M, Kosarikov D, Ding K,.Young T,.Sun R, Kornegay J.
Roche Molecular Systems, Alameda California, USA
Background: Testing women for the presence of human papillomavirus (HPV) is valuable in
triage to Pap testing and may be adopted as a primary screen for cervical cancer.
Amplification of HPV DNA by PCR is the most sensitive method for detection of infection,
and detection of amplicon using immobilized probes pooled in a MWP format allows for
highly specific detection of the high-risk HPV types. We describe an amplification and
detection system targeting the L1 gene that has been optimized in the Roche AMPLICOR®
MWP format.
Methods: A non-degenerate pool of primers is used to amplify a 170bp fragment from 13
high-risk genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68). HPV amplicon is
bound to the MWP using a pool of capture molecules coated in the wells followed by
colorimetric detection. All reagents for detection of HPV amplicon utilize Roche
AMPLICOR® chemistry. A human genomic DNA fragment is co-amplified with HPV and
detected in a separate well for each sample to control for sample adequacy and the presence of
inhibitors. Analytical sensitivity and specificity of the assay was assessed using purified
control template spiked into genomic DNA background. Effects of cellular background and
sample preparation methods on amplification efficiency were assessed using HPV positive
and negative cultured cell lines.
Results: Sensitivity of this system has been determined analytically to be less than or equal to
100 copies HPV per PCR. Specificity for high-risk HPV infection is excellent, and crossreactivity with low risk genital infections has been minimized to avoid false positive results.
Sample preparation, target amplification, and detection have been optimized to minimize
effects of cell load and potential inhibitors. Clinical specimens collected in different liquidbased cytology media have been tested and compared to results from independent assays to
assess sensitivity and specificity compared with other available HPV detection systems. An
HPV test on the AMPLICOR® MWP platform will provide reliable results in a format
amenable to both low and high-throughput clinical laboratories.
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SS5-04
HPV DETECTION AND GENOTYPING BY BROAD-SPECTRUM SFP10
CPR AND REVERSE HYBRIDIZATION ON A LINE PROBE ASSAY
Quint, W.G.V.; Molijn, A.C.; Kleter, B.; van Doorn. L.J.
Dept. of Medical Microbiology, MAS University Hospital, Malmö, Sweden
Multiple HPV genotypes are often detected in infected patients. However, our knowledge
about the true prevalence and clinical relevance is limited.
First, detection and identification of multiple genotypes greatly depends on the technology
used. Hybrid Capture is not suitable, since it only detects presence or absence of HPV, with a
possible distinction between high-risk and low-risk types. Multiple genotypes can be
identified by type-specific PCR, but this approach is not suitable for routine applications.
Broad-spectrum PCR is more efficient, but the detection of multiple genotypes strongly
depends on the primers used as well as on the post-PCR identification method. Direct
sequencing of amplimers underestimates the prevalence of multiple genotypes, and only
identifies the major type. Reverse hybridisation to a type-specific probe array like the line
probe assay (LiPA) is one of the most efficient tools for simultaneous identification of
multiple genotypes.
Secondly, the prevalence of multiple genotypes is associated with the clinical status of the
patient. It has been shown that a large proportion (up to 75%) of immune-compromised
patients carries multiple high- and low-risk genotypes. This may be due to an increased risk of
infection, as well as to an inadequate immune response. The prevalence of multiple infections
increases in the higher grade lesions up to CINIII, while patients with cervical carcinoma
often contain only a single high-risk genotype, which is compatible with the hypothesis that
these carcinomas are clonal, although underlying lesions can not always be excluded.
Thirdly, there is evidence that patients infected with multiple genotypes have an increased
risk for developing cervical neoplasia, as compared to patient, carrying a single genotype.
Recent studies indicated that also the response to treatment appears to be associated with the
presence of multiple HPV genotypes.
Thus, identification of multiple genotypes is an important issue, and requires further studies
by adequate molecular diangostic tools.
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SS5-06
P16INK4A: A POSSIBLE MARKER FOR DIAGNOSIS OF CERVICAL
PRE-CANCER - AN ALTERNATIVE TO HPV TESTING?
Bisgaard Kirsten
DakoCytomation A/S, Immunohistochemistry, Glostrup
Cervical cancer is the most common cancer type among women in the world. Currently the
diagnosis is based on the PAP staining and relies on subjective evaluation of cellular
morphological changes and the distinction between benign epithelial and neoplastic changes
can often be a challenge.
It has been proposed that an over-expression of the cyclin dependent kinase inhibitor
p16INK4a occurs due to the HR-HPV oncogene E7 mediated inactivation of the pRB
pathway. The p16 protein is therefore a good candidate for an indirect biomarker for the
activation of HR-HPV in cervical epithelium.
Today, the offered HPV tests are the only real supplement to the PAP test. These tests,
however, only identify women having potential risk of developing cancer and not those
women who already show the presence of pre-cancer or cancer stages.
A simple immunostaining method on smears using the p16 biomarker in combination with
morphological features is therefore more likely to provide the women with a more precise
diagnosis as the p16 biomarker will be indicating disease progression.
We have for that reason developed a simple, rapid and effective p16 immunostaining method
maintaining the morphological interpretation for application on cervical smears.
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SS5-07
HIGH LEVEL EXPRESSION OF HPV-16 E7 ONCOPROTEIN IN
CERVICAL BIOPSIES REVEALED BY IMMUNOHISTOCHEMISTRY:
A NEW METHOD FOR CERVICAL CANCER SCREENING
Fiedler M (1,2),. Müller-Holzner E (3),. Widschwendter A (3),.Viertler H (2),. Pfister G (2),. JansenDürr P (1,2),. Zwerschke W (1,2)
(1) Tiroler Krebsforschungsinstitut, Innrain 66, A-6020 Innsbruck, Austria, (2) Institut f.
Biomedizinische Alternsforschung der Österreichischen Akademie der Wissenschaften, Rennweg 10,
A-6020 Innsbruck, Austria., (3) Department of Obstetrics and Gynaecology, University of Innsbruck,
Innsbruck, Austria
Human papillomaviruses of the high-risk type are recognized as major etiological agents of
cancer of the anogenital region, in particular, cervical cancer. HPV-16 infection is associated
with the majority of cervical carcinomas world-wide. Despite the excellent epidemiological
evidence for a direct role of HPV-16 in the pathogenesis of cervical carcinoma, the molecular
pathways of carcinogenesis in vivo remained obscure. Whereas it is known that the products
of the two early genes E6 and E7 are required for immortalization of human cells in vitro,
much less is known about their role for tumorigenesis in vivo. While most HPV-positive
cancers retain the open reading frames of E6 and E7 intact, and the E6/E7 transcript can be
measured in tumor cells, both genes are known to code for unstable proteins and the actual
abundance of E6 and E7 protein is not known. Many attempts to detect the E7 protein in
cervical carcinoma biopsies were unsuccessful, and this led to the speculation that these
proteins may be expressed only shortly during the development of HPV-positive tumors. We
have developed a new protocol to generate highly specific antibodies to HPV-16 E7, based on
immunization of rabbits with highly purified recombinant E7 protein, purified to
homogeneity. Using these antibodies, we found that the E7 protein is indeed abundant in
sections of HPV-positive carcinoma cells; we also found that the protein is present in both
cytoplasm and nucleus of the tumor cells in vivo. In further experiments, we found that his
antibody is also able to detect high level E7 expression in Pap smears, a conventional
diagnostic method for cervical cancer screening. These results suggest that the antibodies
developed by us can be used to considerably improve cervical cancer screening.
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SS5-08
PROSPECTS FOR ENHANCED SIGNAL AMPLIFICATION-BASED
HPV TESTS
Lorincz Attila
Digene Corp, Research, Gaithersburg, Maryland, USA
The basic steps of Hybrid Capture (HC) are 1) target DNA denaturation, 2) liquid
hybridization with RNA probes, 3) hybrid capture, 4) RNA-DNA antibody conjugate binding,
5) signal amplification, and 6) reading of emitted light by a luminometer. HC2 can detect less
than 5,000 HPV DNA molecules and has similar clinical accuracy to PCR performed in
expert research labs. Over 10 population screening trials with a combined total of over 75,000
women have used HC2. Sensitivity of the test for CIN 3+ was 85% to 100%, a much higher
detection rate than the Pap test; however, the Pap test had higher specificity in most studies.
To improve sensitivity and specificity we developed HC3 to eliminate cross-reactivity.
Enhanced specificity in HC3 is achieved by DNA capture oligos to unique regions with
accompanying RNA signal probes directed to other regions. HC3 can be used to differentiate
and accurately quantify multiple HPV types from clinical specimens. HC3 was evaluated on
4,372 baseline cervicovaginal lavage specimens from our Kaiser Portland cohort study.
Considering cumulative CIN3+ cases over 3 years, the optimal cut point of 0.6 pg/ml for HC3
gave 79.7% (95%CI = 72.4%-86.9%) sensitivity, and 85.2% (95%CI = 83.7%-86.9%)
specificity, while HC2 (1.0 pg/ml) gave 75.4% (95%CI = 67.7%-83.2%) sensitivity and
86.0% (95%CI=85.6%-86.5%) specificity. By comparison the Pap test in this study had a
sensitivity of less than 40%. In a concurrent HC3 reproducibility study the Spearman
correlation was 0.92 (n = 1426) and the Kappa was 0.94 (95% CI = 0.90-0.97). To enable
high volume HPV testing the robotic Rapid Capture System (RCS) was developed. RCS is a
96-well microplate processor that integrates liquid and plate handling, incubations, shaking
and washing directly from bar-coded primary tubes, allowing a single user to process up to
352 specimens (4 microplates) in an 8-hour shift. In conclusion, Hybrid Capture has evolved
into a flexible and accurate method for the routine detection of HPV. Work on HC3 continues
with a view to adding multiplex detection capabilities.
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SS6-01
PERSISTENT HPV INFECTION: ROLE OF HPV DNA TESTING
Ferenczy Alex
McGill University and The Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Canada
The high point prevalence of latent HPV infection among sexually active young women and
its dramatic decrease by 30 years of age is reflective of the transient nature of most cases of
HPV infection. In contrast, persistent HPV infection over many years leads to genetic
alterations, development of precancer and progression of precancer to cervical cancer. As
such, persistent HPV infection appears to play a central role in the pathogenesis of cervical
cancer. Persistent infection is arbitrarily defined when the same HPV type is detected at least
twice over a period of one or more years. Risk factors for persistent HPV infection include
increasing age, impaired cell-mediated immunity, genetic predisposition and non-European
HPV molecular variants. P53 polymorphism on codon 72 and high viral load may be
additional risk factors.
Primary screening for HPV DNA detects prevalent infection and when applied at age 30 years
or older, identifies those with a persistent type-specific infection. These women are at high
risk for either having or developing high-grade cervical precancer. Detection of cervical
precancers using hybrid capture technology for HPV DNA assay (HC-IIâ) is consistently
superior to cervical cytology in both primary and secondary screening modes. However,
additional studies are needed to define the appropriate cut-off levels of HPV DNA load,
women of various ages and those at various degrees of risk to further assess the value of
molecular methods of detecting the highest number of lesions and their likelihood of
progression at the lowest false-positive rates.
Identification of precancers through cytologic and molecular screening methods and
eventually their prevention through HPV vaccination and public health measures will lead to
a significant decrease, if not complete eradication of cervical cancer.
(Ferenczy A, Franco E. Persistent human papillomavirus infection and cervical neoplasia. The
Lancet Oncology 2002;3:11-16.)
(Ferenczy A, Franco E. Cervical cancer screening beyond the year 2000. The Lancet
Oncology 2001;2:27-32.)
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SS6-02
CLINICAL ROLE OF VIRAL LOAD
Cuzick Jack
Cancer Research UK
The clinical utility of measuring viral load is still a hotly debated area. Viral load can be
estimated crudely, e.g. by Hybrid Capture II RLU levels or very precisely by real time PCR
with an additional measurement of total DNA. There is clear evidence that high viral loads are
more strongly associated with the existence of high grade CIN at the time of testing and in
persistence of the virus. Very little is known about the type specific importance of viral load.
Recent data from the HART study and other projects will be reviewed.
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SS6-03
SCREENING BY SELF-SAMPLING FOR HUMAN PAPILLOMAVIRUS
DNA
Hillemanns P., (1)Siebert U., Dannecker C.
Klinikum der Universität München - Grosshadern; (1) Harvard Center for Risk Analysis, Harvard
School of Public Health, USA
The majority of cervical cancer cases is associated with absent or deficient screening though
most affected women were seen in primary care outpatient clinics in the three years preceding
their diagnosis. Using a cytobrush for self sampling we have demonstrated a good sensitivity
(92%) in detecting CIN 2-3 in an earlier study (Lancet, 1999). Other techniques
(cervicovaginal lavage, tampon, Dacron swab) have shown lower sensitivities. Self sampling
with a cotton tip swab even missed 50% more cancers than did physician sampling.
We performed a prospective study with follow up of HPV positive and HPV negative women
in two referral outpatient clinics for internal medicine (oncology, gastroenterology). 560
women were asked to take a HPV self sample. 435 women (78%) performed HPV self
sampling. 134 women (31%) tested positive for high-risk type of HPV. There were significant
differences between HPV positive and negative women with respect to: mean age (42y vs.
46y), number of women aged under 16 at first coitus (35% vs. 23%), and history of drug
abuse (8.3% vs. 2.6%). Only 1.5% considered self sampling as difficult. Colposcopy could be
performed for 70 HPV positive women: CIN was identified in 7 women with CIN 2-3 (10%)
and in 10 with CIN 1 (14%). Test performance for detection of CIN 2-3 after correction for
verification bias: sensitivity 100%, specificity 71%; NPV 100%, PPV 10%. HPV persistence
was associated with a 5.7-fold risk of detection of CIN 2-3 at follow up (p = 0.001).
Our data show that self-assessment for HPV DNA is an easy, feasible and well-accepted
method of testing for HPV and it offers the chance of cervical cancer screening not only in
gynaecological office practices but also in other medical fields such as internal medicine.
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SS6-04
RATIONALE FOR MODULATION OF CYTOLOGIC SCREENING
INTERVALS BASED ON HPV TESTING IN WOMEN 30+ YEARS OF
AGE
Kinney Walter
Permanente Medical Group, Department of Obstetrics and Gynecology, Sacramento, California
Scientific Basis of Policy:
1) HPV is present in virtually all invasive cervical cancer (ICC)
2) HPV infection is common but usually transient
3) Sojourn time from CIN2/3 to ICC is many years in the immunocompetent woman
4) HPV testing plus cytology is very sensitive for CIN 3+ and negative predictive value of the
combination approaches 100%
5) HPV testing predicts subsequent CIN2/3+
6) Screening has limited influence on ICC incidence prior to age 30
7) All cervical cancer screening tests have poor positive predictive value for CIN2/3+,
prompting prolonged, resource intensive and frequently unnecessary evaluation
8) Risk of ICC is proportional to both sensitivity of screening methods and screening interval
9) Risk of ICC doubles between a one year interval and a 2-3 year interval using conventional
cytology
Conclusion from Scientific Observations: If both cancer risk and unnecessary visits and
interventions are to be minimized, the ideal screening program involves utilizing the most
sensitive test at the longest possible interval.
Observations Specific to the Permanente Membership:
1) Conventional cytology is currently used
2) 95% of our ICC and 75% of our Paps are in women 30 and older
3) Providers and patients have not accepted the recommendation for increasing screening
interval to 2 years (following 2 negatives) promulgated in December of 1996
Current Policy: Female members 30 and older may choose between
1) Recommended: Pap plus HPV every 3 years if both tests are negative -Colpo for cytologic
abnormalities. Rescreen with both tests in one year if HPV positive cytology/cytology
negative
2) Annual Cytology Cancer protection acceptable but unnecessary tests/procedures
3) Biennial Cytology after 2 consecutive negatives Fewer tests and procedures but increased
cancer risk
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SS6-05
HPV TESTING CAN REDUCE THE NUMBER OF FOLLOW-UP VISITS
IN WOMEN TREATED FOR CERVICAL INTRAEPITHELIAL
NEOPLASIA GRADE 3
Zielinski G.D., Rozendaal L., Voorhorst F.J., Berkhof J., Snijders P.J.F., Risse E.J.K., Runsink
A.P., de Schipper F.A., Meijer, C.J.L.M.
From the Departments of Pathology (G.D.Z., P.J.F.S., L.R., E.J.K.R., C.J.L.M.M.) and Clinical
Epidemiology and Biostatistics (F.J.), Vrije Universiteit Medisch Centrum, Amsterdam
Objective. We evaluated high-risk HPV testing by Hybrid Capture II (HC II) in addition to
cytology to predict recurrent/residual CIN 2/3 and cervical cancer in women treated for CIN
3.
Methods. Follow-up study of 108 women with histologically confirmed CIN 3.
Results. Pre-treatment, in 96% (104/108) of the smears high-risk HPV DNA was present.
Post-treatment, 71% (77/108) of the women had normal cytology and negative HC II test and
none developed recurrent/residual disease during a median follow-up of 28.8 months with a
range of 2.4-64.8 months. One of the 12% (13/108) of women with normal cytology and
positive HC II test was diagnosed with cervical adenocarcinoma. One of the 7% (8/108) of
women with abnormal cytology (borderline dyskaryosis or worse) and negative HC II test
was diagnosed with CIN 2. Three of the 9% (10/108) of women with abnormal cytology and a
positive HC II test were diagnosed with CIN 2/3. These results show an increased risk for
recurrent/residual CIN 2/3 and cervical carcinoma when at least one post-treatment test is
positive. The highest relative risk (72.9 95% CI 25-210) was present in women with both tests
positive.
Conclusions. HPV testing with HC-II in conjunction with cytology can be used as a tool to
select women with an increased risk for recurrent/residual CIN 2/3 and cervical cancer. The
standard policy in The Netherlands is cytology at 6, 12 and 24 months post-treatment.
However, for women with both normal cytology and negative HC II test at 6 months the
chance to develop recurrent/residual CIN 2/3 and cervical carcinoma is so low that retesting at
12 months can be omitted.
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SS6-06
VALUE OF HUMAN PAPILLOMAVIRUS TESTING AFTER
CONIZATION FOR HIGH GRADE SQUAMOUS INTRAEPITHELIAL
LESION
Collinet P., Houfflin Debarge V., Vinatier D., Ego A., Devisme L., Leroy JL.
Hôpital Jeanne de Flandre, Chirurgie Gynécologique, CHRU Lille
Objective
The aim of our study was to evaluate Human Papillomavirus (HPV) testing in the follow up
of patients after conization for high grade squamous intraepithelial lesion (SIL).
Methods
A prospective study was conducted on 205 patients who underwent conization for high grade
squamous intraepithelial lesion (CIN II or III). Loop electrosurgical excision procedure
(LEEP) was used in all cases.
The patients underwent high risk HPV testing by the Hybrid Capture II system before and
three months after conization.
Results
Of the 205 patients , 193 (94.1%) were positive for the HPV test before treatment. 71 (34.6
%) were HPV positive after conization. The margins were positive in 36.1%. Residual disease
was observed in 27 cases (13.2%). We didn’t find any correlation between pretreatment HPV
testing and the residual disease or recurrence. Patients with positive margins were
significantly more likely to have residual disease than those with negative margins
(P<0.0001). Furthermore , Residual disease was more likely to occur when the post treatment
HPV test was positive (p<10-7). Four patients developped recurrence after a mean follow up
of 15.12 months (+/-10.92). All these recurrences were observed in patients with positive post
treatment HPV test (p<0.05).
Conclusion
Post treatment HPV testing could be useful in the follow up of patients after conization. It
correctly predict residual and recurrent disease with a sensitivity of respectively 81 and 100%
and a predictive negative value of 96 and 100%.
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SS6-07
CORRELATION OF VIRAL INTEGRATION AND VIRAL LOAD
AMONG HPV 16 INFECTED WOMEN
Syrjänen Stina
Inst. of Dentistry, Faculty of Medicine, Oral Pathology, Turku
Cervical tumors develop slowly from intra-epithelial neoplastic lesions (CIN) which may
regress or persist. Several earlier studies have shown that HPV DNA is present as an episomal
form in CIN lesions while the principle form of the viral DNA in invasive cancer is
integrated. HPV is always integrated in cell lines derived from cervical carcinomas or in cells
immortalized by transfection of HPV 16 or HPV 18 DNA. Integration of HPV DNA is
considered as an important step in tumor progression. Integration of the viral genome into the
cellular DNA can have impact on the initial stage of cell transformation on the maintenance of
the transformed phenotype and/or on tumor progression. Integrated viral genome may also
lead to the expression of proteins with transforming activity. Viral integration may gain the
whole genome of viral transforming genes with a new regulatory mechanism involving either
the loss of viral regulatory mechanism or in addition of new ones of cellular origin.
HPV DNA integration seems to occur at random pattern but is preferentially located near
chromosomal break points and fragile sites. Integration frequently leads to disruption of HPV
E1-E2 region. Elimination of HPV 16 E2 protein expression results in up regulation of the
transcription of the E6 and E7 oncogenes. Recently, deletions/disruptions of the E1/E2 ORFs
were mapped in large a series of HPV 16 positive carcinomas. and multiple patterns were
found, the most common being deletions in E2 "hing" region (1).
We have recently developed a new real-time PCR system for simultaneous measurement of
HPV 16 viral load and integration status, using 31 cervical lesions (non-CIN to CIN 3) from
24 women, prospectively followed up for 10 years. The method is based on measurement of
the absolute values of the E2 and E6 open reading frames in HPV16 positive DNA-samples.
Only one sample contained exclusively episomal HPV 16 DNA and this lesion regressed
spontaneously. A sample from an other patient with only integrated HPV 16 rapidly
progressed from CIN 1 to CIN 3 in two years. In all other patients episomal and integrated
HPV 16 DNA was found coexistent. Rapid progression of CIN lesions was closely associated
with high-viral load and of integrated HPV 16 (2).
In conclusion, virus typing in conjunction with the evaluation of the integration status may
improve predicting of outcome of the disease. We are emphasizing that the initial high viral
loads will increase the probability of integration in the chromosomal site favorably selected
on as gaining a growth advantage. This will explain the high frequency of mixed episomal
and integrated form of the viral DNA as these precancer cases could still be in the selection
phase.
1. Kalantari M, Karlsen F, Kristensen G, Holm R, Hagmar B, Johansson B (1998). Disruption
of the E1 and E2 reading frames of HPV 16 in cervical carcinoma is associated with poor
prognosis. Int. J. Gynecol. Pathol. 17:146-153.
2. Peitsaro P, Johansson B, Syrjanen S. Integrated human papillomavirus type 16 is frequently
found in cervical cancer precursors as demonstrated by a novel quantitative real-time PCR
technique. J Clin Microbiol. 40:886-91, 2002
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SS6-08
EPIDEMIOLOGY OF HPV INFECTION IN PICARDY AND VIRAL
LOAD
Boulanger JC* - Bauville E *-Nasreddine A* - Ghighi C** - Sevestre H **, Gondry J* - Leroy JL***
*Centre de Gynécologie-Obstétrique CHU Amiens France, **Service d’Anatomie Pathologique CHU
Amiens France, ***Maternité Jeanne de Flandre CHU Lille France
Background: Human papilloma virus (HPV) is thought to be the primary cause of cervical
cancer. Indeed there are many potential uses for HPV typing in cervical pathology: screening,
triage, follow up of treated CIN.
In Picardy, the mean prevalence of high risk HPV is 14.68 %, highest among women 25-29
years of age and progressivly lowering in older age group as seen in table I, but still at 9 %
above 60.
So the use of HPV typing is limited by this high prevalence infection. For this reasons we
thought to study the viral load
6
17
,2
3
6
8,9
9
10
,6
12
12
,5
,8
6
14
15
4
,2
2
15
,5
15
,4
5
15
,3
8
20
21
,6
8
25
10
5
0
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
Objective: To assess the interest for screening of determination of the viral load
Material: 157 cases of histologically proven High Grade lesions (HGSIL) or
invasive cervical cancer (IK)
Methods: The viral load of high risk - HPV DNA was estimated with Hybrid
Capture II by the ratio of relative lights units to positive control values in the
samples.
Results: HR-HPV DNA was present in 138 of 144 cases of HGSIL and 12/13 cases
of invasive cancer. So the sensitivity is 94.9 % for HGSIL and 92.3 % for invasive
cancer.
For HGSIL with a threshold of:
- 1: the sensitivity is 94.9 %
- 2: the sensitivity would be 90.6 %
- 5: the sensitivity would be 85.6 %
- 10: the sensitivity would be 83.3 %
The invasive cervical cancers are too few to be studied.
We have to make the choice of a treshold keeping an acceptable sensibility.
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SS6-09
EVALUATION OF UNIVERSAL COLLECTION MEDIUM (UCM) FOR
THE DETECTION OF HUMAN PAPILLOMAVIRUS (HPV),
NEISSERIA GONORRHOEAE (NG) AND CHLAMYDIA
TRACHOMATIS BY THE HYBRID CAPTURE II (HCII) AS A
MOLECULAR TEST
Dôres, Gb (1),Taha (2), N; Focchi (2), J; Castelo,A (2); Taromaru (1), E**; Mielzynska,I (3);
Lorincz,A (3)
Digene Brasil (1), Federal University of São Paulo (2); Digene Corporation (3)
Collecting cervical-vaginal material in liquid media enables simultaneous evaluation for both
oncologic cytology and molecular tests for the detection of HPV, NG and CT, besides other
markers like p16 and p53. UCM has been developed to fulfill this objective. The aim of this
study was to compare HC II results for HPV, NG, and CT from specimens collected in the
current standard transport medium (STM®) versus UCM®. Three cervical specimens were
collected in the following sequence from each of 883 women referred for colposcopy: 1st.
endocervical material collected with the accompanying brush of the STM kit and ectocervical
material collected with Ayre spatula were used to prepare the Pap smear; 2nd. the same brush,
with residual endocervical cells, was again used to scrape the ectocervix and posterior vaginal
wall and subsequently placed conditioned in a 1 ml STM vial; 3rd. endocervical, ectocervical
and posterior vaginal wall cells were collected with another similar brush and placed in a 1 ml
UCM vial and stored for variable periods up to and over 3 months. The HC II results from
samples taken from STM and UCM media were compared by using simple linear regression
analysis.
HC II results from the 2 media were highly correlated: high-risk HPV (k= 0.883; R2=0.882),
low-risk HPV (k=0,774; R2=0.913), NG/CT (k=0,909; R2=0.819). In conclusion, despite
being based on a third specimen collected, UCM HC II results for HPV, NG, and CT were
stable and equivalent to those obtained with the standard medium STM.
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SS6-10
A CROSS-SECTIONAL STUDY OF PHYSICIAN AND PATIENT
COLLECTED CERVICAL MATERIAL FOR CYTOLOGY AND HPV
TESTING
Garcia F (1), Barker B (1), Santos C (2), Mendez-Brown E (3), Nuño T (1), Giuliano A (1), Davis
JR (1)
(1) From the University of Arizona, (2) Tucson Arizona USA, Instituto Nacional de Enfermedades
Neoplasicas, (3) Lima Peru and, ISSSTE, Hermosillo Mexico
Objective: To assess the performance of patient and physician obtained cytology and HPV
testing for the detection of high-grade cervical dysplasia.
Methods: A cross-sectional study was performed involving 334 women seen at three
dysplasia clinics (Tucson Arizona USA, Hermosillo Mexico, Lima Peru). Subjects selfcollected specimens for cervical cytology and human papilloma virus (HPV) testing. They
subsequently underwent physician collection for cytology and HPV, followed by complete
colposcopic evaluation with directed biopsy. Cytology was processed using thin-layer
technology and HPV was determined using polymerase chain reaction technique. Test
performance characteristics were determined using the histopathologic diagnosis as the
reference standard, and designating high-grade cervical dysplasia (cervical intraepithelial
neoplasia 2/3 as well as invasive cancer) as clinically significant disease for the purpose of the
analysis.
Results: The sensitivity and specificity of patient-collected cytology was significantly lower
(55.0% and 84.1%) compared to physician directed sampling (85.2% and 73.4%). Patient
collected HPV had significantly lower sensitivity (49.0%), compared to physician sampling
(82.2%), although specificity was not significantly different.
Conclusion: Patient-collection is a feasible, although inferior alternative to physician
collected cervical cytology and HPV testing.
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SS7-03
THIN-PREP IMAGING SYSTEM
Linder Jim
Cytyc Corporation, USA
The Cytyc Corporation ThinPrep Imaging System uses computer-aided imaging with
automated microscopy to assist the review of ThinPrep Pap Test slides. The ThinPrep
Imaging System presents to the screening cytologist, during their rescreening of ThinPrep
slides, the fields of view on the ThinPrep slide that include objects of interest. If all presented
fields are determined by the reviewer to contain only normal cells, the entire slide may be
considered to contain only normal cells. The ThinPrep Imaging System therefore reduces
screening time in the vast majority of cases. Reducing time spent examining normal cells can
increase overall productivity, reduce the turnaround time or increase the time spent examining
abnormal cells.
The operation and design of the ThinPrep Imaging System are grouped into two major
functions. First, the ThinPrep Pap Test slide is analyzed by a computer controlled microscopic
imaging device to locate the objects of interest. The x and y locations of these objects on the
slide are saved in a database. Second, an automated reviewing microscope retrieves the
locations of the objects of interest from the database, then sequentially positions these
locations for rescreening by the Cytotechnologist. This ensures that every slide is screened by
a cytologist for final determination of abnormality
Studies conducted with the ThinPrep Imaging System have successfully demonstrated the
robustness of the device to produce consistent cytologic diagnoses for descriptive diagnosis
and specimen adequacy according to Bethesda System 2001 criteria. Specifically, these
studies have validated that the instrument will consistently display abnormal cells within the
22 fields of view, including the consistent representation of cancer. The studies also show
inter-instrument, intra-instrument and inter-review scope reproducibility is consistent with a
manual review method. The variability between Cytotechnologists is also similar between a
manual and ThinPrep Imaging System review. Lastly, the studies show that counting cells in
the 22 fields selected by the imager are sufficient to determine specimen adequacy.
Clinical tests assessing the effectiveness of the ThinPrep Imaging System to assist in primary
cervical cancer screening of ThinPrep Pap Test slides for the presence of atypical cells,
cervical neoplasia, including its precursor lesions (Low Grade Squamous Intraepithelial
Lesions, High Grade Squamous Intraepithelial Lesions), and carcinoma as well as all other
cytologic criteria as defined by the Bethesda System for Reporting Cervical/Vaginal
Cytologic Diagnoses support the following conclusions:
•
For all sites combined for ASCUS+, the improvement in sensitivity of the Imager
Review method over the Manual Review method is statistically significant. This increase
is 6.3% with a 95% confidence interval of 2.6% to 10.0% for all sites combined. The
differences in sensitivity varied among the sites from –2.8% to +14.4%. For LSIL+ and
HSIL+ the sensitivity of the Imager Review method is equivalent to the Manual Review
method.
•
For all sites combined for HSIL+, the improvement in specificity of the Imager Review
method over the Manual Review method is statistically significant. This increase is 0.2%
with a 95% confidence interval of 0.06% to 0.4% for all sites combined. The differences
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in specificity varied among the sites from –0.1% to +0.7%. For ASCUS+ and LSIL+ the
specificity of the Imager Review method is equivalent to the Manual Review method.
•
Specimen adequacy can be determined with the Imager Review method using cell
counting techniques based on the recommendations of Bethesda 2001.
•
Use of the ThinPrep imaging system typically allow a doubling of the number of slides
that could be screened each day, (e.g. 120 to 200 slides/day) without a loss of screening
accuracy,
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SS8-01
THE VALUE OF REAL TIME SCREENING METHODS
Singer Albert
The Whittington Hospital, Department of Gynaecology, London
Automated real time screening methods are associated with several advantages, including
facilitation of patient management, an easily interpretable "normal versus abnormal" result
and simplified patient communications. An example of a real time screening system is the
TruScreen device (Polartechnics Limited, Sydney, Australia). The device detects abnormal
changes on the basis of structural alterations to tissue architecture, and is currently being
introduced as an adjunct to the Pap smear for primary screening.
The instantaneous output of the device allows the clinician to immediately provide some
feedback to the woman on the screening result, even when the device is used in adjunctive
mode. If the TruScreen result is "abnormal" the woman can be immediately counselled and
the follow-up process discussed. Potentially, a follow-up appointment can be booked before
the patient leaves the clinic, or if the setting permits it, follow-up colposcopy may be
performed immediately.
The dichotomous output of "normal" or "abnormal" provided by the TruScreen simplifies
explanations to women. The device does not use equivocal classification categories (such as
borderline dyskaryosis or ASCUS), and therefore very clear-cut management
recommendations can potentially be developed. This should assist both the practitioner and
the patient in the follow-up of abnormal results.
In conclusion, the introduction of real time technology for cervical screening has far-reaching
implications for the clinician in terms of patient management and patient communications.
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SS8-02
OPTOELECTRONIC METHODS IN PRIMARY AND SECONDARY
SCREENING
Quek, S.C.
KK Women's & Children's Hospital, Gynaecologic Oncology Unit, Singapore
Optoelectronic technology provides an alternative screening modality which has a potential
role in both primary and secondary screening. Optoelectronic methods, as incorporated in the
TruScreen device, utilise low-level stimuli which yield information about cervical tissue
structures. This information is derived from a combination of optical tissue scattering effects
and the response to electrical stimuli. The signals obtained from each tissue type enable the
identification of tissue via its unique optoelectronic signature. The optoelectronic signals are
processed in a fashion which provides an immediate output to the clinician.
In order to automate the cervical screening process, the processing software must be "trained"
to recognise the optoelectronic signatures of various tissue types. In the case of TruScreen,
this was achieved by obtaining data on over 1,500 patients from a diverse range of
demographic and racial groups. The training data included the optoelectronic signals, which
were then matched with a "gold standard" colposcopic and/or histological diagnosis at each
point on the cervix. For each normal and abnormal tissue type, as determined by the "gold
standard", a databank of optoelectronic signals was constructed. These signals were then
analysed to determine the range of optoelectronic measurements associated with each tissue
type. In clinical operation, the device draws on this previously collected information in order
to classify cervical tissue.
The combination of two or more alternative technologies for screening increases overall
sensitivity if the detection capabilities are complementary, such that CIN lesions missed by
one screening test are identified by the adjunctive test. The use of complementary technology
thus minimises the overall potential for false negative screening results. The TruScreen has
been investigated as an adjunct to the Pap smear for cervical screening, and results from a
recent multi-centre trial demonstrate that the adjunctive test combination is highly sensitive
for the detection of both high and low grade CIN.
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SS8-03
IN VIVO MICROSCOPIC IMAGING OF CERVIX BY FIBER OPTIC
CONFOCAL MICROSCOPY
Milbourne,A.(1), Sung,K-B(2)., Liang,C.(3), Descour,M.(3), Follen,M.(1), Malpica,A(1), RichardsKortum,R.(2)
(1) The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, (2)
Biomedical Engineering, University of Texas, Austin, (3) Optical Sciences Center, University of
Arizona, Tucson
Confocal microscopy has been shown to image cell morphology at sub-cellular level in
epithelial tissue. The application of confocal microscopy in vivo may offer a useful adjunct to
standard histopathology for early detection of precancer and cancers. The objective of this
pilot study is to investigate the feasibility of using fiber optic confocal microscopy to image
cervical epithelial tissue in vivo. We have built a fiber optic confocal reflectance microscope
for use in the clinical setting that is capable of imaging epithelial tissue at 15 frames per
second. A fiber optic bundle consisting of 30,000 optical fibers is located between the
scanning mechanism and objective lens, wherin the illumination laser light is focused onto a
single fiber within the bundle so that each fiber serves as the illumination and detection
pinhole at the distal end. The illumination fiber is imaged onto tissue by the objective lens and
backscattered light from the tissue is transfered through the fiber toward a beam splitter and a
photodetector. Backscattered light from out of focus regions in the tissue will be largely
rejected by a secondary pinhole located at a conjugate image plane in front of the detector.
Two dimensional confocal imges are achieved by raster scanning the illumination spot across
the proximal end of the fiber bundle. Index matching liquid is utilized to reduce the specular
reflection from fiber end faces. The objective lens is miniaturized to an overall outer diameter
of 7mm. A suction device is developed to change the depth of image plane in the tissue and to
hold the objective lens against the tissue. The measured spatial resolution of the system is 3
micrometers laterally and 10 micrometers axially. Eighteen patients participated in this study,
signed an informed consent, and were recruited from the colposcopy clinic of the University
of Texas M.D. Anderson Cancer Center. For each patient, 1-2 colposcopically abnormal sites
and one normal site on the cervix were imaged during the standard colposcopic examination
and the confocal images were recorded into digital video files. Biopsies were taken from the
imaged sites and examined by an experienced gynecologic pathologist blinded to the
colposcopic diagnosis. Individual confocal images were extracted from the video files and
processed for better presentation. Cell nuclear morphology and tissue architecture could be
appreciated from these images. The results show that sub-cellular resolution can be achieved
in reflectance images of cervical epithelial tissue in vivo by fiber optic confocal microscopy.
The system has the potential to augment current cancer diagnostic methods in all organ sites.
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SS8-04
CERVICAL SPECTROSCOPY AS AN ADJUNCT TO COLPOSCOPY
Thomas C. Wright, Jr
Columbia University, New York, NY
Over the last several decades a considerable amount of work has gone into developing realtime optical detection methods for the identification of cervical intraepithelial neoplasia
(CIN). Early work focused on utilizing fluorescence spectroscopy to identify fundamental
differences in fluorescence emission spectra between normal and neoplastic tissues. More
recently, optical detection methods have been expanded to incorporate not only fluorescence
spectroscopy, but also reflectance (white light backscatter) and video imaging to distinguish
between normal and neoplastic tissues. Currently large pivotal clinical trials are underway to
determine the effectiveness of these devices as an adjunct to colposcopy for the identification
of cervical
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AUTHORS
SS8-07
SINGLE VISIT APPROACH TO CERVICAL CANCER PREVENTION:
SAFETY AND ACCEPTABILITY IN RURAL THAILAND
Blumenthal PD (1), Gaffikin L (2), Limpaphayom K (3), Lumbiganon P (4), Warakamin S (5),
Srisupundit S (3), Ringers P (2)
(1) Johns Hopkins University and JHPIEGO Corporation, Baltimore, USA; (2) JHPIEGO Corporation,
Baltimore USA; (3) Royal Thai College of Obstetricians and Gynecologists, Bangkok, Thailand; (4)
Khon Kaen University, Khon Kaen, Thailand; (5) Ministry of Public Health, Bangkok, Thailand
Objective: To assess the safety and acceptability of a single-visit approach using a
combination visual inspection of the cervix with acetic acid wash (VIA) and cryotherapy
when provided by nurse-midwives in district hospitals and village health centers.
Methods: 12 nurse-providers were trained in VIA and cryotherapy, after which they became
part of mobile (village health centers) and static (hospital based) teams providing cervical
cancer screening, and treatment or referral in 4 districts of Roi-et Province. Over 6 months
5,999 women were tested for cervical cancer or precancer using VIA. If positive, after being
counseled, they were offered cryotherapy and counseled again about the benefits, potential
risks and likely side effects of cryotherapy. If acceptable to the patient and if eligible by
protocol, cryotherapy was then provided immediately.
Results: The overall VIA test-positive rate was 13.3%. Among those eligible for cryotherapy,
99.7% accepted immediate treatment. 739 women received cryotherapy, and 85.5% returned
for their 3-month follow-up visit. There have been no major complications. Less then 3% of
the cryotherapy patients returned for any clinical problem. Less than 1% of the women with
any complaint post-cryotherapy required any management other than reassurance regarding
side effects. Both VIA and cryo were highly acceptable to the patients with over 95%
indicating being satisfied or very satisfied with their experience. At one year, most cryo
patients had a clearly visible squamo-columnar junction and less than
Conclusion: A single visit approach using VIA and Cryotherapy appears to be safe and
acceptable to women and providers in rural Thailand, and has the potential to be a efficient
method of cervical cancer prevention in such settings.
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SS9-01
EPIDEMIOLOGY AND PATHOGENESIS OF AIN IN MEN
Palefsky Joel
UCSF, Medicine, San Francisco
The incidence of anal cancer is up to 35/100,000 among HIV- men who have sex with men
(MSM) and is estimated to be approximately 70/100,000 among HIV+ MSM. Our earlier
studies showed that nearly all HIV+ MSM and 60% of HIV- MSM have anal HPV infection,
often with several concurrent HPV types and almost always with at least one oncogenic HPV
type. The prevalence and incidence of high-grade AIN are also very high, with approximately
one half of HIV+ men showing AIN 2 or 3 at baseline in a recent study. Data on the effect of
highly active antiretroviral therapy (HAART) indicate that HAART has little effect on the
natural history of AIN, suggesting that the incidence of anal cancer may continue to rise if
HIV+ individuals with AIN live longer but are not screened or treated for AIN. Consistent
with this, recent analysis of anal cancer incidence data in San Francisco County show a
continued increase in anal cancer among men aged 40-64 years since 1996 when HAART was
first introduced. More data are needed to define the molecular pathogenesis of AIN and
interactions between HIV and HPV, to determine optimal treatment approaches for AIN and
to confirm that treatment of AIN reduces the incidence of anal cancer. Until then, however,
cost-effectiveness modeling shows that screening and treatment of AIN should be costeffective to prevent anal cancer among both HIV+ and HIV- MSM. Ideally screening
programs will be implemented in a structured environment to permit data collection to
determine the effect of treatment on AIN and on the incidence of anal cancer.
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SS9-02
WOMEN AND AIN, THE PERSPECTIVES OF THE GYNAECOLOGIST
HEARD Isabelle
Hop. Eur. G. Pompidou
Invasive anal squamous cell carcinoma is a relatively uncommon tumor that occurs more
frequently in women than in men. An increased incidence of anal cancer among both men and
women has been reported in the United States over the last decade and a rise in anal cancer
was observed among women in Denmark from 1957 to 1987. Although the etiology of anal
cancer is unknown, a number of studies have indicated similarities between invasive
squamous cell carcinoma of the anus and of the cervix. Both tumors appear to develop from
squamous cell precursors, and both are associated with specific types of human
papillomavirus (HPV). As in the cervix, the anus displays change ranging from anal
intraepithelial neoplasia (AIN) I to AIN III. AIN I is not though to progress directly to cancer,
whereas AIN II and AIN III are likely to be precursors to anal cancer. Several studies have
shown a strong association between anal cancer and AIN and papillomavirus HPV. HPV 16,
18, 31, 33 and 45 are most strongly associated with anal squamous intraepithelial lesions, the
putative anal cancer precursor.
Women at high risk for AIN and anal cancer include those with high-grade cervical lesions
and cervical and vulvar lesions. Several studies have shown that HIV-positive women are at
increased risk of cervical intraepithelial lesions when compared with the general population.
Little is known about AIN in HIV-positive women. Nevertheless recent data suggest that the
incidence of invasive squamous cell carcinoma of the anus is increased among HIV-positive
women. Data from the US AIDS Cancer Registry Match Study showed that the relative risk
of invasive anal cancer was 7 in HIV-positive women compared with the general population.
In a recent study, HIV positivity and severe immunodeficiency was associated with increased
risk of anal HPV infection. A high proportion of HIV-positive women (26%) had abnormal
anal cytology, with ASCUS or low-grade lesions in 25% and high-grade lesions in 1%.
In the setting of HIV, gynecologist in care of women should perform a complete examination
of the entire genital tract, due to the multifocal nature of HPV-related neoplasm. Systematic
anal cytologic examination should be added for screening for AIN by rotating a watermoistened Dacron swab in the anal canal. Women with abnormal anal cytology should be
referred for a high-resolution anoscopy with biopsy of visible lesions. High-resolution
anoscopy is similar to cervical colposcopy and uses identical equipment. It permits the
identification and biopsy of lesions. Algorithms for the treatment of AIN have been presented.
Few studies have been performed on the efficacy of treatment for AIN.
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SS9-03
DIAGNOSTIC METHODS FOR AIN
Darragh Teresa
UCSF, Pathology and Ob/Gyn, San Francisco, CA, USA
The evaluation of HPV-related lesions of the anal canal parallels that used for the cervix: anal
cytology, high resolution anoscopy and directed biopsy.
Anal cytology is gaining acceptance as a screening tool for these lesions, particularly in
"high-risk" populations, especially those with HIV infection and gay/bisexual men.
Diagnostic criteria are similar to those used for cervical cytology. Use of Bethesda system
terminology is encouraged. Specimen adequacy has not been critically evaluated; it is
important to have sufficient numbers of nucleated squamous cells for evaluation. The
presence of transformation zone components (rectal columnar and squamous metaplastic
cells) should be noted.
Patients with abnormal anal cytology may be evaluated with high resolution anoscopy;
criteria are similar to cervical colposcopy. Acetowhite epithelium with punctuate and mosaic
vessel changes often accompany high grade lesions of the anus.
The histologic features of HPV-related lesions of the anus are remarkable similar to their
cervical counterparts. Lesions are frequently encountered in the metaplastic epithelium of the
transformation zone.
Examples of the various lesions encountered on anal cytology, anoscopy and biopsy will be
presented.
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SS9-04
CONVENTIONAL SURGICAL TREATMENT AND IRC TREATMENT
OF AIN (REFERENCE SS9)
GODEBERGE Philippe
Institut Mutualiste Montsouris, Unité de Proctologie, Paris
Treatment for anal intra epithelial neoplasia (AIN) remains challenging. Even if the incidence
of the infection by human papillomavirus increase in the general population , the incidence of
the anal neoplasms does not grow dramatically. Apart from high risk population (HIV
positive patients, CD4 rate below 400/ mm3 , anal sexual intercourse, 16 -18 serotype), there
is no standard for screening program to identify affected individuals at an early stage of the
disease. Nevertheless, AIN is easier to treat when the lesions are small.
The conventional treatment remains the electro coagulation in most of the cases, under local
or general anaesthesia. Several data suggest that intervention directed by high resolution
anoscopy is safe and better eliminates even high grade squamous intra epithelial neoplasia.
But a multiple staged procedures and continued surveillance is necessary , particularly in HIV
positive. The highly active anti retroviral treatment do not interfere with the incidence of HPV
and the local consequences of the infection.
The colposcopic appearance of the different grades of AIN is similar to those describe for the
cervix. So the procedures of gynaecologists, could be transposed to the anus.
The unsatisfactory high rate of recurrence , leads to use alternative treatment, mainly
immunotherapy: interferon, imiquimod, HspE7, vaccination. The aim of the specific
immunologic pathway is the production of cytotoxic T Lymphocytes. The non specific
activation of the immunity includes a local production of interferon or cytotoxines.
Recent data strongly suggested that local application of drug like imiquimod could decrease
the size of anal warts and later, the rate of recurrence. A combination of the conventional
treatmen twith the immunomodulation could be promising; the aim of immunomodulation
could be to decrease the size of the lesions before surgery, or to maintain the remission in
high risk population. The possibility such combination the treatment is still in debate,
particularly regarding the topography of the lesions.
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SS10-01
NEW DIRECTIONS IN HPV EPIDEMIOLOGY (SESSION SS-10)
Franco Eduardo
McGill University, Division of Cancer Epidemiology, Montreal
As cervical cancer control moves to exciting new fronts in primary prevention via
immunization against HPV and screening with HPV tests it is imperative that we have a fuller
understanding of the important milestones in the natural history of cervical neoplasia. The
following are critical issues that should be targeted by future research in the area:
We need a better understanding of the dynamics of transmission of the virus. With HPV
testing being increasingly considered as a primary screening tool either alone or as an adjunct
to cytology it becomes essential to characterize the circumstances and variables mediating
acquisition and clearance of infections with the different HPV types. A high proportion of
women screened with HPV will not have lesions and will be told that they harbor an infection
by a potentially oncogenic virus that is transmitted by sexual activity. This will lead to
considerable uncertainty and its consequent psychosocial impact on quality of life of patients.
The existing knowledge base concerning the epidemiology of HPV is insufficient in that
respect and physicians are ill prepared to answer all the questions that their patients may have
regarding the significance of a positive HPV finding or of the circumstances leading to it,
such as inter-partner transmissibility. Future epidemiologic studies should incorporate the
designs and methods that are appropriate to answer these questions from a multidisciplinary
standpoint, i.e., covering the putative behavioral, reproductive, environmental, and hostsusceptibility variables that mediate risk of infection.
We also need to understand the duration of the protection conferred by a negative HPV test:
The published literature on HPV testing is based on cross-sectional assessments of the
relation between positivity and lesions, but provide reassuringly high negative predictive
values. However, no studies have yet appeared providing information on the long term lesion
risk of women found to be HPV negative at first screen. Such studies are needed to orient
future policy decisions concerning screening intervals and the need for ancillary tests to
improve prognostic performance.
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SS10-02
HORMONES AND OTHER RISK FACTORS FOR CERVICAL CANCER
F. Xavier Bosch
Institut Català d’Oncologia, Servei d’Epidemiologia i Registre del Càncer, L’Hospitalet de Llobregat, Spain
Because of the growing evidence that HPV is a necessary factor in cervical cancer, it soon
became a standard procedure in the reports of case control studies to include analyses
restricted to HPV positive cases and controls to properly assess the contribution of additional
factors to the risk of cervical cancer. In relation to invasive cervical cancer, the leading project
is the multicenter case control study on cervical cancer undertaken by the IARC in 1991. In
these studies the long term use of oral contraceptives and high parity were shown to be risk
factors for progression.
ORAL CONTRACEPTIVES: Ever OC use was associated with a significant increase in risk
(OR=1.47[1.02-2.12]). Use of OCs for <5 years was not related to cervical cancer
(OR=0.77[0.46-1.29]) but the risk increased significantly for 5-9 years of use (OR=
2.72[1.36-5.46]) and for 10+ years (or=4.48[2.24-9.36]). The evidence for an association of
cervical cancer with the use of oral or other hormonal contraceptives is not entirely consistent.
A number of studies that investigated HPV positive women found no associations or only
weak associations in subgroup analyses. These apparently conflicting results may reflect the
increased cytological surveillance of women that are taking OCs in developed countries and
the use of different case definition (from ASCUS upto HSIL / CIN3 as opposed to cervical
cancer) in cohort studies.
PARITY: HPV positive women who reported seven or more full term pregnancies had a
four-fold increased risk of cervical cancer as compared to similar HPV positive women that
were nulliparous (OR: 3.8, 95% CI 2.7-5.5). There was still a two-fold increased risk when
women reporting 7 or more pregnancies were compared to HPV positive women who
reported 1-2 full term pregnancies. Similar results were obtained in Costa Rica and Thailand
as well as among women with pre-invasive disease in the Portland cohort study. In Denmark
and in the Manchester cohort study, two populations with low parity, the effects are less
visible.
Recommended reading:
1. Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal relation between human
papillomavirus and cervical cancer. J Clin Pathol 2002;55:244-65.
2. Moreno V, Bosch FX, Munoz N, Meijer CJ, Shah KV, Walboomers JM et al. Effect of
oral contraceptives on risk of cervical cancer in women with human papillomavirus
infection: the IARC multicentric case-control study. Lancet 2002;359:1085-92.
3. Muñoz, N., Franceschi, S., Bosetti, C., Moreno, V., Herrero, R., Smith, J.S., Shah, K.V.,
Meijer, C.J.L.M., Bosch, F.X., for the International Agency for Research on Cancer
(IARC) Multicentric Cervical Cancer Study Group., 2002. Role of parity and human
papillomavirus in cervical cancer: the IARC multicentric case-control study. Lancet 359,
1093-110
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SS10-03
UPDATE ON MEN'S ROLE
Castellsagué Xavier, F. Xavier Bosch
Institut Català d’Oncologia, Servei d’Epidemiologia i Registre del Càncer, L’Hospitalet de Llobregat, Spain
Experimental, clinical, and epidemiological evidence strongly suggests that genital HPVs are
predominantly sexually transmitted. As with any other sexually transmitted disease men are
implicated in the epidemiological chain of the infection. Penile HPVs are predominantly
acquired through sexual contacts. Sexual contacts with women who are prostitutes play an
important role in HPV transmission and in some populations sex workers may become an
important reservoir of high-risk HPVs. Acting both as "carriers" and "vectors" of oncogenic
HPVs, male partners may markedly contribute to the risk of developing cervical cancer in
their female partners. Thus, in the absence of screening programs, a woman's risk of cervical
cancer may depend less on her own sexual behavior than on that of her husband or other male
partners. Although more rarely than women, men may also become the "victims" of their own
HPV infections as a fraction of infected men are at an increased risk of developing penile and
anal cancers.
Male circumcision status has been shown to reduce the risk not only of acquiring and
transmitting genital HPVs but also of cervical cancer in their female partners.
This presentation will review further recently accumulated evidence showing the importance
of the male role in cervical carcinogenesis.
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SS10-04
NATURAL HISTORY STUDIES
Schlecht Nicolas F
Albert Einstein College of Medicine, Epidemiology & Social Medicine, Bronx
Although few would dispute nowadays that human papillomavirus (HPV) infection is the
central cause of cervical cancer, most of the epidemiologic data have come from
retrospective, case-control studies, which do not provide information on the dynamics of
exposure to cervical HPV infection. In the natural history of the disease, preinvasive lesions
of cervical neoplasia can be transient and reoccur over time. Women may develop low and
high grade squamous intraepithelial lesions (SILs); LSIL may progress on to HSIL and cancer
or may regress back to a normal state. While the likelihood of a lesion persisting or
progressing to cancer may be dependent on the characteristics of HPV infections, the strength
of the observed association with HPV can be influenced by methodological issues such as the
measure of cumulative exposure used in the study design. Natural history studies must
likewise contend with issues of misclassification and bias. To date, cohort studies of HPV and
SIL have differed in the frequency with which subjects are re-evaluated over time, the HPV
testing and cervical cancer screening methods employed, as well as in the time elapsed
between these measurements. While all of these studies support a causal relationship between
HPV and incidence of SIL, there is a lack of consensus on the magnitude of the effect and
little is known about the possible waning risk over time. Longitudinal studies with repeated
measures present a unique challenge for the statistical analysis of observational data and the
investigation of disease associations due to the inherent correlation between measures.
Considering the public health and economic importance of cervical cancer and the current
widespread interest in the development of HPV vaccines and in using HPV testing to augment
existing cytology screening programs there is a clear need for prospective, long-ranging
multidisciplinary studies of the natural history of HPV infection as it progresses to preinvasive cervical lesions.
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SS10-05
OTHER STDS ISSUES
Smith John
Royal Hallamshire Hospital, Dept Histopathology & Cytology, Sheffield, UK
Whilst there is strong evidence that HPV is the principal aetiological agent in cervical
neoplasia 1, some other sexually transmitted agents may either contribute to or protect against
cervical carcinogenesis.
Epidemiological studies suggest herpes simplex virus (HSV) may have a role in cervical
neoplasia, but there is no clear supportive experimental evidence. Two hypotheses have been
devised to explain this: the "hit and run" hypothesis 2 and synergism between HSV and HPV
3. Of these there is more epidemiological and experimental support for the latter.
Serological studies have revealed no difference in prevalence of antibodies to
cytomegalovirus (CMV) and Epstein-Barr virus (EBV) between patients with cervical cancer
and controls, and assessment of exposure by culture and special stains showed no differences
between cases and controls for HSV2, CMV, Chlamydia trachomatis, Neisseria gonorrhoeae,
Gardnerella vaginalis, Ureaplasma ureolyticum, Mycoplasma hominis, and Candida albicans
4. However longitudinal seroepidemiological studies have provided evidence that Chlamydia
trachomatis is an independent risk factor for the development of cervical squamous carcinoma
and this association is serotype specific 5.
The increased risk of cervical neoplasia in patients infected with HIV has been recognised for
over a decade and HIV may interact with HPV either by altering HPV gene transcription or
by immunosuppression 6.
Finally extensive experimental and limited epidemiological evidence suggests that adenoassociated viruses (AAV) have antioncogenic activity in man and may protect against the
development of cervical cancer. At present the mechanism of this action is unclear but may
relate to AAV-induced regulation of HPV gene expression and the HPV life cycle 7.
References
1. Bosch FX, Lorincz A, Munoz N et al. The causal relation between human papillomavirus
and cervical cancer. J Clin Path 2002; 55: 244-65.
2. Galloway DA, McDougall JK. The oncogenic potential of herpes simplex viruses: evidence
for a "hit and run" mechanism. Nature 1983; 302: 21-24.
3. Zur Hausen H. Intracellular surveillance of persisting viral infections: human genital cancer
results from deficient cellular control of papillomavirus gene expression. Lancet 1986; ii:
489-491.
4. Guijon FB, Paraskevas M, Brunham R. The association of sexually transmitted diseases
with cervical intraepithelial neoplasia: a case-control study. Am J Obstet Gynecol 1985; 151:
185-190.
5. Antilla T, Saikku P, Koskela P et al. Serotypes of Chlamydia trachomatis and risk for
development of cervical squamous cell carcinoma. JAMA 2001; 285: 47-51.
6. Southern SA, Herrington CS. Molecular events in uterine cervical cancer. Sexually
Transmitted Infections 1998; 74: 101-109.
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7. Agrawal N, Maine M, Chiriva-Internati M et al. Temporal acceleration of the human
papillomavirus life cycle by adeno-associated virus (AAV) type 2 superinfection in natural
host tissue. Virology 2002; 297: 203-210.
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SS10-06
ADVANCES AND PERSPECTIVES IN HPV VACCINES
Franceschi Silvia
International Agency for Research on Cancer, Unit of Field and Intervention Studies, Lyon
Every year approximately 25,000 women in the European Union (EU) develop cervical
cancer. A dozen types of human papillomavirus (HPV) have been identified in 99% of biopsy
specimens from cervical cancer worldwide and, in Europe, HPV 16 has been reported in 56%
of over 3,000 cervical cancer specimens (Clifford et al., in press). Five HPV types (HPV 16,
18, 31, 33, 45) account for more than 85% of European cervical cancer specimens. In control
women, the prevalence of the indicated HPV types is several dozen-fold lower. There is no
effective medical treatment against HPV, but very sensitive and specific tests for the detection
of HPV DNA in cervical cells have become available. There is sufficient evidence for
recommending HPV testing among women who show borderline or low-grade cytological
abnormalities. Additionally, HPV testing improves the follow-up of women who have been
treated for cervical intra-epithelial lesions (CIN) and, pending results of ongoing trials, may
offer a more sensitive alternative to cytology in primary cervical cancer screening. A
prophylactic vaccine, based on late (L) 1 HPV 16 proteins, has been shown to be safe, highly
immunogenic, and efficacious in preventing persistent HPV infections in a trial of 1523 HPV
16-negative young women in the United States (Koutsky et al., 2002). A multivalent vaccine
against the most common oncogenic HPV types may thus ultimately represent the most
effective way to prevent cervical cancer worldwide alone or in combination with screening.
Vaccination would benefit women who do not attend screening programs in the EU and, if
combined to current screening programs, it would allow substantial savings (i.e., less frequent
screening tests, fewer treatments, etc.). In developing countries, it would be important to start
as soon as possible a few large randomized trials in order to demonstrate the effectiveness of
HPV vaccine in field conditions, i.e., in those points of the world which do not have the
resources to mount effective cervical screening programs, yet suffer the major burden of
mortality from cervical cancer.
References:
Clifford GM, Smith JS, Plummer M, Muñoz N, Franceschi S. Human papillomavirus in
invasive cervical cancer worldwide: a meta-analysis. Br J Cancer (in press)
Plummer M., Franceschi S. Strategies for HPV prevention. Virus Res (special issue) (in press)
Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, Chiacchierini LM,
Jansen KU for the Proof of Principle Study Investigators. A controlled trial of a human
papillomavirus type 16 vaccine. N Engl J Med 2002;347:1645-1651
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SS10-07
HPV TRANSMISSION IN FAMILIES
Syrjänen Stina
Institute of Dentistry , Faculty of Medicine
Human papillomavirus (HPV) infections in the genital tract are regarded as a sexually
transmitted disease (STD). Because of the fact that also a non-sexual transmission of both
high- and low-risk mucosal HPV types has been recently documented in adults and children,
there is an urgent need for studies on the exact modes of HPV transmission in the families.
HPV infections of the larynx and oral mucosa are regarded as typically paediatric diseases.
The potential modes of transmission of these pediatric HPV infections include perinatal
transmission, auto- and hetero-inoculation, sexual abuse and possibly, indirect transmission
via fomites. In the early days, it was thought that genital warts in children are all contagious.
It was subsequently reasoned, that childhood sexual abuse might be the most common mode
of viral transmission in such cases. However, the most recent data suggest that perinatal
infections and auto- or heteroinoculation may be much more prevalent than previously
expected. More recently, Sonnex and coworkers (1999) showed that both men and women
with genital HPV infections might harbour detectable amounts of HPV also in their fingers,
thus favouring the possibility for a non-sexual transmission of HPV. Accordingly, anogenital
warts in children have been shown to develop as a result of hand warts of his/her own, or
those of their adult household members via non-sexual contacts. By the end of 1997, a total of
268 anogenital warts in children have been analysed for the presence of HPV DNA in the
literature. HPV types 6/11 were the most prevalent (55%), followed by HPV types 1-4
(11.6%) and HPV 16 (3.8%). There is also evidence that HPV transmission might take place
through tanning beds, exposure to gymnasium showers, shared objects, bath towels or bathing
and even through underwear. During the past few years, increasing evidence supports the
view that the child can acquire HPV infection from an HPV infected birth canal of the mother
during the vaginal delivery. Intrauterine transmission or post-natal acquisition seem to be
possible as well. Debate continues as to the frequency of asymptomatic infections developed
as a result of vertical transmission. These data are of particular conceptual significance, with a
number of important implications e.g. in disease prevention and planning of HPV vaccination
programmes.
Also an accurate elaboration of the predominant modes of acquisition of anogenital warts in
children is of particular importance, because of the implications that the diagnosis of genital
wart data might arise the necessity for child-protective services. In 1998, we started the
Finnish HPV Family Study, which is a prospective follow-up (cohort) study, designed to
assess the prevalence of high-risk HPV infections in parents and neonates. The main aim is to
improve our understanding on the modes of HPV transmission as well as on the clinical
significance of HPV infections acquired in utero, at birth or during the early post-natal period.
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SS10A-03
CERVICAL CANCER SCREENING IN EUROPE: DATA ON
SEVEN/EIGHT YEARS OF FOLLOW-UP IN DENMARK
Kjaer SK (1), Svare EI (1), Munk C (1), Junge J (2), Iftner T (3)
(1) Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark, (2) Hvidovre
Hospital, Department of Pathology, Copenhagen, Denmark, (3) University Clinic Tuebingen, Section
for Experimental Virology, Tuebingen, Germany
Even though cytological screening has reduced the cervical cancer incidence, the success is
based on repeated testing and intensive follow-up. It has been suggested that adding HPV
testing would safely allow screening less often.
In 1991-93 we established a cohort of some 11,000 Danish women (20-29), randomly chosen
from the general population. The participants had a gynaecological examination with a Pap
smear and a cervical swab for detection of human papillomavirus (HPV) DNA. In addition,
they were interviewed about potential cervical cancer risk factors. All women in the cohort
were invited for a second visit two years later, and 8656 women participated. Again, the data
collection included a personal interview as well as a cervical cytological examination and a
cervical swab.
Based on data from the second phase, we randomly selected 2920 women who were
cytologically negative and HPV negative, and these were invited for another examination.
From October 2001 to June 2002, we included a total of 2352 women (81%), the data
collection being identical to those in the first two phases of the study. At this point, the
women were 29-40 years of age (median age: 35 years). The follow-up time since the second
examination ranged between 7.1 years and 8.8 years (median follow-up time: 7.8 years).
A total of 131 women participated with an interview only, leaving 2221 women for study. At
the third examination, 39 women had an abnormal smear, covering 18 women with
atypia/mild dysplasia/ unclassified dysplasia, 12 moderate/severe dysplasias, 7 women with
CIS, and 2 women with squamous cell cervical cancer. The HPV prevalence in women with
normal cytology was 8.8%, 56% in atypia/mild dysplasia/ unclassified dysplasia, 83% in
moderate/severe dysplasia, 86% in CIS and 100% in the cancers.
The cohort has been linked to the Pathology Data Bank, which is a nationwide register
containing information on all (normal and abnormal) cytological and histological
examinations at least 20 years back in time.
Results from the linkage related to follow-up time and HPV results will be presented.
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SS10A-04
HPV TESTING IN PRIMARY SCREENING WITH HYBRID CAPTURE
II: AN EXPERIENCE OF 5 YEARS IN A FRENCH POPULATION.
Clavel C(2), Bory JP (1), Cucherousset J(2), Lorenzato M(2), Gabriel R(1), Quereux C(1),
Birembaut P(2).
1. Department of Obstetrics and Gynecology. C.H.U. de REIMS. France - 2. Laboratoire Pol Bouin.
C.H.U. de REIMS. France.
The aim of this study was to determine whether high-risk HPV (HR-HPV) DNA detection in
primary routine screening could represent a sensitive and reliable technique for the detection
of high-grade squamous intraepithelial lesions (HGSIL).
Laboratory analysis using conventional (CC) and liquid-based cytology (LBC), HPV testing
with Hybrid Capture II assay (HCII), followed by colposcopic examination of women with
abnormal cervical finding and/or persistent HR-HPV infection was conducted in 10 569
women who had routine cervical examination. Women with normal smears without HR-HPV
infection (negative control population) were also included.
The sensitivity of HPV testing for detecting a histologically proven HGSIL was 100.0% and
97.5%, higher than that of CC (72.7%) and LBC (80.3%). The low specificity of 87% of
HPV testing was slightly increased to 89.5% if HPV testing was reserved to women > 30
years old. The negative predictive value of the HPV testing was close to 100%. In that
particular approach, we monitored by cytology, HR-HPV testing, colposcopy and biopsy,
3091 women with normal smears at the first entry. In our population of 659 HR-HPV
infected women, 241 (36.6%) had a positive HR-HPV test at 2 to 4 examinations with a final
histological diagnosis of HGSIL in 51 cases (21.2%) within 4 to 36 months, while women
with regressive HPV infection did not develop any lesion during the same period. In the
cohort of 2432 women testing negative for HR-HPV infection, only 2 women (0.08%)
developed a HGSIL. Both were HR-HPV positive 18 and 24 months after the first entry, at
the time of diagnosis of disease. The RR of incident HGSIL when a HR-HPV was detected at
enrollment in women with normal smears, was 96.7 (95% CI, 95.8-97.7). The RR increased
to 237.3 (95% CI, 222.8-251.8) when the HR-HPV test remained positive at 2 controls, and
to 314.3 (95% CI, 260.7-367.9) when the HR-HPV test was positive at 3 controls. The
evaluation of the viral load of HR-HPV by the HC-II did not represent a sensitive approach to
predict the recurrence of HR-HPV infection and/or the apparition of HGSIL. Nevertheless, a
recurrent HR-HPV infection detected with HC-II represents a reliable tool to select
populations at risk for the development of HGSIL.
HR-HPV testing could be proposed in primary screening of HGSIL in association with
cytology. It significantly improves the detection of HGSIL especially with CC. A positive
HR-HPV test selects population of women at high risk for developing HGSIL. Considering
the high specificity of LBC in our series (94.8%), cytology on the same sample could be only
performed in this population. In another way, a negative HR-HPV test selects populations at
low risk who could benefit a different algorithm of screening of 2 to 3 years.
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SS10A-05
PRIMARY SCREENING FOR HUMAN PAPILLOMAVIRUS
INFECTION
Dillner Joakim
Dept. of Medical Microbiology, University Hospital, 205-02 Malmö, Sweden
Primary screening for HPV is the use of HPV testing that has the greatest inherent potential to
further reduce the incidence of cervical cancer. It is, however, important that evaluations of
primary HPV screening are designed in manner that will evaluate maximally cost-effective
HPV screening strategies under real-life conditions.
The Swedescreen randomised HPV screening trial evaluates a "once in a lifetime" HPV
screening strategy targeted to women 35 years of age. The trial started in 1997 and enrolled
12542 women 32-38 years of age attending the population-based organised invitational
cervical screening programme in Sweden.6265 women were randomised to the HPV testing
arm. By GP5+/6+ PCR-EIA with subsequent HPV typing, 433 women (6.9%) were positive
for any one of 14 oncogenic HPV types. 21% of these women were already referred to
coloposcopy because of CIN in the concomitantly taken Pap smear. The HPV-positive
women with normal Pap smears were invited to a new HPV test at least 12 months later (on
average 18 months) together with an equal number of women chosen at random from the
control arm. 81% of these women attended. Among the women in the testing arm, persistent
positivity for the same HPV type was found among 44.4% of the women. Thus, by restricting
the age group eligible for HPV testing and testing for persistent HPV positivity for the same
HPV type, only 1.9% of the population was referred to colposcopy because of the HPV
screening (2.4% if there had been complete attendance). An equal number of control women
were also referred. Colposcopy was performed with both colposcopists and women blinded to
HPV status. 60% of women with HPV persistence and 41% of control women had some
abnormal colposcopic finding. All 16 cases of histopathologically confirmed CINII/III and
8/10 cases of CINI were detected among women with abnormal colposcopy. Koilocytosis was
a common finding, but was neither related to the HPV test nor to the colposcopy. Among
women with HPV persistence, 8 (11%) had CINIII, 7 (10%) had CINII and 6 (8%) had CINI.
Among population-based control women, 1 (1%) had CINIII and 4 (6%) had CINI.
The predictive value of HPV persistence for detection of CINII/III among 32-38 year old
women with a normal Pap smear is 21%. Only few lesions were detected in blind biopsies,
indicating that colposcopy is adequate for detection of high grade CIN also among women
with high risk HPV persistence having had normal smears.
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SS10A-06
THE MISCAN MODEL: EXPERIENCE FROM THE DANISH TRIALS
COOL Thomas
The objective of the ECCC project is to develop mathematical models of HPV/cytology based
cervical cancer screening protocols for the evaluation of the health and cost-benefits for EU
member states. The long-term performance of a combined HPV/cytology regimen on a
country-specific basis is established from screening trials that are running in 6 different
European countries and combined at a European level. In addition, the costs of existing
cervical cancer screening programs and related healthcare actions are collected. These data
then will be used to develop mathematical models that will be used to evaluate clinical
outcomes and healthcare cost benefits for different scenarios. The modelling group at
Erasmus MC will use the MISCAN model for this. The outcome of this analysis will be used
to develop interim, fully costed, country- and EU-specific cervical cancer screening protocols,
which will be used to start an informed debate leading to the development of a new European
consensus policy for screening of cervical cancer. At this stage, we can look at the results of
the Danish trials so far. The MISCAN modelling approach will be compared with other
modelling approaches.
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SS11-01
IMMUNOBIOLOGY OF HPV INFECTIONS
Stanley Margaret
University of Cambridge, Pathology, Cambridge
HPV infection in the genital tract is common in young sexually active individuals, the
majority of whom clear the infection without overt clinical disease. Those who develop
lesions, in most cases, mount an effective mediated immune response and the lesions regress.
Regression of ano-genital warts is accompanied histologically by a CD 4 T cell dominated
Th1 response, animal models support this and provide evidence that the response is
modulated by CD4 T cell dependent mechanisms. The central importance of the CD4 T cell
population in the control of HPV infection is shown by the increased prevalence of HPV
infections in individuals immunosuppressed either as a consequence of organ transplantation
or HIV infection. Although it seems clear that the CD4 T cell sub set is critical for the
induction and regulation of the host response to HPV the nature of the effector response
remains obscure.
There is increasing evidence that both NK cells and antigen specific CTLs are important
effectors but these responses are poorly understood.
Humoral responses to the capsid proteins accompany the induction of successful cell
mediated immunity and these responses are certainly protective against subsequent viral
challenge in natural infections in both animals and humans suggesting that prophylactic
immunisation against the capsid protein will be effective in controlling HPV induced genital
disease. If the cell mediated response fails to induce lesion regression and viral clearance then
a persistent viral infection results which, in part, is due to operational immune tolerance. This
seems to be reflected by the detection in vitro, in persistently infected individuals, of
enhanced cellular and humoral responses to early viral proteins but the failure to clear virus in
vivo.
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SS11-02
T CELL RESPONSES AND ANTIGEN PROCESSING IN CERVICAL
CANCER
Man Stephen
University of Wales College of Medicine, Section of Infection and Immunity, Cardiff
Many laboratories are engaged in development of therapeutic vaccines for cervical cancer.
These vaccines aim to induce cytotoxic T lymphocytes against the E6 and E7 oncogenes
expressed in HPV transformed cells. However there has been little study of how these cells
actually process and present HPV E6 and E7 proteins to CD8+ CTL. We have shown that
some cervical carcinoma cell lines fail to present certain CTL epitopes derived from HPV or
from influenza M1. This correlates with low level expression of HPV E6 and of molecules
involved in MHC class I antigen processing. However these defects do not affect the
processing and presentation of a CTL epitope derived from HPV16 E711-20. This dichotomy
in presentation of HPV derived peptides to CTL has implications for vaccine design. Effective
therapeutic vaccines should preferentially boost CTL responses against epitopes actually
presented by cervical carcinomas.
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SS11-03
RELATIVE IMMUNOGENICITIES OF HPV16 ANTIGENS IN WOMEN
WITH DIFFERENT DEGREES OF CERVICAL DYSPLASIA
STEELE J (1), MANN C (2), ROBERTS S (1), LUESLEY D (2), GALLIMORE P (1).
(1) CRUK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, B15 2TT,
UK, (2) Dept. of Gynaecological Oncology, Birmingham Womens Hospital, Edgbaston, Birmingham,
B15 2TG, UK
The design of effective immunotherapies for high risk HPVs requires a greater understanding
of the mechanisms whereby viral antigens expressed within localised epithelial lesions are
accessed by the immune system. We have assessed the relative immunogenicities of HPV16
antigens expressed at different stages of the virus life cycle, and therefore in epithelial cells at
various stages of differentiation, in women with different degrees of cervical dysplasia. We
have focussed on five proteins: E6 and E7, which are made early in basal/parabasal cells, E4,
which is made suprabasally in differentiating cells, and L1 and L2, late proteins which do not
appear until the infected keratinocyte reaches the highly differentiated upper spinous layers.
Method: Using HPV16 VLPs as a source of L1/L2, and overlapping 30-35mer peptides
covering the sequences of the other proteins (HPV16 E6, E7, and E4), we have screened
CD4- and CD8-enriched populations of cells from 41 women with varying degrees of cervical
dysplasia using ELISPOT assays of IFN-gamma release. Significantly, cells were used
directly ex vivo without undergoing in vitro restimulation.
Results: We demonstrated T cell reactivity in the majority (78%) of samples. CD8+ T cell
reactivity was detected more frequently (30/41) than CD4+ reactivity (16/41). The women
with no CIN or cervical cancer were more frequent CD4 responders than those with low and
high grade disease (no CIN 50%; low grade 37.5%; high grade 25%; cancer 60%). There was
a dominant CD8+ T cell response to peptides covering E6, with 93% of the CD8 positive
samples demonstrating this reactivity.
Conclusions: Our results suggest that there are significant differences in how viral antigens
are handled by the immune system during progressive disease of the cervix. The absence of
CD4 reactivity during progressive disease suggests that the CD4+ T cell response is critical
for HPV clearance. Since the dominant CD8+ T cell response to E6 was present across all
disease grades, E6-specific CD8+ T cells may be less important. Whether the differences in
relative immunogenicities of the HPV16 antigens revealed in this study reflect changes in the
antigen-processing and presenting function of cervical epithelial cells at different stages of
differentiation is currently under investigation.
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SS11-04
THE ANTIBODY RESPONSE IN HUMAN PAPILLOMAVIRUS
INFECTIONS
Dillner Joakim
Laboratory Medicin, Dept. of Medical Microbiology, MAS University Hospital, Malmö, Sweden
The antibody response to papillomavirus VLPs is a key determinant of protective immunity.
Most human antibodies against HPV16 VLPs can be blocked by the neutralising monoclonal
antibody (H16.V5). Transferring the segments of the capsid protein that encode the V5
binding site between different VLPs have suggested that the major serologic reactivity against
HPV is directed towards the C-terminal part of the protein and that the H16.V5 binding site
appears to be a major serologically reactive epitope of HPV16.
HPV VLP serology is also an important epidemiological tool for the assay of past and present
HPV infections and for prediction of HPV-associated cancers and their precursor lesions.
HPV serology is preferable in epidemiological studies where an understanding of the
cumulative exposure to HPV, rather than mere point prevalences, is desired. Another major
application of serology is in transmission studies, where serology can provide information on
whether presence of virus DNA reflects mere contamination or a biologically relevant
infection. As a marker of cumulative exposure, HPV seroepidemiology has been used to
elucidate the spread of HPV infection in various populations, the natural history of HPV
infection and that exposure to HPV per se is associated with increased risk for several human
cancers in addition to cervical cancers. Several prospective studies have implicated HPV16
infection as a major cause of also vulvar, vaginal, anal, penile, fingertip, tongue and tonsillar
cancers.
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SS11-8a
CLINICAL ASPECTS OF IMMUNOLOGY
Moscicki Anna-Barbara,
With the onset of new technologies, there have been striking advances in our knowledge of
the host immune response to HPV. Studies strongly suggest that neutralizing antibodies at the
cervical and systemic level are important in preventing primary infection. Recent vaccine
trials using VLPs as the stimulating antigens document not only protection but the induction
of high levels of antibodies. Studies have also shown that cell-mediated immunity is most
likely critical in controlling HPV infection. That is, women with HPV persistence most likely
have cell-mediated immune dysfunction. This has been underscored by the difficulty of
treating HPV-related disease in HIV infected women and men. Study of persons with HPV
clearance will give us important insight into regulatory mechanisms of HPV and important
antigens/eptiopes. Therapeutic vaccines based on using early proteins as antigenic stimuli are
promising. Studies of cervical immunity have been consistent with the cell-mediated immune
response theory in that Th1 cytokines seem important in eliminating HPV from cervical
tissue. Therapies that stimulate the Th1 pathway should be promising.
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SS11-8b
CLINICIAN PANEL: TRANSLATING IMMUNOLOGY INTO THE
PRACTICE
Isabelle Bourgault Villada
Human papilloma virus (HPV) infections are controlled by cellular immunity. Several clinical
observations strengthen this assertion such as the increase of HPV infection in immunocompromised patients with T cell immune defects. In addition, in spontaneously regressive
HPV diseases as condylomas or cutaneous warts, T cell infiltrates are observed at the site of
the clearance of lesions and both CD8 and CD4 T cells are involved in the elimination of the
HPV-infected keratinocytes. A good knowledge of HPV viral cycle as well as the
immunological mechanisms implicated in host defense of the HPV-infected individuals
allows us to understand and modify the immunological responses during the treatment or the
prevention of such diseases. Two clinical applications directly derived from such
understanding are local therapy with imiquimod and vaccine development against HPV 16.
1- Local therapy with imiquimod demonstrated its efficacy in condylomas with total clearance
of the lesions in 33% of male and 72% of female patients after 16 weeks of treatment. This
efficacy has been correlated to an increase of in situ mRNA of Th1 cytokines such as IL12,
IFN and TNF . Nevertheless, To date, implication of immune specific T cell responses has
not been proved.
2- Vaccination against HPV was recently tested in human and has shown a true efficacy for
the prevention of HPV 16 primo-infection. Virus like particles administrated intramuscularly
as vaccine induce high titers of anti-VLP antibodies which are able to protect against HPV 16
mucosal infection. This type of vaccine could be capable of eradicating the oncogenic viruses
in the near future but is not the ideal means to eliminate previously HPV-infected
keratinocytes. Other types of vaccine are therefore currently under investigation.
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SS12-01
EPIDEMIOLOGY AND PATHOGENESIS OF HPV AND CIN IN HIVPOSITIVE WOMEN
HEARD Isabelle
Hop. Eur. G. Pompidou, Paris
Epidemiologic and laboratory studies have shown that the association of human
papillomavirus (HPV) with cervical cancer is strong, independent of other risk factors and
consistent in several countries. Cancer-associated HPV types are detected more frequently in
HIV positive than in HIV negative women. HPV infection is furthermore characterized by
high viral load and infection with multiple HPV types. HIV-infected women are also more
likely to demonstrate persistence of HPV infection over time. Advanced HIV disease is the
strongest independent risk factor for cancer-associated HPV infection. Several reports
including cross-sectional, case-control and cohort studies have indicated a high prevalence of
abnormal cervical cytological findings, ranging between 20 and 40%, in HIV-1 infected
women. The presence of SIL was shown to correlate with HPV infection and HIV-induced
immune compromise. Spontaneous regression of low-grade SIL, which occurs in 60% of HIV
negative women, is three time less frequent in HIV positive women and progression of lesions
to high grade SIL is more frequent. Up to now, the impact of highly active antiretroviral
treatment (HAART) on cervical disease has been poorly documented and controversial data
have been published. HAART was associated with a beneficial effect in some studies,
whereas it was not in others.
Standard surgical treatment for SIL is associated with a success rate of 95%. Therapeutic
results for SIL in HIV-infected women have been less predictable with rates of
persistence/recurrence ranging from 39% to 56%. Incomplete ablation of cervical disease may
account for the difference in treatment outcome. Recurrence is also highly related to
immunodeficiency, reaching 90% in severely immunocompromised women.
Case reports of unusual cervical cancers in AIDS patients led to the inclusion of cervical
cancer as an AIDS defining illness by the CDC in 1993. Nevertheless, the role of HIV in
invasive cervical cancer (ICC) development is not clear. Data published in 1998 showed a
non-significant increase in cervical cancers in HIV positive women. Data from AIDS and
cancer registries in the USA found a significantly increased overall risk for in situ (RR=4.6;
95%CI 4.3-5.0) and for invasive cervical cancer (RR=5.4; 95%CI 3.9-7.2). In several studies
the degree of immune suppression was not associated with cervical cancer. There was no
significant change in the incidence rate for cervical cancer since the widespread use of
HAART in developed countries (RR=1.97; 95% CI 0.77-4.56). It is unknown whether
screening practices for this cancer changed in HIV-infected women since the introduction of
HAART. The major risk factors associated with cervical cancer detection are similar in HIVpositive and HIV-negative women and include lack of screening and prolonged duration of
symptoms. Some investigators also reported a higher risk of ICC in injecting drug users.
Given the higher prevalence and progression rate of cervical precancerous lesions in HIVpositive women and the altered response to treatment, HIV-positive women should have a
complete gynecologic examination, including a Pap test and pelvic examination as part of
their initial HIV evaluation.
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SS12-03
EFFECT OF HAART ON CIN
Money Deborah
University of British Columbia, Dept Obstetrics and Gynaecology, Vancouver, Canada
Cervical intraepithelial neoplasia (CIN), cancer of the uterine cervix, and of the anus are
associated with HPV infection by oncogenic types. Most HIV infected women are
concurrently infected with HPV. Oncogenic HPV types, 16,18,31,33,45 and 52 have been
most associated SIL, and are implicated in both cervical dysplasia in both HIV infected and
uninfected women. Most studies suggest that HIV infected women have higher rates of
squamous intraepithelial neoplasia (SIL) of the cervix.
Highly active antiretroviral therapy, HAART, has resulted in immune reconstitution and
increased survival and time to AIDS in HIV infected persons. Unfortunately, this immune
response is not complete, and there are often functional memory lymphocyte populations that
are not uniformly restored. This results in questions surrounding the impact of HAART on
other chronic viral infections.
The impact of HAART on CIN has not been fully elucidated. Evidence from the literature is
mixed and does not clearly show benefit of HAART on CIN progression. Small series have
shown reduction in progression and increase in regression with HAART. Some studies have
shown a clear correlation of regression to CDR cell counts without association of clearance of
HPV DNA. However, Italian investigators, have shown an increase in cervical cancer since
the introduction of HAART. The Women's Interagency HIV Study have reported that women
on HAART were less likely show progression of SIL on HAART. The Canadian Women's
HIV study group has shown an association of HAART with regression of SIL, despite
immune suppression. The main concern is that with partial immune reconstitution of HAART,
cervical dysplasia may or may not be favorably affected. In addition, a confounding factor
with the impact of HAART is the sexual behaviour of women and their potential acquisition
of oncogenic HPV over time as they are living longer and in better general health on HAART.
This is clearly critically important to determine for development of future management
guidelines. In the interim, women with HIV infection should be managed with careful
attention to their increased risk of cervical dsyplasia and cancer regardless of use of HAART.
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SS12-04
LONG TERM EFFECT OF HIGLY ACTIVE ANTIRETROVIRAL
THERAPY ON HPV INFECTION AND RELATED LESIONS IN HIV
POSITIVE WOMEN
Flavia B. Lillo (1), Davide Ferrari (2), Sara Lodini (1), Salvatore Reina (3), Franco Ameglio (3),
Maria Angela Grasso (1), Giulia Gallotta (4), Augusto Ferrari (2), Gianluca Taccagni (5), Adriano
Lazzarin (4), Caterina Uberti-Foppa (4)
Laboratory of Virology 1, Department of Obstetrics and Gynecology 2, Department of Statistics 3,
Department of Infectious Diseases 4, Department of Pathology 5 IRCCS San Raffaele Hospital, Milan,
Italy
Bakground: The role of human immunodeficiency virus (HIV) disease in the evolution of
human Papillomavirus (HPV) infection and related cervical pathology is well documented.
HIV-positive women have an increased incidence of biopsies positive for SILs with different
levels of dysplasia, more rapid progression to high-grade SIL and invasive cervicocarcinomas The effect of highly active antiretroviral therapy (HAART) and related
immunereconstitution on AIDS related malignancy has been established for Kaposis’s
sarcoma and primary central nervous system lymphoma but is still a matter of debate as
regards to HPV related ano-genital lesions
Methods: We analysed 154 women longitudinally followed up every 6-12 months in our
gynaecological unit (mean follow-up: 36.4 - 10.4 months) by means of PAP smears,
colposcopy (with biopsy when indicated), and cervicovaginal swabs for the detection and
typing of HPV genomic sequences. CD4 and log-adjusted HIV-RNA values were analysed to
ensure the baseline homogeneity of the patients who were subsequently divided into those
clincally stable (group S) who did not introduce or change therapy, and those with clinical or
virological worsening (group W) who switched to a more potent HAART. The characteristics
of HPV-DNA were evaluated using the Chi-square test, contingency tables and Fisher’s exact
test as necessary.
Results: HR-HPV persistence was observed both in women on-HAART of group S and in
those switching to a more potent therapy (group W) in spite of a significant increase of their
CD4 cell count (p=0.017 and p=0.0001 respectively) and constant (p=0.054) or reduced
(p=0.016) level of HIV viremia. Analysis of variance showed that there was no relationship
between the type of anti HIV therapy and PAP test diagnosis and modification over time. A
significant reduction in positive biopsies was observed among the group S women
(p=0.00008) and in on-HAART women of the same group (p=0.0006). Of note, however, the
number of surgical resections of HgSIL in group S was higher, although not statistically
evaluable (39.4% vs 19.3%).
Conclusion: Our data show that, analysing comparable groups of treatment, HPV related
histological lesions are reduced only in patients on long-term stable clinical picture including
those on effective HAART. The strict surveillance of patients, particularly those with
persistent high risk HPV infection, is still the best preventive scheme for invasive lesions also
in the era of HAART.
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SS12-05
ROLE OF MUCOSAL IMMUNITY IN THE NATURAL HISTORY OF
HPV INFECTION IN HIV INFECTED AND NON INFECTED WOMEN:
PRELIMINARY REPORT
Casolati E, Valieri M., Maffeis G*, Agarossi A, Clerici M.*, Ferrazzi E.
Dept Obstet Gynecol DSC Sacco, *Dept Clin Immunol. DISP Lita. University of Milan. Italy
BACKGROUND: Specific types of Human Papillomavirus are known to play a causal role
in the development of cervical cancer. HPV-associated anogenital malignancies occur more
frequently in HIV positive patients and it has been hypothesised that an impaired immune
response may contribute to the progression of HPV lesions. Cytokines, that modulate
immunologic control, may be of particular importance in regulating tumor growth.
OBJECTIVE: The primary aim of this study was to assess the relative influence of HIV and
HPV infection on mucosal immunity as represented by local cytokine production. The
secondary aim of the study and the association between immune activation and severity of
cervical disease.
METHODS: Cervical biopsies were obtained from 48 patients: 7 HIV-negative/HPVnegative, 16 HIV-infected/HPV-negative, 14 HIV-negative/HPV-infected (with or without
lesions) and 11 HIV-infected/HPV-infected (with or without lesions). IFN γ (cytokine type 1),
IL5, IL10 (cytokine type 2) level were determined by immunoistochemical staining.
RESULTS: In the HPV-negative subgroups, HIV infected women had higher concentration
(p=0.02) of IFN γ and significantly lower concentration of IL5 (p=0.05) compared to HIV
negative patients.
In the HPV-infected subgroups, HIV infected women had lower concentration (p<0.01) of
IFN γ and significantly higher concentration of both IL5 and IL10 (p<0.04)
In the HPV-infected subgroups, HIV negative women higher concentration of IFN γ (p=0.06)
and lower level of IL5.
In HPV-infected HIV infected cases CIN III lesions was associated to increased
concentrations of IL5 and IL10 (p<0.04)
CONCLUSIONS: HPV infection in HIV negative women is associated with increased
production of type 1 cytokines (IFN γ). This modulation enhance cell-mediated immunity.
Coinfection of HPV and HIV results in lower production of type 1 cytokines and, on the
contrary, higher type 2 cytokines (IL5, IL10) which modulates the humoral-mediated
immunity. This latter response is ineffective in controlling HPV infection and related
dysplasia. This interpretation was strengthened by the correlation of the most severe form of
dysplasia with the higher concetrations of type 2 cytokines.
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SS12-08
EPIDEMIOLOGY AND PATHOGENESIS OF AIN IN MEN
Palefsky Joel
UCSF, Medicine, San Francisco
The incidence of anal cancer is up to 35/100,000 among HIV- men who have sex with men
(MSM) and is estimated to be approximately 70/100,000 among HIV+ MSM. Our earlier
studies showed that nearly all HIV+ MSM and 60% of HIV- MSM have anal HPV infection,
often with several concurrent HPV types and almost always with at least one oncogenic HPV
type. The prevalence and incidence of high-grade AIN are also very high, with approximately
one half of HIV+ men showing AIN 2 or 3 at baseline in a recent study. Data on the effect of
highly active antiretroviral therapy (HAART) indicate that HAART has little effect on the
natural history of AIN, suggesting that the incidence of anal cancer may continue to rise if
HIV+ individuals with AIN live longer but are not screened or treated for AIN. Consistent
with this, recent analysis of anal cancer incidence data in San Francisco County show a
continued increase in anal cancer among men aged 40-64 years since 1996 when HAART was
first introduced. More data are needed to define the molecular pathogenesis of AIN and
interactions between HIV and HPV, to determine optimal treatment approaches for AIN and
to confirm that treatment of AIN reduces the incidence of anal cancer. Until then, however,
cost-effectiveness modeling shows that screening and treatment of AIN should be costeffective to prevent anal cancer among both HIV+ and HIV- MSM. Ideally screening
programs will be implemented in a structured environment to permit data collection to
determine the effect of treatment on AIN and on the incidence of anal cancer.
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SS13-03
ADJUNCT TEST TO COLPOSCOPY: THE ROLE OF HPV DNA
TESTING
Ferenczy Alex
McGill University and The Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Canada
Evidence-based data indicate that HPV DNA testing using either the hybrid capture (HC-II)
or PCR technology is superior to sort out those women with pre-existent or at risk for
developing high-grade cervical intraepithelial neoplasia (H-CIN) than both the repeat
cytology programme or screening colposcopy. As such, HPV DNA testing can be used as a
powerful biomarker for detecting precancer and helps to make better and more cost-effective
management decisions in women with cervical cytological abnormalities. At present, there are
four potential indications for HPV DNA testing, although only one has so far been approved
by the US-FDA, i.e. "reflex HPV testing" for managing women with ASC-US. The latter has
been suggested to be the preferred option over repeat cytology and immediate colposcopy for
detecting H-CIN in women with an initial ASC-US Pap test.1 The remaining indications
include post-treatment follow-up and follow-up of colposcopy/histology negative women
whose initial Pap test was reported atypical squamous cells of undetermined significance
(ASC-US), atypical squamous cells rule out high-grade squamous intraepithelial lesion (ASCH), low-grade squamous intraepithelial lesion (LSIL) or atypical glandular cells not otherwise
specified (AGC-NOS), and primary screening at age 30 years and older. In these conditions,
HPV DNA testing is used "off-label". Algorithms for each of the aforementioned indications
are available from the consensus guidelines for the management of cervical cytological
abnormalities1 and personal experience.2
Overall, HPV DNA testing in both primary and secondary screening modes and follow-up
schemes has the potential to make better and more cost-effective management decisions than
the repeat cytology programme or colposcopy. Longitudinal studies are needed to provide
further insight into the diagnostic yield and potential pitfalls of HPV DNA testing before
accepting it as the gold standard for primary screening for cervical cancer and follow-up of
women after therapy and latent HPV infections.
(1. Wright TC, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of
women with cervical cytological abnormalities. JAMA 2002;287:2120-2129.)
(2. Ferenczy A, Franco E. Cervical cancer screening beyond the year 2000. The Lancet
Oncology 2001;2:27-32.)
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SS13-05
TECHNOLOGY ASSESSMENT OF FLOURESCENCE AND
REFLECTANCE SPECTROSCOPY
Milbourne,A. (1) , Benedet,J.L. (3) , Chang,S. (2) , Mackinnon,N. (3) , MacAulay,C> (3) , Follen,M.
(1) , Richards-Kortum,R. (2)
(1) Department of Gynecologic Oncology, UT M.D. Anderson Cancer Center, Houston, TX and
UTHSC, Houston, Texas, (2) Department of Biomedical Engineering. University of Texas, Austin, (3)
Department of Imaging, British Columbia Cancer Center, Vancouver, Canada
Cervical cancer is the second most common cancer in women worldwide and the leading
cause of cancer mortality in women in developing countries. In the United States (U.S.) over
$6 billion are spent annually in the evaluation and treatment of low-grade precursor lesions.
Cervical cancer goes undetected in developing countries because of the cost of the tests and
the lack of trained personnel and resources to screen and diagnose. In the U.S., resources are
wasted on the evaluation and treatment of lesions not likely to progress to cancer. Both the
screening and detection of cervical cancer could be vastly improved by technologies, which
improve, automate, and decrease the cost of screening and detection. The goal of this program
project is to assess the emerging technologies of fluorescence and reflectance spectroscopy
and quantitative cytology and histopathology for the diagnosis of cervical neoplasia. The
program project seeks to address: (1) Biologic Plausibility, by examining the
fluorescence/reflectance and quantitative images of cell lines, tissue cultures, and live tissue
sections; (2) Technical Feasibility, by conducting large screening and diagnostic trials of
fluorescence and reflectance spectroscopy and quantitative cytology and histopathology; (3)
Intermediate Effects, by using the fluorescence and reflectance spectrometer in a randomized
clinical trial; (4) Patient Outcomes, by assessing patient and provider acceptability of
fluorescence and reflectance spectroscopy and quantitative cytology and histopathology; and
(5) Societal Outcomes, by assessing the performance and cost-effectiveness of fluorescence
and reflectance spectroscopy and quantitative cytology and histopathology in the screening
and diagnostic setting. The four cores will support the projects by focusing on (A)
Administration, (B) Biostatistics and Informatics, (C) Instrumentation, and (D) Pathology.
Fluorescence and reflectance spectroscopy could significantly impact care in the U.S. by
decreasing costs, allowing less biopsies to be performed and fewer unnecessary treatments to
occur. Fluorescence and reflectance spectroscopy could significantly impact care worldwide
by providing automated diagnosis at a screening visit by less-trained health care workers.
Quantitative cytology and histopathology could decrease costs in the U.S. if it could better
separate those lesions more likely to progress and in the world by allowing automated
screening which would decrease the need for trained personnel. Emerging technologies
should be evaluated by an approach, which addresses: biologic plausibility, technical
feasibility, intermediate effects, patient outcomes, and societal outcomes. Our group is a
multidisciplinary one including obstetrician gynecologists, gynecologic oncologists,
pathologists, cell biologists, epidemiologists, behavioral scientists, and decision scientists
from The University of Texas M. D. Anderson Cancer Center in Houston, Texas, biomedical
engineers from The University of Texas in Austin, Texas, and biomedical engineers and
gynecologic oncologists from the British Columbia Cancer Agency in Vancouver, British
Columbia, Canada. Preliminary results from a clinical trial of 800 diagnostic patients will be
presented.
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SS13-07
EXPLORING THE CHARACTERISTICS OF A COLPOSCOPY
SCORING SYSTEM
Strander B (1), Franzén S (2), Rådberg T (1)
(1) Dept Obstetrics & Gynecology, (2) Dept Urology, University of Göteborg, Sweden
Aim: To construct a simple and easily understandable scoring system for colposcopic
examination that can facilitate education of colposcopists and increase the accuracy of
evaluation
Materials and methods: Included to date are 169 examinations which have been performed
in women referred for colposcopy according to the current protocol for the Western Region of
Sweden. Histology results were as follows: 27% benign, 20% LSIL, 53% HSIL or cancer.
Five variables were scored: aceto-whiteness, margins & surface, vessels, lesion size and
iodine staining. Each variable could be assigned 1 of 3 ordered values. Exclusion criteria were
post-menopausal, pregnant and puerperal women, and incomplete colposcopy. Multiple
logistic regression was used to assess the ability of each single score to predict HSIL+ in
histology (cone or biopsy)
Results: All five studied variables independently predicted for HSIL or cancer. The analysis
resulted in an ideal weighted scoring system which performed well with respect to sensitivity
and specificity (area under the ROC-curve 0,91). However, the values generated involved
decimal places which reduced the practical use of this system. Rounding off of each weight
gave a more useful and simple scoring system with values of 0, 1 or 2 without any significant
change in the area under the curve, 0,89. The possible total score was then 0 to 10. A score of
³6 points identified all HSIL+ and ³8 points had a specificity of 93%. No patient with HSIL+
in histology scored 0 with respect to aceto-whiteness and margins&surface
Discussion: In a series with a high prevalence of HSIL this colposcopic scoring system safely
identified those with LSIL or normal findings thus allowing 25% to be followed only by
colposcopy or cytology. Furthermore it could select women for see-and-treat without more
than 7% of cases having less than HSIL. With this strategy only about one third of the cases
in this material would have needed biopsy in the evaluation. The performance of this scoring
system in a series with a lower prevalence of HSIL needs further evaluation
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SS13-08
AN AUDIT ON THE FOLLOWUP AFTER THE TREATMENT AFTER
CIN
Ramanathan.P, Kaul.V.
Homerton Hospital, Obstetrics And Gynecology, London, Pinderfields and Pontefract NHS trust,
Yorkshire, United Kingdom.
AIM:To evaluate the standards in the colposcopic follow up after the treatment of Cervical
intraepithelial neoplasia.
STANDARDS: Standards published by the National Health service cervical screening
programme (1)
SETTING: Pinderfield General Hospital and Pontefract General Infirmary, West Yorkshire,
United Kingdom.
METHODS: Retrospective analysis of women diagnosed to have Cervical intraepithelial
neoplasia in histology from October 1999 till October 2001. The North West Yorkshire
Screening agency ,the centralized database was searched for follow up smear results. The
family doctors of patients whose follow up could not be chased have been contacted for the
reason to find the failure to follow up. SUBJECTS: 883 women had treatment at colposcopy
clinics and genitourinary medicine clinics between October 1999 and October 2001.
DATA COLLECTED: 221 out of 883 (25%) had colposcopy for follow up. 557 (63%) had
smears for follow up. 17 (1.9%) had hysterectomy , 87 (9.8%) follow up was not
available.306 (46.2%) had one follow up smear, 182 (27.5%) had 2 smears, 149 (22.5%) had
3 smears. Seventeen cases (2.5%) had 4 smears and 7 (1.0%) had 5 smears . 11.4% of cases
had first abnormal dyskaryotic smears. Recurrent Cervical intraepithelial neoplasia after first
abnormal smear was 5%. 210 ladies had colposcopy for followup after the intial treatment.
Out of them 49 (23.3%) had positive colposcopies and 161 (76.7%) had negative
colposcopies. In positive colposcopies concurrent smear revealed dyskaryosis in 40 out of 49
(81.6%). 5.5% had second smear dyskaryotic during their follow up. Recurrent CIN was
4.4%. 2.9% the third smear was dyskaryotic and Recurrent CIN was 1.4% after third smear. 5
out of 883 (0.56%)had microinvasive carcinoma during follow up. 120 could not be chased in
the hospital database, 55 were chased at the central database. 17 had moved homes. 10 had
treatment at genitourinary medicine clinics . The general practicioners are being contacted for
the reason .
RECOMMENDATION: Communication ,multidisciplinary approach, defaulters protocol
and auditing .
(REFERENCE:1. NHSCP Publication No 2 .Standards and Quality in Colposcopy.)
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SS13-09
IMPLEMENTATION OF FAST TRACK REFERRAL FOR
COLPOSCOPIC EXAMINATION
Kaul Veena
Pontefract General Infirmary, Obstetrics and Gynaecology, Pontefract
Objective-To establish a direct referral system for colposcopic examination
Method: A pilot study of the implementation of a direct referral system for colposcopic
examination. Six GP practices took part in the study. The participants were 70 women with
abnormal cervical cytology who needed colposcopic examination. 35 women were managed
using the fast track referral system, while the other 35 were managed using the traditional
approach of general practitioner referral. The main outcome measures were the time interval
between the smear report and the first offered colposcopy appointment; the number of
patients who cancelled colposcopy appointments and patient satisfaction was measured using
questionnaires.
Results: In the group that had undergone the fast track referral system, there was a
statistically significant reduction in the time interval between the smear report and the first
offered colposcopy appointment time, together with statistically significant reduction in the
colposcopy appointment cancellation rate. Additionally, there was a statistically significant
increase patient satisfaction in the fast track group, while the patient anxiety score was not
significantly different between the two groups.
Conclusion: The results suggest that a fast track referral system for colposcopic examination
offers a more efficient system with which to manage women with abnormal cervical smear
results. The resulting reduction in the time interval between smear reporting and colposcopic
examination allows for greater patient satisfaction and a decrease in non-compliance. These
results were presented at two meeting where local general practitioners were present. Before
the meetings, many GPs were sceptical of the new approach. Since then, with the GP’s
approval, this fast track system of referral has been implemented at a district level.
Author: Kaul, V. Consultant Obstetrician and Gynaecologist, Mid Yorkshire NHS Trust,
Pontefract General Infirmary, Pontefract, England.
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SS13-10
A POPULATION-BASED STUDY OF COLPOSCOPIC FINDINGS
AMONG WOMEN WITH HPV DNA PERSISTENCE
Elfgren K (1), Rådberg T (2), Strander B (3), Paajanen K (4), Sjöberg I (5), Dillner J (6), Rylander
E (7)
(1).Dept of Obstetrics and Gynecology, Karolinska Instutet, Huddinge University Hospital Stockholm,
Sweden (2) Dept of Gynecology, Sahlgren´s University Hospital Gothenburgh, Sweden (3)
Onkologiskt Centrum Sahlgren´s University Hospital Gothenburgh, Sweden (4) Dept of Obstetrics and
Gynecology, MAS University Hospital, Malmö, Sweden, (5) Dept of Obstetrics and Gynecology, Umeå
University Hospital, Umeå, Sweden (6) Dept of Medical Virology MAS University Hospital, Malmö,
Sweden, (7) Dept of Obstetrics and Gynecology, Karolinska Instutet, Danderyds University Hospital,
Danderyd, Sweden.
Background: The predictive value of HPV DNA persistence for CIN development has been
shown in numerous cohort studies.
Aim & Methods: To evaluate population-based screening for HPV DNA persistence, a total
of 12577 women aged 32-38 years attending the population-based invitational cervical
screening program in Sweden were enrolled into a randomised intervention trial. Women
were randomised 1:1 to no test or to HPV testing by GP5+/6+ PCR and subsequent typing.
HPV positive women in the intervention arm (and an equal number of random control
women) were HPV tested again at least 12 months later. 74 women who were positive for the
same type of HPV DNA in both tests and 70 random control women were referred to
colposcopy. Both women and colposcopists were blinded to HPV test results. In case of
normal colposcopic findings blind biopsies were taken.
Results: 57% of women with HPV persistence and 43% of control women had abnormal
colposcopic findings.
19 of 20 cases of histopathologically confirmed CINII/III and 10/13 cases of CINI were
detected among women with abnormal colposcopy. Koilocytosis was a common finding, but
was not dependent on the HPV test or the colposcopy. Among women with HPV persistence,
9 (10%) had CINIII, 10 (11%) had CINII and 8 (9%) had CINI. Among population-based
control women, 1 (1%) had CINIII and 5 (5%) had CINI.
Conclusions: The predictive value of HPV persistence for detection of CINII/III among 3238 year old women having had a normal Pap smear is 20%. Only few lesions were detected in
blind biopsies, indicating that colposcopy is adequate for detection of high grade CIN also
among women with high risk HPV persistence having had normal smears.
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SS14-01
QUALITY STANDARDS IN COLPOSCOPY
Kitchener Henry Charles
University of Manchester, Academic Unit of Obstetrics & Gynaecology, Manchester
Quality in colposcopy means achieving certain standards in practice in order that women can
be sure of a timely and satisfactory examination conducted in a suitable setting. In order to
ensure quality it is necessary to define standards, and to develop the service such that these
standards are adhered to.
Quality in colposcopy requires to take account of the training of the practitioner, the cytology
and histopathology examinations, the standard of communication and information, the
infrastructure of the clinic setting and documentation. Good clinics should also have good
data capture and video facility for the patient and for teaching.
In order to achieve a quality service in a systematic way, quality assurance needs to be
developed using peer reviewed standards which are achievable and based on evidence. These
standards should apply to all aspects as described.
It is important to distinguish between quality and guidelines. Guidelines describe how to
manage clinical problems, quality standards define certain processes and outcomes.
For example "large loop excision should be avoided in a see and treat setting for women with
LSIL" is a guideline, whereas "not more than 15% of women who have LLETZ or LEEP
should have CIN absent from the specimen" is a quality standard.
Ideally quality standards should apply to all colposcopists and National Societies can play a
major role in defining these.
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SS14-04
INVASIVE CERVICAL CANCER: ANALYSIS FROM THE UK
NATIONAL SCREENING PROGRAMME
Walker Patrick
British Society for Colposcopy and Cervical Pathology
The United Kingdom National Health Service introduced a call and recall population based
cervical screening programme in 1988. Since political devolution there are now individual
screening programmes within the National Health Service in England, Scotland, Wales and
Northern Ireland.
Since the introduction of the formal call and recall programme, the NHSCSP has been very
successful in reducing the incidence of cervical cancer from 16 per 100,000 in 1986 to 9.3 per
100,000 in 1997. There has been an increasing fall in mortality from 1-2% per year to 7% per
year. Although this has decreased to 5% in recent times, mortality is now 4.0 per 100,000
compared with 7.3 per 100,000 in 1989.
The major success of the NHSCSP has been achieved because of population coverage. Over
85% of women in the at-risk age group have been screened within the last five years. Because
of this, an increasing proportion of women who do develop invasive cervical cancer will at
some stage have interacted with the screening programme. In measuring the effectiveness of
the screening programme it is important to audit cases where women develop invasive
cervical cancer despite participating in the programme. Audit of their personal history can
yield information. In addition, review of events and specimens from participation in the
programme can highlight valuable learning points for health professionals. It is believed that
the results of such audit activity nation wide, collected over several years, could possibly
yield a great deal of information about the effectiveness of cervical screening in general.
A national audit of invasive cervical cancers presents a complex challenge to healthcare
professionals. Since May 2001 practitioners in the United Kingdom have been advised that
should a woman develop invasive cervical cancer there should be a review of her previous
screening history. The patient should be informed that such a review is taking place and she is
also informed that she can have access to the published results of such a review if she wishes
to request it. There are three major aspects to consider:
1)
A review of the screening history to include details of the patient’s call and recall
history and details of referral and appropriate follow-up. A review of any
gynaecological management, a review of cervical biopsies if performed, a review of
treatment if performed and a review of cervical smears.
2)
There are psychological issues raised about when is the appropriate time to provide
information to the woman and her family that the audit of her history is taking place.
There are also issues about the confidentiality of such a review. There are also issues
about the psychological impact upon the woman of the knowledge of any errors that
may have arisen during the course of her previous management.
3)
There are medico-legal issues that will inevitably arise when providing patients in a
transparent environment about errors that may have occurred during the course of the
management of their individual case.
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For colposcopists it is necessary that each individual case is audited against defined areas of
practice. Guidelines for the Critical Review of Cancer Cases – Colposcopy Audit are yet to be
defined, but the British Colposcopy Society has recommended that the following items should
be recorded:a)
Was the patient seen for colposcopy within a reasonable time, as dictated by the
cervical smear report?
b)
If the patient did not attend following referral, was there appropriate correspondence
with the referring doctor?
c)
If the smear was of a low-grade abnormality and the findings at colposcopy were
normal, was appropriate follow-up arranged for the patient with her primary care
physician?
d)
If the findings at colposcopy suggested low-grade disease, were biopsies taken and if
so how many?
e)
If conservative management was employed rather than treatment, was this appropriate
for the individual patient?
f)
If local destruction techniques were employed, was this in accordance with the criteria
defined by the Royal College of Obstetricians & Gynaecologists in 1981?
g)
If the smear was high-grade, were appropriate biopsies taken or appropriate treatment
implemented? If treatment was arranged, and the new squamo-columnar junction had
not been visible at colposcopy, was the treatment excisional?
h)
Was the size of the treatment biopsy acceptable?
i)
Did the histopathology confirm the status of the excision margins? Was appropriate
follow-up arranged for the patient after treatment?
j)
If the patient did not attend for follow-up after conservative or excisional treatment,
were appropriate measures taken to inform the primary care physician?
k)
If previous treatment had been with local destruction was any second treatment, if
performed, excisional?
l)
If the smear abnormality was glandular, were appropriate steps taken to assess the
endocervix?
m)
If the patient was pregnant at the time of any investigation, was appropriate expert
advice sought?
As can be seen from the above provisional list, which is not exhaustive or exclusive, even the
small colposcopy contribution towards the audit of the case of a woman who subsequently
develops cervical cancer after previous screening is controversial.
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SS14-07
MODELLING COLPOSCOPY SERVICES IN THE UK:
IMPLICATIONS OF THE PROPOSED GUIDELINE CHANGE WITH
RESPECT TO A SINGLE MILDLY DYSKARYOTIC SMEAR
Hadwin Richard
Royal Free Hospital, Department Of Colposcopy, London
Background: In the UK an expert committee has recommended a change in the NHSCSP
guidelines: referral for colposcopy after a single mildly abnormal smear. Concern has been
expressed about the impact of this policy change on colposcopy clinic workload.
Objectives: To model current and expected increase in annual colposcopy clinic workload for
each woman referred with cytology suggesting low grade disease, stratified by type of clinic those with low, intermediate or high intensity use of colposcopy in patient management.
To integrate data from our ongoing study into the use of HPV PCR for modifying follow-up
of patients with biopsy proven low grade disease.
Method: Three types of colposcopy clinic were identified by their respective use of see &
treat policies, early discharge of normal colposcopy to the community, treatment for CIN1
and use of colposcopy post treatment; and the clinics were defined as high, intermediate or
low intensity. Using our own published data and information from published peer reviewed
practice from other centres we produced models for each service in terms of clinic
appointments generated per referral.
Results: By a detailed analysis we are able to show that the number of appointments
generated per patient (c) in each clinic setting is 2.6 for high, 2.0 for intermediate and 1.7 for
low intensity services, giving an equation for the total number (x)
x=n.c where n is the number of patients referred
To calculate the number of new appointments (y), needed for a rise in referrals
y=n. (%increase in referrals/100).c
and x + y is the total number of apointments in the new setting.
At the Royal Free Hospital, 240 patients are currently referred per year with a mildly
dyskaryotic smear, which currently generates approximately 480 appointments per year. A
30% increase in referrals is expected, which would require 144 new appointments as an
intermediate service.
Discussion: To minimize the increased workload it will be necessary to alter the number of
appointments generated per new referral. Change in practice for each type of service to effect
a reduction, using HPV PCR in biopsy proven low grade disease will be presented.
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SS14-08
IMPLEMENTING DIGITAL COLPOSCOPY: HOSPITAL
NETWORKING AND TELECOLPOSCOPY
Pisal N., Tully F., Chow C., Skladnev V.
The Whittington Hospital
Digital colposcopy systems allow integration of patient management on two different levels.
Within the hospital, digital systems in each clinic can be networked and connected to a
centralised database, allowing clinicians to retrieve data from any colposcopy machine linked
into the system. In the future, it is expected that this networking capability will be extended to
link databases between hospitals, facilitating recall of patient data from any site.
Linking a digital colposcopy system to a wider hospital information network offers several
administrative benefits, including the elimination of duplicate entry of patient data. However,
linking different software applications can be challenging, as they often make use of
incompatible technology. Communication protocols are under development to assist in
bridging this compatibility gap.
The ability to keep a permanent record of images, diagnosis, treatment, outcomes and other
data is a particularly useful feature of a computer-based system. The archive can be quickly
searched, analysed, and hard copy reports generated. These reports may be used to ensure that
performance is consistent between colposcopists, clinics and hospitals, and that a suitable
quality of service is being maintained. An example of this type of quality assurance protocol
is the recently introduced KC65 standard in the UK. This standard is used to monitor the
performance of colposcopy clinics, tracing such factors as the number of patients, waiting
times for referral and results, types of procedures and the results of colposcopic
investigations. This information is monitored to ensure consistency and quality of service at
local, regional and national levels. It is expected that similar programs will be adopted in
other national health organisations in the near future.
In conclusion, the digitisation and networking of colposcopic images allows efficient linkages
with patient records to be established. The information can then be centralised, facilitating
patient monitoring and/or follow-up, and quality assurance of the patient management
process.
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SS15-02
MULTISPECTRAL DIGITAL COLPOSCOPY FOR THE DETECTION
OF CERVICAL NEOPLASIA
Milbourne A. (1), Benavides J.M. (2), Chang S. (2), Mackinnon N. (3), MacAulay C. (3), Follen M.
(1), Richards-Kortum R. (2)
(1) Department of Gynecologic Oncology, UT M.D. Anderson Cancer Center, Houston, Texas, (2)
Department of Biomedical Engineering. University of Texas, Austin, (3) Department of Imaging, British
Columbia Cancer Center, Vancouver, Canada
Fluorescence and reflectance spectroscopy have the potential to identify cervical
intraepithelial neoplasia (CIN) in vivo. However, the instrumentation required for in vivo
spectroscopy measurements is usually expensive relative to current diagnostic tools. The goal
of this study was to develop a cost-effective imaging technology to accurately detect premalignant lesions on the cervix. In this presentation we present a multi-spectral digital
colposcope (MDC) that has been developed to measure multi-spectral images of the cervix
using auto-fluorescence, and reflectance. The measured reflectance and fluorescence light was
captured and filtered using a color camera. The spectrum of the measured light was resolved
using the color camera's Cyan Magenta Yellow (CMY) filters. The choice of illumination and
detection wavelengths was based on data from our previous clinical trials using a Fast
Excitation Emission Matrix System (FEEM). In order to predict the diagnostic capability of
the MDC, we simulated the MDC spectral response by multiplying the measured FEEM
fluorescence and reflectance spectra from 351 sites in 146 patients by the camera's CMY
spectral response curves. Then, we applied a classification algorithm to the simulated MDC
spectral response and evaluated the MDC's diagnostic performance for CIN and compared it
to that obtained using FEEM data. After simulating the MDC's spectral response and
diagnostic performance for a combination of two emission spectra at 340nm and 440nm
excitation, we achieved the following results: 93% Se (sensitivity), 83% Sp (specificity) for
Squamous Normal (SN) vs. Columnar Normal (CN); 72% Se, 40% Sp for SN vs. Low Grade
Squamous Intraepithelial Lesions (LG) (SIL); 80% Se, 61% Sp for SN vs. High Grade (HG)
SIL; 61% Se, 87% Sp for CN vs. LG SIL; 28% Se, 50% Sp for SN vs. HG SIL. When
applying the classification algorithm to the FEEM emission spectra at the same excitation
wavelengths we obtained the following results: 90% Se, 89% Sp for SN vs. CN; 66% Se, 35%
Sp for SN vs. LG-SIL; 77% Se, 78% Sp for SN vs. HG SIL; 83% Se, 85% Sp for CN vs. LG
SIL; 39% Se, 50% Sp for SN vs. HG SIL. When using reflectance spectroscopy for CN vs.
HG SIL we achieved 78% Se, 88% Sp for the MDC simulated data and 83% Se and 81% Sp
for FEEM data. We also present in vivo fluorescence and reflectance images of the cervix
measured during a pilot study of 20 patients. We expect that two-dimensional imaging of the
cervix using fluorescence and reflectance excitation conditions best suitable for detection of
lesions can improve optical pre-cancer diagnosis. Preliminary results indicate that this method
is a promising tool for clinical research and non-invasive diagnosis.
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SS15-04
OPTICAL DETECTION OF HIGH-GRADE CERVICAL NEOPLASIA
IN VIVO IN 30 SECONDS
Huh, W.K. (1) , Cestero, R.M. (2) , Garcia, F.A. (3) , Gold, M.A. (4) , Guido, R. S. (5) , McIntyreSeltman, K. (5) , Harper, D.M. (6) , Burke, L. (7) and Alvarez, R.D. (1)
Departments of Obstetrics and Gynecology, U. Alabama at Birmingham (1) , AL, Arrowhead Regional
Medical Center (2) , Colton CA, U. Arizona (3) , Tucson AZ, U. Oklahoma (4) , Oklahoma City OK,
Magee Women's Hospital (5) , Pittsburgh PA, Dartmouth Medical School (6) . Hanover NH, and Beth
Israel Deaconess Medical Center and Harvard U. Medical School (7) , Boston MA
OBJECTIVE: To assess the in vivo optical detection of high-grade cervical neoplasia (CIN
2/3+) on the whole cervix with a non-contact, spectroscopic device.
STUDY DESIGN: Cervical scanning devices collected intrinsic fluorescence and broadband
white light spectra and video images from 604 women during routine colposcopy exams at six
clinical centers. A statistically significant dataset was developed of intrinsic fluorescence and
white light-induced cervical tissue spectra correlated to expert histopathology. Based on a
retrospective analysis of the acquired data, a classification algorithm was developed,
validated, and optimized.
RESULTS: Intrinsic fluorescence, backscattered white light, and video imaging each
contribute complementary information to diagnostic algorithms for high-grade cervical
dysplasia. More than 10,000 measurements were made on colposcopically-identified tissue
from over 500 subjects, and were the basis for algorithm training and testing. Algorithm
performance demonstrated a sensitivity of 90% of higher. This performance was confirmed
using various training methods. Using a multivariate classification algorithm, optical
detection detected 31% more CIN 2/3+ than colposcopy.
CONCLUSIONS: Full cervix optical interrogation for the detection of high-grade cervical
dysplasia is feasible and appears capable of detecting more high-grade cervical dysplasia than
colposcopy alone. Using this classification algorithm, a multi-institutional, randomized trial is
underway comparing the combination of optical detection and colposcopy versus colposcopy
alone.
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SS15-05
MULTIMODAL SPECTROSCOPIC IMAGING OF THE HUMAN
UTERINE CERVIX FOR TRIAGE OF PATIENTS WITH
INDETERMINATE CERVICAL CYTOLOGY
Twiggs L. (1), De Santis T. (1), Chacktoura N. (1), Ferris D. (2), Dickman E. (2), Horowitz I. (3)
Flowers L. (3), Lashgari M. (4), Wilkinson E. (5), Bambot S. (6), Agrawal A. (6), Mongin D. (6)
(1) University of Miami, USA (2) Medical College of Georgia, Augusta, USA (3) Grady Hospital, Emory
University, Atlanta, USA (4) St. Francis Hospital and Medical Center, Hartford, USA (5) University of
Florida, Gainesville, USA (6) SpectRx, Inc., Norcross, USA
Indeterminate cervical cytology outcomes lead to unnecessary expenditures, morbidity, and
anxiety in detecting the true precursor of cervical cancer (i.e., CIN 3). Therefore, an accurate
triage test to identify the population that will benefit from colposcopic examination and
biopsy is needed. Multimodal spectroscopic imaging was evaluated as a triage test for patients
with indeterminate cervical cytology results. This technology was evaluated using SpectRx,
Inc.'s (Norcross, Georgia) Cervical Neoplasia Detection System (CNDS) in a multicenter
study of 414 women referred to colposcopy for an abnormal cervical cytology or follow up of
pre-existing cervical disease.
Methods and Materials: Study participants were scheduled to receive CNDS evaluation,
conventional or thin layer cervical cytology and colposcopy on the day of study. An algorithm
combining the cervical cytology result with the spectroscopic data was developed on the first
258 evaluable cases and then applied prospectively to the next 140 cases. For evaluating the
sensitivity of CNDS to detect cervical disease at the CIN2 threshold or above, the gold
standard was histopathology. To determine the specificity of CNDS in ruling out sub-CIN2
(normal/benign tissue and CIN1) lesions, the gold standard was histopathology when
indicated and expert colposcopy when no significant lesion was seen and biopsy was not
performed.
Results: Of the 414 subjects we evaluated, cervical cytology results were available for 398
and tissue for histopathology was available for 305 subjects. Ninety-two women had CIN2+
lesions, 75 had CIN1 Lesions, 90 had benign lesions, and 141 had normal cervices. The
primary objective of the data analysis was to determine the increase in specificity that
spectroscopy added over cervical cytology alone at 90% sensitivity for detection of CIN2+
disease. This was done to demonstrate the potential number of women with benign disease
that could have avoided colposcopy and biopsy if spectroscopy had been used adjunctively
with cervical cytology to rule out CIN2+ disease. Based on ROC curve analysis, the
specificity of the Pap test alone at 90% sensitivity was 24% for the training set of data and
26% for the validation set of data. For cervical cytology plus spectroscopy at 90% sensitivity,
specificity increased to 54% for the training data set and 56% for the validation set, an
increase of about 30% over cervical cytology alone.
Conclusion: These results indicate that multimodal spectroscopic imaging, when combined
with the Pap test result, can be an effective precolposcopy triage tool. The similarity of these
results between training and validation indicate that the technique is robust. Furthermore, the
test is noninvasive, safe, can provide an immediate result and can be operated by a skilled
professional, such as a physician or nurse.
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SS15-07
DIAGNOSTIC EFFICACY OF OPTICAL COHERENCE
TOMOGRAPHY FOR PREINVASIVE AND INVASIVE CANCER OF
THE CERVIX AND VULVA.
Escobar PF (1), Belinson JL (1), White A (1), Shakhova NM (2), Feldchtein FI (3), Kareta MV (3),
Gladkova ND (4).
(1) Cleveland Clinic Foundation, Cleveland,Ohio,Usa; (2) Institute of Applied Physics of RAS,Nizhny
Novgorod,Russia; (3) Imalux,Cleveland, Ohio,USA; (4) Nizhny Novgorod Medical Academy, Nizhny
Novgorod, Russia.
Objective: The purpose of this study was to understand the capabilities and utility of Optical
Coherence Tomography (OCT) in characterizing tissue from patients with pre-cancer and
cancer of the cervix and vulva. Optical coherence tomography is an optical technique that
uses a low-coherence interferometer to develop a two dimensional image of optical scattering
from internal tissue microstructure.
Methods: This is a prospective study designed to develop diagnostic criteria. Women
undergoing colposcopic evaluation secondary to an abnormal Pap smear or visualized grossly
abnormal vulvar lesion comprised the study population. Under colposcopic visualization the
OCT device was applied to normal regions in all patients, and abnormal areas when present,
and images captured. Each subject then underwent multiple directed biopsies. Images were
then reviewed and compared with matched histology.
Results: A total of 50 women were recruited for the study. Of the 50 patients evaluated, 18
(36%) had CIN II - III, 14 (28%) had CIN I, 13 (26%) had metaplasia / inflammation, two
patients had invasive squamous cell carcinoma of the cervix and three patients had a diagnosis
of Paget’s disease of the vulva. Analysis of the tomograms showed a repetitive OCT image
that represented normal squamous epithelium of the cervix in 100% of the normal biopsies.
Images of the 18 patients with histologically proven CIN II - III showed an unstructured
homogeneous highly backscattering region with fast attenuation of the signal in 16 (89%) of
the patients.
Conclusions: Optical coherence tomography is a new approach for the early identification of
cervix and vulvar malignancies. Using information inherent to the returning photon signals
from tissue, early morphological, and light scattering changes can be detected during
tumorigenesis. OCT has the potential to be a true optical biopsy. If diagnostically comparable
to a biopsy, then clearly the ability of OCT to provide point of service care would serve a
significant advantage.
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SS15-08
DETECTION OF CERVICAL NEOPLASIA USING NON-INVASIVE
FIBRE-OPTIC CONFOCAL MICROSCOPY
Dr McLaren W (1), Dr Tan J & A/Professor Quinn M
Royal Women's Hospital, Grattan Street, CARLTON VIC 3053, Australia
(1) Optiscan Pty Ltd, 15-17 Normanby Road, NOTTING HILL VIC 3168, Australia
Screening and detection of precancerous changes of the cervix could be vastly improved by
optical imaging modalities that enable the resolution of subcellular structure in vivo without
the need for tissue biopsy. The present study aimed to assess the design, performance and
biological image results of a prototype rigid confocal endomicroscope that uses laser light and
fibre-optic technology. The human research ethics committee at the Royal Women's Hospital,
Melbourne, Australia, approved all experiments. Fifty patients undergoing normal colposcopy
for treatment of low or high grade cervical intraepithelial neoplasia (CIN1 - CIN3
respectively) were recruited for examination. To enhance the colposcopic features of the
atypical region, 5% (v/v) acetic acid solution was applied topically to the mucosal surface of
the cervix. The cervix of the anaesthetised women was then imaged using a prototype rigid
confocal endomicroscope (fitted to an Optiscan F900e personal confocal system; excitation
488 nm argon ion laser, detection >505nm; field of view = 400 um) following the topical
application of the fluorescent contrast agents Acriflavine (0.05% in saline; Sigma
Pharmaceuticals) or Fluorescein Sodium (0.1% in saline; Pharmalab). The tip of the probe
was gently placed against the cervical epithelium to image the cells in a plane parallel to the
tissue surface. Following the imaging procedure, the region of abnormality was treated with
conventional laser ablation or the loop electrical excision procedure (LEEP).
Confocal images of the squamous epithelium of the cervix showed significant differences in
nuclear density and size between the colposcopically normal and abnormal regions.
Morphological changes associated with CIN1 - CIN3 including increased nuclear size,
nuclear pleomorphism, hyperchromasia and keratinisation could be detected using this
technology. The border between the atypical and normal epithelium could be clearly
delineated. Similarly, the morphology of the normal squamous epithelium and the columnar
epithelium could be differentiated. The results suggest that the device would be useful for the
in vivo detection of pathology.
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SS15-06
CERVICAL FULL-FIELD FLUORESCENCE IMAGING FOR HIGHGRADE CIN
Ferenczy A (1), Wright TC (2), Dattamajumdar AK (3), Parnell JR (3) and Ganguly D (3)
(1) McGill Universityand The Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Canada; (2)
Columbia University, New York, USA; (3) LifeSpex, Inc., Bothell, WA, USA.
Colposcopy has been used as a major histological predictor of cervical cancer precursors in
women with an abnormal Pap test. It suffers, however, from high false negative and positive
rates with potential medical, financial and occasionally, legal implications. A novel, full-field
multi-spectral tissue fluorescence imaging system (CerviscanTM) designed to detect the
highest grade SIL (HSIL) in real-time has been developed by LifeSpex, Inc. (Bothell, WA,
USA). We report preliminary experimental results from a multi-site North American clinical
trial for evaluating the efficacy and safety of the device.
Clinical prototypes of this investigational device were studied and compared with
colposcopy-directed biopsy results at six sites in USA and Canada. Subjects included women
with abnormal and normal (healthy volunteers) Pap test results. Study subjects had a
CerviscanTM examination followed by colposcopy-directed biopsies. These were analyzed by
an independent panel of three pathologists using the consensus approach. A subset of the
subjects was treated with loop electrosurgical excision procedure (LEEP) and the samples
were examined by histology. Data recording included a safety profile of the device and
localization of high-grade CIN. A spectroscopic classification algorithm was developed using
data from 125 subjects selected at random. The diagnostic performance of CerviscanTM was
evaluated on the remaining 97 independent, prospective test set subjects. The algorithm was
then used to determine if CerviscanTM detected high-grade CIN in subjects with LEEP
results which might have been missed by colposcopy-directed biopsies.
Complete data were available on 222 consecutive women. No adverse effects or safety
problems were observed with the use of CerviscanTM. CerviscanTM had a sensitivity of 88%
and a specificity of 80% for distinguishing high-grade CIN from normal and metaplastic
cervical epithelium (NonCIN) in the 97 independent, prospective test subjects. Of the 138
subjects treated with LEEP, 80 had high-grade CIN by histology either in their LEEP
specimens or pre-LEEP colposcopy-directed biopsies. Colposcopy detected 66 of 80 (82.5%)
and CerviscanTM detected 10 of the 14 which were missed by colposcopy. Overall,
CerviscanTM detected 95% (76/80) of the women with high-grade CIN, for a 15% (10/66)
increase in high-grade CIN detection over colposcopy-directed biopsy.
CerviscanTM provides an immediate full-field image and point measurement of clinically
significant lesions on the ectocervix. The device, as an adjunct to colposcopy, has the
potential for increasing the detection of high-grade CIN yet decreasing the number of
unnecessary biopsies.
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SS15-09
A RANDOMIZED PLACEBO-CONTROLLED STUDY OF ZYC101A
FOR THE TREATMENT OF HIGH GRADE INTRAEPITHELIAL
NEOPLASIA
Petry KU (1), Garcia F (2), Gold MA (3), Muderspach L (4), Braly P (5), Crum CP (6), Urban R (7),
Hedley ML (7) and Beach K (7)
(1) UHannover,Germany ; (2) UArizona,Tucson,AZ; (3) UOklahoma,OklahomaCity ; (4)
NorrisCancerCenter,LosAngeles; (5) NewOrleans,LA; (6) BrighamandWomen’s Hospital, Boston ; (7)
Zycos,Lexington, MA.
A study was conducted to evaluate the safety and efficacy of ZYC101a, a plasmid DNA
formulation based on the viral proteins E6 and E7 of HPV16 and 18 and encapsulated in PLG
microparticles, as a medical treatment for high-grade intraepithelial neoplasia. Women ³18y
with punch biopsy confirmed CIN2/3 were randomized and dosed with either placebo or one
of two dose levels of ZYC101a (either 100mg or 200mg DNA) IM every 3 wks for a total of
3 doses. Disease status was monitored by monthly physical exams and colposcopy, bimonthly
by cytology and HPV testing and by LEEP at 6 mo. An independent pathology panel (IPP)
confirmed or excluded CIN2/3 at entry (biopsy) and at exit (LEEP). Success was defined as
the resolution of CIN2/3 disease.
161 pts from 17 sites in US or Europe were randomized and dosed (safety population). The
modified Intent-to-treat (MITT) population (efficacy) consisted of 127 women with CIN2/3
(IPP did not confirm 27 initial cases and did not provide a final diagnoses from LEEP for 7
pts). Six pts did not complete the study; no pt discontinued due to AE’s. The median age was
28y and 55% were positive for either HPV16 or 18 at entry. The most common AE’s were
related to the injection site and included pain, induration, and erythema, and were reported
about twice as often in study drug compared to placebo. They were mild to moderate in
severity and were not cumulative. In the MITT the proportion of pts who resolved was higher
in ZYC101a compared to placebo (43 vs 27%) but was not significant (p=0.12, Fisher’s Exact
test); however, in a prospectively defined population of less than 25 y (n=43) the resolution
was higher in the combined ZYC101a compared to placebo (70% vs. 23; p<0.01, Fisher’s
Exact test). Women with HPVs other than 16/18 were as likely to demonstrate resolution
when treated with ZYC101a as those associated with HPV16/18.
This rigorously designed trial is the first to demonstrate a significant increase in the resolution
of CIN2/3 with a medical therapeutic. Additional trials are currently being designed to
confirm the efficacy of ZYC101a as an alternative for LEEP.
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SS15-10
A MULTICENTRE STUDY OF A PRIME-BOOST VACCINATION
STRATEGY IN WOMEN WITH ANOGENITAL INTRAEPITHELIAL
NEOPLASIA.
Kitchener H (1), Tristram A (2), Davidson E (1), Ann Tomlinson (1), Sterling J (3), Dobson J (4),
Man S (2), Fiander A (2).
(1) St Mary’s Hospital, Manchester, UK, (2) University of Wales College of Medicine, Cardiff, UK, (3)
Addenbrookes Hospital, Cambridge, UK, (4) Xenova Research Ltd, Cambridge, UK
A multi-centre investigation of the response to a prime-boost vaccination strategy in women
with non-cervical anogenital intraepithelial neoplasia will be presented.
Background
HPV oncoproteins E6 and E7 are expressed by neoplastic cells, thus acting as tumour specific
antigens and providing targets for immunotherapy. Previous clinical trials using a vacciniavector vaccine (TA-HPV) have shown variable clinical and immunological responses. Trials
in animal models have shown that the response can be improved by priming with a
recombinant L1/E6/E7 protein (TA-CIN), before boosting with TA-HPV.
Methods
Women with stable, non-cervical disease were recruited in three centres: Cambridge, Cardiff
and Manchester. Three doses of TA-CIN were given, at four-weekly intervals, followed four
weeks later by a single dose of TA-HPV. Women were followed up for 12 weeks following
completion of vaccination. Safety, clinical response, immunological response and viral status
were assessed.
Results
29 women were vaccinated, 27 of whom were HPV 16 positive at enrolment. The regime was
shown to be safe and well tolerated. Symptomatic improvement was seen. A number of partial
responses, as defined by a reduction in area of at least 50% have been seen. To date there has
been one complete response, confirmed by histological examination and viral clearance.
Assessment of immunological response is ongoing.
Conclusion
The prime-boost vaccination strategy using TA-CIN and TA-HPV has been shown to be safe.
Clinical responses have been demonstrated and warrant further study.
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SS15-11
APPLICATION OF IMIQUIMOD BY SUPPOSITORIES (ANAL
TAMPONS) EFFICIENTLY PREVENTS RECURRENCES AFTER
ABLATION OF ANAL CANAL CONDYLOMA
Kaspari Markus
Hannover Medical University
Introduction: The detection of anal canal condyloma (ACC) is sometimes the beginning of
long lasting disease. Because of the hidden location, diagnosis is often made at a progressive
stage, which makes diagnostic procedures uncomfortable and therapy painful. Moreover,
ACC have a higher risk of recurrence compared with extragenital warts. A cream formulation
of 5% imiquimod has been successfully used in the therapy of anogenital condyloma. Here,
we report the successful postoperative application of imiquimod-suppositories (anal tampons)
in patients following ablation of ACC.
Patients and Methods: After electrosurgical ablation of widespread and severe ACC 15 male
patients (HIV negative) received a follow-up treatment with imiquimod-suppositories for 3 - 4
months, three times a week. Each suppository contained about 5,2 mg of imiquimod in adeps
solidus.
Results: Overall this mode of imiquimod therapy was well tolerated. The treatment had to be
interrupted in only one patient because of mild erythema with pain, there were no systemic
sideeffects. Early initial recurrences in some patients cleared after treatment with imiquimod
anal tampons. Within a mean follow-up of 9 months, no patient demonstrated recurrence of
ACC.
Conclusion: These data suggest that imiquimod anal tampons are save and may represent a
new therapeutic option to prevent and cure recurrences of ACC after therapy. Moreover,
administration of imiquimod in this easy-to-use way is the first possibility for a home
treatment in patients with ACC.
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SS15-12
PHASE 1-2 STUDY OF CIDOFOVIR GIVEN INTRALESIONALY IN
CERVICAL INTRAEPITHELIAL NEOPLASIA GRADE 2 OR 3
VAN PACHTERBEKE Catherine
CHU Brugmann, OB.GYN., Bruxelles
Haouari F1, Bossens M.2, Van Pachterbeke C.1, Bourgain C.3, Nemec E.4, Snoeck R.5
1CHU Brugmann, Ob.Gyn., 1020 Brussels, 2 Association Hospitalière Ixelles/Etterbeek,1050
Bruxelles, 3AZ VUB, 1090 Bruxelles,4CHU Brugmann, Anatomopathology, 1020 Brussels
5KUL, 3000 Leuven, Belgium
Cervical intraepithelial neoplasia grade 1, 2 and 3 are a continuum spectrum of cervical
epithelial anomalies caused by the presence and the persistence of oncogenic HPV. A few of
these lesions could, without an appropriate treatment, progress, after several years, to an
invasive cancer. Treatments available are not aetiologic and are based on excision or
destruction of the dysplastic tissue. These different technics involve different complications,
including obstetrical complications, especially annoying in young women who represent the
target population.
We report the results of the first randomized double-bind study for the use of cidofovir, a
potent antiviral and antiproliferatif agent, in the treatment of cervical intraepithelial neoplasia
grade 2 and/or 3. Forty women have been enrolled, twenty receiving cidofovir and twenty a
placebo. Population’s characteristics were similar in the two groups. 15% (3/20) of patients
presented a complete disparition of lesions with a return to a normal histology in the treated
group compared with only 5% (1/20) in the placebo group. 20% (4/20) of patients presented a
partial regression in the treated group compared with only 5% (1/20) in the placebo group.
50% (10/20) of patients of the treated group had no histologic modification of their lesions
compared with 75% (15/20) in the placebo group. A progression was observed in patients in
the two groups. We have also studied the presence of HPV before and after treatment. Those
tests are still in progress. No systemic toxicity was observed. These results, although not
significant because of the small size of the tested population, suggest the superiority of
cidofovir compared with placebo for the treatment of cervical intraepithelial neoplasia,
especially for cervical intraepithelial neoplasia grade 2 and among younger women.
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SS16-01
OPTICAL DETECTION OF CERVICAL NEOPLASIA: EFFECT OF
BIOLOGICAL AND PROCEDURAL VARIABLES
Cestero, R (1), Alvarez, R (2), Huh, W (2), Garcia, F (3), Gold, M (4), Guido, R (5), McIntyreSeltman, K (5), Harper, D (6), Soto-Wright, V (7), and Burke, L (8)
Departments of Obstetrics and Gynecology, Arrowhead Regional Medical Center (1), Colton CA; U.
Alabama at Birmingham (2), Birmingham, AL; U. Arizona (3), Tucson AZ; U. Oklahoma (4), Oklahoma
City OK; Magee Women's Hospital (5), Pittsburgh PA; Dartmouth Medical School (6), Hanover NH;
Boston U. Medical Center (7), Boston MA; and Beth Israel Deaconess Medical Center and Harvard U.
Medical School (8), Boston MA.
STUDY DESIGN: The effects of cytologic sampling upon the performance of a new noncontact, in vivo optical scanning device for the detection of high-grade cervical intraepithelial
neoplasia (CIN 2/3) were studied. Fluorescence and reflectance spectral measurements were
obtained before and after cytologic sampling. Spectral data and algorithmic tissue
classification were then compared. The effect of two acetic acid delivery methods, swab or
automated spray, were separately compared.
RESULTS: Reflectance spectra after cytologic sampling suggested an increased influence of
hemoglobin, and were consistent with a biological response such as histamine-induced
vasodilation caused by the cervical scraping. Spectral obstruction due to the presence of blood
showed a greater than six-fold increase. Fluorescence spectra and algorithmic tissue
classification predictions of CIN 2/3 were not significantly affected, while the false positive
rate increased significantly from 13% before sampling to nearly 33% after sampling. No
significant spectral differences were observed when comparing acetic acid application
methods utilizing a cotton swab or an atomizer spray delivery system.
CONCLUSIONS: Epithelial surface alterations and/or bleeding caused by cytologic
sampling can inhibit the performance of optical detection systems. Acetic acid application
methods utilizing a swab or an atomizer are equally effective and do not affect spectral
measurements.
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SS16-03
DIGITAL CERVICOGRAPHY
STAFL Adolf,
Milwaukee, Wisconsin, USA
It is now generally accepted that Pap smear alone is not a completely sufficient method for
cervical cancer screening and that other adjunct methods are necessary. These include HPV
testing, screening colposcopy, speculoscopy, visual examination of the cervix with acetic
acid, cervicography and Polar Probe. Each of these methods has been sufficiently evaluated in
respect to sensitivity, specificity and cost effectiveness.
Cervicography was developed in 19981 and represents a natural development of colposcopy.
It replaces subjective colposcopic evaluation with objective cervicography assessment and
provides a permanent documentation. It was demonstrated that the results of colposcopy an
cervicography evaluated by the same observer are similar. In cervicography all diagnostic
parameters are identical to colposcopy, only the instrument is different.
The published results demonstrated that cervicography with Pap smear can improve detection
of cervical neoplasia. Cervicography was developed 20 years ago. The technical progress in
that time was significant and the traditional cervicography became outdated. To improve the
traditional cervicography, digital cervicography was developed.
The digital cervicography apparatus consists of Olympus Camedia Ultra Zoom Digital
Camera C-700, Olympus CLA4 Lens Adapter Tube, Macro-Converter Lens and light for
focusing. All these components are commercially available.
The main advantage with the digital cervicography is that does not use film, does not need
film developing, the instrument is much smaller and lighter, the provider can immediately see
if the image is satisfactory, the image can be sent by e-mail anywhere in the world for
evaluation. The images can be stored for permanent documentation on the computer, floppy
disc or CD disc. Digital cervicography, in comparison with the traditional cervicography, is
also more cost-effective. The initial cost of the instrument is 4x times lower and there is no
cost of film, developing and sending of slides for evaluation.
As an adjunct to cytology digital cervicography can be sensitive and cost effective alternative
in cervical cancer detection.
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SS16-04
PERFORMANCE OF THE ACETIC ACID TEST WHEN USED IN
FIELD CONDITIONS AS A SCREENING TEST FOR CERVICAL
CANCER
Claeys P (1), De Vuyst H (1), Gonzalez C (2), Garcia A (2), Bello RE (3), Temmerman M (1)
(1) International Centre for Reproductive Health, Ghent University, Belgium
(2) Universidad Nacional Autonoma de Nicaragua, Managua, Nicaragua
(3) Servicios Medicos Comunales, San Juan del Sur, Nicaragua
Background: The cost and the operational problems related to cytology-based programmes
result in the lack of quality screening programmes in resource-poor settings. To improve the
success, new screening tools have been developed, one of them being visual inspection of the
cervix with acetic acid (VIA). The sensitivity and specificity of this test varies between 70%
and 76%, with a specificity of 64.1% to 79% . Yet, most of these promising results have been
obtained in research settings, with specially trained research staff or health providers
performing the test under adequate supervision. The current study aims to assess the field
performance of VIA.
Methods: Health providers of different health structures in Rivas District, Nicaragua,
provided screening, after receiving training in VIA as well as a refresher course in cytology.
VIA and PAP smear were done concurrently on women attending the screening programme,
mainly women aged 30 and more who hadn't been screened in the last 3 years. Women with
either positive test result were referred for colposcopy and biopsy when indicated. The
performance of VIA was compared to PAP smear by comparing the relative true positive and
relative false positive rate (RELTPR and RELFPR), and this for a low and a high threshold
for the biopsy (CIN1 or a higher grade and CIN2 or a higher grade, respectively). We further
determined the trade-off between both tests by calculating the ratio of extra false positives
detected through extra true positives (EFP:ETP ratio).
Results: 1076 patients were screened with both tests. Nearly 33% had a positive screening
test, 12.6% had at least a low-grade dysplasia on biopsy. VIA detected 110 but PAP smear
only 47 of the 138 lesions. Using a low threshold, the RELTPR (VIA to PAP) was 2.34 and
the RELFPR 7.80, with a EFP:ETP ratio of 2.15. This indicates that for every extra diagnosis
by VIA of at least CIN1 on histology, two extra false positives had to be examined at the
referral level. For a high threshold, the RELTPR was 1.96, the RELFPR 5.02 and the
EFP:ETP ratio 8.04, indicating that for every extra case by VIA of at least CIN2, 8 extra false
positives had to be attended.
Conclusions: VIA spectacularly increases the number of CIN and invasive cancer detected.
The relatively high false positive rate is a concern for the organization of the referral level.
Further evaluation is needed to assess its performance in field conditions, and how to increase
its specificity.
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SS16-05
USE OF P16INK4A AS A DIAGNOSTIC MARKER IN CERVICAL
DYSPLASIA AND CERVICAL CANCER, BASIC ASPECTS AND
CLINICAL APPLICATIONS
von Knebel Doeberitz Magnus
Institute of Molecular Pathology
Although cervical cancer screening programs based on cytology led to a significant reduction
of cervical cancer associated mortality, the poor reproducibility and significant inter-observer
variability of the cytological screening methods underlines the demand for improved
screening technologies. Cervical dysplasia is induced by persistent high risk human
papillomavirus (HR-HPV) infections. Deregulated expression of the viral E6 and E7
oncogenes induces chromosomal instability in replicating basal and parabasal cells of the
epithelium and represents the initial step in HPV-mediated neoplastic transformation.
Expression of the viral oncogenes in replicating basal or parabasal cells of the epithelium,
however, requires the inactivation of intracellular surveillance factors that seem to control
viral gene expression in non-transformed cells. In contrast to the abundant HR-HPV
infections, deregulated expression of the viral oncogenes in basal and parabasal cells occurs
only in few HPV induced epithelial lesions. Expression of the viral E7 oncogene product
results in marked over-expression of the p16ink4a protein in replicating epithelial cells. Thus,
the expression of p16ink4a highlights replicating epithelial cells, that express the viral
oncogenes and is therefore an interesting candidate marker to identify dysplastic cells in
biopsy samples as well as cytology samples. Initial clinical studies showed, that the interobserver variability in the interpretation of H&E stained histological section of cervical
lesions can be markedly reduced through the concomitant application of p16ink4a
immunohistochemistry. In agreement with these initial applications, more recent work
demonstrates, that the application of p16ink4a immuno-cytology facilitates the identification
of dysplastic cells in cervical smears or solution based cytology. The application of this new
method and results from early clinical trials will be discussed.
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SS16-06
CYTOLOGICAL AND HISTOLOGICAL DETECTION OF P16 IN
CERVICAL PRECANCEROUS LESIONS
Nielsen M., Platz-Christensen J.J., Hariri J.
Departments of Pathology and Gynecology, Soenderborg Hospital, Denmark.
Background: Cyclin dependent kinase inhibitor P16 is activated by tumor suppressor protein
pRb. High risk HPV oncoprotein E7 inactivates pRb leading to over expression of P16, which
is inactive in the absence of functional pRb. P16 over expression is well documented in
histological and to some extent also cytological analysis of cervical dysplasia. The aim of our
prospective pilot-study was to explore the feasibility of p16 to differentiate between
dysplastic and normal cervical epithelium in histology and liquid based cytology (LBC).
Materials and methods: LBC was sampled immediately before cone biopsies in 25
consecutive cases of HSIL. In a control group, similar material was collected from 25 cases of
total abdominal hysterectomies for benign lesions, where uterine cervices were totally
sectioned as we did in cone biopsies. P16 immunocytochemistry and immunohistochemistry
was performed on all LBC samples and on selected histological sections from both groups.
Results: Cytological and histological positive reaction for P16 was detected in all cases of
HSIL. Reactive (benign) glandular epithelium showed similar positive reactions in LBC and
to a lesser extent also in histological sections from both groups.
Conclusions: It seems that the cytological and histological sensitivity of P16 to detect HSIL
is high. Further investigations are needed as regards to LSIL and ASCUS. It may also be
necessary to deal with the positive reaction in benign glandular epithelium.
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SS16-08
SWISS HPV PRIMARY SCREENING TRIAL: COMPARING CANCER
PRECURSOR DETECTION SENSITIVITY AND SPECIFICITY OF
LIQUID-BASED CYTOLOGY AND HYBRID CAPTURE II IN 15 000
WOMEN.
Gilbert Bigras and Floriane de Marval
Laboratoire Cytopath (Unilabs SA)
Introduction
This study compares cancer precursor detection sensitivity and specificity of liquid-based
cytology and Hybrid Capture II. One hundred and twenty (120) gynecologists, from private
setting, enrolled 15,000 women aged 30 years or older from five cantons of Switzerland
(Genève, Lausanne, Fribourg, Neuchâtel and Tessin). The study was sponsored by DIGENE
corporation and received ethical review approval. Inclusion criteria encompassed all women
currently accepted for routine liquid-based Pap screening.
Material and Methods
Women entering the study was administered a brief questionnaire and provided a standard
specimen of cervical cells for liquid cytology and an HPV test (employing the HC2 HPV
procedure); no additional specimens were obtained. Women positive by either the liquidbased Pap test (as-cus and more) or the HC2 HPV test or both were referred to colposcopy
with biopsy.
The biopsy was guided by colposcopic anomaly. If no anomaly was observed, an
endocervical curettage was obtained. Women with high-grade disease (cervical intraepithelial
neoplasia grades 2 and 3 or equivalent) or invasive cancer of the cervix (by histopathology)
were referred for treatment. Women negative for both tests were discharged from the study;
however, a random control set of 500 women from the group was selected for colposcopy to
demonstrate the rate of residual high-grade disease by histopathology. HC2 HPV procedure
employing probes for carcinogenic HPV types only (types 16, 18, 31, 33, 35, 39, 45, 51, 52,
56, 58, 59 and 68). McNemar's test was employed to measure significance of differences
between the test means.
Results
8.6% of all women were positive for HC2 HPV test, while 3.4% were positive for liquidbased Pap test. Only 2.2% of all women were simultaneously positive for both test. 50 highgrade disease demonstrated by histopathology were found. 49 of the latter were detected by
HC2 HPV test (sensitivity of 98%) while 23 were detected by liquid-based Pap test
(sensitivity of 46%). Difference of sensitivity was found statistically significant. Other results,
including epidemiology, are presented.
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SS16-07
INITIAL RESULTS FROM WESTERN AUSTRALIA OF HPV REFLEX
TESTING USING PCR
Frost F, Brestovac B and Smith D. Divisions of Tissue Pathology & Microbiology
The Western Australian Centre for Pathology and Medical Research, Nedlands, Western Australia
6009.
Background: We report 26,000 cervical smears annually and 10% include liquid samples. In
an earlier study we validated HPV testing using PCR, achieving a sensitivity of 92.6% for
biopsy proven high grade (HG) lesions.
Aim: To assess the value of HPV testing in women with indeterminate results ie Non Specific
Minor Changes (NSMC) and Inconclusive;possible high grade abnormality (INC),the
Australian terminology similar to Bethesda's ASCUS and ASC-H.
Methods: During 2001, 302 HPV tests on 298 women using PCR were performed on all split
samples with abnormal cytology, when requested by the clinician or with a recent low grade
smear abnormality. The HPV DNA result was expressed as No HPV, HPV detected but not
high risk (HR-) and High Risk HPV DNA detected (HR+). Follow up was obtained from our
laboratory records and the West Australian Cervical Cytology Registry.
Results: Of 157 smears reported as NSMC, 22 (14.0%) were HR+ and of these 6 (27.3%)
were HG on biopsy. No high grade lesions have been found on smear or biopsy followup in
cases where no HPV was detected or were HR-. Of 21 INC smears, 7 were HR+ and of these
3 were HG on biopsy. Five (5) cases were HR- and 3 of these were HG on biopsy. Of the 8
cases where no HPV was detected, 1 was HG on biopsy. There were 19 cases reported as
High Grade Epitheial Abnormality (Bethesda HSIL and AIS)), and 12 were HR+. So far 10 of
these are biopsy proven. There were an extra 3 HG biopsies in HGEA smears which were
HR-. From this study the sensitivity of HPV testing using HR HPV DNA may have fallen.
Conclusions: This small study suggests that women with a smear abnormality less than HPV
or CIN and with no HPV detected using PCR may safely return to screening without further
investigation. Women with smears showing a possible high grade abnormality should still be
referred for colposcopy. It is important to monitor accuracy of not only smears and biopsies,
but also HPV testing if it is used to triage women either to colposcopy or screening.
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SS17-00
IMPACT OF HEALTH ECONOMICS ON CERVICAL CANCER
PREVENTION
Jenkins David
University of Nottingham, Division of Pathology, UK
The health economic approach to cervical cancer prevention is very important in providing a
long look at the entire process of translating scientific development into medical practice and
then into benefiting people's health. It serves to synthesise individual expertise and interests to
the overall goal of improving health. This simple statement raises the first question? How do
we define and measure the burden of cervical cancer? Mortality appears a simple enough
measure, but incidence is only a partial measure of morbidity down-staging of invasive
disease is an important achievement, but not reflected in overall incidence. In large parts of
the world where there is no effective prevention, such measures serve, but in Western
countries with established cervical screening, we need to understand more complex issues
around morbidity, particularly that generated by anxiety from cervical screening.
A key issue is to understand how women (and men) outside the professional worlds of HPV
and cervical cancer, or of media and political hyperbole, understand cervical cancer
prevention. We will look at some relevant new research. Such knowledge is important in
calibrating models of cervical cancer prevention used to aid decisions.
There are really difficult questions about how to interpret current evidence in the light of such
overall goals, and how to put these pieces of evidence together to make the best decisions
about strategies for achieving these goals. This requires a framework within which evidence
can be placed,a way of appraising the quality of the evidence and a mechanism for
synthesising the knowledge to guide decision-making. Elements can be borrowed from
"evidence-based medicine" but new techniques are needed to synthesise knowledge for
making preventive decisions.
A framework for approaching evidence on screening tests is presented. The use of
mathematical modelling to evaluate the relationship between evidence and the overall goals is
discussed, and the way in which this relates to health economic analysis of cost-effectiveness
and cost-benefit discussed. The same framework can also be used to assess the use of
vaccines.
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SS17-01
EVALUATING THE EVIDENCE FOR NEW TECHNOLOGY IN
CERVICAL CANCER PREVENTION
David Jenkins
University of Nottingham
Evidence for new technology in cervical cancer prevention needs to be considered in a
framework that links the different types of evidence to overall goals of reducing cervical
cancer mortality and morbidity. This is difficult because HPV infection and precancer are
common, the natural history is complex, and, especially in a screened population, invasive
cervical cancer is a rare and late event, taking 10-40 years to develop. The assessment of the
ability of new screening or triage tests to influence such an outcome as invasive cervical
cancer is therefore complex. Such assessment requires knowledge of natural history,
diagnostic test performance, outcomes of management procedures combining diagnosis and
treatment on interim endpoints such as high-grade precancer, and understanding of financial
costs to the health system and the personal and psychological costs to the women
participating.
Current evidence is largely about natural history and diagnostic performance of new
technology such as HPV DNA testing. There have been several systematic reviews of this
evidence and these have clearly established the criteria by which such studies can be
appraised and indicated the feasibility of using HPV DNA testing in triage and probably in
screening. Such evidence is limited. Even accurate and transferable information on sensitivity,
specificity and reproducibility of a diagnostic test does not enable us to extrapolate directly its
impact on clinical, financial or personal outcomes. This is a current problem with HPV DNA
testing which gives improved reproducibility and sensitivity compared to cytology for
detecting CIN2/3, but reduced specificity. The increased sensitivity should lead to improved
effectiveness, but how big is the effect in a complex screening process? Lower specificity
could reduce efficiency through over-referral of women with false-positive tests. How
disadvantageous is this and how do effectiveness and efficiency trade-off between different
tests? Experimental evidence can only come from clinical trials. But these have limitations,
particularly the use of short-term, surrogate endpoints that are ill-defined and ill-understood.
It is important not to over-estimate the quality of current diagnostic evidence and to use novel
ways of synthesising and evaluating evidence such as mathematical modelling, to guide
decisions about cervical cancer prevention programmes and about developing relevant, new
technologies.
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SS17-02
MEASURING COSTS
DAVID WHYNES
UNIVERSITY OF NOTTINGHAM
Policy makers have become acutely conscious of the rising costs of health care. Over the past
few decades, the average growth of health spending has exceeded that of the economy in
every industrialised country. Realising that such relative growth will prove unsustainable over
the longer term, policy makers have become intent on devising cost-control strategies. In
public care systems, forms of rationing are being introduced and governments look to the
economic evaluation of health care technologies as a rational basis for rationing decisions.
Economic evaluation is the search for value-for-money, a consideration of the outcomes in
relation to the resources required to realise those outcomes. Evaluation thus informs the
judgement as to whether or not such outcomes are actually worth paying for and whether,
indeed, better health outcomes might be achieved by using the same resources in a different
way.
Resource costs are half of the evaluation equation, and confidence in evaluation results is
therefore a direct function of the quality of cost estimation. In this session, we review some
basic principles of cost measurement, including perspective (who bears the cost ?), the
discounting of future costs and the influence of the characteristics of the specific health care
delivery system. The issues are illustrated by results from studies of costs of cervical cancer
screening. It will be shown, for example, that, whilst tending to use the same screening
technology (Pap smear), the screening protocols used in the industrialised world are
sufficiently varied to produce very wide international variations in resource costs. By
implication, the resource use implications of new screening technologies, such as HPV
testing, are likely to impact differentially in different settings.
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SS17-03
IMPACT OF HEALTH ECONOMICS ON CERVICAL CANCER
PREVENTION: MEASURING OUTCOMES
Harper DM
Dartmouth Medical School, Department of Gynecology, Lebanon, NH, USA.
Cervical cancer screening, early detection and treatment are the goals of a prevention
program. Each of these processes, [screening, early detection and treatment], imposes some
level of medical intervention onto the subject that differs from the subject’s normal life
experiences.
Measured outcomes for the purposes of determining economic viability of a prevention
program can be restricted to all possible medical results of the screening, early detection and
treatment and their associated monetary costs. But, measured outcomes can also be expanded
to include other parameters besides the pathologic state of the cervix. These outcomes are
called ‘quality of life’ parameters.
Quality of life can be measured from two different perspectives. Psychosocial measurements
of a subject’s state of health include such tools as the SF-36, the HUI –III and the Euro-QoL
to estimate the impact of the prevention program within different health domains: physical
functioning, role physical, bodily pain, general health, vitality, social functioning, role
emotional, and mental health. These measures must be converted into econometric measures
before including them in a cost analysis of a public health screening program.
The econometric method was developed in response to the inherent disregard for the value of
life when gains were strictly financial and losses were costs associated with disability and lost
production. ‘Utility’ becomes the econometric indicator that combines both quality and
quantity of life usually measured in quality-adjusted life years (QALYs). The QALY is an
indicator of the disability that can occur from cervical cancer prevention programs (causing
emotional distress and preventing a person from working) replacing a perfectly healthy one
year of life with the person’s judgment of a fraction of a perfect one year of life, such as 0.70.
The applications of utilities to cervical cancer screening and their incorporation into costeffectiveness models allows a more complete health picture to judge the success of public
cervical cancer prevention programs.
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SS17-04
PUTTING IT TOGETHER: SCREENING
Myers Evan
Duke University Medical Center, Obstetrics & Gynecology, Durham, NC, USA,
Assessing the cost-effectiveness of cervical cancer screening interventions is difficult for a
variety of reasons. First, ideal study designs have not done, and are probably not feasible.
Therefore, estimating the health and economic impacts of screening programs are dependent
on modeling. Although models for cervical cancer are better than those for most other
cancers, considerable uncertainty remains. Second, the quality of the data on many of the
important inputs to models-test characteristics, efficacy of treatment, impact on quality of lifeis either of poor quality or missing altogether. Despite these difficulties, multiple costeffectiveness analyses based on models have derived some consistent general principles: (1)
Screening prior to age 30-35 incurs very high costs (because of high incidence of transient
disease) and prevents relatively few cancers; (2) as screening frequency increases, marginal
costs increase much more rapidly than marginal gains in cancer prevented or life expectancy;
and (3) increasing test sensitivity and/or decreasing test specificity increase overall costs,
independent of the cost of the test. The key parameters for comparing the cost-effectiveness of
different screening options are (1) ages to begin and end screening, (2) screening frequency,
and (3) screening test sensitivity and specificity. Current conclusions about the costeffectiveness of conventional cytology, liquid-based cytology, and HPV testing will be
discussed.
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SS17-05
COMBINING PRIMARY AND SECONDARY PREVENTION:
POTENTIAL HEALTH AND ECONOMIC IMPACT OF ADDING A
HUMAN PAPILLOMAVIRUS VACCINE TO SCREENING PROGRAMS
Kulasingam S. and Myers E.
Department of Obstetrics and Gynecology and Center for Clinical Health Policy Research, Duke
University, Durham, North Carolina
Context: Recently published results suggest that a vaccine that reduces the incidence of
cervical cancer-associated human papillomavirus (HPV) may become available within the
next decade.
Objective: To examine the potential clinical and economic effects of an HPV vaccine to
identify characteristics which drive cost-effectiveness in the setting of existing screening.
Design: A Markov model was used to estimate lifetime costs and life expectancy of four
strategies incorporating a vaccine, with 10 years duration of efficacy targeted against a
defined proportion of high-risk HPV types, given once to a cohort of 12 year old girls: 1)
vaccination only; 2) conventional cytological screening only, beginning at age 18; 3)
vaccination followed by screening beginning at age 18; and 4) vaccination with screening
delayed to ages 22-30, depending on screening interval. Each strategy, which included
screening, was evaluated at screening intervals of 1, 2, 3, and 5 years.
Setting and participants: Women aged 12 to 85 who participate in cervical cancer screening in
the United States
Main Outcome Measures: Mean life expectancy, lifetime costs, and incremental costeffectiveness ratios.
Results: Vaccination plus biannual screening beginning at age 24 had the most attractive
cost-effectiveness ratio ($25,400), although the combined strategy of vaccination with annual
screening beginning at age 18 had the largest overall reduction in cancer incidence and
mortality, at a cost of over $187,000 per life-year gained. The cost-effectiveness of
vaccination plus delayed screening was highly sensitive to overall vaccine effectiveness,
duration of efficacy, and costs of vaccination.
Conclusions: The cost-effectiveness of an HPV vaccine as an adjunct to screening depends
on providing reductions in incidence during the ages of peak oncogenic HPV incidence. In
addition to vaccine efficacy and duration, identifying the optimal age for vaccination should
be a top research priority.
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SS17-06
EXAMINING THE ECONOMIC BURDEN OF GENITAL WARTS:
LESSONS FROM THE FIELD
INSINGA R.
Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA
Objectives: (1) To discuss methods and challenges in examining the economic burden of
genital warts in the general population. (2) To present an in-depth illustration from a study
using administrative data from a set of private U.S. health plans.
Methods: Prior literature on the incidence, prevalence and costs associated with genital wart
diagnoses are reviewed. Strengths and limitations of prior studies and major data sources
available to researchers are discussed. Data for the in-depth illustration are derived from the
Medstat Marketscan® database, containing fee-for-service health insurance claims from 3.7
million privately insured U.S. individuals. The database scope is limited to cases for which
health plan reimbursement was sought. Data on the incidence, prevalence and costs associated
with genital wart diagnoses in 2000 were compiled using ICD-9 codes, with results stratified
by sex and age.
Results: In the U.S. and most other countries, there are no nationally representative disease
registries or surveys from which to construct a national estimate of genital wart economic
burden. Though limited in scope to a specific institution or payor, administrative data and
medical chart review currently represent the best available data sources for these analyses.
From the Medstat data, we identified 5,095 prevalent genital wart cases (1.7 per 1,000 personyears) billed through private health plans during 2000. Prevalence and costs were highest
among females age 20-24 (6.2 cases and $1,400-1,700 in costs per 1,000 person-years) and
males age 25-29 (5.0 cases and $1,500-1,700 in costs per 1,000 person-years). Similar trends
were observed with respect to incident episodes of care, with an average cost per episode of
$436.
Conclusions: It is not currently possible to estimate the global economic burden of genital
warts from a single data source. Administrative data can provide limited but valuable
information towards this endeavor. This analysis reports the first age and sex-specific
estimates of the prevalence and costs of genital warts in a broad U.S. population. The
economic burden of genital warts in private health plans was found to be highest in the 20-29
age group, with a higher burden at older ages than might have been expected based upon prior
accounts.
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SS18-04
HPV INDUCED CERVICAL CANCER: PROVIDING ANSWERS TO
PATIENT QUESTIONS
Cox JT
University of California - Santa Barbara, California, USA
One of the most difficult tasks that we face in taking care of patients with human
papillomavirus (HPV) infections is the myriad of questions that most will have when given
the diagnosis. While most of our patients have heard about other common STDs, the majority
is completely unaware of human papillomavirus (HPV) and of the relationship of this virus
with certain abnormal Pap results and with cervical cancer. Incomplete understanding of the
natural history and epidemiology of HPV amongst clinicians adds to the anxiety, as the
patient often receives conflicting information. Although some questions remain without solid
answers, what is known about the epidemiology and natural history of HPV does provide
enough insight to be able to provide guidance and reassurance. In this manner we may be best
able to provide the information necessary to empower our patients to protect their health
while removing undue anxiety. The questions most frequently asked by our patients include:
What is HPV and why have never heard of it? Where did I get it? If I have HPV what are my
risks? Why is cervical cancer so uncommon when HPV is so common? If this is sexually
transmitted, will I give it to my partner? What about future pregnancies, are any children that
I have at risk? Since I have heard that there is no cure, does that mean I will always have it? Is
there anything I can do to help get rid of it? A wealth of knowledge about HPV provides
definitive answers to most of the questions, but there are still gaps in our knowledge and
sometimes we just have to say “This is what we know, and this is what we don’t know”.
Where possible, responses to patient questions can be formulated to provide maximum
reassurance first, followed by enough knowledge to encourage diligent follow-up. Fear and
ignorance are each patient’s enemy. Often the biggest challenge in the care of our patients is
the elimination of these negatives as quickly and completely as possible. Understanding the
natural history of HPV can also help in counseling patients regarding possible events in their
lives that may decrease their chance of having a good immune response. Certainly anything
that would normally be recommended to increase one’s chances of fighting an infection
should be recommended, even if definitive evidence may be lacking. Such recommendations
would include asking the patient about lifestyle habits which could be a problem, such as poor
sleep, poor diet, stress, smoking, and excessive alcohol and drugs. Developing a lifestyle that
is healthy cannot be criticized and may play a part in a successful response to this virus.
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SS18-05
"LIGUE CONTRE LE CANCER" ACTIONS FOR WOMEN'S
PREVENTION ON BREAST CANCER SCREENING
May-Levin Françoise
Ligue contre le Cancer, PARIS
"Ligue contre le cancer" is a federative stucture, associating 102 "Comitees" , on in each
administrative structure, called a " department". Then Ligue is able to be close to people and
more effective.
Informing people on cancer prevention is one of the main Ligue tasks.
Since many years, we are working for promoting breast cancer screening: the communication
is aimed for each woman to make screening a very natural action.
During 1997, we communicated through several women's magazines, in order to present
screening as a scheduled time in a woman's life. Nevertheless only few of them, about 40 to
50% responded to screening invitation. Why this lack of interest ? A large population study
showed that main reason is a psychological fear. Therefor, the League, associated with the
health professionnals, Social Security and women themselves, undertook a national
programme breast screening.
This program is aimed to target women between 50-74 , and will spread over France in order
to be extended in 2004 to the whole country. In the same time, a personnal letter is mailed to
all of the concerned women.
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SS18A-03
IMPLEMENTATION OF CERVICAL CANCER SCREENING IN LATIN
AMERICA AND THE CARIBBEAN: IS IT FEASIBLE?
Sylvia C., Robles , Merle Lewis, Roberto Del Aguila
Pan American Health Organization
For years, it has been known that incidence and mortality from cervical cancer have not
declined significantly, despite the fact that cytology screening has been widely available since
the 1960s. As we have learned more about the natural history of this disease, new screening
and treatment methods have been and continue to be researched. However, the questions are
not simply about which test and treatment to use, but from a public health perspective, how
can these new and old technologies be applied in practice, so that they can be as effective as
demonstrated under research conditions. The TATI study in the Amazonia of Peru was
designed to answer this question. It was based on previous data on barriers to screening as
well as facilitating factors. It was particularly important to evaluate the feasibility of a singlevisit screening and treatment approach in a low resourced setting; the mechanisms for followup of women who have been treated; and the population effectiveness of visual inspection
with acetic acid in an unscreened population. Preliminary data related to the first two issues
will be presented for 20,000 women who have been screened, together with some quality
indicators of ten health centers that participated in this study. A more limited role for
conventional cervical cytology is proposed.
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SS18A-04
COMPARING PAP SMEAR CYTOLOGY, AIDED VISUAL
INSPECTION (VIA), SCREENING COLPOSCOPY, CERVICOGRAPHY
AND HPV TESTING BY HCII (NORMAL AND SELF-SAMPLING) AS
OPTIONAL SCREENING TOOLS IN LATIN AMERICA.
EEXPERIENCE FROM THE LAMS STUDY*
Syrjänen K (1), Naud P (2), Derchain Sm (3), Roteli-Martins C (4), Longatto-Filho A (5), Tatti S
(6), Branca M (1), Erzen M (7), Serpa-Hammes L (2), Gontijo R (3), Lima Tp (4), Maeda M (5),
Lorincz A (9), Dores Gb (10), Syrjänen S (11)
(1) ISS, Rome, Italy; (2) Hospital de Clinicas de Porto Alegre; (3) Universidade Estadual de Campinas;
(4) Hospital Leonor M de Barros, São Paulo; (5) Instituto Adolfo Lutz, São Paulo; (6) First Chair
Gynecology Hosp. de Clinicas. BA, Argentina; (7) SIZE Diagnostic Center, Ljubljana, Slovenia; (9)
Digene Corp., Maryland, USA; (10) Digene Brazil, Sao Paulo; (11) Department of Oral Pathology,
University of Turku, Finland. *(LAMS: Latin American Screening Study, funded by EC, INCO-DEV
Contract # ICA4-CT-2001-10013).
OBJECTIVES: The performance of conventional diagnostic techniques (PAP smear and
liquid-based cytology, screening colposcopy) is compared with 1) two optional screening
tools (VIA, cervicography) and with 2) Hybrid Capture II, from a) conventional samples and
b) using self-sampling, in women at different risk for cervical cancer in Brazil and Argentina.
STUDY DESIGN: In this cross-sectional- and prospective cohort study, consecutive women
attending the clinics during the first 12 months (expected n=12.000) are screened using the six
diagnostic tools (quality controlled by the EC partners), and women with biopsy-confirmed
low-grade CIN are enrolled in the cohort to be prospectively followed-up for 24 months. Data
on the risk factors are collected, and cervical biopsies are analysed for pathogenetic and
prognostic factors using e.g. cDNA microarrays, real-time PCR and immunohistochemistry.
RESULTS: During the first nine months, over 9.000 women have been examined by the
clinics, randomised according to the 6 diagnostic arms. Significant differences in many of the
key demographics of the patients between the different clinics will be discussed in the context
of the clinical findings and HPV data.
EXPECTED OUTCOME MEASURES: This study design provides data necessary for
designing new strategies for a cost-effective control of cervical cancer in low-resource
settings. Furthermore, the prospective follow-up of women in different regions permits
analysis of whether variations in cervical cancer incidence in these regions is due to 1)
different natural history of the precursor lesions, or 2) due to different level of exposure to the
known risk factors, e.g. HPV.
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SS19-04
POTENTIAL COST-EFFECTIVENESS OF ADDITION OF HPV
VACCINATION TO ORGANIZED SCREENING PROGRAMS.
Myers E, Kulasingam S
Department of Obstetrics & Gynecology, Duke University, Durham, NC, USA
BACKGROUND: Organized screening programs have been highly successful in reducing
the incidence of invasive cervical cancer. It is unclear how effective vaccines against
oncogenic HPV types might impact on current screening programs.
OBJECTIVE: To explore the potential impact of an HPV vaccine on the cost-effectiveness
of screening strategies similar to those used in Europe.
METHODS: We revised the previously described "Duke" mathematical model. Base case
assumptions included: (1) conventional cytology, (2) ASCUS and LSIL managed by repeat
cytology in 6-12 months, (3) cytology sensitivity of 56% and specificity of 95% for CIN 2/3,
(4) vaccine efficacy of 90% against 70% of oncogenic HPV types, with a duration of efficacy
of 10 years, (5) vaccine administered at age 12, (6) overall vaccine cost $200 USD, and (7)
100% compliance with vaccination, screening, and follow-up. Screening strategies were
screening every 3, 5, 7, and 10 years, beginning at ages 20, 25, and 30. Incremental costs per
life-year saved were calculated.
RESULTS: In the base case, adding vaccine to screening beginning at age 20 cost $40,612
per year of life saved for screening every 3 years, $27,034 for screening every 5 years,
$21,333 for screening every 7 years, and $17,720 for screening every 10 years. For screening
at age 25, incremental cost-effectiveness for vaccination ranged from $27,909 for screening
every 3 years to $17,046 for screening every 10 years. For screening at age 30, the range was
from $18,139 every 3 years to $14,290 for screening every 10 years. Cost-effectiveness ratios
were sensitive to the cost, efficacy and duration of efficacy, proportion of oncogenic HPV
covered, and age of administration of the vaccine. Values for age at administration and/or
duration of efficacy which contributed to protection during the ages of peak HPV incidence
(ages 17-25) led to more favorable cost-effectiveness ratios.
CONCLUSIONS: Effective vaccines against oncogenic HPV may be cost-effective additions
to existing organized screening programs. Duration of vaccine efficacy and age at
administration will be key parameters that drive cost-effectiveness.
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SS20-01
GEOGRAPHIC VARIATION IN HPV INFECTION
Franceschi S (1), Shin HR (2), Sukvirach S (3), Anh PTH (4), Matos E (5), Molano M (6), Thomas
J (7), Herrero R (8)
(1) International Agency for Research on Cancer, Lyon, France; (2) National Cancer Center Research
Institute, Goyang-si, Gyeonggi-do, Republic of Korea; (3) National Cancer Institute, Bangkok,
Thailand; (4) National Cancer Institute, Hanoi, Vietnam; (5) University of Buenos Aires, Buenos Aires,
Argentina; (6)National Cancer Institute, Bogota, Colombia; (7) University of Ibadan, Ibadan, Nigeria; (
8) Guanacaste Project, Costa Rican Foundation for Health Sciences, San José, Costa Rica
Prevalence surveys among random samples of women drawn from the general population list
were carried out by the International Agency for Research on Cancer in South Korea (Busan),
Thailand (Songkla in the south and Lampang in the north), Vietnam (Hanoi and Ho Chi Minh
City), Argentina (Cordoba), Colombia (Bogota), and Nigeria. Questionnaire information, and
samples of exfoliated cervical cells and of blood were collected. Type-specific prevalence of
HPV DNA from cervical cells was analysed using GP5+/6+ primers, whereas anti-VLPs for
HPV 16, 18, 31, 33 and 58) and HSV-2 were assessed using ELISA. A summary of the results
from each study regarding the prevalence of risk factors for HPV infection will be presented.
It is important to bear in mind that it has turned out to be very difficult, notably in Asia, to
perform pelvic examinations of unmarried/virgin women. The following findings are,
therefore, truly representative of HPV DNA prevalence among married/sexually active
women, chiefly in the 25-to-65-year age range.
Korea: 863 sexually active women were studied. Overall prevalence was 10.4% for HPV
DNA and 19.8% for anti-VLPs.
Thailand: 1035 women from Lampang, in the North, and 706 from Songkla, in the south were
studied. HPV DNA and anti-VLPs were more common in Lampang (8.0% and 29.2%,
respectively) than in Songkla (3.8% and 10.9%, respectively).
Vietnam: 922 women from Ho Chi Minh City and 994 from Hanoi were studied. HPV DNA
prevalence was 10.9% and 2.3%, respectively.
Argentina: 987 women were studied. The prevalence of HPV DNA among sexually active
women was 17.7%.
Colombia: 1859 cytologically normal women were studied in Bogota. The overall prevalence
of HPV DNA was 14.8%.
The most common HPV types were HPV 16, 31, and 33. However, HPV 70 was found
frequently in Korea, HPV 52 in Thailand, CP8304 in Vietnam, HPV 35 in Argentina, and
HPV 45 in Colombia.
References:
Shin HR et al. Prevalence of human papillomavirus infection in women in in Busan, South
Korea. Int J Cancer (in press)
Sukvirach S et al. Population-based human papillomavirus prevalence in Lampang and
Songkla, Thailand. J Infect Dis (in press)
Anh PTH et al. Human papillomavirus infection among women in South and North Vietnam.
Int. J. Cancer (in press)
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Matos E et al. Prevalence of human papillomavirus (HPV) infection among women in
Concordia, Argentina: a population-based study. J Sex Transm Dis (submitted)
Molano M, Posso H, Weiderpass E et al. Prevalence and determinants of HPV infection
among Colombian women with normal cytology. Br J Cancer 2002;87:324-33
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SS20-02
A RANDOMISED PLACEBO CONTROLLED TRIAL OF
IMMUNOTHERAPY FOR CIN
Frazer I.H. (1), Quinn M. (2), Nicklin J. (3), Tan J. (2), Perrin L. (3), Ng P. (4), O'Connor V. (5),
White O. (1), Wendt N. (1), Martin J. (1), Mitchell S.V. (6) McKenzie A. (6), Crowley J. (6),
Edwards S. (6), Maher D. (6)
(1) Centre for Immunology and Cancer Research, The University of Queensland, Princess Alexandra
Hospital, Brisbane, Queensland; (2) Royal Women's Hospital, Parkville, Victoria; (3) Royal Women's
Hospital, Brisbane, Queensland; (4) Mater Mother's Hospital, Brisbane, Queensland; (5) Queen
Elizabeth II Jubilee Hospital, Brisbane, Queensland; (6) CSL Limited, Parkville, Victoria, Australia
Aim: Establish the safety, tolerability and immunogenicity of HPV16 specific
immunotherapy for CIN.
Methods: A double blind trial using CerVax16TM, a fusion protein of E6 and E7 from
HPV16 combined with ISCOMs, a saponin based adjuvant. 31 women with CIN 1-3 were
randomly allocated to receive active treatment (n=24) with one of three dose levels of antigen
(20µg, 60µg, or 200µg), or placebo (n=7). Up to three injections were given intramuscularly
over 6 weeks.
Findings: Subjects were assessed for adverse events, immunogenicity, and HPV16 viral load
in cervical biopsies taken before and after treatment. Local site reaction (mild n=11, moderate
n=11, severe n=2) and systemic symptoms (mild n=11, moderate n=8, severe n=3) were
observed in active and placebo groups. Specific antibody was induced for all 24 subjects
given active vaccine. 12 of 20 evaluable subjects given active vaccine demonstrated a γinterferon response. CTL responses were detected in some subjects. In general, responses
increased with multiple vaccinations. No major changes in colposcopic appearance or in
cervical histology were observed. Of 14 HPV16 +ve subjects treated, 13 had lower mean
HPV copy number per cell after treatment. Mean viral load fell from 50±22 viral copies per
cell pre-treatment to 12±8 post-treatment (p<0.05; paired t test). Mean viral load did not fall
significantly in women given placebo (p=0.34).
Conclusions: Cervax16TM is safe and immunogenic in patients with HPV16-associated CIN,
and may reduce the load of HPV16 in infected cervical tissue.
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SS20-03
PROPHYLACTIC HPV VACCINE DEVELOPMENT
Schiller John
National Institutes of Health, Laboratory of Cellular Oncology, NCI, Bethesda, MD
The results of clinical trials of prophylactic HPV L1 VLP vaccines are uniformly
encouraging. The vaccines consistently induce high titers of virus neutralizing antibodies with
minimal side effects. Merck recently reported that three intramuscular injections of an HPV16
L1 vaccine in naïve young women induced greater than 99% seroconversion and provided
100% protection from acquisition of persistent cervical HPV16 infection and HPV16-induced
cytologic changes. Although there is considerable optimism that L1 VLP-based prophylactic
vaccines will ultimately prove to be safe and effective at preventing cervical cancer, the
current vaccines have several potential liabilities that might be overcome by secondgeneration HPV vaccines. Many of the liabilities are expected to be especially problematic for
vaccine implementation in developing countries, where more than 70% of cervical cancers
occur. Three potential liabilities of the current prophylactic vaccine candidates that are
currently being addressed are A) limited therapeutic potential, B) type specific protection, and
C) expense of administration. Limited therapeutic potential is being addressed by inclusion of
early viral antigens in the VLPs as fusions with the L1 or L2 virion proteins. Alternatively
early viral antigens might be delivered as shuffled genes in HPV psuedoviruses. The type
specificity of VLP-based vaccines is being addressed by developing L2-based vaccines that
induce more broadly cross-neutralizing antibodies. The anticipated expense parenteral
delivery is being addressed by studies to develop effective strategies for mucosal
immunization.
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SS20-05
DEVELOPMENT OF AN ADJUVANTED HUMAN PAPILLOMAVIRUS
TYPE 16/18 L1 VIRUS LIKE PARTICLE VACCINE
Dubin, G
GlaxoSmithKline
The recognition that genital human papillomaviruses (HPVs) are the etiologic agent in almost
all cervical carcinomas suggests that the incidence of these cancers could be significantly
reduced by prophylactic vaccination. Globally, HPV-16 and HPV-18 are responsible for the
majority of cervical cancers. GlaxoSmithKline (GSK) Biologicals has developed a vaccine
containing HPV-16 and -18 L1 virus-like particles (VLPs) produced in a baculovirus
expression system. Pre-clinical assessment of different adjuvant formulations suggests AS04
adjuvant, which contains alum and 3-O-deacylated-monophosphoryl lipid A, affords superior
vaccine immunogenicity. Phase I and II trials of the candidate vaccine demonstrated it to be
well tolerated and highly immunogenic, inducing HPV-16 and 18-specific antibody titers that
far exceed those found in women following infection. These trials confirmed that vaccine
with AS04 adjuvant was most immunogenic. Based on these results, GSK Biologicals
initiated a double blind, randomized pilot efficacy trial of the HPV-16/18 VLP-AS04 vaccine
in the United States, Canada, and Brazil. Approximately 1100 women between the ages of 1525 years were enrolled according to the following criteria: having 6 or fewer lifetime sexual
partners, normal cervical cytology, HPV-16 and -18 seronegative, and free of high-risk HPV
cervical infection (as determined by PCR). Candidate vaccine or placebo was administered by
intramuscular injection on a 0, 1, 6 month schedule. Study follow-up with periodic
assessments for acquisition of cervical HPV infection are ongoing. The primary analysis of
this trial, planned for mid-2003, will evaluate prevention of HPV-16 and/or -18 infection in
recipients of three vaccine doses.
Challenges for the further development and licensure of this and other HPV vaccines include:
1) defining optimal efficacy endpoints that will allow regulatory and public health authorities
to conclude that these vaccines are likely to prevent cervical cancer; 2) identifying target
populations for vaccination; 3) defining implementation strategies that will maximally reduce
the incidence of neoplastic cervical disease.
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SS20-06
STATUS OF PROPHYLACTIC VACCINES AGAINST CERVICAL
CANCER
Jansen Kathrin
Department of Microbial Vaccine Research, Merck Research Laboratories, West Point, Pennsylvania,
USA
Human papillomaviruses (HPVs) infect cutaneous, genital and respiratory epithelia in a
tissue-specific manner. Infection with HPVs is widespread throughout the world, and viral
infection is closely associated with both benign and malignant lesions. The overall percentage
of HPV infection ( either current or previously encountered) in a population could be as high
as 75%. There are now over 100 HPV types described; from a public health standpoint
however, only a small number of these different HPV types cause the majority of clinically
important diseases. HPV16 and 18 are strongly associated with high-grade anogenital lesions
and invasive cancers and are found in ~70% of all cervical squamous cell carcinomas and
~90% of adenocarcinomas. The causal link of HPV and cervical cancer has been clearly
established both from population based studies as well as animal models. Despite the
existence of good screening programs for precursor lesions of cervical cancer in the US, there
are still ~14,000 cases diagnosed each year and ~5,000 women will die from the disease and
screening is expensive. In developing countries where access to routine cervical cytological
screening is nonexistent or difficult, cervical cancer is the most common malignancy with an
estimate of ~500,000 new cases and ~200,000 associated deaths annually. Therefore, an
effective and safe prophylactic vaccine would be highly desirable. Approaches to vaccine
design and data from early phase phrophylactic clinical trials will be discussed.
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SS20-07
HPV 16 L1/E7 CHIMERIC VIRUS-LIKE PARTICLE (CVLP)- AND
CHIMERIC CAPSOMERE VACCINES
Lutz Gissmann
Deutsches Krebsforschungszentrum, D-69120 Heidelberg
In our attempts to generate combined prophylactic and therapeutic HPV-specific vaccines we
analyzed virus-like particles (VLPs) and capsomeres, L1/E71-60 CVLPs and L1/E7full-length
chimeric capsomeres of HPV 16 for their ability to trigger a cytotoxic T cell (CTL) response.
Subcutaneous (s.c.) as well as intranasal immunization of C57BL/6 mice triggered an L1specific CTL response. Antibody responses (serum and vaginal) were less robust after
capsomere immunization. In addition, s.c. vaccination with HPV 16 L1 capsomeres induced
regression of established C3 tumors expressing L1 determinants. Immunization with L1/E7
CVLPs or chimeric capsomeres triggered both L1 and E7-specific T cells. Mouse bone
marrow derived dendritic cells loaded with VLPs or capsomeres in vitro presented HPVspecific MHC I epitopes with similar efficiency.
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SS20-08
NEUTRALIZING AND CROSS-NEUTRALIZING ANTIBODIES
INDUCED BY L1 AND L1+L2 VIRUS-LIKE PARTICLES.
Bousarghin L (1), Combita A L (1,2), Germon S (1), Touze A (1), Debrus S (3), P Coursaget (1).
Laboratoire de Virologie Moléculaire, INSERM EMIU 00-10 and USC INRA, Faculté des Sciences
Pharmaceutiques, Tours, France, 2) Laboratorio de Immunologia, Instituto Nacional de Cancer,
Bogotà, Colombia, 3) GlaxoSmithKline Biologicals, Rixensart, Belgium
Neutralizing antibodies directed against high-risk Human Papilloma Viruses (HPVs) were
characterized using pseudovirion infectivity assay. Neutralizing antibodies against HPV-16,
HPV-18, HPV-31, HPV-33 and HPV-58 were first investigated in mice immunized with HPV
L1 virus-like particles (VLPs). The results evidenced the presence of cross neutralizing
antibodies against closely related HPV types.
The neutralizing activity of antibodies raised against L1+L2 VLP's of types 16, 18, 31, 33 and
58 was also investigated. The results indicated a higher level of cross-reactivity when the
VLP's contained the L2 protein.
Administration of HPV-18 L1 VLPs to mice did not result in neutralizing antibodies
induction, although the corresponding pseudovirions were able to transfer the reporting gene.
A point mutation was identified in the L1 gene that seems responsible for the loss of the
major HPV-18 neutralizing epitope without affecting the gene transfer capacity of the HPV18 VLP's. The HPV-18 L1+L2 pseudovirions could be a usefull tool in order to study specific
anti-L2 cross-neutralizing antibodies.
In order to investigate the production of neutralizing and cross-neutralizing antibodies in
humans, sera obtained from 79 HPV-DNA negative women immunized with a papillomavirus
vaccine containing HPV-16 and -18 L1 VLPs were also tested for the presence of neutralizing
antibodies against HPV-16, HPV-31, HPV-33 and HPV-58. Neutralizing antibodies against
HPV-16 were detected in 95% of the HPV vaccine recipients. The results also indicated that
38% of them developed neutralizing antibodies against types other than those included in the
vaccine, suggesting that VLP's not only induced type-specific neutralizing antibodies but also
cross-neutralizing antibodies in human.
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SS21-02
ROLE OF HPV TESTING FOR MANAGING WOMEN WITH
ABNORMAL PAP SMEARS: LSIL, HSIL AND AGC
Kinney Walter
Permanente Medical Group, Department of Obstetrics and Gynecology, Sacramento, California
OBJECTIVE:
Description of current clinical practice and the underlying scientific basis for options that
involve HPV testing.
METHODS:
Review of pertinent scientific publications, consensus recommendations and outcome of
research and clinical practice in the Permanente Medical Group
RESULTS:
1) LSIL: Current ASCCP recommendations permit primary evaluation of "low risk"
postmenopausal women and of adolescents with LSIL Paps with cytology at 6 month
intervals times 2 or HPV testing once at 12 months. This is consistent with our knowledge of
the time course of HPV infection, the reproduceability of LSIL cytology and unpublished
information from Manos et al concerning the rate of HPV positivity in women over 40 with
KSIL Pap smears.
The most common outcomes of colposcopy following an LSIL Pap are a negative satisfactory
exam or a CIN 1 biopsy and a satisfactory exam. Cytology at 6 month intervals times 2 or
HPV testing at 12 months are also recommended in this setting, based on information from
the ALTS trial.
2) HSIL: Colposcopy and frequently a diagnostic excisional procedure are the most common
sequelae of an HSIL Pap, and CIN2/3 the most common histologic diagnosis. Although not
currently part of the ASCCP recommendations, there is literature support for the idea that risk
of recurrence post treatment and hence intensity of followup is best assessed with HPV
testing. Our Clinical Practice Guidelines recommend 2 Paps at 6 month intervals before
annual screening, or alternatively patients with a normal Pap and a normal HPV test at 6
months may return directly to annual testing.
3) AGC: Current ASCCP recommendations don’t include a role for HPV testing in evaluation
of AGC smears. Published data from Ronnett et al concerning 136 AGC smears with HPV
and biopsy correlation demonstrate 29% HPV positivity and 11/12 CIN2/3 and all 5 AIS
included in the HPV positive group. Subsequent unpublished experience in our clinical
practice confirms and expands these observations. Our Clinical Practice Guidelines
discourage conization in women with a single AGC smear and a negative initial evaluation
and negative HPV test.
CONCLUSION:
As additional information emerges, the role of HPV testing as a powerful complement to
cytology is being clarified, and indications for its use in clinical practice are expanding.
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SS21-03
THE IMPACT OF LARGE LOOP EXCISION (LLETZ) ON
TREATMENT OF CIN
Kitchener Henry Charles
University of Manchester
More conservative colposcopic methods of treating CIN are an advance on the historical
approach using knife cone biopsy. Such treatment can be better tailored to individual patients,
cause less morbidity and are associated with better cervical function long term, particularly
fertility. Excisional methods have taken over from ablative methods and the large loop
excision is an efficient proven technique using robust and fairly cheap equipment, when
compared within laser excision for example. A number of case series have demonstrated that
LLETZ can produce cure rates compatible with ablative techniques, in the region of 90 – 95%
with a simple treatment. It also has the advantage of being employable as a means of
conisation for endo cervical disease, largely avoiding the need for knife cone or laser cone.
Like all surgical techniques it requires training, experience and skill. In the correct hands it is
associated with a high rate of intact specimens, complete excisions and low rates of treatment
failure. In the wrong hands, it can result in poor quality excisions which are impossible to
interpret, high rates of incomplete excision, high rates of treatment failure and if used too
liberally for “see and treat” too many women with low grade cytology will have an excision
specimen showing no CIN.
It is important to use appropriately sized loops for each case in order to avoid excessive or
inadequate excision. Young women and older women have higher treatment failure rates due
to incomplete excision at the ecto and endocervical margins respectively. While involved
margins do not mandate re excision they are associated with higher rates of treatment failure.
Colposcopists should audit their overall treatment failure rates and “no CIN” rates in cases of
“see and treat”.
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SS21-04
IS DESTRUCTIVE TREATMENT OF CERVICAL PREINVASIVE
DISEASE OBSOLETE? A 13-YEAR EXPERIENCE WITH
CRYOSURGERY AND LASER.
Guijon Fernando
University of Manitoba, Dept OB-GYN, Canada
Cryosurgery continues to be the most used method of treatment for Cervical Intraepithelial
Neoplasia (CIN) in the world. Laser vaporization has been extensively reported, specially in
North America and Europe.
OBJECTIVE: To evaluate whether treatment of CIN with crysurgery is as effective as laser
therapy, particularly in CIN grades 2 and 3 and to determine the optimal time for follow up in
these patients.
MATERIALS AND METHODS: A nonrandomized, cohort population of patients referred
to the Colposcopy Unit, Health Sciences Centre, Winnipeg, from January 1985 to December
1998 was studied. Patients with biopsy-proven CIN, treated with crysurgery or laser were
included. The groups were compared for grade of CIN, demographic data, rate of recurrence
and time to recurrence. Data was analyzed using Chi-square and Student t-test.
RESULTS: 2240 eligible patients were included, 1126 of which were treated with laser and
1114 with cryosurgery. Patients with CIN 1 at initial presentation (39.2%) were 4.8 times
more likely to be treated by cryosurgery than those with a higher grade lesion (CIN 2/3); OR
4.8 (95%C.I. 4.0, 5.8). Ninety-two percent (1036/1126) of patients in the laser group and
91.6% (1021/1114) in the cryosurgery group had no evidence of CIN after a median followup of 60 months. The 183 patients with recurrent / persistent disease were re-treated with the
same modality of treatment as initially received. Eighty-seven of the 90 (96.7%) patients retreated with laser had no further evidence of CIN, and 90 of the 93 patients (96.8%) re-treated
with cryosurgery had no further evidence of CIN. A total of 6 out of the 183 (3.3%) patients
with recurrent / persistent disease failed to respond to re-treatment by the initial form of
treatment modality.
The majority (128/183; 75.4%) of recurrent / persistent disease was detected within the first
18 months after treatment. Recurrences in the laser group were bimodal with the second peak
between 36-48 months after treatment. Invasive carcinoma was not detected after treatment
either by laser or cryosurgery.
CONCLUSION: Cryosurgery and laser vaporization are excellent and safe methods of
treatment for CIN. Recurrences of CIN 2/3 could be bimodal with a second peak two years
after treatment. Optimal follow-up would be two years for CIN 1 lesions and five years for
CIN 2/3 lesions.
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SS21-06
GUIDELINES FOR MANAGEMENT OF WOMEN WITH CERVICAL
CYTOLOGICAL ABNORMALITIES
J.C. BOULANGER* - J.L. LEROY**
Centre de Gynécologie Obstétrique – CHU AMIENS – France
The French guidelines were revisited last year by " l ’Agence Nationale d’Accréditation et
d’Evaluation en Santé " (ANAES) and the conclusions are in progress. They are very similar
to US guidelines, depend of cytological conclusions.
- High grade lesion = there is a large consensus. Colposcopy must be performed. It localizes
the lesion and targets the biopsy. Should the colposcopy be unsatisfactory an excisional
procedure has to be done.
- Low grade lesion = as in US guidelines, either immediate colposcopy, or repeat
cytologycal testing at 6 months is recommended. HPV typing is not recommended because of
80 % positivity in this lesion.
-
Atypical squamous cells.
According to the new Bethesda they are classified as follows:
- ASC H
- ASC US
- AGUS
ASC H: as in US, immediate colposcopy should be done
ASC US: the guidelines are also the same: repeat Pap smear, colposcopy or DNA testing.
Colposcopy remains the most attractive solution for the gynecologists.
At least: atypical glandular cells and AIS: colposcopy with cervical biopsy or ECC are
recommended and, under particular conditions endometrial curettage.
As a whole our guidelines are very similar to the US ones. In practice, HPV testing is difficult
to perform as the french health care system does not pay for it.
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SS22-01
DIAGNOSIS OF INTRAEPITHELIAL LESIONS OF THE
CERVIX:WICH IS THE GOLD STANDARD?
CORTES BORDOY, X.; CRESPI, S.; VILIMELIS, J.
POLICLINICA MIRAMAR, ONCOLOGIA, PALMA DE MALLORCA, ESPAÑA.
A series of 118 cytological diagnosis of low grade squamous intraepithelial lesions
(LG.SIL)has been evaluated with human papiloma virus (HPV) test (Hybrid Capture II) and
colposcopy; biopsies were taken from the areas with atypical colposcopy.
This triple evaluation has allowed within this series:
-To diferentiate CIN I with ability to progress (HPV+) from the one which is
regressive/residual.
-To identify HPV carriers women without current lesions.
-To control the quality of the cytological and histological diagnosis.
Given that the presence of HPV is necessary for the development of CIN I and even accepting
that the histologic lesion could be residual and regressive after the cleaning up of the viral
infection, it is probable that a diagnostic pool consistent of the triple test used in this paper
provides more information, is more reliable and is more in accordance with present
knowledge and disponibility than a diagnostic protocol which does not include the HPV test.
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SS22-03
HOW TO MANAGE PATIENTS FOLLOWING INVOLVED MARGINS
CONIZATION
Agostini A, Franchi F, Blanc B.
Department of Obstetrics and Gynaecology. La Conception Hospital.
Management of patient with margins involved by CIN (positive margins) after conization is
not standardized .Risk of persistent or recurrent CIN is higher in patients with positive
margins after conization. However, positive margins are not systematically associated with
residual cervical disease. So , immediate reoperation is often unnecessary. Cytology and
colposcopy follow-up at 3 month and latter is a reasonable practice. This follow up detect
persistent or recurrent disease and decrease rate of unnecessary reoperation. Place of HPV
testing follow-up in patients with positive margins seems interesting and need confirmation.
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SS22-04
ASSESSMENT OF VAGINAL VAULT AFTER HYSTERECTOMY
Peroni M
University of Bari (Italy)
In the study of the vaginal vault, the use of the 3-step standard colposcopy is of high interest.
The elements to consider are: age of the patient, indications to hysterectomy, kind of
performed intervention and possible complementary therapies. The suture line of the vault is
revealed by early colposcopy as well as its evolution and the trophism of the mucosa: trophic,
with early sectors of atrophy, sub-atrophic and atrophic. At the level of the suture line, it is
frequent to observe the presence of inflammatory granuloma that can be simply evoked or
clearly revealed. It is not rare to find fibrous neoformations, both simple or multiple, whose
nature is confirmed by negative cytology. The flogosis of the vault can be easily revealed in
iodine-positive sectors where either a lymphoid colpitis or a vascular pattern are often found:
the acid-sensitiveness and the partial iodine-positiveness are suggestive of HPV etiology.
Such pictures are more frequent in the event of pre-existing and bad-treated CIN/HPV or in
case of plurifocal viral lesions.
As for the intracavitary radiotherapy for early or secondary neoplastic pathologies, the
resulting picture is a sclerotic, whitish and iodine-negative vault. In case of radiotherapy for
external fields the image is made up by regular acid-sensitive neoformations of vessels
suggestive of a benign epithelium, negative at Schiller's test. Sometimes hyperkeratosis
evoking a HPV lesion can be found surrounded by a DES-like pattern at later Schiller's Test.
Biopsy of the hyperkeratosic sector revealed CIN2/HPV. VAINs may appear as simple or
multiple, congested sectors thus acidophilous and iodine-negative at Schiller's test, whose
nature, degree of epithelial atypia and HPV association can be clearly identified only by
biopsy. As for the cancers of the vault, the metastatic ones resulting from endometrial - or
rarely endocervical - adenoK are frequently observed as exophytic patterns with irregular
papillary, bleeding schemes with necrotic sectors evoking their true nature at colposcopy. In
all the cases of preneoplastic or neoplastic conditions, the cytology of the vault is
characterized by abnormalities suggestive of the diagnosis.
In conclusion, before a surgical intervention above the vagina it is necessary to carry out a
careful examination of the cavity as it may host a downward extension of the overlying
pathology, that wouldn't be included by the intervention; such procedure has to be associated
with follow-up every six months and then every two years. Current protocols suggest checks
every 3-4 months for the first two years in case of preexisting neoplastic pathologies while a
delayed follow-up is recommended in the event of benign or benign-supposed pathologies.
Also in our opinion such procedures are good and necessary especially when the side recessi
of the bottom of the vault are carefully inspected as possible locations of deceitful and often
serious pathologies.
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SS22-06
THE CLINICAL AND ECONOMIC BENEFIT OF HPV-LOAD
ASSESSMENT IN THE FOLLOW-UP AND MANAGEMENT OF
WOMEN POST-CONE BIOPSY DUE TO HIGH-GRADE CERVICAL
INTRAEPITHELIAL NEOPLASIA
Almog B, Gamzu R, Bornstein J, Levin I, Fainaru O, Niv J, Lessing JB, Bar-Am A.
Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center
Aim: To evaluate the clinical and economic implications of integrating human papilloma
virus (HPV) load testing to the follow-up and management protocol of women postconization for high-grade cervical intraepithelial neoplasia (CIN2-3).
Methods: We studied 130 qualifying women: 63 were screened biannually by pap smears
(“conventional approach”) and 67 had additional HPV load testing (“HPV approach”). The
former enabled stricter criteria for colposcopy or reconization compared to the latter. Both
approaches were analyzed for cost-effectiveness.
Results: There were 33/67 (49.2%) colposcopic referrals and 24/67 (35.8%)
reconization/hysterectomies compared to 9/63 (14.2%), and 7/63 (11.1%) women. CIN2-3
residual disease was detected in 7/67 (10.5%) and 7/63 (11.1%) women. The "conventional
approach" had more negative colposcopic biopsies and negative reconization/hysterectomy
histologies than the “HPV approach”; the respective cost per detection of one case of residual
disease was US$3573 and US$3485.
Discussion: The "HPV approach" requires fewer colposcopic and reconization procedures to
detect one case of residual CIN2-3. Its higher positive predictive value than cytology provides
a significant decrease in false positive rates and a reduction of US$88 per detected case.
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SS22-05
CONSERVATIVE TREATMENT OF PRECANCEROUS AND EARLY
INVASIVE LESIONS IN MENOPAUSAL WOMEN.
Zanardi Claudio
III Department of Gynecology and Obstetrics, Bologna University, Italy.
Most women in developed countries will live a third of their lives after the menopause. The
inevitable consequence of such an aging population will be a net increase in chronic diseases
and greater risk of cancer.
It also seems that among the cervical neoplasia in the age group between 60 and 70 the high
grade lesions (CIN 2-3) and invasive carcinoma have a prevalence in the ratio of 36% and
45% respectively.
In Italy, between 1993 and 1998 were registered 345 cases of cervical cancer reported: of
these 166 (49%) were in women between 45 and 64 while 109 (32%) were in women over 64
years of age.
Cervical cancer continues to be a main cause of death in older women. Despite benefits of pap
smear screening in reducing mortality, older patients are excluded from most routine
screening programmes.
The lack of estrogens in post-menopausal women is at the root of atrophic epithelial and
connective modifications which reduce uterus size and, in particular, that of the cervix.
This simplifies conservative treatment and thus reduces intra and post-operative
complications.
Conservative treatment such as conization (e.g. by laser CO2) of precancerous and early
invasive lesions (stage IA1) in menopausal women is preferred to hysterectomy because there
is no significant difference in the mortality and relapse percentage rates between the two
surgical techniques.
What is more, the lesions usually arrest themselves at the endocervical isthmus level and only
in exceptional circumstances do they go any further: therefore, incomplete conization (2%) is
no more frequent after menopause than before.
Early detection and possibility for a more conservative approach of preinvasive and early
invasive carcinoma in older women have the potential to decrease mortality and to insure a
reasonable cost to society.
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SS22-07
SINGLE CELL DNA ANEUPLOIDY IS ASSOCIATED WITH
ONCOGENIC HPV INFECTION IN ASCUS AND SIL
Bollmann Reinhard
Institute of Pathology Bonn-Duisdorf, Bonn
Background: Cellular atypia in cervical cytological samples were suggested to be
consequences of a pre-existing human papillomavirus infection. In addition, occurrence of
cells with abnormal DNA-content and high-risk HPV type delineate progressive changes
within the patient group with borderline cytological findings (ASCUS) as well as in squamous
intrapithelial lesions (SIL) according to The Bethesda System.
Aims: Our aim was to analyze the frequency and association of different HPV-types with the
occurrence of DNA-aneuploid cells and whether these findings support the cytological
diagnosis in 44 samples with ASCUS, 63 samples with LSIL and 49 samples with HSIL when
performed from liquid based cytological samples (ThinPrep). DNA-cytometry was performed
by laser scanning cytometry following restaining of the Pap-slides with the DNA-stain
propidium-iodide and at least 10,000 cells were analyzed. HPV-typing was performed by
direct sequencing using the consensus primers GP5+/GP6+ and MY09/MY11.
Results: Oncogenic HPV types were identified in 27% of ASCUS, 76% of LSIL and 96% of
HSIL samples. DNA aneuploid cells occured in 7%, 8% and 92% of ASCUS, LSIL and
HSIL, respectively. Almost half (52/105, 49.5%) of the cases with a high-risk HPV infection
presented aneuploid squamous cells with >9c DNA-content, whereas none of the low-risk
HPV positive or HPV negative cases showed any aneuploidy. Aneuploid cells were found in
three of the six samples (50%), in which an unknown-risk type was demonstrated.
Conclusions: HPV-typing and DNA-content measurements can be efficiently performed from
liquid based cytological samples. High-risk HPV-types and aneuploidy were tightly
associated and characteristic for high-grade lesions. High-risk HPV and cells with >9c DNAcontent in samples with lower degre of atypia (ASCUS, LSIL) probably also refer to
potentially progressive lesions - biologically resembling HSIL - and indicate the need for
active medical management.
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SS23-01
IMPLEMENTATION OF SCREENING PROGRAMMES
Miller A.
In implementing programmes, the prerequisites for success must be kept in mind. Screening
programmes should be planned as part of National Cancer Control Plans, with adequate
consideration given to provision of the necessary resources by the Ministry of Health.
Screening can not succeed without effective treatment of detected abnormalities; there is no
point in attempting to initiate screening if the necessary health care facilities are not available.
These not only comprise facilities for screening and for the treatment of precursors, but also
for the treatment of the invasive cancers that will undoubtedly be detected in the early phases
of the programme. Every programme must be initiated in conjunction with adequate
programmes of professional and public education, the latter carefully planned to take note of
existing cultural beliefs. Without this, it is unlikely that adequate compliance with screening
will be obtained. Further, there should be no financial barrier to participating in programmes.
Just as important, the professional education component should be designed recognising that
physicians rarely understand the requirements for effective public health-oriented screening
programmes, and they must be informed on these, especially guidelines relating to age for
initiating and stopping screening, frequency of repeat screens for those who test negative, and
recommended treatment policies for those who test positive, if cost-effective programmes are
to be delivered. Staff must therefore be adequately selected and trained. Quality control
programmes must be delivered, not least to ensure that if trained staff are not performing well,
arrangements are made to re-train them. In general, national programmes should be preceded
by carefully designed pilot projects, so that potential problems can be identified and solutions
devised.
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SS23-02
RENEWING THE ORGANIZED SCREENING PROGRAME IN
FINLAND
HAKAMA Matti, Ahti Antilla, Pekka Nieminen
School of Public Health, University of Tampere, FINLAND
In Finland the organised screening programme was started in 1963 and it was gradually
expanded to cover the total female population in the country. Women between ages 30 to 60
are personally invited to attend. The screening interval is 5 years. Due to screening the
incidence rates decreased from about 15 to less than 5 per 100’000 woman years. The trend in
risk was increasing before the programme started and the reduction in risk was probably 80 %.
New technologies in cervical cancer screening have emerged. Computer-assisted
methods and testing for HPV are among those most probable to be applicable in large scale
screening programmes. If vaccination against HPV infection will be available, it will affect
the organising and extent of screening programmes. In Finland, mass screening registry
provides means to actively design any renewal of the programme. The implementation of the
new technologies was done as experiment; most important characteristic of the design was
randomising the target population at individual level.
Annual number of invitations in the organized programme is 200’000 and 150’000
women attend in the screening. About 600 cancers and dysplasias are detected. In 1999 one
third of the screenees were randomised into a computer-assisted screening arm. The process
and first year detection rates were described (Nieminen et al. Int J. Cancer, 2003). In 2003 the
women will belong in the same arm round after round. The evaluation between the tests is in
terms of interval cancer incidence. Organised screening programme with mass screening
registry provides the framework to actively design the elements of the programme in such a
way that unbiased evaluation will be possible.
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SS23-03
TESTING OPTIONAL SCREENING TOOLS FOR CERVICAL
CANCER IN THE NEW INDEPENDENT STATES (NIS) OF THE
FORMER SOVIET UNION
Syrjänen K.J. (1) , I.P (10). Shabalova (2,3), Petrovichev N (2). Kozachenko V.P (2,3), Pajanidi A
(2,3), Podistov J.I (2,3), Chemeris G (2,3), Sozaeva L.G (2,3), Zakharova (2) Lipova E.V., (3),
Tsidaeva I. (4), Ivanchenko O.G (4), Pshepurko A.A (4), Zakharenko S (5), R. Nerovjna (6), L.B.
Kljukina (7), O.A. Erokhina (7), M.F. Branovskaja (8), M. Nikitina (9), Griunberg A. (9),
Griunberga V. (9), Juschenko A. (9), Tosi P (10), Cintorino M (10), Santopietro R (10), S.
Syrjänen (1)
National Institute of Health (1)Turku, Finland; (2,3,4) Moscow, Russia; (5,6) Novgorod, Russia; (7,8)
Minsk, Belarus; (9) Riga, Latvia, (10) Siena, Italy.
EC-Project IC15-C98-0321 Research Group: Background and Objective: The incidence and
mortality rates of cervical cancer are rapidly rising in the new independent states (NIS) of the
former Soviet Union. An EC-funded (INCO-COPERNICUS) cross-sectional and cohort study
was recently completed, analyzing the performance of HPV test (HCII) as a potential
screening tool for cervical cancer in these countries.
Methods: A series of 3.175 women (screening-, gynecological-, and STD patients) from six
clinics in Russia, Belarus and Latvia received routine cytology and HPV testing with HC II.
Women with HPV positive results or abnormalities in cytology were examined by colposcopy
and biopsy. The performance characteristics (SP, SE, PPV, NPV, ROC) were calculated for
HCII and PAP smear cytology.
Results: Pap smear cytology detected high-grade lesions with sensitivity of 64.0% (44.883.2), specificity 89.1% (84.5-93.7), PPV 44.4% (28.8-61.0) and NPV% 94.8 (91.2-98.4). Of
the 3.086 samples analyzed by HCII, 33.01% were positive for oncogenic HPV types, with a
wide variation (from 23% to 45%) between the three diagnostic categories (P<0.0001). The
presence of high-grade cytology was significantly associated with HCII-positivity at all cutoff levels (OR 14.4, 95% CI 8.4 to 24.5; Chi-square p<0.0001; 1pg/ml threshold). In ROC
curve, the HCII cut-off point most closely balancing the sensitivity (83.1%) and specificity
(75.6%) was 2pg/ml. The presence of high-grade histology was associated with HCIIpositivity (cut-off 1pg/ml) (OR 4.8, 95% CI 0.7 to 34.2; p=0.047). At the cut-off (1pg/ml),
sensitivity of HCII test was 96.6% (90.0-100), specificity 15.9% (10.6-21.2), PPV 15.1%
(9.9-20.3) and NPV 96.8% (90.3-100).
Conclusions: HCII assay is more sensitive but less specific than PAP test in detecting
significant pathology. Negative HCII test practically precludes high-grade CIN (NPV >95%).
The cost-benefit issues in different settings will be the critical factor for the use of this test as
a screening tool.
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SS23-04
SHANXI PROVINCE CERVICAL CANCER SCREENING STUDY II:
SELF-SAMPLING FOR HPV COMPARED TO DIRECT SAMPLING
FOR HPV AND LIQUID BASED CERVICAL CYTOLOGY.
Belinson JL (1), Qiao YL (2), Pretorius RG (3), Zhang WH (2), Wu LY (2), Washington MF (1), Li L
(2), Fife D (1).
(1) Cleveland Clinic Foundation, Cleveland, Ohio,USA; (2) The Cancer Institute/Hospital, Chinese
Academy Of Medical Sciences, Beijing, China; (3) Kaiser Permanente Fontana, California,Usa
Objectives: To compare the sensitivity and specificity for detection of cervical intraepithelial
neoplasia (CIN) II or worse of a new technique for self-sampling for high-risk human
papillomavirus (HPV) with that of a direct sampling technique for HPV and the liquid based
Pap smear.
Methods: In rural Shanxi Province, China, we examined 8,497 women between the ages of
27-56 years. Each subject underwent a self-sample for HPV (by HC-II assay). The selfsample HPV specimens were obtained with a conical-shaped brush (Digene Cervical
Sampler) that was placed into the upper vagina and rotated. The conical brush was then
placed in STM transport media (Digene, Corp). An average of nine months (range 3-16
months) following the self-sample, subjects were screened with liquid-based cervical
cytology (Autocyte system (TriPath Corp), obtained with the Rovex cervical brush, and direct
HPV tests (specimen obtained from the endocervix the conical-shaped brush and placed in
UCM transport media (Digene, Corp.) Subjects with positive self or direct HPV or abnormal
Pap underwent colposcopy with directed biopsy and endocervical curettage. If no colposcopic
abnormalities were detected, biopsies of the squamo-columnar junction in each quadrant and
an ECC were obtained.
Results: Mean age of the subjects was 40.9 years. 4.4% of subjects had
>=CIN II. 25.6% of subjects had positive self-sample and 23.7% had positive direct test for
HPV (cut point 1 pg HPV DNA). The sensitivity for detection of >=CIN II was 87.5% for
self-sampling for HPV and 96.8% for the direct test for HPV (p<.001). The specificity for
detection of >=CIN II was 77.2% for the self-sample and 79.7% for the direct test for HPV.
With an abnormal Pap defined as ASCUS or greater the sensitivity of the Pap for the
detection of >=CIN II was 88.3% and the specificity was 81.2%.
Conclusion: The new technique of self-sampling for HPV is eight percent less sensitive for
>=CIN II than is direct test for HPV but similar to the liquid based Pap. Current studies are
ongoing to further improve the self-sampling technique, which appears to be well suited for
overcoming barriers to screening in many areas of the developing world.
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SS23-06
WHEN TO START SCREENING ?
Anna-Barbara Moscicki, MD
Most of the cervical cancer screening guidelines in the U.S. recommend that women begin
Pap smear screening when they initiate sexual activity. For most young women in the US this
is during their adolescence. It is also well recognized that HPV infections are most common
in young women, particularly adolescents and young women with incidence rates of up to
70% occurring within 5 years after the onset of sexual activity. In parallel with the high rates
of HPV infections, CIN I or low grade squamous intra-epithelial lesions (LSIL) also peak in
adolescents and young women. In a study of young women, 25% of those infected with HPV
developed a LSIL lesion within 3 years. However, contrary to adult studies where regression
rates of LSIL are reported between 65% and 75%, LSIL regresses in almost all young women.
In a cohort study of young women in the U.S., 95% had regression of their LSIL within 3
years. Studies also show that invasive cancers are extremely rare in adolescents. The 1994-98
SEER data show no cases of invasive cancer among women under 19 years of age and only 2
cases per 100,000 in women aged 20-24 years. HSIL is also rare in this age group: crosssectional studies of large number of Pap smears report rates between 0.1%-2%. Based on this
evidence and expert opinion, American Cancer Society recently released new guidelines for
Pap smear screening in the U.S. which included, “when to start screening”. The guidelines
suggest that cervical cancer screening should begin within 3 years of the onset of vaginal
intercourse but no later than 21 years of age. It also recognized that a huge effort will need to
be made in the U.S. to educate the public and health care professionals regarding the fact that
cervical cytology does not equate pelvic examination and that adolescents must be
encouraged to obtain gynecological health care including contraception and detection of STIs.
The safety net of 21 years was established for women who are unwilling/unable to reveal the
onset of sexual activity and for clinicians who do not screen adequately for the onset of sexual
behavior. Mathematical modeling showed that screening based on years sexual activity,
particularly after 3 years of onset of sexual activity with a cap at 21 years of age was more
cost-effective than universal age based screening at age 18 years. In summary, the new Pap
smear guidelines for when to start screening take into account that there appears to be little
risk of HSIL within the first 3-5 years after initial exposure to HPV and almost no risk of
invasive cervical cancer. In addition, since most lesions regress in adolescents, over-diagnosis
and over-referral are extremely problematic in the US in these young women.
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SS23-07
ESTIMATES OF LIFETIME RISK OF CERVICAL CANCER USING
DATA FROM WOMEN WITH MULTIPLE NEGATIVE PAP TESTS IN
A LARGE PRE-PAID HEALTH PLAN.
Kulasingam S (1), Myers E (1), Sung H (2), Kinney W (3), Miller M (2), Kearney K (2), Hiatt R (4),
Sawaya G (5)
(1) Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina; (2)
Department of Quality and Utilization, Kaiser Permanente Medical Care Program (KPMCP), Oakland,
California; (3) Division of Gynecologic Oncology, KPMCP, Sacramento, California; (4) Division of
Research, KPMCP, Oakland, California; (5) Department of Obstetrics, Gynecology and Reproductive
Sciences and Department of Epidemiology and Biostatistics, University of California, San Francisco,
San Francisco, California.
Context. Current guidelines support screening for cervical neoplasia less often than annually
in women with prior negative cytology. However, the impact of various screening strategies
on lifetime risk of cervical cancer has not been well-characterized.
Objective. To determine lifetime risk of developing and dying from invasive squamous-cell
cancer in women, if adherent to screening every 1, 2 or 3 years.
Design and Setting. The 3-year incidence of cervical cancer in women in a large pre-paid
health plan was estimated and stratified by age (20-39, 40-64) and screening history (1, 2, or
3+ consecutive negative tests). The prevalence of undetected LSIL and HSIL was obtained
using a previously validated mathematical model and combined with the incidence estimates
to determine lifetime risk in the absence of further screening and under adherence to
screening every 1, 2 or 3 years using conventional cytology. Women were assumed to enter
the model at age 34 or 50 (the mean age for women with 3+ consecutive negative tests in each
age group), were screened until age 65, and followed until either death or age 85.
Results. In the absence of further screening, women with one previous negative test had an
estimated lifetime 1.21% (age 20-39) to 0.64% (age 40-64) risk of developing cervical cancer
and a lifetime 0.40% (age 20-39) to 0.20% (age 40-64) risk of dying from cervical cancer. In
comparison, women with 3+ consecutive negative tests had a 1.01% (age 20-39) to 0.30%
(age 40-64) risk of developing cervical cancer and a 0.32% (age 20-39) to 0.08% (age 40-64)
risk of dying from cervical cancer. Screening women aged 20-39 with one previous negative
Pap triennially, biennially, and annually reduces the risk of cervical cancer to 0.33%, 0.25%
and 0.15% and cancer death to 0.08%, 0.06% and 0.03%. Screening women aged 20-39 with
3+ consecutive negative tests triennially, biennially, and annually reduces the risk of cervical
cancer to 0.30%, 0.23% and 0.15% and cancer death to 0.07%, 0.05% and 0.03%,
respectively. Screening women aged 40-64 with 3+ consecutive negative tests triennially,
biennially, and annually reduces the risk of cancer incidence to 0.17%, 0.16%, and 0.13% and
cancer death to 0.04%, 0.04% and 0.03%.
Conclusions. As prior number of negative Pap tests and age increase, lifetime risks of
cervical cancer incidence and mortality decrease. These estimated risks should be placed in
the context of benefits accrued to cervical cancer prevention from screening compared to
costs expended to achieve that benefit with contemporary screening guidelines.
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SS23-10
INTERVENTION TO INCREASE ATTENDANCE AT SCREENING
FOR CERVICAL CANCER. A LARGE POPULATION-BASED
RANDOMISED CONTROLLED TRIAL IN SWEDEN.
Eaker S (1), Adami HO (1,2), Granath F (1), Wilander E (3), Sparén P (1)
(1) Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden, (2) Department of
Epidemiology, Harvard University, Boston, USA, (3) Department of Genetics and Pathology, University
Hospital, Uppsala, Sweden
BACKGROUND: Although cervical cancer is one of the potentially most preventable
malignancies, it is still fairly common. The main reason in settings with screening programs
seems to be non-compliance.
OBJECTIVE: To test whether modifications of the invitation and call-recall system can
increase the compliance to Pap smear screening.
METHODS: We conducted a randomised controlled trial including all 12,240 women invited
to organized screening during 17 weeks in 2001 in Uppsala County, Sweden. Three
successive interventions were tested: 1) modified invitation versus the standard invitation
letter, 2) reminder letter to non-attenders after the first intervention versus no reminder letter,
and 3) phone reminder to non-attenders after the reminder letter versus no phone reminder.
We analysed the proportion of women attending screening after each intervention and the
cumulative proportion after the interventions as well as cumulative proportions of cytologic
abnormalities.
RESULTS: Whereas the modified invitation did not increase attendance compared to the
standard invitation letter (difference 1.3%; 95% CI 2.6 to 2.9), the reminders did. A reminder
letter increased the proportion attending with 9.2% (95% CI 7.9-10.5) compared to women
who did not receive a reminder letter, and a phone reminder increased the proportion
attending with 31.4% (95% CI 26.9-35.9). Combinations of modified invitation, written
reminder and phone reminder almost doubled attendance within 12 months, and the number
of detected cytologic abnormalities was more than tripled.
CONCLUSION: Simple reminders by mail and phone can drastically increase women’s
participation in Pap smear screening (notably those at high risk for cervical cancer), increase
the number of detected precursor lesions and thereby save lives.
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SS24-01
INNOVATION IN CYTOPATHOLOGY
Meisels Alexander
Université Laval, Dept. Path, Québec
Gynecological cytopathology as we know it today may not survive indefinitely. Newer
techniques will tend to replace the manual labor involved in present day practice. Search for
papillomaviruses can be automated and will be very useful in women over 30 years of age,
since at that time about 85% of women will prove virus-free. Taking into consideration the
almost 100% negative predictive value of HPV determination, women who prove negative for
HPV could be screened at considerably increased intervals. Looking for cellular markers
present only in intraepithelial or invasive lesions (i.e. p16ink4a) could result in complete
automation of the screening process. However some conventional cytology will persist in
areas where the newer techniques are not yet available.
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SS24-04
HISTOLOGICAL CORRELATION OF CONVENTIONAL AND
LIQUID-BASED SMEARS WITH REFERENCE TO HPV TESTING
Roger Dachez (1,2), Eve Lefort-Mossé (1)
(1) LCL, Department of Pathology, 37 Rue Boulard, F-75014 Paris, France, (2) University of Paris VII,
Department of Anatomical Sciences
Objective. To evaluate specificity of cytological diagnoses obtained with the ThinPrep Pap
Test (TP), by way of biopsy of the cervix, with reference to HPV testing.
Methods. 688 biopsies of the cervix were examined after a cytological diagnosis of ASCUS
(favor reactive -ASCUS/R - or favor neoplasia - ASCUS/N -, LGSIL or HGSIL, 233 of wich
following a conventional smear and 455 following a smear obtained by the TP method.
Results. Histologic correlations were fairly iderntical for the ASCUS category with the
conventional and the TP methods. HPV Testing was used for triage of these cytological
results. The cytological diagnosis of LGSIL was confirmed in 64% of cases after a
conventional smear, and 68% after a TP. For HGSIL, 73 % of patients had a CIN II or III
after a diagnosis obtained by conventional smear, and 84% after a TP smear.
Conclusion. The TP method has a gretear specificity than the conventionnal smear for
detecting true HGSIL.
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SS24-05
DNA-CITOLIQ SYSTEM (DCS) LIQUID-BASED CYTOLOGY DIAGNOSTIC PERFORMANCE IN RESIDUAL CERVICAL SAMPLES
Dores G B (1), Alves VAF (2), Castelo A (3), Longatto-Filho A (2), Vianna R (4), Taromaru E (1),
Lorincz A (5)
DNA-CITOLIQ Working Group, Brazil. Digene Brasil. (1), Pathology Division Adolfo Lutz Institute,
Brazil (2), Department of Epidemiology Federal University of São Paulo (3), São Paulo Medical School
of University of São Paulo (4), Digene Coorporation (5)
DCS is a recently developed liquid-based cytology system for oncological study of cervical
samples collected into Universal Collection Medium (UCM). Our objective was to compare
DCS diagnostic performance with conventional Pap. Paired specimens were obtained from
3316 women. After cervical scraping with Ayre spatula and endocervical brushing, the
sample was immediately smeared on the slides and alcohol-fixed. The same brush with
residual endocervical cells was again used to scrape the ectocervix and placed in a tube with
UCM and processed according to the DCS protocol. Slides were Pap stained and examined in
6 labs. Unsatisfactory or non-normal cases were re-viewed in a second lab. Discordant
opinions were adjudicated by a panel of cytopathologists. Conventional smears were
satisfactory in 84.2%, limited in 15.7% and unsatisfactory in 0.1%. DCS percentages were
78.3%, 20.5% and 1.2% respectively. Absence of lesion, by both methods occurred in 2893
cases (92.3%); ASCUS was detected in 49 conventional smears (1.6%) and in 53 DCS
samples (1.7%) (p=0.80). CIN 1, CIN2 and CIN3 were detected in 76 (2.4%), 11 (0.4%) and
11 (0.4%) of conventional smears and in 83 (2.6%), 30 (2.0%) and 26 (0.8%) DCS samples
(p<0.001). Three invasive cancers were detected by DCS while only two were detected by
conventional Pap. Only a single "in situ" adenoCa was detected by both methods and no
invasive adenoCa was detected. AGUS was seen in 22 Pap smears and in 8 DCS samples
(p=0.13). We conclude that DCS, even with the limitation of residual endocervical cells,
detected significantly more squamous lesions than conventional Pap, including HSIL (59 vs
24, p=0.0001).
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SS24-06
EVALUATION OF HYPERCHROMATIC GROUPS (HCG) IN
CERVICAL SMEARS: EXPERIENCE WITH LIQUID BASED
CYTOLOGY (AUTOCYTE® PREP) SMEARS
Chivukula Mamatha
medical college of wisconsin, pathology, milwaukee
Hyperchromatic crowded groups (HCG) are frequently observed in cervical smears. Their
association with serious lesions, although uncommon, is a significant potential pitfall. HCG
were defined as groups of dark crowded cells measuring more than 100 µm and easily
detectable at low magnification. We evaluated liquid based (AutoCyte® PREP), PAP stained
cervical smears from 601 women (age- 17 - 74 years (mean- 29.4 years). The cervical
specimens were collected with Cervex-Brush® in SurePathTM collection medium. HCG were
observed in 477 cases. All smears were satisfactory with reference to the endocervical
component. The mean size of HCG was 239.5 µm and their numbers ranged from 1 to 50
(mean19.5) per smear. Predominantly, HCG were benign and represented normal
endocervical cells in 79% (379/477), reactive endocervical cells in 6% (29/477), endometrial
cells in 0.2% (1/477), parabasal cells in 5% (15 atrophic and 7 post-partum- 22/477), and
clusters of inflammatory cells in 5% (25/477). 21 (4%) were associated with epithelial cell
abnormality (ECA): 18 were below 40 yrs and 3 were =/> 40 years. The cytologic
interpretation was ASCUS in 28% (6/21), LGSIL/HPV-CIN 1 in 57% (12/21), and
HGSIL/CIN 2-3 in 14% ( 3/21). The association of HCG with ECA was statistically
significant (p = 0.0174, Chi square test). In the group with ECA, biopsy results were available
in 10 cases. After cyto-histo correlation one LGSIL case showed HGSIL/CIN II in the biopsy.
Thus, a total of 4 HGSIL cases were associated with HCG. Among these four cases, HCG in
the smear actually represented the atypical cells in 3 cases (one case- HGSIL/CIN 2 by
cytology / histology, two cases- ASC-H by cytology but HGSIL/CIN 2 by histology).
Although, the total number of cases in this series is not large enough, most interestingly none
of the 124 cases without HCG showed epithelial cell abnormality. We conclude: a. HCG are
observed in high proportion of cervical smears. b. In the vast majority of cases, HCG were
benign. c. ECA was observed only in cases showing HCG. This is consistent with the
hypothesis that, the presence of HCG in cervical smear represents adequate sampling of
transformation zone and endocervix, thus increasing the chances of detecting epithelial cell
abnormality. d. Only a few cases with HCG were associated with serious ECA. Routine
mandatory and closer scrutiny of all HCG at higher magnification is warranted to avoid
potential pitfall as some of these HCG represented HGSIL cell groups.
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SS24-07
LIQUID BASED CYTOLOGY AN INNOVATIVE METHOD EIGHT
YEARS RESULTS OF EXPERIMENT
Hammou Jean-Claude
Objectives:Evaluation of the thinlayer technique we have developped (CMDH test GENERIC VISION)
Materiel and method:An adequate shaking, a calibration and a centrifugation in liquid phase
are the essentiel an specific stages of this technique.More than 160 000 samples were
prepared according to this methodology in 8 years.
Results:The immediate profit of the technique is the increase of the number of interpretable
samples: 99.9%.First years: net increase of the lesion detection rate in comparison with
conventional cervical smear.
- 1.7% versus 0.9% for the low grade lesions
- 1.0% versus 0.4% for the high grade lesions
After 3 years the detection rate of low grade lesions remained raised: 1.7% while the
ASCUS/AGUS and high grade lesions decreased to reach respectively 1.1% and 0.4%.
Discussion and conclusion:The quality of the thinlayer, the best approach of the endocervical
pathology, the possibility to identify rare events, allowed us at first to increase the detection
of the lesions. After 3 years of "picking up" of lesions forgotten by conventionnal cervical
smear, the rate of lesions of high grade stabilized in 0.4%. It is advisable so to take into
account the notion of times as for the estimate of the lesion rate of the thinlayer technique
compared with of the conventional cervical smear.
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SS24-08
A PROSPECTIVE AND RANDOMISED PUBLIC-HEALTH TRIAL ON
NEURAL NETWORK ASSISTED SCREENING FOR CERVICAL
CANCER IN FINLAND
Nieminen P (1), Hakama M (2),Viikki M (3),Tarkkanen J (4) and Anttila A (3)
1 Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland 2
Tampere University School of Public Health, Tampere, Finland 3 Finnish Cancer Registry, Helsinki,
Finland 4 Department of Pathology, , Helsinki University Central Hospital, Helsinki, Finland
Objective: To evaluate the feasibility and relative validity of interactive neural network
assisted screening (Papnet) in primary mass screening for cervical cancer as a public health
policy (routine screening).
Methods: A randomised, still ongoing trial involving in the first year 152 969 invitees and
108 686 attenders in the organised mass screening in Finland 1999. While drawing invitations
from the population registry, the women were two to one randomised at an individual level to
have their smear analysed either conventionally or with Papnet. The distribution of smears to
different cytological categories, detection rates of dysplasias, in situ carcinomas and cancers
were estimated with smears analysed either conventionally (72461) or by Papnet (36225).
Results: Altogether 108 686 smears were screened and 449 were histologically confirmed as
dysplasias and carcinomas. The detection rates for histologically verified carcinoma in
situ/severe dysplasia, moderate and mild dysplasias were 0.14%, 0.14% and 0.13% with
conventional and 0.14%, 0.14% and 0.11% with Papnet, respectively. The detection rate of
invasive cancer was 0.06? (N=4) with conventional method and 0.08? (N=3) with Papnet.
None of the differences were statistically significant (p > 0.05). Papnet was able to identify
92.5% of healthy women (normal cytology), and the specificity of conventional smear was
92.9%. The positive predictive value (Pap classes III-V) of Papnet was slightly but not
significantly better (55% vs. 51%).
Interpretation: Papnet screening was feasible as a part of routine screening and performed
equally well compared to conventional one as used in Finland there organised mass screening
was practised very successfully in the last 38 years. We are going to continue the trial as
planned to study the potential trends in cervical cancer incidence in both study arms. The
results of years 2000 and 2001 are presented in the congress.
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SS24-09
THE FEASIBILITY OF FOKALPOINT IN PRE-SCREENING OF
CONVENTIONAL SMEARS AND REDUCTION OF WORK LOAD
Hariri Jalil
Soenderborg Hospital, Departement of Pathology, Soenderborg
Background: Our trial revealed that FocalPoint (previously called AutoPap 300) missed
3.5% of the HSILs in primary screening of conventional smears at a cut-off rate of 50%.
These cases were detected by the cytotechnologists. However, due to shortage of
cytotechnologists, we needed the device as a labour substitute even though some of the
smears will have to be screened manually as our work-load exceeds Focalpoint’s capacity.
Further, the trial also revealed that most of the missed cases of HSIL were macroscopically
pale (hypocellular) smears. In an attempt to improve the diagnostic results, we excluded the
"pale smears" from cases examined by FocalPoint.
Materials and methods: 3077 consecutive coventional smears were used for primary
screening by FocalPoint at a cut-off rate of 50%. A selection was then done by excluding 854
(27%) macroscopically "pale smears" and the results were compared.
Results: FocalPoint missed 5 HSILs out of 3077 non selected smears (5/3077 = 0.162). Three
of these 5 smears (60%) were among the 854 "pale smears" that were excluded (3/854 =
0.351). Further, the percentages of both "process review" and smears incorrectly labelled by
"no endocervical cells" were decreased.
Conclusion: In cases where the work-load exceeds the capacity of FocalPoint, it is rational to
screen the "pale smears" manually and subject the rest of the smears to automated screening.
This improves the diagnostic results of the FocalPoint and reduces the work-load of the
cytotechnologists.
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SS25-02
HPV/HIV INTERACTION
MONEY Deborah
University of British Columbia, Dept Obstetrics and Gynaecology, Vancouver, Canada
It has been well established that human papillomavirus (HPV) infection with oncogenic
subtypes causes squamous intraepithelial neoplasia (SIL) and cervical and anal cancer. HIV
infection predisposes to HPV infection in the anogenital tract. This is thought in part to be due
to associated risks of sexual acquisition of these viruses as well as the impact of HIV on cell
mediated immunity. There are high rates of cervical dysplasia reported from studies of HIV
infected women, with up to one-third with SIL at cytology or cervical dysplasia at
colposcopy. The main association with dysplasia and HPV infection is related to persistence
of oncogenic HPV subtypes. Persistent HPV infection is found more often in HIV infected
women than in HIV uninfected. Predictors of persistent infection include, CD4 less than 200,
being unmarried and having a history of injection-drug use. Another association between SIL
and HPV is the amount of HPV DNA present. One study revealed that colposcopically
normal, HIV seropositive women had 7-fold higher amounts of HPV DNA in the genital tract
compared to HIV seronegative women. Some studies have shown an association between the
level of HPV virus and SIL, but overlap of viral load ranges was significant between groups
with and without dysplasia. Another study of an HIV infected women's cohort, has shown that
HPV-16 viral load was 3-fold higher in women with HSIL than in women with normal
cervical cytology. The association of integrated forms of HPV-16 has been associated with
the progression of cervical dysplasia, but the interaction between HIV and HPV integration
has not been well worked out. It is hypothesized that HIV could influence HPV infection
through interactions with the HPV genome to cause SIL, independently from the immune
suppression induced by HIV.
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SS25-05
REAL TIME PCR QUANTIFICATION OF HPV16 DNA LOAD
Dalstein V., Prétet JL., Monnier-Benoit S., Madoz L., Mougin C.
Centre Hospitalier Universitaire de Besançon, Laboratoire de Biologie Cellulaire et Moléculaire,
Besançon
High risk HPV (HR-HPV) are necessary for the development of cervical cancer.
Nevertheless, only few HR-HPV infections persist, and hence will lead to severe cervical
intraepithelial neoplasia. Thus, a single qualitative detection of HR-HPV DNA is not
sufficient, there is a need for additional markers that could predict the outcome of HR-HPV
infections. In this setting, HPV DNA load has been proposed by authors as a predictor for
HPV persistence, and future development of high grade squamous intraepithelial lesions
(HGSIL).
The aim of the present study was to assess whether the viral load profile could be of
predictive value for the appearance of precancerous lesions. We explored such a profile in
HR-HPV infected women who developed a HGSIL.
Two assays were used to estimate HPV load in cervical samples:
- Hybrid Capture II® assay (HCII®, Digene), which is routinely employed in our laboratory,
and provides an approximate determination of the global DNA amount of 13 HR-HPV types.
Results are considered as semi-quantitative, and are given in ng of HPV DNA per mL of
sample.
- A real-time PCR method, which was designed to quantify separately HPV16 E6 and
albumine genes (Taqman technology). Calibration curves were established with serial
dilutions of SiHa cell DNA and human genomic DNA (Roche), respectively. Results are
given as a number of HPV16 copies per cell.
Thirty one women developed a HGSIL, all of them being tested positive for HR-HPV with
HC-II at baseline and all along the follow-up. Between entrance in the study and HGSIL
diagnosis, 67.7% of women demonstrated an increased HCII load, 25.8% a stable load and
6.5% a decreased load.
Among samples from these 31 women, 22 were available for real-time PCR analysis, which
showed the presence of HPV16 at baseline in 11 women (50%). In a parallel study, we have
also found a good correlation between HCII and real time PCR for results comprised between
1 and 1000 pg/mL
The profiles of quantitative HPV load of the 11 HPV16 positive women are under
investigation, and results are expected to be consistent with those obtained with HCII.
Moreover, results for HR-HPV infected women who did not develop a HGSIL during followup will also be presented.
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SS25-07
RAPID AND SENSITIVE DETECTION OF HSV DURING PREGNANCY
AND BEFORE LABOR BY DFA WITH MONOCLONAL ANTIBODIES
Askienazy-Elbhar M (1), Azoulay M (2)
(1) Laboratoire de Biologie Magenta, Paris, (2) Service de Gynécologie-Obstétrique, H. des
Diaconnesses, Paris
INTRODUCTION. Screening for HSV infections before delivery is consensual due to the
neonatal contamination risk and consequences for the newborn. We developed a DFA
providing detection and typing within 2 hours with a high sensitivity vs. cell culture when
performed, allowing negative women to deliver while positive had a caesarean section (CS)
PATIENTS and METHODS. From 1999 to 2002, 101 HSV typing were performed for
pregnant women (PW). 15 (15%) of 6-8 month pregnancy had symptomatic recurrent
infection (RI), or were asymptomatic with history of HSV in the couple; 45 were in their 8th
month, 61 in their 9th month or before delivery and checked after treatment. They were
cautiously sampled from vaginal walls, fornices, exo and endocervix, and vulva ulcers or
vesicles by rubbing one cotton swab per site and HSV type, then discharged in 2SP. Pellets (3
per site, 1 per type and 1 control) as well as positive HSVI and HSVII controls were laid on a
DFA slide, then processed according to standard DFA procedures with HSVI or HSVII Mab
FITC conjugated (Biorad), then read under epi-fluorescence (X400). 2SP test vials were
stored at -80°C for virus culture.
RESULTS.19/101 PW (18%) were positive, HSVI in 1, HSVII in 15 (78%). 3 PW (17%)
with a doubtful test had CS. Primary infection (absence of HSV antibodies) was found in only
1 of the PW. Of the 100 PW with suspected RI, 65 (65%) had a history of HSV, most of them
being in their last month of pregnancy. 35 (35%) with 3-7 month of pregnancy had no history
of HSV but a partner with symptoms or HSV antibodies and were unaware of a previous
contact. Acyclovir was given during the 9th month to the 16 positive patients. Negative
subsequent tests allowed delivery. Only 5 treated patients were found positive a few hours
before delivery and underwent CS. No positive culture was found with a negative DFA (high
NPV). 3 positive DFA had negative cultures.
DISCUSSION. Given the high prevalence of gestational herpes (18%) and the fear of CS and
neonatal contamination, DFA test performed properly should be recommended in the
screening of PW in the last month and just before delivery preferably to culture.
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SS25-08
ASSESSMENT OF THE RISK FACTORS, PATHOGENETIC
MECHANISMS AND PROGNOSIS OF HPV INFECTIONS AND
CERVICAL CANCER IN HIV-POSITIVE AND HIV-NEGATIVE
WOMEN WITH IMPLICATIONS IN SCREENING AND
MANAGEMENT (HPV-PATHOGENESIS STUDY)
BRANCA M (1), GIORGI C (1), BENEDETTO A (2), FAVALLI C (2), CIOTTI M (2), PICCIONE E (2),
SESTI F (2), SBIROLI C (3), MARIANI L (3), VECCHIONE A (4), COSTA S (5), SANTINI D (5),
AGAROSSI A (6), DI CARLO A (7), DI BONITO L (8), SYRJÄNEN K. (1)
(1) Istituto Superiore di Sanità (ISS), Roma; (2) Università di Tor Vergata, Roma; (3) Istituto Regina
Elena, Roma; (4) Università La Sapienza, Roma; (5) Azienda Ospedaliera S. Orsola Malpighi,
Bologna; (6) Ospedale Luigi Sacco, Milano; (7) Istituto San Gallicano, Roma; (8) Università di Trieste,
Trieste; ITALY
HPV infections are more common in patients with HIV-associated immunosuppression, and
in these patients, HPV infections are usually more severe and refractory to conventional
treatment, and the risk of progression to a high-grade CIN and cervical cancer in these
patients is significantly increased. The mechanisms responsible for this different clinical
behaviour have not been systematically explored as yet. Compared with the situation 10 years
ago, when an invasive cancer was an infrequent cause of death in these women, the disease
profile of AIDS has significantly changed, with clearly prolonged survival times and more
protracted clinical course, making the progression of CIN to cervical cancer a clinically
relevant issue.
The general long-term objective of this multidisciplinary (HPV-PathogenISS) project is to
increase our understanding on the basic mechanisms regulating the biological behaviour of
cervical HPV infections and cancer precursors in both HIV-negative and HIV-positive
women. This project is a combination of a cross-sectional (prevalence)- and a prospective
follow-up (cohort) study of two series (HIV+ and HIV-) of women with different risk of
cervical cancer. In addition to detailed epidemiological survey, regular colposcopic
examination and biopsy, the patients will be meticulously sampled for HPV typing (PCR),
HPV serology and real-time PCR (TaqMan) to assess viral integration and viral load. Biopsies
will be subjected to immunohistochemical (IHC) analysis using a carefully selected set of
antibodies monitoring the key molecular events in cancer biology, initially tested in a
retrospective series of CIN and cervical cancer. This type of combined cross-sectional and
cohort study, supplemented with an extensive retrospective analysis, should give answers to
the key questions mandatory for designing new strategies of early detection, diagnosis and
treatment of these patients, as a part of an organised cervical cancer prevention policy.
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SS25-04
DIAGNOSIS OF SEXUALLY TRANSMITTED INFECTIONS (STI)
USING NON-INVASIVE SPECIMENS
Garland S.
Royal Women's Hospital, Department of Microbiology & Infectious Diseases
The transmission of HIV is increased in the presence of other STIs, with the attributable risk
for each varying with the prevalence within a population. Interventions that lower the
prevalence of STIs have reduced HIV transmission. Hence HIV public health prevention
approaches must include STI control strategies. Reduction of STIs is particularly difficult as
the majority of infections are asymptomatic (yet is a pre-requisite for successful STI control).
Hence reliance on the treatment of symptomatic disease alone is unlikely to significantly
affect the transmission dynamics at a population level. Moreover where screening is
incorporated in STI control strategies, lack of access to appropriate services (especially in
rural and remote areas), reluctance of at-risk populations to attend for treatment, fear of
invasive genital examinations, and lower sensitivities of conventional diagnostic assays
reduces the effectiveness of programmes.
With the advent of molecular technologies (polymerase chain reaction [PCR], ligase chain
reaction, transcription mediated amplification), diagnoses of STIs have been revolutionized
and allow the use of non/minimally - invasive sampling techniques e.g. first-catch urine,
cervico-vaginal lavage, low vaginal swabs and tampons. We have extensively studied the
utility of self administered tampon from women for diagnosis of STIs e.g. in a study of 660
women who had urine, tampon analyzed by PCR and genital specimens, by conventional
assays for detection of Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas
vaginalis, that detection of all 3 organisms was significantly greater by PCR than
conventional assays. Further positivity rates by PCR for C. trachomatis, N. gonorrhoeae and
T. vaginalis were 6.5, 10.1 and 17.9% for urines whereas 7 (p=0.45), 21.2 (p<0.001) and 22%
(p<0.001) of tampon specimens respectively.
Self-sampling collection devices for detection of various STIs, methods which have a high
patient compliance, are robust during various transport conditions and ultimately could be
applied to STI prevention programmes.
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SS25-06
IS PRESERVCYT TRANSPORT MEDIUM SUITABLE FOR
CHLAMYDIA TRACHOMATIS DETECTION ?
1
2
Anne Bianchi ( ) Christophe Ronsin ( ) .
1
Laboratoire Départemental de Seine-Saint-Denis, Conseil Général, Bondy , L.C.L Service de Biologie
2
Moléculaire, Ivry sur Seine
Chlamydia trachomatis infection is one of the most common sexually transmitted infection
(STI) and represents a major public health problem. Thus, it is important that C. trachomatis
is diagnosed at an early stage and that infected persons are treated. High-risk populations,
such as sexually active young women, should be screened for C. trachomatis (using molecular
diagnostic methods based on nucleic acid amplification tests such as PCR, LCR, TMA or
SDA) and monitored for pre-cancerous lesions of the cervix, however, the major problem is
the technical feasibility of this kind of screening program. The ideal situation would be if a
single specimen could be used both for cytological monitoring and to detect a number of
pathogens so that the patient does not have to be examined repeatedly.
The ThinPrep Pap Test preserves endocervical cells in a liquid alcohol (PreservCyt® transport
medium, Cytyc Corporation) to ensure optimal morphological preservation. Many studies
have evaluated the detection of HPV DNA in the residual sample volume of liquid-based Pap
tests and two recent studies demonstrated that ThinPrep cervical cytologic specimens can be
used to detect the herpes simplex virus. Three recent studies reported the technical feasibility
of detecting C. trachomatis from the ThinPrep Pap Test by use of molecular methods and by
use of a direct fluorescence assay. We carried out a prospective study to evaluate the ability of
the automated PCR COBAS Amplicor CT/NG test to detect C. trachomatis in the PreservCyt
transport medium used for the ThinPrep Pap Test (1) and our results prove that this medium is
a suitable collection medium for the routine screening of C. trachomatis infections. The
ThinPrep Pap Test can be used both to monitor for cervical cancer and to screen for C.
trachomatis and others STI from the same specimen, without repeatedly examining the
patient.
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SS26-02
RATIONALE OF IMMUNOTHERAPY FOR GENITAL WARTS
Stanley Margaret
University of Cambridge, Pathology, Cambridge
HPV infection in the genital tract is common in young, sexually active individuals, the
majority of whom clear the infection without overt clinical disease. Those who develop
lesions, also in most cases, mount an effective cell mediated immune response and the lesions
regress. Lesions in which productive viral infection is occurring (ano-genital warts and
LGSIL) are not associated with inflammation or histological evidence of immune activity.
Regression of ano-genital warts is accompanied histologically by a response characteristic of
delayed type hypersensitivity, animal models support this and provide evidence that the
response is regulated by CD4 T cell dependent mechanisms. The increased prevalence of
HPV infections in individuals immunosuppressed either as a consequence of organ
transplantation or HIV infection demonstrates the central importance of the CD4 T cell
population in the control of established HPV infections. Although it seems clear that the CD4
T cell subset is critical for the induction and regulation of the host response to HPV the nature
of the effector response remains unclear. There is increasing evidence that both natural killer
cells and antigen specific cytotoxic T lymphocytes (CTL) are important effectors but these
responses are still poorly understood. The fact that a natural HPV specific immune response is
associated with lesion clearance opens up strategies for immunotherapy. This approach would
require the induction of a virus-specific immune response, either by immunomodulatory
agents and/or immunisation with the relevant viral antigens.
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SS26-03
COMBI-THERAPY FOR EGW´S – WHICH ARE THE OPTIONS?
Von Krogh G.
Condylomas are to 90% caused by HPV types 6/11, but long-lasting cases coexist in 1/3 with
oncogenic HPVs (16/18 etc). Condylomas are per se not associated with increased cervical
cancer risk. Papular and macular lesions should be biopsied for differential diagnosis
including Bowenoid papulosis and Bowen´s disease.
No therapeutic ”recipe” exists; most modalities achieve clearance within 1-6 months, but
relapses occur for months or years in 20-30% of patients due to failure of specific immune
recognition. Choice of therapy depends on a combination of factors; wart numbers,
anatomical distribution, morphology, and patient preferences. Podophyllin and 5-FU are not
recommended because of efficacy/toxicity problems. Psychosexual counselling, condom use
and cotial rest periods may be important.
Management has elements for co-operation between primary and specialists care. Small
lesions may be quickly and effectively treated with ablative therapy such as cryotherapy or
electrosurgery, excision and laser, or by trichloroacetic acid (TCA). Self-treatment is based
podophyllotoxin products and/or imiquimod (5% cream). Cyclic use of podophyllotoxin 0.5%
solution or 0.15% cream for 3 days at 4 days intervals is cost-effective and convenient for
first-line self-therapy, curing up to 80% of acuminate warts. Imiquimod 5% cream is highly
valuable against “problem cases”, when cell mediated immune response for clearance may be
stimulated, but is costly and takes on average 7-8 weeks. Intra-anal, vagina, intraurethral and
cervical warts may be treated by TCA, electrosurgery and laser. Combination therapies are
often used in clinical practise but evidence based proof is missing.
Warts may enlarge in early pregnancy but often regress spontaneously after delivery. Risk of
the infant developing laryngeal papillomatosis is 1/400. There is no proof that treatment
diminishes this risk. Anti-symptomatic and conservative treatment with TCA or surgery is
recommended. Caesarean section is only indicated because of blockage of the vaginal outlet.
Many recurrent cases require repeated surgery, when adjuvant interferon may has be tried but
with controversial results. HIV infection and transplant-grafted patients are linked to increase
of multicentric and oftentimes refractory condylomas. Topical therapy with cidofovir 1-3%
cream/solution is sometimes successful.
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SS26-04
IMMUNOTHERAPY FOR EXTERNAL GENITAL WARTS
Garland S.M.
Royal Women’s Hospital, Melbourne, Australia
External genital warts (EGW) are caused by human papillomavirus (HPV 6 11) and are one of
the commonest sexually transmitted infections (STI). EGW estimated to infect 1% of the
sexually active population. Genital HPV infections are very common (as measured by HPV
antibodies) and up to 70% of sexually active individuals have been infected at some time,
with around 15% (HPV DNA positive as measured by polymerase chain reaction) actively
infected at any one time.
Management of the EGW is largely cytotoxic or physically destructive. As these treatment
nodalities do not specifically eradicate latent HPV infection, there is a high recurrence rate
(20-70%).
A new agent imiquimod, the first member of a new class of immune response stimulators,
enhances both the innate and acquired immune pathways (particularly TH1 cell mediated
immune response). This results in antiviral, anti tumour and immunoregulatory responses. In
clinical trials, Imiquimod as a patient applied topical 5% cream is clinically efficacious and
safe in the management for EGW, for which it has been licensed since 1997. Although not
licensed, it has encouraging activity against HPV related intraepithelial dysplasias such as
VIN and VAIN.
Apart from immunomodulation, prophylactic vaccines have the greatest potential to reduce
disease globally, in the long term. Preliminary data with sub-unit prophylactic vaccines show
a robust immune response, prevention of infection and of disease to the genotypes contained
within the vaccine.
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SS26-06
GLOBAL APPROACH TO GENITAL WARTS MANAGEMENT
Langley Paul
3M Pharmaceuticals, International Marketing, ST PAUL MN
Improving public and provider awareness of the management of any disease state requires a
thorough understanding of both the clinical presentation and outcomes of therapy
interventions. Key elements would include the distribution of therapy interventions, the extent
of practice pattern variation, resources used to support therapy and the cost-effectiveness of
existing and new therapies. The purpose of this presentation is to show how, in Europe,
through a series of clinic and provider-based chart reviews, 3M Pharmaceuticals has
attempted to improve awareness of external genital warts. This was prompted by the entry of
a new 3M product Aldara (imiquimod), an immune response modifier, into the market place.
These chart reviews, which occurred in 6 countries over the period 200-2002 identifed, in
selected clinics and practice settings, treatment patterns, outcomes and costs. Issues that had
to be be addressed were: survey and questionnaire design, identification of clinic and
physician practices, data extraction and quality control, database assembly and the analysis
and dissemination of results. Given the focus was on both treatment patterns and costs, care
had to be taken in identifying the total costs of treatment within practice settings from the
perspective of the payor. This was the first time chart reviews had been attempted on such a
scale (with over 15,000 patient charts evaluated) and pointed to the extent to which treatment
choice impacted costs - where these costs reflected not only difference in unit costs but the
distribution of visits reported to achieve a completed outcome. The analysis showed how
treatment costs varied by EGW presentation (e.g., significantly higher costs associated with
perianal warts) and choice of therapy. In a number of treatment settings it was possible to
show that inappropriate therapy choice (e.g., podophyllin) was associated, after standardising
for patient and wart presentation characteristics, with significantly higher costs. The
management implications were significant and supported a more data driven approach to
patient management algorithms and the choice of initial therapy.
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SS27-02
ABDOMINAL RADICAL TRACHELECTOMY
Bosze Péter
Saint Stephen Hospital, Department of Gynaecology, Budapest
Cervical cancer in early stages is highly curable with the exceptions of a few cases associated
with adverse prognostic factors. The reported 5-year survival rates are 90-98% in most series
depending on the actual stage of the disease. Many affected women are in the reproductive
age, and a substantial number wish to preserve their fertility. Consequently, there has been an
attempt to preserve the uterine body, and Dargent and his co-workers have introduced the
vaginal radical trachelectomy. As an alternative, we in international collaboration have
developed the abdominal radical trachelectomy, and our firs experience is reported. Since
1997, all patients with IB1/2 and a desire to retain fertility were considered for this procedure.
Thirty-four women underwent this procedure. In all cases the menses returned within 3
months. Complications were the same as with abdominal radical hysterectomy, and only one
patient required secondary abdominal hysterectomy due to p5 smear, but no residual tumour
was found. Seven women have tried to conceive: one miscarriage occurred at 5 weeks, one
had a 4-week old pregnancy at the time of surgery, which ended in miscarriage 4 weeks later,
one delivered a healthy baby after full time pregnancy and one is currently pregnant (33
weeks). The indications and advantages of the abdominal trachelectomy as compared to the
vaginal counterpart and abdominal radical hysterectomy will be discussed, as well as
technical details will be addressed.
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SS27-03
VAGINAL RADICAL TRACHELECTOMY
Querleu Denis
Institut Claudius Regaud Toulouse, France
Fertility sparing procedures are common in the field of cervical intraepithelial neoplasia and
early invasive (IA1) disease. Dargent, in xxxx, demonstrated the technical feasibility of a
radical (laterally extended with colpectomy) trachelectomy (removal of the cervix sparing the
upper endocervix and the uterine corpus) in the surgical management of invasive cervical
carcinomas in young patients. The vaginal operation is preceded by a laparoscopic pelvic
lymphadenectomy that participates to the surgical management of the disease and defines the
node status, knowing that conservative management is not indicated in node positive patients.
The outcome of patients is now available in several concordant studies, including a casecontrol study [Covens 1999]. The overall survival is not affected by uterine conservation, and
no uterine recurrence has been observed. This is due to the attention paid to exclude patients
presenting with tumors larger than two centimeters and tumors extending into the endocervix
in whom a 1 centimer margin cannot be obtained without definitively impairing fertility.
Pregnancies occur in approximately one-third of patients. There is a definite risk of premature
birth or late abortion that is only partially prevented by permanent isthmic cerclage and
additional cervical closure during pregnancy. Eventually, 60% of pregnancies give birth to
viable newborns.
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SS27-05
RADICAL VAGINAL TRACHELECTOMY FOR INVASIVE
CERVICAL CANCER: THE QUÉBEC EXPERIENCE.
Roy M, Plante M, Renaud MC.
CHUQ-Pavillon Hôtel-Dieu Québec, Québec.
Introduction: The use of operative laparoscopy in gynecologic oncology has paved the way
to a more conservative approach in radical treatments of some cancers, particularly cervical
cancer. After the vaginal approach which shortens the hospital stay and the morbidity of a
radical hysterectomy, a new fertility-preserving radical treatment has been proposed: the
Radical Vaginal Trachelectomy (RVT).
Results: This technique has been used since 1991 in Québec. Until February 2003, 66 patients
with early-stage cervical cancer desiring to retain their fertility were treated by a laparoscopic
pelvic lymphadenectomy (LPL) and RVT. The median age was 31 (22-42). Twenty-one (21)
were FIGO stage Ia2, 39 Ib1, 2 IIa and 4 Ia1 (VSI+). Most of the tumors were squamous (39),
grade I (38), and the lesion was 2 cms or less in 58 patients. Median operating time was 250
minutes ( 220 for the last 40 cases), and mean blood loss 200cc. Complications were mainly
due to the LPL (3 arterial injuries) rather than the RVT (one iatrogenic cystotomy and one
parametrial bleeding). No operative or post-operative complications in the last 44 cases. The
mean follow-up is 58 months. Two patients recurred including one who had a small-cell
neuroendocrine tumor. Nineteen (19) patients had a total of 33 pregnancies with 22 live
births. One newborn died of E.Coli-septicemia and one of a cardiac malformation. Six (6)
patients had early miscarriages, 1 a TAB and 2 second trimester abortions (17 and 20 weeks).
Four (4) babies were premature (< 34 weeks). Two patients are currently pregnant (33 and 8
weeks).
Conclusions: LPL-RVT seems to be a good treatment modality for early-stage cervical
cancer. It preserves fertility without lowering the chances of survival. But because of the risk
of prematurity, pregnancy is high risk.
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SS27-07
RADICAL VAGINAL TRACHELECTOMY RESULTS IN A USA
CENTER
Burnett Alexander
University of Southern California, Dept Gynecologic Oncology, Los Angeles, USA
Objective: To examine our experience with radical vaginal trachelectomy in women with
early cervical cancers who desire to maintain fertility.
Methods: Women who underwent radical vaginal trachelectomy with pelvic
lymphadenectomy over a six year period are the basis of this report. Subjects were selected
for this treatment on the basis of favorable cervical tumors and a desire to maintain fertility.
All subjects were informed that this therapy did not represent standard treatment for early
stage cervical cancer. Obstetrical and oncologic outcomes were evaluated.
Results: 25 women underwent this procedure. The median age was 30.4 years (range 22-43).
19 were nulliparous, 4 had one prior child, and 2 had two or more children. Mean tumor
diameter was 1.1 centimeters (range 0.3-3.0). Mean operative time was 318 minutes, with
mean blood loss of 293 cc, and average hospital stay was 3 days. Three patients had transient
neuropathy post-operatively. No patient required laparotomy. Two patients had completion of
radical vaginal hysterectomy for an inability to clear the cancer with trachelectomy and one
had post-operative radiation for high risk features on final pathology. With an average followup of 24 months, there has been one recurrence which occurred at three years after the
procedure. Four women have become pregnant: one woman delivered twins at 24 weeks, one
woman delivered a singleton at term, one patient had rupture of membranes and
chorioamnionitis at 20 weeks gestation, and one is currently pregnant in the second trimester.
Conclusions: Radical vaginal trachelectomy with pelvic lymphadenectomy permits
preservation of fertility in selected patients. To date, with more than 150 cases reported in the
literature, recurrence rates are comparable to those seen with radical hysterectomy.
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SS27-08
RECENT PROGRESS ON FERTILITY PRESERVING TREATMENT
OF INFILTRATIVE CERVICAL CANCER CLINICAL
APPLICATIONS.
Pomel Christophe
Institut Gustave Roussy, Gynecologic Oncologic Surgery, Villejuif
In 1994, Daniel Dargent proposed a conservative management of the uterus body in cervical
cancer patient. This was called the radical vaginal trachelectomy. The fertility results from a
few teams show interesting results. In our institution we performed a radical trachelectomy
with complete dissection of both uretere and uterine artery throw laparoscopy in 8 patients.
Patients of less than 40 years old wanted to preserve the fertility were eligible. The tumor
should be less than 2 cm. Intra-operative endo-cervical margin and pelvic iliac nodes at frozen
section must be free of disease. These patients were informed about the risk of relapse and
about the risk of early term and late spontaneous abortion, and that infertility may be an issue.
Mean patient’s age was 32 Parity less than 1.The mean patient’s weight was 63Kg. The mean
operative time was 210 minutes. There were no laparotomy conversion or blood transfusion. 5
over 8 patients have had a section of the uterine artery with 3 accidental sections of both
uterine arteries and two sections of a single uterine artery. There were two uterine
perforations. An average of 19 pelvic lymph nodes was removed. The mean postoperative
hospital stay was 7.7 days. Bowel motility resumed after a mean time of 1.5 days. A bladder
catheter was left in place for a mean period of 6 days (4-13). One patient was reoperated eight
days later for umbilical evisceration under local anesthesia. Three patients had postoperative
urinary retention with a bladder dysmotility. One patient had tumor emboli on the cardinal
ligament at the specimen examination, therefore a completion of combined radiation and
chemotherapy on the pelvis area was mandatory. Except of the patient mentioned above all
patients had menstruation even these with bilateral uterine artery section.
To date, two patients desired a pregnancy. Only one pregnancy was noted with an early
spontaneous abortion. To date, there were no recurrence. The mean follow-up is 28 months
(3-46). Laparoscopic radical trachelectomy is a feasible, reproducible surgical procedure. A
very careful patient’s selection must be done in order to reduce the risk of relapse.
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SS27-09
RECENT PROGRESS ON FERTILITY PRESERVING TREATMENT
OF INFILTATIVE CERVICAL CANCER
Onnis A.
Past Head Professor of Padua University
The progress in the conservative treatment of cervical cancer is correlated with the high
progress we have reached in the last 25-30 years in the field of early diagnosis.
In the past, gynecological cancers were nearly always advanced with a poor prognosis, a bad
quality of life and heroic treatments with heavy radiotherapy or enlarged operations. In that
period the clinical application on Pap smears, colposcopy and micro-colposcopy were at the
beginning.
On the contrary, today all over the world the surgical management of female genital cancers
are radical without mutilation, like for early cases of cervical cancer (conization, radical
trachelectomy), vulvar cancer (non-mutilating radical vulvectomy).
This is possible because of the results of colposcopy and pap smears which are fascinating,
allowing very early diagnosis. Today, in the management of early-infiltrative cervical cancer
a conservative surgical strategy can be followed, which is very important in young women
who desire children.
Fertility can be preserved with a radical trachelectomy technique with endoscopic
lymphadenectomy proposed by D. Dargent with a great success all over the world.
The problem of the management of early cervical cancer in young women who have not had
children has always been felt. I would like to recall here that half a century ago, with these
aims, Prof. Franc Novak of Ljubliana proposed a "radical abdominal subcorporeal extirpation
of the cervix with bilateral pelvic lymph node dissection in cancer in situ of the cervix uteri"
published in Acta Medica Yugoslavica, Vol. VI, 1, 59, 1952.
In that period this surgical proposal was not followed, but now the surgical progress is very
strong. The vaginal radical trachelectomic technique by D. Dargent allows us to preserve the
uterine corpus and respect the wish of children for young women.
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SS28-01
INTEGRATION OF HUMAN PAPILLOMAVIRUS GENOMES IN
ADVANCED CERVICAL DYSPLASIA, BASIC CONCEPTS AND
CLINICAL APPLICATIONS
von Knebel Doeberitz Magnus
Institute of Molecular Pathology, Department of Pathology, Heidelberg
Cervical dysplasia is induced by persistent high risk human papillomavirus (HR-HPV)
infections. Although in the initial stages of cervical dysplasia HPV genome persists as
episomal molecule, they are frequently integrated in advanced dysplasia or cervical cancers.
The detection of integrated HPV genomes therefore might indicate the rapid progression of
cervical precancers into invasive carcinomas. Moreover, since the integration site of the viral
genome in independent dysplastic lesions is never the same, the detection of a cell population
with a specific viral integrate suggests persistence of a dysplastic cell population and might be
a useful marker in the post therapy management of patients with cervical or lower genital tract
disease. Integrated HPV genomes are transcribed in fusion transcripts with the viral E6 and
E7 oncogenes at their 5`ends and cellular sequences at their 3`ends. These integrate derived
transcripts can be detected and further characterized by the recently described APOT assay.
Using this assay, we found that progression of cervical precancers into cervical carcinomas is
associated with emerging cell clones that express integrate derived viral oncogene transcripts.
We further found, that persisting dysplasia or multi-focal disease is associated with a high
prevalence of lesions that express integrate derived viral oncogene transcripts. Basic concepts
and potential diagnostic applications of this assay will be discussed.
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SS28-02
CLINICAL SIGNIFICANCE OF GENETIC ALTERATIONS OF
CHROMOSOME 3,7,X AND EGFR GENE IN UTERINE CERVICAL
CANCER PROGRESSION.
Cianciulli AM * Corrado G.** Merola R.*Vizza E.** Marzano R.* de la Iglesia Lopez F.*Vincenzoni
C.**, Galati G.M.**Sbiroli C.**
Department of Clinical Pathology, ** Department of Gynecology Oncology, Regina Elena Cancer
Institute, Rome, Italy
Premalignant lesions of the uterine cervix represent a pathological continuum of mild to
severe epithelial dysplasia. Aim of this study is to investigate the possible role of genetic
alterations in the genesis and progression of cervical dysplasia and to determine the clinical
significance of genetic alterations.To verify that, we analyzed the aberrations of chromosomes
3,7, X and the status of EGFR gene by fluorescence in situ hybridization (FISH). Fifty four
women (22 to 75 years of age) were included in this study and grouped according to the
Bethesda System. These surgical specimens consisted of 27 cases of high-grade squamous
intraepithelial lesions (HSIL) but also of low-grade SIL (LSIL) of the cervix, 14 cases of
cervical carcinoma (CC) and 13 fibromatosis (as control). The average numbers of
monosomic and polisomic cells of LSIL, HSIL and CC, for evaluated chromosomes, groups
were significantly higher than those observed in fibromatosis group. The mean number of
polisomic nuclei for chromosome X in LSIL samples showed a statistical difference when
compared with cervical carcinoma cells (p<0.009). No significant difference in terms of
fraction of polisomic nuclei for chromosome X emerged between LSIL and HSIL groups.
While the chromosome 3 and X polisomy is the most consistent chromosomal aberration in
CC, in addition it defines the transition from HSIL to CC: in fact the statistical difference is
present (p<0.002 and p<0.0001 respectively) when we compared the chromosomal 3 and X
aberrations in HSIL and CC groups. Using the ratio between the EGFR and chromosome 7
centromeric signals, no samples showed gene amplification. Our results demonstrate the
importance of the increase of DNA copy number of chromosomes 3 and X in the
development and in progression from HSIL to CC. Moreover the status of chromosome 3 and
X could be a useful genetic marker not only to predict the risk of progression of high-grade
SIL, but also to evaluate their possible relationship to HPV infection.
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SS28-03
GENETIC SUSCEPTIBILITY OF ONCOGENIC HUMAN
PAPILLOMAVIRUS (HPV) IN CERVICAL CANCER
Dao D.D. (1), Sierra-Torres C.H. (2), Robazetti S.C. (4), Naranjo de Gomez M. (3), König, R. (4),
Lester J. (1), Au W.W. (4), Tyring S.K. (4)
(1) Houston Advanced Research Center (HARC); (2) Universidad del Cauca, Popayán, Colombia; (3)
Universidad Central de Venezuela, Caracas, Venezuela; (4) The University of Texas Medical Branch,
Galveston, TX, 7755, USA.
The role of certain HPV infection in the development of cervical cancer may be influenced by
genetic composition and environmental exposure. The relationships of human leukocyte
antigen (HLA) polymorphisms with cervical cancer provide another scenario to the infection
process, the clearing of HPV infection, or the development of cervical cancer. The presence of
specific HLA alleles indicates an increased risk for cervical cancer, whereas other HLA
alleles are associated with a decreased risk for cervical cancer. Although there are some
expected differences in HLA genes based on ethnicity, certain HLA alleles occur with
increased frequency in patients with cervical neoplasia. Previously isolated ethnic groups may
express gene frequency differences related to genetic susceptibility. This study investigated
associations between genetic susceptibility and the presence of cervical cancer in Venezuelan
women. To understand better the contributions of ethnicity to cervical cancer development,
115 Venezuelan women (36 positive for cancer and 79 negative) of varying cervical cancer
status provided a personal summary of behavioral, familial, and environmental factors. Blood
samples, cervical swabs and a cervical biopsy were obtained for subsequent HLA typing,
PCR analysis of HPV DNA presence, and HPV typing. Quantitative data included cervical
cancer status scores, DQB1 haplotypes, and presence of specific alleles. The distribution of
cervical cancer across a number of DQB1 alleles varies significantly from the expected values
under the null hypothesis of independence. Risk ratios indicate that the cancer risk associated
with alleles 0201/0202 and 0402 is significantly higher. The results of this Venezuelan
population differ from those of other ethnic studies such as Honduran, African American
women and other Hispanic subpopulations.
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SS28-04
GENOMIC INSTABILITY AND CHROMOSOMAL ABERRATIONS IN
POLYPLOID CELLS OF HIGH-GRADE SQUAMOUS
INTRAEPITHELIAL LESIONS (HSIL)
Mehes Gabor
University of Pecs, Department of Pathology, Hungary
The persistant infection with human papillomavirus (HPV) is related with increasing
cytological atypia (SIL) the potential of which is unclear in a given time point of monitoring.
Initially, HPV induced genetic instability result in low frequency random chromosome
aberrations. On the other hand, HPV also induces polyploidization in squamous cells.
Recently, we demonstrated a correlation between the occurrence of highly
polyploid/aneuploid cells in the cervical cytological samples and high risk HPV infection. In
the present work we analyzed, whether these cells reflect genomic changes at the
chromosomal level.
Methods: 13 samples with the cytological diagnosis of HSIL according to the Bethesda
System were selected. HPV typing and DNA content measurements were performed from the
same liquid fixed cytological samples. Nuclear DNA content was measured in monolayer
preparations by laser scanning cytometry (LSC). Hyperdiploid cells with >5c and with >9c
DNA content were further analyzed for numerical aberrations of the chromosomes 3 and 17
by fluorescence in situ hybridization (FISH) following repositioning.
Results: The number of cells analyzed by LSC ranged between 42,000 and 72,000. Cells with
>5c DNA content were found more frequently than cells with >9c DNA content (5-122 and 144 cells, respectively). The FISH analysis demonstrated polysomy of chromosome 3 and 17 in
the majority of the cells. However, the rate of aneusomy (other, than 2, 4, 8 and 16
chromosome copies) was significantly higher in cells with >9c DNA content than in cells with
>5c DNA content or the normal diploid cells. The imbalance of chromosome 3 and 17 copy
number was also increased in cells with >9c DNA content. Moreover, in three out of the 13
analyzed HSIL samples, recurrent abnormal chromosome 3/17 ratio was demonstrated in a
significant part of the cells, suggesting a clonal origin of these cells.
Conclusion: Highly polyploid/aneuploid cells in HSIL accumulate cytogenetic aberrations
which are detectable by FISH analysis. These cells may reflect early genetic aberrations of
stemlines with tumorigenic potential in a very concentrated fashion.
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SS28-06
CHROMOSONE 9 POLYSOMY: USE AS AN INTERMEDIATE
ENDPOINT BIOMARKER IN INTERIM ANALYSIS
Vlastos AT (1), Follen M (2), Yamal JM (3), Atksinon EN (3), Hittelman WN (2)
Department of Gynecologic and Obstetrics, Geneva University Hospital, Geneva, Switzerland (1).
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center,
Houston (2), Texas .Department of Biomathematics, The University of Texas M. D. Anderson Cancer
Center, Houston, Texas (3)
Background: Several genetic alterations have been described in cancers including: subtle
sequence changes, alterations in chromosome number, chromosome translocations, and gene
amplications. All of these changes have been described in the cervix.. While cervical cancer is
considered to be causally linked with HPV, for which E6 and E7 genes are oncoproteins,;
there remains much to discover about the role of genetic alterations in this process.
Methods: We conducted a randomized clinical trial of 4-HPR in 39 patients with three
blinded histopathologic reviews. In interim analysis, the 6 month response rate was not
statistically significantly different but it favored one group. At 12 months, the results were
statistically significantly poorer in one arm. When code was broken, the treatment faired more
poorly that the placebo arm. No confounders were indentified. In the present study, in situ
hybridization analysis of Chromosome 9 polysomy was carried out and quantitative
measured.
Results: The cell index, the ratio of the number of total chromosome 9 copies to the total
number of ells, increases significantly in 4-HPR arm over the 6 months of treatments (p=0.02)
The percentage of monosomic clones decreases significantly in the 4-HPR arm (p=0.03).
While the percentage of cells with a triploid index is not statistically significantly different;
those with greater than 2 copies are increased at 6 months in the 4-HPR arm (p=0.06).
Conclusions: These results support the clinical histopathologic reading in a quantitative
manner suggesting that 4-HPR at 200 mg/day may be inhibiting the regression seen in the
placebo arm by inducing genetic instability.
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SS28-07
THE DETECTION OF HPV 16 SPECIFIC CD8+ T LYMPHOCYTES IN
THE PERIPHERAL BLOOD OF WOMEN WITH VIN 3 USING AN
ELISPOT ASSAY OF INTEFERON GAMMA RELEASE.
Todd R, Steele J, Etherington I, Luesley D.
Institution: Birmingham Womens' NHS Trust, Birmingham , UK.
INTRODUCTION: VIN is increasing in incidence and appears to be associated with HPV
16 in up to 90% of cases. The observation that HPV related disorders such as VIN are seen
more commonly in immunosuppressed individuals suggests a critical role for cell mediated
immunity in the resolution and control of HPV infection. Before effective immunotherapies
can be developed, a better understanding of the immune responses to HPV are needed. Much
of the work to date has focused on cervical disease. In this study we have screened for and
detected CD8+ T cell responses to HPV 16 proteins in 22 women with active VIN 3.
METHODS: 22 women with active VIN 3 were identified and venous blood samples
obtained. Following CD4+ T cell depletion, the cell populations were used in an ELISPOT
assay of interferon-g release to screen ex-vivo for CD8+ T cell responses to HPV16 E6, E7
and E4.
RESULTS: Of the 22 samples obtained, 19 were suitable for analysis. 58% (11/19) of the
patients demonstrated CD8+ T cell reactivity to one or more of the proteins with the
magnitude of responses varying. Many of the samples recognised more than one protein and
more than one peptide on the same protein. Responses were more prevalent and generally
greater in magnitude to E7 peptides being seen in 9/19 (47%) compared with 32% and 16%
for E6 and E4 respectively. There was no obvious correlation between patient characteristics
and the magnitude or specificity of the responses obtained.
CONCLUSION: The responses seen were encouraging given the suggested paucity of HPVspecific T cells in peripheral blood. This may reflect the high sensitivity of the ELISPOT
assay and that it is not restricted by the individuals HLA type. While these results are in
keeping with those reported by others looking at cervical disease, the question remains why
these patients have persistent HPV infection and VIN despite having HPV 16 specific CD8 T
cells. It is likely that the T cells are either non-functional or that other problems with antigen
presentation exist. As far as we are aware this is the first report describing the detection of
HPV-specific T cells in peripheral blood of women with VIN.
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SS28-08
RELATIVE DISTRIBUTION OF ONCOGENIC HPV TYPES IN
BENIGN AND PRE-MALIGNANT CERVICAL BIOPSIES. A STUDY
WITH HPV DNA SEQUENCE ANALYSIS.
Andersson S, Mints M, Holmqvist M, Wilander E
Institute for Clinical Science, Division of Obstetrics and Gynaecology, Huddinge University Hospital,
Karolinska Institute, Stockholm
Direct DNA sequence analysis of HPV DNA is the most specific method at present available
for identifying genital oncogenic HPV types. We investigated 170 consecutive ß-globin and
HPV positive genital biopsies with benign or pre-malignant light microscopic alterations by
sequence analysis of HPV DNA obtained by PCR with primers GP5+/GP6+, amplifying a
140 bp DNA sequence of the HPV L1 gene. Fifteen different oncogenic HPV types were
identified (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 70 and 73). Most common were
HPV 16 (51%), HPV 31 (8%), HPV 18 (7%) and HPV 45 (6%). The prevalence of HPV types
39, 52, 56, 59 and 73 was <1%. All virus types occurred in SIL´s (squamous intraepithelial
lesions) except HPV type 39 and 52, which were present only in a few benign alterations. We
also investigated eighty consecutive biopsies with cervical high grade squamous
intraepithelial lesions (HSIL) and a positive reaction for HPV16, with regard to
polymorphism in codon 83 (T or G, nucleotide 350) of the E6 gene by employing a rapid PCR
and SSCP based method. 62.5% of the cases contained HPV 16-P (prototype) and 37.5%
HPV 16-V (variant, L83V). However, the relative frequency of HPV 16-P varied with age. In
women younger than 40 years it was 25%, whereas the corresponding figure for women older
than 50 years was 58%. This difference was statistically significant (p < 0.05)
By dividing the women in age categories it was further evidenced that the proportion of HPV
16 E6-V increased with age. Our results demonstrate that at least thirteen different oncogenic
HPV types are present in preinvasive cervical lesions and that 16 E6-V seems to give a more
permanent (and oncogenic) infection than HPV 16 E6-P.
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SS28-09
P16 IS FREQUENTLY EXPRESSED IN HIGH GRADE SQUAMOUS
LESIONS OF THE GENITAL TRACT
Finegan M (1), Han A (2), Edelson M (3), Rosenblum N (3)
(1) Department of Obstetrics and Gynecology, (2) Department of Pathology, The Reading Hospital
and Medical Center, West Reading, PA; (3) Section of Gynecologic Oncology, Fox Chase Cancer
Center, Philadelphia, PA
AIM: To examine the role of p16 in the pathogenesis of squamous carcinoma of the
gynecologic tract.
METHODS: Squamous carcinoma and carcinoma in situ (CIS) from the female genital tract
were examined for the expression of p16 by paraffin immunohistochemistry.
RESULTS: Seventy-four percent (40/54) of cases showed p16 expression. By primary site
77% (23/30) of cervical, 67% (6/9) of vaginal, and 85% (11/13) of vulvar primaries expressed
p16, but two endometrial primary squamous carcinomas were negative (0/2). In addition, p16
was not identified in non-dysplastic tissue and low grade dysplasia. Cases where there were
matched vaginal or vulvar and cervical primaries in a given patient there was concordant
positive p16 expression.
CONCLUSIONS: p16 is frequently expressed in squamous carcinoma of the cervix, vagina,
and vulva, but not seen in cases of benign and low grade lesions, It may be a marker of
transformation from a low grade to a high grade lesion, and could be useful as an adjunctive
marker for progression to a high grade lesion. More cases of endometrial primaries need to be
studied to see if these evolve by a p16 independent pathway
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SS28-10
DETECTION OF "HIGH-RISK" ONCOGENIC HPV16 E6 DNA BUT
NOT HPV18 DNA IS A FREQUENT FINDING IN VULVAR LS AND LSASSOCIATED SCC.
Regauer S, Aigelsreiter A, Liegl B, ReichO (1), Beham-Schmid Ch.
Institute of Pathology and 1 Department of Gynecology, University of Graz, Austria
Vulvar squamous cell carcinomas (SCC) occur in two distinct groups: 1) basaloid SCC with
HPV-related cytopathic changes and 2) keratinizing SCC in longstanding vulvar lichen
sclerosus (LS) without histological evidence of viral cell changes. LS-associated vulvar
carcinogenesis is not understood but believed to be unrelated to viral oncogenesis. We tested
this hypothesis and investigated multiple tissue blocks of archival, formalin-fixed, paraffinembedded biopsies / excisions of 60 women with LS (average age 60.6 years), 35 patients
with LS-associated keratinizing SCC (average age 70.6 years), 25 patients with basaloid SCC
unassociated with LS (average age 69.5 years) and 25 patients with biopsies of "normal"
vulva by PCR with primers corresponding to the E6 region of HPV16 and HPV18 DNA. In
20/25 patients with basaloid SCC, we detected strong HPV16 DNA signals in all tested
samples along with histo-morphological proof of HPV-infection on H&E stained sections,
e.g. koilocytes with multiple nuclei, nuclear membrane irregularities, perinuclear halo.
Despite the lack of viral cell changes, we identified HPV16 DNA signals in 23/65 patients
with LS, 14/35 patients with LS-associated SCC and in 9/25 control biopsies. HPV18 DNA
could not be demonstrated in any of our cases indicating a role for epidermotropic HPV16 but
not mucosotropic HPV18 in vulvar carcinogenesis. We demonstrate a high prevalence of
high-risk HPV16 DNA integration into vulvar epithelium in the normal population and in
patients with LS. The clinical significance of these findings is presently unclear. For basaloid
SCC it is likely that HPV may be the sole etiological agent in carcinogenesis, but for LSassociated carcinogenesis, the integrated oncogenic HPV16 DNA may only play a role after a
change in the host’s immune status and / or after other genetic events may have occurred.
Since our understanding of vulvar LS-associated carcinogenesis at this moment is rather
rudimentary, a routine PCR-screening in lesions of vulvar LS for HPV may identify women
who might be at higher risk for developing a SCC.
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SS28-11
CYCLIN B1 (CB1) EXPRESSION IN CERVICAL INTRAEPITHELIAL
NEOPLASIA (CIN)
Vlastos AT, Pelte MF (*), Soria JC (**), Hamilton D (***), Beffa V, Bischof P
Departement of Gynecology and Obstetrics. Geneva University Hospital. (*)Departement of Pathology.
Geneva University Hospital. (**) Institut Gustave Roussy. Paris. (***)Houston Medical School. The
University of Texas Houston
Purpose: CB1 is a key molecule for G2/M transition during the cell cycle and is
overexpressed in various tumor types. Overexpression of CB1 has been recently evaluated in
other types of squamous cell carcinomas like lung and tongue. However, the expression status
of CB1 in cervical dysplasia and its clinical significance are still unknown. Experimental
Design: We used immunohistochemistry to examine the expression of CB1 in 66 specimens
obtained from patients with a histologically proved CIN I (15), II (18), III (13) and normal
control (15 and 5 normal atrophy).
Results: Interestingly, expression of CB1 was more frequently observed in CIN III as
compared to normal or atrophic cervix, CIN I, and CIN II (P=0.0001 in every cases).
Medianes of the percentage of cells expressing CB1 range from 3% to 3.6% in normal to CIN
II lesions whereas it is 18.8% in CIN III lesions. Receiver operating characteristic (ROC)
curves demonstrates a specificity of 77% with a sensitivity of 100% when 5% positive cells
are taken as cutt-off. For 98% specificity, the sensibility is 69% but the cut off rises to 11,6%
of positive cells.
Conclusions: Our study indicates that CB1 is overexpressed only in CIN III lesions. If
confirmed by a larger study, CB1 expression could be then tested on screening cytological
specimens.
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SS28-12
THE POTENTIAL OF MIB1 AS A MARKER FOR CERVICAL
INTRAEPITHELIAL NEOPLASIA GRADE 3 IN CERVICAL SCRAPES.
Bekkers RLM (1), Bulten J (2), de Wilde PCM (2), Menko EM (1), Gemmink JH (2), Melchers WJG
(3), Hanselaar AGJM (2), Massuger LFAG (1).
Departments of Gynecology/Obstetrics (1), Pathology (2), and Medical Microbiology (3), University
Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands.
Goal: To asses whether the MIB1 labeling index (LI) in cervical scrapes can be used to
identify patients with cervical intraepithelial neoplasia (CIN) grade 3 among patients referred
with ASC-US, mild-, or moderate dyskariosis scrapes.
Methods: The MIB1 LI was assessed in AgarCyto cell blocks of cervical scrapes from 320
patients and was related to the presence of CIN grade 1-3, and the presence of hr-HPV. Linear
logistic regression analysis was used to assess the value of the MIB1 LI and/or hr-HPV
detection as a classifier for the presence of CIN 3.
Results: There was a highly significant relation (p<0.001) of the MIB1 LI with the presence
of CIN 3 and also with the degree of CIN detected, regardless of the referral cervical scrape.
There was also a highly significant relation (p<0.001) of hr-HPV detection with the presence
of CIN 3. Logistic regression analysis and calculation of ROC curves showed that the MIB1
LI is a better classifier than hr-HPV detection for the presence of CIN 3. However, the MIB1
LI classification, as well as the hr-HPV classification, can not identify all patients with CIN 3
in the different subgroups of referral cervical scrapes, even if a higher threshold is used.
Conclusion: There is a highly significant relation of the MIB1 LI in cervical scrapes with the
presence CIN 3 in patients referred with ASC-US, mild-, or moderate dyskariosis. However,
neither the MIB1 LI as hr-HPV detection can accurately predict the presence or absence of
CIN 3 in the individual patient.
References:
1. Bulten J, van der Laak JA, Gemmink JH, Pahlplatz MM, de Wilde PC, Hanselaar AG.
MIB1, a promising marker for the classification of cervical intraepithelial neoplasia. J Pathol.
1996;178:268-73.
2. Dunton CJ, van Hoeven KH, Kovatich AJ, Oliver RE, Scacheri RQ, Cater JR, Carlson JA
Jr. Ki-67 antigen staining as an adjunct to identifying cervical intraepithelial neoplasia.
Gynecol Oncol 1997;64:451-5.
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SS29-01
THE NATURAL HISTORY OF VULVAL INTRAEPITHELIAL
NEOPLASIA (VIN)
Jones Ron
National Women's Hospital, Colposcopy, Auckland, NEW ZEALAND
VIN (HPV related; warty/basaloid)
The natural history of squamous VIN continues to be the subject of considerable debate.
While some consider the lesion to have a significant invasive potential, others consider that
only symptomatic lesions require treatment. A number of important points need to be
addressed when considering the natural history of VIN.
(1) A clear distinction needs to be made between HPV related (warty/basaloid) VIN and non
HPV related differentiated VIN.
(2) VIN 1 is an uncommon histological diagnosis and usually represents HPV effect or
reactive change alone. Most VIN lesions present as high grade (VIN 3) histology.
(3) There is no evidence that the VIN 1-3 histological spectrum represents a biological
continuum.
(4) Clinical observations have been of considerable assistance in defining the natural history
of this lesion, e.g. spontaneous regression.
(5) Discussions on the natural history of VIN have been confused by failure to clearly
differentiate between the outcome of treated and untreated VIN.
The current (1986) classification of squamous VIN is similar to CIN. The International
Society for the Study
of Vulvovaginal Disease (I.S.S.V.D.) has recommended (2003) a change to the current
classification. VIN 1 will no longer exist as it refers only to reactive of HPV effect, and VIN 2
and 3 will be combined and termed VIN. VIN will be reclassified into VIN (HPV positive,
warty/basaloid) and differentiated VIN (HPV negative) types.
Background
By 1960 the body of clinical observations had firmly established that carcinoma in situ of the
vulva (VIN 3) was a precursor of invasive vulval cancer. Coinciding with the increasing
frequency of the condition from the 1970s, there was a significant shift of opinion with
respect to its invasive potential. This related to the reported "low progression" rates to
invasive cancer of 2-5%. It was not generally appreciated that these "low progression" rates
reflected the outcome following treatment and not the natural history of the untreated
condition. The nature of VIN was also questioned in a number of case reports of spontaneous
regression of the lesion. Finally, it was considered that the 30 year interval between the mean
ages at presentation of VIN and vulval cancer tended to exclude a causal association.
Morphological evidence of the neoplastic potential of VIN
VIN 3 can be demonstrated adjacent to approximately 30% of squamous cell carcinomas of
the vulva. Nearly all
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Stage 1A vulval cancers arise in a field of VIN 3. These "associations" provide circumstantial
evidence that VIN 3 is a cancer precursor.
There is very little documented evidence of histological or clinical progression of VIN 1 to 3.
The VIN grading system should therefore be seen as a convenient histological description of a
spectrum of intraepithelial changes and it should not be inferred that it is a biological
continuum.
Clinical Evidence
a) Progression.
Untreated VIN 3. There are very few reports of the outcome of untreated VIN 3. One study
reported progression in seven of eight untreated cases to invasive cancer, including three
women in their 30s.
Treated VIN 3. Almost all large series of treated VIN 3 report invasion to occur in 2-5% of
cases during follow-up. This is approximately ten times the rate of cervical cancer following
treatment of CIN 3. The reported transit time to invasion is less than 10 years in more than
90% of cases. However, when follow-up extends for sufficiently long periods, "new" vulval
cancers are seen to arise many years following adequate treatment of VIN 3. Small VIN
lesions may rapidly progress to invasion, while others may slowly extend over large areas of
adjacent skin before becoming invasive. Immunosuppressed women have a small increased
risk of progression.
Two mechanisms exist for the development of vulval cancer in women with a history of VIN.
First, cancer may arise as a consequence of the progression of persisting VIN and second, by
the de novo development of cancer in a "field of risk". The latter possibility is supported by a
large Norwegian study which reported 8 of 16 (50%) women who later developed vulval
cancer, had negative resection margins at the time of primary surgery for VIN.
Two studies report that the increasing incidence of VIN seen over the past 20-30 years may
now be responsible for a changing pattern of squamous cell carcinoma of the vulva. In one
study, two cohorts of women with squamous cell carcinoma of the vulva and separated by at
least two decades were reviewed. In the earlier cohort, only 1 of 56 (1.8%) patients was aged
under 50 years, whereas in the more recent cohort, 12 of 57 (21%) patients were aged under
50 years. Ten of the 13 (77%) of women aged under 50 compared with 13 of 100 (13%) of
women aged over 50 had HPV related warty or basaloid VIN associated with the invasive
vulval carcinoma.
The behaviour of VIN 1 and VIN 2 lesions is poorly documented. VIN 2 is a relatively
uncommon histological
diagnosis and like its counterpart on the cervix, should at present be regarded for management
purposes as a high
grade abnormality.
Up to 90% of the common warty/basaloid VIN lesions are HPV positive. Such lesions should
be considered to be part of a contiguous field of risk. HPV 16 has been demonstrated serially
in the vulva of women with VIN 3 and in their subsequent VIN related squamous cell
carcinomas. Up to one half of all women with VIN have at some time had preinvasive or
invasive disease of the cervix and vagina. While recurrences of VIN or the development of
invasive cancer may occur at the margins of incompletely resected disease, such events may
occur anywhere in the field of HPV infected (and previously normal) vulval, urethral, perianal
and vaginal skin.
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b) Regression
Spontaneous regression of high grade VIN occurs in a well defined clinical setting. It is
generally seen in non white women under 30 years. The median transit time to complete
regression is less than one year. The lesions are frequently asymptomatic and may be seen in
association with pregnancy. The lesions are usually multifocal, pigmented and papular.
2. Differentiated VIN (HPV negative)
This HPV negative lesion is relatively uncommon and seen mainly in older women with
lichen sclerosus and/or squamous hyperplasia and has a strong association with keratinising
carcinoma. It has subtle histological features largely limited to the basal epithelium and the
VIN 1 to VIN 3 grading system is not applicable. Differentiated VIN appears to have a
relatively brief intraepithelial phase before progressing to invasion.
A comprehensive list of references can be found in:
Jones RW. Vulval intraepithelial neoplasia: current perspectives. Eur J Gynaec Oncol XXII,
2001; 6: 393-402.
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SS29-02
THE ROLE OF HPV IN VIN
M. van Beurden, M van Seters
Netherlands Cancer Institute and Academic Medical Center, Amsterdam, the Netherlands
In 1982 HPV DNA was for the first time detected in VIN 3. Since then several large PCR
studies for HPV DNA detection showed a very high prevalence of HPV DNA between 78%
and 92%, most of the VIN 3 lesions contain HPV-16 DNA. HPV DNA is more often present
in multifocal lesions than in unifocal lesions and more often present in VIN 3 lesions
coexisting with other dysplasitc multicentric lesions in the vagina and cervix than in
unicentric VIN 3 lesions. All HPV DNA-16 DNA positive VIN 3 lesions contain HPV RNA,
corresponding with the E6 and E7 gene product. This transcriptionally active HPV-16
underlines the oncogenic activity of HPV-16 in these lesions.These data support the etiologic
role of HPV in the pathogenesis of VIN 3 and coexisting multicentric VAIN and CIN. The
high prevalence of HPV-16 DNA in the lesions suggests that these women may have a
genetic predispostion causing a less adequte immune response to HPV-16.
Therefor imiquimod 5% cream, an immune response modifier with indirect antiviral and
anitumor properties, has been investigated and it was shown in several pilot studies to be
effective and safe in multifocal VIN 2/3. Results of larger randomized trials are being awaited
for in the near future.
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SS29-03
VIN: CONVENTIONAL TREATMENT MODALITIES.
Roy M.
CHUQ-Hôtel-Dieu de Québec, Québec, Canada
The incidence of vulvar intraepithelial neoplasia (VIN) is raising, specially in the young
population. Therefore, the treatment must be conservative and individualized. Many factors
have to be considered: age of the patient, risk of invasion, symptomatology, and distribution
of lesions.Today the therapeutic choices for the clinician are between local destructive
methods or excision. In young patients, where lesions are usually multifocal, C02 laser
vaporization seems to be the treatment of choice except in pregnancy. In that situation, postpartum spontaneous regression has been reported and the therapeutic decision should be
postponed until re-evaluation four months after the delivery. In post menauposal patients,
where invasion is more frequent, the treatment of choice is excision. This technique has the
advantage of giving a specimen for histo-pathologic studies to confirm the absence of stromal
invasion. Local excision should also be the treatment of choice in young patient who are
immuno-suppressed, and in cases where the lesion is raised with an irregular surface and
invasion cannot be ruled out. The success rate of those different therapeutic modalities is
between 70 to 90%, but recurrence is at least 30 to 40%. Because of this high recurrence rate,
the multifocality of VIN and the importance of the vulva in the psycho-sexual life of patients,
the clinician has to take into consideration, not only the cure rate of the treatment, but the long
term effects on the psychological life of the patient. Today’s treatment modalities leave
sequellae: loss of tissue and scrarring with excision, and long healing time, loss of hair,
vitiligo and pain with laser vaporisation. Imiquimod, an immune response modifyer, has been
successful in treating external warts with minimal side effects. It has been reported to control
VIN in some patients. If further studies confirm the efficacy of Imiquimod in VIN, this would
be a major addition to the treatment modalities of this affection.
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SS29-05
CHRONIC VESTIBULITIS: NEW DEVELOPMENTS AND
UNDERSTANDING
Micheletti L., Bogliatto F., Chieppa P., Massobrio M.
Department of Gynaecology and Obstetrics, University of Torino, Italy
The best management of a disease depends on a good communication among physicians
dealing with the disease. Therefore, an appropriate terminology, which leads to a
classification and to a correct diagnostic and therapeutic approach, is essential. Under this
light, the term “vestibulitis”, accepted for more than 20 years to describe a disease entity
characterized by vulvar pain with no visible cause, has been recently criticized following a
better understanding of the complex pathogenesis of this entity.
Actually, the disease identified by the word “vestibulitis” is not essentially an inflammatory
condition, as a consequence the ISSVD in 1999 has recommended to abandone this term,
ambiguous and partially responsible to perpetuate much of the confusion surrounding vulvar
pain. This confusion is demonstrated by the wide range of treatments reported in the
literature: surgery, diet, oral and topical antimycotics - corticosteroids, interferon topical
injections, antidepressants, psychological therapy, biofeedback techniques, ecc.
According to ISSVD terminological recommendations, the term “vestibulodynia” should
substitute the term “vestibulitis” to identify more precisely the pain localized to the vestibule.
Regarding pain neurophysiology it must be known that the painful signal from mucouscutaneous pain receptors and nociceptors is carried to the spinal cord and travel up in the
lateral spinothalamic columns to the thalamus reaching the cortex. As a result of these
connections both central and peripheral neurones can become sensitized, leading to an
amplification of the painful signal which provokes local hyperesthesia (touch
hypersensitivity) or hyperalgesia (painful stimuli hypersensitivity).
The better understanding of pain neurophysiology underlines that “vestibulodynia” (formally
vestibulitis) is a complex syndrome where physiological, sensory, affective, behavioural,
cognitive, and sociocultural factors variously interact. Therefore, a physician dealing with a
case of vestibulodynia may know that the woman requires time and discussion and
reassurance as well as the plan for management which may include a psychologic, sexologic
or psychiatric counselling.
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SS29-06
SENTINEL NODE IN VULVAR CANCER
Sideri Mario
Efferent lymphatic channels drain mainly into the superficial (inguinal) lymphnode group,
situated along the medial half of the inguinal ligament and around the proximal long
saphenous vein; a second group of nodes, the femoral nodes are situated below the level of
the superficial fascia. Di Saia et al. suggested that omission of the femoral lymphadenectomy
with the of decreasing morbidity without compromising survival. This hypothesis was tested
in GOG study which reported 6 recurrences in 121 patients with a T1 N0,1 tumor after
superficial groin node dissection containing negative inguinal nodes. This modification of the
groin dissection is lilkely to increase groin recurrence, and therefore mortality.
Levenback et al. reported on the use of blue isosulfan dye for the identification of sentinel
node (SN). In their latest series of 21 patients reported in 1995 in no case was a non sentinel
node positive if a sentinel node was negative. However, with blue dye the SN was missed in
34% of the evaluated groins and no lymphatic channel was identified in 24% of the patients.
Di Cesare et al. reported thec use of lymphoscintigraphy as another method for localizing
SN). It has been proposed as a technique to localise the sentinel node in substitution of the
dye injection, in melanoma and breast cancer patients (28, 5). This modification of the
original technique allows to localize and remove the sentinel nodes during surgery; Two
subsequent reports have been published on the technique in squamous cell vulvar cancer. In a
preliminary study coducted in our Institution using lymphoscintigraphy and gamma detecting
probe on 50 patients with early vulvar cancer, the pathologic status of the sentinel node was
predictive of the groin status in 100% of cases; there was no "skip" metastasis and the
nineteen patients who showed negative sentinel nodes resulted negative for lymph node
metastasis
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SS29-08
INCIDENCE OF HPV 16 AND 33 IN PATIENTS WITH
MULTICENTRIC LOWER GENITAL TRACT DYSPLASIAS
Hampl, M., Bender, H.G., Küppers, V.
Heinrich Heine University of Duesseldorf, Department of Obstetrics and Gynecology, Duesseldorf,
Germany
BACKGROUND: The incidence of cervical, vulvar and vaginal intraepithelial neoplasia
Grade II and III (CIN,VIN and VAIN II-III) is increasing and is diagnosed at a younger age
than previously. In some patients, CIN coexists with dysplastic lesions at the vulva and less
frequent vagina. Both, moderate and severe CIN and VIN most have been found to contain
human papillomavirus (HPV) DNA of the high risk or intermediate risk types. Aim of this
study was to analyse the prevalence of HPV-DNA type 16, 33 and others in concomitant
lesions of patients with CIN and VIN/VAIN and to determine if concordant or discordant
HPV typing exists in these concomitant lesions.
METHODS: Histologic analysis and human papillomavirus DNA detection were performed
on alternating slides of paraffin embedded biopsies taken colposcopically during the same
operation. DNA was extracted by standard method and polymerase chain reaction was
performed with general and type specific primers for HPV DNA.
Results: 15 patients with concomitant CIN II/III and VIN/VAIN II/III were included in the
study. CIN and VIN coexisted in 13 cases, 2 patients were diagnosed with CIN and VAIN.
Human papillomavirus DNA of the high risk type 16 was detected in about the same
frequency than HPV 33 DNA. We did not find any discordant HPV infections when the
biopsies were taken at the same time, in all cases, the same virus type was found in both
lesions. One patient was found to have a multicentric HPV 67 infection (CIN, VIN, AIN), a
virus type with unknown oncogenic potency.
Conclusions: Theses results indicate that identical HPV types are responsible for the
induction of dysplastic cervical and vulvar/vaginal lesions in the same patient if biopsies are
taken at the same time point. The oncogenic HPV types 16 and 33 are predominantly found in
those lesions as well as rarely HPV type 67 DNA, a virus with so far unknown oncogenic
potency.
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SS29-09
OVEREXPRESSION OF P53, P16 AND PTEN IN VULVAL
INTRAEPITHELIAL NEOPLASIA
Tasker G, Dean D, Charnock F, Wojnarowska F, Manek S
Oxford Radcliffe Hospitals NHS Trust, Dept Dermatology, U.K.
The oncoproteins E6 & E7 of HPV (human papillomavirus) bind to various cell-regulating
proteins. Mutated p53 has a long half-life and is easily detectable by immunohistochemistry.
Overexpression of p53 has been found in vulval cancers and VIN (vulval intraepithelial
neoplasia). pRB (retinoblastoma gene product) normally inhibits the transcription of p16, but
is inactivated by E7. Increased expression of p16 in CIN (cervical intraepithelial neoplasia)
has been found, however the results are contradicted in vulval neoplasia. Although pTEN
mutations have been demonstrated in vulval cancer, pTEN expression in VIN has not been
reported.
A retrospective immunohistochemical study of histology specimens of high-grade VIN was
undertaken. All specimens were reviewed and lichen sclerosus excluded. HPV-typing was
performed using PCR. Specimens were stained with monoclonal antibodies to p53, p16 and
pTEN. The staining pattern in dysplastic epithelium was compared with adjacent epithelium,
and graded by intensity, thickness and pattern of staining.
In total 34 vulval biopsies were selected from 10 women in each decade of age at initial
diagnosis (30’s, 40’s and 50’s) and 4 women in their 60’s. Three were diagnosed with VIN 2,
twenty-five with VIN 3, and six had VIN 3 and minimally invasive carcinoma. 19 specimens
were positive for high-risk HPV.
Normal epithelium adjacent to the dysplastic tissue showed no staining with p16. There was
increased expression of p16 in almost all specimens, with only one negative for p16; 65%
showed 3+ intensity, 85% full thickness expression and 79% a diffuse staining pattern, with a
trend to increased expression in the more severe lesions. There was increased expression of
p53 in the dysplastic tissue with 50% showing 3+ intensity, 79% full thickness staining and
71% a diffuse staining pattern, compared with only the occasional positive basal cell in
adjacent epithelium. pTEN was expressed in normal tissue, but fewer cells were positive and
the staining became less intense further from the basal layer, whereas in the dysplastic
epithelium the staining was extremely intense throughout the epithelium. 97% showed 3+
intensity, 91% full thickness staining and 82% a diffuse pattern of expression.
An interesting pattern of expression was noted in three cases. Positive p53 cells in the core of
the rete ridges were found corresponding to areas deficient of p16 and pTEN. Further
evaluation may provide evidence for the use of immunohistochemistry as a diagnostic aid in
VIN.
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SS29-10
CLINICAL EFFECTS OF A VACCINE (TA-HPV) IN ANOGENITAL
INTRAEPITHELIAL NEOPLASIA.
Tristram A (1), Man S , Smith K (2) and Fiander A (1)
Department of Obstetrics and Gynaecology (1) and Section of Infection and Immunity (2) University of
Wales College of Medicine, Cardiff, Wales, UK
Introduction
Anogenital Intraepithelial Neoplasia (AGIN) is caused by high risk types of human
papillomavirus (HR HPV) in over 90% of cases. Surgical treatment can be mutilating and is
not universally available, therefore the development of novel treatments is required.
TA-HPV is a recombinant vaccinia vaccine, which expresses the open reading frames for the
E6 and E7 produced by HR HPV types 16 and 18. Previous trials in our department have
demonstrated HPV specific CTL responses against HPV 16 and HPV 18 following TA-HPV
immunisation; clinical responses were not investigated.
Methods
Patients with high grade AGIN (7 cervical, 3 vulval and 1 vaginal) had samples taken for
HPV testing, histology and immunohistochemistry. Images of the disease were recorded.
TA-HPV was administered by dermal scarification.
Clinical assessment of the lesion with repeat imaging was made 8-12 weeks after vaccination.
Samples for histology, immunohistochemistry and HPV testing were repeated. Blood was
taken for immunological testing (ELISPOT) at baseline, 4, 8 and 12 weeks.
Results
11 patients have been vaccinated and followed up for between 3 and 20 months. All patients
demonstrated vaccine "take", with no adverse effects. However no complete clinical
responses were seen and all patients have had subsequent surgical treatment. Immunological
and immunohistochemical responses will be presented.
Conclusions
In contrast to experience in other centres, there was no demonstrable clinical effect in
response to TA-HPV vaccination in this study. This suggests variability in response that may
be a patient-dependent and further investigation is warranted.
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SS30-01
HIGH CUMULATIVE PREVALENCE OF HPV IN WOMEN WITH
NORMAL CERVICAL CYTOLOGY
Van Ham M; Melchers W; Hanselaar A; Bekkers R; Boonstra H; Willemsen W; Massuger L.
University Medical Center Nijmegen, gynaecologic oncology, Nijmegen
Background: In the last few years much attention has been focused on the implementation of
human papillomavirus (HPV) detection in population based screening programmes to identify
women at risk for cervical cancer. However, short-term fluctuations in the detection of HPV
have been described and may be restrictive to mass screening policy. To obtain more insight
in this important aspect, the fluctuations of HPV prevalence in a single menstrual cycle were
investigated.
Methods: Cervical swabs for HPV detection were taken from 20 women with fertility
problems on a weekly basis at four visits during their fertility screening cycle. Cervical
cytological classification was performed by an experienced pathologist. HPV status was
assessed using a short-fragment polymerase chain reaction hybridization line probe assay
(SPF10-LiPA), which is capable of detecting and genotyping 25 different genital HPV types
simultanously.
Findings: Eighty cervical smears for HPV detection were obtained from the study group.
Cytological classification was normal in 18 women. In 2 women cytology showed atypical
sqamous cells of undetermined significance (ASCUS). The point-prevalences of HPV varied
from 20% during menstruation to 55% in the follicular phase. The cumulative prevalence of
HPV was 75% (15/20).
Interpretation: The very high cumulative prevalence of lower genital tract HPV, obtained in
cervical smears in one menstrual cycle suggests that single point detection of HPV
underestimates the true prevalence of HPV in women.
These results may have important implications for population-based HPV screening.
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SS30-02
HIGH PREVALENCE OF HUMAN PAPILOMAVIRUS TYPE 58 IN
MEXICAN WOMEN
González-Losa MR (1), Rosado-Lopez I (2), González-Valadez N (1), Puerto-Solís M. (1)
(1) Virology Laboratory, Regional Research Center "Dr. Hideyo Noguchi", Autonomous University of
Yucatan, Mérida, Yucatán, México. (2) Clinic of Dysplasias, O'Horan General Hospital, Health
Ministry, Merida, Yucatan, Mexico.
Background. Cervical cancer is the most common cancer in Mexican women (1). Infection
with high risk human papillomavirus is an important risk factor associated to cervical cancer
(2). The aim of this study was to determine the prevalence and genotypes of human
papillomavirus in biopsies of women with squamous intraepithelial lesion (SIL) and cervical
cancer (CC) of patients attended at General Hospital O´Horán in Merida, Yucatan, Mexico.
Method. Two hundred sequential women were studied during one year. The patients were
referred with abnormal pap smear; each subject was examined by colposcopy; two adjacent
biopsies were taken from lesion suspected to be SIL or CC ; one biopsy were for virology
analysis and one for histological diagnosis. The quality of the sample was assessed by PCR
using betaglobin primers GH20 and PCO4 to confirm the presence of an adequate DNA. The
presence of HPV DNA in the biopsies was determined by L1 consensus primers polimerase
chain reaction assay using MY09/MY11 primers, for genotyping line blot hybridisation was
used.
Results. A total of 186 women were b globin positive; 104 (55.9%) had histology diagnosis
of low-grade SIL, 67 (36.0%) high-grade SIL and 15 (8.0%) CC. The prevalence of HPV was
56.4%; HPV 58 was founded in 28.5% of all positive women, HPV 16 in 25.7%, HPV 18 in
13.3%, HPV 33 11.4% and 31 8,5%. Conclusion. The genotype 58 was the most frequent in
our study, it was found in every spectre of the disease, and always took first place in
frequency, this doesn't agree with that reported by literature since the genotype 16 is the most
frequent, usually detected in more than 50% of the CC (3).
It is necessary to carry out large epidemiological studies in which we can better identify the
role of genotypes other than 16 have in the aethiology of CC.; since all the effort into
developing an vaccine against HPV is focused on the type 16.
References
1.- Lazcano-Ponce E, Herrero R, Muñoz N, et al. Int J Cancer 2001;91:412-9.
2.-Muñoz N, Bosch FX, de Sanjosé S, et al. Int J Cancer 1992 ;52:743-9.
3.- Bosch FX, Manos MM, Muñoz N, Sherman M, Jansen AM, Peto, J et al. J Natl Cancer
Inst 1995 ;87:796-802
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SS30-03
COMPARATIVE EFFICACY OF VISUAL INSPECTION WITH
ACETIC ACID, HPV TESTING AND CONVENTIONAL CYTOLOGY
IN CERVICAL CANCER SCREENING: A RANDOMISED
INTERVENTION TRIAL IN MAHARASHTRA STATE, INDIA
Sankaranayanan R (1), Nene BM (2), Dinshaw KA (3), Jayant K (2), Keskar VR (2), Rajeshwarkar
R (2), Chauhan MK (2), Budukh AM (2), Shastri SS (3), Chinoy R (3), Kane S (3), Malvi SG (3),
Mahe C (1), Parkin DM (1)
(1) International Agency for Research on Cancer, Lyon, France, (2) Nargis Dutt Memorial Cancer
Hospital, Barshi, India, (3) Tata Memorial Centre, Mumbai, India
A randomized intervention trial involving 160,000 women aged 30-59 years is on-going in
Western India to evaluate the efficacy and cost effectiveness of screening with visual
inspection with 4% acetic acid (VIA), cytology, and HPV DNA testing in cervical cancer
prevention. This is the only on-going randomized intervention trial of primary screening by
VIA or by HPV testing. Eligible women in 502 villages under 52 primary healthcare center
units of Osmanabad district in Maharashtra State, Central India, have been randomized to
receive one of the above interventions or to be part of a 'control' group. Approximately 40,000
women in groups 1-3 will receive VIA, cytology, HPV testing, respectively over a period of
30 months. Women with positive screen tests will be investigated for cervical
precancer/cancer and treated. Women in the control group will receive health education on
cervical cancer. The study groups are followed up for cervical cancer incidence and mortality.
On 31 July 2002, a total of 45,986 women had been screened. The detection rates of cervical
intraepithelial neoplasia (CIN) 2-3 diseases in the different arms are as follows; VIA 1.3%;
cytology: 1.4%; HPV testing: 1.2%. The detection rates of CIN 1 disease are as follows; VIA:
1.4%; cytology: 0.5%; HPV testing: 0.5%. Of the screened women, 3.2% are currently being
treated either with cryotherapy or loop electrosurgical excision procedure. The detection rates
of high-grade cervical precursor lesions are similar with VIA, HPV testing and cytology
screening. Cryotherapy treatment rates are three times higher in the VIA screened group as
compared to the others. Updated results up to 31 March 2003 will be presented.
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SS30-04
SCREENING FOR CERVICAL CANCER PRECURSORS USING
VISUAL INSPECTIONS METHODS COMPARED TO CYTOLOGY IN
JAIPUR, INDIA
Sharma R, Gupta R, Naruka N, Malhotra S, Sharma A, Sankaranarayanan R*
Bhagwan Mahaveer Cancer Hospital & Research Centre (BMCHRC), Jaipur, India
*International Agency for Research on Cancer, Lyon, France
Cervical cancer is the most common cause of death among middle-aged women in many
developing countries. Despite the public health importance that cervical cancer deserves, there
are no effective prevention programmes in place for cervical cancer control in most
developing countries. Visual inspection with acetic acid (VIA) or with Lugol’s iodine (VILI)
are currently being investigated as low technology alternatives to Pap smear for cervical
cancer prevention in low-resource settings. 4836 women aged 25-59 years had screening by
conventional cytology, VIA and VILI in Jaipur and surroundings. Positive cytology was
defined as ASCUS and above. To assess the reference diagnosis, all the women were
subjected to colposcopic examination and biopsy were directed when required. Accuracy of
cytology, VIA and VILI for the detection of cervical intraepithelial neoplasia grades 2-3 (CIN
2-3) lesions were computed directly, as all women had reference investigations. Of the
women screened, 76.9% were aged 30-49 and 97.9% were married. The test positivity rate
was 8.5% for cytology, 25.4% for VIA and 27.4 % for VILI. Biopsies were performed in
1347 women and the reference diagnosis was based on histology for 64.0% of CIN 2-3
lesions. The detection rate of CIN 2-3 lesions was 10.3/1,000. The sensitivity and specificities
of VIA and VILI were similar (sensitivity: 92.0% and 90.0%; specificity: 74.8% and 72.9%).
The specificity of cytology was high (91.6%) but the sensitivity was very low (34.7%). VIA
and VILI are useful methods for the early detection of cervical neoplasia in low-resource
settings.
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SS30-05
COMPARISON OF VISUAL SCREENING METHODS AND
CYTOLOGY FOR THE DETECTION OF CERVICAL CANCER
PRECURSORS IN TRIVANDRUM, INDIA
Somanathan T., Wesley R, Sankaranarayanan R*, Thara S, Dhakad N, Chithrathara K, Abraham
E, Krishnan Nair M.
Regional Cancer Centre, Trivandrum, India
*International Agency for Research on Cancer, Lyon, France
Simple and cheaper methods based on visual examination of cervix are currently being
investigated as alternative methods of cervical screening.
The test characteristics of visual inspection with 4% acetic acid (VIA), and Lugol’s iodine
(VILI) and conventional cytology to detect cervical intraepithelial neoplasia grade 2-3 (CIN
2-3) were investigated in a cross-sectional study involving 4444 women aged 30 to 65 years
in Kerala, India. While detection of any acetowhite area constituted a low-threshold positive
VIA, detection of well-defined, opaque acetowhite lesions close to or touching the
squamocolumnar junction constituted a high-threshold positive VIA test. Detection of definite
yellow iodine non-uptake areas in the transformation zone close to the squamocolumnar
junction constituted a positive VILI test. Cytology was considered positive if reported as
atypia or worse lesions. All screened women were evaluated by colposcopy and biopsies were
directed in 1644 women (37.0%). The final diagnosis was based on histology or colposcopy,
which allowed direct estimation of sensitivity, specificity and predictive values. True disease
status was defined as CIN 2 and worse lesions. A total of 149 (3.4%) women had CIN 2 or
worse lesions.
The sensitivities of low-threshold VIA, high-threshold VIA, VILI and cytology to detect CIN
2 or worse disease were 88.6%, 82.6%, 87.2% and 81.9%, respectively; the corresponding
specificities were 78.0%, 86.5%, 84.7% and 87.8%. VIA and VILI are suitable alternate
screening tests to cytology for detecting cervical neoplasia in low-resource settings.
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SS30-06
SCREENING FOR CERVICAL CANCER PRECURSORS USING
VISUAL INSPECTION METHODS IN BAMAKO, MALI
Dolo A (1), Bayo S (2), Mahe C (3), Sankaranarayanan R (3)
(1) Hôpital Gabriel Touré, Bamako, Mali, (2) Institut National de Recherche en Santé Publique
(INRSP), Bamako, Mali, (3) International Agency for Research on Cancer, Lyon, France
Cervical cancer is the most common cancer among women in Mali. More than 80% of the
cervical cancers are diagnosed in advanced stages, for which no treatment facilities are
available in Mali. The entire country has only two pathology services and there are no
radiotherapy facilities. There are no early detection programmes and early detection based on
cytology is not feasible in Mali, in view of limited technical, manpower and financial
resources. We conducted a cross-sectional study in Bamako, to evaluate the accuracy of visual
inspection with acetic acid (VIA) or with Lugol’s iodine (VILI) as low-technology
alternatives to cytology. 4084 women aged 25-65 years were screened with VIA and VILI by
trained midwives. Of these, 90.0% were aged 30-49 and 90.1% were married. To assess the
reference diagnosis, all the women were subjected to colposcopic examination and biopsies
were directed based on colposcopic abnormalities. The accuracy of VIA and VILI to detect
cervical intraepithelial neoplasia grades 2-3 (CIN 2-3) lesions were computed directly as all
participants received the reference investigations. The test positivity rates were 12.6% for
VIA and 15.2% for VILI. Biopsies were taken in 474 women; the reference diagnosis was
based on biopsy for 86.6% of CIN 2-3 lesions. The specificities of VIA and VILI were similar
(89.4% and 87.6% respectively) but the sensitivity of VIA (67.0%) was lower than the one of
VILI (96.9%). During the study, 147 women were treated with either cryotherapy (28.6%) or
with loop electrosurgical excision procedure (LEEP, 71.4%). This programme has evolved in
to focal point for early detection of cervical neoplasia and for training health care personnel in
the early detection and treatment of cervical precancers.
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SS30-07
SCREENING FOR CERVICAL CANCER PRECURSORS USING
VISUAL INSPECTION METHODS IN GUINEA
Keita N, Koulibaly M, Kabba I, Mahe C*, Sankaranarayanan R*
University Hospital of Guinea, Conakry, Guinea
*International Agency for Research on Cancer, Lyon, France
Cervical cancer is the most common cancer among women in Guinea. There is no organised
early detection programme for cervical cancer in Guinea. There are very limited diagnostic
and treatment facilities for cervical cancer in this country. There is a single pathology service
for the whole country and no radiotherapy facility is available. Until the establishment of the
current cross-sectional study, no cervical precancers were diagnosed and treated in Guinea.
We investigated the accuracy of visual inspection with acetic acid (VIA) or with Lugol’s
iodine (VILI) in detecting cervical intraepithelial lesions grades 2-3 (CIN 2-3) lesions. 7462
women (aged 25-65 years) were screened by VIA and VILI in Conakry and suburbs. The tests
were provided by the nurses. 81.9% of the participants were aged 30-49 and 89.5% were
married. The squamocolomnar junction was visible in 72.4% of the women. All screen
positive women were subjected to colposcopic examination and biopsy were directed in those
with abnormal colposcopic findings. The approximate specificity and the ratio of sensitivities
for the detection of CIN 2-3 lesions were calculated. The test positivity rate was 9.4% for VIA
and 11.9% for VILI. The test positivity rates decreased from 23% to 5% over the study period
without affecting the detection rates of lesions. Biopsies were directed in 859 women and the
reference diagnosis was based on biopsy for all CIN 2-3 lesions. The detection rate of these
lesions was 9.6/1000. The approximate specificities of VIA and VILI were 93.2% and 89.8%
respectively. During the study, 121 women were treated with loop electrosurgical excision
procedure (66.1%) or cryotherapy (33.9%).
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SS30-08
COMPARISON OF VISUAL SCREENING METHODS AND
CYTOLOGY IN THE EARLY DETECTION OF CERVICAL
NEOPLASIA IN CALCUTTA, INDIA
Mandal R, Sankaranarayanan R*, Das P, Roy C, Chatterji R, Chattopadhyay U, Basu P, on
behalf of the Calcutta cervix neoplasia early detection study group (CEDS)
Chittaranjan National Cancer Institute, Calcutta, India
*International Agency for Research on Cancer, Lyon, France
Visual inspection of the cervix after application of 3-5% acetic acid (VIA) is a potential
alternative to cytology for screening in low-resource countries. The present study evaluated
the performance of VIA, VIA with magnification (VIAM) and cytology in the detection of
cervical neoplasia in Kolkata (Calcutta) and suburbs in eastern India. Trained health workers
with college education concurrently screened 5844 women aged 30 to 64 years with VIA,
VIAM and by conventional cervical cytology. Detection of well-defined, opaque acetowhite
lesions close to the squamocolumnar junction constituted a positive VIA or VIAM. Cytology
was considered positive if reported as atypia or worse. All women were evaluated by
colposcopy, and biopsies were taken in those with colposcopic abnormalities. The final
diagnosis was based on histology (if biopsies had been taken) or colposcopic findings, which
allowed direct estimation of sensitivity, specificity and predictive values. True disease status
was defined as cervical intraepithelial neoplasia (CIN) 2-3 disease. VIA and VIAM were
positive in 1092 (18.7%) and 1033 (17.7%) women, respectively. Of the 5090 women who
underwent cytology, 416 (8.2%) tested positive. The sensitivities of VIA and VIAM to detect
CIN 2-3 disease were 55.7% and 60.7%, respectively; the specificities were 82.1% and
83.2%, respectively. The corresponding sensitivity and specificity of cytology were 29.5%
and 92.3%. VIA and VIAM were more sensitive than cytology in our study; the specificity of
cytology was higher than that of VIA and VIAM. Magnification was associated with
improved the accuracy of VIA to detect cervical neoplasia in this study.
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SS30-09
DNACITOLIQ LIQUID-BASED CYTOLOGY SYSTEM VERSUS
CONVENTIONAL PAP SMEAR IN A HIGH RISK POPULATION.
ANALYSIS OF 925 SPLIT SAMPLES AND COMPARISON WITH
HYBRID CAPTURE II ASSAY.
LONGATTO-FILHO A (1), PEREIRA SMM (1), UTAGAWA ML (1), MAKABE S (2) ; MAEDAMYS
(1), MARQUES JA (2), AGUIAR LS (1), PITOLLI JE (1), SANTORO CLF (2), DI LORETO C (1)
(1) Pathology Division of Adolfo Lutz Institute, São Paulo, Brazil; (2) Pérola Biygnton Hospital, São
Paulo, Brazil.
New technologies are being intended to improve detection of cytologic alterations frequently
missed in conventional smears (CS). Liquid-based cytology are believed to be best sensitivity
than the Pap smears and offers the possibility to realize molecular assay. The goal of this
work was to study the performance of CS and DCS in a split sample protocol in a high risk
population and to compare the results with the HC II for high risk HPV. The samples were
collected from consecutive women enrolled in the ongoing study examined at Pérola
Biygnton Hospital with clinical suspicious of low genital tract lesion. The material was
obtained using the DCS brush. Following CS preparation, the brush was introduced again in
the cervix-uterine region and a new sample was collected and rinsed in the UCM preservative
medium of the system. The residual UCM material was used to HC II. Cytological slides were
examined in a blind fashion protocol. From 925 cases, DCS present 4 (1,51%) unsatisfactory
cases and CS, 100 (10,81%). The DCS was superior to the CS performance: the diagnosis
increment of DCS was 86% in satisfactory samples, 92,76% in atypies+ (including glandular),
83% in LSIL+ and 86,84% in HSIL+. One case of cancer was diagnosed with DCS and
missed in CS. HC II positive analysis were observed in 144 CS cases and 266 DCS cases with
abnormalities. Considering DCS cases with atypia of undetermined significance (squamous
and glandular), 85 (77,27%) were positive for HC II high risk. Our results have showed that
DCS was superior to CS in a high risk population, and HC II positive reactions presented a
high concordance with DCS results, including the atypical alterations.
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SS30-10
THE PRESENCE OF CERVICAL INTRAEPITHELIAL NEOPLASIA
(CIN)IN ADOLESCENT GIRLS
Vlasta H., Sikanic-Dugic N, Hirsl-Hecej V, Kani D, Domljan ML
Children's Hospital Zagreb,Reproductive Health Department,Croatia
Objectives:The aim of this study was to investigate: 1.The frequency of abnormal cervical
findings (CIN )in adolescents (aged 15-19 y), 2.The correlation between CIN with the
presence of infection, 3.To assess correlation of risky sexual behavior on frequency of
abnormal findings.
Methods:The study included 927 adolescents (aged 15-19 y)who have come for the first time
to gynecological outpatient unit of the Children's hospital Zagreb in 2001.y.We have analysed
cervical smears (PAP test)and their sexual behavior obtained by the questionnaires.
Results: In 927 PAP smears we have found 198 (21,3%) cervical intraepithelial neoplasia
(CIN): CIN I in 156 (78,8%), CIN II in 34 (17,2%)and CIN III in 8 (4%)patients. Early
beginning of sexual intercourse (under 16 y)was found in 113 (57,1%)cases: in CIN I in 87
(55,8%),in CIN II in 23 (67,6%)and in CIN III in 3 (37,5%) cases. The number of partners
was directly connected with presence of CIN:in CIN I was mostly one partner (55%),but in
23% were more than 3 partners, in CIN II 47% of girls had 3 and more partners and in CIN III
25% of girls had more than 3 partners. The causes of infection were found in 145 cases
(73,2%): Chlamidia trachomatis in 6 (4,1%),Gardnerela vaginalis and Candida albicans were
in 15 (10,3%), Trichomonas vaginalis in 1 case (0,7%), and HPV in 108 (74,5%). 88,4% of
all patients didn't use condom or used it periodically, and 18,7% girls used oral contraceptive
pills.
Conclusion: Because of high prevalence of abnormal cervical findings in adolescents the
most important is an education of young people to change their risky sexual behavior. It is
also important to enhance the role of early and regular gynecological and cytological
examination.
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SS30-11
ORGANIZATION AND IMPLEMENTATION OF CERVICAL
SCREENING PILOT PROGRAM IN COUNTY OF CLUJ,
TRANSILVANIA
Suteu. O. (1,2), Lazar L. (1,2), Irimie A. (1,2), Nicula F. (1), Coza D. (1), Duma M. (1), Pais R. (3),
Neamtiu L. (1)
(1) Institute of Oncology "Prof. I. Chiricuta", Cluj, (2) University of Medicine and Pharmacy , Cluj, (3)
Diagnosis & Treatment Center, Cluj, - Cithology Laboratory
Background: In the absence of a national, organized cervical screening program, 3000 new
cases and 1800 deaths occur annually in Romania, corresponding to a standardized incidence
and mortality rates of 25.55 cases/100000, respectively 11/100000.
Objectives: Organization and implementation of a cervical screening pilot program in county
of Cluj, which will be replicated in other 18 from the 42 counties of Romania,
methodologically coordinated by the Oncological Institute from Cluj. Ministry of Health &
Family financially support the program.
Methods: The program provides cytology smears to women aged 25-65 years, once every 3
years, according to the European guidelines, sampled by general practitioners and
gynecologists in community clinics or in private offices. Starting from January 2002 a
regional working group developed the infrastructure, trained the staff involved and elaborated
surveillance mechanisms for screening, investigating, treating and following up the targeted
women. Since December 2002 the women were convocated by written, nominative invitation,
signed by their own general practitioner. A regional cytology register was founded as well as
a centralized call-recall system, at the Oncological Institute, which was also involved in the
quality control of all aspects of the cervical screening.
Results: The program trained 111 general practitioners, 60 gynecologists and 6 cytologists,
with a consensus of medical participants. During the last 6 months of the year 2002, a total of
5261 smears were processed for 5067 women. The smears were performed as conventional
cytology (85%) and also as liquid-based cytology. Only 6% of the smears were taken in
general practice. 152 positive results were found (2.88%): LSIL-89 cases, HSIL-48 cases and
invasive carcinoma 15 cases. The prevalence of unsatisfactory smears was 3.4% (179 smears).
80% of women was tested in this program for the first time in their life.
Conclusions: Population screening services are now operational. The extension of screening
network in primary health care is essential to assure a high coverage and to provide an
infrastructure sufficient to screen a target population of 200000 women.
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SS30-12
INTERLABORATORY QUALITY CONTROL (QC) OF PAP SMEAR
CYTOLOGY AS A PART OF THE MULTICENTRE TRIAL
COMPARING SIX OPTIONAL SCREENING TOOLS IN LATIN
AMERICA (THE LAMS STUDY*)
BRANCA M (1), ERZEN M (2), ALDERISIO M (1), LONGATTO-FILHO A (3), SYRJÄNEN K (1)
(1) Istituto Superiore di Sanità (ISS), Rome, Italy; (2) SIZE Diagnostic Center, Ljubljana, Slovenia; (3)
Instituto Adolfo Lutz, São Paulo; Brazil
OBJECTIVES: This multi-centre trial is comparing the performance of conventional
diagnostic techniques (PAP smear and liquid-based cytology, screening colposcopy) with 1)
two optional screening tools (VIA, cervicography) and with 2) Hybrid Capture II, from a)
conventional samples and b) using self-sampling, in women at different risk for cervical
cancer in Brazil and Argentina.
STUDY DESIGN: As a part of the external quality control (QC) programme incorporated in
controlling all diagnostic tests in this study, the reproducibility of the cytological diagnosis in
the laboratories examining the PAP smears of these women (n=12.000 to be enrolled) is being
controlled using an inter-laboratory QC approach. A total of 80 slides (clear-cut cases
comprising all categories from inadequate to invasive cancer) have been selected among the
routine cytological smears submitted to ISS (coordinating centre) by the participating
laboratories. These 80 cases were divided into four sets of slides (20 in each), containing in
different proportions six categories of smears: 1) inadequate, 2) negative for SIL, 3) ASC,
ASC-US, AGC, LSIL, 4) HSIL or CIN2, 5) HSIL or CIN3, and 6) invasive cancer. All
cytological diagnosis were made as consensus diagnoses by three cytopathologists, to be used
as the gold standard in this trial. In the final analyses, the reproducibility (inter-laboratoryand laboratory/consensus diagnosis) will be tested using both non-weighted and weighted
kappa, as well as calculating three indexes measuring variability: A) between CIN1 and
CIN2; B) between CIN2 and CIN3, and C) CIN1 versus CIN2, CIN3, invasive cancer.
RESULTS: Until now, two sets of slides have been assessed by one laboratory each. The
overall agreement with the laboratory- and the consensus diagnosis of the cases in these two
sets is substantial: non-weighted k=0.712 (95%CI 0.548-0.876) for both sets together. An
almost perfect agreement is reached with one of the two slide sets, with non-weighted
k=0.873 (95%CI 0.705-1.00), and a substantial with the other one: k=0.608 (95%CI 0.3500.866).
EXPECTED OUTCOME MEASURES: This study design provides valuable data on the
quality standards of the individual laboratories and helps pinpointing the eventual problem
areas in their performance, where continuous quality improvement (CQI) could be helpful.
*(LAMS: Latin American Screening Study, funded by EC, INCO-DEV Contract # ICA4-CT2001-10013).
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SS31-01
NATURAL HISTORY OF HPV INFECTIONS: RECENT
DEVELOPMENTS
SYRJÄNEN KJ
National Institute of Health (ISS), Roma
To elucidate the natural history of cervical cancer and its precursors, a prospective cohort
study is mandatory, in which a cohort of women with cancer precursor (CIN) lesions is being
prospectively followed-up without any therapeutic intervention for an extended period of time
(i.e. many years). In the world literature, a substantial number of such prospective cohort
studies are reported, several of them already long before the start of the “HPV era” from the
late 1970’s. Several conceptual problems are encountered in these natural history studies
conducted during the past several decades (to be discussed). Most importantly, we must
accept the fact that progression of any lesion to CIN III should be considered as a surrogate
marker of progression to invasive disease, because continuation of the follow-up beyond CIN
III is unethical.
Natural history of CIN and cervical HPV infections is identical, as neatly shown by the
practically identical figures for regression, persistence and progression reported for different
grades of CIN by the meta-analysis of the world literature (Östör, 1993), and those established
for HPV-CIN I, HPV-CIN II and HPV-CINIII by the 20-year prospective cohort study in
Finland (Syrjänen, 2000). This natural history of HPV/CIN is characterised by two key
determinants: 1) spontaneous regression is time-dependent, reaching up to 70% in 10 years
(for all CIN taken together), and 2) progression rates stabilise more rapidly; those 15% of
lesions destined to progress are disclosed within the first 24 months of prospective follow-up.
However, the natural history of cervical HPV infections is more complicated, as shown by our
long-term cohort study, where at least 6 distinct disease patterns can be demonstrated: 1) early
regression, 2) persistence, 3) fluctuation, 4) late regression, 5) progression, and 6) recurrence.
Because cervical cancer precursors only develop from clinically manifest HPV lesions (and
not directly from latent HPV infections), it is of prime importance to a) establish the risk
factors for clinical HPV infections, and b) to elaborate the factors predicting the progression
of clinical HPV lesions. The former are closely linked with the issues such as the biological
significance of latent infections by the oncogenic HPV types. The latter, in turn, are related to
the ongoing search for molecular markers predicting disease outcome in individual women,
which is not possible at the moment.
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SS31-02
PROGNOSTIC VALUE OF PERSISTENCE AND LOAD OF HIGH RISK
HPV DNA IN THE PROGRESSION TO CERVICAL HIGH-GRADE
LESIONS.
MOUGIN C, DALSTEIN V, RIETHMULLER D, SAUTIERE JL, SCHAAL JP.
CHU Jean Minjoz. Université de Franche Comté. Laboratoire de Biologie Cellulaire et Moléculaire. EA
3181. Institut d'Etude et de Transfert de Gènes, Besançon, France
Oncogenic HPV types are the major cause of worldwide cervical cancer, but only a small
proportion of infected women will develop high grade cervical lesions (HGSIL) or invasive
cancer.
We performed a prospective follow-up (FU) study including 781 women with or without
minor cervical abnormalities (ASCUS/LGSIL). High risk (HR) HPV testing was performed
using the Hybrid Capture II (HCII) assay. We investigated the clinical outcome, especially
progression to CIN2/3 according to HPV persistance and viral load.
At enrollment: the median age of patients was 35.7 yrs. The mean number of visits was 2.5
and the median FU period was 22 months. The rate of HPV infection was 27% in normal
smears, 54% in ASCUS and 70% in LGSIL. The HPV positive women were younger (32.2)
than HPV negative ones (37.7).
During FU: among the 516 women who were HPV negative at entrance, 41 acquired an
incident HR HPV infection and women < 30 yrs were 3.5 fold more likely to be infected than
older women. Among the 257 HPV positive women, more than half cleared their virus in 7.5
months ; the rate of viral clearance did not depend on initial cytology, nor on age, but was
significantly associated with low viral loads. HPV clearance was also associated with
cytological regression. Whatever the baseline smear diagnosis was, cytological and
histological evolution only depended on virological evolution. Development and maintenance
of ASCUS and LGSIL were significantly more frequent in women with repeated HR-HPV
positive results, compared to HPV negative women or women becoming HPV negative
during FU. Progression to histologically proven CIN2/3 was achieved only in women with
persistent HR-HPV infection and concerned 31 women. The 24-month cumulative probability
for development of HGSIL was also the highest (33%) when viral load at baseline was >100
pg/mL. Conversely, women found to be consistently HR-HPV negative or transiently HPV
positive with a normal or abnormal smear at enrollment did not develop CIN2/3 during a twoyear FU.
Our data suggest that women who are repeatedly tested positive for HR-HPV by HCII are at
increased risk of developing HGSIL, even when they are screened as cytologically normal. A
high viral load could be used as a short term marker of progression towards precancerous
lesions, although lower load does not inevitably exclude progressive disease.
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SS31-04
DOES TELOMERASE HAVE A ROLE IN HPV INDUCED
CARCINOGENESIS?
Syrjänen Stina
Inst. of Dentistry, Faculty of Medicine, Oral Pathology, Turku
elomeres are specialized repetitive sequences, acting as protective caps at the ends of the
chromosomes. In humans, telomeres are made up of {TTAGGG}n repeats and extends for an
average of 5000 15 000 base pairs. They are complexed with specific telomere-binding
proteins. The general functions of telomeres are to protect chromosome ends from
exonuclease digestion, prevent aberrant recombination, and to prevent the chromosome ends
from activating checkpoint controls that sense DNA damage. For each cell division 50-200
bases of the telomeres are removed and this limits the life-span of the cells.
Telomerase is a ribonucleoprotein reverse transcriptase that confers immortality upon cells by
elongating the telomere and keeping it in a state of dynamic length equilibrium. This enzyme
is active in the majority of human tumors and tumor cell lines as well as in embryonic tissue
and germ cells, but not in normal somatic cells. It has emerged as a potential prognostic
molecular marker and therapeutic target for cancer treatment. The gene for the telomerase
catalytic subunit, hTERT, has been mapped, and the promoter region contains cognate
sequences for various transcription factors.
HPV and telomerase
Telomerase is expressed in cervical cancer cell lines, transformed with "high risk" HPV.
Disruption and deletions in the HPV E2 gene upon integration of the viral DNA into the
cellular chromosomes will upregulate and stabilize expression of mRNA for the viral
oncogenes E6 and E7 due to removal of the repressor function of the E2 protein. HPV 16 E6
protein is able to activate telomerase by a mechanism not completely clarified, although E6
interactions with c-myc and Sp1 sites of the hTERT promoter have been proposed. Also, it
has been shown that E6 does not induce hTERT transcription by inducing expression of cmyc, but rather that E6 and the E6AP may target a regulator of hTERT expression. Evidence
for the presence of a repressor of hTERT on chromosome 6 have been presented. There has
been controversy, however, as to whether expression of E6 in the context of the whole HPV
16 genome can activate telomerase. Using cervical epithelial cells transduced with HPV
E6/E7 oncogenes, Baege and coworkers (2002) recently reached the conclusion, that levels of
E6 expression are not related to expression levels of hTERT. In their model system the E6/E7
expression was stable over at least 30 passages, whereas the hTERT expression sharply
increased. An additional recent study indicated that HPV 16 by itself does not necessarily
cause telomerase activation in cervical keratinocytes, but rather supports a model in which
HPV 16 facilitates telomerase activation in conjuntion with other viral or cellular changes
over time (Spargue et al 2002). It was recently shown that E2 inhibits the hTERT promoter
and Sp1 biding site in hTERT promoter is important for the E2 mediated repression. (Lee et
al. 2002).
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SS31-05
COMPARISON OF HPV TYPE DISTRIBUTION IN HSIL AND
CERVICAL CANCER: A META-ANALYSIS
Clifford Gary
International Agency for Research on Cancer, Unit of Field and Intervention Studies, Lyon
Particular types of human papillomavirus (HPV) infection may preferentially progress from
high-grade squamous intraepithelial lesions (HSIL) to squamous cell carcinoma of the cervix
(SCC). We performed a meta-analysis of published data to compare HPV type distribution in
HSIL and SCC. The three most common types in SCC world-wide, namely HPV16, 18 and
45, were each more prevalent in SCC than HSIL, and associated with SCC:HSIL prevalence
ratios of 1.18, 1.70, and 1.76 respectively. In contrast, the reverse was true for other high-risk
(HR) types including HPV31, 33, 52 and 58. These data suggest that HSILs infected with
HPV16, 18 and 45 preferentially progress to SCC, and that the distribution of HPV types in
HSIL is not entirely representative of those that progress to cancer. These findings have
implications both for follow-up protocols of future HPV-based cervical cancer screening
programs and for type-specific HPV vaccine trials, for which the ability to prevent cancers
will be estimated from the prevention of HSIL.
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SS31-06
RELATIONSHIP BETWEEN COEXISTING HIGH-GRADE
GLANDULAR AND SQUAMOUS CERVICAL LESIONS AND HUMAN
PAPILLOMAVIRUS INFECTIONS.
Ruud L.M. Bekkers (1), Hans Bulten (2), Anne Wiersma-van Tilburg (3), Marcel Mravunac (4),
Charles P.T. Schijf (1), Leon F.A.G. Massuger (1), Wim G.V. Quint (5), Willem J.G. Melchers (6).
Departments of Gynecology/Obstetrics (1), Pathology (2), and Medical Microbiology (6), University
Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, the departments of Pathology of the
Rijnstate Hospital Arnhem (3), and Canisius Wilhelmina Hospital Nijmegen (4), and Delft Diagnostic
Laboratory, Delft (5), the Netherlands.
Introduction: The prevalence of high-risk human papillomavirus (hr-HPV) genotypes in
patients with ACIS with coexisting CIN, ACIS without coexisting CIN, and high-grade CIN
(CIN 2/3) without ACIS was studied, in order to gain more insight in the relation of hr-HPV
infections and the development of coexisting squamous and glandular lesions.
Methods: The SPF10 LiPA PCR was used to simultaneously detect 25 different HPV
genotypes in biopsies obtained from 90 patients with CIN 2/3, 47 patients with ACIS without
coexisting CIN, and 49 patients with ACIS and coexisting CIN.
Results: Hr-HPV was detected in 84 patients (93%) with CIN 2/3, 38 patients (81%) with
ACIS without CIN, and in 47 patients (96%) with ACIS and coexisting CIN. HPV 31, 52, and
multiple hr-HPV genotypes were significantly more often detected in patients with CIN 2/3,
while HPV 18 was significantly more often detected in patients with ACIS, either with or
without CIN. There were no significant differences in the prevalence of specific hr-HPV
genotypes between patients with ACIS with-, or without coexisting CIN.
Conclusions: The prevalence of specific hr-HPV genotypes is similar in patients with ACIS
without CIN and patients with ACIS and coexisting CIN, but is significantly different from
patients with CIN 2/3 without ACIS. These findings may suggest that squamous lesions,
coexisting with high-grade glandular lesions, are etiologically different from squamous
lesions without coexisting glandular lesions.
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SS31-07
HUMAN PAPILLOMAVIRUS (HPV) TYPE DISTRIBUTION IN HIVSEROPOSITIVE AND -SERONEGATIVE ITALIAN WOMEN
Tornesello ML (1) , Duraturo ML (1) , Salatiello I (1), Buonaguro L (1), Sansone M (2), Piccoli R
(2), Buonaguro FM (1)
(1) National Cancer Institute, "Fond. Pascale", Division of Viral Oncology and AIDS Reference Centre,
Naples ; (2) University of Naples, Gynecology Dept., Naples - Italy.
Background: Cervical human papillomavirus (HPV) infection is more common among HIV+
than HIV- women and is associated with higher rates of cervical squamous intraepithelial
lesions (SIL). In HIV+ women a large number of HPV types are present and little is known on
the relationship between HPV types and evolution of HPV-related lesions.
Methods: 112 HIV+ and 92 HIV- women from Southern of Italy were studied. A
questionnaire was administered on behavioral and other risk-factor data and a physical exam
was performed. Cervical samples were analyzed by PCR for the presence of HPV DNA using
HPV L1 consensus primers, MY09 and MY011, which amplify a broad spectrum of HPV
types. PCR products were subjected to direct sequence analysis followed by homology studies
in order to characterize individual HPV types. Lymphocytes CD4 counts and plasma HIV
RNA viral load were performed for each patient.
Results: HPV DNA was detected in 49 out of 112 (43.75%) HIV+ and in 10 out of 92
(10.86%) HIV- women (RR = 4.03, 95% CI 2.2-7.5). HPV 16 was the most common type
being found in 13.39% of the HIV+ and 5.43% HIV- women, respectively. The number of
specific HPV types was higher in HIV+ women [20 different HPV genotypes (6, 16,18, 31,
33, 35, 45, 52, 53, 55, 58, 61, 62, 66, 70, 72, CP8304, MM7, MM8, LVX820)] than HIVwomen [6 HPV genotypes (16, 18, 52, 61, 62, 66)] (p = .0032). The distribution of HPV types
in HIV-positive women was 38.9, 27.1, and 37.3% for high-risk, intermediate- risk, and lowrisk HPVs, respectively. Abnormal Pap smears were highly correlated with HIV
seropositivity but not with degree of immunosuppression or HIV viral load: only 3.3% of
HIV-seronegative women, compared to 17% of HIV-seropositive women and 21.0% of
women with CD4 counts <500, had an abnormal Pap smear. In addition, Pap smear
abnormalities were highly correlated with the presence of HPV risk category.
Conclusions: Several "low-intermediate risk" HPVs, rarely found in HIV- women, are
frequently detected and considered "high-risk" HPVs in HIV+ women being associated in this
group with increased risk of cervical SIL. The prevalence of cervical HPV infection in HIV+
women is not significantly correlated nor with lower CD4 levels neither with RNA viral load
suggesting a some not yet defined specific immunodeficit and/or a direct role of HIV-1 in the
activation and expression of latent HPV infections.
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SS31-08
HIGH RISK HPV DNA AFFECTS TO PH OF SPERM
Rintala M (1), Grénman S (1), Pöllänen P (2), Syrjanen S (3)
(1) Department of Obstetrics and Gynecology Turku University Central Hospital, (2) Institute of
Biomedicine, (3) Institute of Dentistry and MediCity Research Laboratory, Faculty of Medicine,
University of Turku, Turku, Finland
Background: Human papillomavirus (HPV) DNA has been previously detected in semen,
especially in sperm cells, where HPV is also actively transcribed. Sperm washing does not
eliminate the risk of HPV transmission to recipients. The consequences of HPV-infected
sperm are not known. In this study, a detailed semen analysis was made to assess the eventual
effects of seminal high-risk HPV DNA to composition, motility and viability of sperm cells.
Methods: Sperm samples were collected from 65 healthy males included as fathers in the
ongoing Turku HPV Family Study. The presence of high-risk HPV DNA was analyzed by
nested polymerase chain reaction (PCR) and confirmed by Southern blot hybridization.
Semen samples were analyzed for the quality of semen, quantity and motility of sperm cells.
Results: Altogether, 10/65 males (15.4%) had high-risk HPV DNA in their semen samples.
The sperm concentration (3.7ml vs. 4.3ml), the sperm motility (54.2% vs. 56.5%) and sperm
vitality (65.2% vs. 69.6%) were all lower in the males with seminal high-risk HPV DNA, but
the differences did not reach statistical significance. The only statistically significant
difference was the lowered pH of the semen in HPV DNA-positive males (7.37 vs. 7.51,
p=0.041).
Conclusions: High-risk HPV DNA in the semen samples is not an uncommon finding, being
detected in 15% of healthy males. Presence of HPV DNA was significantly associated with
the lowered pH of the semen, possibly attributable to inflammatory reaction evoked by the
viral infection. However, the presence of high-risk HPV DNA did not significantly affect the
concentration, motility and vitality of the sperm cells.
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SS31-09
A COMPREHENSIVE ANALYSIS OF HIGH-RISK HPV
INVOLVEMENT IN ADENOCARCINOMA AND ADENOCARCINOMA
IN SITU OF THE CERVIX
Snijders P, Zielinski D, Rozendaal L, Fransen Daalmeijer N, Risse E, Voorhorst F, Jiwa N, van
der Linden H, de Schipper F, Runsink A, Meijer C.
Depts of Pathology and Epidemiology & Biostatistics, VU University Medical Center, Amsterdam;
Dept. of Obstetrics & Gynaecology, Hospital Walcheren, Vlissingen; Dept. of Pathology, District
Laboratory Zeeland; Dept. of Pathology, Medisch Centrum Alkmaar; Dept. of Pathology, Bosch
MediCentrum, Den Bosch; The Netherlands.
The exact proportion of adenocarcinomas (ACA) of the cervix that can be attributed to highrisk HPV (hrHPV) functions is still a matter of debate. Here, we performed a comprehensive
study on hrHPV presence in adenocarcinoma in situ (ACIS) and ACA of the cervix.
Archival formalin-fixed specimens that originally were classified as ACIS or ACA of the
endocervix, were retrieved from 4 different hospitals. Specimens were revised blindly and
undisputable endocervical ACIS (n=65) and ACA (n=77) were tested for hrHPV DNA by
GP5+/6+ and type-specific E7 PCR. Further immunostainings for p16INK4A and p53 were
performed to assess for alternative pathways of carcinogenesis.
HrHPV DNA was found in all (100%) ACIS and 72 (94%) of the endocervical ACA, whereas
none of 20 endometrial ACA scored HPV+. HPV 18 was most prevalent in both ACIS and
endocervical ACA. Diffuse immunostaining for p16INK4a, a potential marker of hrHPV E7
function, was significantly more frequent in hrHPV+ endocervical ACA (19/20; 95%)
compared to hrHPV- endocervical ACA (1/5; 20%; p<0.001). Immunostaining for p53,
pointing to stabilized wild-type or mutant p53 protein, was significantly more frequent in
hrHPV- endocervical ACA (4/5; 80%) than in hrHPV+ endocervical ACA (3/20; 15%;
p=0.01).
We collected evidence for hrHPVs playing a prominent role in the development of
endocervical ACA and its precursors. Only a minority (i.e.6%) of endocervical ACA
displayed absence of HPV DNA, and immunostaining profiles suggestive of an HPVindependent etiology. Nevertheless, incorporation of hrHPV testing in cervical cancer
screening programs is likely to markedly decrease the incidence of endocervical ACA.
EUROGIN 2003
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SS32-03
HIGH COPY NUMBER OF HUMAN PAPILLOMAVIRUS TYPE 92 IN
TWO CASES OF BASAL CELL CARCINOMA
Forslund O (1), Handisurya A (2), Kirnbauer R. (2), DeVilliers E.M. (3), Dillner J. (1)
(1)Department of Medical Microbiology, Lund University, Malmö University Hospital, Malmö, Sweden.
(2)Lab. of Viral Oncology, Department of Dermatology, University of Vienna Medical School, Vienna,
Austria. (3)Division for Tumorvirus Characterization, Deutsches Krebsforschungszentrum, Heidelberg,
Germany.
At least 200 different HPV types infect the human skin and DNA of epidermodysplasia
verruciformis (EV)-related types has been found in non-melanoma skin cancers (NMSC).
However, because of the very low viral copy numbers in such lesions the role for HPV in the
pathogenesis of NMSC is still unclear.
We recently isolated HPV type 92 from a basal cell carcinoma (BCC) from the temple of an
immuno-competent Australian man, 89 years old. PCR for HPV 92 was positive in 6 of 64
skin samples (2/25 BCCs, 2/16 solar keratosis, 2/23 SCCs) from Australian patients.
By quantitative PCR for HPV 92, about 94 viral copies were present per cell in a BCC
strongly suggesting a pathogenic role. In another BCC, about one viral copy per cell was
found. Lower copy numbers were found in two solar keratoses that contained each 1 copy per
33 cells and 1 copy per 60 cells, and two SCCs that harboured each only 1 copy per 436 cells
and 1 copy per 1143 cells.
The genome of HPV 92 comprises 7461 bp that demonstrated the typical pattern of reading
frames of HPV located on one DNA strand, separated by a non coding region (NCR) of 390
base pairs. Analysis of NCR revealed 3 E2 binding sites and one E2 site within the E6 ORF.
Phylogenetically HPV 92 was grouped within EV-related types and its L1 ORF showed
highest similarity to HPV 49 (72%), but was distantly related to other HPVs.
For functional studies of the HPV 92 L1, high-molecular weight complexes from L1
expressing cells were analysed by electron microscopy. Spherical particles or capsomer
subunits were observed indicating that also HPV 92 L1 can self-assemble into virus like
particles (VLPs). Studies are under way to determine whether these VLPs might be useful for
sero-epidemiology, and whether HPV 92 VLP antibodies can be used in
immunohistochemistry.
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SS32-04
COEXISTENCE OF VIN AND VULVAR CANCER WITH
INTRAEPITHELIAL OR INVASIVE CHANGES WITHIN UTERINE,
CERVIX AND VAGINA IN YOUNG WOMEN AS A CLINICAL
PROBLEM.
Basta A., Adamek K
Chair and Department of Gynecology, Obstetrics and Oncology, Jagiellonian University, Cracow,
Poland
Objectives: There has been observed an increase of frequency of VIN and vulvar cancer in
young women. An important clinical and therapeutical problem is coexistence of VIN ahd
vulvar carcinoma with intraepithelial neoplasia and invasive carcinoma of the vagina and
uterine cervix.
Aim: 1. Evaluation of VIN and vulvar cancer frequency in young women under 45 yrs their
coexistence with CIN, cervical invasive carcinoma and/or VAIN and vagina cancer. 2.
Estimation of the frequency of HPV infection accompanying these cases.
Material and methods: 148 patients aged 22 to 45 yrs observed, diagnosed and treated of
VIN and vulvar invasive carcinoma in last 25 years in Chair and Department of Gynaecology,
Obstetrics and Oncology, Jagiellonian University;. the diagnosis of VIN, VAIN, CIN and respectively - invasive changes was based on cytological, colposcopic and histological
examination of colposcopy - directed biopsy. HPV diagnosis was based on hybridisation in
situ test and hybrid capture II test.
Results: An increase of frequency of VIN and vulvar cancer in young women within 25 years
was observed. In clinical material there has been found that cytology in connection with
colposcopy give higher diagnostic precision in comparison with each one method performed
alone, especially in cases of coexisting intraepithelial as well as invasive changes within
vulva. VIN and invasive vulvar cancer presented in 37% unifocal, and in 63% multifocal
localisation. Simultaneous occurrence of CIN or invasive cervical cancer and/or VAIN and
vaginal invasive cancer in 16 (10,8%) cases was found. There has been observed a high
percent (81,3%) of high oncologic potential HPV types infection in the study group, which
was statistically frequent connected with multifocality of intraepithelial changes coexisting
within vulva, vagina and uterine cervix.
Conclusions: 1.) A high percent of multifocal VIN and invasive vulvar carcinoma,
localization obliges to a very precise colposcopy diagnosis of the whole vulva region. 2.)
Coexistence of VAIN and invasive vagina cancer, CIN and invasive cervical cancer with
vulvar changes forces to cytology and colposcopy examination of the uterine cervix and
vagina. 3.) Coexistence of HPV infection of the same type accompanying VIN, VAIN, CIN
and invasive carcinoma of the vulva, cervix and vagina is an indirect proof for close
coherence between low female genital tract carcinogenesis and HPV infection.
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SS32-05
TREATMENT PATTERN OF VULVAR CANCER IN ELEDRELY
PATIENTS: A POPULATION BASED STUDY.
Beffa V, Neyroud I (*), Usel M. (*), Pelte MF (**), Schaefer P, Bouchardy C (*),Vlastos AT
Departement of Gynecology and Obstetrique. Geneva University Hospital. (*) Geneva Tumor Register.
(**) Departement of Pathology. Geneva University Hospital.
Introduction: Vulvar cancers are rare accounting for 1% of women cancer and 4-5% of
gynecological cancer. The disease typically develops in the 7h or 8th decade.
Aim: to evaluate the treatment pattern of vulvar cancer in our population after 80 y.o.
Method: a 20 years retrospective study (1979-1999) from the Geneva Tumor Register.
Results: 230 patients presented with vulvar cancer. 49 (21%) patients were over 80 years.
Median age was 44 years (21-93). Patients less than 50 were diagnosed at stage 0 in 99% of
the cases whereas patients over 80 were diagnosed at stage 0 in only 32% of the cases. Same
way, patients over 80 years were diagnosed at stage 4 in 18% whereas patients under 80 were
diagnosed at stage 4 in only 5%. Surgery was at least part of the treatment in 90% (208) of the
cases. Respectvely 94% (101 cases) under 80 years, and 76% (37 cases) over 80 years
(p=0.032). Of the 18 cases who had palliative cares only, 12 (67%) were over 80 years. 5
years survival curves show 93% survival in stage 1 compared to 21% survival in stage 4
emphasizing the need for early diagnosis of the disease.
Conclusion: Vulvar cancers are rare tumors involving most of the time patient after their
50th. Patients over 80 years are diagnosed at later stage and because of their poor global
status treated less agressively. With the aging population public health care provider will need
to establish new screening programs in order to diagnose the disease at earlier stage were
adequate treatment is feasible in the elderly population.
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SS32-06
BEHAVIOUR OF MICROINVASIVE (MIC) SQUAMOUS- AND
ADENOCARCINOMA OF THE UTERINE CERVIX IN THE LIGHT OF
WORLD LITERATURE AND EXPERIENCE FROM OUR CLINIC
ERZEN, M., RAKAR, S., CAVIC, M., SINKOVEC, J., KOPAC, D.
Department of Obstetrics & Gynecology, University Medical Centre, Ljubljana, Slovenia
OBJECTIVE: To critically assess the progression- and recurrence rates of microinvasive
(MIC) Stage IA cervical carcinoma, based on Medline search, and to compare these data with
our own experience on these tumours in Ljubljana Medical Centre.
STUDY DESIGN: In the 25 published studies covering the years 1976-1999, a total of 4.311
squamous cell MICs were reported, including 2.967 stage IA1 lesions, 1.269 in stage IA2, and
75 cases of occult stage IB, classified according to FIGO or SGO classifications. Our
experience in Ljubljana is based on the management of 400 stage IA squamous cell
carcinomas (SCC), accumulated in the past 30 years and 33 early invasive adenocarcinomas
(AC) collected in 5 years.
RESULTS: In the reported 4.311 SCC MIC cases, lymphatic space involvement was
recorded in 342 (8%) cases, and in 53 of those, the disease recurred, and progressed to death
in 15 patients. In 14 series, MICs were associated with 72 (1.7%) recurrences. In seven series,
20 (0.5%) cases of death due to cancer were reported. Lymph node metastasis were found in
30 (0.7%) cases. Even when stage IA1 and IA2 carcinomas were treated with conservative
surgical approach, very low risk of recurrence (1.7%), lymph node disease (0.7%), or death
caused by cancer (0.5%) was reported by these studies. Most authors conclude that MIC with
the depth of invasion <3 mm, without confluent growth or lymphatic invasion can be safely
treated with conization. During 1966-1972 lymphadenectomy was included in 290 operations
of MIC in Ljubljana. The pelvic LNs were invariably free of cancer. The 5-year survival was
97%, while 6 patients were lost to follow-up. In Medline search 1.170 cases of stage IA ACs
were analysed in a 35-year period. Lymph node metastasis were found in 15 (1.3%) of 531
cases with lymphadenectomy, complicated with recurrent disease in 11 (2.1%) cases
Compared to the SCC MIC, the risk of recurrence in AC was considerably higher, 3.4% and
progression to death 1.4% (436 cases analysed by Östör, 2000). In our 33 AC patients
diagnosed in stage IA there was no recurrence or death of disease.
CONCLUSIONS: According to the world literature and our own experience, the prognosis
of MIC of both squamous and glandular type is very favourable. This suggests that
conservative management of stage IA cervical cancer is indicated and safe when strict
evaluation of tumour extension and surgical margins of the cone are assured.
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SS32-07
USING OF FLOW CYTOMETRY PARAMETERS FOR CERVIX
CARCINOMA TREATED WITH BRACHYTHERAPY
O. Kravetz, L. Marijna, V.Bogatirev
Cancer Research Center, Moscow, Radiosurgery, Moscow
The clinical base for the study during one year period formed 12 patients with carcinoma of
the uterine cervix TNM stage T2b-3b N0-1 M0-1. All patients were treated with combined
external irradiation and brachytherapy with 60Co sources. On the 1st step was external
irradiation of the whole pelvis (30Gy). The 2nd step brachytherapy: 60Co 10Gy/4fr/40Gy to
point A; During intervals between brachytherapy cycles the external irradiation of
parametrium and pelvic lymph nodes was performed (20Gy). DNA - flow cytometry
(analizator EPICS-XL, Coulter, USA) were used for invistigation tumor cells for this group of
patients in dynamic: before the treatment, after the 1st step, and after the whole course of
treatment. Among all patients of this group 6 (50%) have a positive results; 3 (25%) without
any dynamic; 3 (25%) have negative dynamic according to the aneuploid tumors and number
tumors, S and G2+M cell phase. It was Soft Ware MultiCycle, Phoenix Flow Systems,1994,
USA. According to our previous results we suggest that 90% of patients with aneuploid
tumors were more radiosensitive than diploid tumors.
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SF-01
STRATEGIES OF CANCER PREVENTION AT THE
GYNECOLOGIST'S CLINIC. CONTRIBUTION TO THE PROTOCOLS
FOR THE ANNUAL VISIT
F. Xavier Bosch
Institut Català d’Oncologia, Servei d’Epidemiologia i Registre del Càncer, L’Hospitalet de Llobregat, Spain
The annual visits to the gynecologist constitute a major achievement of preventive medicine.
Women in developed countries benefit from regular health-related encounters and have the
expectation that their chances of early diagnosis of cancer would increase. Initially this
applied to cervical cancer and Pap smears and expanded to breast cancer, endometrial cancer
and perhaps ovarian cancer. However, scientific evidence that regular visits add a significant
benefit in many of these instances is lacking.
Two major developments are relevant to help to define the contents of the regular visits on the
basis of evidence based medicine.
The first one is the rampant mortality of lung cancer among women in many developed
countries. Lung cancer is already the number one cancer related cause of death in northern
Europe North America and other countries, well above the mortality due to breast cancer.
Second is the advances achieved in the HPV technology and their applications to predict the
risk of cervical cancer.
To recognize the importance of the regular visits and, at the same time, to rationalize the
visit's protocols while maximizing protection against cancer, it is suggested that anti smoking
strategies and protocols be developed and incorporated into the preventive action of the
gynecologist. Cervical cancer screening could benefit from a diligent incorporation of new
technology and safely increase the testing intervals without compromising its sensitivity and
the level of protection offered.
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SF-02
IS PREVENTION OF BREAST CANCER POSSIBLE ?
Thierry Maudelonde
Lab. Biol Cell, CHU de Montpellier, U540 INSERM
With one million new cases in the world each year, breast cancer is the most frequent
malignancy in women and constitutes 18% of all female cancers. Incidence of breast cancer is
increasing and a politic of prevention has to be a major problem of Public Health. Although
most of estrogen actions in healthy women are beneficial, experimental and clinical data
indicate that most breast cancers are estrogen dependent for their development. Early
menopause can substantially reduce the incidence of breast cancer but the cost of a long-term
lack of estrogen caused by adverse effect (osteoporosis….) is unacceptable. An ideal
prevention of breast cancer should be only antiestrogen on breast and uterus but not in the
other target tissues of estrogen since the treatment has to be taken for a long time. Research of
drugs having such a profile are in progress. These are mainly the Selective Estrogen
Receptors Modulators (SERMs). First of them is the tamoxifen which was proved to have
chemopreventive properties by the reduction of second primary breast cancer in a metaanalysis of breast cancer survivors who took the drug for five years [Early Breast Cancer
Trialist Group, 1992]. Several large breast cancer prevention trials have confirmed this
observation but the adverse effects (hot flashes, endometrial cancer incidence increased,
thrombophlebitis..) are not acceptable in a large politic of prevention. A second SERM,
raloxifen, showed also good efficacy in the breast cancer prevention, but except the absence
of risk of endometrial cancer, the secondary effects are the same. The ideal SERM has to be
found out. It should be able to reduce the risk of breast cancer, osteoporosis, cardiovascular
disease, vasomotor symptoms, urinary incontinence, loss of cognitive function without
increasing the incidence of thromboembolism or carcinogenesis. Another way of research for
estrogen antagonism is the use of aromatase antagonists which are able to suppress the tissue
production of estrogen but their efficiency, in premenopausal women, has to be tested.
References
McPherson K et al. ABC of breast diseases. Breast cancer epidemiology, risk factors, and
genetics. Br M J 321:624-628, 2000.
Powles TJ. Anti-estrogenic prevention of breast cancer-the make or brake point. Nature
Reviews-Cancer.2:787-794, 2002.
Lawrence JA et al. Clinical development of estrogen Modulators for breast cancer
chemoprevention in premenopausal vs postmenopausal women. J Cell Biochem. Suppl
34:103-114, 2000.
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SF-03
LA CONTRACEPTION ET INTERRUPTIONS DE GROSSESSE
COMME DERNIER RECOURS POUR LES FEMMES, POSITION
QUÉBÉCOISE
Jocelyn Bérubé
Québec
Selon certaines données statistiques, environ 40 % des grossesses survenant chez les femmes
québécoises seraient non planifiées et presque la moitié d’entre elles se termineraient par un
IVG. Au Québec en 2001, on dénombrait environ 40 IVG pour 100 naissances vivantes. Le
taux d’IVG est plus élevé chez les adolescentes notamment chez les plus jeunes. Environ 70
% des grossesses survenant chez des filles de 17 ans et moins se terminent par un IVG.
Les raisons expliquant le nombre des grossesses non désirées sont multiples, complexes et
difficiles à bien cerner. Toutefois, on peut penser que des changements dans les choix de
société et les difficultés financières dues à la précarité des emplois et à l’augmentation de la
pauvreté sont des facteurs à considérer. L’Étude canadienne sur la contraception a également
fait ressortir qu’il y a des lacunes quant aux connaissances de la population en matière de
sexualité et de contraception, notamment au sujet de la contraception postcoîtale. Les
professionnels de la santé seraient en partie responsables de cet état de fait. L’attitude des
femmes et des couples face à la contraception est également la causse d’un nombre important
de grossesses non désirées.
Il est difficile d’intervenir sur tous les paramètres liés au phénomène des grossesses non
désirées. Toutefois, les intervenants en planification familiale, notamment les médecins,
peuvent certainement contribuer à améliorer les connaissances de la population et à modifier
certaines attitudes. Pour ce faire, il existe deux approches : l’approche populationnelle et
l’approche individuelle.
L’approche populationnelle s’applique surtout à la clientèle adolescente, puisque la littérature
scientifique ne reconnaît à ce jour aucune approche populationnelle efficace susceptible de
diminuer le nombre des grossesses non désirées dans la population adulte. Parmi les mesures
efficaces de prévention de la grossesse à l’adolescence, on note les programmes de prévention
en milieu scolaire et communautaire ainsi que l’accès à des cliniques de planification des
naissances, ou cliniques jeunesse.
Quant à l’approche individuelle, elle se situe à plusieurs niveaux mais doit obligatoirement
inclure une plus grande accessibilité à la contraception (continue ou d’urgence). Les médecins
peuvent intervenir de façon efficace dans leur pratique en modifiant certaines habitudes ou
attitudes notamment en ce qui a trait à la prescription des contraceptifs oraux.
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SF-04
CHLAMYDIA TRACHOMATIS ET LUTTE CONTRE L’INFERTILITE.
Bertille de Barbeyrac
Laboratoire de Bactériologie. Centre National de Référence des infections à Chlamydia. Université de
Bordeaux2. France
Les infections urogénitales à C. trachomatis sont cause de morbidité, notamment chez la
femme où elles peuvent être à l’origine de complications sévères, grossesse extra utérine et
stérilité tubaire. L’infection étant souvent asymptomatique, le sujet infecté constitue un
réservoir important de transmission et, de plus, les réinfections successives contribuent à
l’établissement de l’inflammation chronique qui conduit à la stérilité tubaire chez la femme.
La fréquence de ces complications est mal connue en France car les données disponibles ne
permettent pas de connaître la proportion effective de GEU et de stérilité tubaire imputable à
C. trachomatis , ni de savoir si le risque de complications à long terme diffère selon que les
personnes ont une infection génitale basse symptomatique ou non. La lutte contre l’infertilité
passe par le diagnostic précoce, rapide et sensible des infections symptomatiques et surtout
par le dépistage des formes asymptomatiques. Les techniques commercialisées, de détection
des acides nucléiques de C. trachomatis avec amplification génique in vitro, ont montré leur
performance dans les deux situations cliniques et sont capables de détecter C. trachomatis
dans des échantillons biologiques non invasifs comme le 1er jet d’urine chez l’homme et
l’écouvillonnage vulvo-vaginale chez la femme. L’utilisation de ces test sur des échantillons
qui peuvent être auto-prélevés, rend possible le dépistage chez les sujets asymptomatiques.
L’objectif d’un programme de dépistage étant de faire diminuer la prévalence et la morbidité
associée, il devrait cibler l’ensemble de la population sexuellement active, homme et femme
de moins de 25 ans. En France, aucune recommandation n’a pour le moment été publiée,
cependant le dépistage systématique des personnes consultant en CPEF, CDAG, DAV et en
centres IVG serait justifié.
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SF-05
MUTILATIONS GÉNITALES
Claude-A. Fortin MD
Montréal Canada
Depuis des millénaires la mutilation génitale s’est répandue à travers plusieurs régions du
monde. Même si le terme "circoncision féminine" a été utilisé longtemps, celui de "mutilation
des organes génitaux féminins" (MOGF) semble le plus approprié dans les circonstances.
En effet cette pratique ayant vu le jour en Afrique, comporte plusieurs types qui de par leur
description relèvent de la pure mutilation. De la simple circoncision (excision du prépuce) la
procédure peut aller jusqu’à l’infibulation "pharaonique" (excision du clitoris, des petites
lèvres et de toute la longueur des grandes lèvres, suivie de suture des rebords de la plaie.
La prévalence variant d’un pays à l’autre l’on estime que plus de 125 millions de femmes ont
subi la mutilation à des âges différents selon les us et coutumes de chacun. ( de la naissance
jusqu’après les 1er accouchements. L’intervention est pour la plupart du temps pratiquée dans
des conditions non hygiéniques par des personnes sans connaissance de l’anatomie et les
complications fréquentes seront immédiates ou tardives. Hémorragie, trauma des organes
adjacents, infection, choc et même décès. Les séquelles tardives seront le dysfonctionnement
des voies urinaires et génitales de même que la sexualité, infertilité, problèmes si grossesse et
mode d’accouchement sans oublier toutes les difficultés d’ordre psychologique et bien
d’autres.
Pourquoi pratique t-on encore la MOGF ? Quels sont les meilleurs moyens pour prévenir ? De
quel droit se prévaloir pour intervenir ?
Profondément ancrée dans une culture, la mutilation contribuerait à l’amélioration de
l’hygiène féminine et de l’esthétique. De plus elle protégerait contre la mortinaissance,
l’infertilité et aiderait à éliminer les maladies. Elle serait également une protection contre
l’infidélité, le viol en plus de préserver l’honneur de la famille.
Toutes ces raisons et bien d’autres n’ayant aucune preuve ou valeur scientifique sont
réfutables une après l’autre et dès lors il est devenu notre rôle d’intervenir.
Beaucoup de professionnels et d’organisations internationales sont opposées aux MGOF et
travaillent pour y mettre fin. Les femmes du monde entier luttent contre cette pratique
‘’barbare ‘’ mettant en danger la santé et la vie de ces enfants. Des traités et des lois ont été
passé interdisant la torture ou tout traitement dégradant cruel ou inhumain infligé à ces
enfants et jeunes femmes. Mais malgré tout la MGOF continue dans certains pays et régions
difficiles d’accès médiatique et interventionnel.
Il faudra que la communauté internationale redouble d’ardeur en suivant l’exemple de certains
pays qui ont à cœur l’abolition de la mutilation.
Par exemple au Canada nous avons fait une étude auprès des fournisseurs de soins de santé de
même que des groupes d’immigrants originaires du pays ou la mutilation génitale est
pratiquée.
Les résultats ont mis en évidence la divergence de perception des femmes immigrées face aux
soins de santé comparativement à ceux qui les prodiguent. Ne connaissant pas beaucoup le
système, elles sont méfiantes et craignent d’autres interventions. De plus il y a souvent une
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barrière linguistique et culturelle. Cette étude a également mis en évidence un manque de
formation de la part des enseignants et des professionnels de la santé que ce soit pour
l’approche psychologique ou encore le type d’intervention à effectuer ou non-face à la
condition.
Par la prévention on peut intervenir. Les recommandations sont nombreuses et s’adressent à
tous. Il faut promouvoir un respect sans faille à l’égard des cultures afin d’établir un dialogue
de départ. Les gouvernements ont à jouer leur rôle de législateur et d’informateur. Les
services communautaires d’éduquer les communautés sur les effets nocifs de la MOGF par
des programmes efficaces et concertés compte tenu des réalités culturelles. Les professionnels
de la santé doivent conjuguer leurs efforts pour combler les lacunes et acquérir des
compétences et attitudes appropriées. De plus par des réseaux nationaux et internationaux on
pourra aider les groupuscules démunis. Ex : base de données, centres de ressources régionales
et nationales.
L’éradication de la mutilation génitale est prioritaire. Cependant il reste beaucoup de travail à
accomplir. Ce travail passe par l’éducation et la compréhension mutuelle. Quoique la
diffusion des ces messages soit difficile à réaliser dans certains endroits de la planète, il y a
lieu d’espérer qu’avec la concertation de tous les réseaux de soutien, de tous les programmes
particuliers et internationaux nous réussirons à pénétrer partout où la nécessité s’impose.
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AUTHORS
SF-06
DÉPISTAGE DE LA VIOLENCE CONJUGALE ET PROTOCOLE
MÉDICO-SOCIAL AUPRÈS DES VICTIMES D’AGRESSION
SEXUELLE
Line Langlois
La violence faite aux femmes est plus qu’un problème social dont la fréquence n’est plus à
démontrer. Elle se répercute inexorablement sur la santé physique et psychologique des
femmes victimes de violence sous toutes ces formes, devenant par son incidence et son
impact un problème de santé publique incontournable. On n’a qu’à penser à l’incidence des
blessures, des problèmes d’anxiété, de dépression et de stress post-traumatique, à la
consommation d’alcool et de tranquillisants, aux MTS, avortements, autres complications de
la grossesse, etc.
La violence conjugale
Quelques statistiques supportent la nécessité, voire l’obligation, pour les médecins de dépister
la violence conjugale. Pour n’en citer que quelques-unes, entre 22 et 35 % des femmes qui
consultent à l’urgence, quelle que soit la nature du problème, sont là en raison de symptômes
reliés à la violence conjugale (Howard et al. 1994). Quatre-vingt pour cent des femmes qui
consultent trois fois et plus à l’urgence pour des blessures sont susceptibles d’être victimes de
violence conjugale (Flitcraft, 1995). Quarante-cinq pour cent des femmes qui ont des
problèmes d’abus d’alcool les développent suite à des actes de violence conjugale (Howard et
al. 1994). Vingt-cinq pour cent des femmes qui consultent en obstétrique sont victimes de
violence conjugale (Flitcraft, 1995). D’ailleurs, la violence conjugale se manifeste souvent
pour la première fois lors d’une première grossesse.
La nier ou l’ignorer contribue à maintenir les femmes et leurs enfants dans une situation
morbide qui ne peut que se détériorer voire même les diriger pour certaines vers la fatalité de
la mort. D’ailleurs, tenter de traiter un problème physique ou psychologique chez une femme
victime de violence non dépistée risque de se solder par un échec, puisqu’ aucune intervention
n’est posée sur la cause réelle de ses difficultés.
Les étapes de fécondité de la femme (contraception, grossesse et ménopause ) de même que le
dépistage des cancers féminins amènent inévitablement les femmes dans le cabinet du
médecin. Le médecin a donc l’occasion de rencontrer la femme dans les diverses étapes de sa
vie et se trouve, par le fait même, en position privilégiée pour dépister les conditions de
violence que vivent d’entre elles. Certains se sont penchés à élaborer une méthode rapide et
efficace de dépistage systématique de violence conjugale à l’aide de quelques questions
précises posées à la femme. Le dépistage peut aussi se faire de façon plus personnalisée en
fonction des indicateurs de violence dans le bureau du médecin.
Une fois la violence identifiée, le rôle du médecin consiste à référer la femme aux ressources
compétentes après avoir bien évalué la dangerosité, le cas échéant, et à jouer son rôle habituel
en tenant au dossier les informations pertinentes, en traitant les problèmes physiques qui en
découlent, et ce, en adoptant une attitude de respect envers le rythme et le choix de la femme
dans cette démarche tout en lui signifiant le caractère inacceptable de toute forme de violence
envers quiconque, et à son égard, en particulier.
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Les agressions sexuelles
Autre phénomène malheureusement présent à tout âge de la vie et excessivement néfaste sur
la santé tant physique que psychologique chez les victimes: les agressions à caractère sexuel.
Le dépistage et l’approche nécessitent une connaissance de l’impact sur les victimes afin
d’accueillir et d’éviter d’aggraver les réactions émotionnelles générées par une telle agression
et comprendre l’ambivalence vécue par les femmes quant au désir de poursuite ou non.
Un protocole médico-social a été élaboré par le Ministère de la santé et des services sociaux
du Québec afin de pallier à la complexité de cette problématique d’un point de vue médical,
psychosocial et juridique. Les difficultés inhérentes au traitement des victimes et au recueil
d’éléments utiles advenant une procédure judiciaire dans un contexte d’agression sexuelle en
sont facilitées par l’élaboration d’un guide qui comprend la démarche et les attitudes à adopter
face aux victimes de même que les étapes de l’évaluation médicale en terme de collecte des
données à l’histoire, du traitement des MTS, de prévention de la grossesse, des éléments de
preuve physique ou biologique à recueillir et du suivi à accorder à ces victimes. Les éléments
de preuve contenus dans cette trousse médico-légale peuvent souvent suffire pour que le
processus judiciaire poursuive son cours sans témoignage sur place du médecin, du moins
chez les victimes de plus de 18 ans.
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SF-07
LES ASSOCIATIONS FEMININES VOUS PARLENT :
RESEAU QUEBECOIS D’ACTION POUR LA SANTE DES FEMMES
Lise Lamontagne
Réseau québécois d’action pour la santé des femmes (RQASF)
Au cours des cinquante dernières années, la conception de la santé des femmes a
considérablement évolué. Auparavant, la santé des femmes était en grande partie déterminée
par leurs fonctions sexuelles ; la physiologie et la pathologie de leur appareil génital
constituait la clé maîtresse de la compréhension de leurs caractéristiques physiques, mentales
et morales.
De nombreux praticiens et concepteurs de politiques ont adhéré à cette perspective
traditionnelle axée sur les aspects génitaux, et on a continué à définir la santé des femmes
avant tout en fonction de la procréation, des menstruations et de la ménopause : qu’il s’agisse
de processus physiologiques normaux ou pathologiques, le tout demandait une attention
médicale.
Le mouvement des femmes s’est insurgé contre cette façon de concevoir la santé des femmes.
Nous sommes différentes des hommes : constatation simple s’il en est une mais complexe
lorsqu’il s’agit de l’appliquer dans les recherches et les programmes en santé. En plus de la
fonction reproductive et du métabolisme hormonal, nous nous distinguons par la
morphologie, la taille, le volume des organes, la répartition du volume adipeux, le
pourcentage d’eau... De plus, nous réagissons autrement aux médications et aux traitements.
Les féministes ont présenté la santé comme un continuum qui s’étend sur toute la vie et qui
est essentiellement et étroitement lié aux conditions de vie. La santé est fonction de relations
complexes entre la biologie, le comportement à l’égard de la santé et le contexte historique,
économique et sociopolitique dans lequel vivent les femmes.
Nous sommes généralement plus pauvres que les hommes à cause d’un ensemble de facteurs,
notamment : emplois traditionnellement féminins moins bien rémunérés, perte de revenu liée
aux grossesses, monoparentalité et responsabilité des enfants assumée par les femmes,
appauvrissement lié à la séparation du couple, accès difficile aux promotions à cause des
responsabilités familiales, etc.
Le sexisme et la discrimination encore présents aujourd’hui maintiennent chez plusieurs
d’entre nous des sentiments d’impuissance, de dépression et de culpabilité. Ils entraînent des
exigences comme la minceur et l’éternelle jeunesse qui vont à l’encontre de la santé des
femmes ou excluent un grand nombre de certains milieux. La violence faite aux femmes dans
tous ses aspects, conjugale — familiale — médicale — psychiatrique — sexuelle, créent un
sentiment d’angoisse et de peur qui paralysent et augmentent le stress.
Notre défi est donc le renouvellement et la promotion des valeurs d’égalité, de dignité et de
sécurité pour tous, femmes et hommes, qui sont à la base des changements nécessaires pour
une vie en santé. En terme de prévention, nous devons insister sur l’éducation à la santé mais
surtout travailler pour l’amélioration des conditions de vie. Dans ce contexte la lutte à la
pauvreté, la réduction des inégalités sociales ressort comme un objectif de santé hautement
prioritaire.
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SF-08
NOUVEAUX MODES DE VIE ET CONSEQUENCES SUR LA
REPRODUCTION
Eric SEDBON
Paris
Le début du 21ème siècle est profondément marqué par une accélération considérable des
modes de communication et par une mondialisation des enjeux économiques. Le rôle et la
place des femmes dans les sociétés industrialisées se sont modifiés donnant à celles-ci la
possibilité d’accéder à un statut équivalent à celui des hommes dans le monde du travail et les
postes à responsabilité élevée. La maîtrise de la contraception aidant, les femmes ont, dans les
grandes cités cosmopolitaines, des enfants de plus en plus tardivement, et moins d’enfants,
alors qu’augmente également le nombre de divorces. Or, si on sait bien en matière de fertilité
que le principal facteur pronostic tourne autour de l’âge féminin, les biotechniques de la
reproduction médicalement assistée autorisent les femmes à penser, à tort vraisemblablement,
qu’elles peuvent attendre et repousser leur projet de maternité ultérieurement pour assurer une
assise professionnelle stable, processus parfois long et aléatoire, ou préserver leur image
corporelle. Parallèlement, dans le monde scientifique, pour la première fois de son histoire,
l’humanité maitrise son génôme et sa reproduction et il n’est pas de décennie sans
qu’apparaisse une nouvelle révolution biotechnologique faisant reculer les limites médicales à
traiter les problèmes d’infertilité : fécondation in vitro, congélation d’embryons, ICSI,
transfert de cytoplasme, clonage, etc…. Aujourd’hui, dans les pays industrialisés, 20% des
couples sont dits infertiles et devront avoir recours à des techniques de procréation
médicalement assistée. Ces techniques, parfois sophistiquées, peuvent dans certains cas jeter
un flou sur les origines de l’enfant à naître et dans tous les cas ont eu pour conséquence
obligée la mise en place d’une réglementation stricte voire d’une législation propre visant à
encadrer la pratique de nouvelles biotechnologies dans le cadre de la reproduction humaine.
Chaque pays, selon sa sensibilité socio-culturelle, éthique et religieuse, fixera ses propres
limites légales. C’est ainsi que pour certains il est possible d’envisager le prêt d’utérus ou le
don de gamètes non anonyme, l’insémination d’une femme célibataire, homosexuelle ou postmortem, etc…. La liste des possibilités médicales offertes en alternative aux traitements de
l’infertilité est aujourd’hui telle, qu’elle rassure vraisemblablement faussement les femmes et
les couples, les confortant dans leur décision de retarder l’âge de la maternité. Aujourd’hui, le
désir d’enfant peut à lui seul suffire à justifier le tourisme procréatif et la mise en route de
biotechnologies complexes obtenues grâce à des traitements lourds dont on devra attendre,
vraisemblablement plusieurs générations, pour en connaître les conséquences à la fois sur
l’individu mais également sur la cellule familiale et, en particulier, sur le développement de
l’enfant à naître. Enfin, les femmes détiennent, sans en avoit conscience, un « trésor
procréatif », le stock d’ovocytes, irremplaçable crédit de fertilité qui s’épuise très rapidement
avec le temps. Le médecin de la procréation se doit de l’en informer clairement, évitant ainsi
parfois souffrance, gachis et catastrophe psychologique.
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SF-09
SEXUALITE ET QUALITE DE VIE
François Piette
Les sexualités masculine et féminine présentent de nombreuses différences tout au long de la
vie. Avec certes de nombreuses exceptions, mais de façon schématique, chez les adultes
jeunes, l’absence de désir sexuel, l’anorgasmie et l’insatisfaction vis-à-vis de la sexualité sont
plus fréquentes chez la femme. Mais on observe une quasi stabilité de la prévalence de ces
symptômes au cours de l’avance en âge au moins jusqu’à la ménopause, alors qu’à l’inverse
la fréquence des anomalies de la sexualité masculine augmente régulièrement avec l’âge. Si
l’anomalie la plus fréquente est le dysfonctionnement érectile, la baisse du désir peut aussi
survenir et est souvent associée à une hypo-androgénie et un état dépressif avec risque
suicidaire qui peut être hormono-sensible.
La poursuite d’une sexualité après la ménopause est largement conditionnée par deux
phénomènes liés entre eux qui sont la prise d’un traitement hormonal substitutif et l’existence
d’un partenaire. Les androgènes (et très transitoirement la DHEA) augmentent le désir sexuel
féminin mais les inconvénients dépassent les avantages.
Au-delà de 75 ans, la sexualité féminine se heurte à la rareté et à la fréquente défaillance des
partenaires masculins, ce qui mène souvent au renoncement, à un désintérêt affiché et à
l’abstinence.
La qualité de vie est en moyenne à tous âges jugée comme moins bonne chez la femme et ceci
contraste avec l’incidence plus élevée des suicides chez l’homme.
La part de l’épanouissement de la sexualité dans la qualité de vie est vraisemblablement très
importante mais elle est mal chiffrée.
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SF-10
INTRODUCTION A LA SESSION FEMMES ET LONGEVITE
François Piette
Un surcroît de longévité féminine (4 ans dans le monde, 8 ans en France) par rapport à celle
des hommes se retrouve dans pratiquement tous les pays et peut être rapproché d’un surcroît
de même ordre chez les femelles par rapport aux mâles dans la quasi totalité des espèces
animales.
Les pays qui font exception (Afghanistan, Bangladesh, etc...) soulèvent la question d’un
traitement discriminatoire réservé aux femmes. D’une façon générale, l’importance de l’écart
dépend certes de l’espérance de vie moyenne (elle-même fortement reliée au niveau
économique), mais aussi d’autres facteurs. Elle est ainsi particulièrement importante dans les
pays slaves (11 ans), notamment en Russie (13 ans).
Les travaux réalisés chez les primates mettent en avant comme variable explicative majeure la
faible participation du père aux tâches d’élevage des descendants. Il est assez vraisemblable
qu’il existe une corrélation négative chez les animaux mâles entre la participation à l’élevage
des descendants et l’existence de conduites à risques.
Dans l’espèce humaine, la sur-mortalité masculine possiblement d’origine comportementale
(conduites à risque) n’est évidemment pas antinomique avec le rôle des hormones mâles et
femelles dans la longévité.
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SF-11
"FEMMES POUR TOUJOURS"
Nicole Kremer
Association Française pour l’information sur la ménopause et la prévention de l’ostéoporose
Plus que jamais l’information en terme de santé et de prévention d’une population
grandissante de femmes de plus de 45 ans est nécessaire.
La nécessité d’études françaises relatives aux bénéfices/risques des THS, la sensibilisation à
la prévention de l’ostéoporose post-ménopausique, les campagnes d’information sur les
risques sanitaires liés à l’augmentation de la longévité, nous amènent à une véritable
réflexion en matière d’éducation du public pour les années à venir.
« Femmes pour toujours » créée en Novembre 1998 par une femme non médecin représente
aujourd’hui une véritable innovation dans cette nouvelle approche des patients.
Un partenariat efficace avec le Corps médical a permis d’apporter à l’immense population de
femmes concernées une information de pointe validée par les meilleures spécialistes.
Le développement rapide qu’a connu notre association - qui nous a tous surpris par son
ampleur - est la preuve tangible de la nécessité de son action.
Quel est le bilan des actions entreprises au cours de ces quatre années et quel impact ont elles
sur notre développement futur ?
Notre implication dans l’information et l’éducation du public en terme d’amélioration du
bien-être physique, psychologique et social de la population féminine, entre très exactement
dans le cadre d’une politique de santé et de prévention et constitue les points forts de notre
action :
SOLIDARITE ! EFFICACITE ! UTILITE
« Femmes pour toujours » est devenue aujourd’hui l’association de référence dans
l’information sur la santé des femmes dès la périménopause.
Face à une population grandissante de consommatrices avisées exigeant à juste titre une
information personnalisée, elle a su lever le voile sur de nombreux tabous liés à la ménopause
et favoriser l’amélioration de la qualité de vie.
Cet immense succès l’a conduite à réaliser de nouvelles actions, créer de nouveaux services,
de nouvelles prestations destinées à satisfaire son public de plus en plus nombreux.
« Femmes pour toujours » souhaite aujourd’hui amener les principaux acteurs de la santé en
France à une nouvelle réflexion sur la prise en charge de la santé féminine dont la longévité
favorise l’émergence de nombreuses pathologies.
« Femmes pour toujours » souhaite aujourd’hui amener la population féminine à une
nouvelle responsabilisation et un autre regard sur sa santé.
Rappelons qu’une Française de 50 ans sur 4 vivra 90 ans, que la moitié des petites filles qui
naissent actuellement deviendra centenaire !
Rappelons également qu’avec le risque d'ostéoporose, la femme ménopausée est exposée à
une morbi-mortalité évitable :
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" Près de 40% de la population féminine de plus de 50 ans sera concernée par une fracture
par fragilité osseuse due à l’ostéoporose,
" Pour 50% de ces femmes, ce risque n'est pas diagnostiqué,
" 1 500 000 femmes présentant une fracture vertébrale ne bénéficient pas de traitement,
" Les fractures du col du fémur déterminent une surmortalité évitable de 20 % après
fracture,
" En France les fractures liées à l'ostéoporose représentent 595 millions d'euros par an
(USA 13.8 billiards de $ - étude NORA)
" Plus de 150 millions de personnes sont touchés par cette maladie à travers le monde
LES CAMPAGNES DE SENSIBILISATION DOIVENT DANS LES ANNEES A VENIR
AMENER LE PUBLIC A UNE PRISE DE CONSCIENCE DES RISQUES.
C’EST LE BUT DE LA CAMPAGNE « L’OS…EN QUESTIONS » PREVUE SUR 3 ANS
MENEE PAR L’ASSOCIATI0N.
EN RESUME
! FPT a fait la preuve que lorsque des femmes parlent aux femmes, l'audience est acquise et
le message accessible,
!FPT fait la preuve du besoin exprimé d'information, en matière de ménopause par la
population des femmes âgées de plus de 45 ans,
!FPT fait la preuve qu'une association de patients, indépendante du Corps médical et de
l'industrie du médicament est nécessaire, attendue et utilisée,
!FPT fait la preuve, à l'instar de certaines associations de « patients », que le média
« association de patients » est un incontournable promoteur d'information essentielle, valide et
utile.
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SF-12
MOUVEMENT FRANÇAIS POUR LE PLANNING FAMILIAL
Françoise Laurent
Le MFPF est un mouvement constitué de 67 associations départementales (AD), d’une
association nationale appelée « confédération nationale » et de fédérations régionales.
Depuis bientôt 50 ans, il poursuit les mêmes buts militants : «agir pour que chaque personne
puisse avoir le droit à l’information et à l’éducation permanente. Le MFPF est donc un
mouvement d’éducation populaire, pour créer les conditions d’une sexualité vécue sans
répression ni dépendance, pour le droit à la contraception et à l’avortement, contre
l’oppression spécifique des femmes, contre toutes formes de discriminations et de violences,
notamment sexuelles. En cela le MFPF est un mouvement féministe.
Ses interventions sont bâties sur des pratiques développées en direction du public, dans
l’objectif de leurs offrir écoute, information et « counselling ».
La difficulté des pouvoirs publics et des professionnels à prendre en compte les rapports
sociaux de sexe dans leurs actions, leurs interventions et leurs politiques, concernant le droit
des personnes au libre choix en matière de sexualité et de reproduction, nous a conduit
progressivement à accentuer la visibilité, dans nos activités et dans nos actions, de la question
des violences sexistes et sexuelles et à souligner l’importance de l’aspect « prévention des
comportements sexistes » de toute intervention.
Le rôle d’organisme de formation du MFPF, dévolu logiquement aux fédérations régionales,
prend alors une importance accrue dans tout le mouvement.
Par ailleurs, à côté des actions développées localement et nationalement en direction des
politiques, des services publics, des institutions, des professionnels et des associations, pour
faire avancer les droits et l’accès aux droits en matière de choix dans les domaines de la
sexualité et de la santé de la procréation, ou pour lutter contre leurs reculs, de nombreuses
actions de solidarité internationales se développent depuis plusieurs années.
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FC1-01
HUMAN PAPILLOMAVIRUS AND CERVICAL CANCER:
KNOWLEDGE, INFORMATION PROVISION AND ATTITUDES TO
TESTING.
Tristram A, Fiander A
Department of Obstetrics and Gynaecology, University of Wales College of Medicine, Cardiff, Wales,
UK
Aims
The aims of this study were to establish the level of background information regarding human
papillomavirus (HPV) and cervical cancer, to produce an appropriate educational leaflet
explaining this link and to canvass women's opinion on the prospect of being tested for HPV.
Methods
A survey set in two coloposcopy clinics and a genitourinary clinic. Women were asked about
their background knowledge of HPV and cervical cancer. An HPV information sheet was
produced and given to the women, with a second questionnaire asking for feedback on the
leaflet and for their opinion on being tested for HPV. After initial analysis, a revised leaflet
was produced and the survey repeated.
Results
The response rate was over 90%.
91% of women were positive about having received the information. Comments regarding
content and layout were used to redesign the leaflet.
77% of the women would have agreed to being tested for HPV.
Details and examples will be presented.
Conclusions
The background knowledge of HPV was low and information was well received. If HPV
testing is introduced, it should be accompanied by a public health education programme, with
written information.
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FC1-02
A RANDOMISED TRIAL ON HPV TESTING FOR PRIMARY
CERVICAL SCREENING: STUDY DESIGN
Ronco G. (1), Segnan N. (1), Confortini M. (2), Vettorazzi M. (3), Naldoni C. (4), Dalla Palma P.
(5), Brezzi S. (6), Giorgi-Rossi P. (6), Carozzi F. (2), Cuzick J. (7)
(1) Unit of Cancer Epidemiology, CPO Piemonte, Turin, Italy (2) CSPO, Florence (3) Veneto Cancer
Registry, Padua (4) CPO, Ravenna (5) Trento Hospital (6) ASP Lazio, Rome (7) Cancer Research
UK, London, UK.
BACKGROUND. There is evidence that molecular testing for HPV is more sensitive (but
less specific) than conventional cytology in detecting CIN. However no direct evaluation of
protection against cancer is currently available. Some of the excess lesions found by HPV
could be regressive. Screening by cytology is protective and simply adding a new test at the
same intervals could lead to unfavourable cost-effectiveness. HPV infection seems to precede
intraepithelial lesions by a long time and could be used to select women (HPV negative) at
low risk of developing high grade CIN for years, who could be screened at long intervals.
Also, those who are HPV positive are at relatively high risk and should have closer follow-up.
OBJECTIVES. Evaluating: A) the protection provided by HPV testing at long intervals
compared to conventional cytology every third year B) costs in terms of number and type of
tests needed and undesired effects. C) the best age of starting and stopping and (D)
management of positive women.
METHODS. A multicentre randomised controlled trial involving 9 organised screening
programmes in 6 Italian Regions. Women aged 25 to 60 years coming for a new screening
round are eligible. Study size: 50,000 women randomised to each study arm over two periods.
Conventional arm: conventional cytology every third year. Experimental arm: in period 1
liquid sample tested for HPV (Hybrid Capture II probe mix B) and thin layer cytology. In
period 2 HPV test only. In period 1 HPV positive, cytologically negative women are directly
referred for colposcopy if age <=35 years, repeat after 1 year if age < 35. If colposcopy is
negative, HPV positive women are followed-up yearly. Women in both arms will be screened
by conventional cytology 3 years after recruitment. The main outcome measures will be
Detection Rate of histologically confirmed CIN2/3 at recruitment (also by individual
experimental test) and after 3 years and the time of diagnosis of CIN2/3.
Recruitment started in spring 2002. At the end of 2002 some 18303 women had been
randomised to the conventional arm and 18499 to the experimental arm.
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FC1-03
HIGH RISK-HPV AND BORDERLINE AND MILD DYSKARYOSIS IN
CERVICAL CANCER SCREENING; PRELIMINARY RESULTS
POBASCAM
Bulkmans N (1), Snijders P (1), Brule vd A (1), Rozendaal L (1), Voorhorst F (2), Boeke A (2), v
Kemenade F (1), Verheijen R (3), v Groningen K (4), Boon M (5), Keuning H (6), Meijer C (1).
(1) Dept. of Pathology, (2) Institute EMGO, (3) Dept. of Obstetrics and Gynaecology, VUmc,
Amsterdam, The Netherlands; (4) Dept. of Pathology, Spaarne Ziekenhuis, Heemstede, The
Netherlands; (5) Leids Cytology and Pathology Laboratory, Leiden, The Netherlands; (6) Stichting PA
Laboratorium Kennemerland, Haarlem, The Netherlands
Borderline and mild dyskaryosis (BMD) account for 75% of the abnormal cytology diagnosis.
However, only 10% of BMD women have CIN3. We aim to find out whether high-risk HPV
(hrHPV) testing can be used to better select women at risk of "CIN3.
POBASCAM is a population-based randomised controlled trial which compares hrHPV
testing (GP5+/6+PCR-EIA for 14 hrHPV types) + cytology (experimental group) with
cytology alone (reference group). 44.102 women participating in the Dutch screening
programme were included. The endpoint is the number "CIN 3 lesions. Referral policy for
women with BMD in the reference group: when repeat smear "BMD at 6 or 18 months.
Referral policy women with BMD experimental group: when at 6 months BMD/HPV+, or
>BMD; or at 18 months "BMD or hrHPV+.
At baseline 34.7% of the women with BMD was hrHPV+. During follow-up, 6.4% of women
with BMD in the experimental group had lesions "CIN3. For women with BMD/hrHPV+ the
rate of "CIN3 was 20.0%, compared to 0.4% for women hrHPV-. In the reference group the
rate of "CIN 3 was 7.3% for women with BMD. At 6 months there were 8% less referrals in
the experimental group. One CIN3 was found in the BMD/HPV- group. This scrape contained
HPV 67, a type, which was originally not screened for.
Conclusively, hrHPV identifies the group of women with BMD at highest risk of "CIN3.
Since all lesions "CIN3 were found in women with BMD who tested hrHPV+ at baseline,
direct referral on the basis of hrHPV positivity at baseline seems possible. After completing
the follow up, more results will be obtained and a cost effectiveness study will be done.
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FC1-04
HPV DNA TESTING IN ROUTINE CLINICAL PRACTICE FOR
IDENTIFICATION OF UNDERLYING CIN2/3+ IN WOMEN WITH
ASC-US AND AGC PAP SMEARS.
Fetterman Barbara
Kaiser Permanente Regional Laboratory, Cytology Department, Berkeley, CA
OBJECTIVE: To assess the relationship of HPV DNA test results and histologic CIN2/3+ in
women with ASC-US and ASG-US Pap diagnoses in routine clinical practice in a large
Health Maintenance Organization (HMO).
METHODS: We are a regional HMO laboratory serving over 600 providers and 67
pathologists. Conventional Pap smears are used. Specimens for HPV testing are collected into
STM tubes and tested for high-risk HPV using Hybrid Capture II (Digene). Either co- or
follow-up collection of the HPV sample is done, at the discretion of the clinician.
RESULTS: In 2001, 7,241 women had ASC-US Paps, and 4,093 (57%) of these were tested
for HPV. Of the 2,530 women whose ASC-US cases were HPV negative, 110, or 4.3% had
biopsies. Of the 1,563 women that had positive HPV results, 869 (56%) had biopsies within 6
months, for a total of 979 women with ASC-US that had Pap, HPV, and biopsy results. There
were 162 CIN2/3+ biopsies (16.5%), including 4 invasive squamous cancers and 1
adenocarcinoma in situ (AIS). The HPV results were positive for 158 (97.5%) of the women
with CIN2/3+, including all 4 (100%) invasive carcinomas and the AIS. This compares with
the 87.2% sensitivity for CIN2/3+ reported in Manos et al. using the 11 probe prototype of
HCII (JAMA 1999; 281:1645-7), and 97% reported by the ALTS group using the current 13
probe test (J Natl Cancer Inst. 2000; 92: 397-402). Among the 110 women that were biopsied
who had ASC-US Paps and negative HPV tests, 4 had histologic CIN2/3+, and 81 (73.6%)
had benign results. In addition, ASC-US cases with negative biopsies fell 20%, from 49% in
1999 to 39% in 2001.
Of 1,103 women with AGC Paps, 425 (39%) had HPV results, and of those, 132 were
biopsied. Eighteen of the 132 biopsied women had CIN2/3+, including 1 squamous
carcinoma, 1 AIS, and 2 invasive adenocarcinomas of the cervix. All 18 women had HPV+
results (100%). In the study by Ronnett et al. (Human Pathol. 1999; 30:816-25), 11 of 12
(92%) CIN2/3+ and all 5 AIS were HPV+.
CONCLUSIONS: The results of HPV triage in routine practice have matched or exceeded
the expectations from research studies. Women with invasive carcinomas were 100% HPV+.
The women who had ASC-US Pap tests and CIN2/3+ biopsies were 97.5% HPV+, with 4
HPV- cases. Since the women with ASC-US and HPV- results were biopsied relatively rarely,
and not randomly, sensitivity and specificity cannot be calculated. Provider education about
the appropriate response to a positive HPV test is a work in progress.
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FC1-05
HPV GENOTYPING BY SPF10 PCR LIPA IN COMBINATION WITH
COMPLEMENTARY SEQUENCE ANALYSIS
Molijn, A.C.; Kleter, B.; van Doorn, L.J.; and Quint, W.G.V.
Delft Diagnostic Laboratory, Delft
Background and aim: The SPF10 PCR amplifies a 65-bp fragment from the L1 region, and
the product can be used directly on a line probe assay (LiPA) to identify 25 genotypes by
reverse hybridization. Other genotypes can be identified by sequence analysis of the 22 bp
interprimer region.
Materials and Methods: Cervical scrape samples were obtained from women from different
geographic origins, and were analyzed by SPF10 primers. PCR products were first tested on a
microtiter-based hybridization assay, using a mixture of general probes, to detect HPV-DNA
positive samples. PCR products from HPV-positive samples were subsequently analyzed by
LiPA, which allows identification of 25 genotypes (HPV 6, 11, 16, 18, 31, 33, 34, 35, 39, 40,
42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68/73, 70, and 74). HPV-DNA positive, but
LiPA-negative samples were analyzed by direct sequencing of the 65-bp SPF10 PCR product.
Interprimer sequences were compared to GenBank using the BLAST software.
Results: Of the 3201 samples, 1005 (30.5%) were HPV-DNA positive. Of these, 852 (84.8%)
yielded a genotype on the LiPA. Of the remaining 153 cases, 136 (88.9%) could be
sequenced. 92 (67.7%) sequences fully matched the sequence of a known low-risk HPV
genotype. From 44 (32.2%) cases, the sequence did not fully match any known HPV
genotype, but showed at least 1 mismatch in the interprimer region. Genotyping of these
samples required further sequence analysis of other genomic regions. None of the sequenced
samples yielded any genotype, for which a probe is present on the LiPA.
Conclusions: These results show that (1) the current LiPA efficiently detects 25 HPV
genotypes, (2) the SPF10 PCR not only permits amplification of a very broad spectrum of
HPV genotypes, but also (3) the small SPF10 interprimer region is suitable for rapid
identification of a large number of HPV genotypes.
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FC1-06
ROUTINE HPV DETECTION BY PCR OR AN AUTOMATED IN SITU
YBRIDIZATION TECHNIQUE - A COMPARATIVE ANALYSIS AND
CLINICAL RELEVANS.
Cajander S, Backlund I, Nister M, Shokohideh L, Sigurdardóttir S, Sällström J, Wilander E,
Pakbaz* M. and Wikström* I.
Centre for Laboratory Medicine and Department of Obstetrics and Gynecology*, University Hospital,
751 85 Uppsala, Sweden
Clinical management of patients with various lesions on the uterine cervix is mainly
depending on cellular morphological analysis. However, pathological diagnostic consistence
and consensus on grading CIN and determination if atypia is reactive or neo-plastic is highly
subjective. It seems important to add an objective biological marker to the morphological
diagnosis in order to improve the quality and safety of adequate patient management.
PCR technique is sensitive and reliable for detection and sub-typing of HPV but cellular
localization of virus and its correlation to morphological/neo-plastic alterations is not
possible. We here compare PCR with an automated in situ hybridization (ISH) technique for
detection of high-risk (HRV) and low-risk (LRV) viral types.
Materials and Methods. 120 mainly gynecological cases were controlled for the occurrence
of HPV. DNA was isolated from paraffin blocks of which the preceding section had been
used for morphological diagnosis and the following for ISH. PCR-positive cases were HPVtyped by direct PCR DNA sequencing, using GP5+ as sequencing primer. The DNA
sequences were compared to known HPV sequence databases.
ISH analysis was performed with the INFORM® (ASR) probes and the automated ISH assays
for tissue, HRV (genotypes 16,18,31,33,35,39,45,51,52,56,59 and 70) and LRV (genotypes
6,11,42,43, and 44) from Ventana Medical Systems Inc, Tucson, Arizona on the BenchMark
Automated Slide Stainer.
Findings. With PCR 105 cases (87.5%) were HPV positive and 78% (82) of HR viral type.
With ISH 101 cases (84%) were HPV positive and 87% (88) of HR type. 17 cases with
inflammatory changes without or with a slight non-defined squamous cell atypia showed
29%, 18% positivity for PCR-HRV, PCR-LRV while 24% showed HRV with ISH. 11 cases
with CIN1 showed with PCR 55% and 64% positivity for HRV and LRV types respectively
while ISH showed 64% and 36% positivity for HRV and LRV respectively. 17 cases with
CIN2 showed with PCR 88% and 6% positivity for HRV and LRV types respectively while
ISH showed 94% and 6% positivity for HRV and LRV respectively. 100 % of invasive
cervical adeno-carcinoma (n=7), were positive for HRV types with both PCR and ISH.
Conclusions. The use of automated ISH technique appears sensitive enough for detection of
HPV. An obvious advantage in comparison with PCR is the simultaneous localization of the
virus to specific cells with or without neo-plastic changes as seen by microscopy.
Management algorithms based on clinical data, morphology and HPV analysis will be
presented and discussed.
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FC1-07
DETECTION OF HPV AND SUBTYPING OF HPV IN PAP-SPIN
MEDIUM COLLECTED CERVICAL CELLS.
Ramael M., Van Steelandt
H. Dept. Molecular Pathology. General Hospital St. Elisabeth. Herentals Belgium
PAP-SPIN medium preserved cervical cells of 400 patients (age 25- 70 years) with aberrant
cervical cytology including 155 ASCUS, 168 LSIL, 72 HSIL and 5 squamous cervical
carcinomas were morphologically evaluated and an aliquot of 4 ml was digested overnight
with Proteinase K followed by column purification. The integrity of the DNA was confirmed
by PCR for segments of the beta-globin gene (amplicons ranging from 110 bp upto 536 bp ).
HPV DNA was detected both by Short PCR fragment (SPF) PCR and PCR with
MY11b/MY09 primers (amplicon 450 bp). All the samples that were HPV positive were
sequenced using the SPF amplicon and the MY11b/MY09 as template. The presence of high
risk HPV types was investigated by high risk HPV PCR targeting a region situated in the E6E7 gene of the HPV virus (amplicon 200-250 bp ) thereby detecting in one PCR reaction the
high risk types HPV 16, 18, 31, 33, 35, 52 and 58. Sequencing was carried out as a
confirmatory test.
HPV DNA was found in approximately 40 % of ASCUS with a dominance of high risk types
(65 %) such as 16, 18, 31, 33, 35, 39, 45, 52, 58, 61, 66, 68, 82. Low risk types found
included types 5, 6, 11, 53, 62. All cases of LSIL, HSIL and cervical carcinoma were positive
for HPV DNA. LSIL lesions displayed HPV high risk types (16, 18, 31, 33, 35, 39, 45, 52, 58,
61, 66, 68 ) in the majority of cases (75%). The remaining LSIL harboured low risk HPV
types such as HPV 6, 11, 13, 30, 53, 62, 70. Novel types such as HPV 82, 83 and 87 were
found rarely. In three cases unknown HPV types were found displaying sequence homology
less than 80 % with known HPV types. HSIL and all cervical squamous carcinomas contained
only high risk HPV types. HPV 16 and HPV 18 were the most prevalent types but other HPV
types such as HPV 31, 33, 66, 73 were also frequently encountered.
We conclude that PAP-SPIN medium not only preserves excellent cellular morphology but
also permits HPV detection on the same cytological sample thereby enabling various kinds of
PCR amplifications upto at least 500 bp as well as sequencing. SPF PCR and MY11/MY09
PCR followed by sequencing was able to detect and subtype all HPV infection. PAP-spin
medium permits identification of so called "novel " HPV types as well as detection and
sequencing of unknown HPV types.
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FC1-08
FREQUENT GENITAL SHEDDING OF HUMAN PAPILLOMAVIRUS
HARBORING ATYPICAL DISTRIBUTION OF HIGH-RISK
GENOTYPES IN CHILDBEARING-AGED WOMEN LIVING IN
LIBREVILLE, GABON
Si-Mohamed A (1, 2), Ndjoyi A (3), Cuschieri K (4), Ozouaki F (5), Le Goff J (1,
2), Bugi A (2), Cubie H (4), Bélec L (1, 2)
(1) Hôpital Européen Georges Pompidou, Unité de Virologie, Paris, France; (2)INSERM U430, Paris,
France; (3) Faculté des Sciences de la santé, Service de Microbiologie, Libreville, Gabon; (4)
Specialist Virology Centre, Edinburgh, U.K.; (5) Maternité Joséphine Bongo, Libreville, Gabon
Background. Cervical cancer is a major cause of mortality in women living in sub-Saharan
Africa, and high-risk human papillomavirus (HR-HPV) may have a unique distribution in this
setting.
Objective. To assess the extent of HPV shedding and type specific diversity within genital
secretions from women of child-bearing age in Libreville, Gabon.
Methods. Paired endocervical swab and blood samples were obtained from 360 consented
women attending the Joséphine Bango Maternity, Libreville, for either family planning
(n=90), STD-related symptoms (n=147) or issues relating to pregnancy (n=123). Detection of
HPV DNA was performed by PCR using the MY09/MY11 primer set. All PCR positive
specimens were subjected to direct sequncing and HPV types indentified on the basis of
>95% sequence homology in the L1 region using BLAST (http://hpv-web.lanl.gov/) . The
Roche reverse line blot assay was performed in all cases where the genotype could not be
resolved by sequencing alone.
Results. HPV DNA was detected in 163 (45%) of the genital swabs. HPV genital shedding
was associated with younger age (p<0.05), a positive diagnosis of STI (p=0.09) at the time of
swab and HIV seropositivity (p<0.02). We detected a high prevalence of diverse high risk
genotypes including HPV-83 (28%), HPV-58 (22%) and HPV-16 (22%), within the HPV
positive group. The most prevalent low-risk HPV types detected being HPV-53 (30%) and
HPV 54 (26%). Interestingly, 40% of HPV positive women harboured types which are
attributed to confer an unknown oncogenic risk.
Conclusion. Analysis of this cohort would suggest that HR-HPV genital infection has a high
prevalence in women of child-bearing age in Gabon. Moreover, the most frequently detected
high-risk genotypes differ dramatically from those that typically predominate in Western
countries. These observations serve as further justification for the organisation of a cervical
cytology screening program within Central Africa. Larger studies which evaluate the
molecular epidemiology of HR-HPV types within this central African population are required.
These would inform appropriate vaccine design and refine the choice of HPV detection
strategy should HPV testing be implemented to manage cervical disease in this population.
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FC1-09
HUMAN PAPILLOMAVIRUS AND HERPES SIMPLEX VIRUS
TESTING ON SELF-COLLECTED SPECIMENS IN WOMEN WITH
PRIOR NORMAL PAP SMEARS IN BALTIMORE
Khanna N (1), Arnold S (1), Lee C (1), Bell L (2), Ramachandran S (2), Lorincz A (2)
(1) University of Maryland School of Medicine, Baltimore, MD USA; (2) Digene Corp, Gaithersburg MD
USA
Introduction: Our main objective was to identify the prevalence of human papillomavirus
(HPV) and herpes simplex virus (HSV) DNA in an urban university clinic female population
presenting for routine Papanicolaou smear screening. A secondary objective was to compare
vaginal self-sampling with clinician sampling for accuracy and acceptability.
Methods & Population: Annually, 41,000 patients visit the University of Maryland Family
Medicine clinic and approximately 4,000 Pap smears are conducted per year.
Study Design: Cross-sectional HPV and HSV prevalence study with nested HPV follow-up.
Lab Methods. Hybrid Capture (HC) 2 and 3 (Digene, Gaithersburg) were used to detect the
carcinogenic group of HPVs and for genotyping. HC3 and polymerase chain reaction (PCR)
were employed for HSV detection.
Results: 712 women were offered participation and 212 refused. Five hundred women met
inclusion criteria and provided a clinician-obtained specimen, with 397 women also agreeing
to provide a vaginal self-collected specimen. Refusers mainly had concerns with the
technique of obtaining the sample, which involved touching their genitalia. Mean age for
women enrolled in the study was 32 years, 51.6 % were African American and 41.4% were
never married. Women who refused to participate were 71.2% African American, average age
34 years, 62.6% never married, and 89.5% with a high school diploma or greater. At least one
member of the group of 13 carcinogenic HPV DNAs were detected using HC2 in cervical
clinician-collected samples in 82 (16.4%) of 499 women. HC3 tested positive for HPV 16 in 8
(1.6%) and HPV 18 in 6 (1.2%) of clinician samples. The HPV carcinogenic group tested
positive in vaginal self-collected samples using HC2 in 102 (25.7%) of the 397 women. HC3
tested positive for HPV 16 in 10 (2.5%) and HPV 18 in 5 (1.3%) self-samples. HSV was
present in only 4 (0.8%) of 493 clinician samples by HC3 and HSV PCR was positive in 10
(2.0%) women. HSV testing using HC3 in self-samples resulted in 4 (1%) positives. Follow
up: HPV tests will be repeated in HPV positive women at 1 year from baseline screening.
Conclusion: Preliminary data indicate a relatively high prevalence of carcinogenic HPV
DNA but a low prevalence of HPVs 16 or 18 in these women. Self-collection is a possible
alternative to speculum assisted clinician-obtained specimens that may be acceptable for HPV
DNA testing in the large majority of women undergoing routine Pap screening. Public health
measures need to consider the significance of currently undiagnosed HPV DNA when
designing programs promoting sexual health and reproductive decision making.
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FC1-10
HPV DNA AS A MARKER TO PREDICT RECURRENT CERVICAL
DYSPLASIA IN WOMEN POST TREATMENT
Tan J, Garland S, Saville *, Tabrizi S, Quinn, M.
Royal Women's Hospital, Oncology & Dysplasia Unit, * Victorian Cytology Service Melbourne
Objective: To evaluate whether human papillomavirus (HPV) DNA is a reliable predictor of
adequacy of treatment and is a marker of recurrent disease following the surgical management
of cervical intraepithelial neoplasia (CIN).
Methods: Patients undergoing ablative therapy by laser, cautery or loop excision and coldknife cone biopsy were enrolled in the study at time of treatment and then reviewed at 4, 10,
16 and 22 months post treatment. At each visit, cervical brush and spatula for Papanicolaou
smear (pap) and HPV Hybrid Capture were obtained. The cells were smeared onto a glass
slide and remaining cells were dislodged in a PreservCyte for detection of high-risk HPV
types. Colposcopy was performed, with cervical biopsy for histology when indicated.
Results: 625 women were recruited between May 2001 and September 2002. The abnormal
squamous intra-epithelial lesions (SIL) based on histology at clinic prior to or at treatment
were: HSIL (High) 406 (65%), LSIL (Low) 184 (29.5%), Malignancy 2 (0.3%). 33 had no
histological confirmation of SIL (5.2%).
406 (65%) had positive HPV test: HSIL (71%), LSIL (51%), Malignancy (100%) and Normal
(61%).
At 4 months post operatively, 370 women had a follow up HPV test. Cytological or
histological abnormality were: HSIL 10 (2.7%) and LSIL 57 (15.4%).
112 (30%) tested HPV positive: HSIL (100%), LSIL (61%) and Normal (22%).
At 10 months post operatively, 125 women had a follow up HPV test. Cytological or
histological abnormality were: HSIL 1 (0.8%) and LSIL 19 (15.2%).
26 (21%) tested HPV positive: HSIL (100%), LSIL (37%) and Normal (16%).
Conclusions: From the preliminary results of this study, the negative predictor value of HPV
holds promise as a marker of adequacy of treatment of High Grade Intra-epithelial Squamous
Lesions.
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FC1-11
HPV TYPING AND QUANTITATION IN SURGICALLY REMOVED
HGSIL, COMPARISON WITH PRE AND POST SURGICAL CERVICAL
BRUSH
Flavia B. Lillo (1), Ferrari Davide (2), Lodini Sara (1), Grasso Maria Angela (1), Taccagni
Gianluca (3), Lazzarin Adriano (4), Uberti-Foppa Caterina (4)
(1) Laboratory of Virology, (2) Department of Obstetrics and Gynecology, (3) Department of
Pathology, (4) Department of Infectious Diseases– IRCCS San Raffaele Hospital, Milan, Italy
Background: HIV-positive women have an increased incidence of biopsies proven SILs,
more rapid progression to high-grade SIL and invasive cervico-carcinomas and more frequent
and persistent HPV infection. Multiple infections are often detected with a possible
summatory effect in the oncogenic process.
Methods: Thirty one HIV positive and 15 negative women who underwent surgical removal
of cervical lesions are included in the study. All patients had at list one pre and one post
surgical visit including colposcopy, PAP test, biopsy if necessary and sampling for HPV
typing by specific probe hybridisation. Quantitation of total HPV DNA was performed by real
time PCR using consensus primers in the L1 region to verify a further parameter possibly
related to the development of lesions
Results: HgSIL was diagnosed in 97% and in 40% HIV positive and negative women
respectively. All had high risk (HR) HPV infections in the baseline cervical brushing in a
range of 1 to 8 and 1 to 6 different types. Coinfection with multiple HR viral types was
detected in the surgical sample of 93.5% of HIV positive and 80% of HIV negative women
with a mean of 4 (range 1-10) and 2.5 (1-4) respectively. The most frequently detected types
in the surgical sample of HIV positives were HPV-18 (77.4%), 31 (64.5%), 16 (38%), while
in HIV negatives were HPV 56 (46.%) 18 (33.3%) and 16 (20%). After surgical treatment,
HSIL recurred in 2 HIV positive patients (6.4%) and LSIL in 33.3 % of both groups.
Persistence of at list one of the oncogenic types detected in the surgical sample was observed
in the two relapsed HSIL and in 87% of the LSIL. Quantitation of total HPV DNA in a subset
of 16 HIV positive women (none relapsed) showed a mean of 2.9x107copies/µg of genomic
DNA in the pre-surgical cervical swab, of 4x107 copies in the surgical sample and of 1.8x103
copies in the post-surgical swab.
Conclusions: Multiple HR-HPV types are detected in both HIV positive and negative women
with an apparently different distribution of the most prevalent types. Persistence of HR-HPV
is a key marker in the development of lesions but its re-evaluation in the prospective of
identifying further predictive markers may probably include viral burden: both total and type
specific. high level of HPV DNA is in fact detected in the lesions and is drastically reduced
by its removal.
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FC2-01
THE VALUE OF ENDOCERVICAL CURETTAGE IN THE
EVALUATION OF ABNORMAL PAP SMEARS
Goodman Annekathryn
Massachusetts General Hospital, Obstetrics and Gynecology, Boston
Introduction: Colposcopy has been the standard method for evaluating abnormal cervical
cytology for the last 25 years. Historically, enocervical curettage (ECC)was a routine part of
the colposcopic evaluation. However, in the late 1980's, several authors have shown that ECC
added little information in the assessment of cervical cytology for the expert colposcopist.
This study looked at whether ECC improves diagnosis of dysplastic lesions.
Materials and Methods: Data was obtained from records of the Massachusetts Genral
Hospital Colposcopy clinic. Patients were evaluated by a gynecologic oncology fellow. Pap
smear and ECC were performed on all non-pregnant patients. Records from 1999-2000 were
abstracted for a total of 610 colposcopy visits. The results of the pap smear and ECC were
compared as well as results of other biospy specimens.
Results: 376 of the 610 papa smears were normal. Of these, 17 had abnormal ECCs: 11
atypical, 2 low grade squamous intraepithelial lesion (SIL), one high grade SIL. All atypical
and low grade ECCs subsequently had at least 2 negative Pap smears and ECCs in follow-up.
The 3 women with HSIL underwent LEEP procedures. Two of the LEEP specimens were
negative for dysplasia, one showed moderate dysplasia/ CIN 2. Of the 234 abnormal pap
smears, 42 also had abnormal ECCs. There were no cases of invasive cervical cancer found.
Conclusion: In this sample of 610 patients undergoing colposcopy, pap smear, and ECC for a
previously obtained abnormal Pap smear, only one dysplastic lesion was found based on ECC
alone. We conclude that routine ECC is not a valuable tool in diagnosing cervical dysplasia.
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FC2-02
THE IMPORTANCE OF THE CELL SAMPLE IN CERVICAL
CYTOLOGY-REVISITING THE ENDOCERVICAL COMPONENT
GRACE J.
The importance of sampling the transformation zone in cervical cytology has been recognised
for 20 years. There have been many publications concerning its identification in cervical
smears. There has been a lack of consensus concerning the definition and significance of
endocervical cells or metaplastic cells in conventional smears particularly in European
studies. The Bethesda System (TBS) was published in 1998 and modified in 1991 and defined
an adequate endocervical component as ‘at a minimum two clusters of well-preserved
endocervical and /or metaplastic squamous cells , with each cluster composed of a minimum
of least 5 appropriate cells.
Five publications since 1990 have been reviewed that examined the absence of an
endocervical component in ‘false negative’ smears. These papers used definitions ranging
from TBS to ‘cylindrical’ cells. Despite this variation all papers reported a lower rate of
endocervical or metaplastic cells in the ‘false negative’ smears than in the abnormal smears.
Two studies examined smears from cases of invasive cancer (Robertson and Woodend, 1993
and Kristensen etal, 1990) and three from cases of cervical intraepithelial neoplasia (CIN)
(Mitchell and Medley, 1992, Beeby et al, 1993 and Bauldauf et al, 1997). The rates of
endocervical component in ‘false negative’ smears ranged from 36% to 60.8% and for
abnormal smears 80% to 93%.
Other factors that are associated with ‘false negative’ smears include small lesions, lower
grades of CIN and lesions high in the endocervical canal. Robertson and Woodend reported
that on review of ‘false negative’ smears the finding of scanty abnormal cells was associated
with a deficiency in the endocervical component (66%).
Sampling error is a significant reason for a ‘false negative’ smear. Despite numerous
publications reviewing conventional smears and showing an association with an absent
endocervical component there is no consensus concerning the definition or significance.
Recommendations will be suggested using these publications and discussing the influence of
liquid based cytology and programs’ screening intervals.
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FC2-03
WHEN WILL NEW CYTOLOGICAL TECHNOLOGIES FOR
CERVICAL CANCER SCREENING BE COST-EFFECTIVE?
Meerding WJ, van den Akker-van Marle ME, van Ballegooijen M, Habbema JDF
Erasmus MC, University Medical Center Rotterdam, Department of Public Health, Rotterdam
Objective To indicate what sensitivity, specificity and unit cost is required by new
cytological technologies for cervical cancer screening in order to be at least as cost-effective
as the Pap test, and to compare the findings with observed test characteristics and costs of
newly developed technologies.
Methods With the MISCAN microsimulation model for the evaluation of screening policies
we calculated the incremental health benefits, costs and savings of cervical screening when
test sensitivity and/or specificity would be enhanced for several screening intensities. Baseline
sensitivity of the Pap test is 80% for pre-invasive lesions, and incidence and screening
attendance represent the Dutch situation. For different combinations of test sensitivity and
specificity we calculated the extra costs of any test, for which it would be equally costeffective as the Pap test. We conducted a literature review to determine the test
characteristics, trial design and costs of AutoPapT, Papnet, ThinPrepT, AutoCyteT PREP and
AutoCyteT SCREEN.
Results For a five year interval screening programme between 30 and 60 years with 80%
attendance, extra costs of a test with 100% sensitivity and specificity should not exceed ? 3.10
in order to be as cost-effective as the Pap test. This cost threshold is lower in case of more
intensive screening policies, as used in most western countries, but is higher in case of a lower
Pap test sensitivity, a higher background incidence or a lower screening attendance. A critical
review of trials revealed that AutoCyteT PREP and PapnetT show similar performance
compared to the Pap test, while there is weak evidence that ThinPrepT, AutoCyteT SCREEN
and AutoPapT are more sensitive than the Pap smear, at the loss of some specificity. Costs of
these new technologies are $2.50 to $7.00 per test higher than Pap testing.
Conclusion Several trials show higher test sensitivity for ThinPrepT, AutoCyteT SCREEN
and AutoPapT compared to the Pap smear, at the loss of some specificity, but the evidence is
weak. With realistic assumptions, each of these technologies is less cost-effective than the
Pap test.
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FC2-04
ADJUNCT CERVICAL CANCER SCREENING TESTS: THE ROLE OF
PAP SMEAR, VISUAL INSPECTION AND HYBRID CAPTURE II
Gontijo RC (1), Derchain SFM (1), Sarian LOZ (1), Zeferino LC (1), Guarisi R (1), Syrjänen KJ (2)
(1) ObGyn Department Universidade Estadual de Campinas Campinas Brazil, (2) Cytopathology Unit,
Laboratory of Epidemiology, National Institute of Health (ISS), Rome, Italy.
Background and objective: Cervical cancer is the third most frequent malignancy in women
in Brazil. In order to improve detection of cervical lesions using the Pap smear in screening, a
number of adjunct tests have been proposed. The purpose of this study linked to INCO-DEV
project ICA 4-CT-2001-10013, is to evaluate the performance of visual inspection with acetic
acid (VIA) and hybrid capture II (HC II) with the Pap smear in detecting neoplastic and preneoplastic cervical lesions.
Methods: Between February and December 2002, 1193 women underwent routine cervical
cancer screening in one Basic Public Health Unit. Pap smear was performed in 1193 women,
VIA in 1192 and HC II for HPV DNA detection was collected in 636 women. When one of
the three tests was positive, colposcopy was performed. Targeted biopsies were taken from 58
women from any suspicious lesions found in colposcopy. CIN 1 or higher was biopsyconfirmed in 20 women. Sensitivity and specificity of each test were evaluated. The
distribution of sequential testing scenarios provided estimates of the test performance in
paired combinations and allowed for comparisons with the individual test qualities.
Results: Pap smear, VIA and HC II were positive in 6%, 5% and 20% of all women screened
respectively. The sensitivity of Pap smear, VIA HC II was 75%, 50% and 69%, respectively
and the specificity of the tests was 66%, 79% and 33%, respectively. VIA showed higher
positive predictive value (27%) followed by the Pap smear (25%) and HCII (13%). Regarding
the negative predictive value, Pap smear had the best performance (95%), followed by VIA
(91%) and HC II (87%). The results for sequential testing options showed that among the five
women with negative Pap smear and CIN 1 or higher (biopsy proven disease), VIA was
positive in four and HC II in two.
Conclusions: VIA can be combined with the Pap smear as a screening test to yield a higher
detection rate of biopsy-confirmed cervical pathology than the Pap smear alone or with HC II.
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FC2-05
MANAGEMENT OF "ASCUS" IN POSTMENOPAUSAL WOMEN
Cristiani P (1), Abruzzese A (4),Benedetti M (4), Cama G (1), Campana A (4), Costa S (3), De
Nuzzo M (1),Galletti A (4), Garutti P (2),Greci P (4), Lombardozzi L (4), Terzano P (3), Tiboni M
(5), Veronesi C (1)
(1) Ausl Bologna Sud,Bologna, (2) Az.Osp.Ferrara,Ferrara, (3) S.Orsola Hospital, Bologna, (4) Ausl
Parma,Parma, (5) Ausl Cesena,Cesena, Italy
Use and management of cervical cytology diagnosis of Atypical Squamous Cells of
Undetermined Significance (ASCUS) are controversial. Many investigators have found that
cervical dysplasia is not uncommon when follow-up data are obtained from ASCUS patients.
On the other hand, data from the Emilia Romagna screening program have focused on the
higher prevalence of ASCUS in perimenopausal women (2%) compared with that in younger
ones (0.9%). Nevertheless, ASCUS in older women is less likely to predict dysplasia than in
youngers: 6.7% versus 28.8% CIN 2-3 on punch biopsy. Based on the view that all grades of
abnormality represent a potential cancer precursor that requires colposcopy, the ASCUS
category in older patients represents a problematic issue. In fact recall for colposcopy
increases the burden of the available services, the screening costs and is often associated with
overdiagnosis, overtreatment and psychological morbidity. In order to overcome this situation
we provide a course of intravaginal Promestriene followed by a repeat cervical cytology taken
approximately seven days after completion of the regimen. By removing the cytological
abnormalities essentially due to atrophic changes, Pap smear is expected to properly reflect
the actual state of abnormal epithelial changes. Data collected so far have generally supported
our triage protocol. In fact the results showed that 76% of the ASCUS patients reverted to
normal or benign cellular changes, while 24% persisted as ASCUS or SIL lesions.
Many unfavourable implications of the ASCUS diagnosis, such as workload increase and
inconsistent predictive value for squamous intraepithelial lesions have been reported. The
intravaginal application of Promestriene followed by a repeat Pap smear may reduce the
colposcopy rate and screening costs in post-menopausal women.
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FC2-06
ATYPICAL GLANDULAR CELLS AND HIGH RISK-TYPES HUMAN
PAPILLOMAVIRUS DETECTION BY HYBRID CAPTURE II
Derchain SFM (1),De Oliveira ERZM (1), Gontijo RC (1), Dos Santos SHR (1,3), Zeferino LC (1),
Westin MCA (2), Amaral RG (1,3)
(1) ObGyn Department, (2) Cytopathology Unit, Universidade Estadual de Campinas Campinas (3),
Faculdade de Farmácia Universidade Federal de Goiania - Brazil (3)
Background and objective: The use of HPV-DNA testing in women with atypical glandular
cells (AGC) at Pap smear is still controversial. To compare the result of follow-up Pap smear
and high-risk types HPV-DNA detection in women referred to Colposcopy Clinic for AGC
result in Pap smear.
Material and methods: For this clinical descriptive study, 91 women admitted at the
Colposcopy Unit of the Universidade Estadual de Campinas due to an abnormal Pap smear
showing ACG were included. All women were submitted to a new Pap smear, and material
for HPV DNA detection was collected using Hybrid Capture II (HC II). Referral and second
Pap smear were available for all women and the diagnostic was rendered according Bethesda
System (2002). Chi-square and Fisher tests were used for statistical analysis.
Results: Regarding the new Pap smear result, 28 (30.7%) cases presented only normal or
inflammatory features, 14 (15.3%) showed atypical squamous cells of undetermided
significance (ASC-US), 4 (4.4%) showed atypical squamous cells cannot excluded high
squamous intraepithelial lesion (ASC-H), 6 (6.5%) presented HSIL, 5 (5.5%) in situ
adenocarcinoma, 4 (4.4%) invasive carcinoma and 30 (32.9%) remained as AGC, associated
with ASC-H in four cases and with HSIL in nine. Among the 91 studied women, HC II test
was positive in 33 (36.2%). Detection of high risk-types HPV-DNA was significantly
associated (p<0.01) with AGC (13 HPV-DNA positive/30 cases), HSIL (5 HPV-DNA
positive/5 cases) and in situ adenocarcinoma (5 HPV-DNA positive/6 cases) at the new Pap
smear. Among women with normal or inflammatory result, ASC-US or ASC-H at new Pap
smear, the HPV-DNA detection rate was significantly lower.
Conclusion: Detection of high-risk types HPV-DNA was significantly associated with
morphological abnormalities at new Pap smear, in women referred for AGC.
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FC2-07
COLPOSCOPIC FOLLOW-UP STUDY OF PATIENTS WITH
ASCUS/POSSIBLE HIGH GRADE ABNORMALITY ON
PAPANICOLAOU SMEARS
SKINNER R.
MELBOURNE
A small proportion of patients with Atypical Squamous Cells of Uncertain Significance
(ASCUS) in PAP smears, have cell changes suggesting a possible high grade abnormality. In
Australia, these abnormalities are reported as being Inconclusive/Possible High Grade
Abnormality, with a recommendation for referral to a gynaecologist for colposcopy. This
study is based on a colposcopic follow-up of 102 patients referred to a gynaecologist. At the
initial colposcopy, all of the 102 patients had a colposcopic biopsy performed. A total of 51
patients were found to have high grade intraepithelial lesions (HGSIL) on histology, 36
patients had low grade intraepithelial lesions (LGSIL CIN 1 and/or HPV change) and 15
patients had normal histology. 20 of the 36 patients with LGSIL underwent a LLETZ
procedure. Histological examination of the LLETZ specimens confirmed LGSIL in 10
specimens and showed HGSIL in 5 specimens. The other 16 patients with LGSIL have been
followed up for an average 2.0 years. Of these, 1 was found to have HGSIL on follow-up
colpsocopy and biopsy. To date, of the original 102 patients with possible HGSIL on PAP
smears, 57 (56%) have biopsy confirmed HGSIL. None of the 15 patients with normal initial
colposcopic biopsies has developed HGSIL, although in 2, LGSIL lesions were found in 3 to
6 years of follow-up. These findings emphasise the need for close colposcopic and cytologic
follow-up in patients with equivocal HGSIL on PAP smear.
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FC2-08
REAL TIME DEVICES FOR THE SCREENING AND DIAGNOSIS OF
CERVICAL DISEASE
Chow Carl
Whipps Cross Hospital, Department of Gynecology, London
Real Time Devices (RTDs) utilise in vivo measurement techniques and computerised analysis
to provide immediate feedback to the clinician. These devices incorporate optical and/or
electrical biosensors, which are linked to processing systems designed to classify tissue types.
The technology operates on the basis that certain primary tissue characteristics, such as
cellular composition, cellular morphology and vascular structure, can be used to distinguish
between the various types of normal and abnormal cervical epithelium. Secondary (or
derived) effects of these primary characteristics, which can be directly measured, include
tissue reflectance and absorbance, tissue autofluorescence, the intensity and direction of
backscattered light and the electrical impedance of the tissue.
Two major applications have been proposed for RTDs. The first is as a tool for the
colposcopist, with the RTD used as an aid to identifying and classifying abnormal tissue
locations on the cervix. The second major application is in cervical screening, where the
device is utilised by the general practitioner or women's health clinic as a routine screening
instrument. In this situation, RTD technology is likely to be introduced initially as an adjunct
to cervical cytology, although longer term the technology has the potential to operate as an
autonomous screening test. One of the major benefits associated with RTDs when compared
to other cervical technologies is the automation, and consequent standardisation, of the test
process. The second major advantage of RTDs is in the provision of immediate feedback to
the clinician or screener.
The accuracy of RTDs for classifying cervical disease is device-dependent. For each RTD
type, accuracy is intrinsically dependent on both the specific choice of biosensor(s) used and
the processing software used to convert the information obtained from the biosensor into a
clinically relevant tissue classification. The various real time technologies under development
will be reviewed, and the available clinical results and clinical applications discussed.
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FC2-09
DIAGNOSIS OF CERVICAL IMAGES CAPTURED WITH A DIGITAL
VIDEO COLPOSCOPY SYSTEM
PISAL, N. , JELINIK, C. , KOVASEC, N. TULLY, F. AND CHOW, C.
The Whittington Hospital, Department of Women's Health, London
Introduction: Digital telecolposcopy has the potential to bring the expertise of the senior
colposcopist to remote and rural areas. A digital video of the colposcopy session, including
the time-dependent effects of the administration of contrast agents, is captured locally, and
sent to the expert colposcopist for review or real time evaluation. These systems can be used
for training, and for quality assurance monitoring of the biopsy site choice and/or treatment
decision.
The reviewing colposcopist does not have a stereoscopic (three-dimensional) view of the
cervix, and therefore a theoretical concern has been that the reviewer may have less
information upon which to assess the cervix, thus impacting the quality of review. However,
it is expected that high resolution imaging systems should alleviate this problem.
Methods: We have performed a study to assess the agreement between the original
colposcopic impression and a remote diagnosis performed from digital video. The system
used for the study was the MediScan high resolution digital colposcopy system (Polartechnics
Limited, Sydney, Australia). A total of 650 women undergoing colposcopy at the Whittington
Hospital in London had the colposcopy session recorded for review. Because this study was
designed to evaluate differences in colposcopic evaluation due to the mode of review, expert
colposcopists were used both locally and for the review.
Results: A high level of agreement was obtained between the original and review colposcopic
impression and biopsy site choice. The agreement was found to be higher than the interobserver agreement for colposcopy previously reported in the literature.
Conclusions: High resolution digital video provides a viable means of performing accurate
colposcopy review in telecolposcopy applications. We speculate that the high agreement
between original and review colposcopy found in this study was due both to the high quality
digital image presented to the review colposcopist, and to the experience level of the two
participating colposcopists.
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FC2-10
VIDEO COLPOSCOPY IN DIAGNOSIS OF CERVICAL SQUAMOUS
INTRAEPITHELIAL LESIONS
Song Xuehong, Wang Qiuxi, Song Yufen, et al
Dept of OB/GYN, Capital Medical University affiliated Chaoyang Hospital,
Objective To study the accuracy and efficiency of video colposcopy in diagnosis of cervical
squamous intraepithelial lesions and clinical significance of seven colpocopic signs.
Methods Two hundred and seventy five patients with an abnormal cervical smear or vulva
condyloma acuminata were re-evaluated by video colposcopy. 265 cervical biopsies
performed under the guidance of video colposcopy for pathological study, as well 8
endocervical curettage (ECC) and 237 loop electrosurgical excision procedure (LEEP).
Results The sensitivity, specificity and positive rate of video colposcopy in evaluation of
cervical squamous intraepithelial lesions were 95.9%, 77.7%, and 84.5%. video colposcopy
diagnostic accuracy was 93.8% tally with the pathological results in observing normal
transformation zone. False negative rate was 6.1%. 76.2% of cases with subclinical
papillomavirus infection by acetowhite epitheliun, while false negative rate was 23.7%. Twin
signs, triple sings and cervical carcinoma were 100.0% tallying with the diagnosis of cervical
lesions.
Conclusions Video colposcopy can be a very accurate diagnostic method in clinical practice.
It is quite sensitive in diagnosis of severe cervical lesions. However, there was a relative high
false negative rate in diagnosing mild cervical lesions.
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FC2-11
LOOP ELECTROSURGICAL EXCISION PROCEDURE (LEEP) OF
THE CERVIX - A FIVE YEAR EXPERIENCE
Fernandes Élia
Hospital Distrital de Santarém, Gynaecology, Santarém
Since May 1998, 195 LEEP of the cervix were performed in the department of gynaecology
of the Hospital Distrital de Santarém. We have reviewed the data regarding this 195 women
including patient`s age, parity, cervical cytology or biopsy, colposcopy, indication for LEEP
as well as histological findings.
The indications for LEEP were high grade squamous intraepithelial lesion (53,8%), persistent
or recurrent low grade lesion (including condyloma) or low grade lesion associated with
unsatisfactory colposcopy (29,2%) and discrepancy between cytological and colposcopic
findings (12%). Glandular disease lead to 5% of LEEP.
The correlation between indication and histological results was good in high grade lesion with
a 80% diagnostic accuracy.In low grade lesion, LEEP confirmed the indication in 57%,
revealed a high grade CIN in 5% of the patients and showed no dysplasic lesion in 38%.
When discrepancy was the indication, the majority of histological results showed no dysplasic
lesion (60,9%) or a low grade CIN (21,7%).
The data found at this retrospective review confirm the one published by most authors.
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FC2-12
OPTICAL COHERENCE TOMOGRAPHY IN DIAGNOSIS OF
CERVICAL NEOPLASIA.
Shakhova N. (1,3), Kuznetzova I. (1), Kachalina T. (2), Gladkova N. (2), Gelikonov V. (3),
Kamensky V. (3)
(1) Regional Hospital, (2) Medical Academy, (3) Institute of Applied Physics of Russian Academy of
Science.Nizhny Novgorod, Russia.
Uterine cervical cancer holds one of the leading places in the structure of oncological
pathologies. The fact that cervical cancer is curable if detected early. The traditional method
is colposcopically guided biopsy, but a rate of false-negative results is as high as 56 % (1). So,
the reason for seeking new effective ways of diagnosis becomes obvious.
In our study we present results of estimation of optical coherence tomography (OCT)
application for cervical neoplasia detection.
OCT can generate real-time structural images of biological tissues at a depth of up to 2 mm
with a spatial resolution of 15-20 mm (2). Such OCT characteristics as high resolution,
noninvasiveness, absence of side effects, fast operation coupled with potential costeffectiveness make the OCT imaging attractive for clinicians.
When used in the course of colposcopy OCT provides features of morphological states of the
uterine cervix at the level of tissue layers (3). We have established that an OCT sign of benign
processes can be the well-defined structure of optical images, whereas its loss is a criterion of
malignant processes.
In our study estimation of OCT diagnostics effectiveness is presented. The method sensitivity
is 82%, specificity is 78%, and diagnostics accuracy is 81% with good agreement coefficient
kappa amounting to 0.65.
For our opinion, the most promising directions in clinical use of OCT in cervical cancer are
the following: directed biopsy, detection of margins of lesions for stage determination by
linear parameters, further planning and control of tumor resection in organ-preseving
treatment.
We would like to present optical coherence microscopy (OCM), special adaptation of OCT
technology for enhanced resolution (3-5 mm) and contrast in biological tissues. In our study
cervical OCM images in comparison with OCT once are presented.
(1Hopman1998,2Huang1991,3Shakhova2002)
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FC2-13
EVALUATION OF LOOP ELECTROSURGICAL EXCISION
PROCEDURE (LEEP) IN DIAGNOSIS AND MANAGEMENT OF
CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN): A
PROSPECTIVE STUDY
Song Xuehong , Wang Qiuxi , Liu Jun , Song Yufen , Zhang Zhenyu , et al .
Dept of OB/GYN, Capital Medical University affiliated Chaoyang Hospital,
Objective To study the importance of loop electrosurgical excision procedure (LEEP) in
diagnosis and management of cervical intraepithelial neoplasia (CIN) and the out comes of
CIN post LEEP intervention.
Methods 1012 patients with CIN were diagnosed and treated from Jan 1997 to May 2002:
CIN1 (n=807), CIN2 (n=99), CIN3 (n=97) and microinvasive carcinoma (n=9). The
histologic findings in the specimens provided by colposcopically directed biopsies and LEEP
were compared in 205 CIN2, CIN3 and microinvasive carcinoma using before-after study.
Results The overall cure rate of CIN1, CIN2, CIN3 after LEEP were 99.9%, 98.0%, 98.7%,
respectively. The out come of CIN grade 2 and 3 after colposcopically directed biopsies was:
regression 69.8%, keep with the same 19.5%, progression 10.7% including microinvasion.
Complications of LEEP occurred in 4.3% (44/1012) including hemorrhage, infection and
stenosis.
Conclusions LEEP is a very important method for the management of CIN and it’s effective
to avoid misdiagnosis of high grade CIN and mircroinvasion carcinoma. CIN grade 2 and 3
after intervention could be regressed mainly.
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FC2-14
IMPROVING HEALTH SYSTEMS TOWARDS EQUALITY-BASED
CONTROL OF CERVICAL CANCER IN LATIN AMERICA.
COMPARING PAP SMEAR CYTOLOGY, AIDED VISUAL
INSPECTION, CERVICOGRAPHY AND HUMAN PAPILLOMAVIRUS
(HPV) TESTING AS OPTIONAL SCREENING TOOLS IN BRAZIL AND
ARGENTINA.
MULTICENTRIC STUDY - DESCRIPTION OF DATA FROM PORTO
ALEGRE – BRAZIL
Naud P (1), Syrjänen K (2), Hammes L (3), Matos JC (3), Barcelos MC (3), Campos C (3), Dias E
(3), Magno VA (3), Niederauer CE (3), Pereira C (3), Prati R (3), Stuczynski J (3), Rose A (4),
Pütten AC (5), Ferreira P (6), Campos E (7), Lorincz A (8), Dores G (8), Artigalas O (9), Costa F
(9), Fontana G (9), Höblick M (9), Mano Mc (9), Marques Pereira C (9), Moreira I (9), Olijnyk JG
(9), Piccoli E (9), Thome JG (9).
(1) Hospital de Clinicas de Porto Alegre - HCPA (Scientific Co-ordinator, Porto Alegre Centre Coordinator); (2) ISS, Rome, Italy (Project Co-ordinator); (3) HCPA MD ObGyn; (4) HCPA Psychologist;
(5) HCPA Pathologist; (6) Moogen Cytology Laboratory; (7) Caism Laboratory ; (8) Digene Corp; (9)
Federal University of Rio Grande do Sul Medical Students.
Introduction
The most vulnerable groups for cervical cancer are the poorest women. To improve this
ominous situation in two Latin American countries, Argentina (ASIR: 27.60) and Brazil
(ASIR: 30.55), which both belong among the high-risk countries of cervical cancer (i.e. ASIR
>22/100.000) it is being developed a study of cervical cancer screening and control strategies.
Objectives
1. To compare the performance and cost-effectiveness of aided visual inspection (AVI),
Human Papillomavirus (HPV) testing, cytological (Pap test) and cervicography in cervical
cancer screening.
2. To improve the basic understanding of the epidemiology and pathogenic mechanisms of the
disease in Brazil and Argentina.
Methods
This is a multicentric study that includes patients from Brazil (Porto Alegre, Campinas and
São Paulo) and from Argentina (Buenos Aires). At first visit women were submitted to Pap
test, HPV testing and AVI. Cervicography were not performed at Porto Alegre site. If woman
had any alteration in these exams was submitted to colposcopy and, if necessary, biopsy.
Patients with HSIL were promptly treated and followed-up for 36 months. Patients with LSIL,
HPV infection or Pap test alteration are being followed-up until 36 months. 20% of all normal
women will be submitted to HPV testing at 24 months to detect new incidents cases.
Results
Until 31st December 2002 we have enrolled 2755 patients. Characteristics of this group
(mean - std.dev): 41.29 - 10.70 yo, 8.05 - 3.59 y education, 18.80 - 4.05 yo at first sexual
intercourse, 2.88 - 4.23 sexual partners since first sexual intercourse, 0.90 - 0.49 sexual
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partners last 12 months and 3 - 1.91 pregnancies in all life. From the all group, 13.2% referred
previous STD and the most used contraceptive method (54.1%) was hormonal.
Results of Pap test were available from 1821 women: 1763 (96.8%) normal, 13 (0.7%) LSIL,
16 (0.9%) HSIL, 26 (1.4%) ASCUS, 1 (0.1%) AGCUS and 2 (0.1%) carcinomas. Results of
HPV testing were available from 545 samples: 66 (12.1%) abnormal and 479 (87.9%) normal.
AVI was altered in 22.9% of all patients. Results of biopsies were available from 114
specimens and 36 of them were altered: 5 (13.9%) HPV infection no-CIN, 2 (5.6%)
condyloma acuminatum, 19 (52.8%) CIN I , 1 (2.8%) CIN II, 8 (22.2%) CIN III and 1 (2.8%)
carcinoma.
Conclusion
After the complete analysis of our data (n=3000) we can compare the performance
characteristics and cost-effectiveness of conventional and optional screening tests in our set.
We also will be able to improve the understanding of this disease and pre-malignant lesions in
our region.
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FC2-15
LIGHT EMITING DIODES IN LGT DIAGNOSTICS
Vaitkuviene A. (1,2), Auksorius E. (1), Balkevicius P. (3), Smilgeviciute A (4)
Institute of Materials Science and Applied Research, Vilnius University, Lithuania (1). Clinics of
Obstetrics&Gynecology, Vilnius University, Lithuania (2). EXPLA Ltd, Vilnius, Lithuania (3), Central
Policlinic, Vilnius, Lithuania (4)
Application of light emiting diodes for tissue spectral diagnostics in lower genital tract
promises to simplify the device and remains a possibility to choose a set of optimal excitation
wawelengths. The requirements of such system were found for Cervical mucus and scrapings
diagnostics by application of tunable picosecond parametric laser (210 nm-1800 nm).
Fluorescence excitation emission matrices were analysed. After optimal exication wawelenght
selection coincident wawelength LEDs were applied for on-site spectrometry. Multivariate
linear regression was used to correlate spectra with medical indication. Principal component
analysis and in particular partial least-squares analysis was used to extract information that
correlates with the concentration of a certain tissue constituent and medical indication.
Cervical maturation during pregnancy was discriminated with a sensitivity of 86% and
specificity of 92%. LED 375 nm exitation fluorescence spectra in cervical mucus were
analysed. Two wawelengths 415 and 475 were found to differentiate two groups: matured and
not matured cervix. Cervical mucus and scrappings from nonpregnant cervix were
investigated in the same manner. HR HPV infection discrimmination was successful.
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FC3-01
TRENDS IN THE INCIDENCE OF INVASIVE CERVICAL CANCER IN
US WOMEN UNDER AGE 30 YEARS
Sawaya G (1), Chan P (2), Sung H (3).
(1) Department of Obstetrics, Gynecology and Reproductive Sciences and Department of
Epidemiology and Biostatistics, University of California, San Francisco (UCSF), San Francisco,
California; (2) School of Medicine, UCSF; (3) Institute for Health and Aging, School of Nursing, UCSF,
USA.
Context. The effectiveness of screening women under age 30 years in the United States for
cervical neoplasia has not been well described. Despite overall declines in the incidence of
invasive cervical cancer (ICC), several prior studies have demonstrated increasing rates in
younger women, particularly in adenocarcinoma (AC).
Objective. To update and examine the trends in the incidence of ICC by histologic type in
women under age 30 years in the United States from 1973 to 1999.
Design and Setting. Incidence rates were obtained from the National Cancer Institute's
Surveillance, Epidemiology and End Results (SEER) Database and stratified by age and 3
histologic categories: all histologic types, squamous cell carcinoma (SCC), and AC. The
estimated annual percentage change (EAPC) was calculated to measure the incidence trends
during both the entire evaluation period (1973-1999) and a recent sub-period (1985-1999). To
identify apparent changes in the incidence trends, a joinpoint regression analysis was applied.
Results. Incidence rates of ICC overall and of SCC in particular declined steadily from 1973
to 1999. The EAPCs for all histologic types and SCC were -0.94% (95% CI -1.47, -0.41) and
-1.10% (95% CI -1.59, -0.62), respectively. Rates of AC increased in young women with an
EAPC of +2.90% (95% CI 1.34, 4.49), though recent trends show a stabilization from 1990 to
1999: -0.85 (95% CI -6.29, 4.91). The number of annual cases of AC reported in the SEER
catchment areas ranged from 3 to 17 cases per year, corresponding to annual incidence rates
ranging from 0.7 to 2.7 per million women. For SCC, the annual incidence rates ranged from
8.0 to 14.3 per million women.
Conclusions. Rates of SCC have declined over the last 3 decades in women under age 30
years in the US. More investigation is necessary to determine the contribution of screening to
reducing cancer rates in this age group. The etiology of the increases in AC rates requires
further investigation. Although caution must be exercised in interpreting these trends since the
number of observed cases upon which it is based is small.
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FC3-02
ESTIMATING THE NATURAL HISTORY OF CERVICAL CANCER
FROM SCREENING DATA
Sparén Pär
Karolinska Institutet, Dept. of Medical Epidemiology, Stockholm, Sweden
The aim of screening against cervical cancer is to detect pre-cursors to the disease and remove
them before they become invasive. The time from when a pre-cursor is detectable by
screening until the disease becomes invasive is named the pre-invasive detectable phase.
Before this screening is by definition not beneficial to prevent invasive cervical cancer.
Screening is neither beneficial to prevent disease in the occult invasive phase, since the
disease has already become invasive. This study aimed at estimating: a) the detectable preclinical phase (DPCP) of cervical cancer by age and follow-up time; b) the length of the
occult invasive phase (OIP); c) the pre-invasive detectable phase (PIDP). A case-control
sample was drawn from a population-based cohort, where the occurrence of cervical cancer
screening could be certified for 25 years.
The length of the OIP can be estimated by taking the ratio of the prevalence of invasive
asymptomatic cases and the expected incidence of invasive cancer in the same population. In
this case it was estimated by taking the ratio of the peak prevalence of squamous cell cervical
cancer after screening, in a previously un-screened Swedish population during 1967 through
1970, to the incidence of squamous cell cervical cancer in the Swedish population in 1965
through 1966, before the onset of screening. By estimating the DPCP and the OIP the length
of the PIDP could be calculated, using simple subtraction: DPCP = PIDP + OIP => PIDP =
DPCP - OIP. The OIP was estimated to 59.7/24.8 = 2.4 years. Of 797 squamous cell cancers,
546 were considered to be clinically detected, and 318 (58%) of these occurred in women
without any registered smear. The relative risk of squamous cell cancer was significantly
lowered up to 11 years, for women with a negative Pap smear, compared to not screened
women. The estimated decrease in relative risk immediately after a normal Pap smear was
0.33 (95% CI = 0.23-0.49), and the estimated length of time for the point estimate to reach
unity was 18 years. The relative risk was significantly lowered only up to two years for
women below 50 years of age, and the length of time before reaching unity around five years.
For women aged 50 and above the model indicated a curvi-linear shape of the DPCP;
showing a significantly decreased risk of squamous cell cervical cancer up to 14 years after a
normal smear, with an estimated time before the estimate reached unity was 17.5 years.
Women with one or two Pap smears during the PIP showed a halved risk of squamous cell
cervical cancer, compared to women with no Pap smears. The risk of squamous cell cervical
cancer was significantly lower for women with up to 5 Pap smears. After this the point
estimates still indicated a halved risk, while for women with 10 or more Pap smears the point
estimates where above unity. For women with one or several negative screening tests during
the PIP there was a continuous lowered risk of squamous cell cervical cancer.
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FC3-03
CERVICAL CANCER SCREENING IN THE NATIONAL BREAST AND
CERVICAL CANCER EARLY DETECTION PROGRAM
Benard VB, Lawson H, Eheman CR, Blackman D, Lee NC
Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and
Health Promotion, Division of Cancer Prevention and Control, Atlanta, Georgia, USA
Objective: To describe results of cervical cytology screening among low-income and
uninsured women in the United States National Breast and Cervical Cancer Early Detection
Program (NBCCEDP) for years 1995-2001.
Methods: We analyzed data from 750,591women aged 18 years and older who received their
first Papanicolaou (Pap) test in the NBCCEDP program during the time period July 1995
through March 2001. Rates were age-adjusted by the direct method to the age distribution of
the 2000 NBCCEDP-screened population.
Results: Of the women screened in the program, nearly eighty-five percent were 40 years of
age or older. Almost half of the women were members of racial or ethnic minority groups.
Over seventy-five percent of the women in the program reported a prior Pap test. In the first
screening round, 2.0% of Pap tests were reported abnormal, defined as low- or high-grade
squamous intraepithelial lesions or squamous cancer, and 1.4% were reported abnormal in the
subsequent rounds. Overall, the percentage of abnormal Pap test results decreased with
increasing age. In the first screening round, the age-adjusted rate of biopsy-detected cervical
intraepithelial neoplasia (CIN) II or worse was 6.0 per 1,000 Pap tests; it was 3.4 per 1,000
Pap tests in the subsequent rounds. The rates of CIN were highest in the younger age groups;
however, the rate of invasive cancer increased with age and peaked among women 50 to 64
years of age. White women had the highest age-adjusted percentage of abnormal Pap tests and
rate of biopsy confirmed CIN II or worse in both screening rounds.
Conclusions: This analysis contributes important information on outcomes of cervical cancer
screening and follow-up for U.S. women who have diminished opportunities for cervical
cancer screening and a higher mortality from cervical cancer than most women in the U.S.
Half of the women in the program are older than 50 and a large percent are members of racial
or ethnic minority groups. Results from unique programs such as the NBCCEDP provide
important information on the prevalence of cervical neoplasia and invasive cancer and make a
significant contribution toward understanding the epidemiology of these abnormalities among
special populations.
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FC3-04
CAN CHANGES IN SEXUAL BEHAVIOUR EXPLAIN THE OBSERVED
INCREASE IN CERVICAL CANCER INCIDENCE IN FINLAND?
Barnabas R (1,2), Laukkanen P (3), Läärä E (4), Koskela P (5), Kontula O (6), Garnett G (1),
Lehtinen M (7)
(1) Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College, London,
UK; (2) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; (3) Finnish Cancer
Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland; (4)
University of Oulu, Oulu, Finland; (5) National Public Health Institute, Oulu, Finland; (6) Family
Federation of Finland, Helsinki, Finland; (7) University of Tampere, Tampere, Finland
Cervical cancer incidence has increased markedly among young Finnish women. For women
aged 35-39 incidence increased from 4.1/100 000 women in 1985 to 7.7/100 000 women in
1999. To ensure effective prevention potential explanations of this trend, including viral
factors (increased virulence and predominance of high-risk types) and host factors (changes in
sexual behaviour and immunity), need to be examined. Detailed questionnaire studies
between 1971 and 1999 show striking changes in Finnish sexual behaviour; lifetime number
of sexual partners increased from 2.6 to 7.7 and age of sexual debut decreased from 18.9 to
16.6 years.
Laukkanen and colleagues found a steady increase in HPV 16 incidence during 1983-97
among Finnish women between 23 to 31 years with at least two pregnancies and increased
seroprevalence of HPV 16 from 17% to 24%. To examine HPV transmission dynamics we
construct a mathematical model reproducing the Finnish study population, stratified by age
and sexual activity. HPV progression and regression parameters were taken from the
literature. Observed prevalence by age over time was used to estimate the transmission
probability of HPV 16 from infected to susceptible person using binomial log-likelihoods.
Changes in the reported number of partners and the age of sexual debut over time were also
included. The incidence of cervical cancer was estimated until 2010 using observed patterns
of screening.
The peak prevalence for asymptomatic HPV occurs among 20 year olds with a shift towards
older women as disease progresses. HPV transmission probability was estimated to be 0.3
with the resulting model prevalences showing a good fit to observed prevalences for different
age groups over time. These results show that changes in model parameters, particularly
sexual behaviour, over time allow for a better fit to observed HPV prevalences and that the
increased incidence of HPV-16 can explain observed increases in cervical cancer incidence.
In summary, we have developed a well parameterised model consistent with the observed
HPV epidemiology in Finland that will be used to explore the impact of interventions.
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FC3-05
MULTIETHNIC COHORT STUDY OF SERUM MICRONUTRIENT
CONCENTRATIONS AND CERVICAL HUMAN PAPILLOMAVIRUS
PERSISTENCE
Goodman MT, Hernandez B, McDuffie K, Franke AA, Wilkens LR
Cancer Research Center, University of Hawaii, Honolulu, Hawaii
Exploration into the nature of the association of HPV with cervical carcinogenesis is a rapidly
evolving area in epidemiological research. The persistence of HPV in cervical tissue may be
necessary for the progression from pre-malignant disease to invasive cervical cancer. Given
that cervical carcinoma may require years to develop, the duration of HPV infection may have
pathological significance, distinguishing women who develop carcinoma from those who do
not. The degree to which the persistence or resolution of HPV infection parallels exposure to
other risk factors for cervical dysplasia and cancer has been an active area of research,
although only a few studies have examined nutritional co-factors. We have established a
multiethnic cohort of HPV-positive women for active follow-up to identify factors that
influence the transience or persistence of the virus. The cohort is followed longitudinally with
repeated measures of cervical cytology, HPV-DNA analysis, serum micronutrient levels, as
well as other risk factors. We examined the association of serum micronutrient levels with
HPV persistence using a generalized logistic model where pairs of visits are entered as
observations and multiple records are allowed per woman. An autoregressive correlation
structure was assumed. Persistence was defined as HPV-positive for an oncogenic HPV type
on two consecutive visits (+/+). The control group or 'resolvers' were defined as HPV-positive
for an oncogenic type on one visit followed by HPV-negative on the following visit (+/-). In
this preliminary analysis, we included 206 women representing 226 +/+ events and 143 +/events, modeling change in micronutrient status between visits by subtracting the
micronutrient concentration in the first visit from the micronutrient concentration in the
consecutive visit. Strong, inverse relations to the risk of persistence were found by increased
serum concentrations of lutein, a-cryptoxanthin, ß-cryptoxanthin, and total carotene. For
example, the odds ratios for HPV persistence associated with the three upper quartiles
compared with the lowest quartile of positive change in ß-cryptoxanthin level between
consecutive visits was 0.47, 0.57, 0.42 (95% confidence interval 0.19-0.94), respectively.
These results suggest that increased levels of certain antioxidant nutrients may be associated
with enhanced clearance of cervical HPV infection.
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FC3-06
HPV PREVALENCE IN SOUTH OF BRAZIL.
Naud P (1); Matos J (2); Hammes L (2); Vettorazzi J (2);Brouwers K (2); Magno V (2); Crussius P
(2), Osanai M (1), Zubaran L (1), Barcellos M (1), D’Avila A (3); Campos C (3); Mano M (1); Hoblik
M (3); Mano M (3); Hoblik M (3), Oliveira L (4).
1- Medicine Professor Universidade Federal do Rio Grande do Sul (UFRGS)
2- Physician from STD/HIV Ambulatory
3- Medicine Student UFGRS
4- Psychologist Student UFRGS
Universidade Federal do Rio Grande do Sul - Hospital de Clínicas de Porto Alegre, Brazil
There are estimated by WHO to be over 400.000 new cases of cervical cancer each year, at
least ¾ of them in developing countries. HPV accounts over than 99% of cervical cancer.
Unfortunately, data about HPV prevalence in developing countries is rare.
Methods: This study is the screening phase of a multicentrical protocol on HPV vaccine
(GSK) .500 women from general population were screened for cervical lesions and HPV
infection by ThinPrep and PCR of cervical sample plus detection of serum IgG anti-HPV 16
and 18. Selection criteria was age 15-25 years old, no more than 4 lifetime sexual partners, no
previous known HPV infection / cervical lesions, no immunosuppression and no major
diseases.
Results: The mean age at screening was 20.09 years old (15-25y; max 25y; SD 4.04y),
majority was white (74.2%), followed by black (14%), mixed (11%) and others (0.8%).
19.8% didn’t have previous sexual intercourse. The whole group had a mean of 1.78 partners
through life. The ThinPrep data is: 84.57% normal, 9.82% ASCUS, 4.41% LSIL and 1.20%
HSIL. HPV DNA was found by PCR in 159 patients from a group of 500 (41.8%). The
prevalence of different subtypes in the group of 500 was: HPV6-0,4%; HPV11-0,6%;
HPV16-6,4%; HPV18-2,8%; HPV41-4%; HPV45-2,2%; HPV49-1,2%; HPV44-1,6%;
HPV45-0,8%; HPV51-4%; HPV52-4,4%; HPV54-2,6%; HPV54-1,2%; HPV56-2%; HPV581,2%; HPV59-1%; HPV66-4%; HPV68-1,4%; HPV70-1%..Serum IgG for HPV-16 was
positive in 21.48% and 14.04% for IgG anti-HPV 18.
Conclusions: This healthy population has a high prevalence of HPV infection and abnormal
cervical cytology. It is important to consider the transient HPV infection that occurs in young
ages and which may be responsible for this high level of viral prevalence. However, this data
is a warning of HPV widespread (that in our group occurs on 41.8% of young women), which
contributes to the high incidence of cervical cancer in our region (estimated to be 26.72 cases:
100.000 women).. A good a solution to this situation may be the HPV vaccination, preventing
the HPV contamination and posterior development of cervical lesions.
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FC3-07
CERVICAL SCREENING AMONG HIV-INFECTED WOMEN IN
ITALY
Piselli P., Serraino D., Pavia C., Khoeler B., Cocco A., M. Di Pasquale, Pisani G., Angeletti C.,
Ippolito G.
INMI "L. Spallanzani" IRCCS, Rome, Italy
Background: HIV-infected women are at increased risk of infection with human papilloma
virus infection (HPV) and invasive cervical cancer (ICC), than age-matched women in the
general population. A 10-fold excess risk was estimated in a longitudinal study conducted in
southern Europe, and such risk was more evident among women who acquired HIV infection
through use of intravenous drugs (IDU) than among heterosexuals. It was thus postulated that
HIV-positive women, particularly IDUs, are less likely than other women to receive
appropriate cervical Pap-smear screening. The study aim was thus to describe the use of Papsmear screening among HIV-positive women who voluntarily attended an outpatient
gynaecological clinic in Rome, Italy.
Methods: Between April and December 2002, 254 HIV-positive women (median age 37 yrs,
range 21-72), were interviewed before they underwent a gynaecological examination.
Information on the frequency of Pap test, on previous abnormal Pap-smears and on HIV
infection and AIDS was elicited through an interview.
Results: The median time between interview and first HIV-positive test was 6,5 years (range:
0-18 years), and the median age at the first Pap-test was 23 years (range: 18-43 years). On
average, these 254 HIV-positive women underwent 5 Pap-tests after acquisition of HIV
infection. The number of Pap-tests increased with increasing duration of HIV infection up to
5 years, whereas it remained stable thereafter (p=0.02). 47 of these 254 women (18.5%) were
diagnosed with AIDS, and they had a lower number of Pap-tests as compared to women who
were not diagnosed with AIDS (p<0.05). No difference emerged in the frequency of Pap-tests
between IDU and non-IDU women, though IDU reported a 6-fold increase in the frequency of
in situ carcinoma.
Conclusions: In this group of HIV-positive women, the frequency of Pap-smear screening
was inversely associated with increasing severity of HIV infection (i.e., the diagnosis of
AIDS), whereas no association emerged with history of in situ carcinoma in IDU women.
These findings confirm that HIV-positive women, particularly IDU women, need a
specifically tailored program of cervical screening.
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FC3-08
IMPACT OF HIV INFECTION ON INVASIVE CERVICAL CANCER IN
KENYAN WOMEN
Gichangi P (1), Bwayo J (2), Estambale B (2), De Vuyst H (3), Ojwang S (1) Rogo K (4), Abwao H
(5), Temmerman M (3)
(1) Department of Obstetrics and Gynecology, University of Nairobi, Kenya, (2) Department of Medical
Microbiology, University of Nairobi, Kenya, (3) International Center for Reproductive Health, Ghent
University, Belgium, (4) Nairobi Oncology Center, (5) Radiotherapy Unit, Kenyatta National Hospital.
Objectives: To determine the association between invasive cervical cancer (ICC) and HIV
infection in Kenyan women.
Study design: Case-control, cases being patients with ICC and controls, non-cancer patients
with uterine fibroids.
Methods: From January 2000 to March 2002, 367 ICC, and 226 patients with fibroids were
recruited. All women received pre- and post test HIV counseling. HIV testing was done using
ELISA. CD4 cell count was done with flow cytometry.
Results: ICC patients were older than fibroid patients (48 vs 41 years, p<0.001). HIV
seroprevalence was 15% in cases and 12% in controls (p>0.05). However, cases 35 years or
younger were 3-times more likely to be HIV infected than controls of similar age (35% vs
17%, p=0.043). ICC HIV seropositive patients were 10 years younger than HIV seronegative
patients (40 vs 50 years, p<0.001). Eighty percent of HIV seropositive and 77% of HIV
seronegative ICC patients were in FIGO stage IIb and above. Yet, HIV seropositive ICC
patients were 3-times more likely to have poorly differentiated tumors (77% vs 52%,
p=0.038) after adjusting for histological cell type and clinical stage. Mean CD4 cell count was
833 cells/mm3 in ICC and 1025 cells/mm3 in fibroid patients, p=0.001.
Conclusion: ICC patients were 3-times more likely to be HIV infected as compared to fibroid
patients. HIV infection was associated with poor histological differentiation of the tumors.
Our data suggest an accelerated clinical progression of premalignant cervical lesions to ICC
in HIV-infected women as demonstrated by a significant lower age at presentation.
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FC3-09
HUMAN PAPILLOMAVIRUS VIRAL LOAD IN PREDICTING
DISEASE SEVERITY IN WOMEN SHOWING ATYPICAL PAP
SMEARS
SARIAN, LOZ (1); DERCHAIN, SFM (1); FERREIRA-SANTOS, AL (2); SYRJÄNEN KJ (3)
(1) Obgyn Department, Universidade Estadual de Campinas (2) Universidade de Taubaté (3),
National Institute of Health, Rome, Italy
Objective: To assess the performance of Hybrid Capture II (HCII) in predicting the grade of
cervical lesions in women with Pap smears showing atypical squamous cells, evaluating
different cut-off points of relative light unit/positive control ratios.
Subjects and methods: For this study, linked to FAPESP 00/06394-0 and 99/11264-0
project, between August 2000 to November 2002, 174 women admitted to the Universidade
Estadual de Campinas and 135 to the Universidade de Taubaté Colposcopy Clinics due to an
abnormal Pap smear were recruited into this multi-institutional cross-sectional study.
Histological disease confirmation was done by biopsy or large loop excision of the
transformation zone according to the Pap smear result and colposcopy. Referral Pap smear,
available for review from all the patients, was assessed using the Bethesda System (2002) and
classified as ASC, LSIL or HSIL. The specimens for HCII were tested for high-risk HPVs
types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 and the viral load was estimated in
relative light units/positive control ratios (RLU/CO). Receiver Operating Characteristics
(ROC) analysis was used to test the diagnostic performance of HCII test in different cut-off
points of RLU/CO.
Results: Histological findings included 14 (4,5%) cervicitis, 126 (40,8%) CIN1, 157 (50,8%)
CIN2/3, 2 (0,6%) "in situ" adenocarcinoma and 10 (3,2%) invasive carcinoma. CIN2 and
above was considered as severe disease. Severity of histological findings correlated positively
to HSIL at Pap smears (OR13.8; CI95% 7.4-26.0), and to major colposcopic abnormalities
(OR10.0; CI 95% 5.6-17.9). ROC curve analysis showed the best sensitivity/specificity cutoff point for HCII at 20RLU. HCII cut-off point of 20 RLU/CO showed a sensitivity of 73%
and a specificity of 64%, compared to a sensitivity of 90% and specificity of 49% at
1RLU/CO cut-off. Higher viral loads were detected by HCII in lesions CIN2 and above: 1-20
RLU/CO (OR 5.8; CI95% 2.5-13.6) and >20 RLU/CO (10.46; CI95% 5.3-20.8).
Conclusions: HSIL at Pap smear and major colposcopic findings were significantly
associated with histological CIN2 or above. Best cut-off point for HCII was found to be at
20RLU.
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FC3-10
HPV DNA TESTING IN FOLLOW-UP AFTER TREATMENT FOR CIN:
A SYSTEMATIC REVIEW OF THE LITERATURE
Paraskevaidis E (1), Sotiriadis A (1), Koliopoulos G (1), Tofoski J (2), Diakomanolis E (3)
(1)Department of Obstetrics & Gynecology, University Hospital of Ioannina, Ioannina, Greece,
(2)Department of Obstetrics and Gynecology, University Hospital of Skopje, FYROM, (3)1st
Department of Obstetrics and Gynecology, Athens University, Alexandra Hospital, Greece.
Much research has been focused lately on the status of HPV viral load after treatment of
cervical intraepithelial neoplasia as an early index of residual / recurrent disease. A systematic
review of the literature was carried out concerning the role of HPV DNA testing in the
follow-up period after conservative treatment for CIN.
A MEDLINE and EMBASE search was done (1985 to March 2002), using the keywords
HPV/HPV DNA, together with CIN, follow-up, recurrence and LLETZ. References of
retrieved articles were also screened. Selection criteria were original published Englishlanguage reports of prospective or retrospective studies including women with an initial
diagnosis of cervical intraepithelial neoplasia, who received conservative surgical treatment
and were followed with HPV DNA testing in addition to cytology, colposcopy and/or biopsy);
the latter methods were used for verification of residual or recurrent disease.
There is a marked heterogeneity in the design, population, intervention and follow-up policy
across different studies, with a lack of randomized controlled trials. The sensitivity of HPV
DNA testing in detecting treatment failures was quite good in most studies, reaching 100% in
four of them, whereas the specificity of the test differed across the studies, ranging from 44%
to 95%. Among women in whom the treatment was considered to be successful, 85.1% had a
negative postoperative HPV DNA test and 14.9% a positive one. The corresponding rates for
cases with treatment failures were 17.1% and 82.8%, respectively. A positive HPV DNA test
often preceded an abnormal cytology in cases of treatment failure. This rate ranged between
25% and 50% across studies. At present, the design of the studies precludes quantification of
this lag, as well as prediction of these particular cases.
It seems that a positive HPV test, even in the presence of normal cytology, can pick up
quicker and more accurately a treatment failure. However, cytology and colposcopy may still
be needed in order to rule out false positive and false negative results.
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FC3-11
QUANTITATIVE ANALYSIS OF MORE THAN 1500 CERVICAL
DYSPLASTIC BIOSPIES: CORRELATION WITH PATHOLOGY
GRADES AND HPV STATUS
GUILLAUD Martial
BC Cancer Research Centre, Cancer Imaging, Vancouver
Histological grading of Cervical Intra-epithelial lesions (CIN) remains a subjective task,
resulting in inter-and intra-observer variability and poor reproducibility of the diagnosis of
cervical lesions. This study presents some results obtained from the quantitative analysis of
intra-epithelial lesions of the cervix using a semi-automatic image cytometer. The objective
was to extract information at the tissue level, by measuring changes in the spatial organisation
of cells within the diagnostic area, and at the cellular level by measuring changes in the
morphology and the texture of the nuclei.
More than 1500 biopsies were obtained from more than 767 patients enrolled in a screening
and diagnostic trial for the detection of SILs of the uterine cervix using
fluorescence/reflection spectroscopy (NCI Program Project PO1-CA82710). All the biopsies
were classified at least twice. Discrepancies between the first and the second reading were
resolved by a consensus review and a final diagnosis was assigned. HPV testing (by hybrid
capture II and DNA PCR), Pap smears cytological classification and clinical information were
available for each patient. The diagnostic areas were mapped by an experienced pathologist
and biopsies were classified into 5 groups: negative specimen (n=1012), koilocytosis
specimen (n=131), CIN I (n=57), CIN II (n=40), and CIN III/CIS (n=79). Four microns
sections were stained with a stoichiometric DNA staining. Using the Cyto-Savant imaging
system, we calculated 25 architectural features, which describe the global organisation of the
cells within the epithelium and 110 morphometric features, which describe nuclear
characteristics, in terms of morphology, chromatin, texture, and DNA optical density.
We will show how an histometric score can be derived from these quantitative features and
used to improve the accuracy and the precision of the diagnosis.
Furthermore, morphometric analyses of negative specimen (900 specimen) show statistical
differences between specimen coming from a normal cervix and specimen coming from a
cervix in which one or two abnormal lesions were found. Among a sub-set of 1100 specimens
for which the HPV hybrid capture test was performed, we found statistical differences in the
morphometric features between HPV positive and HPV negative specimens for the different
histo-pathological classifications.
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FC3-12
HUMAN PAPILLOMAVIRUS (HPV) TYPE 16 VARIANT
DISTRIBUTION IN THE ITALIAN POPULATION
Tornesello ML (1), Duraturo ML (1), Salatiello I (1), Buonaguro L (1), De Stefano M (4), Piccoli R
(4), Losito S (2), Botti G (2), Stellato G (3), Greggi S (3), Stefanon B (5), De Palo G (5),
Buonaguro FM (1)
(1) Viral Oncol-AIDS Ref Centre, (2) Dpt of Pathology and (3) Div of Gynecol - Natl Cancer Inst "Fond.
Pascale", Naples; (4) Inst of Gynecol, Univ of Naples;Federico II, Naples, Italy; (5) Preventive and
Predictive Medicine, Natl Cancer Inst, Milan, Italy
Background: HPV16 classes (E, AA, As, Af-1, Af-2) and their variants have different
geographic distribution and different degrees of association with cervical lesions. This study
was designed to evaluate the prevalence of HPV16 variants in case patients (affected by
invasive cervical carcinomas [ICC] or cervical intraepithelial neoplasias [CIN2-3 and CIN1]),
versus control subjects.
Methods: 331 subjects of Italian Caucasian descent have been enrolled: 57 patients with ICC,
48 patients with CIN2-3, 39 patients with CIN1 and 187 control subjects. HPVs were detected
by L1 and E6/E7 gene-specific polymerase chain reactions and HPV16 classes and subclasses
were identified by direct nucleotide sequencing.
Results: HPV16 was detected in 63.2% of ICC, 43.7% of CIN2-3 and 43.6% of CIN1, but
only in 8.6% of controls. HPV16-E (Ep-T350 and E-G350) and -Ax (AA and Af-1) variants
were found statistically more often in case patients (E=42.1% of ICC, 35.4% of CIN2-3 and
38.5% of CIN1; Ax=21.0% of ICC, 8.3% of CIN2-3 and 5.1% of CIN1) than in controls
(E=8.0% and Ax=0.5%). The odds ratio for ICC (OR=49.6; 95% confidence interval
[CI]=6.4-1047.6), CIN2-3 (OR=13.8; 95% [CI]=1.6-308.6) and CIN1 (OR=10.1; 95%
[CI]=0.5-596.2) associated with Ax variants were significantly higher than those associated
with Ep variants, in particular the OR for ICC associated with Ax variants was 26.1 higher
than that associated with Ep variant.
Conclusions: The high frequency of HPV16 AA and Af-1 variants in invasive and noninvasive neoplastic lesions suggests that Ax variants are more oncogenic than E variants, with
the relevant implication for the need of HPV16 variant identification and optimization of
diagnostic/therapeutic protocols, including development of specific vaccines.
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FC3-13
INCIDENCE AND SURVIVAL RATE OF WOMEN WITH CERVICAL
CANCER IN THE LARGER AMSTERDAM AREA
¹Meijer, CJLM, ²Visser O, ¹Rozendaal L, ³Verheijen RHM, ¹Bulk S
(1) Department of Pathology (3) Gynaecology, VUmc (2) Comprehensive Cancer Centre Amsterdam,
Amsterdam, the Netherlands
Introduction: Population-based cervical cancer screening has been introduced in The
Netherlands in 1988. To evaluate a possible effect on incidence of malignant cervical lesions
in The Netherlands, we investigated the incidence and survival of cervical cancer registered
by a cancer registry in the larger Amsterdam area.
Methods & Results: Data on incidence, histology, stage and survival were used. The
incidence rate of squamous cell carcinoma decreased significantly from 9.2/100.000 women
in 1988 to 5.9/100.000 in 2000 (P <0.001), whereas the incidence rate of adenocarcinomas
remained stable. Moreover, the prognosis of women with squamous cell carcinoma increased
significantly during the study period. No significant change in prognosis was found for
women with an adenocarcinona of the cervix. In addition, after adjustment for age, stage and
lymph node involvement, the relative risk of dying was 1.6 times higher for patients with
adenocarcinoma of the uterine cervix than for patients with squamous cell carcinoma (95%CI
1.2-2.1).
Conclusion: These results indicate that the present screening programme for cervical cancer
in The Netherlands is associated with a decreased incidence and increased survival of patients
with squamous cell carcinoma, but fails to detect (pre-) malignant lesions of adenocarcinoma.
Since at least 94% of cervical adenocarcinomas and their precursor lesions contain high-risk
HPV DNA, adding high-risk HPV testing to the Pap smear might improve the present
screening programme in detecting adenocarcinoma and its precursor lesions.
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FC4-01
RISK FACTORS FOR HSV2 INFECTION IN INDIVIDUALS WHOSE
PARTNERS HAVE GENITAL HERPES
Rana RK (1), Paavonen J (2), Tyring S (3), Pöder A (4), Strand A (5), Cook SF (1), Pimenta JM (1)
(1) GlaxoSmithKline, UK, US (2) Uni.Helsinki, Finland (3) Uni.Texas, Galveston, US (4) Tartu Uni.,
Estonia (5) Uni.Hospital, Uppsala, Sweden
Objective: This study evaluated risk factors for HSV2 infection in individuals whose partners
had genital herpes (GH) and compared risk factors from independent analyses based on the
person with GH and their partner respectively.
Methods: Both partners in monogamous, heterosexual couples (n=1193) completed a crosssectional questionnaire on demographic, behavioural and knowledge factors. This included
476 men and 717 women with GH confirmed by HSV2 serology ("source’). Their partners
("non-source’) did not have a history of GH; on confirmation, 419 were HSV2 positive
(35%). Two separate logistic regression models were developed using data from (1) the nonsource partner only and (2) the source partner only to assess risk factors for HSV2
seropositivity.
Results: In the non-source partners, the following factors were significantly (p<0.01)
associated with HSV2 infection: longer partnership (for each extra year, adjusted odds ratio,
aOR 1.1 95% CI 1.1-1.2), vaginal sex during GH episodes compared to those abstaining (aOR
1.6 CI 1.1-2.4), female gender (aOR 3.1 CI 2.3-4.2), a prior STD (aOR 1.7 CI 1.2-2.5), never
using condoms (aOR 2.2 CI 1.4-3.3) and lower knowledge of GH. Similar results were seen
in source partners for partnership duration, vaginal sex during GH episodes and male gender.
In addition, a recent diagnosis of GH was associated with an increased risk of HSV2 in their
partners (for each extra year since diagnosis, aOR 0.9 CI 0.8-0.9, p<0.001).
Conclusion: Vaginal sex during GH episodes, never using condoms and lower knowledge
about GH were identified as potentially modifiable risk factors for HSV2 infection. In this
study, analyses of rarely available partner data did not add substantially to risk factor
information derived from the individuals (non-source partners).
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FC4-02
LOWER LEVELS OF SEXUAL CONTACT AND HIGHER LEVELS OF
CONDOM USE REPORTED DURING PERIODS OF SYMPTOMATIC
GENITAL HERPES
Rana RK (1), Sekhin SV (2), Stratchounsky LS (2), Gubelin W (3), Dainys B (4), Morel P (5),
Rosenberg DM (1), Pimenta JM (1)
(1).GlaxoSmithKline, UK; (2).Smolensk State Med Acad, Russia; (3).Universidad de Chile, Chile;
(4).Vilnius University Hosp, Lithuania; (5).Saint-Louis Hosp, Paris
Background: Herpes simplex virus type 2 (HSV-2) is the primary cause of genital herpes
(GH) and is shed both during periods with and without recognised symptoms (defined as
"symptomatic" and "asymptomatic" periods respectively). Little is known about differences in
sexual behaviour between symptomatic and asymptomatic periods; this study aimed to assess
these differences.
Methods: Between 1998 and 2001 at worldwide clinical sites, a cross-sectional questionnaire
on demographic and behavioural factors was undertaken by 476 men and 717 women selfidentifying with GH in monogamous, heterosexual partnerships ("source" partner). Their
partners reported no prior GH; on confirmation, 419 were HSV-2 positive and 774 were
HSV-2 negative.
Results: During symptomatic compared to asymptomatic periods, source males reported
substantially less vaginal (44% vs 99%, p < 0.001), oral (27% vs 74%, p < 0.001) and anal
(12% vs 26%, p < 0.001) sex. Similarly, during symptomatic periods, source females also
reported less vaginal (39% vs 98%, p < 0.001), oral (33% vs 80%, p < 0.001) and anal (11%
vs 24%, p < 0.001) sex. Furthermore, during symptomatic compared to asymptomatic periods,
sexually active source males generally reported higher levels of consistent condom use
(vaginal: 42% [84/198] vs 19% [85/459], p<0.001; oral: 12% [13/113] vs 3% [10/328],
p<0.001; anal: 12% [6/51] vs 5% [6/117], p = 0.23).
Conclusions: During asymptomatic periods, a relatively small proportion of men reported
consistent condom use (19%). During symptomatic periods, people engaged in substantially
fewer sexual acts, and for vaginal and oral sex, men used condoms more frequently. Even so,
the majority of men did not report consistent condom use when engaging in vaginal
intercourse during GH symptoms. These results highlight that further education on genital
herpes transmission may be warranted.
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FC4-03
ONCE DAILY VALACICLOVIR REDUCES TRANSMISSION OF
GENITAL HERPES
PATEL R (1), SACKS S (2), TYRING S (3), PAAVONEN J (4), STRATCHOUNSKY L (5), PÖDER A
(6), WADDELL R (7), HARRIS J (8), COREY L (9)
(1) Southampton Univ Hosp., Southampton, UK, (2) Viridae Clin Sci and Univ of British Columbia,
Vancouver, Canada, (3) Univ of Texas, Galveston, TX, USA (4) Univ of Helsinki, Helsinki, Finland, (5)
Smolensk State Med Acad, Russia, (6) Clin of Dermatol. Tartu Univ, Tartu, Estonia, (7) Sexually
Transm. Dis Services, Adelaide, Australia, (8) GlaxoSmithKline R&D, Greenford, UK, (9) Univ of
Washington, Seattle, WA, USA.
Background: Transmission of genital herpes to a sexual partner is a major concern to
patients. Daily valaciclovir suppresses genital herpes clinical recurrences and HSV shedding.
We investigated the efficacy of once-daily valaciclovir suppressive therapy in the source
partner for reducing genital herpes transmission to the susceptible partner in heterosexual,
monogamous, HSV-2 discordant couples.
Methods: In a randomized double-blind study, HSV-2 seropositive source partners with a
history of <10 episodes/year received valaciclovir 500mg once daily or placebo for 8 months.
HSV-2 seronegative susceptible partners were monitored monthly for acquisition of genital
herpes. Couples were offered condoms and counseled on safer sexual behavior at all visits.
The primary endpoint was the proportion of susceptible partners with a first episode of
symptomatic genital herpes (confirmed by HSV-2 culture, PCR or seroconversion). All
endpoints were ratified by an endpoints committee prior to unblinding the study.
Results: 1484 couples participated in the study. 741 source partners received placebo and 743
received valaciclovir. 488 susceptible partners were women and 996 were men. Sixteen
(2.2%) subjects in the placebo, vs 4 (0.5%) in the valaciclovir group acquired symptomatic
genital herpes, relative risk = 0.25, 95% CI 0.08, 0.74, P=0.011, a 75% reduction in the risk.
Twenty-seven (3.6%) of placebo vs 14 (1.9%) of valaciclovir treated partners transmitted
genital HSV-2 infection (measured by laboratory-confirmed symptoms or seroconversion). At
any time the risk of transmitting HSV-2 infection was reduced by 48% (hazard ratio = 0.52,
95% CI 0.27, 0.99, P=0.039). Adverse events were similar in nature and frequency between
treatment groups.
Conclusions: Once daily valaciclovir suppressive therapy significantly reduces the
transmission of genital herpes among heterosexual HSV-2 discordant couples. This is the first
randomised controlled trial of an antiviral demonstrating a reduction in sexual transmission of
an infection.
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FC4-04
INCIDENCE OF GENITAL WARTS AMONG PRIVATELY INSURED
PATIENTS IN THE UNITED STATES
Koshiol J (1,2) Pimenta JM (3) St.Laurent S (2)
Univ. of North Carolina,Chapel Hill,US (1); GlaxoSmithKline,RTP,US (2) & Greenford,UK (3)
Background: Surveillence data from STD clinics indicate that genital warts (GW) is the most
commonly diagnosed viral STD. However, data from non high-risk populations are lacking;
this study describes incidence of GW among privately insured patients in the United States
(US).
Methods: Using a large US health claims database (Integrated Healthcare Information
Service) comprising 9 geographic regions and 17 million members, data were derived from
adults aged 15-59 years with at least 6 months of continuous enrollment. GW cases were
defined using ICD9 codes combined with GW-specific treatment or procedure codes. Incident
cases were defined as people with GW and at least 6 months free from GW prior to diagnosis.
Incidence rates are reported per 100,000 person years of observation (PYO).
Results: From 1 Jan. 2000 to 31 Dec. 2001, 7,457 cases were diagnosed from 4,716,816
members contributing 5,840,391 PYO (median follow-up 1.17 years). The overall incidence
rate was 128 [95% confidence interval (CI): 125-131]. In both sexes, rates peaked in 20-29
year olds (men: 211 [95% CI: 199-225]; women: 219 [95% CI: 207-231]) and declined
thereafter, decreasing more rapidly in women. In those aged 30 and above, incidence rates
were higher in men than women (overall rate men: 140 [95% CI: 136-145]; women: 116
[95% CI: 113-120]). The ratio of female to male rates in 15-19 year olds was 3.1:1 (168 [95%
CI: 153-184] vs. 54 [95% CI: 46-63]). From 2000 to 2001, the overall incidence rate
increased by 30%; this rise was seen for both sexes and in all age groups, with the largest
increase in 15-19 year olds (women: 45%; men: 54%).
Conclusions: This study provides rare estimates of the incidence of GW in a large privately
insured US population. Data suggest that incidence of GW is highest in 15-29 year olds,
higher in young women than men (15-19 years) and may have increased between 2000 and
2001. Changes in health seeking behaviour and reporting may have contributed to this rise.
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FC4-05
HPV AND OTHER STDS IN CROATIA
Grubisic G (1), Grce M (2)
(1) University Hospital "Sestre Milosrdnice", University of Zagreb, Department of Obstetrics and
Gynecology, (2) Rudjer Boskovic Institute, Division of Molecular Medicine, Zagreb, Croatia
Syphilis and gonorrhoea have been clearly decreasing since mid-80s, according to the
Register of Croatian National Institute of Public Health. HIV infection shows a relatively
favourable trend with 8-16 AIDS patient annually in the last 12 years. Thus, AIDS in Croatia
did not follow Western European models, as there have not been any explosive growth.
Hepatitis B has shown for decades in Croatia a practically stationary low endemic trend with
an average of 200-250 people infected per year. Chlamydial infections have shown also a
stationary trend ranges between 200 and 300 cases per year that represent 10% and 29%
infected women and adolescents, respectively.
Cervical cancer in Croatia is in the third place following breast and stomach cancer. Thus,
from 1990 HPV DNA was continuously analysed by hybridization methods and from 1994 by
PCR. Genital samples collected from 1990 to 1993 showed the increase from 5% to 37% of
HPV infections both in men and women (1). Through years, there was an increased interest
for HPV diagnosis, justified by the increase of HPV infection ranging from 40% to 80% from
1995 to 1998, respectively (2, 3). From 1999 to 2001 a stationary state is observed, HPV
DNA was found in 60, 71 and 63% women, respectively. Approximately half HPVs were
typed as being HPV 6/11, 16, 18, 31 and/or 33, while the others remained untyped. Multiple
HPV infections are not uncommon, as they were found in approximately 5-10% of HPVpositive samples. The most frequently observed HPV type was HPV 16 and it is mostly
associated with high-grade cervical epithelial lesions independently of patient's age. So, HPV
16 can be considered as the major risk factor for cervical cancerogenesis. However, infection
with other risk types and unknown HPV types should not be underestimated.
High prevalence rate of HPV infections found among Croatian women, especially HPV 16
represents a significant health concern. Moreover, young women (15-24 years) exhibited the
highest rate of HPV infection and they are therefore, exposed to cervical cancerogenesis very
early in life and their reproductive possibilities are endangered as well as it is by other STDs,
i.e. chlamydia.
(1) Grce M et al. Anticancer Res 1996;16:1039
(2) Grce M et al. Eur J of Epidemiol 1997;13:645
(3) Grce M et al. Anticancer Res, 2001;21:579
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FC4-06
CERVICAL AND VAGINAL INFECTIONS IN CHILEAN WOMEN:
PROBLEMS AND SOLUTIONS
Castro E (1)., Domínguez M (2), Boggiano G (3), Zemelman R (2).
(1) Depto. Obstetricia y Puericultura, Facultad de Medicina; (2) Depto. Microbiología, Facultad de
Ciencias Biológicas; 3Depto. Salud Pública, Facultad de Medicina. Universidad de Concepción.
The genital infections have an important impact in the reproductive health of our women.
Only few studies have been conducted in Chile to determine the prevalence of the cervical
and vaginal infections. OBJETIVES: We want to evaluate the frequency of these infections in
fertile age women from 8th Region's public health centers of Chile. We put into practice a
pilot proyect to diagnose these infections in these centers. METHODOLOGY: 1500 women
have been included in this study since 1999 until 2002. Bacterial vaginosis, Neisseria
gonorrhoeae and Chlamydia trachomatis were the principal infections investigated. We
trained a group of professionals who work in our public health centers in the diagnosis of
these infections.
Results: We obtained upper 60% of women without Lactobacillus spp. The positive test for
C.trachomatis were seen in an important frequency of women (35%). Asymtomatic sexual
workers had C.trachomatis y/o N.gonorrhoeae. Geografical variations in the distribution of
these infections were obtained. 60 professionals are employing the same criteria and protocols
for diagnosis of vaginal and cervical infections.
Conclusions: This work show the first results about epidemiological variations associated to
these infections in chilean women. We have a pilot project to diagnose bacterial vaginosis
clinically.
This investigation was supported by Grant Dirección de Investigación N°99.84B.008
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FC4-08
THE DEVELOPMENT OF A SELF-LEARNING WEB BASED MODULE
ON STI FOR HEALTHCARE PROFESSIONALS
Mann J, Wong T, Cormier L, Steben M
Health Canada, Centre For Infectious Disease Prevention and Control, Ottawa, Ontario
Background: Health Canada produces and widely distributes The Canadian STD Guidelines,
the latest edition being produced in 1998. The Guidelines are written to assist primary health
care providers in the prevention and appropriate management of STI in Canada. The Expert
Working Group for the 1998 edition expressed the need for such guidelines to be marketed in
ways that would help them to be adopted by healthcare professionals.
For this purpose, an STD Self-Learning, Web-based Module has been developed. The
Module, which has been peer reviewed for content and approach and is available in both
English and French, consists of a number of clinical cases highlighting different STIs and
their associated prevention and management issues. In addition a Clinical Slide Gallery offers
photographs of the various disease conditions, normal variations and diagnostic procedures to
compliment the content of the cases.
The Module is a key tool allowing healthcare professionals to enhance their knowledge and
skills regarding STI by promoting use of the Guidelines. The module is widely accessible
through the Health Canada website. Healthcare professionals can access the module at a time
that is convenient to them and work through the various cases at their own pace, to suit their
own learning needs and goals. Where appropriate self-study credits can be claimed for
professional accreditation.
The web format allows links to be made to the web version of The Canadian STD Guidelines,
in addition to links to other useful information already available on the web. This format
allows the cases to be continually updated and improved as new information becomes
available. In 2003, as Health Canada embarks on the most recent update to The Canadian
STD Guidelines as well as a National Consensus meeting on Cervical Cancer and HPV
screening, the cases will be updated and the links changed to reflect the results of the updating
process. This allows practical information that reflects recent changes to be conveyed to
practicing healthcare professionals in a timely fashion.
Proposal: A demonstration of the Module (available on CD-ROM or via the Internet) through
either an oral presentation, or through a hands-on exhibit during poster presentations would
allow attendees to experience the Module themselves. Participants could evaluate its utility,
accessibility and value as a learning tool and learn how to develop or adapt such a Module for
training of healthcare professionals in their countries. CD-ROM copies of the Module could
also be made available to conference attendees.
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FC4-09
TREPONEMA PALLIDUM HIV INTERACTION: SINGS AND
SYMPTOMS OF VARIOUS FORMS OF NEUROSYPHILIS IN HIVINFECTED PATIENTS AND ITS TREATMENT
Bessarab Timur (1), Potekayev Sergei (2)
(1) Moscow AIDS Center, (2) Federal AIDS Center
Now the interaction between Treponema pallidum (TP) and the human immunodeficiency
virus (HIV) is known. Such TP is more aggressive with enhanced multiplying.
Purpose: To summarize signs and symptoms of various forms of neurosyphilis (NS) and
optimize its treatment in our HIV-infected patients (pts).
Methods: The diagnosis of HIV-infection is confirmed with ELISA and Western blot, of NSwith complement-linking reaction and RIT in CSF and in blood, FTA-200 and FTA-ABS in
blood, FTA with undiluted CSF and Lange reaction in CSF. Total 10 pts with HIV and NS
were examined, all homosexual males aged 24-41, with CD4+ abs ranged 450-50 cells/mm3.
Results: Two pts had asymptomatic NS (HIV: 1 GLP, 1 seborrhoic dermatitis). Four pts had
tabes dorsalis (HIV: 2- asymptomatic, 1 severe polyneuropathy of the feet and of the legs, 1
had AIDS: pulmonary tbc, cachexy, sensoneural hearing loss, central vestibulatory
syndrome). In two pts tabes dorsalis manifested by extremely severe pain and "cold"
sensation in the legs, in one by unusually prominent Argyll-Robertson sign. One pt had
paralysis progressiva-like NS (HIV: clinically unusual pityriasis versicolor of the trunk). NS
in this pt was remarkably reversible due to treatment. Two pts had encephalitis (HIV: 1
asymptomatic, 1 GLP). Encephalitis in both was distinguished by severe headache and
hemiparesis, in 1 pt HIV-infection progressed from asymptomatic to more advanced stage. In
one pt NS was represented by gummatous meningoencephalitis (HIV: candidiasis of oral
cavity). All pts received high-dose IV Benzyl penicillin by scheme of our Center with obvious
effect.
Conclusion: TP-HIV interaction was characterized with severe and unusual signs and
symptoms of NS and sometimes of HIV-infection in our pts. The use of high-dose IV benzyl
penicillin was quite effective.
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S1-01
HPV AND CERVICAL CANCER BURDEN IN EUROPE
F. Xavier Bosch
Institut Català d’Oncologia, Servei d’Epidemiologia i Registre del Càncer, L’Hospitalet de Llobregat, Spain
On several occasions, estimates of the burden of HPV infections and of the closely associated
cervical lesions have been produced. Data on invasive cervical cancer extrapolated to the
existing population indicate for Europe some 65.000 new cases per year and an age-stardard
rate of 13 new cases per 100.000 per year.
Some Cancer Registries provide information on the incidence of pre-neoplasic cervical
lesions (CIN3, carcinoma in-situ). The summary graph of two population-based registries in
Spain (Mallorca and Tarragona) indicates that the development of CIN3 is a very common
event in the young age groups (rates for CIN3 reached values of 70 and 110 per 100 000 in
the age groups 30 to 40) and strongly suggests that an important proportion of these lesions
are not true precursors of invasive cancer.
Data on genital warts, the most clinically visible manifestation of HPV infentions are rare. It
is generally estimated that the prevalence ranges from 1% to 2% of the sexually active
population in most populations.
Data on genital HPV DNA prevalence in representative samples of populations in different
countries are limited. Typically the proportions of HPV DNA carriers have been placed in the
15-40% range in the young, sexually active, age groups and between 3-10 % range in the 35
and above age groups. Prevalence in the male external genitals is only available for a few
countries and the evidence suggests that may be roughly similar to the prevalence in women.
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S1-02
MODE OF ACTION OF IMIQUIMOD AND ITS POTENTIAL FOR THE
TREATMENT OF STI’S
Stanley Margaret A
Department of Pathology, Tennis Court Road, Cambridge CB2 1QP
A central development of the past decade has been in our understanding of the interactions
between and interdependence of, the innate and adaptive immune response. Innate immunity
recognises “danger” signals and activates adaptive immunity in a targeted, appropriate and
effective response. Dendritic cells and macrophages have a central role in this process and
pharmacological agents that modulate the functions of these cells could have therapeutic
value. The imidazoquinolone compounds of which Imiquimod, formulated as Aldara, is the
best characterised to date are such molecules. Imiquimod and its homologues act by activating
macrophages and other cells via binding to cell surface receptors, such as Toll like receptor 7,
thereby inducing secretion of pro-inflammatory cytokines, predominantly IFN-α, TNF-α and
IL-12. This locally generated cytokine milieu biases to a Th1 cell mediated immune response
with the generation of cytotoxic effectors.
Regression of genital warts, caused by human papillomavirus infection, is associated with a
cell mediated Th1 response suggesting that immunotherapies eliciting such a response will be
effective. Imiquimod has been shown to be significantly more effective than placebo in
clearing genital warts and mechanism of action studies indicate that this is related to the
ability to generate proinflammatory cytokines and a Th1 response. Intra-epithelial neoplasms
of cutaneous and mucosal surfaces are associated with HPV infection and there is some
evidence that immune response modifiers may have therapeutic value for these lesions.
Topical immunotherapy with immunomodulators shows potential for effective and patient
friendly treatment of viral STI’s. These compounds also have adjuvant properties that could
significantly enhance conventional vaccine strategies.
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S1-04
GENITAL WARTS AND PSYCHOLOGICAL ISSUES
O'Mahony Colm
Countess of Chester Hospital, Dept Genito-Urinary Medicine, Chester, UK
As professionals, we know that genital warts are a cosmetic nuisance. They have no long term
medical implications. We know that using the correct treatments almost all clinically obvious
genital warts can be dealt with successfully. Our patients, however, have a different
perspective. Most patients are deeply upset and distraught with such an unpleasant diagnosis.
The fact that the majority are sexually transmitted also contributes to the guilt and anxiety.
Effective home treatments are a big help in reducing the psychosexual damage.
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S3-01
THE USE OF LIQUID-BASED CYTOLOGY IN CERVICAL
SCREENING: A META-ANALYSIS
Klinkhamer P (1); Meerding W (2); Hanselaar A (3)
(1) PAMM-Laboratory of Pathology, Eindhoven, The Netherlands, (2) Department of Public Health,
Faculty of Medicine, Erasmus University, Rotterdam, The Netherlands, (3) University Medical Center,
Department of Pathology, Nijmegen, The Netherlands.
Liquid based cytology has been recently introduced in the preparation and evaluation of
cervical smears. This study evaluates, using evidence-based methods, whether the available
literature has enough evidence to warrant introduction of these methods in the cervical
screening in The Netherlands. The diagnostic value of liquid based cytology was compared
with conventional screening for the detection of atypia and higher (ASCUS+), mild dysplasia
and higher (LSIL+) or moderate dysplasia and higher (HSIL+). The study was limited to the
two major techniques available in Europe: AutoCytePrep and ThinPrep. A total of 136 articles
were selected using Pubmed, Medline and personal files. They were screened on having
abstracts in the English language, whether they appeared in a peer-reviewed magazine, and
whether they concerned cervical cytology in relation to AutoCytePrep and/or ThinPrep. The
60 remaining articles included all the studies selected by three recently published systematic
reviews. Of 10 studies a complete standard questionnaire, with questions concerning study
design and results, could be answered (4 on AutoCytePrep, 6 on ThinPrep). In one study the
absolute sensitivity and specificity was presented. The remainder had incomplete follow-up of
negative cases. In these studies the detectionrate, and relative sensitivity and specificity were
calculated. Concerning the AutoCytePrep-system there are indications that, for ASCUS+, a
lower detection rate and lower specificity was found compared with the conventional
screening method. No conclusion was possible for LSIL+, and HSIL+, due to conflicting
results. Concerning the ThinPrep-system there are indications that, for ASCUS+, this method
has a higher detection rate with slightly lower relative specificity compared to the
conventional screening method. It is likely that ThinPrep has a higher detection rate with
equal or only slightly less relative and absolute specificity for LSIL+ and HSIL+, compared to
conventional screening. It is concluded that there are no medical contra-indications for the use
of ThinPrep in the Dutch organized screening program, however further studies to evaluate
the cost-effectiveness of this method are needed. Also further studies that comply with the
standards used in this study are needed to further evaluate the AutoCytePrep-sytem.
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S3-02
EVALUATION OF THE THINPREP METHOD IN A SWEDISH
SETTING
Walter Ryd
MD, PhD, Dept. Pathology and Clinical Cytology, Sahlgrenska University Hospital, Göteborg, Sweden
Introduction: There is a large series of publications showing a better sensitivity for LSIL,
HSIL and glandular lesions with LBC (liquid based cytology) compared to conventional Pap
smears. The ASCUS rate and the number of non-diagnostic samples are reduced in several
studies. On the other hand, the cost of a single LBC test is higher.
Why test LBC when it is already so well described in the literature?
Cytology laboratories in different countries work under different circumstances. In the U.S.
the legal system makes sensitivity very important. The rate of non-diagnostic smears varies
considerably in reports from different countries from less than 1 % over10 %. The sensitivity
for HSIL in Pap smears in some countries is as low as 40-50 %. A reduction of the nondiagnostic smears or an increased sensitivity might immediately give economic support to a
new and more expensive technique.
We were interested to find the effect of LBC within our own population. With the support of
Cytyc the opportunity for this study arose.
Method: The study was based on split sample testing of 180 women. A conventional Pap
smear was first produced and the remaining material in the brush was rinsed off in the liquid
medium (ThinPrep vial).
The study population was comprised of women who were referred for investigation of
abnormal cervical smears or dysplasia. The ThinPrep slide and the Pap smear were diagnosed
independently of each other. The two diagnoses were then compared with the following
biopsy.
Results: Of the biopsies 45 did not show dysplastic or malignant lesions, 54 showed LSIL, 73
showed HSIL, 5 showed squamous cell carcinoma and 2 showed AIS.
There were 11 ThinPrep and 15 Pap smear false negatives in 73 biopsy HSILs. ThinPrep
identified 49, and Pap smear 33, of the 73 HSILs. ThinPrep reported “severe lesion” (HSIL,
AIS or cancer) in 56 and Pap smear in 49 of 80 of these lesions. This difference for “severe
lesion” was significant, with p < 0,003.
Discussion: The results are interesting and definitely far more divergent than we had
expected. They confirm that ThinPrep gives a more specific diagnosis and reduces the number
of under-diagnosed HSIL.
This study does not give any information on the effect of ThinPrep on the ASCUS rate and on
the number of sub-optimal and non-diagnostic smears. We are now doing a larger study on
8000 women within the organized mass screening project and some preliminary data will be
presented.
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S4-02
HPV TYPE DISTRIBUTION IN CERVICAL CANCER. WHAT CAN WE
ANTICIPATE FOR VACCINE COMPOSITION
F. Xavier Bosch
Institut Català d’Oncologia, Servei d’Epidemiologia i Registre del Càncer, L’Hospitalet de Llobregat, Spain
Given the strong relationship between HPV infections and cervical cancer, prevention of
persistent HPV infections seems to be a desirable target and perhaps the only realistic option
for developing countries.
Since HPV type-specific cross protection is limited, one of the central issues in exploring
products destined to widespread use is the number of viral types that are to be included.
The cumulative prevalence of HPV types in over 2000 cases of invasive cervical cancer from
over 25 countries shows that four HPV types,16, 18, 45 and 31 explain close to 80% of the
types involved in cervical cancer worldwide. The variability is somehow less marked for
cervical adenocarcinomas, where HPV types 16, 18, 45 and 59 account for 93% of the types
found in cases.
In series of women without cervical lesions, the HPV type specific distribution embraces a
much larger series of viral types. HPV 16 remains again the most common type (some 20 %
of the HPV DNA positive) followed by HPV 18 (some 10% of the HPV DNA positive) HPV
45 (some 8% of the HPV DNA positive) HPV 59 (some 2 % of the HPV DNA positive) and
smaller proportions of up to 30 additional HPV types.
As in other vaccination schemes, population coverage is an important determinant, probably
with a most important impact on the global efficiency of the system than the number of HPV
types included in the vaccine.
Therapeutic vaccines may offer interesting alternatives in populations where a large fraction
of young adult women are already permanent carriers of HPV DNA. These products
incorporate modified fragments of the E6 and/or E7 genes, the viral products consistently
expressed in persistent infections and in cervical cancer. Chimeric VLPs have been shown to
induce antigen-specific protection in mice from challenge with E7-expressing tumor cells.
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S5-01
RATIONALE FOR REAL TIME SCREENING
Hacker Neville
Royal Hospital for Women, Department of Gynaecologic Oncology, Sydney
Cytological screening programs in the developed world have proved successful in reducing
overall mortality from cervical cancer. However, there remains room for improvement in at
least three distinct areas.
(1) Accuracy. The accuracy of conventional cytology has been shown to be limited, and two
major meta-analyses published in recent years have demonstrated that the sensitivity of the
Pap smear for high grade lesions is as low as 50% in some settings. Because of this limitation,
cytological screening programs rely on re-testing every 1-5 years, in the context of slowly
progressing CIN lesions. However, presumably due to biological differences between lesions,
particularly with respect to intracellular adhesiveness, certain tumours do not shed a large
number of cells, so repeat smears are also likely to be read as negative, even though there are
a small number of abnormal cells present.
(2) Developing World Coverage. Generally, cytological screening programs have not been
successfully implemented in the developing world, due to difficulties in establishing a
laboratory infrastructure, training cytologists, maintenance of quality control, and loss-torecall in remote and rural areas.
(3) Time Delay in Availability of Results. Cytology involves laboratory turnaround times of
1-4 weeks, depending on the setting. This turnaround introduces significant overheads into the
screening process and presents problems when dealing with disadvantaged and/or
underscreened groups, when attempting to recall women with abnormal smear results for
further evaluation.
New real time screening technologies provide an instantaneous result, thereby potentially
alleviating loss-to-recall difficulties in disadvantaged or developing world populations.
Furthermore, initial clinical results demonstrate that the technology is capable of achieving
sensitivities equivalent to, or improved upon, that of the conventional Pap smear. Therefore,
real time screening has the potential to resolve many of the problem areas inherent in
currently implemented screening programs.
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S5-02
SCREENING PRACTICE VARIATIONS AND POTENTIAL ROLE OF
REAL TIME SCREENING
Dexeus Santiago
Dexeus Universitary Institute, Barcelona, Spain.
Practice norms in cervical screening vary between continental Europe, the UK, and the USA.
Practice variations include the tests used for cervical screening, the level of organisation of
screening programs (whether coordinated locally, regionally or nationally), and the
recommended screening interval.
In the cytological screening model as practiced in the USA and UK, regular Pap smears are
used to designate a proportion of women for colposcopic evaluation. Choosing the
appropriate screening interval and the cytological referral threshold for colposcopy have been
ongoing issues. In these settings, the immediate role of real time devices such as TruScreen is
likely to be an adjunct to cytology. The device would be used in order to increase overall
screening sensitivity in the determination of at-risk women requiring referral to colposcopy.
The screening environment in continental Europe is much more heterogeneous, with some
active regional cytological screening programs, some opportunistic screening, and some
centralised colposcopic screening at specialist centres. Therefore, real time screening devices
may be appropriate as cytological adjuncts in some European scenarios, but in others may be
more useful as an adjunct to screening colposcopy. In settings where colposcopic examination
is used for screening, a positive result from the real time device, obtained immediately, could
trigger a more detailed colposcopic examination and potentially a lower threshold could be
used for biopsy.
The patient management process and the flow of women through the screening and diagnostic
process for the various screening environments will be discussed.
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S5-03
TRUSCREEN - REAL TIME TECHNOLOGY
Canfell Karen
Polartechnics Limited, Sydney, Australia
The TruScreen is a real time device designed as an adjunct to the Pap smear for cervical
screening. The device uses a combination of three biosensors to assess cervical tissue - optical
backscattering, direct reflectance and electrical decay curves. The device incorporates optical
fibre technology and electrodes in a probe-shaped handpiece and is used without application
of acetic acid solution. The 5mm diameter distal tip of the handpiece is covered with a
disposable tissue-contacting sensor element and applied to the cervix. Tissue is illuminated at
four discrete optical wavelengths in the visible and infra-red regions of the spectrum, and low
level electrical pulses are applied. These biosensors provide information about vessels and
other structures beneath the tissue surface.
The detected signal from the handpiece is filtered, sampled and processed by a
microcomputer within a portable console to interpret and classify the tissue response. The
expert system software has been "trained" to recognise various normal and abnormal cervical
tissue types using a previously obtained database of over 1,500 patients collected from a
geographically diverse range of centres. These specific tissue type classifications are grouped
in a manner useful for cervical screening. The TruScreen returns one of two possible final
patient screening results - "normal" (normal squamous epithelium, columnar epithelium,
physiologic metaplasia) or "abnormal" (CIN 1-3, invasive cancer).
Real time feedback in the form of lights on the back of the handpiece guides the operator
through the examination process, which is completed in approximately one minute. When the
examination is complete, the operator presses a button on the handpiece and the device prints
out the final screening result. This automated testing process is expected to minimise inter-test
variability and facilitate training in the use of the device.
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S5-04
TRUSCREEN MULTI-CENTRE CLINICAL TRIAL RESULTS
Singer Albert
The Whittington Hospital, Department of Gynecology, London
Full-scale clinical evaluation of real time technology for screening must directly assess
overall accuracy, and ideally provide some comparative information against cervical
cytology. Previously, early proof-of-principle trials of TruScreen have demonstrated that the
technology is capable of distinguishing CIN from normal tissue types. Recently, a major trial
of the technology as an adjunct to the Pap smear has been conducted in ten centres in the UK
and Australia.
Results will be presented for the 651 subjects entered into the study. Three-quarters of
subjects were recruited as volunteers from the general population, and one quarter were
recruited in the colposcopy clinic environment. All women underwent testing with the
TruScreen device, the Pap smear, and colposcopy. One or more biopsies were taken if any
abnormal areas were identified colposcopically. Independent laboratories, blinded to the
results of the TruScreen and the Pap smear tests, performed the cytology and histology
readings. Cytology readings were performed in a quality-controlled setting. In normal clinical
use the TruScreen immediately prints a screening result. However, a trial version of the
device was designed to output the results in an encrypted form, in order to prevent any
possible verification bias resulting from the colposcopist knowing the screening results during
the diagnostic examination. The accuracy of the screening tests was assessed using
histologically determined CIN lesions as the diagnostic gold standard.
The study results show that the sensitivity of the TruScreen as a stand-alone screening tool is
comparable to that of a quality-controlled Pap smear for CIN 2/3. For CIN 1, the sensitivity of
the TruScreen is higher than that of the Pap smear. When TruScreen and cytology are used
adjunctively for screening, some loss of specificity results from combining the two tests.
However the combined TruScreen/Pap test achieved very high sensitivities (>90%) for high
and low grade CIN.
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S5-05
TRUSCREEN EXPERIENCE IN ITALY
De Palo G.
Istituto Nazionale Tumori, University di Medicina Predittiva-Preventiva, Milan
TruScreen is an automated cervical screening device which utilises electrical and optical
signals to determine the normal or abnormal status of cervical tissue. The handpiece is a
probe-shaped stimulating and sensing device, which is covered by a single use sensor and
applied to the cervix. The device will be used initially as an adjunct to the Pap smear for
screening.
In general terms, the accuracy of screening tests partially depends upon setting-dependent
issues such as the prevalence of disease in the population, the age distribution of the
population, the local infrastructure for cytological evaluation, and training procedures. We
undertook a major trial to determine the performance of TruScreen within the Italian setting.
The aim of the study is to determine the accuracy of TruScreen and the accuracy of the
adjunctive combination of Truscreen and the Pap smear. The study, which commenced in
mid-2002, is being conducted at three centres in Italy - the Istituto Tumori in Milan, Carreggi
Hospital in Florence, and a private gynecological practice in Bologna. Several hundred
women have been recruited for the study.
All women in the study undergo examination with the TruScreen device, followed by
sampling for a Pap smear. Colposcopy is performed using the 1990 IFCPC classification.
Biopsy is performed in cases where major changes are observed colposcopically. Cytological
and histological evaluation is performed by the hospital or local service.
Preliminary results will be presented. The potential role of automated real time screening
methods in the Italian setting will be discussed.
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S5-06
CLINICAL MANAGEMENT IMPLICATIONS
Cox Thomas
University of California, Santa Barbara, Women's Clinic, Santa Barbara
Attempts to improve cervical screening have concentrated on three main areas - these are
improvements to cytology (liquid-based cytology and automated cytology review systems);
molecular techniques including HPV DNA testing and molecular progression markers; and
automated real time screening devices, which incorporate biosensors to directly measure
pathological changes in tissue physiology.
In the developed world, real time technology is likely to be introduced as an adjunct to
cytology. Even in adjunctive mode, the use of such technology has the potential to speed up
the screening process, since a proportion of women will immediately be flagged with an
abnormal screening result by the real time device. The implications for the clinician will be
reviewed and management algorithms that combine real time devices with other technologies
such as HPV DNA testing will also be discussed.
In the developing world, real time technology offers an alternative to Direct Visual Inspection
(DVI). In this setting, it is likely that the use of automated screening technology could reduce
the training requirement as compared to DVI and therefore facilitate adoption.
In both the developed and developing world, cost-effectiveness and reliability of the new
technology is yet to be fully evaluated. However, clinicians should be aware that real time
technology is likely to emerge as a screening alternative in a variety of settings.
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S6-01
PREDICTING CERVICAL LESIONS: COMPARISON OF ISH HPV
AND HC2 HPV
Qureshi N.
Dept. of Pathology, Bayonne Medical Center, Bayonne, and Lakewood Pathology Associates,
Lakewood, NJ, USA
Human Papillomavirus (HPV) is widely accepted to be the primary agent involved in the
development of squamous cell intraepithelial lesions (SIL) and cervical cancer. The recent
American Society of Colposcopy and Cervical Pathology (ASCCP) guidelines strongly
recommend that all women with a positive HPV test should have a repeat Pap test or a
diagnostic procedure to provide cytological or histological confirmation of their disease i.e.,
the presence of a lesion. Studies using the Hybrid Capture 2 (HC2) test have demonstrated
that HPV testing using this assay is more sensitive, although less specific, than Pap smears in
detecting high-grade dysplasia. The use of a diagnostic test, such as HC2 with low specificity,
despite high sensitivity, risks referring women to unnecessary colposcopies and expensive
follow-up diagnostic procedures.
Results will be presented from a study comparing two distinctly different molecular based
testing methodologies: Digene’s HC2 (Gaithersburg, MD) and Ventana Medical System’s in
situ hybridization (ISH) INFORM®HPV analyte specific reagent (Tucson, AZ) for the
detection of HPV DNA. These two testing methods were evaluated for their ability to screen
for histologically proven squamous intraepithelial lesions, both low-grade and high-grade.
The sensitivity, specificity and overall disease predictability of each method was assessed.
Additionally data comparing the ability of the two methods to further triage patients with an
initial cytologic diagnosis of LSIL will be discussed.
The results to be presented document the increased diagnostic utility of ISH HPV over HC2
HPV due to its comparable sensitivity but higher specificity for predicting the presence of
histologically proven disease, setting the acceptable minimum standard higher for techniques
utilized in predicting cervical disease. In view of the results of the study ISH HPV has the
potential to eliminate many unnecessary colposcopic examinations. This would have a
significant impact in reducing adverse medical, social, and psychological consequences for
the patient while diminishing overall global healthcare costs.
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S9-02
SEROPREVALENCE OF HSV-2 AND HSV-1 INFECTIONS IN THE
UNITED STATES AND EUROPE
Smith J.S. (1), Hopkins Johns (2), Robinson N.J. (3)
(1) Epidemiology Department, (2) Bloomberg School of Public Health, Baltimore, Maryland,
(3)GlaxoSmithKline Research and Development, Greenford, United Kingdom
Information on age- and sex-specific prevalence of herpes simplex virus type-2 (HSV-2) and
type-1 (HSV-1) infections is essential to optimize genital herpes control strategies. Based on
a review of peer-reviewed publications of type-specific HSV seroepidemiological surveys
worldwide, HSV-2 prevalence was generally higher in the United States of America and
Northern Europe than in Western and Southern Europe. Trends of higher HSV-2 prevalence
with increasing age were seen in all geographical regions. Age-specific HSV-2 prevalence is
generally higher in women than men, and in populations with higher-risk sexual behavior.
An increase in HSV-2 prevalence was seen in the United States; national data from other
countries are not available. HSV-1 infection is acquired during childhood/adolescence, and is
markedly more widespread than HSV-2.
HSV-2 in the United States of America:
NHANES III estimated HSV-2 seroprevalence in a representative national sample of the US
population over 12 years of age. Overall, HSV-2 prevalence in females and males was 26%
and 18%, respectively, and consistently increased with age from the mid-teens to 35 years.
Other studies in different states showed that HSV-2 prevalence varied, depending on region,
population, age, and sex, and were generally consistent with NHANES III.
HSV-2 in Europe:
Data from general populations are available for many countries, including Denmark, Finland,
France, Germany, Greenland, Italy, Norway, Spain, Sweden, Switzerland, and the United
Kingdom. The highest prevalence of HSV-2 in non high-risk populations was found in
females from Greenland, at 57% among those aged 20–24 years and rising to 74% in those
aged 25–39 years. In Spain, HSV-2 prevalence appears relatively low, ranging from 2% to
6% in different geographical areas. In Scandinavia, HSV-2 prevalence was generally higher
than in other areas in Europe, of the order of 15–35% among women aged 25–34 years. In the
UK, HSV-2 prevalence was consistently lower than in Northern Europe, and the highest
prevalence was reported for females in London (3% in those aged 18-25 and 25% in those
aged 41-45).
HSV-1:
In New Mexico in the United States, HSV-1 prevalence was 59% among children aged 1-5 years and
79% in those aged 6–15 years. In Germany, HSV-1 prevalence was lower among children aged 1–5
years (31%), increasing to 44–49% among those aged 6–16 years. HSV-1 prevalence ranged from 34
to 71% among young American women (aged approximately 18–24 years) and ranged between 46
and 85% in young women (aged 15-25 years) in Finland, Germany, Italy, and Spain. Further studies
are required in many regions, particularly among young adolescents.
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S9-03
HSV VACCINES: PROSPECTS AND CHALLENGES
STANBERRY LAWRENCE
University of Texas Medical Branch - Galveston, Sealy Center for Vaccine Development, Galveston,
USA
The genital herpes epidemic is a global public health problem that has continued to spread
despite the availability of effective antiviral drugs. The only practical strategy for effective
control of the epidemic will be the development and widespread use of safe and effective
vaccines. Two recently completed multicenter trials evaluated the effectiveness of a vaccine
composed of HSV-2 glycoprotein D, alum and monophosphoryl lipid A. The trials were
conducted in 2714 subjects whose regular sexual partners had a history of genital herpes
disease. Subjects received either vaccine or control at months 0, 1, 6 and were evaluated for
19 months to determine the overall rate of development of genital herpes disease. Results of
the trials showed that the vaccine protected HSV seronegative women from genital herpes
disease with a vaccine efficacy of 73% (p = 0.01) in study 1 and 74% (p = 0.02) in study 2 but
afforded no protection to HSV-1 seropositive women or to men.
Mathematical modeling of the results of these trials indicated that widespread use of the
vaccine could impact the epidemic spread of genital herpes in both men and women. A third
phase III trial of the vaccine sponsored by the US National Institutes of Health begin in late
2002 and will further investigate the effectiveness of the vaccine in protecting HSV
seronegative women against genital herpes.
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S9-04
THE EPIDEMIOLOGICAL DETERMINANTS OF THE IMPACT OF A
GENITAL HERPES VACCINE: MATHEMATICAL MODEL RESULTS
BASED ON THE OBSERVED EFFICACY OF A GENITAL HERPES
VACCINE
Garnett GP, Williams JR
Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London, UK
Background In trials a candidate HSV-2 vaccine significantly reduced the risk of genital
herpes disease (efficacy 73%) and indicated a trend to reduced infection (efficacy 42%).
However, the vaccine was only effective in HSV-1 and 2 negative women.
Methods: A mathematical model of the transmission dynamics of HSV-2 was developed to
explore the epidemiological impact of a partially effective HSV-2 vaccine or antiviral
treatment. The model has been further developed to explore the pattern of HSV-2 infection by
age, the impact of vaccination schedules and the incidence on neonatal herpes. The model
uses the numerical solution of ordinary and partial differential equations to explore a number
of different scenarios.
Results: HSV-2 has a moderately potential for spread amongst a large fraction of the
population and under such conditions a vaccine, even one with low efficacy, can have a
significant impact if it reduces asymptomatic shedding of the virus. Control of infection in
one sex can have a dramatic influence on the incidence in the other. The vaccine or
suppressive therapy needs to be widely used to have a major impact. The background
prevalence of HSV-1 in the vaccinated population is critical to the impact of the vaccine. If
the vaccine can increase the mean age of infection through a reduced force of infection it
delays incident herpes infections to ages where fertility is lower and hence has a
disproportionate impact on neonatal herpes, which is a serous, often fatal consequence of
genital herpes.
Conclusions: A prophylactic genital herpes vaccine which is restricted to HSV-1 and 2
negative women could still prove a useful tool in the control of HSV-2.
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S10-02
CURRENT UNDERSTANDINGS OF THE IMMUNE RESPONSE TO
HPV INFECTION OF THE VAGINA AND CERVIX
Cox JT
University of California, Santa Barbara, California, USA
Ultimately, it is primarily the success of the host immune response that determines whether
disease persists or regresses, the extent and severity of the lesions, and the success of therapy.
Since HPV-induced preinvasive disease does not penetrate below the basement membrane,
the primary immunological exposure is to the epithelial host defense mechanisms, which
HPV is quite proficient in evading. Epithelial cells are not good antigen-presenting cells, so as
long as the cell remains intact, HPV remains unrecognized within. Since HPV does not lyse
or otherwise kill the host cell, the virus may remain sequestered from the monocytes,
dendritic cells and macrophages that initiate immune recognition. Delay in recognition of the
presence of HPV is responsible for the recalcitrant nature of HPV-induced lesions for many.
When an immune response occurs, it is cellular immunity that plays the primary role.
Macrophages and monocytes release cytokines such as interferon alpha, beta and gamma, and
various interleukins in response recognition of the presence of HPV. Interferon limits
production of HPV and has anti-proliferative activity that slows growth of HPV infected cells.
Cytokines also act as chemoattractants, promoting the accumulation of increasing numbers of
monocytes, macrophages, and dendritic cells. Activated dendritic cells more readily identify
HPV antigens within infected cells and present these antigens on their cell surface. Activated
dendritic cells migrate through draining lymphatic channels to the regional lymph nodes
where they present the HPV antigen to undifferentiated T-lymphocytes. Once this antigen
presentation has occurred, the now HPV-specific cytotoxic T-cells (CD8) multiply and return
via the blood stream to the site of the HPV infection. The HPV specific T-cells and natural
killer cells kill HPV infected cells. Monocytes and macrophages phagocytose the cell debris
including the HPV DNA. The combined effects of these actions result in reduction of HPV
lesional size and eventual clearance. These events remain the same whether the HPV lesions
are due to low- or high-risk HPV and whether external or in the vagina, on the cervix or in the
anus.
The family of immune response modifiers circumvents the requirement that HPV be
identified before an immune response is initiated. In this way the variability in immune
recognition is circumvented. Trials of an immune response modifier in the treatement of
cervical and vaginal HPV-induced lesions are now underway. Discussion of the mechanism
of action of IRMS and of potential algorithms in the use of IRMs in the treatment of vaginal
and cervical HPV infections and lesions will be discussed.
HPV specific T-cells provide immune memory and prevent wart recurrence.
The effectiveness of the local cellular immune response can be measured by several
parameters. Rising and falling viral levels probably mirror the effectiveness of the host
cellular immune response. When CIN persists, dendritic cells are decreased and HPV type
appears to influence the threshold for dendritic suppression. The activity of natural killer cells
(NKCs) also appears to be related to HPV type. Decreased production of interferon gamma
and interleukin-2 by NKCs has been detected in persistent condylomata.
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This process will occur spontaneously in as many as 20 to 34% of infected individuals,
marking the end of any clinically apparent episodes. In another 60% of patients, localized
destruction of condylomas stimulates this process, leading to a lasting clinical remission.
However, in the approximately 20%, HPV induced lesions do not result in an immune
response and prove refractory to standard office treatments. Immunomodulatory agents, such
as imiquimod or interferon may help stimulate an immune response in these individuals, and
carbon dioxide laser may be necessary to reduce lesion volume.
After an average of about 9 months, patients diverge into two groups: those who remain in
sustained clinical remission and those who continue to have active disease expression. Not
completely clear is whether latent HPV is eliminated in all, or at least, most individuals in
sustained clinical remission or whether latent HPV infection may persist within the anogenital
epithelium for an indeterminate period of time. The expression of HPV disease in a
significant percentage of immunosuppressed transplant patients would argue for long-term
viral persistence in at least some individuals, but supporting molecular biologic data remains
incomplete. If HPV returns to a latent state, it may once again be found only in the basal cells
in extremely low copy number. Since the late genes (L1 and L2) required for forming
infectious viral particles are not actively transcribed in the basal epithelium, latent HPV is not
contagious.
HPV induced oncogenesis requires long-term viral persistence. Hence, the subset that is at
risk for neoplastic progression is the 10-20% of patients who either remain in active disease
expression, or who "recur" after a lesion-free interval. Presumably, most people in this subset
have a reduced immunocompetence to HPV of unknown etiology. When immunity to HPV
does occur, it appears to be type specific.
Imiquimod has no direct antiviral activity, however pre-clinical studies have shown that
topical application up-regulates production of the T- cell cytokines TNFα and IFNα locally at
the application site (Stanley, 1999). Studies in GW patients show that imiquimod treatment
also stimulates a significant increase in mRNA for CD4+ T cells within wart tissue (Arany,
1999). This suggests activation of a cell mediated immune response similar to that recorded in
spontaneously regressing warts, which is characterized by a predominance of CD4+ T cells
within the wart stroma and surface epithelium (Coleman, 1994). Imiquimod treatment has
also been shown to reduce HPV viral load by over 90% which may help prevent recurrence of
lesions (Arany, 1999). Treatment may also lead to the development of an immunologic
memory of HPV that would prevent recurrence, however further studies are needed to
investigate the mode of action of long term protection through treatment with imiquimod.
A preliminary study in four patients with external GW and vaginal and /or cervical
condyloma shows that imiquimod 5% cream may alter the progression of lesions distant to
those treated (Iliya, Eurogin 2000 Abs). Three patients who had ≥95% clearance of treated
external warts also had ≥95% clearance of warts at other locations, suggesting that treatment
may trigger a systemic response to HPV infection. Further studies are needed to investigate
the immunological mechanism of this response to imiquimod treatment.
Imiquimod for the treatment of other HPV related conditions
Because of imiquimod’s mode of action it may be useful for the treatment of other cutaneous
viral infections. Several case studies on imiquimod treatment for viral vulvar intraepithelial
neoplasia (VIN) caused by infection with HPV 16 suggest that imiquimod may be an effective
alternative to current treatments for this indication (Figure 2) (Davis, 2000). VIN lesions are
often multifocal, multicentric and often present in women treated for CIN. Clinical symptoms
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include severe itching and development of fistulas that can make intercourse painful.
Progression of the disease may lead to the development of vulvar cancer. Partial vulvectomy
and CO2 laser ablation commonly used for the treatment of VIN often do not prevent disease
recurrence, which can occur in up to 57% of cases (Kaufman, 1995). These treatments also
require the use of general anaesthesia, and healing may be painful and slow.
A pilot study by Davis et al (2000) investigated the efficacy of treatment with imiquimod in 4
patients diagnosed with viral VIN III; 3 with recurrent disease and 1 with a new infection.
Self-application of imiquimod 5% cream 3 days per week for up to 16 weeks cleared lesions
in all 4 patients. Recurrence one month after clearance in one patient was resolved by
repeating the treatment protocol for another month. A year after treatment 3 patients remained
disease free at the application sites. Some physicians have also successfully used imiquimod
in combination with laser therapy for the treatment of VIN (personal communication, Dr.
Rylander), however recurrence rates after treatment have not yet been determined. Clearly
further research is needed to assess clearance and long term recurrence rates associated with
imiquimod for the treatment of this disease.
Another viral infection successfully treated with imiquimod is molluscum contagiosum (MC).
MC is caused by a pox-virus that is transmitted by skin to skin contact, and is characterised by
small firm papules approximately 1mm to 5mm [1 cm would have to be as rare as hens teeth!]
1cm wide (Valentine, 2000). The virus infects squamous epithelia and can therefore be
present at any site on the body. Infection in children and sexually active adults can be selflimiting over a period of several years, however the disease is a major problem in
immunosuppressed patients. In a study by Hengge et al (2000) imiquimod cleared lesions in
53% (8/15) of patients who had been refractory to previous treatments. Approximately 80%
(12/15) had a reduction of >50% in lesion size, and there was no difference in response
between HIV positive and immunocompetent patients. A preliminary study on the treatment
of MC in children with imiquimod suggests that it is also safe for this patient group (Barba,
2001); treatment every night for 4 weeks did not cause systemic side effects, and temperature
and white blood cell counts remained normal throughout treatment. Imiquimod is therefore a
promising treatment for MC (Figure 3), particularly for patients with persistent or
disseminated disease.
Conclusions
Imiquimod 5% cream is an effective patient applied therapy for GW with low recurrence rates
and good cosmetic outcome, particularly in women. Female patients with recurrent disease
believed imiquimod was better than other treatments they had received, including
cryotherapy, laser therapy and podophyllotoxin. Imiquimod is recommended for the treatment
of GW in the USA, Latin America and in Europe, and recent studies have shown that it may
be an effective treatment option for VIN and MC, also caused by cutaneous viral infections.
Further studies are needed to evaluate the efficacy and safety of imiquimod treatment for
these conditions.
EUROGIN 2003
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S11-01
LIQUID-BASED CYTOLOGY: OPTIMIZING SAMPLING PROCESS
Bigras Gilbert
Laboratoire Cytopath, Carouge
Evaluate the cellular material loss when discarding the collecting device in liquid-based
cytology. Loss was computed from a pair of sub-samples obtained from the same clinical
sampling. The collecting device was rinsed in one vial and discarded in an other one.
Endocervical component was also assessed between sub-samples. Material loss was analyzed
according to the intensity of the rinsing process.
Globally more than the third of cellular material is lost when collecting device is discarded.
The intensity of the rinsing process reduces the loss, but the magnitude of the cellular transfer
is poorly predictable. Furthermore endocervical elements are frequently kept on the collecting
device and discarded with it.
EUROGIN 2003
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S11-02
THE TRIPATH FOCALPOINT IMAGING SYSTEM
Wilbur David
Massachusetts General Hospital, Pathology, Boston, USA
The FocalPoint System (FPS) for primary screening of cervical cytology specimens is
currently utilized in several formats. In the United States (US), the FPS is approved as a
primary screening device for the triage of slides into two broad populations. The "no further
review" population of slides may be archived and reported as "negative" with no manual
screen. The "review" population consists of slides at greater risk of containing abnormal cells
and must be manually screened. Quality control rescreening is then performed on the highest
scoring slides called "negative" on manual review. Data from the use of this system shows it
to be more accurate and efficient than the routine manual screening process. In countries
outside the US, the FPS can be used with an additional cell localization feature (location
guided screening (LGS)) which allows for review of device selected fields of view only in the
"review" population as the method of slide triage to full, or no manual screening. Use of the
LGS system has the potential to further increase productivity and accuracy of the cervical
screening process. Data supporting the use of each application noted above will be presented
in the body of the presentation.
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S11-03
PERFORMANCE OF THE LOCATION-GUIDED SCREENING FOR
CERVICAL CANCER
Pierre Vassilakos, Patrick Petignat, Stefan Spoerri, David Stucki
Institute of Pathology, Geneva and Canton Hospital, Fribourg, Switzerland
OBJECTIVE: To study the performance of the location-guided screening of thin-layer
liquid-based cervical samples.
STUDY DESIGN: 3647 liquid-based Surepath (Tripath) samples were evaluated. All slides
were initially processed according to the routine manual screening using the FocalPoint
assisted practice. The slides were then blindly submitted for an automated location-guided
screening using the Slide Wizard, a station interfaced with the FocalPoint system. The final
cytologic diagnoses of each screening procedure was independently made and then compared
for agreement. The order of the field of view selected by the system and the first observed
atypical cell was related. The mean screening time was also evaluated.
RESULTS: The diagnoses of 3647 slides were compared. The agreement for WNL was
99,4%, for ASCUS 92,9% for LSIL 95,7% for HSIL 94,1% and for SC carcinoma 100%. The
manual screening missed 16 ASCUS cases and 4 LSIL while the location-guided screening
missed 5 ASCUS and 3 LSIL. For 99% of the ASCUS+ cases the first observed atypical cell
was included in the first six fields of view selected by the system. For 100% of the HSIL+ the
first atypical cell was observed in the 1st and 2nd field of view. The mean screening time
(including review and non further review slides) was 1,7 min/slide for the manual screening
and 1,1 min/slide for the location-guided screening.
CONCLUSION: The diagnostic performance of the location-guided screening is comparable
to the manual screening. The system triage slides accurately for a full manual review. The
combination of the location-guided screening and the possibility of archiving slides without
further manual screening could improve the workload of the laboratory.
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S11-04
IMPLEMANTATION OF LOCATED GUIDED SCREENING IN A
EUROPEAN LABORATORY
Neumann Heinrich
Institut fuer Pathologie Nordhorn
Aims:
a) to share our experience during installation of TriPath’s Slide Profiler and Guided screening
System into the laboratory and the screening routine
b) to present preliminary results of a study comparing our standard practice of manually
screening PrepStain thin layer slides to location guided screening (LGS) of the same slides.
Methods:
a) Reference to the Focalpoint report summaries is done to estimate the instrument’s
performance in respect of rejection of slides and workload. The history of our present use of
the instrument is highlighted. b) we set up a study comprising 5.000 PrepStain Thin Layer
slides. These are screened manually and reported in the normal way. Then they are processed
by the FocalPoint instrument. Finally they are reviewed at a microscope with SlideWizard
workstation using the LGS- software.
Results:
a) optimal performance of the screener requires optimised processes during preparing of
slides. We needed to modify our coverslipping and did some fine tuning to the PrepStain. Of
11.619 slides during June to August 2002 the FocalPoint classified 72 (0,6%) rerun, 298
(2,6%) process review, 2.749 (24,4% of qualified , 23,7% of total) no further review (nfr). For
these slides average processing time per slide was 327 sec. With a replacement instrument, of
12.384 slides from end of November 2002 to February 2003 64 (0,5%) slides were classified
rerun, 342 (2,8%) process review and 2.636 nfr (22,0% resp. 21,3%). For 11.256 of these
slides average processing time per slide was 368,9 sec. This is equivalent to processing 234
slides per day (i.e. 24 h) or 1638 slides per week (7 days). Cytotechnicians’ productivity
increases when working with the LGS. The finding and classification of endocervical cells is
not yet perfect.
b) preliminary data will be presented. The evaluation of cases, especially the verification of
diagnoses by external cytopathologists has not yet been finished.
Conclusions:
a) In our institute FocalPoint Slide Profiler’s productivity with PrepStain slides exceeds the
expectations. Both the slide profiler and the Location guided screening could be intergrated
into the daily routines.
b) the results of the study need to be awaited.
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S11-05
IMMUNE CHANGES AND CYTOKINE PROFILE INDUCTIONS
RELATED TO HPV INFECTION AND CLEARANCE
Gostout B, Barton D, McGovern R, Loprinzi C
Mayo Clinic, Rochester MN, USA
Purpose: Clinical outcomes following exposure to HPV range from complete eradication of
asymptomatic infection to progression to invasive cancer. In a randomized controlled trial we
are attempting to augment cytotoxic response to HPV infection through topical application of
imiquimod to the uterine cervix in women with dysplasia. Herein, we report the cytokine
responses from the first women treated with imiquimod in this trial.
Methods: Eligible women have biopsy confirmed CIN II or III or persistent biopsy confirmed
CIN I. Participants were randomized to either no pre-treatment or to five applications of
imiquimod to the cervix prior to undergoing standard therapy. Swabs of cervicovaginal fluid
were obtained before and after each application of imiquimod. Interferon gamma (IFN γ),
Tumor Necrosis Factor alpha (TNFα), and Interleukin 4 (IL4) levels were evaluated using
ELISA. Cytokine levels, standardized to total protein content, are reported as fold increase
from baseline values.
Results: Fifty women have been entered on the trial to date. Cytokine levels are have been
analyzed for 11 imiquimod treated women. Compared to baseline cytokine levels, 9 of 11
women demonstrate peak IFN γ levels at least 2 times above baseline levels during imiquimod
treatment. The maximum response ranged from 1.1 to more than 600 times the baseline IFN
γ level with a mean increase of 106 fold. Ten of 11 women responded with TNFβ levels at
least two times their baseline. The mean TNF increase was 116 fold over baseline. Ten of 11
women respond with at least doubling of intravaginal IL4 levels, however baseline and post
treatment IL4 levels are overall considerably lower than IFN γ and TNF β levels. One subject
had a decrease in IL4. The increase in IL4 ranges from 1.1 to 339 fold in the 10 subjects
showing an increase, with a mean increase of 40 fold.
Conclusions: Intravaginal application of imiquimod, as used in this randomized clinical trial,
results in significant cytokine activation. IFN γ and TNF β activation are the dominant
responses, favoring a desirable cytotoxic T cell response. Analysis of cytokiines from
additional subjects and data regarding HPV eradication versus persistence is underway.
EUROGIN 2003
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P001
THE EVOLUTION OF THE INFECTION BY HUMAN
PAPILLOMAVIRUS (HPV) IN WOMEN OF PARAKANÃ TRIBE PARA -AMAZONIA –BRAZIL
Brito EB; Silva IDCG; Stávale JN; Villa LL; Taromaru E; Martins JS; Menezes RC
Universidade Federal do Para, Nucleo de Medicina Tropical
The women` s accompaniment in the villages of Parakana tribe in the North of Para since
1991 to investigate STD and to accomplishing Pap test, the infection for HPV was found.
The present work review the discoveries about techniques of molecular biology by
Polymerase Chain Reaction (PCR), Hybrid Capture II (HC II) and Papanicolaou Test (Pap
test) in the years of 1993 and 2001.
In 1993 among 49 collected samples , 42 were analyzed by PCR, 6 of these were probed for
HPV infection, 3 showed HPV 16, one of these associated with HPV 58, HPV 53 (1) and
without subtypes (2). In 2001, 49 women were appraised by Pap test, PCR and HC II for
HPV. The PCR showed 12 (22,4%) positive cases with the subtypes of HPV: 16 (1) , 18 (2),
58 (3) , 39 (1), 61 (1), 33 (1). 35 (1), without subtypes (2). Among the 49 cervical specimens
for analysis of HPV DNA low and high risk groups, 48 were analyzed, where 19 (39,58% )
were positive for the high risk group and 4 (8,33%) for the low risk group. Nine cases of
negative PCR showed positive HC II, which viral load varied between 1,18 to 17,32 and 2
positive cases by PCR ( one non identifie and one HPV 18) presented negative HC II and the
Pap test showed abnormalities. About age, the limits were 14 and 81 years old, with the
largest viral load observed of RLU/PCB = 1588,11. In a 15-year-old patient, HPV 39 and Pap
test CIN I and one of 81 year old patient presented HPV 58, viral load RLU/PCB= 7,62 and
RLU/PCA=1,25 and Pap test ASCUS. The molecular biology showed positivity in 21 samples
among the 49 studied and the pap test of these positive ones correponded at 15 abnormal
smears and 6 inflamatory, only 3 suggested smaller alterations of viral citopatic effect.
The women of Parakana tribe evaluated in the two periods showed that was increase of the
incidence of the HPV infection of 14,3% to 42,85% by the methods of molecular biology and
the last pap test among 21 smeats posityve by the molecular biology technique only 3 cases
indicated HPV infection by pap test.
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P002
A NOVEL FUNCTION OF HPV16 E6 ONCOPROTEIN: INCREASE OF
CELL ADHESION
Epshtein,A., Gonen, P. and Sherman, L
Department of Human Microbiology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Infection of the anogenital mucosa with HPV type 16 referred to as "high risk" or "oncogenic"
is a major factor for the subsequent development of cancer. Previous studies showed that
expression of the E6 oncoprotein of HPV16 in human foreskin keratinocytes, that were
induced to differentiate by serum and calcium, led to a significant reduction in cell
stratification and cell death by apoptosis. The reduction of apoptosis could result from E6
ability to alter matrix association. In the present study we investigated the effect of E6 on cell
adhesion. Adhesion ability was tested by seeding cells on tissue culture dishes coated with
increasing concentrations of poly(HEME) and determination of the proportion of viable cells
attached to the substratum. Assays were carried out with primary human foreskin
keratinocytes (HFKs), immortalized human keratinocytes (HaCaT) and human 293T cells.
The E6 gene was transduced via retroviral infection or DNA transfection. Results of these
assays indicated that expression of E6 increased the proportion of cells that attached to
poly(HEME). This was observed in the virally infected HFKs and HaCaT cells, and in the
transiently transfected 293T cells. Several HPV16 E6 mutants were also tested in the above
assay. E6 truncation mutants M141 and M132, as well as the point mutation mutant G136,
were active in this assay, indicating that the C-terminal region of E6 spanning residues 132151 is dispensable for this activity. Mutant d118-122 that lacks five amino acids within the E6
second putative Zn-finger failed to increase cell adhesion. Mutant M132 and d118-132 were
previously shown to act oppositely in p53 degradation. These data argue that E6 function in
cell adhesion is independent of p53 degradation.
EUROGIN 2003
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P003
P53 CODON-72 POLYMORPHISM AND RISK OF CERVICAL
CANCER: NO EVIDENCE OF ASSOCIATION
Torres A (2), Arias MD (1), Pavcovich M (1), De Lera JM (1), Sánchez MA (1), León L (1), FalcónSantana JM (2), Morín, JC (2), Lubrano A (2), Falcón-Vizcaino O (2), Salido E (4), Barrios Y (4),
Andújar M (1,3)
(1) Department of Pathology, (2) Obstetrics and Gynecology, (3) Molecular Pathology Laboratory.
Research Unit. Hospital Universitario Materno Infantil de Canarias. Las Palmas de Gran Canaria. (4)
Molecular Biology Laboratory. Research Unit. Hospital Universitario de Canarias. Tenerife. Spain.
Introduction: High-risk types HPV (HPV16 and HPV18) are implicated in the
carcinogenesis process of cervical cancer. E6, an HPV-oncoprotein, play a crucial rool in this
process binding to tumor suppressor protein p53 and inducing its degradation through the
ubiquitin pathway. Storey et al reported in 1998 the association between a precise
polymorphism at codon 72 of p53 resulting in translation to Arg or Pro. Women homozygous
for the Arg allele were seven time more susceptible to cervical cancer than Arg/Pro
heterozygous women. Several studies have failed to confirm this original description with few
exceptions. To test this controversial association, we have performed a retrospective study in
our hospital.
Material and Methods: A total of 122 subjects with primary cervical carcinoma and
followed at Hospital Universitario Materno Infantil de Canarias and 122 healthy women from
Screening Research Program of Cervical Cancer at Las Palmas de Gran Canaria, were
included in the study. All cancer specimens were positive for HPV16, and control subject
were negative at Pap examination and PCR test. DNA was obtained from blood samples in
the cases and from fresh cervical samples in control subjects. The molecular analyse of codon
72-p53 polymorphism was done by digestion of a 280-bp product from PCR, with BstUI,
which cleaves CG/CGX ;2 analysis was used to examine differences in the proportions.
Results: The distribution of alleles is very similar to previous studies in cacausian population.
In all patients studied the prevalence was: 54,1% Arg/Arg, 37,7% Arg/Pro and 8,2% Pro/Pro.
In case group the distribution was: 55,5% Arg/Arg, 34,4% Arg/Pro and 9,8% Pro/Pro. In
control group was: 52,5% Arg/Arg, 41,0% Arg/Pro and 6,6% Pro/Pro. There was no
significant differences between groups (P=0,446). Comparing homozygotic groups there was
no significant differences too (P=0,479) with OR=0,708 (95% CI=0,272-1,845).
Conclusion: We have found no evidence of association between Arg/Arg genotype of p53 at
exon 72 and cervical cancer in this group of patients.
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P004
MOLECULAR DIAGNOSIS OF HPV INFECTION IN SCREENING
RESEARCH PROGRAM IN GRAN CANARIA, SPAIN.
PRELIMINARIES RESULTS
Torres A (2), Arias MD (1), Pavcovich M (1), De Lera JM (1), Sánchez MA (1), León L (1),
Hernández T (1), Vega B (2), Flacón-Santana JM (2), Morin JC (2), Lubrano A (2), FalcónVizcaino O (2), García JA (2), Galván L (2), Blanco-Soler, JC (2), Salido E (4), Barrios Y (4),
Doreste J (5), Andújar M (1,3).
(1) Department of Pathology, (2) Obstetrics and Gynecology, and Molecular Pathology, (3) Laboratory.
Research Unit,. Hospital Universitario Materno Infantil de Canarias. Las Palmas de Gran Canaria. (4)
Molecular Biology Laboratory. Research Unit. Hospital Universitario de Canarias. Tenerife.
(5).University of Las Palmas de Gran Canaria Spain.
Introduction. Although Pap test is very useful tool in cervical screening, it has some
limitations and other techniques are being searching to improve diagnostic results. Molecular
detection of high-risk type of HPV is one of the most promising test to add to Pap test. Many
prevalence population studies have been performed and some consensus and guideline
recommend this type of studies. Knowing population variables would be possible to adapt old
screening programs and new vaccine programs in our communities.
Objective. The objective of this study is to determine the prevalence of HPV infection in
women between 18 to 65 years, in Gran Canaria, Spain.
Patients, material and methods. Women were recruited by random selection from official
heath base data, in a proportional manner according general population and health basic areas
of the island. Nine age group was obtained dividing in intervals of five years, except the first
group between 18 to 24 age. The population was invited to participate by mail and telephone
call. After consent was obtained a standardised questionnaire was used to collect clinical
information and samples (for PAP and PCR) were taken. PCR employed consensus primers
My09/11, primers for b-globin to test quality of DNA, and specific primers to typing HPV16
and HPV18. Statistical analysis was made using SPSS 10.0 software. Here we report the first
372 women of 2272 that constitute the total sample.
Results. These 372 women represent 16,37% of the total study population. The lowest
percentage of participant was found in the first age group (18-24), and the highest percentage
in 30-34 years. Cytological positives to HPV were 4,8%. Molecular positives were found in
5,91%. In both test the highest percentage was found in 25-29 years group (p <0,001). All
positive HPV samples were HPV16 and no high-grade cytological features were found.
Conclusions. The percentage of HPV positive cervical samples from this population study is
very similar to other european screening studies, at least in its preliminary data. The most
prevalent type of HPV, HPV16, is confirmed in the present results.
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P005
P16INK4A OVEREXPRESSION ON PREMALIGNANT AND ORAL
SQUAMOUS CELL CARCINOMAS INFECTED WITH HUMAN
PAPILLOMAVIRUS INFECTION.
Fregonezi, P.A.G. a; Teresa, D.B. a; Duarte, R.A. a; Neto, C.B.b; Oliveira, M.R.B. b; Soares, C.P.
a.
a Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo State
(UNESP), Brazil. b Department of Physiology and Pathology, School of Dentistry, University of São
Paulo State (UNESP), Brazil
HPV is thought to promote the oncogenic process and the correlation between viral
oncoproteins and dysfunction of p16INK4A tumor suppressor protein in oral lesions is
controversial. To test the hypothesis that anogenital HPV types participate in disruption of
regulation of suppressor of p16INK4A protein in oral lesions, we analyzed forty oral biopsies
for the presence of HPV 6/11 and 16/18, by in situ hybridization (ISH), and for p16INK4A
expression by immunohistochemistry. Fourteen (35%) of the 40 oral lesions were positive for
HPV and 38 (65%) were HPV-negative. HPV 6 11 DNA was found in 4 (10%) and HPV
16/18 in 10 (25%) out of 40 biopsies. Nine of the 14 HPV-positive oral lesions (64%),
assessed by CSA-ISH, gave high intensity p 16INK4A immunostaining. They comprised 1
(11%) OSP positive for HPV 6/11, 1 (11%) OPL HPV 6/11-positive and 1 (11%) OSCC HPV
6/11-positive. These results showed a strong association between overexpression of p16
protein and malignant oral lesions, mainly those infected by HPV 16/18 (P=5.320 E-04;
p<0.05). We can conclude that high-risk HPV types are associated with p16 overexpression
which may be related to viral integration and dysfunction of this tumor suppressor protein.
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P006
CORRELATION BETWEEN CYTOLOGICAL FINDINGS AND HPV
DETECTION ON THIN LAYER SMEARS
B. Samama*, Ch. Schaeffer*, V. Lindner**, N. Boehm*
* Institut d’Histologie- Faculté de Médecine - Strasbourg - France
** Institut de Pathologie - Faculté de Médecine - Strasbourg – France
Liquid based cervical cytology allows performance of both the Pap test and HPV detection on
the same sample. In a preliminary study we showed that In Situ Hybridization (ISH) with
catalysed reporter deposition (CARD) can be applied on thin layer smears for HPV detection.
We report here our results on 451 cervical samples processed by ISH with CARD using
commercial HPV DNA probes (HPV 6, 11, 16, 18, 31, 33, 51) after cytological examination.
73 smears were also processed by Hybrid Capture II test (HC II). Human carcinoma cell lines
(SiHa, HeLa, CaSki) were processed in the same way as cervical smears and served as
controls. HPV positivity in the different groups of the Bethesda system was as follows:
normal and benign cellular changes (31/193 16%), ASCUS (77/138 56%), LSIL (89/93 96%),
HSIL (26/26 100%), carcinoma (1/1 100%). High risk HPV types were mainly present alone
or associated with low risk HPV whatever cytological findings. A good correlation between
ISH and HC II was observed. Moreover ISH provides data on the physical state of the virus,
since episomal (diffuse signal) and integrated (punctate signal) can be distinguished. In our
study the carcinoma Pap smear showed only the integrated form of the virus. Half of the
HSILs also showed the same integration pattern. The association of both episomal and
integrated form of the virus was observed in some ASCUS Pap smears. We showed that this
ISH technique can also been applied on urinary smears. In conclusion, ISH with CARD is a
reliable technique. Combination of both cytological findings and HPV detection by ISH
improves screening of cervical cancer. Automatisation of the ISH technique would be helpfull
since handling remains time consuming.
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P007
EFFECTS OF AMINOGUANIDINE AND L-ARGININE ON
ENDOTOXIN-INDUCED PULMONARY INJURY IN RATS
Zhang Jianxin , Li Liping , Li Lanfang , Li Guofeng , et al .
Hebei Academy of Medical Sciences , Shijiazhuang , Hebei 050021 , P.R.China
To observe the role of nitric oxide and the effects of nitric oxide donor L-arginine and
inducible nitric oxide synthase inhibitor aminoguanidine on acute endotoxin-induced
pulmonary injury in rats . The model of endotoxin-induced pulmonary injury were established
by intravenous injection of lipopolysaccharide (LPS) in rats . The right common carotid artery
of rat was isolated and cannulated with a catheter and connected with a pressure transducer .
Mean arterial pressure (MAP) was measured and recorded in PowerLab/AD instruments .
Three hours later , rats received intraperitoneal injections of aminoguanidine (100mg/kg,n=9)
, L-arginine (500mg/kg , n=9) , aminoguanidine and L-arginine (300mg/kg , n=9) , or vehicle
(n=9) . Drugs were administered for 3 consecutive hours . Contents of Nitric oxide (NO) and
MDA , activity of nitric oxide synthase (NOS) and superoxide dismutase (SOD) in the injury
pulmonary tissue were determined . LPS-induced pulmonary injury led to the reduction of
MAP , the enhancement of NOS activity , the increase of MDA and NO content and water
content in pulmonary , the decrease of SOD activity . Administration of aminoguanidine and
L-arginine alone enhanced the MAP significantly , reduced the content of NO , MDA and
water markedly , inhibited the activity of NOS remarkably , raised the activity of SOD in the
injury pulmonary tissue respectively (P<0.01 versus vehicle , ANOVA and Tukey’s test) .
Administration of aminiguanidine and L-arginine alone decreased significantly the pulmonary
edema , the atrophy of pulmonary alveolus ,the proliferation of blood capillary , the
infiltration of pulmonary interstitial cellulars respectively . Administration of aminoguanidine
plus L-arginine did not influence all symptoms after induction of LPS . It may be concluded
that the aminoguanidine and L-arginine have beneficial therary on the pulmonary injury
induced by LPS in acute stage .
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P008
DEVELOPMENT OF ORGAN TRANSPLANTATION AND THE
PROBLEM OF URGENT SOLVING
Cao Xuanlin
Hebei Medical information institute , Shijiazhuang , Hebei , P.R.China
1, The development of organ transplantation in the world
The origin of organ transplantation in the world begins in 18th century . The tissue and organ
transplantation was limited in animal experiment . In 1936 , Russia scientist practice kidney
transplantation in uremia patient . In 1954 , kidney transplantation between identical twin
brother obtain long-term survival . In 1959 , America and France scientists practice kidney
transplantation also, the kidney get long-term survival because the recipient accept general
irradiation . In 1962 , the kidney transplantation had been done in America , they obtain longterm survival because immunosuppression medicine have been used at the same time . In 60’
last century , the same race organ transplantation is developed in succession , including liver,
lung, spleen, pancreas, heart, intestine and so on . In 1978, the effect of transplantation is
more succeeding , because of new immunosuppression medicine (ciclosproin) developed . In
1912-1996 , transplantation have made a great progress .
2, Organ transplantation in our country have situated at the world advanced level
In our country , organ transplantation have strided to the rank of world advanced level .
According to the statistics of our country , we have done kidney transplantation 80 examples,
liver transplantation 54 examples , thyroid transplantation 25 examples , heart transplantation
3 examples , lung transplantation 2 examples , bone marrow transplantation 3 examples . To
the end of 2000 year kidney transplantation have reached 35000 examples . The one year
survival rate of kidney transplantation reach to 80%. The longest survival time reach to 23
years. Now the amount of organ transplantation in our country have residented to the second
position of the world . The variety of operation and the ratio of succeeding have reached to
the international advanced level .
3, The problem of organ transplantation
3.1, Organ donor insufficient seriously .
Almost 1000000 patients wait for organ donor , only 1% can obtain normal operation . The
increasing uremia patient every year is 120000 , patient is waiting for donate kidney at least
for one year , they have to spend a lot of money for dialysis . A great number of patient’s
health is seriously affected , the life guality is descending seriously .
3.2, Organ transplantation is waiting urgently for law of brain death
Heart beat stop is death standard in our country . According to this standard , the donate organ
is not so good in guality , and even can not used in clinical . The brain death standard have
been used in many foreign country now . In another word , brain function including brain
stem function which have ceased irreversibly can be concluded death . The donate organ of
brain death have good guality , using this kind of donate organ the result of transplantation is
better .
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The brain death standard is not only remising the insufficient of donate organ and avoid great
waste of economy caused by nonsense rescue , but also a great advance in self-value, life
significance and dignity concept .
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P009
IMMUNOLOGICAL RESPONSE IN SQUAMOUS INTRAEPITHELIAL
LESIONS (SIL) IN THE PRESENCE AND IN THE ABSENCE OF HIV
INFECTION.
Gonçalves, M.A.G. (1), Soares, E.G. (2), Pienna, C.S. (3), Donadi, E.A (1)
1.Division of Clinical Immunology, 2.Department of Pathology,University of São Paulo, Ribeirão Preto,
São Paulo, Brazil.3.Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, University of
São Paulo State, Araraquara, São Paulo, Brazil.
Background: Squamous intraepithelial lesions (SIL) are more frequently observed in Human
Immunodeficiency Virus (HIV)-positive than in HIV-negative women. Increased serum level
of interleukin-2 receptor (IL-2R), a known marker for immune activation, has been associated
with an increased frequency of cervical neoplasia The aim of this study was to analyze the
cellular immune response in SIL biopsies of HIV+ and HIV- patients.
Methods: Biopsies from 35 HIV+ and 47 HIV- patients with normal cervix or low- or highgrade SIL were studied. The expression of CD4, CD8, IL-2R (CD25) and CD28 were
evaluated by immunohistochemistry. HPV detection was performed using polymerase chain
reaction. Mann-Whitney test, unpaired t test and Fisher´s exact test (p £ 0.05) were used for
statistical analysis.
Results: Particularly in the stroma of patients with HPV18 infection, CD4 activation showed
to be significantly increased when compared with the slides without HPV 18 (P = 0.0130).
Although the detection of HPV 16 tended to stimulate the epithelial activation of CD8 (P
=0.09), HPV type 16 seemed to inhibit the stromal activation of CD8 cells, when compared
with slides without HPV16 (unpaired t test P = 0.0008). In opposition, CD25 activated cells
were more frequently detected in the epithelia and in the stroma infected with HPV16 (P=
0.004 and P = 0.003) and in HG-SIL areas (epithelial: P = 0.044, stroma: P = 0.034), than in
the absence of HPV16 and in the LG-SIL. In regard to HIV infection, CD28 was more
frequently detected in the epithelium of HIV+ patients than in the controls specimens (P <
0.0001) and CD8-positive cells were localised more frequently in the stroma surrounding the
metaplastic epithelium of HIV+ patients (unpaired t test P = 0.0010). Both the epithelia and
stroma of CIN/HIV+ group, presented with a greater expression of CD8 cells than control
tissues (respectively, P = 0.068 and 0.016).
Conclusions: According to the type of HPV involved in the lesion, a response CD8 or CD4
might be initiated. The persistence of HPV 16 infection leading to the occurrence of highgrade lesions is associated with the stimulation of IL-2, independently of HIV status and, with
the stimulation of CD8 in HIV-positive patients. These results might reflect a compensation
of a local deficient T-cell system in order to respond to antigens as HPV and HIV.
Acknowledgments: To FAPESP (01/02908-2) for the financial support and for the technical
assistance of Mrs. Ana Maria Anselmi Dorigan.
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P010
CYTOKINE LEVELS INFLUENCE THE OCCURRENCE OF HPV 16
INFECTION AND SQUAMOUS INTRAEPITHELIAL LESION (SIL)?
Fernandes, APM (1), Gonçalves, MAG (1), Cunha, F (1), Pienna, CS (2), Donadi, EA (1).
1.Division of Clinical Immunology, Department of Medicine, University of São Paulo, Ribeirão Preto,
Brazil. 2. Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, University of São
Paulo State, Araraquara, São Paulo, Brazil.
AIM OF THE STUDY: To analyse whether women who are genetically predisposed to
produce high, medium, or low levels of cytokines are more likely to produce different local
cytokine levels and in consequence of this, to develop human papillomavirus (HPV) 16
cervical infection and squamous intraepithelial lesions (SIL).
MATERIALS AND METHODS: Blood samples and cervical biopsy were collected from
43 women presenting with low- and high-SIL. DNA was extracted using a salting-out
procedure. Cytokine polymorphism was evaluated by sequence specific probe analysis. DNA
HPV detection and typing was performed using PCR techniques. Local cytokines levels were
evaluated using ELISA. The unpaired t test, and the non-parametrics Mann-Whitney and
Kruskall-Wallis were used for statistical analysis.
RESULTS: A significant association was found between IL-10 low-producers and HPV 16
(p=0.02), and a trend association between TNF-a low-producers for those who developed
high-SIL (p=0.06). Among patients presented with HPV 16 infection, significant associations
were observed with increased IFN-g intralesional levels (p=0.03), and increased IL-10
intralesional levels (p=0.05), particularly among those with low-SIL (p=0.09).
DISCUSSION: The balance between the cytokine levels and genetically determined cytokine
polymorphism may determine the progression to or regression of SIL.
Acknowledgments: To FAPESP (01/02908-2) for the financial support.
EUROGIN 2003
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P011
IS A PRIOR CAESAREAN SECTION A RISK FACTOR FOR
ADENOMYOSIS
Antsaklis A, Daskalakis G, Thomakos N, Hatziioannou L, Papadopoulos D, Koutsodimas N,
Michalas S
1st Department of Obstetrics and Gynaecology, University of Athens, Athens, Greece
Objective: To examine if there was an increased incidence of adenomyosis in women who
have had previous caesarean section.
Methods: Cases with histologically diagnosed adenomyosis were reviewed from a
computerized database in our Hospital. Ninety-eight consecutive patients with adenomyosis
on hysterectomy specimens were compared with ninety-eight cases, which were selected by
including the following woman who underwent hysterectomy the same period. Gravidity and
parity were recorded along with the mode of delivery. The incidence of caesarean section was
determined between the two groups to determine if there was a significant difference.
Nulliparous women were excluded from the study.
Results: Mean age at hysterectomy was 44.6 years for the adenomyosis group and 45.8 years
for the group without adenomyosis. The incidence of caesarean section was 11.8% and 13.1%
in the two groups, respectively. This difference was not statistically significant.
Conclusions: Hysterectomy closure has been thought to be a source of transplanting
endometrium into the myometrium, thus leading to adenomyosis. However, our results have
seen that a prior caesarean section does not appear to be a risk factor for adenomyosis.
EUROGIN 2003
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P012
DETECTION OF HIGH RISK HUMAN PAPILLOMAVIRUS DNA IN
MALIGNANT MELANOMAS AND DYSPLASTIC NEVI
Bonvicini F. [1], Venturoli S. [1], Ambretti S. [1], Cricca M. [1], Gentilomi G. [1], La Placa M. [2],
Zerbini M. [1], Musiani M. [1]
Departement of Clinical and Experimental Medicine, Division of Microbiology [1] and Division of
Dermatology [2], University of Bologna, Italy
Little is known about the etiological factors involved in cutaneous malignant melanomas.
Environmental, hormonal and genetic factors have been implicated in its pathogenesis, these
include lower skin phototypes, with fair or red hair and blue eyes, the amount of sun exposure
and previous sunburns, a familiar predisposition and increased number of dysplastic nevi. The
role of human papillomavirus (HPV) in many neoplastic diseases, including cervical cancer
and non-melanoma skin tumours, has been widely studied. Moreover, HPV has been detected
in some biopsy specimens from malignant melanomas, suggesting that HPV can be correlated
with a more rapid melanoma progression and a poorer clinical outcome. In this study, to
further investigate the presence of HPV DNA, we performed two different PCR-ELISA
methods on 54 malignant melanomas, 33 dysplastic nevomelanocytic nevi (Clark's nevi) and
15 healthy skins. We utilized two different consensus primer sets to optimize the detection of
HPV DNA and, in particular, the consensus primer pair MY09/MY11 to amplify a 450 bp
segment of the L1 gene of 30 HPV genotypes and the consensus primer pair GP5/GP6 to
amplify a 150 bp segment of the L1 gene of 24 HPV genotypes. In both PCR-ELISA assays,
amplified products were separately hybridized with 8 type-specific probes for high-risk HPV
genotypes (HPV 16, 18, 31, 33, 35, 39, 45 and 52). HPV DNA was detected in 9 (17%)
melanomas and 5 (15%) dysplastic nevi with MY PCR-ELISA, while with GP PCR-ELISA,
HPV was identified in 13 (24%) melanomas and 8 (24%) dysplastic nevi. All HPV positive
samples in MY PCR were positive also in GP PCR. The presence of HPV in malignant
melanomas was not correlated to Breslow thickness microstage or other severity parameters.
In conclusion the presence of high-risk human papillomaviruses in a relevant number of
malignant melanomas and of dysplastic nevi should stimulate future studies to investigate if
HPVs play an etiological role in the molecular mechanism of melanoma development.
EUROGIN 2003
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P013
RISK FACTORS FOR CERVICAL CANCER AMONG PATIENTS
ACCESSING THE PAP SMEAR SERVICES AT THE UNIVERSITY
COLLEGE HOSPITAL, IBADAN
ADESINA OLUBUKOLA
UNIVERSITY COLLEGE HOSPITAL IBADAN, NIGERIA
Cancer of the cervix is thought to be a sexually transmitted disease. In Nigeria, as in most
other developing countries and organised screening program for cervical cancer exists. Low
resource countries attempting to set up a screening program should target the screening on
high-risk women.
Cervical cytology screening services are available at the University College Hospital, Ibadan.
This study was undertaken to determine the presence of risk factors in the women accessing
the service with the aim of determining if the client who really need the service are being
attended to.
This retrospective study, November 1st 2000 till January 31st 2001, reviewed 110 consecutive
clients who were interviewed using a structured self-administered questionnaire. Only at 97
(88.2%) of questionnaires were found suitable for analysis.
The mean age of the respondents were 43.45 years (S.D. ± 9.29). Most (91.7%) were married
with almost 1 in 6 in polygamous union. The mean age at coitairche was 24.25 years (S.D. ±
3.25 while almost 1 in 2 had had more than 1 sexual partners.
The studied population indeed appears to risk factors for cervical precancer and cancer.
EUROGIN 2003
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P014
PROFILE OF PATIENTS ACCESSING PAP SMEAR FACILITIES AT
THE UNIVERSITY COLLEGE HOSPITAL, IBADAN AND ITS'
IMPLICATION FOR CARE
ADESINA OLUBUKOLA
DEPARTMENT OF OBSTETRICS & GYNAECOLOGY
The acceptance and utilisation of cervical cancer screening programs by the target population
is determined by a number of factors including socioeconomic barriers, disease knowledge
and culturally related perceptions. These characteristics not only affect participation in
preventive health but may affect adherence and follow-up. The objective of the study was to
describe the sociodemographic characteristics of clients accessing the pap smear facilities at
the University College Hospital, Ibadan.
Commencing Nov 1st, 2000, 110 consecutive clients were reviewed. The mean age of the
respondents was 43.45years- (S.D ± 9.29). Most clients fell in the parity modal group of 1-4.
Three quatres of the clients had postprimary education. Most clients were married with 16.5%
in polygamous unions.
The typical profile is that of a middle-aged married woman with children and at least
postprimary education, supporting the role of education in accessing pap smear facilities.
EUROGIN 2003
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P015
CERVICAL CYTOLOGY SERVICE IN NIGERIA:PROVIDER
PERSPECTIVE
ADESINA OLUBUKOLA
University College Hospital, Department Of Obstetrics & Gynaecology, Ibadan
It has been noted that efforts to organize an effective screening program in developing
countries will have to find adequate financial resources, develop the infrastructure, train the
needed manpower and elaborate surveillance mechanisms. In our study, we set out to
determine:
(a) Just how frequent is cervical cancer, to warrant the investment of funds in screening
programs?
(b) What proportion of surveyed health facilities offer a cervical cytology-screening program?
(c) What basic facilities are currently available where such programs exists:
Pre-tested, self-completed questionnaire was sent to heads of department of Obstetrics and
Gynaecology in public tertiary and secondary care hospitals in Nigeria as well as major
mission hospital.
Response rate was 63%, monthly consultations included a mean of 114 (± 11.7) new
gynecological patients and an average of 5 (4.7 ± 0.8) cervical cancer cases. One-half of the
institutions had a hospital - based cervical screening program with an average of 27 patients
being screened monthly. Finance was the main difficulty encountered in maintaining a
screening service. Only 4 had a certified gynecologic oncologist.
In conclusion, there is a dismal utilization of available services and a dearth of trained
specialists should any cervical cancer-screening program be considered.
EUROGIN 2003
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P016
A NATIONAL QUALITY REGISTER FOR CERVICAL CANCER
SCREENING IN SWEDEN
Andrae B (1), Andersson-Ellström A (2), Dillner J (3,5), Ryd W (4), Sparén P (5), Strander B (6),
Törnberg S (7)
(1) County Hospital, Gävle, Sweden; (2) Central Hospital, Karlstad, Sweden; (3) Dept. of Medical
Microbiology, University of Lund, Malmö, Sweden; (4)Cytology Laboratory, Sahlgrenska hospital,
Gothenburg, Sweden; (5) Dept. of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden;
(6) Regional Oncologic Center, Gothenburg, Sweden; (7) Regional Oncologic Center, Stockholm,
Sweden
Population-based cervical cancer screening started in Sweden in the end of the 1960s. Around
30 percent of the Pap smears are taken inside the organized program, while the majority of
tests are taken through opportunistic screening. Since the introduction of Pap smear screening
there has been a drastic decline in the incidence and mortality of cervical cancer, although the
decline has leveled off, and the incidence seem to have stabilized at around 10 per 105
women. Despite extensive screening efforts with almost one million Pap smears taken yearly,
in a population of around 4.5 million women, there has been no co-ordination or quality
assurance on the national level. Pap smear screening in Sweden is organized county-wise
without any national co-ordination. To increase the effectiveness of cervical cancer screening
in Sweden, a National Quality Register for Cervical Cancer Screening is set up, starting in
2003, with support from the National Board of Health and Welfare. The Quality Register will
comprise prospective information on all Pap smears taken, and include relevant information
on cytological and histological diagnoses, and invitations to screening. Retrospective
information of Pap smear screening, up to 30 years back in time, will also be included, in
order to make possible longitudinal follow-up on an individual basis. At a later stage
information on treatment will also be included in the Quality Register. Data on cancer
occurrence and mortality from the National Swedish Cancer Register, and the National
Causes of Death Register will be merged to the National Quality Register on a yearly basis.
The Quality Register will also be linked to the National Swedish Population Register to trace
women who do not participate to screening for cervical cancer, or who emigrate. These
women will also be followed up for cancer and death. Quality indicators, to measure the
effectiveness of cervical cancer screening, will be produced on a yearly basis for every
laboratory, county, and for all of Sweden.
EUROGIN 2003
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P017
RISK FAKTORS FOR THE CERVICAL INTRAEPITHELIAL
NEOPLASIAS (CIN)
KONTOU S., ANGELIDOU E., BARDIS A., MAGIAKOS G.
Department of Gynecology, "ELPIS" Hospital, Athens, Greece
Aim: Study of the risk factors for the appearance of CIN and their relationship with the
severity of the lesions.
Material-methods: Since 2000-2001 we examined colposcopically (with biopsies) and
treated 476 patients with suspect Papanicolaou Smear. These patients answered a
questionnaire concerning their age, the age of first menstruation, the age of beginning of
sexual relationships, sexually transmitted diseases of them or their partners, smoking and
contraceptive methods. The 138 of these 476 patients were diagnosed with LGSIL (28,99%),
the 83 with HGSIL 17,43%), the 14 with invasive cervical carcinoma (2,94%) and 1 with
lymphoma (0,2%). The rest 240 women had cervical inflammations. We investigated the
statistical correlation between the above mentioned risk factors and the appearance-severity of
the cervical lesions.
Results: The age of the patients and smoking did not present any stastistically significant
relationship with the development of CIN, whereas the difference between the age of first
menstruation and the age of beginning of sexual life, the existence of a sexually transmitted
disease and the contraceptive methods showed a statistical significance ( P - value: < 5% ).
Conclusion: There was a negative stat. significant correlation between the difference of these
two ages and the development of CIN, whereas a positive one was proved concerning the
presence of sexually transmitted diseases and the non use of a contraceptive method with the
appearance of CIN.
EUROGIN 2003
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P018
PROGNOSTIC VALUE OF ASCUS-DIAGNOSIS AMONG PRE- AND
POSTMENOPAUSAL WOMEN
KONTOU S., ANGELIDOU E., BARDIS A., MAGIAKOS G.
Department of Gynecology," ELPIS" Hospital, Athens, Greece
Aim: A retrospective study of the significance and the prognostic value of the
cytopathological diagnosis ASCUS between the 2 age-groups of women (pre- and
postmenopausal). We clarify which squamous cell lesions should characterized as ASCUS
and describe methods in order to avoid diagnostic mistakes.
Material-methods: We reevaluated 18000 Papanicolaou Smears of women, which we
examined the last 4 years (1999-2002) in our clinic. We found 108 women with ASCUS
diagnosis and we separated them in 2 groups, concsidering their menopausal status. These
108 women underwent colposcopy and cervical biopsie ( when it was necessary ), as well as
repeated Papanicolaou Smears. All the postmenopausal women ( at least 1 year after
menopause) were treated with local estrogen cream for 15 days and then we repeated the
cytologic examination in order to differentiate the atrophic from the really dysplastic lesions.
The follow up period of these women varied from 2-4 years.
Results: We diagnosed 84 premenopausal ( average age 39,85 years) and 24 postmenopausal
women ( av. age 55,87 years ) with ASCUS. The 51/84 (60,7 %) and the 6/24 (25%)
developed SIL or invasive cancer. The statistical analysis proved that age and menopausal
status at the time of ASCUS diagnosis have a strong statistically significant relationship (Pvalue <1%) with the development of SIL or invasive cervical carcinoma.
Conclusion: There is a decrease of the ASCUS diagnosis and the ASCUS --> SIL
transformation with the increase of age.
EUROGIN 2003
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P019
SCREENING FOR CERVICAL CANCER: COMPARING HEALTH
WORKERS AND THEIR RELATIVES WITH PUBLIC HEALTH
SERVICE USERS.
Bragança JF, Sarian LOZ, Gontijo R, Da Silva SM, Zeferino LC, Natalin R, Derchain SFM,
Syrjänen KJ.
ObGyn Department Universidade Estadual de Campinas Campinas, Brazil, Cytopathology Unit,
Laboratory of Epidemiology, National Institute of Health (ISS), Rome, Italy
Objective: to compare epidemiological characteristics and proportion of altered Pap smear,
Hybrid Capture II (HC II) and Visual Inspection with Acid Acetic (VIA) results in health
workers and their relatives with Public Health Service users, in a cervical cancer screening
program linked to INCO-DEV project ICA 4-CT-2001-10013.
Material and methods: A cross-sectional study was designed with 375 female health
professionals working at a Women Assistance Health Hospital (group A) and 1260 selected in
one Basic Public Heath Unit (group B), during 2002. The women answered a sociodemographic questionnaire and underwent gynaecological examination. Conventional Pap
smear, randomised HC II (340 in group A and 676 in group B) and VIA were done at the first
visit. Chi-square and odds ratio (OR) testes with 95% confidence interval (95%CI) were used
for statistical analysis.
Results: Comparing group A with group B, the first one presented better formal education
(0.04 95%CI 0.02-0.06) and high life-time number of Pap smear (0.46 95%CI 0.26-0.80).
Life-time number of sexual partner was fewer in group A than in group B (0.58 95%CI 0.400.84) as also number of pregnancies (OR 0.67 95%CI 0.52-0.88). The two groups did not
present statistical difference regarding the previous sexually transmitted disease and smoking
history. Abnormal Pap smear results were found in 7% and 7.6%, positive HC II were found
in 16.9% and 18.6% and VIA was positive in 10.4% and 5% in group A and B, respectively.
The total number of women with at least one positive test was significantly higher in health
workers group. Among the studied characteristics, age, formal education, age at first
intercourse, and the number of life-time Pap smear were significantly associated with the
prevalence of positive screening tests.
Conclusions: Although the health workers group had fewer life-time sexual partners, better
education, and higher number of life-time Pap smears, the prevalence of abnormal screening
test was higher in the studied population.!
It could be due to their higher attendance rates in cervical screening program and the use of
HCII.
EUROGIN 2003
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P020
FACTORS ASSOCIATED WITH ALTERED PAP SMEAR, VISUAL
INSPECTION AND HYBRID CAPTURE II RESULTS IN ONE BASIC
HEALTH UNIT IN BRAZIL
Gontijo RC (1), Derchain SFM (1), Sarian LOZ (1), Zeferino LC (1), Nascimento R (1), Syrjänen
KJ (2).
ObGyn Department Universidade Estadual de Campinas ; Campinas ; Brazil, Cytopathology Unit,
Laboratory of Epidemiology, National Institute of Health (ISS), Rome, Italy.
Objective: Cervical cancer is a common cause of morbidity and mortality in developing
countries. In Latin America, the incidence rates in several cities are among the highest
worldwide, probably due to a high frequency of risk factors /or a low screening coverage for
cervical cancer. The purpose of this study linked to INCO-DEV project ICA 4-CT-200110013, was to evaluate the association of socio-demographic and reproductive factors with
abnormal Pap smear, visual inspection with acetic acid (VIA) and hybrid capture II (HC II)
results.
Methods: In this cross- sectional study, 1193 women were evaluated in one Basic Public
Heath Unit. All of them answered a socio-demographic questionnaire. Pap smear was
performed in all 1193 women, VIA in 1192 and HC II for HPV DNA detection in 636
women. To access the relation between groups, odds ratio (OR) were calculated with 95%
confidence interval (CI95%).
Results: Pap smear results were normal in 93,8% of the women. Atypical cells were found in
74 (6,2%) women, including 51 ASCUS, one glandular atypia, 17 CIN 1 and five CIN 2 or 3.
VIA was positive in 58 (5%) women and HC II was positive in 124 (20%) of the women
tested. At least one positive screening test was found in 210 (18%) women. Age less than 35
years (OR 2.3 CI95% 1.6-3.2), living without a sexual partner (OR 1.8 CI95% 1.3-2.5),
studying more than four years (OR 1.9 CI95% 1.3-2.7), smoking (OR 1.8 CI95% 1.3-2.5), age
at the first intercourse less than 18 years (OR 2.1 CI95% 1.6-3.0), more than one sexual
partner in last year (OR 3.9 CI95% 2.0-7.3), and two or more deliveries (OR 1.7 CI95% 1.22.4) were significantly associated with the positive screening test results. However, only the
never having a Pap smear taken was associated with the presence of significant cervical
disease (OR 3.48 CI95% 1.07-11.17).
Conclusions: Socio-demographic and reproductive factors studied showed association with
the presence of one or more positive screening test results, but only the lack of a previous Pap
smear was associated with a high risk for biopsy-proven cervical disease.
EUROGIN 2003
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P021
CERVICAL CANCER AND INTRAEPITHELIAL NEOPLASIA RISK
OF GRAND MULTIPAROUS WOMEN: A POPULATION BASED
STUDY OF FINLAND
M.Hinkula, A.Kauppila, E.Pukkala, P.Kyyrönen*
Department of Obstetric and Gynaecology, University Hospital, Oulu, Finland. * Finnish
Cancer Registry, Helsinki, Finland
Background:Multiparity has been reported to be a significant risk factor for cervical
neoplasia. In this national cohort study we assessed the role of parity (categories 5,6, 7, 8+),
age at first birth (< 20, 20-24,25+), birth interval (< 2.0, 2.0-3.0, 3.0+ years), age at follow up
(<40,40-49,50-64,65+) and premenopausal pregnancy free period (< 10,10-14, 15+) in the
etiology of cervical cancer and cervical intraepithelial neoplasia (CIN) of grand multiparous
(GM= at least five full-term pregnancies) women.
Study Methods:The Population Register of Finland comprised since 1974 about 90, 000 GMwomen with complete family history. These data were linked with the cervical neoplasia data
of Finnish Cancer Registry. During the follow-up of about 2 million person-years, 220
invasive cervical cancer and 178 CIN cases were obtained. Standardized incidence ratios
(SIR) were calculated by dividing the number of observed cases by the number of expected
cases. Poisson regression modelling, which takes into account the effects of the other
variables as confounding factors, was used in the relative risk (RR) calculations.
Results:Total cervical cancer risk of GM-women was slightly increased (SIR 1.13, 95% CI
0.98-1.29), and that of squamous cell cancer little bit more (SIR 1.21, 95% CI 1.05-1.40). The
risk of adenocarcinoma was decreased (SIR 0.77, 95% CI 0.53-1.10). The SIR for CIN was
1.37 (95% CI 1.17-1.58). The increase in parity did not increase the RR of cervical cancer or
CIN, but young age at first birth significantly increased the RR of both of them, especially in
ages < 50 years. Short interval between births tended to increase the risk of CIN.
Conclusions: In contrast to some recent observations grand multiparity per see seemed to
have a small role in the etiology of cervical cancer in Finland with well-organized Pap smear
screening and free maternal health care. However, also here young age at first birth clearly
increased the risk of cervical cancer and CIN. These risks manifest themselves especially
during the premenopausal years possibly because of human papillomavirus infection in young
mothers.
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P022
INCIDENCE RATES OF CHLAMYDIA TRACHOMATIS INFECTION
AND PARAMETERS OF FEMALE REPRODUCTIVE HEALTH IN
NOVOSIBIRSK, RUSSIA
Khryanin Alexei
Novosibirsk State Medical University, Novosibirsk
Background: Chlamydia trachomatis (CT) infection is the most common cause of pelvic
inflammatory disease (PID) in industrialised countries, and is an important cause of female
infertility world-wide. Objective: To document trends of CT infections recorded in
Novosibirsk (Western Siberia) in 1996-2001.
Methods: Incidence rates of CT infections for the period 1996-2000 were investigated. The
data from all district STD clinics were obtained and registered in the Department of Social
Statistics of the Regional Committee of Statistics of Novosibirsk. The tests available for
detection of CT are PCR and DIF.
Results: Novosibirsk is a largest city of Siberia and the third one in Russia with population
about 1.5 million. There are 405,940 women at the reproductive age. The number of the
population was constant in the recent years. Various parameters of female reproductive health
in Novosibirsk are shown in Table.
Table. Live birth, dead births, premature birth, ectopic pregnancy, abortions, and PID rates in
Novosibirsk (per thousand females reproductive age)
Live births
Dead births
Premature births
Ectopic pregnancy
PID
Infertility
Abortions
1995
19.1
0.9
0.7
1.3
18.2
2.4
65.4
1996
18.3
0.8
0.6
1.2
10.2
3.1
67.9
1997
21.8
0.8
0.6
1.4
9.8
2.8
63.7
1998
20.7
1.0
0.7
1.5
11.1
4.3
65.9
1999
24.2
1.1
2.0
1.4
7.7
3.3
68.1
2000
25.5
0.6
1.8
1.1
6.8
3.2
69.8
2001
26.9
0.2
1.5
0.9
5.5
3.7
69.1
Incidence rates of CT infections were calculated and expressed per 100.000 population. The
data for the entire population of Novosibirsk were as follows: 1996 - 241.0; 1997 - 396.4;
1998 - 385.4; 1999 - 317.2; 2000 - 236.3, 2001 - 179.4. The incidence rates were 2-3 times
higher in females than in males during 1996-2001. The rates were relatively constant through
1996 to 2001.
Conclusions: CT infections are widespread among the general population of Novosibirsk.
These trends are similar to those in other regions of Russia, and higher than in Western
European countries. This problem may threaten public health and demographic situation in
Russia that needs improving of hygiene standards and sex education among the population.
EUROGIN 2003
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P023
PROFILE OF WOMEN UNDER POSTMENOPAUSAL HORMONE
REPLACEMENT THERAPY
Kuntz C (1), Spyckerelle Y (1), Giordanella JP (1,2)
(1) Centre technique d’appui et de formation des centres d’examens de santé, Vandoeuvre-les-Nancy,
France, (2) Caisse primaire d’assurance maladie de Paris, France
To evaluate the profile of women under hormone replacement therapy (HRT), a study was
performed among menopausal women (n = 8011) aged 45 to 74 years (mean age = 58.8 years;
sd=6.4). Data were collected on a specific questionnaire from women attending health
insurance examination centres in 2001.The sample included 75.8 % of married women, 19.5
% of widows or divorced and 4.7 % of singles.
About half of menopausal women (48.7%) used a HRT at the time of the examination, more
often among women aged 55 to 59 years than women 65 to 74 years (58.9% versus 26.2%).
Only 32.5% of precarious social classes used HRT. A total of 80.5% of the women using
HRT declared having had a regular pap smear during the last three years and 98.7% have had
a mammography; these rates are respectively in women without HRT of 55.8% and 90.6%.
The women with HRT have more often high level diploma (57.6% of graduates versus 40.4%
without diploma), live in urban areas (67.7%).The rate of women with HRT is different
according to the areas: 54.5% for the area of Paris, 42.7% for the south-western areas, 40.4%
for the northern areas.
The probability to benefit from a HRT , after controlling for the others eligible factors, was
higher for women aged 55 to 59 years (OR = 1.18), with high level diploma (OR = 1.33),
having had hysterectomy (OR = 2.45) or gynaecological follow-up. On the other hand the
probability was lower for women from lower social classes (OR = 0.67), without diploma or
having had no regular gynaecological follow-up.
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P024
AN OUTBREAK OF CERVICAL CANCER IN SAN LUIS POTOSÍ,
MEXICO
Rosales-Ortuño L.*, Rodríguez-Nieto M.T.**, López-Revilla R.*
*Departamento de Biología Molecular, IPICYT, and **Departamento de Estadística, Hospital Central,
San Luis Potosí, S.L.P., Mexico
Cervical cancer, due to sexually transmited high-risk human papillomaviruses (HPV) [1], is
the second global cause of death by cancer and the first in developing countries [2]. The
highest mortality rates of cervical cancer take place in women of 50-55 years in developed
countries [3] and 30-44 years in Mexico [4]. In this work we determined the prevalence of
HPV infection, cervical intraepithelial neoplasia (CIN) and cancer in three regions of the state
of San Luis Potosí. During the last year 1940 cervical biopsies/cones from regions 1, 2 and 4
were processed at the Hospital Central Department of Pathology for cervical cytology
abnormalities (mean age of sampled women was 37.6 years). The frequencies of lesions
(percentages of the total sample and women's mean age are noted in parentheses) were: 1559
(80.7%) cases of HPV infection among which 522 (33.5%) had no other alterations (36.3
years) and 1037 (66.5%) were associated to CIN (36.8 years); 715 cases (36.9%) of CIN I
(36.3 years), 220 (11.4%) of CIN II (37.8 years), 172 (8.9%) of CIN III (38.6 years); and 65
cases (3.4%) of cervical cancer (45.8 years) conformed by 54 epidermoid carcinomas (45.8
years) and 11 (48.3 years) adenocarcinomas. HPV infection was diagnosed in 99.6% of CIN I,
95.4% of CIN II and 66.8% of CIN III cases. The earliest cancer affected a 21 year-old
woman from Region 4 (Rioverde municipality). There were no significant differences in HPV
infection and CIN frequencies among regions, whereas cancer was significantly more
frequent (p = 0.02) and appeared earlier (36.2 years) in Region 4, suggesting that an outbreak
due to a high-risk genotype of HPV affecting the youngest sexually active women is taking
place there.
1. Muñoz N. J Clin Virol 1999; 19:1-5
2. Giuliano AR et al. Cancer Epidemiol Biomarkers Prev 1999; 8:615-620
3. Lazcano-Ponce E et al. Salud Pub Mex 1993; 35: 65-73
4. www.ssa.gob.mx
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P025
CIGARETTE SMOKING AND LIFETIME NUMBER OF SEXUAL
PARTNERS: ITS ROLE ON THE TIME-TO-ONSET OF CERVICAL
CANCER IN A SOUTHERN EUROPEAN POPULATION
Matos Ana
Portuguese Institute of Oncology - Porto, Gynecology, Porto
Human papillomavirus (HPV) genital infection is a sexually transmitted disease and high risk
HPV types are associated with the onset of high grade SIL (HGSIL) and cervical cancer (CC).
However, not all high risk HPV-infected women have HGSIL/CC and the time between HPV
exposure and the onset of cervical lesions may be variable.
We evaluated the role of smoking and the number of sexual partners as determinants of the
time-to-onset of severe cervical lesions (HGSIL/CC).
In this study 249 consecutive women were recruited from women referred to the gynaecologic
clinic at the Portuguese Institute of Oncology-Porto: 130 with biopsy-confirmed SIL/CC, and
119 without cervical lesions.
We estimated the time-to-onset (TTO) of HGSIL/CC, since the age at first intercourse
(Kaplan-Meier method). Our results indicate that according to cigarette smoking status,
smoking women present a shorter median TTO than non-smokers (17 years 95%CI 15-20 vs
31 years 95%CI 29-34; log rank test: p<0.001). Regarding lifetime number of sexual partners,
we verify that for the group of women with more than 5 sexual partners have a shorter median
TTO (16 years 95%CI 8-24 vs 34 years 95%CI 30-38; log rank test: p=0.005).
The role of cigarette smoking in cervical cancer is not well understood. The immunological
effect of smoking on the cervical epithelium or the formation of carcinogen-DNA adducts in
the cervical tissue, may influence neoplastic transformation. We recently suggested that
genetic polymorphisms associated with smoke detoxification might also influence smoking
status associated with cervical cancer risk (J Cancer Res Clin Oncol 128:678-682, 2002). The
lifetime number of sexual partners effect has been reported by many groups.
Our findings suggest that two putative risk factors, smoking and number of sexual partners,
may influence the time-to-onset of severe cervical lesions (HGSIL/CC) and may lead to an
earlier onset of cervical cancer.
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P026
RISK FACTORS FOR CERVICAL INTRAEPITHELLIAL NEOPLASIA
IN RELATION TO HUMAN PAPILLOMAVIRUS INFECTION
Perovic Milica
Institute of Obstetric and Gynaecology,University clinical center, Belgrade
Smoking, sexual history , parity and oral contraceptive use have been reported as major
environmental risk factor for cervical cancer. After the discovery of the very strong link
between Human Papillomavirus (HPV) infection and cervical cancer, it is unclear whether the
associations of these environmental factors with cervical cancer reflect secondary associations
attributable to confounding by HPV, if they are independent risk factors or whether they may
act as cofactors to HPV infection in cervical carcinogenesis.
Methods: To investigate this issue, we performed a population based case-control study of 68
women with high grade cervical intraepithelial neoplasia ( CIN 2,CIN 3) and 73 healthy age matched women. The women answered a questionnaire on diet, smoking, oral contraceptive
use and sexual history. They were tasted for HPV in cervical samples ( by polymerasa chain
reaction-based hybridization techniques) and underwent a gynaecologic examination with
collection of exfoliated call for a Papanicolaou smear and vaginal wet smear findings.
Results: Pregnancy appeared to be a risk factor in the multivariate analysis
(p<0.0001).Prolonged oral contraceptive use and sexual history were associated with CIN 2-3
in univariate analysis, but these associations lost significanse after takinh HPV into account.
Smoking was associated with CIN 2-3 (OR 2.6), the affect was dose-dependent (p=0.002) and
the smoking-associated risk was not affected by adjusting for HPV, when adjusting for HPV
DNA ( OR 2.5) .
Conclusion: After taking HPV into account, smoking appeared to be most significant
environmental risk factor for cervical neoplasia.
EUROGIN 2003
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P027
COMPARISON OF HPV DNA PREVALENCE IN ASCUS
SUBCATEGORIES AS DEFINED BY THE ORIGINAL BETHESDA 1991
AND THE NEW BETHESDA 2001 SYSTEM
Pirog E (1), Harigopal M (1), Erroll M (1), Centeno B (1), Kleter B (2), Quint W (2)
(1) Department of Pathology, Weill Medical College of Cornell University, New York, USA and (2) Delft
Diagnostic Laboratory, Delft, Netherlands
The new Bethesda system 2001 (TBS 2001) changed subclassification of atypical squamous
cells of undetermined significance (ASCUS). The first goal of this study was to determine the
impact of the new classification on the accuracy of Pap test diagnosis by examining the
prevalence of HPV in different ASCUS subcategories, as defined by the new TBS 2001
versus the original TBS 1991. The second goal was to examine if there are specific
morphologic features of atypical squamous cells which are more frequently associated with
HPV detection.
Consecutive cases of ThinPrep Pap tests with original diagnosis of ASCUS - study group; low
and high grade squamous intraepithelial lesion (LSIL and HSIL) - positive control group; and
NEGATIVE -negative control group, were retrospectively reviewed by a panel of pathologists
to obtain consensus diagnosis. All ASCUS cases were subqualified according to TBS 1991
into: favor reactive (ASCUS-R), favor LSIL (ASCUS-L), favor HSIL (ASCUS-H), and
ASCUS-not otherwise specified (ASCUS-NOS). In a separate review ASCUS cases were
subqualified according to TBS 2001 into: atypical squamous cells of undetermined
significance (ASC-US) and atypical squamous cells, cannot exclude high grade squamous
intraepithelial lesion (ASC-H). Further, morphological ASCUS subtypes were recorded:
atypical mature cells, atypical immature cells, atypical parakeratotic cells, atypical repair,
atypical atrophic cells, and individual morphologic features of atypical cells were recorded.
Broad-spectrum HPV DNA amplification and genotyping was performed using SPF10
PCR/LiPA assays.
Results: In the cases diagnosed according to TBS 1991, HPV was detected in 32% of
NEGATIVE, 49% of ASCUS and in 93% of LSIL/HSIL cases. Upon the second review,
using the diagnostic categories of TBS 2001, which eliminated ASCUS-R category, the
number of ASCUS cases decreased by 45% and HPV was detected in 35% of NEGATIVE,
59% of ASCUS and 93% of LSIL/HSIL cases. The prevalence of HPV in different
morphologic subtypes of ASCUS was not significantly different, and further, none of the 8
individual morphologic features evaluated in the study was more frequently associated with
HPV detection. In conclusion, elimination of "ASCUS, favor reactive" category, with
downgrading of the proportion of ASCUS cases, resulted in a decrease in ASCUS diagnosis
without a significant rise of HPV prevalence in the NEGATIVE cases.
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P028
PREVALENCE AND SEQUENCE ANALYSIS HUMAN
PAPILLOMAVIRUS IN CERVICAL BIOPSY SPECIMENS FROM THE
MAZANDARAN PROVINCE IN IRAN
Severini A (2), Hamkar R (1), Talat TM (1), Limmer B (2), Mahmoodi M (1), Seyedi Rashti SR (1)
and Nategh R (1)
(1) Division of Virology, Department of Pathobiology, School of Public Health and Institute of Public
Health Research, Tehran University of Medical Sciences. (2) National Microbiology Laboratory, Health
Canada, Winnipeg, MB, Canada.
Cervical cancer is one of the most prevalent forms of carcinoma in the developing countries
and it appears to have a high prevalence also in Iran. We have studied the prevalence and the
genotypes of human papillomavirus (HPV) in a group of women in the Mazandaran Province
of Iran. Testing for the presence of HPV was performed on DNA purified from 100
cytomorphologically-classified, paraffin-embedded cervical biopsies, using PCR with the
GP5+/GP6+ primers for L1 gene. Direct sequencing of the PCR products was used to
determine the HPV types in the PCR positive samples. HPV DNA was detected in 34 (80.9%)
cases of cervical carcinoma, 10 (71.4%) cases of dysplasia and 4 (9%) cases of specimen that
were diagnosed cytomorphologically as normal. Among the carcinoma samples, 38.3% were
positive for HPV type 16, 23.6% for HPV type 18, 14.7% and 5.9% were positive for HPV 31
and 33 respectively. Also in HPV positive carcinoma cases we found one specimen positive
for each of HPV types 35, 44, 45 and 51 and 2 for HPV-39. The distribution of HPV types
among HPV positive dysplasia cases was 55.5% for HPV16 and 18, 22.2% for HPV31 and
33, and one case positive for HPV-44. Only HPV 6 and 11 were detected in cytological
normal specimens. The sequences of the amplified region of the L1 gene of the type 16 and
18 isolates were generally identical to previously published sequences, with the exception of 2
type 18 isolates that showed a T to A substitution at nucleotide 6635. These results show that
the prevalence of HPV types in the Mazandaran province of Iran is similar to the prevalence
in most of the rest of the world and the genotypes of HPV type 16, 18 of this cohort do not
seem to be unique of this geographical area. A vaccination strategy aimed at HPV type 16, 18,
and 31 could potentially prevent about 80% of cervical carcinoma cases in this population.
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P029
URINARY TRACT INFECTIONS IN PREGNANT WOMEN
THEODOSI Gjercji
University Hospital for obstetrics & gynecology, Tirana, ALBANIA
Urinary tract infections during pregnancy maybe asimptomatic bacteriuriesor symptomatic
inflammatory processes of the lower urinary system, cystitis and infections of the upper
urinary system pyelonepritis. Among the important consequences of urinary tract infections
are low birthweight, prematurity and preeclampsia. The main symptoms of pyelonephritis are
: fever up to 40°C, lumbal pain, right or bilateral dizziness and vomiting, bacteriuria and
leucocyturia.
Consequence of bacteriuria are : instability of termoregulation, and renal disfunction ; high
levels of creatinemia, high clearance of creatinemia ; low level of platelets. The contamination
of the urinary system maybe : ascendent from vulvovaginal infections or by hematogenic and
lymphogenic mechanism.
The more important bacterial agents are considered : Colibacillus, Proteus, Clebaiella, and not
so often, enterobacter, enterococcus, staphylococcus, streptococcus group “B”. Uropathogenic
factors of colibacilles are considered :
- small number of “O” serotypes ;
- the presence of “K” antigen able to frein fagooytesis ;
- some of colibacilles, can produce haemolsynes, that damage the system of capacitation of
iron (Fe++) ;
- some of endotoxinesmake more problematic the reflux of the urine ;
- colibacilles, have proteic, specific structures – adhesines, which have the possibility to
catch the epithelial urinary tract cells, up to renal parenchyma and to damage them.
Material of our service in Tirana University Hospital : from 1/01/2000 up to 31/12/2002, in
our hospital were treated 264 pregnant women with infectious problems of the urinary system.
- Asymptomatic bacteriuria (less then 100 000 bacteries/ml in 18 cases
- Symptomatic infections in 26 cases (respectively : 6.8 and 9.,2 )
Among them were ; afebrile 97 (37 ), subfebrile 59(22 ) febr. 90(34 )
The age of pregnancy was as follows :
Less then 12 weeks
14
13 – 16
“
26
22 – 28
“
98
29 – 40
“
126
5.3
9.8
37.1
47.7
Pathogenic germs in the urine samples were :
Eschirichia coli
166
Proteus
28
Glebsiella
16
79
13.3
7.6
The results of the cervicovaginal cultures were :
Candidiasis
140
Staphylococcus
36
53
13.5
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P030
CERVIX CANCER IN GEORGIA IN THE SECOND HALF OF THE
XXTH CENTURY.
TSITSISHVILI Z, CHARKVIANI L, CHARKVIANI T, GVAMICHAVA A
Georgian National Cancer Center,Tbilisi
Georgia is a small country in the southern n Caucasus. It has the area of 70,000 km2 and the
population of five million. It was one of the Soviet republic until the breakup of the USSR. It
has been independent since 1991. Standardized index of the female genital cancer during
1964 - 1989 was 23.4 per 100,000 (cervix 12.9, corpus 4.1, ovary 5.3, vulva 0.6, vagina 0.3);
however the intensive index was 27.0 per 100,000 (cervix 14.6, corpus 4.8, ovary 6.2, vulva
0.8, vagina 0.3). Cervix cancer was the most frequent type in female genital cancer. Dynamics
showed a decrease of the cervix cancer cases by 29.9% during 1964 - 1989. The highest
occurrence of cervix cancer affects women between the ages 50-59 (44,5%) and the lowest under 30 years (0.8%). There dynamics of cervix cancer decreases for the age group of 60
years and older but it still high - (20.9%). The practice of screening, prevention and early
stage treatment of cancer has suffered since the breakup of the Soviet Union and that played a
negative role in the process detection of the cervix cancer in the early stages in Georgia. In
1989 I -II stage of cervical cancer was diagnosed in 247 patients (76%), III- stage in 58
(17,85%), IV-stage in 20 (6,15%), but after 10 years the situation changed dramatically: I and
II stage diagnose was made in 119 cases (47%), III-stage in 76 (30,2%) and IV-stage in 57,
(22,6%). If the number of the revealed IV stage diseased was 6,15% in 1989, in 1998 it
became 22,6%, i.e. 4 times more
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P031
THE ROLE OF PAAN CHEWING AND DIETARY HABITSIN
CERVICAL CARCINOMA IN CHENNAI, INDIA
Vaccarella Salvatore
International Agency for Research of Cancer, Unit of Field and Intervention, Lyon
Human papillomavirus (HPV) is the primary cause of invasive cervical cancer (ICC) but nonviral factors contribute to HPV-related carcinogenesis. We investigated the role of paan
chewing and dietary habits among 205 women with ICC and 213 age-matched control women
in Chennai, India. Odds ratios (OR) and 95% confidence intervals (CI) were computed by
means of unconditional multiple regression, taking into account major correlates of ICC risk.
In the age-adjusted model, paan chewing showed a dose-dependent direct association with
ICC (OR for more than 5 paan/day = 4.1; 95% CI 1.3-12.9). Among dietary habits, the
highest intake tertile for vegetables and fruit was associated with an OR of 0.5 (95% CI 0.20.9). Low education level and low body mass index (BMI) were also risk factors for ICC, but
they did not account for the associations with paan chewing and low vegetable and fruit
intake. In the analyses restricted to HPV-positive cases and controls, the inverse association
with vegetable and fruit intake was confirmed. Conversely, the adverse influence with paan
chewing and low BMI on ICC risk seemed to be attributable to a higher prevalence of cervical
HPV infection in women who were chewers or underweight than in women who were not.
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P032
CERVICAL PATHOLOGY IN WOMEN WHITH HUMAN
PAPILLOMAVIRUS
VOLKOV Valery (1), ZAKHAROVA Tatyana (2)
(1) Tula State University, (2) Maternal Hospital No1
Objective.To study the prevalence cervical pathology among young women whith human
papillomavirus 16/18 types infection.
Study Design. From October 1998 until May 1999 we examined 160 women between the
ages of 15 and 24 (mean = 19.5 ± 2.5) years. Huuman papillomavirus-DNA typing of cervical
scrapes was performed by polymerase chain reaction.
Results. Positive results of DNA test were present in 39 cases (24.4%). Histology and
colposcopy verified diagnoses of cervical pathology were present in 19 cases (11.9%) of
cervical intraepithelial neoplasia (CIN) 1,2. Two groups were generated depending on
detection of HPV. Group 1 included 39 HPV-positive (+) women and group 2 (control)
included 121 women, for which HPV was not shown. Cervical pathology (CIN 1,2) were
present in 12 cases (30.8%) of group 1 and in 7 cases (5,7%) of group 2. Among all the
participants with CIN 1,2, 13 (68.4 %) women were smokers.
Conclusions. Our study show that human papillomavirus 16/18 types as a predictor of
cervical intraepithelial neoplasia in young women.
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P033
HUMAN PAPIILOMAVIRUS 16/18 INFECTION AND SEXUAL
BEHAVIOUR IN PATIENT WITH CERVICAL INTRAEPITHELIAL
NEOPLASIA
Zukanoviæ D, Bali R, Èas-Sikosek N, Gorisek B, Takaè I
Matibor Theaching Hospital, Department of Gynecologic and Breast Oncology
Objective: In order to investigate the corelation between the presence of HPV and sexual
behavior we compare the known risk factors for cervical intraepithelial neoplasia (CIN) and
cervical cancer between HPV positive and HPV negative groups of patients with CIN.
Methods: One hundred and four patients with CIN, referred for conisation, were included in
this study. Before conisation, cytological material for in situ hybridisation was obtained from
the uterine cervix to detect the presence of HPV 16 and 18 infection. A questionnaire on
known risk factors in CIN and cervical cancer was filled in for each of the 104 patients.
Results: Among all patients with CIN, 29 (28,0 %) were positive for HPV 16 or HPV 18.
When analysing some already known risk factors (age, number of births, number of abortions,
age at first sexual intercourse, lifetime number of sexual partners, use of oral contraceptives),
no statistically significant difference could be established for any of the factors studied.
Conclusion: No association was found between HPV positivity and other known risk factors
for CIN and cervical cancer, confirming the observation of other authors that sexual behavior,
a significant risk factor for cervical cancer, is not inevitably correlated with risk of HPV
infection.
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P034
FOLLOW-UP OF ASCUS PAP SMEARS
RUTGERS Joanne
Long Beach Memorial Medical Center
Introduction: The Bethesda System (1994) qualified squamous cells of undetermined
significance (ASCUS) as to favor reactive or favor SIL. Bethesda 2001 added a category of
atypical squamous cells, cannot exclude high grade (HG) dysplasia (ASC-H). The clinical
utility of this term has not been widely confirmed. Our laboratory has used the term ASCUS
cannot rule out dysplasia as a term equivalent to ASC-H for more than 10 years. Our
laboratory processes over 100,000 Paps a year, with interpretations by 10 pathologists, thus
we are in a position to determine the usefulness of sub-classification of ASCUS in a
community setting.
Methods: We undertook a study of conventional Pap smears diagnosed as ASCUS in 1998
that had a follow-up Pap smear or biopsy within two years. We divided ASCUS into favor
reative (A-reac), mild (A-mild), favor HPV (A-HPV), and cannot rule out HG dysplasia (Adys). Follow-up was by Pap smear in 338 cases, and by colposcopically directed biopsy in
353. Follow-up was grouped into negative or not negative (atypia, or low grade (LG) or HG
dysplasia). Statistical analysis was by the Chi-square test.
Results:
Benign
Atypia
LG dysjplasia HG dysplasia
ASCUS
#
(%)
(%)
(%)
(%)
Reac
129
82
8
8.5
1.5
Mild
470
77
8
12
3
HPV
69
65
3
28
4
Dys
23
52
9
39
No significant difference in follow-up is found between A-reac and A-mild (P = .13), so we
grouped these together as A-NOS for the remainder of the analysis. There was a difference
between A-NOS and A-HPV (P = .024), and A-NOS vs. A-dys (P = .008). There is no
difference between A-HPV and A-dys for negative vs. not negative follow-up (P=.39),
however, the incidence of low grade dysplasia after a diagnosis of A-HPV vs. high grade
dysplasia following a diagnosis of A-dys is highly significant (P <.001). The statistical
outcomes were similar if atypia on follow-up was grouped with benign instead of not
negative.
Conclusion: There is no reason to separate A-reac from A-mild, which supports the Bethesda
2001 elimination of ASCUS favor reactive. In our hands, A-HPV was significant in
predicting the presence of LG dysplasia. A-dys was associated with the presence of a biopsyproven HG dysplasia in 39%, supporting the current recommendations of immediate
colposcopy for this group. This study also shows that a large pathology group can effectively
sub-categorize ASCUS.
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P036
THE PREDICTIVE VALUES OF THE SCREENING METHODS FOR
THE PRECANCEROSES OF PVU
Milanova E,Naumov J ,Stojovski M, Janevska M,Tanevska P
Clinic of gynecology and obstertrics, MKD
Objective: The aim of the study is to show predicitive values of the screening methods for
LSIL and HSIL.
Methods and materials: The study included 112 patients with histhology confirmed HPV
presence.All of the patients underwent repeat PAP smears,HPV DNA testing and a
colposcopic examination (with biopsies performed on recognised lesions and an endocervical
curettage if there were no visible lesions).Hysthological report focused on those women
was:65 of them (58%) were LSIL, and the other 47 patients (42%) were HSIL. The another
screening method which we used were:citology testing,colposcopic exam (graduate with
Coppleson and Pixley grade), and PCR for HPVDNA testing.
Results: For PAP test sensivity,specifity, positive predictive value, negative predictive value
in order of line were: 79%,62%,86,4%,and 50%.For the colposcopic exams:98%,80% and
61,5%.The coresponding predictive values for PCR HPV DNA testing were 73%, 99% 100%,
and 27%.
Conclusion:Predictive values show us that sensitivity for PCR was 73%.We respected grater
value.In the future we must do PCR analyses on the tissue,not only citobrush and we do
expect better results.Optimal values for test preformance we got for colposcopic degree and
for PAP analysis.
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P037
DIAGNOSTICS TOOLS IN CERVICAL PATHOLOGY (PAP,
COLPOSCOPY, AND PCR) IN 1147 PATIENTS AT MATERNO
INFANTIL HOSPITAL IN GRAN CANARIA, SPAIN
Falcón-Santana JM (1), Morín, JC (1), Lubrano A (1), Falcón-Vizcaino O (1), García JA (1),
Torres A (1), Arias MD (2), Pavcovich M (2), De Lera JM (2), Sánchez MA (2), León L (2),
Hernández T (2), Andújar M (2,3)
(1) Department of Obstetrics and Gynecology, (2) Pathology, and Molecular Pathology, (3) Laboratory.
Research Unit,. Hospital Universitario Materno Infantil de Canarias. Las Palmas de Gran Canaria.
Spain.
Introduction. The diagnosis of infection and typing of high risk human papillomavirus
(HPV) by molecular methods (mainly polymerase chain reaction, PCR) in cervical samples
has became of special interest and many consensus and guidelines recommend to use it in
clinical practice of developed lesions even in population screening.
Objective. The objective of this study is determine the sensitivity (S), specificity (E), positive
predicted value (PPV) and negative predicted value (NPV) for PAP, COLP and PCR as a
Single test or in combination in high grade lesion/cancer of cervix.
Patients, material and methods. 1147 patients had been refereed to Hospital Materno
Infantil de Canarias to colposcopy between 1998 to 2002. After consent was obtained a
standardised questionnaire was used to collect clinical information, samples (for PAP, PCR or
biopsies) were taken, and colposcopy was performed. PCR emploid consensus primers
My09/11, and specific primers for E6 HPV16 and E6 HPV18. The histopathological study
included biopsies and conizations, and these reporters were considered the gold standard.
Statistical analysis was made using SPSS 10.0 software.
Results. It is described the following variables in high grade lesion
PAP: S= 76%, E= 96%, PPV= 90%, NPV= 90%;
COLP: S= 84%, E=46 %, PPV= 39%, NPV= 88%;
PCR: S= 84%, E= 51%, PPV= 41%, NPV= 88%.
There is a similar S for PCR and COLP, that are lightly higher than PAP. In opposite way, de
NPV of PAP is higher than PCR or COLP.
Conclusions. PAP test remains being a very useful test in management of cervical pathology.
Although the NPV of PCR is lightly lower than PAP, its higher S give us important
information in high grade lesion indicates that these technique is very appropriated in
combination with other, overall in ruling out high grade lesion with PAP test negative. So we
recommend its inclusion in clinical practice and management of cervical pathology.
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AUTHORS
P038
VALUE OF HISTIOCYTES DETECTION IN PAPANICOLAOU (PAP)
SMEARS FOR PREDICTING ENDOMETRIAL PATHOLOGY
REVISITED - AN INSTITUTIONAL EXPERIENCE
Nassar, A., M.D (1)., Fleisher, S., CT (ASCP) (2), and Nasuti, J.,M.D (2).
Department of Pathology and Laboratory Medicine, Division of Cytopathology, Emory University
Hospital, Atlanta, GA (1) and University of Pennsylvania, Medical Center, Philadelphia, Pennsylvania
(2), U.S.A
OBJECTIVE: This study was undertaken to determine the clinical implications of the
finding of histiocytes in cervical/vaginal (Pap) smears in our patient population.
STUDY DESIGN: The medical records and Pap smears of patients in which the presence of
histiocytes was mentioned in the diagnosis, between August 1996 and August 2001 were
reviewed in conjunction with follow-up surgical findings. The positive predictive value (PPV)
for significant endometrial pathology for the isolated finding of histiocytes on Pap smear was
determined.
RESULTS: Of the 238,225 women screened over a 60-month period (1996-2001), 325 were
reported to have histiocytes in their Pap smears. Of these 238 patients (73.2%) had subsequent
endometrial sampling, hysterectomy or both and follow-up Pap smears. Two hundred and
seven (87%) failed to disclose endometrial pathology. Thirty one cases (13%) resulted in
significant histopathologic findings including: 12 uterine malignancies, eight endocervical
polyps, seven endometrial polyps, two submucosal leiomyomata, one simple hyperplasia
without atypia and one patient with tamoxifen-related changes. Upon review of the clinical
records, 58% (18/31) of those patients had other significant clinical and/or cytologic findings.
Five of the 18 patients (27.8%) had associated postmenopausal bleeding; 11 had additional
abnormal Pap smear findings (atypical glandular cells 6/18 - 33.3%; endometrial cells 5/18 27.8%); and another two had both postmenopausal bleeding and atypical glandular cells (2/18
- 11.1%). The PPV for significant uterine pathology for women with the isolated finding of
histiocytes on Pap smear is 5.5%, and 60% with additional clinical and/or Pap smear findings.
The PPV for endometrial cancer is 1.3% for women with the isolated finding of histiocytes on
Pap smear, but is 20% for women with histiocytes and additional clinical/or Pap smear
findings.
CONCLUSION: Based on the findings of this study and recently published data, we
conclude that the isolated finding of increased histiocytes in the absence of postmenopausal
bleeding or endometrial cells or atypical glandular cells on Pap smear, is a poor indicator of
uterine disease.
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AUTHORS
P039
IMPROVING HEALTH SYSTEMS TOWARDS EQUALITY-BASED
CONTROL OF CERVICAL CANCER IN LATIN AMERICA.
COMPARING PAP SMEAR CYTOLOGY, AIDED VISUAL
INSPECTION, CERVICOGRAPHY AND HUMAN PAPILLOMAVIRUS
(HPV) TESTING AS OPTIONAL SCREENING TOOLS IN BRAZIL AND
ARGENTINA.
MULTICENTRIC STUDY - DESCRIPTION OF DATA FROM PORTO
ALEGRE – BRAZIL
(1) Naud P, (2) Syrjänen K, (3) Hammes L , (3) Matos JC, (3) Barcelos MC, (3) Campos C, (3)
Dias E, (3) Magno VA, (3) Niederauer Ce, (3) Pereira C, (3) Prati R, (3) Stuczynski J, (4) Rose A,
(5) Pütten AC, (6) Ferreira P, (7) Campos E, (8) Lorincz A, (8) Dores G, (9) Artigalas O, (9) Costa
F, (9) Fontana G, (9) Höblick M, (9) Mano Mc, (9) Marques Pereira C, (9) Moreira I, (9) Olijnyk JG,
(9) Piccoli E, (9) Thome JG.
(1) Hospital de Clinicas de Porto Alegre - HCPA (Scientific Co-ordinator, Porto Alegre Centre Coordinator); (2) ISS, Rome, Italy (Project Co-ordinator); (3) HCPA MD ObGyn; (4) HCPA Psychologist;
(5) HCPA Pathologist; (6) Moogen Cytology Laboratory; (7) Caism Laboratory ; (8) Digene Corp; (9)
Federal University of Rio Grande do Sul Medical Students.
Introduction: The most vulnerable groups for cervical cancer are the poorest women. To
improve this ominous situation in two Latin American countries, Argentina (ASIR: 27.60)
and Brazil (ASIR: 30.55), which both belong among the high-risk countries of cervical cancer
(i.e. ASIR >22/100.000) it is being developed a study of cervical cancer screening and control
strategies.
Objectives: 1. To compare the performance and cost-effectiveness of aided visual inspection
(AVI), Human Papillomavirus (HPV) testing, cytological (Pap test) and cervicography in
cervical cancer screening.
2. To improve the basic understanding of the epidemiology and pathogenic mechanisms of the
disease in Brazil and Argentina.
Methods: This is a multicentric study that includes patients from Brazil (Porto Alegre,
Campinas and São Paulo) and from Argentina (Buenos Aires). At first visit women were
submitted to Pap test, HPV testing and AVI. Cervicography were not performed at Porto
Alegre site. If woman had any alteration in these exams was submitted to colposcopy and, if
necessary, biopsy. Patients with HSIL were promptly treated and followed-up for 36 months.
Patients with LSIL, HPV infection or Pap test alteration are being followed-up until 36
months. 20% of all normal women will be submitted to HPV testing at 24 months to detect
new incidents cases.
Results: Until 31st December 2002 we have enrolled 2755 patients. Characteristics of this
group (mean - std.dev): 41.29 - 10.70 yo, 8.05 - 3.59 y education, 18.80 - 4.05 yo at first
sexual intercourse, 2.88 - 4.23 sexual partners since first sexual intercourse, 0.90 - 0.49 sexual
partners last 12 months and 3 - 1.91 pregnancies in all life. From the all group, 13.2% referred
previous STD and the most used contraceptive method (54.1%) was hormonal.
Results of Pap test were available from 1821 women: 1763 (96.8%) normal, 13 (0.7%) LSIL,
16 (0.9%) HSIL, 26 (1.4%) ASCUS, 1 (0.1%) AGCUS and 2 (0.1%) carcinomas. Results of
HPV testing were available from 545 samples: 66 (12.1%) abnormal and 479 (87.9%) normal.
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AVI was altered in 22.9% of all patients. Results of biopsies were available from 114
specimens and 36 of them were altered: 5 (13.9%) HPV infection no-CIN, 2 (5.6%)
condyloma acuminatum, 19 (52.8%) CIN I , 1 (2.8%) CIN II, 8 (22.2%) CIN III and 1 (2.8%)
carcinoma.
Conclusion: After the complete analysis of our data (n=3000) we can compare the
performance characteristics and cost-effectiveness of conventional and optional screening
tests in our set. We also will be able to improve the understanding of this disease and premalignant lesions in our region.
EUROGIN 2003
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POSTERS
AUTHORS
P040
THE CORRELATION BETWEEN P16INK4A PROTEIN AND HPV DNA
DETECTION IN SCRAPED CERVICAL CELLS
Pientong Ch (1), Ekalaksananan T (1), Kritpetcharat O (2), Kongyingyoes B (3), Swadpanich U
(4), Yuenyao P (5), Ruckait N (6).
(1) Department of Microbiology, (2) Department of Pathology, (3) Department of Pharmacology, (5)
Department of Obstetrics and Gynecology, (6) Department of radiology, Faculty of Medicine, Khon
Kaen University, (4) Khon Kaen Hospital, Khon Kaen, Thailand.
To correlate between p16INK4a protein and HPV DNA detection in scraped cervical cells, we
collected duplicate cervical scrapes from each participant who was screened for cervical
cancer. The first scrape was routinely smeared for Pap test and the second scraped cells were
washed three times and subsequently prepared two aliquots (50-l) of cell suspension. The first
aliquot cells were extracted for DNA that used for examination of HPV DNA and HPV
genotyping by polymerase chain reaction and dot blot hybridization respectively. The second
aliquot cells were lysed in lysate buffer. The lysate was determined for p16INK4a protein
using 14%SDS polyacrylamide gel electrophoresis and subsequently western blot analysis.
SiHa cell and embryonic lung fibroblast cell were positive and negative cell control
respectively.
According to a Pap test, samples were grouped as control (normal cervical cell), mild grade
dysplasia (ASCUS, LSIL) and high abnormality (HSIL, SCC). Thirty samples of each group
were studied. P16INK4a protein was detected in 17 of 30 (56.67%) ASCUS and 10 of 30
(33.33%) LSIL. Interestingly, p16INK4a protein detection in high abnormality group display
high signal level consistent with the large numbers of abnormal cervical cells which increased
to 100% (30 of 30) in HSIL and SCC. Samples of control group were negative for p16INK4a
protein. HPV DNA was detected in 86.67%, 70%, 40%, 43% and 10% in SCC, HSIL, LSIL,
ASCUS and normal cervical cell respectively. High risk HPV was identified in all HPV
positive samples in high abnormality group, whereas only 30% of HPV positive samples in
both LSIL and ASCUS were revealed as high risk. In addition, low risk HPV was identified in
all HPV positive control group. As all the high risk HPV positive samples showed positive
p16INK4a protein, HPV DNA detection was thus considered as less sensitive than p16INK4a
protein detection, probably due to the error of PCR method in scraped cervical cells.
This study showed that p16INK4a protein detection correlated well with high risk HPV
infection in abnormal scraped cervical cells and might be the sensitive method for cervical
cancer screening.
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P041
RIGHT MOTIVATION AS A KEY TO SUCCESSFUL SCREENING
POTANCOK B., SADOVSKY O.
National Cancer Institute Bratislava, Slovakia, Department of Gynecologic Oncology
In Slovakia, the mortality rate of cervical cancer is alarming. Despite of the preventive actions
taken by all previous governments in the last twenty years, the mortality rate increased from
5.4 to 7.9 per 100 000 women between years 1980 and 2000. How could it happen in a
country with a very good standard of the healthcare system, a sufficient number of
gynaecologists and a very good standard of cytology and colposcopy practised as a routine to
diagnose the cervical carcinoma and its precursors ? The answer is complex: it is due to a bad
organisation of the screening practice, medical staff´s apathy and an insufficient public health
knowledge Findings of the survey based on a representative sample of Slovak adult female
population fully confirm these presumptions. The key step in the organisation of mass
screening practice is to find the right motivation for all participants - medical doctors, patients
and insurants. At the moment, we recognise two kinds of the motivation - the positive one and
the negative one. The authors prefer the positive one and offer their projects to increase the
positive motivation for screening practice. They have established premiums for gynecologists
and pathologists for diagnosing an early carcinoma or its precursors and there is also a bonus
system for the patients. Unfortunately, without any advertising on TV, radio, in magazines
and on billboards, oriented to increase the public health knowledge about cervical carcinoma,
the screening practice will remain unsuccessful.
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AUTHORS
P042
BONE MINERAL DENSITY CAN BE PREDICTED FROM PAP
SMEARS
Repse-Fokter A, Fokter SK, Komadina R
Celje general hospital, Dept. for pathology and citology, Celje, Slovenia
Objective: Osteoporosis is an increasingly prevalent bone disease. The key to the treatment of
osteoporosis lies in prevention and requires screening of non-symptomatic population, which
may not be cost-effective. The present study attempted to find out possible coherence between
morphologic characteristics in Pap smears on one side, and BMD as measured by DEXA on
the other.
Method: Four different lumbar spine and left hip regions were automatically scanned in 50
women whom Pap smears for routine cervical cancer screening were taken. The smears were
grouped into atrophic and mature cell patterns, which can easily be recognised during routine
screening. Using astereological analysis, the mean areas of squamous cells, their nuclei,
cytoplasm and nuclear-cytoplasmatic ratio were estimated.
Result: The mean areas of cells and cytoplasm were significantly lower at lower T-scores (p
< 0.01), while the mean areas of nuclei were not (p > 0.5). Nuclear cytoplasmatic ratio was
higher at lower T-scores (p < 0.01). T-scores of all hip and spine regions were significantly
lower in atrophic cell pattern group. The correlation of BMD with cell pattern was more
important than correlation with age (ANOVA). The study group indicated concurrently high
sensitivity and specificity of 80%, with positive predictive value of 85.71%.
Conclusion: These results suggest that a significant number of women with low BMD could
be identified parallel with the routine Pap test for cervical cancer screening without additional
costs.
EUROGIN 2003
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P043
HPV TESTING BY HYBRID CAPTURE II IN SELF-COLLECTED
SWAB AS AN OPTIONAL SCREENING TOOL FOR CERVICAL
CANCER
Roteli-Martins, CM; Galvane, JO, Lima, TP, Silva, CG, Wolf, C, Martins, LM, Cason, S, Arlindo,
FC, Figueredo, SF, Santos, LB, Longatto-Filho, A, Mariani-Neto, C, Pereira, SMM, Utagawa, ML,
Maeda, M, Syrjänen, KJ
Leonor Mendes de Barros Hospital; Sao Paulo; Istituto Superiore di Sanita, Rome, Italy; Adolfo Lutz
Institute, São Paulo, Brazil. (The LAMS Study, supported by the INCO-DEV Program of the European
Commission; Project # ICA4-CT-2001-10013). The contribution of Digene (Dr. Lörincz) and Digene
Brazil (Dr. Dores) is gratefully appreciated.
The optional tools used for screening for cervical neoplasia include testing for HPV
(conventional and self collected). The feasibility of these diagnostic tools will be tested in
target population at different risk for cervical cancer in two Latin American countries.
Objective is to present results from testing for high risk HPV-DNA using cervicovaginal
swabs obtained by self-collected swabs and compare the test performance to cytological
diagnoses.
Methods: Until now, 102 women aging 21 to 57 years have been enrolled in this cohort. The
exclusion criteria were: age above 60 years, previous diagnosis of cervical abnormalities,
pregnancy and presence of immunodeficiency. The women completed study questionnaire
recording general personal information, medical history and implicated risk factors. The
women were instructed to use a self-administered tampon before the physician-directed
cervical samples were collected for conventional Pap smear. All samples were tested for the
high-risk HPV types using Hybrid Capture II (Digene, Brasil). All women with an abnormal
result were referred to colposcopy at the first or second visit
Results: High-risk HPV-DNA was detected in 25 swabs (24.5%). Conventional Pap smear
detected 7 cases (6,8%) of atypical squamous cells of undetermined significance (ASCUS), 1
(0,9%) case of LSIL, 1 case (0,9%) of HSIL, 1 (0,9%) case of AGC and 5 (4,9%) were
considered inadequate. The high-risk HPV-DNA was positive in 14/87 normal smears, 4/7 of
the ASCUS result as well as in the LSIL result. All cervical smears reported as HSIL
presented the high-risk HPV-DNA type. The test was positive also in 14 cases of normal and
adequate cytology and 1 inadequate smear. The biopsy directed by colposcopic examination
showed 2 invasive cancer (1 inadequate and 1 normal smear, both HPV positive by selfsampling)
Conclusions: The results indicate a high prevalence of high-risk HPV among these women
and high-risk HPV-DNA testing using self collected vaginal swabs can be used in populationbased screening to identify women at risk for cervical neoplasia
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P044
HPV TESTING FOR TRIAGE OF ASCUS AND LSIL: A METAANALYSIS.
Tisci S. (1), Hartmann K. (1,2), Hall S. (1), MacLehose R (1). Zolnoun D. (2), Boggess J. (2)
University of North Carolina Schools of Public Health (1) and Medicine (2), Chapel hill, USA.
PURPOSE: To critically appraise the diagnostic characteristics of HPV testing with hybrid
capture II (HCII) for triage of women with low-grade Pap test abnormalities. DATA
SOURCES: We conducted a systematic search of English-language literature from 1966 to
July 2002 using the terms: cervical neoplasms, mass screening, vaginal smears, human
papillomavirus; and screening, in MEDLINE. STUDY SELECTION: We included
publications with ³50 subjects with ASCUS/LSIL Paps and HPV HCII test results, and
required that a colposcopy/histology reference standard be applied so that all cells of a 2x2
contingency table relating HPV to dysplasia status could be completed. DATA
EXTRACTION AND META-ANALYSIS: Two independent reviewers screened abstracts
and the reviewed full publications extracting study design, HPV testing method(s),
population, and results of HPV testing related to colposcopy/histology findings among those
with ASCUS/LSIL. Tests of heterogeneity were assessed and inverse variance weights were
used to estimate test characteristics and confidence bounds.
DATA SYNTHESIS: Six of 1209 publications met criteria. Eligible studies had 3826
participants grouped by classification of initial Pap: 192 ASCUS; 218 LSIL; and 3416
ASCUS/LSIL. Sensitivity for detecting CIN2 or higher grade lesion was 52.2%, 77.4% and
96.2%; specificity, 77.6%, 52.9%, 58.9%; and NPV, 95.3%, 87.8% and 98.9%, respectively
by group. Based on the studies of ASCUS, for each 100,000 women with ASCUS, negative
HPV testing could defer 69,790 colposcopies, which would delay diagnosis of 2,090 cases of
CIN3, with no missed squamous cell cancers. CONCLUSIONS: Despite a robust literature
on detection of cervical dysplasia, relatively few researchers have presented their findings in a
fashion that supports estimation of HPV test characteristics for triage. Our meta-analysis
suggests that HPV HCII testing will be most helpful in deferring colposcopy for HPV
negative women with ASCUS results. Additional research and analysis of existing data may
allow more confident projections about the outcomes of such an approach.
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P045
DETECTION OF HPV ON PARAFIN-EMBEDID CERVICAL
PRENEOPLASTIC AND NEOPLASTIC LESIONS: TWO SYSTEM
COMPARISON
(1) Mirt Dabic M, (2) Babic D, (2) Jukic S, (1) Seiwerth S, (2) Hlupic LJ, (2) Ilic J, (2) Kos M, (3)
Corusic A, (3) Ljubojevic N.
(1) Dpt. of Molecular Pathology, (2) Dpt. of Gynaecological and Perinatal Pathology and (3) Dpt. of
Gynecology and Obstetrics Medical University of Zagreb, Croatia
AIM: To determine the prevalence of type specific HPV infection in 88 randomly chosen
neutral-buffered, formalin-fixed, paraffin-embedded biopsies and cone specimens according
to histopathological diagnosis. Two molecular methods were evaluated: polymerase chain
reaction (PCR) with consensus- and type-specific primers and a novel procedure of in situ
hybridization (CSA-ISH).
METHODS: DNA was extracted from paraffin-embedded samples and used as a template to
amplify with 3 pairs of consensus and 4 type-specific HPV primers. The same blocks were
analyzed with CSA-ISH method using commercial HPV biotynilated probes HPV- 6/11,
16/18 and 31/33/51.
RESULTS: HPV-X (undetermined type) was detected in higher percentage in condyloma
planum or CIN I (33.3%) but it was also found in significant part of high grade lesions - CIN
II, III (25%). HPV-6/11 was detected exclusively in condyloma accuminatum group. In
samples diagnosed as CIN I (73.7%) HPV wasn't detected. HPV-16 was the most prevalent
type, and increases with the grade of lesions (5.3-73.3%). The degree of concordance for PCR
and CSA-ISH was 64.4%.
CONCLUSION: High proportion of CIN I lesions are (HPV)negative 73.7%. Our
assumption is they won't progress. This finding could be important in planning therapy and
avoiding unnecessary treatment. A significantly higher number of positive samples is detected
with PCR then with CSA-ISH method (P < 0.01).In this study a group of 20 high grade
lesions were positive on HPV by PCR, but negative by CSA-ISH, showing that the sensitivity
of this method has to be improved in order to be optimally used in routine practice
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P046
VALUE OF HISTIOCYTES DETECTION IN PAPANICOLAOU (PAP)
SMEARS FOR PREDICTING ENDOMETRIAL PATHOLOGY
REVISITED - AN INSTITUTIONAL EXPERIENCE
Choi HS,Lee GY,Kim SM,Suh SP (1),Park CS (2),Nam JH (2)
Dept. of obstetrics and gynecology, Laboratory Medicine (1),Pathology (2),Chonnam University
Medical School,Gwangju,South Korea
Although the use of cytology in screening has reduced morbidity and mortality from invasive
cervical cancer,there has been limitation because of the low sensitivity and high false negative
rate in the detection of cervical cancer and precancerous lesions. This study was performed to
explore the usefulness of HPV test as a diagnostic method of cervical cancer and precancer.
HPV tests (Hybrid capture II and HPV DNA Chip), Thinprep cytology and biopsy were
performed in 400 women. HPV positivity of Hybrid capture II and HPV DNA Chip test
showed Normal:56.8%,53.8% CINI:91.5%,91.5% CINII:88.1%,81.0% CINIII:88.6%,84.2%
Cancer:92.5%,88.7% respectively. HPV type 16,58,18 and 52 were detected frequently.
Sensitivity of Thinprep cytology,Hybrid capture II and HPV DNA Chip test was
88.4%,89.9%,86.2% respectively. HPV DNA test may be considered as a useful screening
test in cervical cancer screening.
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AUTHORS
P047
USE OF HPV TESTING IN MANAGEMENT OF WOMEN WITH
ASCUS/LSIL
Sesti F. (1), Ciotti M. (2), Paba P. (2), Benedetto A. (2), Criscuolo A. (1), Branca M. (3), Favalli C.
(2), and Piccione E. (1)
University of Rome 'Tor Vergata' (1) Department of Surgery - Section of Gynecology and Obstetrics
(2) Department of Laboratory Medecine - Clinical Microbiology Laboratory (3) Istituto Superiore di
Sanità, Rome, Italy
The appropriate management of the women with equivocal cytological abnormalities (atypical
squamous cells of undetermined significance [ASCUS]) or low-grade squamous
intraepithelial lesions (LSILs) is currently debated and controversial. Sensitive molecular
methods for detecting high-risk types of HPV are now available, and can represent useful
alternatives to traditional approaches for managing the women with minor cytological
abnormalities. Sixty-two women with ASCUS (n=32) and LSIL (n=30) were enrolled into the
study. Their ages ranged between 19 and 66 (median: 39). Twelve women were
postmenopausal. In our series high risk types of HPV were identified in 9% and 43% of
women with ASCUS and LSIL, respectively. In women with ASCUS, the detection of
biopsy-confirmed CIN 1 was 12.5%, and of CIN 2,3 was 3.1%. In women with LSIL, a
biopsy-confirmed CIN 1 was found in 30%, and CIN 2,3 in 16.6%. HPV testing for high-risk
types was positive in all women with biopsy-confirmed CIN 1 or CIN 2,3, whereas was
negative only in one woman with initial LSIL and biopsy-confirmed CIN 1. Our results
confirm the data from the literature that the sensitivity of HPV DNA testing (0.83-1.0) for the
detection of biopsy-confirmed CIN 2,3 in women with ASCUS is elevated, and higher than
the sensitivity of a single repeat cervical cytological test. In contrast, HPV DNA testing does
not appear to be useful for the initial management of women with LSIL, as confirmed by our
data.In conclusion, HPV testing can be the preferred approach in the initial management of
women with ASCUS. All women who test positive for HPV DNA should be referred for
colposcopy. Women who test negative for high-risk types can be followed up with repeat
cytological testing at 6-12 months. In women with LSIL, if biopsy fails to confirm CIN, HPV
testing can be performed in their follow-up. Some problems remain open, such as how to
manage women who test positive for high-risk HPV, but who turn out to have CIN.
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P048
A SIMPLE PROCEDURAL MODIFICATION FOR THE HYBRID
CAPTURE 2 HPV DNA TEST THAT STRENGTHENS ACCURACY
Cullen, A., Modarress, K., Shults, S., Collier, C., Lorincz, A.
Digene Corporation, Gaithersburg, Maryland, USA
The Hybrid Capture® 2 (HC2) HPV DNA Test is an important part of cervical cancer
screening as evidenced by the recent Consensus Guidelines for the Management of Women
with Cervical Cytological Abnormalities (ASCCP) which recommend HPV DNA testing for
High Risk types to assist in proper clinical management of abnormal Pap results. To ensure
that the HC2 test procedure is as robust as possible, we developed a simple procedural
modification that renders the test less dependent on user technique for accurate results.
When HC2 is performed in strict accordance with the product insert instructions, reproducible
results are obtained. Accidental introduction of undenatured clinical material into a later step
of the assay was also evaluated using an improper pipetting technique (IPT) model. A simple
procedural modification to the HC2 assay was then developed that improved denaturation
when using the IPT model; this is accomplished by adding a short incubation of the denatured
specimen in an empty hybridization plate prior to the addition of the neutralizing probe mix.
To verify the modified procedure, 200 PreservCyt specimen pools were evaluated with both
the current and modified test methods using proper technique and IPT. Compared to a
consensus result, the overall agreement of the current method using proper or improper
technique was 97.0% and 67.0%, respectively. However, with the modified method, the
agreement of proper and improper technique to the consensus was 98.5% and 95.5%,
respectively.
These data demonstrated good reproducibility with the HC2 assay when proper pipetting
technique was used and confirmed the existence of a technique-dependent mechanism with
the potential to produce false-positive results as described in the product labeling. The
proposed modified test method reduced false results when IPT was used, while maintaining
the high sensitivity and accuracy of the test for detecting HPV DNA.
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P049
LIQUID BASED CYTOLOGY AND HPV DNA DETECTION IN
WOMEN WITH MINOR GRADE CYTOLOGIC ATYPIA
Divani S, Vardouli A, Margari N, Margari C, Parathira M, Dinou N
Department of Cytology, Volos General Hospital, Greece
Objective : HPV infection contributes to the development of almost all CIN, since it is the
main etiological agent in cervial carcinogenesis. The prevalence of HPV infection is high in
young women and delcines with age. The aim of our study was to investigate the specific
HPV types affecting women mith minor atypia.
Methods : 146 cervical specimens collected and processed according to THIN PREP 2000
method were prepared with the Human Papilloma virus (HPV) In Situ Typing Assay (DNA
hybridization) for cervical speciments. All speciments were obtained from selected women
with atypical sqamous cells of undetermined significance(ASCUS) or low grade squamous
intraepithelial lesions (LGSIL).
Results : HPV infected calls were detected in all cases. The typing results were : HPV 6/11
was found in 84 woman (57,5 %), HPV 16/18 in 86 women (58,9 %) and HPV 31/33 in 98
women (67,1 %). In 8 cases (5,5 %) the HPV 6/11 was the only one that was detected. Both
types HPV 16/18 and HPV 31/33 were found in 88 women (60,3 %).
Conclusion : Biological tests such as the detection of carcinogenic HPV – DNA show often a
higher sensitivity in speciments with minor cytologic atypia. High risk HPV cn be detected in
60,3 % of these cases.
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P050
ATYPICAL GLANDULAR CELLS AND HIGH RISK-TYPES HUMAN
PAPILLOMAVIRUS DETECTION BY HYBRID CAPTURE II
De Oliveira ERZM (1), Derchain SFM (1), Gontijo RC (1), Dos Santos SHR (1,3), Zeferino LC (1),
Westin MCA (2), Amaral RG (1,3)
(1) ObGyn Department, (2) Cytopathology Unit, Universidade Estadual de Campinas Campinas (3),
Faculdade de Farmácia; Universidade Federal de Goiania - Brazil (3)
Background and objective: The use of HPV-DNA testing in women with atypical glandular
cells (AGC) at Pap smear is still controversial. To compare the result of follow-up Pap smear
and high-risk types HPV-DNA detection in women referred to Colposcopy Clinic for AGC
result in Pap smear.
Material and methods: For this clinical descriptive study, 91 women admitted at the
Colposcopy Unit of the Universidade Estadual de Campinas due to an abnormal Pap smear
showing ACG were included. All women were submitted to a new Pap smear, and material
for HPV DNA detection was collected using Hybrid Capture II (HC II). Referral and second
Pap smear were available for all women and the diagnostic was rendered according Bethesda
System (2002). Chi-square and Fisher tests were used for statistical analysis.
Results: Regarding the new Pap smear result, 28 (30.7%) cases presented only normal or
inflammatory features, 14 (15.3%) showed atypical squamous cells of undetermided
significance (ASC-US), 4 (4.4%) showed atypical squamous cells cannot excluded high
squamous intraepithelial lesion (ASC-H), 6 (6.5%) presented HSIL, 5 (5.5%) in situ
adenocarcinoma, 4 (4.4%) invasive carcinoma and 30 (32.9%) remained as AGC, associated
with ASC-H in four cases and with HSIL in nine. Among the 91 studied women, HC II test
was positive in 33 (36.2%). Detection of high risk-types HPV-DNA was significantly
associated (p<0.01) with AGC (13 HPV-DNA positive/30 cases), HSIL (5 HPV-DNA
positive/5 cases) and in situ adenocarcinoma (5 HPV-DNA positive/6 cases) at the new Pap
smear. Among women with normal or inflammatory result, ASC-US or ASC-H at new Pap
smear, the HPV-DNA detection rate was significantly lower.
Conclusion: Detection of high-risk types HPV-DNA was significantly associated with
morphological abnormalities at new Pap smear, in women referred for AGC.
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P051
HPV GENOTYPING BY PCR, RFLP, SEQUENCING AND LINE PROBE
ASSAY
Milutin N, Matovina M, Husnjak K, Grce M
Rudjer Boskovic Institute, Division of Molecular Medicine, Zagreb
In 1993, in Croatia, cervical cancer was in the third place, following breast and stomach
cancer in Croatia. HPV infection is a major risk factor for cervical cancer development. The
objective of this study was to compare different methods of HPV genotyping: polymerase
chain reaction (PCR), restriction fragment length polymorphism (RFLP) analysis, sequencing
and Line probe assay (LiPA, Innogenetics).
The presence of HPV was evaluated in cervical samples collected at different gynaecological
clinics in Zagreb (Croatia). HPV DNA was detected by PCR using two sets of universal
primers (MY09/MY11 and L1C1/L1C2) and type-specific primers for HPV 6/11, 16, 18, 31
and 33 as previously described (1). A subset of MY09/MY11-positive high-grade neoplasia
samples was analysed by RFLP and LiPA test. HPVs undetermined by RFLP and/or LiPA
were further analysed by sequencing.
Out of 225 high-grade cervical intraepithelial lesions specimens, 81.8% were positive, of
which 57.4% were determined by types-specific directed-PCR and 24.4% remained untyped.
The most frequently observed type was HPV 16 in 33.8%. Out of 55 HPV untyped
specimens, 35 were chosen for further analyses by RFLP and LiPA of which some of them
were also sequenced. Thus, single HPV infection was determined in 20 (57.1%) and 21 (60%)
cases, multiple infections in 4 (11.4%) and 10 (28.6%) cases, by RFLP and LiPA,
respectively. RFLP and LiPA did not determine HPV types in 11 (31.4%) and 4 (11.4%)
cases, respectively. The remaining HPV-positive unresolved specimenc were finally defined
by sequencing.
The advantage of sequencing and RFLP of PCR products over LiPA is to allow genotyping of
more different HPV types, but the disadvantage is the disability to discriminate multiple HPV
infections, clearly enough. The overall frequency of multiple HPV infections among highgrade cervical intraepithelial lesions, concidering types-specific directed-PCR and LiPA
findings represents 11.5%. HPV 16, also present in multiples HPV infections, remains the
most abundent HPV type and herein it is found in 40.4% cases.
(1) Grce M et al., Anticancer Res 21: 579; 2001
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P052
COMPARISON OF HUMAN PAPILLOMAVIRUS STATUS IN HIGH
RISK TEENAGE AND ADULT FEMALE PATIENTS:
CYTOHISTOLOGIC CORRELATION
Kanbour A, Puccio A, Kanbour-Shakir A, Shakir N, Guido R.
Magee-Womens Hospital of UPMCHS, Pittsburgh, PA.
Background: Human Papillomavirus (HPV) infection is considered to be the most common
sexually transmitted disease in both teenagers and adults and high risk factor for development
of squamous intraepithelial lesion (SIL) and cancer.
Objectives: To evaluate prevalence of high-risk genital HPV, using Digene Hybrid Capture
II, its association with cytohistological abnormalities in high-risk teenagers and compare them
with high-risk adults.
Material and Method: 314 high-risk patients attending colposcopy clinic from 11/01-7/02
were studied. Forty nine (16%) were 16-19 years old and 265 (84%) were 20-60 years old.
Pap smear specimens were collected and received in Cytyc preservcyt fluid. Thinprep Pap
smears were prepared, stained according to manufacturer's instructions, evaluated and
classified according to 1991 Bethesda classification. The remainder of preservcyt fluid was
used for Digene Hybrid Capture II test for high-risk HPV. Corresponding colposcopic
biopsies were obtained and correlated with Pap smear and HPV testing results.
Result: 20/49 (41%) teenagers had a negative Pap smear and 29 (59%) had epithelial cell
abnormality (ECA). The ECA diagnoses were 11 ASCUS, 16 LSIL and 2 HSIL. 22 (45%)
teenagers had cervical biopsies. The biopsy findings were: 3 reactive epithelial atypia (REA),
16 LSIL, and 2 HSIL.
78/265 (29%) adults had a negative Pap smear, 187 (71%) had ECA, as follows: 90 ASCUS,
76 LSIL and 19 HSIL. 130/265 (49%) had cervical directed biopsy. The biopsy findings were:
32 REA, 75 LSIL, and 23 HSIL.
High-risk HPV testing in teenagers was positive in 45% compared to 40% in adults. A
positive HPV test with negative Pap smear was 25% in teenagers and adults. Correlation of
biopsy diagnoses and the presence of HPV, in both groups, was 44% in the reactive changes
and about 98% in LSIL and HSIL.
Conclusion: The prevalence of ECA in teenagers was 59% compared to 71% in adults. The
positive high-risk HPV testing was 45% in teenagers compared to 40% in adults. Positive
HPV test with negative cytology was 25% in both groups. The HSIL cytological abnormality
in teenagers was 4% HSIL compared to 10% in adults. The latter finding is probably related
to the fact that adult patients had longer history of cervical cytological abnormalities,
compared to the teenagers.
We recommend that teenagers with low-grade cervical intraepithelial lesion and HPV
infection to be managed conservatively with cytology follow-up rather than by colposcopy
and biopsy.
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P053
COMPARISON OF HYBRID CAPTURE II AND PCR TO IDENTIFY
HPV INFECTION IN THE NEW UCM MEDIUM - STUDY IN 263
CONSECUTIVE SAMPLES.
Nonogaki, S (1); Wakamatsu, A (1); Alves, Vaf (1); Pereira, S (1); Utagawa, M (1); Maeda, M (1);
Roteli-Martins, C (2); Syrjänen, K (3); Longatto-Filho, A (1)
Pathology Division of Adolfo Lutz Institute, São Paulo, Brazil 1; Leonor Mendes de Barros Hospital 2,
São Paulo, Brazil; Istituto Superiore di Sanità, Roma, Italy 3
Hybrid capture II is a widely used assay to detect HPV infection under routine conditions and
PCR analysis is frequently used to the research investigation due to its higher sensitivity.
Recently, DIGENE have introduce the new Universal Collection Medium (UCM) to replace
the STM medium. The new medium serves to liquid-based cytology and molecular biology
purposes. The goal of this study was to analyze the performance of the Hybrid-Capture II with
new UCM medium and to compare with PCR assay. The samples were collected from
consecutive women enrolled in the ongoing screening study (INCO-DEV ICA4-CT-200110013) examined at Leono Mendes de Barros Hospital. Negative and positive cases for high
risk HPV detected by HC II were submitted to PCR in the same UCM sample. For PCR
assay, the samples were purified with GFXTM Kit and amplified with PGMY09/PGMY11
primers without biotinylation and GH20/PCO4 for globin, a multiplex PCR assay. Full
agreement between the methodologies results was observed in 102 positive cases and 97
negative cases (76,5%); discordance was observed in 61 cases (23,5%): 33 PCR (+)/HC II (-)
and 28 (PCR (-)/HC II (+). From PCR negative cases, 27 showed HC II positive reaction
inferior to low viral load and 1 between medium viral load. From the PCR positive cases 62
HC II showed positive reaction to low viral load, 13 cases to medium viral load and 27 high
viral load. Three cases were excluded due to technical reasons. Our results clearly
demonstrate that the new medium UCM preserves HPV-DNA for molecular investigation
with results similar to the STM.
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P054
UTILITY OF P16INK4A AS AN ADJUNCTIVE TEST IN LIQUID BASED GYNECOLOGIC CYTOLOGY SUREPATHTM
PREPARATIONS
Nassar, A., M.D., Cohen, C., M.D., Lewis, M., M.D.
Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA, U.S.A.
BACKGROUND: Human papillomavirus (HPV) is recognized as a causal agent for cervical
carcinoma. Assimilation of HPV oncogenes E6 and E7 into the host DNA promotes
upregulation of cyclin dependent kinase inhibitor (CDKI) p16INK4A, detectable by
monoclonal antibody in developing cervical cancer cells. Some investigators have used
p16INK4A in liquid-based cervical - vaginal cytology specimens and have advocated its
utility as a surrogate marker in gynecologic cytology for high-risk HPV infection and for the
development of cervical neoplasia. The aim of this study is to develop a protocol for
p16INK4A immunocytochemical staining on SurePathTM specimens and assess its utility in
a spectrum of benign and neoplastic lesions.
DESIGN: Thirty-eight specimens (10 non-neoplastic/non-dysplastic cases [NN], 9 benign
reactive cellular changes [BCC] , 14 atypical squamous cells [ASCUS], 4 low-grade
squamous intraepithelial lesions [LSIL], and 1 high-grade squamous intraepithelial lesion
[HSIL] were reprepped by SurePathTM . Immunohistochemistry was performed after steam
antigen retrieval with p16INK4A monoclonal antibody (Neomarkers) (1/100), and the Dako
Envision + System. Expression of p16INK4A within the nucleus principally and cytoplasm of
at least 10-15 cells was considered positive. All initial Papanicolaou (Pap) stained discrepant
cases (p16INK4A positivity in NN or BCC, and lack of reactivity in LSIL and HSIL) were
reviewed. In addition, all Pap stained ASCUS cases that showed positivity with p16INK4A
antibody were reviewed.
RESULTS: Five of ten (50%) NN, 1/9 (11.1%) BCC, 2/4 (50%) LSIL and one (100%) HSIL
specimens demonstrated the presence of p16INK4A. Re-evaluation of discrepant cases (8/24 33.3%) revealed that four (3 NN and 1 BCC) were atrophic smears; the diagnosis on all
discrepant cases remained the same. Following reassessment, false positive staining was
present in 6/19 (31.6%) [5 NN and 1 BCC] with 4 atrophic; false negative staining was
detected in 2/4 (50%) LSIL.
Two of 14 (14.3%) ASCUS cases showed positive immunostaining for p16INK4A antibody.
Retrospective review of these revealed rare small HGSIL "litigation" cells, interpreted as
ASCUS favor HGSIL, one in an atrophic background.
CONCLUSION: A p16INK4A immunocytochemical stain can be applied to liquid-based
cervical-vaginal preparations. It can be used as an adjunctive test in ASCUS cases to triage
those that need further investigation (i.e. HPV DNA testing or colposcopic biopsies). Further
assessment of p16INK4A - positive atrophic cases is necessary to decide whether they are
true false positives or atrophic smears with underlying atypia. There is a need to explore the
association between p16INK4A and Digene Hybrid Capture(R) 2 HPV DNA Test (HC).
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P055
PERSISTENCE OF HIGH RISK HPV SPECIFIC GENOTYPES IN
WOMEN
Perrons C (1), Jelley R (1), Kleter B (2), Quint W (2), Brink N (1)
(1) Department of Virology, Royal Free and University College Medical School, London and UCLH,
UK. (2) Delft Diagnostics Laboratory, Delft, The Netherlands
Background: HPV genotypes associated with cervical cancer are termed high risk (HR). For
progression to cervical cancer it is necessary for one or more individual HR HPV genotype to
persist at the cervix. Therefore it is important to know what HPV genotype persists in these
women.
Methods: Women in this study were attending a colposcopy clinic. Cervical samples were
taken at their initial and 2nd visit (approx. 6 months later). HR HPV DNA detection was
performed by Digene Hybrid Capture II (HCII) and the SPF10/LiPA system. The Digene HR
HCII probe can detect single or mixtures of HR HPV genotypes but cannot distinguish
individual genotypes in mixed populations. The SPF10/LiPA system can detect individual
HPV HR and low risk (LR) genotypes and can distinguish individual genotypes in mixed
populations.
Results: Digene HCII detected HR HPV in 100 samples, of which SPF10/LiPA detected 80
HR (80%), 18 LR (18%) and 2 were negative (2%). No HR HPV was detected in the
remaining 176 samples, of which SPF10/LiPA detected 62 HR (35%), 48 LR (27%) and 66
were negative (38%).
Comparison of HR HPV DNA detection with cervical cytology at first colposcopy:
Cytology Digene HCII SPF10/LiPA
Normal
(n=65)
28%
55%
BNC
(n=29)
45%
69%
LSIL
(n=22)
55%
50%
HSIL
(n=22)
77%
72%
HR HPV was detected at 1st and 2nd visit in 37/138 (27%) women by Digene HCII and
47*/138 women (34%) by SPF10/LiPA. *9 (19%) of these had different HR HPV genotype
at their 1st and 2nd visit.
Conclusions: The SPF10/LiPA detected a higher number of HR HPV infections. The
SPF10/LiPA detected more HR HPV infections in the lower clinical grades, but the numbers
were comparable at higher cytological grades. Of the 47 women who had HR HPV detected
by SPF10/LiPA at 1st and 2nd visit, 38 had the same genotype on their 2nd visit, indicating
that 9 of these women did not have a persistent HR infection but a new HR HPV infection.
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P056
HPV CLEARENCE AFTER TERAPY TREATMENT OF CERVICAL
INTRAEPHITELIAL NEOPLASIA
Ribacchi R. (1),Settonce S. (2),Fenocchio D. (1), Cantelmi M.G. (1),Ferranti M.G. (1),Ribacchi F.
(1), Prosperini A.P. (1); Ricciuti G. (2), Baiocchi G. (3),Damiani F. (2), Narducci P.L. (2).
(1) Anatomia e Istologia Patologica-Università di Perugia Italy, (2) Ospedale Assisi- Italy,
(3)Ambulatorio di Patologia del Tratto Genitale Inferiore Università di Perugia
On may 2000, we started HPV-TESTING of cervical intraepithelial neoplasia (CIN) whit the
following aims: 1) to know the epidemiology of HPV types in our geographic area and 2) to
verify the clearance of HPV after treatment of lesions.
METHODS: HPV- TESTING was performed on CIN I-III before and after treatment at
irregular intervals between 3 and 24 months.
Two methods were used: hybrid capture (HC-HR), that was done in an other institution, and
polymerase chain reaction for HPV L1, 6, 11, 16, 18, 31, 33. The patients were treated by
conization and (only few CIN I) by laser.
RESULTS:The sensibility of PCR is 93.1% . HPV, 16 (61.2%) was the most frequent; Types
11 (8.3%); 18 (4,6%); 31 (2.8%); 33 (1.38%); 6 (1.38%); and L1 (6.9%) followed.
One year later, 74 of 115 ( 69.3%) women were HC-HR or PCR negative for HPV. The
clearance of HPV was observed mainly after 3 or 6 months after treatment; in 4 cases (5.4%)
there was a recurrence of the disease. In 41 patients (35.6%) HPV-testing showed persistence
of viral infection and in 11 of them (26,8%) there was persistence or recurrence of the treated
lesions.
CONCLUSION: HPV-testing after surgical treatment showed clearance of the virus in the
majority of the patients. There fore this method is useful for monitoring the follow-up for
recurrence of the lesions.
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P057
VIRAL LOAD OF HUMAN PAPILLOMAVIRUS IN PATIENTS
TREATED FOR HIGH GRADE CIN BY LARGE LOOP EXCISION OF
THE TRANSFORMATION ZONE (LLETZ)
Rodriguez-Iglesias Manuel
Puerto Real University Hospital, Laboratory of Microbiology, Puerto Real (Cádiz)
Large loop excision of the transformation zone (LLETZ) is a method for to erradicate human
papillomavirus (HPV) in cervical displasic lesions. However is possible to found viral
persistence after LLETZ associated to genotype and viral load. We have evaluated
prospectively the HPV persistence in patients treated for high-grade CIN by LLETZ. Twelve
patients were selected obtaining cervical scrapes before LLETZ and three months after.
HPV DNA detection was done by high-risk (HR) and low risk (LR) hybrid capture probes
(HCII, Digene) quantified in pg/ml using a calibrator control and normalized by PCR
amplification of beta-globin gen. Also, all samples were studied by amplification using
GP5/6+ primers in real time PCR protocol. We used a household calibrator set obtained from
HPV-6 and -16 genome inserted in plasmid. Genotyping was done by line blot hybridization
(Innolipa HPV, Innogenetics) after PCR with SPF10 primers.
Before LLETZ in all patients was detected HR-HPV (media viral load = 565.9 pg/ml) and in
two patients mixed infection with LR- and HR-HPV. Negativization was observed in the
follow-up scrapes of 75% (n = 9) of the patients. Three patients were persistent positive after
treatment but with a strong decrease in the HR-HPV viral load (media viral load before/after
= 1,366.0 vs 59.6 pg/ml). It was statistical significance between media viral load in nonpersistent and persistent infected patients (565.9 vs 1,366 pg/ml). Two LR-HPV infections
were not reduced viral load after LLETZ.
In conclusion, using a highly sensitive method we found persistent virus in 25% of the
patients treatd by LLETZ. Viral load of HR-HPV in cervical scrapes after LLETZ for highgrade CIN is associated to the presence of residual CIN. LR-HPV seems more difficult to
erradicate than HR-HPV.
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P058
HPV VIRAL LOAD IN PREDICTING HIGH-GRADE CIN IN WOMEN
WITH ATYPICAL SQUAMOUS CELLS OR LSIL
Ferreira Santos, AL (1); Derchain SFM (3); Martins MR, (2); Sarian LOZ (3); Martinez EZ (3);
Syrjänen KJ (4)
(1) Department of Obstetrics and Gynecology (2) Department of Pathology Universidade de Taubaté
(3) Department of Obstetrics and Gynecology, Universidade Estadual de Campinas (UNICAMP) (4)
Cytopathology Unit, Laboratory of Epidemiology, National Institute of Health (ISS), Rome, Italy.
Objective: To determine whether the assessment of the viral load of the high-risk human
Papillomavirus (HPV) DNA is useful in predicting the detection of high-grade cervical
intraepithelial neoplasia (CIN 2 and 3) in women referred for Pap smears showing only
atypical squamous cells (ASC) or low grade squamous intraepithelial lesion (LSIL).
Methods: This cross-sectional study, linked to FAPESP 99/11264-0, was carried out with a
series of 119 women referred for ASC or LSIL between August 2000 and April 2001. All
women were subjected to a new Pap smear, HPV testing for the high-risk types using Hybrid
Capture II (HC II) and colposcopy, with cervical biopsies (n=97). Cervical lesions were
graded using the CIN classification, where normal colposcopy and/or biopsy-confirmed
cervicitis was classified as normal. Odds ratios (OR) using a 95% confidence interval (95%
CI) and a Receiver Operating Characteristics (ROC) curve analysis were used for calculating
the statistics.
Results: Cervical biopsies disclosed CIN 2 or 3 in 11% of the cases, being equally presented
among women referred for ASC or LSIL. HC II test was positive in 16% of women with ASC
and in 52% of those with LSIL (OR=5.8; 95%CI 1.4-26.7). Among women with positive HC
II test, 7% had normal cervix, 73% had CIN 1 (OR=6.3; 95% CI 1.8-23.8) and 20% had CIN
2 or 3 (OR=33.0; 95%CI 4.2-347.8). In ROC analysis for HCII in diagnosing CIN 2 and 3, the
area under the ROC curve was 0.784, and the viral load cut-off point of 10 RLU/CO
presented 77% sensitivity and 73% specificity. Second cytology showing at least ASC did not
accurately detect CIN 2 or 3 (OR=6.4; 95% CI 1.0-50.9).
Conclusions: The viral load of the high-risk HPV types was significantly associated with the
diagnosis of CIN 2 or 3 in women referred for ASC and LSIL abnormalities in their Pap
smear
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P059
HPV ACTIVITY TESTING IN HPV POSITIVE PATIENTS
Selkov S, Vedeneeva G.
Laboratory of Immunology, Institute of Obstetrics and Gynecology, S.-Petersburg, Russian Federation.
Objective. Human Papillomavirus (HPV) types 16 and 18 are considered to be the main
cause for the development of cervical intraepithelial neoplasia (CIN). The terms of HPV
persistence in the host and, coordinately, the risk of cervical displasia development and
progression are determined in much extent by virus activity.
Methods.181 women with different grades of CIN were investigated. The grade of CIN was
confirmed by Pap-smear. HPV DNA types 16/18 was determined by means of PCR. The
active phase of HPV infection was confirmed in HPV-positive patients by means of
immunocytochemical investigation (ICCI) of cervical smears (Viroactiv, Virofem
Diagnostica GmbH, Germany) and reverse-transcriptase reaction (RT PCR). The ICCI was
based on the detection of viral capsid proteins, which appears in the late phase of an active
infection.
Results. HPV DNA types 16/18 was detected in 84/181 (46.4%) women, among them 10
without atypia, 35 with CIN I, 16 with CIN II, 14 with CIN III, 9 with cervical Ca in situ. The
rates of HPV infection was 28.6% in patients without atypia, 44.9% with CIN I, 44.4% with
CIN II, 70.0% with CIN III, 75.0% with Ca in situ. The positive results by ICCI were
obtained with 11 (13.1%) patients, among them 1 without atypia, 8 with CIN I, 1 with CIN II,
1 with CIN III. The rate of active HPV infection was 10.0% in patients without atypia, 22.9%
with CIN I, 6,3% with CIN II, 7,1% with CIN III. There was no evidence of active HPV
infection in women with Ca in situ. The data of RT PCR correlated with ICCI. Only in one
case with CIN I the RT PCR data were positive while the ICCI results were negative
Conclusions. We had the proof of the active phase of an HPV infection in 13.1% of HPV
DNA positive women, preferably on the early stages of premalignant processes of the cervix.
The data of ICCI correlated with RT PCR data. The progression of CIN is much more
common compared to HPV eliminaion in such cases. Therefore women with active HPV
infection need a more thorough surveillance, examination and treatment.
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P060
DETECTION OF HIGH-RISK HPV TYPES: ANALYSIS OF
DISCORDANT RESULTS BETWEEN HYBRID CAPTURE II AND PCRBASED ASSAY.
Shipulina O., Kuevda D., Shipulin G.
Central Research Institute for Epidemiology, Russian AIDS Center, Moscow, Russia.
BACKGROUND. There are two widely used approaches for the detection of high-risk HPV
types: hybridization-based assay (Hybrid Capture II, cocktail B) and consensus PCR
(MY11/09 and GP5+/6+) with subsequent sequencing. There is no data on specificity and
sensitivity evaluation between these methods.
OBJECTIVES: to evaluate sensitivity and specificity of these methods for detection highrisk HPV types and to analyse discordant results between them.
STUDY DESIGN. 150 cervical samples were tested for high risk HPV with Hybrid Capture
II (cocktail B, detecting 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68 HPV genotypes)
and "nested"-PCR with consensus primers MY11/09 and GP5+/6+ and subsequent
sequencing of PCR product.
RESULTS. From 150 cervical samples 62 were positive in the both tests and 5 of them
contained genotypes not included in the HC II high-risk probe cocktail (53, 66 and 70). 60
samples were negative in both tests. 26 samples were positive only in MY-GP PCR and 8 of
them contained high-risk genotypes (16, 35, 45, 52 and 56). Two samples were positive only
in HC II and we were not able to determine the HPV types in these samples. Thus, we
obtained 15 discordant results (10%) between two comparable methods.
CONCLUSIONS. Hybrid Capture II test has lower sensitivity for high-risk HPV types and in
addition can detect some HPV genotypes not included in the HC II high-risk probe cocktail.
The sensitivity of PCR based method for high-risk HPV genotypes higher than hybridization
based method.
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P061
DETECTION OF HIGH RISK HUMAN PAPILLOMAVIRUS USING
HIBRID CAPTURE II TEST AS A PREDICTOR OF SEVERE
CERVICAL LESIONS
Vasconcelos Andre
Portuguese Institute of Oncology - Porto, Molecular Oncology, Porto
Many epidemiological and molecular biology studies have demonstrated that human
papillomavirus (HPV) is associated with the development of cervical carcinoma. Different
HPV types relative prevalence have been reported in distinct populations and high risk HPV
types are associated with the onset of high grade SIL (HGSIL) and cervical cancer (CC).
Hybrid Capture is a general nucleic acid hybridisation technology applicable for the detection
of HPV DNA. In this study 182 cervical samples, collected into PreservCyt (a preservative
solution), were obtained from women referred to the gynaecologic clinic at the Portuguese
Institute of Oncology-Porto. The detection of HPV status was analysed using the Hybrid
Capture II System. Our results indicate that the detection of a DNA from a high risk HPV
type is strongly associated to the presence of a severe lesion (HGSIL/CC) (OR=28.8 95%CI
12.7-65.2; p<0.001). Furthermore, we found a sensitivity of 82.6% (the ability of the test to
identify true cases of HGSIL/CC), and a specificity of 85.8% (the ability of the test to identify
those cases without HGSIL/CC). Our results demonstrate that further research is necessary
regarding the role of the Hybrid Capture II System in the prediction of the presence of a
HGSIL/CC and it may depend on the population at study.
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P062
DEVELOPMENT OF A PCR CHEMILUMINESCENT ENZYME
IMMUNOASSAY (CLEIA) FOR TYPING HUMAN PAPILLOMAVIRUS
DNAS IN A NOVEL MICROTITER FORMAT
Venturoli S. [1], Cricca M. [1], Bonvicini F. [1], Gallinella G. [1], Manaresi E. [1], Mirasoli M. [2],
Roda A. [2], Zerbini M. [1], Musiani M. [1]
[1] Department of Clinical and Experimental Medicine, Division of Microbiology, University of Bologna,
Italy, [2] Department of Pharmaceutical Sciences, University of Bologna, Italy
We have developed a polymerase chain reaction chemiluminescent immunoassay (PCRCLEIA) for simultaneous detection and typing of seven high-oncogenic-risk human
papillomavirus (HPV) DNAs in a novel polystyrene microtiter plate containing 24 main
wells, each divided into 7 subwells.
Seven different oligonucleotide probes, each specific for a high-risk HPV genotype, were
separately immobilized in the subwells. Subsequently, a digoxigenin-labelled consensus PCR
amplification product was applied to the main well. The PCR product was able to specifically
hybridize to the immobilized probe corresponding to its genotype and was subsequently
detected using a peroxidase-labelled anti-digoxigenin antibody and chemiluminescence
imaging with an ultrasensitive charge-coupled device (CCD) camera. Results obtained on 50
cytological samples were compared with a conventional colorimetric PCR-ELISA.
The method proved to be specific and allowed detection of 50 genome copies for HPV 16, 18,
33, 58 and 100 genome copies for HPV 31, 35, 45. Intra- and inter-assay coefficients of
variation of the method were 5.6% and 7.9%, respectively. All results obtained for clinical
samples were confirmed by the conventional PCR-ELISA.
In conclusion, PCR-CLEIA allows single-well simultaneous detection and typing of seven
high-risk HPV DNAs with the required specificity and sensitivity. This new assay format
offers advantages in terms of multi-test simplification and reductions in reagents' volumes and
analysis time. The same principle could be applied to the development of single-well panels
of tests for other pathological conditions.
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P063
LIQUID-BASED CYTOLOGY BY DNA-CITOLIQ SYSTEM (DCS) EFFICACY IN IDENTIFICATION OF MICROBIOLOGICAL AGENTS
Dores GB (1); Alves VAF (2), Castelo A (3), Longatto-Filho A (2), Vianna R (4), Taromaru E (1),
Namiyama G (2),
for DNA Citoliq Working Group, Brazil. Digene Brasil. (1), Pathology Division Adolfo Lutz Institute,
Brazil (2), Department of Epidemiology Federal University of São Paulo (3), São Paulo Medical School
of University of São Paulo (4)
DNA-CITOLIQ System® (DCS) (Digene, Brasil) is a new liquid based cytology system for
cervical material intended both for oncologic cytology and molecular tests for HPV, Neisseria
gonorrhoea, and Chlamydia trachomatis. Recent studies have shown its efficacy for
identifying epithelial lesions. To compare visual microbiological diagnoses on slides of
cervical material prepared according to DCS and to conventional smear, samples were
collected from 3316 women. After cervical scraping with Ayre spatula and endocervical
brushing, the sample was immediately smeared on the slides and alcohol-fixed. The same
brush with residual endocervical cells was again used to scrape the ectocervical surface and
placed in a tube with Universal Collection Medium (UCM) and processed at the laboratory
according to DCS protocol. All slides were stained by the conventional Papanicolaou method.
Both methods yielded equal results for lactobacilli (p=0.32), cocci (p=0.98), Actinomyces
(p=1.0), Leptotrix (p=0.37), Chlamydia (p=0.45) and Candida (p=0.75). Gardenerella
(p=0.0001) was seen significantly more on DCS slides, whereas Trichomonas was more
frequently seen on the conventional slides (p=0.001). Besides yielding greater sensitivity for
detecting squamous lesions than conventional slides and being suitable for molecular tests as
reported in other studies, DNA-CITOLIQ performed very well in the identification of
microbiological agents.
EUROGIN 2003
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P064
DNA-CITOLIQ SYSTEM (DCS): A NEW LIQUID-BASED SYSTEM
FOR CYTOLOGY AND MOLECULAR TESTS - TECHNICAL
ASPECTS
Dores GB (1), Alves VAF (2), Castelo A (3), Longatto-Filho A (2), Vianna R (4), Taromaru E (1)
for DNA-CITOLIQ Working Group, Brazil. Digene Brazil. (1), Pathology Division Adolfo Lutz Institute,
Brazil (2), Department of Epidemiology Federal University of São Paulo (3), São Paulo Medical School
of University of São Paulo (4).
DCS is a new liquid cytology procedure for cells collected into Universal Collection Medium
(UCM). We sought to assess technical aspects of DCS, under different protocols.
In the first experiment 144 samples were collected at six laboratories. After cervical scraping
with Ayre spatula and endocervical brushing, samples were immediately smeared on slides
and alcohol-fixed. The same brush with residual endocervical cells was again used to scrape
the ectocervical surface and placed in a UCM tube. For each case, 4 slides were prepared
according to DCS procedures, varying the vortexing time (5, 10, 15 and 20 seconds) from
protocols 1 to 4. The second experiment was conducted with 50 samples, with a vortexing
time of 30 seconds. The cytological criteria for sample quality were: cell distribution (empty
areas and clumping), cell fixation artifacts, cellularity and presence of TZC. In experiment 1,
significant differences were detected only between protocols 1 and 4. Compared to
conventional smears, DCS preparations showed fewer empty areas in slides 1 and 4 (p=0.024
and p=0.003). No fixation artifacts and high TZC representation were found in protocols 3
and 4. In experiment 2, although not reaching statistical significance, more cases with TZC
were seen. No adverse effects were found on Pap staining, cytomorphology or on cellular
fixation properties.
These preliminary results with DCS with 20 or 30 seconds vortexing yielded well-preserved
cytomorphology, with high representation of endocervical cells and improved better cell
distribution, thus leading to an expectation of favorable performance in large trials for
assessing diagnostic performance.
EUROGIN 2003
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P065
CYTOHISTOLOGIC DIAGNOSIS OF ATYPICAL GLANDULAR
CELLS OF UNDETERMINED SIGNIFICANCE ON THINPREP
CERVICOVAGINAL SMEAR
Adams C, Modery J, Trucco G, Kanbour A.
Magee-Womens Hospital, Pittsburgh, PA, U.S.A.
Bethesda system 1991 defines atypical glandular cells of undetermined significance (AGUS)
as glandular cells exhibiting changes beyond reactive/reparative but lacking equivocal
features of adenocarcinoma. AGUS, further subdivided into favor reactive and favor
neoplastic, now accounts for 0.1-2.5% of pap smears. The diagnosis of AGUS is difficult and
subjective. It is often followed by cervical conization. Conflicting reports exist on the
accuracy of Thinprep "Cytyc" to diagnose glandular cell abnormalities.
Objective: To determine histologic outcome of patients with diagnosis of AGUS on Thinprep
pap smears.
Design: Computer search of the cytology lab at MWH for June 2000 to October 2001 was
done. AGUS favor endocervical on Thinprep Pap smear was identified and histopathologic
outcomes of AGUS were reviewed.
Result: 46 patients with diagnosis of AGUS endocervical were identified; ages 19-74 years,
average of 43 years. 31/46 (68%) was classified as AGUS NOS and favor reactive, 3/46 (6%)
favor neoplastic, 11/46 (24%) classified glands involvement by SIL and 1/46 (2%) classified
as adenocarcinoma. Histologic follow-up was available on 34 (74%) cases including cervical
and endometrial biopsies and cervical cone biopsies. Interval to subsequent surgical follow-up
was 5-98 days. 15/35 (43%) had significant cervical lesions. 6/15 had squamous lesions with
gland involvement, 5 endocervical gland dysplasia, 1 adenocarcinoma in situ, and 3
endometrioid carcinoma. 20/35 patients (57%) had benign cervical lesions including 3 no
lesion. 10 had reactive atypia, 1 had tubal metaplasia, 2 microglandular hyperplasia, and 4 had
endocervical polyps.
Conclusion: Squamous cell abnormalities, 6/15 (40%), are the most common histologic
findings of AGUS, benign lesions accounted for 57%. Significant glandular neoplastic lesions
are relatively low and account for 4 of 35 (11%). Cytologic criteria of AGUS favor neoplastic
and preneoplastic cervical lesions including increase in N/C ratio, ill-defined cell borders,
nuclear abnormalities, and presence of single cells were helpful for diagnosis of AGUS.
When diagnosis of AGUS is rendered, patient age and prior history of SIL should be taken
into consideration before undergoing surgical procedure that may yield unwanted morbidity.
Finally, replacing the term AGUS with atypical glandular cells (AGC) in the new 2001
Bethesda system may solve some but not all inherent diagnostic problems with the cytological
diagnosis of AGUS.
EUROGIN 2003
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AUTHORS
P066
LIQUID-BASED CYTOLOGY (DNA CITOLIQ®) SYSTEM AND
CONVENCTIONAL PAP TEST: EXPERIENCE FROM THE LAMS
(LATIN AMERICAN SCREENING) STUDY
Longatto-Filho A (1) ; Pereira SMM (1); Utagawa M (1); Maeda MYS (1); Roteli-Martins C (2);
Galvane JO (2); Lima T (2) ; Syrjänen K (3)
Pathology Division of Adolfo Lutz Institute, São Paulo, Brazil 1; Leonor Mendes de Barros Hospital 2,
São Paulo, Brazil; Istituto Superiore di Sanità, Roma, Italy 3
DNACITOLIQ SYETM (DCS) is a recently developed liquid-based cytology system to be
used even for molecular assay such as Hybrid Capture II (HCII). Our goal was to compare
DCS diagnostic performance with conventional Paptest (CP) in a latin American Screening
Program. Specimens in a randomized model. DCS samples were also submitted to HC II for
high risk HPV. CP was obtained with Ayre spatula and endocervical brushing, and
immediately alcohol-fixed. The DCS sample was collected with DIGENE-DNACITOLIQ
brush, scraping the ectocervix and endocervix, placed in a tube with UCM and processed
according to the DCS protocol. Slides were Pap stained and examined in blind fashion
protocol and abnormalities were confirmed by consensus. The age of the CP patients ranging
from 17 to 67 years old (mean 42) and DCS from 18 to 61 (mean 39,5). A total of 1204 CP
was performed: 24 cases were unsatisfactory (2,0%), 1120 negative (93,0%) and 60 abnormal
(5,0%). DCS cases were 802 and percentages were 0,4%, 89,3% and 10,3%, respectively.
Squamous columnar cells (SCC) were observed in 86% of the CP samples and 90,3% of the
DCS. Atypical cells (squamous or glandular) were observed in 35 CP (2,9%) and 63 (7,9%)
DCS; LSIL were 18 (1,5%) in CP cases and 14 (1,7%) in DCS; HSIL were 7 (0,6%) in CP
and 5 (0,6%) in DCS. HCII results showed positive reactions in 31,7% of the atypical DCS;
71,4% of the LSILs and 100% of the HSIL and carcinoma. We concluded that DCS was
superior in percentage of adequate samples and SCC representation. The HC II/DCS results
have showed a strong correlation that should be considered to improve screening of the
atypical cases of undetermined significance.
EUROGIN 2003
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P067
EVALUATION OF ΤHIN PREP PAP TEST RESULTS IN CLINICAL
PRACTICE
MARGARI HARIKLIA
ELENA BENIZELOU, Departement CYTOLOGY, ATHENS
Purpose of the study: Comparison of liquid based cytology Thin Prep (TP) combined with
Hybrid Capture HPV test (HC) to colposcopy - biopsy and detection of the factors affecting
TP Pap Test sensitivity.
Methods: 130 women with previous abnormal smear or under follow up due to SIL HPV,
vulvar HPV, HPV of her partner or chronic cervicitis, were referred to the colposcopy dept..
Prior to colposcopy they underwent TP Pap Test (split sample) and HPV-Hybrid Capture
using the TP preservative.
Results: cyt/colp biopsy: 63 negative (4 Low Risk /LR, 2 High Risk/HR by HC)
27 HPV-LSIL ( 13 LR , 5 HR and 7 LR+HR by HC)
9 HPV-HSIL (8 HR , 1 LR+HR by HC)
cyt: 5 ASCUS favouring neoplasia colp biopsy: 5 LSIL (2 LR by HC)
2 ASCUS favouring neplasia
2 HSIL (1 HR by HC)
5 ASCUS favouring reaction
5 negative (1 HR by HC)
colp biopsy: 1 HSIL cyt: 1 No SIL-Keratinization and parakeratosis (HC negative)
11 LSIL
3 no enthocervical component, 2 previous ctyosurgery, 1 Pap Test a
week before, 1 previous biopsy, 4 NO SIL keratinization and parakeratosis (HC negative).
Sensitivity, specificity and positive predictive value of the TP Pap Test were 75%, 1 and 1
respectively.
Conclusion: It was a good agreement of TP PapTest and HC with colp. biospy. All SIL cases
which were negative in TP PapTest were also negative for LR and HR by HC. The fact that
only the residual material was used in our study, unsatisfactory specimen and specimen
inadequacy due to the absence of endocervical components, were the causes which reduced
the sensitivity of the TP Pap Test and gave negative HPV - DNA findings by the HC method.
EUROGIN 2003
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P068
COMPARATIVE EVALUATION OF THE CONVENTIONAL PAP TEST
AND THE RESIDUAL MATERIAL LEFT ON THE PAP TEST BRUSH
IN THIN PREP LIQUID CYTOLOGY
MARGARI HARICLIA
ELENA BENIZELOU, Departement CYTOLOGY, ATHENS
Purpose of the study: Purpose of the study: To evaluate the importance of the remaining
material from the cervical brush during a Pap Test, which is discarded, analysing both
methods Thin Prep (TP) and conventional smears in order to compare specimen adequacy and
detection of cervical lesions.
Results: Table 1 shows the cases where the findings by both methods were in agreement
TABLE 1
Negative
SBLB
ASCUS
AGUS
LSIL
HSIL
Ca
Conventional
1764
1
22
1
38
2
1
TP
1764
1
22
1
38
2
1
Table 2 shows the cases where TP was superior to the conventional smear
TABLE 2
Conventional
TP
12 negative
12 ASCUS
4 negative
4 LSIL
1 SBLB
1 LSIL
4 SBLB
4 ASCUS
5 ASCUS
5 LSIL
1 HSIL
1 Ca
Statistical significance was: p< 0,001 for SBLB, p<0,01 for negative, p<0,078 for ASCUS, p<
0,001 for LSIL, p<0,07 for HSIL, p< 0,15 for Ca.
Conclusion: The TP Pap Test method performed using the residual material of the brush
following preparation of conventional smear, increased the diagnostic accuracy and hence the
confidence in the Pap Test, as a truly better tool in clinical practice.
EUROGIN 2003
452
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P069
QUANTITATIVE TUMOR CELLS PARAMETERS AS PROGNOSTIC
FACTORS IN OVARIAN NEOPLASMS PATIENTS
Panitchenko I,.Bogatyrev V,.Jordanya K,.Kosachenco V,. Shapiro N
Lab. Clinical Cytology and Department of Gynecology, N.N. Blochin Cancer Research Center,
Moscow, Russia
Objective: the objective of the present study is the assessment of the possibility of DNA-flow
cytometry (DNA FCM) in clinical practice in examination of the patients with ovarian
neoplasms.
Materials and methods: intraoperative tumor bioptatis served the material of the study.
Quantitative cells parameters were studied by DNA FCM (EPICS-XL, Coulter and software
Multicycle, Phoenix Flow Systems, USA) in 77 patients with primary ovarian cancer (POC),
21 patients with borderline ovarian tumors (BodOT) and 12 patients with benign ovarian
tumors (BenOT) served the basis of the study.
Results: Among patients with BenOT all neoplasm's were diploidy. Among BodOT patients
in 8 cases (38.1%) the tumors were diploid (IDNA=1.0), aneuploid neoplasms were observed
in 13 cases (69.9%), out of them 1 case - with chromosomal loss (IDNA<1.0), in 9 aneuploidy within mitotic cycle (IDNA=1.1 - 1.85) and in 3 cases multiclonal tumor type was
detected. Out of 13 patients with aneuploid tumors in 3 (23.1%) aneuploid cells number did
not exceed 20%, in 4 (30.8%) it did not exceed 40% and in 6 (46.1%) it was more than 40%.
At the comparison of tumor cells distribution by cell cycle phases among diploid and
aneuploid tumors it was detected that the cell number in G0/1 phase in diploid tumors was
88,4 + 1,8% and was statistically reliably higher then in aneuploid BodOT (75,6±3,8%),
(p<0.05). The cell number in S, G2+M phases in diploid BodOT was statistically lower, than
aneuploid.
Among 77 patients with POC there were 6 cases (7,8%) with chromosomal loss (IDNA<1,0),
42 cases (54,5%) - aneuploidy within the limits of mitotic cycle (IDNA=1,1-1,85), 2 cases
(2,6%) - tetraploid tumors (IDNA=1,85-2,15), 13 cases (16,9%) - multiclonal tumors and in
14 cases (18,2%) diploid tumors was detected (IDNA=1,0). During 2-year follow-up
67,7±7,4% patients with aneuploid tumors and 93,5±7,9% with diploid ones were alive
(p<0,05). At 2-year analysis, depending on cells quantity in different phases of cellular tumor
cycle the following results were obtained: patients survival with cells quantity in S phase, not
exceeding 6% was 77,6±10,4%, while in the group of patients with that index exceeding 6%,
survival was 67,5±10,2%, (p>0,05). Alongside, true differences were obtained in the survival
depending on cell quantity in G2+M phase: among patients with cell quantity in G2+M
phases not exceeding 10% - 82,2±3,9% were alive, while in patients with that index
exceeding 10%, survival was 66,3±8,0%, (p<0,05%). At the survival analysis depending on
proliferative tumours activity no true difference was obtained. At the informativity coefficient
calculation by Shenon tumor ploidity (3,11), stage (2,11) and grade (1,9) were the most
significant in the disease prognosis.
Conclusion: with the help of DNA-FCM method it was demonstrated, that the ovarian
neoplasm's differ each other not only in clinical manifestation, but also in quantitative
parameters. This fact help to perform the most exact disease course prognosis and to work out
each patient individual management tactics.
EUROGIN 2003
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P070
P16INK4A: A BIOMARKER FOR CERVICAL DYSPLASIA IN LIQUID
BASED CYTOLOGY
Bisgaard K. (1), Lindberg M. (1), Zadeh A. (1), Jensen A. (1), Feldballe O. (1), Reichert A. (2),
Herkert M. (2), Lang H. (2), Trunk-Gehmacher M. (2), Ridder R. (2)
(1) DakoCytomation A/S, Glostrup, Denmark, (2) MTM laboratories AG, Heidelberg, Germany
Background:
Cervical cancer is one of the most common cancer types among women in the world.
Currently screening for cervical cancer is based on the Papanicolaou (Pap)-staining and relies
on subjective evaluation of cellular morphological changes. Therefore, the sensitivity for the
detection of HSIL or carcinoma is in the range from 61% to 84%, whereas the specificity
varies between 69% and 97% in independent studies.
It has been proposed that an over-expression of the cyclin dependent kinase inhibitor p16INK4a
occurs due to the HR-HPV oncogene E7 mediated inactivation of the pRB pathway.
Numerous reports have demonstrated that overexpressed p16INK4a protein detected by
immunohistochemical staining in cervical biopsies represents a promising biomarker,
indicating dysregulation of cell cycle control of cervical epithelial cells due to the
transforming activity of HR-HPV.
Therefore, we analyzed whether p16INK4a immunochemistry may also be used for the
detection of dysplastic cells in cervical cytology specimens.
Design:
The present study represents cumulative data from p16INK4a immunocytochemical stainings of
more than 200 liquid based cytology (LBC) patient samples representing diagnoses of normal,
ASCUS, LSIL, and HSIL. The samples were stained for p16INK4a and Pap to investigate the
value of p16INK4a staining in liquid based cervical cytology.
Results:
Strong p16INK4a immunoreactivity of dysplastic cells was observed in all HSIL samples,
whereas p16INK4a positivity was restricted to a lower number of LSIL and ASCUS samples.
In a number of clinical specimens, there was a small fraction of p16INK4a stained metaplastic
and/or columnar cells. The basis for this staining will be investigated further.
Conclusion:
p16INK4a is a promising marker for detecting dysplastic cervical lesions and may be a good
supplement to the Pap test.
EUROGIN 2003
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P071
STUDY OF CERVICAL INTRAEPITHELIAL NEOPLASIA BY
CALIBRATED FLUORESCENCE IMAGING TECHNIQUE
Cheung, T. H. (1), Wu, Tao (2), Lo, K. W. (1), Yu, M. Y. (3) and Qu, Jianan (2)
(1) Department of Obstetrics and Gynecology and (3) Department of Anatomical and Cellular
Pathology, the Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China. (2)
Department of Electrical and Electronic Engineering, Hong Kong University of Science and
Technology, Hong Kong, China
Colposcopy is the standard investigation for patients with abnormal cervical smear. The
assessment is subjective and the accuracy is operator dependent. Because normal tissues
almost always emit fluorescence more efficiently than neoplastic lesions under the same
illumination condition, optical spectroscopic imaging has been explored as an objective mean
to detect pre-malignant changes in colon, bronchus and uterine cervix.
Method: We instrumented a colposcopy system with combined fluorescence and crosspolarized reflection imaging to study the cervix. The diffusive reflection signals from the
cross-polarization are used to assess the geometry of the region being examined so that
captured fluorescence signal can be calibrated.
Sixteen patients scheduled for LEEP were recruited. Uterine cervix was studied with
fluorescence technique followed by conventional colposcopy. Diagnosis was made to the four
quadrants of the uterine cervix before LEEP was performed. The excised cervical tissue was
divided according to quadrants before sending for pathological examination.
Results: Pathological study of the 64 pieces of cervical tissues showed 23 CIN II or III (high
grade lesions), 34 HPV +/- CIN I (low grade lesions) and 7 normal epithelium. Reduced
fluorescence was recorded in 42.9 and 77.2 % normal and abnormal cervical epithelium
(P>0.05). Sensitivity, specificity, positive predictive and negative value of fluorescence study
for CIN II or III was 91.3, 36.6, 44.7 and 88.2% respectively. The corresponding figures for
colposcopy was 47.8, 80.5, 57.9 and 73.3%.
Conclusion: Fluorescence study with the current design is not useful to differentiate high
grade from low grade lesions.
EUROGIN 2003
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P072
HPV AND P53 POLYMORPHISM MOLECULAR TYPING BY A IN
SITU PCR ON CYTOLOGICAL SPECIMENS.
Russo M.A., G.A.Perrone, C. Conte, R..Gradini, P.Sale, C.Carraio and M.Realacci
Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy
Introduction. Ano-genital carcinoma and epithelial tumours of the head and neck are
polifactorial and polygenic disease in which HPV have been detected in high percentages of
patients. However, it is evident that only certain types of HPV (16,18,31,33) are able to
contribute to malignant transformation and that not all the infections lead to carcinoma.
Recently, it has been suggested that p53 polymorphisms (p53Pro72/p53Arg72) may be
relevant for the interaction leading to p53 inactivation. Therefore, it is important for the
assessment of the individual risk to have a routine typing technique for both HPV strain and
p53Arg72.
Materials and methods. Patients were selected on the basis of HPV infection clinical history
and positive PAP-test and for the presence of histologic lesions, such as condilomata or SIL
or CIN. The in situ PCR our technique includes four basic steps. For the preparation of
samples, clean cell-tak-treated slides, Triton X-100 permeabilization and digestion time by
proteinase K appear to be of critical importance. In situ amplification has been obtained in a
GeneAmp In Situ PCR System 1000 Thermal Cycler (Perkin-Elmer), modifying the times in
relation to the primers and specimens used. This was followed by in situ hybridization in the
same apparatus; optimal times were varied with probes and samples. Visualisation and
imaging have been done with a confocal microscope.
Results and conclusions. Results were consistent with those obtained by classical PCR on
extracted nucleic acids and by in situ PCR on frozen sections from biopsies of the same
patient of the smear. Images obtained appeared of good quality and informative. The overall
technique was highly reproducible.
As negative controls we used smears and tissue from healthy women for HPV typing, while
for p53 polymorphism an homozygous for p53Arg72 was used as a negative control for
p53Pro72, and viceversa an homozygous p53Pro72 was used for p53Arg72.
EUROGIN 2003
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P073
TAKE CARE – CERVICAL CANCER PREVENTION PROGRAM IN
WESTERN UKRAINE
Sluzhynska O.*, Volodko N.**
Charitable SALUS Foundation, Sexual health Centre, Lviv, Ukraine* Regional Oncology Centre, Lviv,
Ukraine**
In April 2002 the project: TAKE CARE - Developing the Cervical Cancer Prevention
Campaign in Lviv, Ukraine started. The project is planned for two years, it is supported by the
PATH.
Incapability of the Ukrainian state medicine to cope with the problem of the cancer influence
on decrease of the women’s health in Ukraine. In particular, the incidence rate of cervical
cancer in West Ukraine region has risen from 12,3 cases in 1988 to 16,7 in 1997 per 100000.
Rather high quality screening program have been created in Soviet Union, but it was
destroyed without government financial support. New information about cervical cancer
cancergenesis and new diagnostic techniques were not introduced in the region. Social
problems and unemployment create special conditions for the Ukrainian women giving them
any possibility to take care for their health. In the conditions of the crisis of the state medicine,
the role of the NGOs dealing with cancer prevention, become more and more important.
The project is focused on women in the age of 35- 50 years old.
The main goals of the project proposal is to provide: spreading information about cervical
cancer epidemiologist, risk factors, primary and secondary prevention, providing access of
women to diagnostic of precancer lesion (cervical cancer) and STIs, improving the knowledge
on cervical cancer among medical workers dealing with women, evaluation the prevalence of
the cervical cancer in the region of Lviv by means of developing the database
The proposed TAKE CARE project implements the following activities: developing
information campaign about the cervical cancer prevention (printed materials,
telephone help line, radio programs), advertising high quality cervical cancer
diagnostics, developing lectures for family doctors, gynecologists and dermatologists,
developing the database of the cervical cancer in the Lviv region.
The following activities have been developed during 8 months of project implementation: 3
leaflets on cervical cancer prevention have been printed and distributed among the women
population of the Lviv region, 40 lectures on cervical cancer prevention for women have been
performed, special telephone help line TAKE CARE has been established, 3 radio programs
on cervical cancer prevention have been broadcasted. The project staff continues to work over
the project with hope that the second year of the project implementation will be as fruitful and
successful as the first one.
EUROGIN 2003
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P074
OCCURENCE OF BACTERIAL INFECTION IN CERVICAL
PRECANCEROSES
Drabek, M., Suska, P., Simko, J., Simoncicova, M.
Comenius University, II.Department of Obstetrics and Gynaecology, Bratislava
INTRODUCTION: Chronic bacterial infection correlates with a higher occurence of
precanceroses. Its connection with a rise and development of carcinomas is not so clear as
correlation between the presence of specifical viruses and precanceroses, but some studies
demonstrate higher incidence of precancerous changes also in the connection with bacterial
infection. The most frequent bacterial patogen mentioned in connection with the cervical
precanceroses is Chlamydia trachomatis, but similar correlation could exist between cervical
pathology and incidence of Mycoplasma hominis and Ureaplasma urealyticum.
OBJECTIVE: The aim of this study was to detect incidence of Chlamydia trachomatis,
Mycoplasma hominis and Ureaplasma urealyticum in cervical smears of patients which
undergo conisation because of presence of serious cervical precanceroses.
METHODS: 101 patients with cervical precanceroses treated by conisation were studied.
Cervical smears were taken in operating room before operation. Chlamydia trachomatis was
detected by PCR (automat COBAS amplicor - Roche), Mycoplasma hominis and Ureaplasma
urealyticum were detected by set Mycoplasma IST (Bio Mérieux).
RESULTS: Mycoplasma hominis was found in 12 cases (11,9%), Ureaplasma urealyticum in
34 cases (33,6%) and Chlamydia trachomatis in 2 cases (2%). The highest incidence (12
cases) of patogens was detected in patients with HGSIL (41,4%).
CONCLUSION: We did not confirm high occurence of Chlamydia trachomatis with suspect
cervical lesions, but incidence of Ureaplasma urealyticum was surprisingly high. Extension of
the study could contribute to explanation of these results.
EUROGIN 2003
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P075
MINIMAL INHIBITORY CONCENTRATIONS (MICS) OF
ANTIBIOTICS FOR N.GONORRHOEAE STRAINS AS COMPARED
WITH GENOTYPING DATA
Kubanova A. (1), Kisina V. (1), Govorun V. (2), Ilina E. (2), Kolieva G. (1), Zubkov M. (1)
(1) Central Research Institute of Dermatology and Venereology, Moscow, Russia; (2) Research
Institute of Physico-Chemical Medicine, Moscow, Russia
Aim: To define the MICs of 12 antibiotics for N.gonorrhoeae clinical strains and compare
them with genotyping data.
Methods: Serial agar dilutions were used to define the MICs of 12 antibiotics for 20
N.gonorrhoeae clinical strains. 20 N.gonorrhoeae clinical isolates were typed using the Por
gene multilocus sequencing method. N.gonorrhoeae isolates were obtained from patients in
Moscow and the Moscow region. The clinical samples were transported in the "Amiec"
charcoal-containing transportation medium (Detalab) and they were inoculated (with the
isolation of a pure culture) on the BioMerieux media. MICs of 12 antibiotics for 20
N.gonorrhoeae clinical isolates were defined with the serial agar dilution method using
chocolate agar with a selective VCAT (Vancomycin, Colistin, Amphotericin B,
Trimethoprim) addition and with the addition of vitamins (PolyVitex) + antibiotics in various
concentrations. We used 0.015, 0.03, 0.06, 0.12, 0.25, 0.5, 1, 2, 4, 8 dilutions. N.gonorrhoeae
49226 ATCC strain was used as control. Our findings demonstrated that the 20 clinical
isolates were sensitive to ciprofloxacin (37%), moxifloxacin (41%), levofloxacin (51.5%,
moderately sensitive - 27.5%), ofloxacin (41%), erythromycin (63.5%), azythromycin
(100%), clarithromycin (100%), penicillin (0%), chloramphenicol (100%), ampicillinsulbactam (100%), tetracycline (0%), cefotaxim (100%). Genotyping showed that one isolate
was a PIA serovar, and the remaining isolates were PIB serovars (PIB2 - 2 serotypes, PIB3 - 8
serotypes, PIB5 - 3 serotypes, PIB 3/5 - 2 serotypes, PIB4 - 1 serotype, PIB7 - 3 serotypes,).
Conclusions: We conclude that the N.gonorrhoeae population is characterized by a
significant genetic heterogeneity and the genotype of a strain correlates with the profile of its
sensitivity to antibiotics and the clinical course of the disease. Our findings suggest that
gonococci are highly resistant to fluoroquinolones, erythromycin, penicillin, tetracycline. All
resistant strains were found to have the Por gene of the PIB type which is associated with
resistance to antibiotics, as the published data show.
EUROGIN 2003
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P076
CLINICAL-MICROBIOLOGIC EFFECTIVENESS OF
MOXIFLOXACIN IN THE TREATMENT OF GONOCOCCAL
INFECTION AND MINIMAL INHIBITORY CONCENTRATIONS
(MICS) OF FLUOROQUINOLONES FOR N.GONORRHOEAE
STRAINS AS COMPARED WITH GENOTYPING DATA
Kubanova A. (1), Kisina V. (1), Govorun V. (2), Ilina E. (2), Kolieva G. (1), Zubkov M. (1)
(1) Central Research Institute of Dermatology and Venereology, Moscow, Russia; (2) Research
Institute of Physico-Chemical Medicine, Moscow, Russia
Aim: To assess the effectiveness of moxifloxacin used to treat uncomplicated gonorrhea; to
define the MICs of fluoroquinolones for N.gonorrhoeae clinical strains and compare them
with genotyping data.
Methods: 77 pts aged 17-60 yrs (69 males and 8 females) with an uncomplicated gonorrhea
underwent a clinical-microbiologic examination. Microscopic, cultural, PCR methods and an
ultrasound study were used. The pts were treated with a 400 mg single dose of moxifloxacin.
MICs of fluoroqionolones for N.gonorrhoeae clinical strains were defined using serial agar
dilutions. 20 N.gonorrhoeae clinical isolates were typed using the Por gene multilocus
sequencing method. N.gonorrhoeae isolates were obtained from pts in Moscow and its region.
The clinical samples were transported in the "Amiec" charcoal-containing transportation
medium (Detalab), and they were inoculated (with the isolation of a pure culture) on the
BioMerieux media. MICs of fluoroquinolones were defined with the serial agar dilution
method using chocolate agar with a selective VCAT (Vancomycin, Colistin, Amphotericin B,
Trimethoprim) addition and with the addition of PolyVitex + antibiotics in various
concentrations. We used 0.015, 0.03, 0.06, 0.12, 0.25, 0.5, 1, 2, 4, 8 dilutions. N.gonorrhoeae
49226 ATCC strain was used as control. The outcome of treatment was tested with
microscopic and cultural methods 48 hrs and 7-10 days after the intake of moxifloxacin dose.
Results: The treatment was effective in 66 pts (70%) who were completely cured as verified
by clinical-microbiologic findings, and ineffective in 11 pts (30%). The 20 clinical isolates
were sensitive to ciprofloxacin (37%), moxifloxacin (41%), levofloxacin (51.5%; moderately
sensitive - 27.5%), ofloxacin (41%). Genotyping showed there were 7 various N.gonorrhoeae
genotypes (1 isolate was a PIA serovar and 19 isolates were PIB serovars).
Conclusions: Gonococci were found to be highly resistant to fluoroquinolones and the
clinical-microbiologic effectiveness of moxifloxacin is not sufficient to treat gonorrhea. All
resistant strains were found to have the Por gene of the PIB type which is associated with
resistance to fluoroquinolones, as the published data show.
EUROGIN 2003
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P077
FREQUENCY OF HPV OF HIGH ONCOGENIC TYPES IN DIFFERENT
GROUPS OF WOMEN
KUBANOV Alexei
Central research institute for skin and venereal diseases
The total number of 359 patients (women aged between 18 and 54 yrs) were examined during
the study. 106 patients (group 1) had clinical manifestations of HPV; 112 patients (group 2)
had other STDs and 32 patients (group 3) had cervical precancerous lesions. The reference
group (group 4) consisted of 109 healthy women.
The cytological examination ( Pap smears) and colposcopy were done at each case. DNA and
bacteriological tests were used to exclude sexually transmitted infections. PCR was used for
typing of genital herpes viruses and HPV. All patients were serologically examined for
syphilis and HIV.
In 19 out of 106 (17,92%) patients from the group 1 highly oncogenic types of HPV (16 and
18) were found. Low oncogenic types of HPV (6 and 11) were found in 76 out of 106
(67,85%).patients form group 1.
16 and 18 types of HPV were also found in 13 out of 112 (11,4%) patients from the group 2
who seek for medical help due to signs of sexually transmitted infections; 31 patients
(27,67%) showed HPV of low oncogenicity .
At the same time in 69,3% patients from the group 1 C. trachomatis was detected .
Association of C. trachomatis with other bacterial agents (BV-associated microorganisms or
Candida sp, genital mycoplasmas, N. gonorrhoeae, T. vaginalis) were found in 80,0% of the
patients. Manifested forms of bacterial vaginosis were revealed in 20,0% of women. In
patients from group 1 genital mycoplasmas (U. urealyticum and/or M. hominis in titer > 104
CFU/ml) in association (or without) with BV-associated microorganisms were detected in
51.4%, and urogenital candidosis in 14,3% of patients.
In 10 healthy women (9,17%) from the reference group 16 and 18 types of HPV were found
and in 5 women (4,58%) HPVof low oncogenic types were detected.
The results of study show the high degree of contamination (17,92%) with high oncogenic 16
and 18 type HPV of the patients with sexually transmitted infections. It significantly exceeds
the rate of this types of viruses among patients with clinical manifestations of the HPV
infection (genital warts) -and healthy women from the reference group (1,57 times and 1,91
times, respectively).
EUROGIN 2003
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P078
GENITAL CHLAMYDIAL INFECTION: EPIDEMIOLOGY AND
CLINICAL MANIFESTATIONS IN FEMALE PATIENTS
Malinova M
Family Planning Clinic, Department of Obstetrics and Gynaecology, Medical University,
Objective: The aim of this study was to determine the prevalence of Chlamydial infection and
clinical manifestations among women presenting for a periodic medical examination and
among family planning patients.
Patients and Methods: Five hundred thirty-five women were examined by the use of the
indirect immunofluorescent test and with the ELISE test.
Results: The prevalence of Clamydial infection in this population was 43%. Proportion in
each age group with initial infection was: 15 - 25 yr - 46,8%; 26 - 35 yr - 38,3%; and 36 - 45
yr - 42,6%. Among 151 oral contraceptive users 31 (20,5%) were with C. trachomatis. The
prevalence is high among women with inferility - 25/ 35 (71%). Among 135 women with
mucopurulent cervicitis or contact bleeding 80 (59%) were with C. trachomatis.
Conclusions: These findings are particularly disturbing. They show that Chlamydial
trachomatis infection is more frequent in our country, than we supposed. Because of the
financial and technical constraints on routine testing for Chlamydia trachomatis, attempts
have to be made to select patients on the basis of patients histories or physical examinations.
EUROGIN 2003
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P080
SYSTEMATIC SCREENING OF CHLAMYDIA TRACHOMATIS
INFECTIONS
Sueur J.M., Mention J., Orfila J.
INTRODUCTION: Chlamydia trachomatis, an obligate intra-cellular parasitic bacterium, is
recognized as the pathogenic agent often associated with sexually transmitted diseases
(leading to urethritis, cervicitis and salpingitis). The symptoms of infection are often mild or
even absent.
It was therefore of interest to investigate the relevance of systematic detection of C.
trachomatis in urine using an amplified molecular biology method in our at risk population,
i.e. patients undergoing elective abortion. This non-invasive sampling process is easy to
perform and is well accepted by patients.1
AIM OF THE STUDY: Studying the relevance of diagnostic tools and measuring the
prevalence of C. trachomatis infections in patients undergoing elective abortion will enable us
to choose between two different clinical approaches:
- systematic in vitro diagnosis prior to treatment if prevalence is < 3 %
- systematic treatment if prevalence is > 6 %
MATERIALS AND METHODS: From June 1999 to December 2002, Chlamydia
trachomatis was detected in first voided urine specimens using an amplified molecular
biology method. A total of 4526 patients were tested. Same day MIF serological diagnosis
was performed for 829 of these patients coming from the Center of Obstetrical Gynecology Amiens (France).
1 - Amplified Molecular Biology Method
AMPLIFIED Chlamydia TRACHOMATIS assay (biomerieux - Gen Probe)
The AMPLIFIED CHLAMYDIA TRACHOMATIS assay , using Transcription Mediated
Amplification (TMA as described in figure 1) is designed of Chlamydia trachomatis in
cervical, male urethral, or male or female urine specimens.
2 - Serology
The presence of immunoglobulins enables differentiation between very recent (negative
serology) and former (positive serology) infections, and therefore short - or long-course
therapy can be appropriately initiated.
Microimmunofluorescence
We used the microimmunofluorescence method described by Wang and Graystone. This
method is based on using the L2 strain (strain LB1) of Chlamydia trachomatis, the IOL 207
strain of Chlamydia pneumoniae and the Loth strain of Chlamydia psittaci as the antigens.
We tested for IgG, IgA and IgM on all three species.
- for each patient, 2-fold dilutions were performed as of the 1/16 dilution. A level of ≥ 1/16
was considered to be positive for IgG and IgA.
- after removal of the rheumatoid factor, a 1/12 dilution was considered to be positive for
IgM.
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RESULTS
1 - Molecular Biology
A total of 116 out of 4526 patients were found to be positive, i.e. a prevalence of 2,56% for
lower tract infections.
2 - Serology:
overall results are shown in Table 1
Table 1
IgM only
IgG + M
IgG +A
IgG only
IgG+M+A
Total
n
0
6
35
54
2
97
%
0
0,7
4,2
6,6
0,2
11,7 %
a – IgG
As regards the microimmunofluorescence results, 97 out of 829 patients (i.e 11,7 %) were
found to be positive.
b – IgA
Only 38 % (37/97) of the patients were found to have specific IgA corresponding to chronic
infection.
c – IgM
In this study, we did not find any isolated positive IgM. IgM were always found to be positive
in association with IgG in 6 of the 97 cases (0,7 %) and with IgG and IgA in 2 of the 97 cases
(0,2 %).
3 – Summary
Consolidated results obtained in molecular biology and serology are given in Figure 2.
Figure 2
IgG + et M et/ou A = 3
TMA ⊕ = 28
IgG = 25
Serology ⊕ = 97
IgG ⊕ et M et/ou A =329
TMA θ = 69
IgG = 37
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4 – Prevalence
IgG
IgG+IgA
Patients aged between 16-20
6,9%
3,8%
Patients aged between 21-25
11,2%
3,3%
Patients aged between 26-30
18,4%
8,1%
DISCUSSION: Our present results confirm those previously obtained in our laboratory. A
preliminary study performed by our laboratory using 191 patients had shown that amplified
methods and serology tests were complementary for the detection of upper- and lower-tract
infections.
Therefore, patients with high titer serology benefited from long-course therapy as they were
suffering from an upper-tract infection.
The present study therefore confirms the relevance of systematically screening at risk patients
(i.e STD Screening Centers or Centers of Obstetrical Gynecology) using both methods:
- direct detection of Chlamydia trachomatis in urine using amplified molecular biology tests
to detect symptomatic or asymptomatic lower-tract infected patients ;
- serological detection to detect chronic and upper-tract infections.
All high positive serology levels for patients without prior history of Chlamydia infection or
those having been appropriately treated for a Chlamydia infection should lead to
complementary investigations to confirm upper-tract infections.
CONCLUSION: Considering the 2,56 % prevalence of Chlamydia trachomatis in urine
specimens and the 11,7% seroprevalence in the population studied, this study confirms the
interest of systematic screening in the general population, using both amplified urine tests and
IgG and IgA serological examinations.
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P081
EVALUATION OF THE APTIMA COMBO GENPROBE TECHNIQUE
IN THE DIAGNOSIS OF CHLAMYDIA TRACHOMATIS INFECTIONS
AND INTEREST OF SYSTEMATIC SCREENING FOR NEISSERIA
GONORRHOEAE.
Sueur J.M., Orfila J., Betsou, F.
Objectives: Evaluation of the performance of the new GenProbe direct detection assay
APTIMA Combo in comparison with the AmpCT assay.
Methods: Frozen urine samples of asymptomatic pregnant patients (n=400) and sexually
transmitted disease patients (n=500) were processed with the AmpCT and the APTIMA
Combo assays.
Results: Overall, 881 concordant results were obtained between the AmpCT and APTIMA
Combo assays. Discordant results concerned 15 APTIMA positive / AmpCT negative and
four APTIMA negative / AmpCT positive urine samples. The presence of inhibitors was
assessed in 1% of the samples with the APTIMA Combo technique. When compared with a
gold standard, sensitivity of the AmpCT and APTIMA Combo was 83,3% and 96,7%
respectively. Specificity was 99,6% and 99% respectively. Neisseria gonorrhoeae was
detected in two urine samples of asymptomatic patients.
Conclusions: The APTIMA Combo technique has excellent sensitivity and specificity, and
shows 97,8% concordance with the AmpCT technique. Furthermore, it shows the interest of
systematic screening for N. gonorrhoeae.
EUROGIN 2003
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P082
THE ROLE OF SONOHYSTEROGRAPHY IN THE EVALUATION OF
PERI- AND POSTMENOPAUSAL BLEEDING
Daskalakis G, Pilalis A, Papadopoulos D, Papantoniou N, Hatziioannou L, Mesogitis S,
Antsaklis A
1st Department of Obstetrics and Gynaecology, University of Athens, Athens, Greece
Objective: The aim of our study was to identify the role of hysterosonography (HS) and of
transvaginal sonography (TVS) in peri- or postmenopausal women with unexplained
bleeding.
Methods: Seventy-six women between 49 and 64 years old were included in the study. All of
them presented unexplained metrorrhage and they gave verbal consent prior to the procedure.
After a transvaginal ultrasound, a saline hysterosography was performed in all cases.
Following this, all women were referred for dilatation and curettage and histology results
were compared to the sonographic findings.
Results: The HS procedure was well tolerated with no significant complications. In 28 cases
an endometrial polyp was found, in 7 cases there was endometrial hyperplasia and in 5 cases
endometrial cancer. In 6 other cases there was a submucosal leiomyoma. The sensitivity of
TVS was 84.8% and of HS 91.3%. Combined use of TVS and HS raised the sensitivity to
93.5%.
Conclusions: HS is superior to TVS in the evaluation of endometrial pathology in peri- or
postmenopausal women with unexplained bleeding. HS enhances the predictive power of the
ultrasound alone for endometrial anomalies and provides additional information especially in
women with atrophic endometrium.
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P083
COLOR DOPPLER EVALUATION IN THE DIFFERENTIAL
DIAGNOSIS OF ADNEXAL MASSES
Daskalakis G, Papadopoulos D, Savopoulos E, Thomakos N, Papantoniou N, Antsaklis A
1st Department of Obstetrics and Gynaecology, University of Athens, Athens, Greece
Objective: To determine the predictive performance of color-Doppler analysis as a method of
assessing ovarian neoplasms.
Methods: We studied 79 patients referred to our Department for adnexal masses. All of them
were evaluated by means of vaginal color Doppler ultrasound noting the blood vessels in the
tumors, the shape of the blood flow ands peripheral resistance. The sonographic findings were
compared to those of the histopathology reports.
Results: Twenty-eight masses were malignant and 51 benign. Blood vessels were localized
centrally more often in malignant tumors than in benign ( 64% vs 6%). A diastolic notch was
present in 82.1% of the benign tumors, but in none of the malignant tumors. The mean RI
(resistance index) and mean PI (pulsatility index) were lower in malignant (0.41 and 0.62,
respectively) than to benign tumors (0.67 and 1.12, respectively).
Conclusion: Color Doppler ultrasonography seems to be a reliable method in the differential
diagnosis of adnexal masses. Low RI and PI values are indicators of tumor growth, as well as
of a malignant potential.
EUROGIN 2003
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P084
COMPARISON OF P16INK4A PROTEIN DETECTION IN SCRAPED
CERVICAL CELLS AND IN ROUTINE CERVICAL CELL SMEAR
Ekalaksananan T (1), Pientong Ch (1), Kritpetcharat O (2), Kongyingyoes B (3), Swadpanich U
(4), Yuenyao P (5).
(1) Department of Microbiology, (2) Department of Pathology, (3) Department of Pharmacology, (4)
Department of Obstetrics and Gynecology, Faculty of Medicine, Khon Kaen University, (5) Khon Kaen
Hospital, Khon Kaen, Thailand.
In this study, the detection of p16INK4a protein by immunocytochemical technique in
scraped cervical cells was compared to that in routine cervical cell smear. Duplicate cervical
scrapes were taken from each participant. The first scrape was routinely smeared on 2 slides,
one for Pap smear test and the other for p16INK4a protein determination. The second scrape
was suspended in 50 ±l PBS and 10 ±l of this cell suspension was dropped in a 5 mmdiameter circle on a glass slide. Slides prepared by both the cell smear and the cell suspension
technique were air-dried, fixed in 0.1% formal saline for 1 hour and in 95% ethanol for 10
min and subsequently kept in 20oC until used. For the p16INK4a protein detection by
immunocytochemical technique, slides were fixed in cold acetone at 20oC for 10 min and
stained with mouse monoclonal anti- p16INK4a as primary antibody. Positive control (SiHa
cells) and negative control (human embryonic lung fibroblast cells) showed 95% and 0.1%
immunoreactive cells respectively. A positive sample must contain > 3 immunoreactive cells
on slide.
Regarding the Pap test 30 samples of each group as control (normal cervical cells), mild grade
dysplasia (ASCUS, LSIL) and high-abnormality (HSIL, SCC) were studied. Using
immunocytochemical technique, the scraped cervical cell slide displayed dispersed cells on
clear background, whereas slide with cervical cell smear showed not only numerous white
blood cells and some mucus but also many cervical cells. The p16INK4a protein on scraped
cervical cell slide was revealed in 17 of 30 (56.67%), 10 of 30 (33.33%), 28 of 30 (93.33%)
and 29 of 30 (96.67%) samples in ASCUS, LSIL, HSIL and SCC group respectively. The
p16INK4a protein detection in routine cervical cell smear was relatively more sensitive since
it showed 100% (30 of 30) positive in HSIL group while leaving comparable results in other
groups. This was probably due to error in preparing aliquot cell samples of the scraped cell
slide. Samples with only normal cervical cells and degenerated malignant cells were
considered immunoreactively negative.
We concluded that the p16INK4a protein detection in routine smear might be a diagnostic
adjunct to the Pap test for the screening of cervical cancer.
EUROGIN 2003
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P085
ATYPICAL GLANDULAR CELLS: TESTING THE CRITERIA FOR
IDENTIFICATION OF CLINICALLY SIGNIFICANT LESIONS
Torres JCC (1), Derchain SFM (1), Gontijo RC (1), Westin MC (2), Martinez EZ (3), Andrade LALA
(4), Syrjänen KJ (5),
(1) ObGyn Department, (2) Cytopathology Unit, (3) Statistic Unit (4) Pathology Department,
Universidade Estadual de Campinas, Campinas, Brazil (5) National Institute of Health, Rome, Italy
Background and objective: Although the recently revised Bethesda reclassified atypical
glandular cells (AGC), well-defined cytomorphological diagnostic criteria are still lacking.
The purpose of this study, linked to FAPESP 99/05598-2 project is to report cytological
features that could help identify a clinically significant lesion and to evaluate the criteria to
differentiate glandular from squamous lesions.
Subjects and methods: We reviewed slides of 73 women with a Pap smear diagnosis of
AGC from January to December, 2000 using the set of 28 criteria, subdivided in three major
categories (cellular arrangement, cytoplasmatic and nuclear features) and correlated with the
histological diagnosis. A logistic regression analysis was performed to model the relationships
between cytological criteria and biopsy-proven significant lesions using odds ratio (OR) with
95% interval confidence (95%IC).
Results: Histological result showed benign lesions in 38 (52%) cases and clinically
significant lesions in 35 (48%): 26 (75%) intraepithelial squamous disease, seven (20%)
adenocarcinoma in situ and two (5%) invasive carcinomas. On univariate analysis, atypical
single cells (OR 11.2 95%CI 3.4-35.8), apolar cells (OR 10.2 95%CI 3.3-31.2), cellularity
(OR 6.7 95%CI 1.3-33.0), cellular overlap (OR 3.2 95%CI 1.1-9.2), cellular dissociation (OR
3.4 95%CI 1.2-9.3), decreased cytoplasm (OR 5.3 95%CI 1.8-15.1), atypical stripped nuclei
(OR 11.2 95%CI 3.4-35.8), dyskeratinized cells (OR 8.3 95%CI 1.6-40.6), irregular nuclear
membranes (OR 6.6 95%CI 2.2-19.2), coarse chromatin (OR 5.6 95%CI 2.0-15.8), nuclear
pleomorphism (OR 4.9 95%CI 1.7-14.1), and thick nuclear membranes (OR 3.1 95%CI 1.18.8) showed a statistical association with clinically significant lesions. The strongest
association, however, was related to increased nuclear/cytoplasm (N/C) ratio (OR 17.5 95%CI
4.4-68.1). In a stepwise logistic regression, adjusted for age, increased N/C ratio and
dyskeratinized cells were the features that remain significantly associated with clinically
significant lesion, rosettes being the determinant morphological criteria of true glandular
lesions.
Conclusions: With the aid of the key cytological criteria, benign AGC lesions can be
separated from clinically significant glandular lesions.
EUROGIN 2003
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P086
DETECTION OF ANTI E6 HPV 16 ANTIBODIES IN SERUM OF
WOMEN WITH CHRONIC HPV INFECTION, CIN AND CERVICAL
CANCER
Kedzia W, Olejnik A, Jacobs N, Spaczynski M.
Division of Oncology, Gynecology and Obstetric, Poznan
The study was conducted on a group of women with chronic HPV infection of the cervix that
lasted from 1998-2000. Thirty two patients with CIN I, forty six patients with CIN III, ninety
one with invasive intraepithelial cervical cancer and twenty two women after radiotherapy
treatment for invasive cancer were included in this study. The control group was comprised of
329 patients without HPV infection within the cervix. The antibodies were detected using
ELISA method. In patients with positive HPV infection, in whom, during 3 years of chronic
form of HPV infection was confirmed, there was constant increase in absorbance from 0,04 in
1998 to 0,06 in 2000. The mean absorbance in seropositive women from control group, which
were HPV negative was form 0,03 to 0,04. The mean absorbance in seropositive women with
CIN I, CIN III, invasive cancer and after oncological treatment were as follows:
0,06;0,14;0,33;0,13, respectively. Above data clearly demonstrate gradual rise of absorbance
with advancing neoplastic process and decline in absorbance with radiotheraphy. Obtained
numbers suggest that chronic cervical HPV infection and rising of anti E6 HPV 16 antibodies
in serum is associated with an increased risk of initiation of carcinogenic process.
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P087
ATYPICAL SQUAMOUS CELLS RELATED TO HPV INDUCED
LESIONS
Mociulschi R, Coman N, Tarlea V, Dinca G, Ionescu M
I.O.M.C.- ''Center for Early Detection of Genital & Breast Cancer''BUCHAREST-ROMANIA
OBJECTIVE: There is always a degree of subjectivity in distinguishing atypical squamous
cells of undetermined significance from mild dyskaryosis in the presence of cytological
evidence of HPV infection. Our objectives were to establish the evolution and management of
cases with persistent ASCUS smear which presented cytopathological changes specific for
HPV infection by appliying the tripod diagnosis (cyto-colpo-hystopathologically evaluation).
METHOD: During a period of 2 year, 9220 new female patients have been cytologically
investigated. From 1761 cases with cellular and nuclear changes specific to HPV infection
(koilocytes, spindle koilocytes, binucleation, multinucleation, borderline nuclear changes and
diskeratosis) , 746 cases with smears included in the ASCUS category were selected. The
cases were followed-up within a period of 18 months, repeating cytology every 6 months.In
followed-up group the mean age was 29 years ( range 18-62 years ).The cases with 2 negative
ASCUS smears, subsequent to an initial ASCUS diagnosis, were considered cases that had
became negative and another PAP test after 1 year was recommended. The cases which at the
second PAP test presented persistent ASCUS smear and those with cytomorphological
aspects who suggested an evolution to SIL (high-grade squamous intraepithelial lesions) were
examinated colposcopically and histopathologically.
RESULTS: From 9220 patients cytologically investigated, 1217 cases have had ASCUS
smears , indicating a prevalence of 13,2 % for ASCUS. In 1761 (19,1 %) cases had been
identified cytological changes specific for HPV infection. Correlating the number of HPV
positive smears that were included in the ASCUS smear category , it has been established that
ASCUS is present in 42,6 % of these .After 6 months when the second PAP test took place
the distribution of cases with ASCUS were as follows: 63 % were included in the type WNL
(with normal limits) ; 21 % with persistent ASCUS smear ; 16% were suggestive for
progression to HG - SIL . Colpo-histopathological investigation of cases with persistent
ASCUS in two successive determinations and those suggestive for progression to HG - SIL
revealed: 31 % Koilocytotic atipia , 39% chronic cervicities and / or squamous metaplasia,
12% CIN 1, 15,9 % CIN2 and 2,1% CIN 3. We agreed that no cell with evidence of HPV
infection is normal and that no smear in which there is evidence of HPV infection should be
reported as negative whether or not there is a substantial nuclear abnormality.
CONCLUSIONS: The follow-up of the cases with persistent ASCUS smear demonstrated an
increasing incidence of LG - SIL and a high risk of evolution to HG - SIL .We consider that
persistent ASCUS at, the second or third PAP test imposes an colpo-histopathologically
examination . The relatively great prevalence of ASCUS smear in the cases investigated by
us, we don't consider it to be as a consequence of misincluding the smears in the ASCUS
category , but we can explain it as the patients that come to our Center (that is the National
Center of Cancer Detection) were initially selected in the clinics and sent to our Center for
clearing up the diagnosis .The great SIL incidence can be explained as well by the cases
selection , on the basis of 2 criteria: referring the smear in the ASCUS category and the
presence of the cytomorpological changes specific for HPV infection. ASCUS are most
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commonly reported in: the presence of Human Papilloma Virus (HPV) infection,
inflammatory epithelial changes (poly STD-cases),the presence of an intrauterine
contraceptive device or cervical polyp,atrophic smears. It is generally not advisable to allow
more than three mildly abnormal smears before recommending colposcopy and even
histopathological assessment, whatever the age of the patient . Referral for clposcopy sould
not imply a need for biopsy when the cytological changes may be explained by cervicitis,
metaplasia, polyps, atrophy or IUD basal hyperplasia.
EUROGIN 2003
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P088
CONISATION AS A TREATMENT FOR PRECANCEROUSE
CERVICAL DISEASE AND HPV TYPES REPRESENTATION
Naumov J, Milanova E, Stojovski M, Janevska M, Tanevska P
Clinic of gynecology and obsterics
Objective: The aim of the study is to show the review of the highrisk HPV types to patients
with precancerouse cervical disease treated with ( cold knife) conisatio.
Material and methods: Report focused on 34 treated women with cold knife conisation
because of HSIL. HPV DNA testing was preformed with PCR.
Results: Hysthology results after conisation treatmen were dysplasia gradus mediocris ( CIN
II ), for 4 patients.Dysplasio gradus gravis ( CIN III) for 12 patients, and carcinoma in situ
PVU for 18 patients. From all cases only one had negative predictive value HPV DNA result,
the other 32 cases had HPV positive tests for high risk types.HPV type 16 appeared in 14
(41%) of samples, HPV type 31 appear in 9 ( 26,5%), and HPV type 18 in 4 (12%) . We
registrated HPV type 58 in 3 (9%) of cases, 2 for HPV type 39 and one patient with HPV type
38.
Conclusion: The most common high risk HPV types at the patients treated with conisation
were HPV type 16 and 31. This was distribution of the small number of cases but the results
colaborate with the results from other studies.
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P089
EZRIN, P16INK, KI67 AND HPV EXPRESSION IN DYSPLASTIC
LESIONS HARBORING HIGH RISK HPV AS IDENTIFIED BY
HYBRID CAPTURE II TEST
Tarkkanen J*, Auvinen E**, Tapper A-M^, Carpen O*
*Haartman Institute and Helsinki University Central Hospital, Departments of *Pathology, **Virology
and ^Obstetrics and Gynaecology, Helsinki, 00029 HUCH, Finland
OBJECTIVE To examine HPV in situ hybridisation (ISH) reactivity and
immunohistochemical p16INK, Ki67, ezrin and HPV reactivity in dysplastic high risk HPV
(hrHPV) cervical lesions identified by Hybrid Capture II test.
METHODS. Tissue specimens were obtained from patients who were referred to colposcopic
LEEP procedure on the basis of biopsy-proven CIN2+ lesion. Cytological samples from the
patients were positive for high risk HPV as measured with Hybrid Capture II test. ISH was
run on Ventana Benchmark with a high-risk HPV probe and IHC was performed using a
LabVision Autostainer automatic immunostaining device.
RESULTS. The material consisted of 15 cervical specimens with histologically verified
CIN2+ lesion. p16INK staining specifically highlighted all dysplastic areas, whereas no
staining was seen in the normal stratified epithelium. Expression of ezrin, a protein involved
in cellular communication was detected in the basal layers of normal stratified epithelium. In
dysplastic areas the staining was more intense and covered the full thickness of the
epithelium. Expression of the proliferation marker Ki67 was increased in all dysplastic areas.
Anti-HPV staining highlighted only some superficial koilocytes (3/15 cases). ISH with high
risk HPV probe was positive in 10/15 cases. The strongest signal was seen in superficial
layers with koilocytes.
CONCLUSION. p16 staining specifically highlighted all dysplastic areas. Expression of
ezrin was increased in dysplastic areas as compared with non-dysplastic epithelium. ISH
positivity was seen in 10/15 cases. IHC with anti-HPV antibodies was quite insensitive except
for replicative foci with koilocytes.
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P090
DETECTION OF ANTI E6 HPV 16 ANTIBODIES IN SERUM OF
WOMEN WITH CHRONIC HPV INFECTION, CIN AND CERVICAL
CANCER
Kedzia W, Olejnik A, Jacobs N, Spaczycski M.
Division of Oncology, Gynecology and Obstetric, Poznan
The study was conducted on a group of women with chronic HPV infection of the cervix that
lasted from 1998-2000. Thirty two patients with CIN I, forty six patients with CIN III, ninety
one with invasive intraepithelial cervical cancer and twenty two women after radiotherapy
treatment for invasive cancer were included in this study. The control group was comprised of
329 patients without HPV infection within the cervix. The antibodies were detected using
ELISA method. In patients with positive HPV infection, in whom, during 3 years of chronic
form of HPV infection was confirmed, there was constant increase in absorbance from 0,04 in
1998 to 0,06 in 2000. The mean absorbance in seropositive women from control group, which
were HPV negative was form 0,03 to 0,04. The mean absorbance in seropositive women with
CIN I, CIN III, invasive cancer and after oncological treatment were as follows:
0,06;0,14;0,33;0,13, respectively. Above data clearly demonstrate gradual rise of absorbance
with advancing neoplastic process and decline in absorbance with radiotheraphy. Obtained
numbers suggest that chronic cervical HPV infection and rising of anti E6 HPV 16 antibodies
in serum is associated with an increased risk of initiation of carcinogenic process.
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P091
A STUDY ON THE CERVICAL EPITHELIUM OF WOMEN IN EARLY
PREGNANCY - HISTOLOGICAL FINDINGS AND HPV-TYPIZATION
Zlatkov V. (1), Kostova P. (2), Makaveeva V. (3), Ganchev G. (4), Danon S. (5)
1-National Transport Hospital - Gynecology Clinic, Sofia, 2- National Oncological Hospital-Gynecology
Clinic, 3-University Hospital of OB/GYN - Dept. of Pathology, Sofia, 4-National Oncological Hospital;
Dept. of Pathology, 5-National Oncological Hospital-Cancer registry, Sofia, Bulgaria
Aim: The aim of our investigation was to study the histological findings of the cervix of
women in early pregnancy, compared to a control group of nonpregnant women and in the
cases with morphological data for HPV infection DNA in situ hybridization for the types 6,
11, 16, 18, 31 & 33 was perfomed.
Materials and methods: The study involved 250 women, aged between 14 and 45 years
(mean 26.5 years), who agreed in writing to be incuded in the diagnostic-research
investigation. 166 Of them were pregnant (to 12 g.w.) and came for interuption, in
compliance with the law and 84 were nonpregnant women. Target cervical biopsy was taken
from all of them, as the biopsy spot was defined according to the presence of atypical
colposcopy finding, or in absence of such, from the preliminary chosen part. In the cases,
when histological results showed the presence of HPV infection (according to Reid criteria)
DNA -ISH was performed. The statistical processing of the obtained results was performed
with the set SPSS / PC + v. 5.01 for Windows. The selected level for statistical significance
being at p= 0.05
Results: Histological findings from the suitable for assessment materials showed morphology
for HPV infection in 29 pregnant (17.7%) and 11 (13.1%) nonpregnant. At the same time
precancer lesions with or without HPVI, were found in 43 pregnant, of whom 40 (24.4%)
with CIN CIN I-II and 3 (1.8%) with CIN III, and in the group of nonpregnant in 20, of whom
17 (20.2%) with CIN I-II and 3 (3.6%) with CIN III. Microinvasive cancer was detected in
one patient of the control group. DNA in situ hybridization was performed to all 54 women
with histological data of HPV infection, 33 of them pregnant and 21 nonpregnant controls.
Conclusions: The performed investigation carried out, determined the statistical significant
difference in comparing histological findings of pregnant and nonpregnant women, which is
due to the higher frequency of the HPV changes and low-grade CIN in the pregnant women.
The distribution of the investigated viral types with DNA in situ hybridization did not show
any difference between the two groups of patients.
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P092
MULTIPLE RECURRENT PRECANCEROSIS OF LOWER GENITAL
TRACT – CASUISTIC
Havrankova A, Kosova T, Svoboda B
Dept. Obstetrics and Gynaecology, Faculty of Medicine, Charles University, Prague
Introduction : Premalignant laesions of lower genital tract may occur very often
simultaneously. Risck factors for appareance of premalignant laesions of cervix vagina and
vulva are similar. Among most frequent risk factors belongs HR HPV infection together with
risky behaviors and life style smoking and imunosupression. A long-term dispensarisation and
high quality following up including well cured premalignant laesions LGT is necessary.
Casuistic : Patient JZ came to the Center for oncological prevention gyn-obst. Clinic of
Faculty Hospital Kràlovské Vinohrady in 1977 (in her 46 years of age). Her diagnose was a
suspect laesion of the cervix HG laesion was confirmed by coloscopy and cytol smear and
laesion cured by conisation – knife was used. Histologically there was found CIN III which
was not presents in the edges of incision. After 5 years of dispensarisation pacient was sent
back to her gynaecologist.
1993 – (in her 62 years of age) she came back to Center for oncological prevention because of
appearance of multiple laesions in skinny and mucous parts of vulva and also in perinea part
confirmed (CIS-Bowen-like type) Tretaed by CO2 laser extirpation of suspect laesions an
vaporisation of the environment. Then ther were no signs of recurrent or new disease on
vulva.
1998 – (in her 67 years) – HSIL in cytil. Smear when negative colposcopy was founf. Made
an excision of external orifice and curratage. Histologically CIN .
1999 - appareance of LSIL cytol. smear endocervically, treated by LEEP and fract do
curettage. Histol was negative (metaplasie, akantosis, kollo).
VII/2000 – appareance of HSIL smear to in Ca and multiple suspect acid white laesions on
vulva.
VIII/2000 – because of this very suspect findings indicated hysterectomy sec Wertherm and
excisions of vulvar laesions. Histol : cervix just CIN III, vulva : lichen sclerosus.
XI/2000 – In 69 years of age) by colposcopy found granulations on vaginal stump, according
with smear HSIL - histolog : extirpated granulation are benign.
III/2001 – V/2001 coloscopically very poor findings but cyto smear is still HSIL – Ca.
Virological test DIGENE is highty positive for HPV virus 16,18.
V/2001 – made excision from vaginal stump histol CIN II.
VII/2001 made new excision – histol CIN III.
Because of age and clinical status of the patient we don’t indicate colpectomy but
brachyterapy on upper part of vagina.
Conclusion : Patient with confirmed risk factors (as HR HPV positivy, smocking) was
followed-up in Center for oncological prevention 25 years. In correspondance with literary
particular and our.
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P093
THE COLPOSCOPIC PICTURE OF THE UTERINE CERVIX IN CASES
OF BACTERIAL AND VIRAL UROGENITAL INFECTIONS
Kubanov A., Kisina V.
Central Research Institute of Dermatology and Venereology, Moscow, Russia
Aim: To study the state of the uterine cervical mucosa in cases of bacterial and viral
urogenital infections.
Methods: 61 women aged 18-46 yrs underwent a clinical-microbiologic, colposcopic
investigation. All patients were divided into 2 groups: group 1 - 35 patients with sexually
transmitted infections (gonorrhea, chlamydiosis, trichomoniasis), group 2 - 26 patients with
clinical manifestations of HSV- or HPV-infection. Microscopic, cultural and PCR methods
(including HPV typing) were used.
Results: HPV of type 16 and/or 18 were found in 11.4% of group1 patients and in 7.7% of
group 2 patients. Colposcopic findings in group 1 indicated benign changes such as cervicitis
(71.4%), ectopia (20%), an incomplete transformation zone (7.7%), endometriosis (5.7%),
polyps (5.7%). In group 2 colposcopic findings indicated no changes (23%), benign changes
(an incomplete transformation zone (26.9%); 11.5% of group 2 patients had various
combinations of changes, such as iodine-negative areas, leukoplakia, an atypical
transformation zone. On clinical examination such patients were found to have insignificant
diffuse hyperemia and contact bleeding of the uterine cervical mucosa.
Conclusions: The occurrence of the highly oncogenic HPV types and the presence of the
transformation zone (which was found in 7.7% and 26.9% of group 1 and group 2 patients
respectively) may promote the development of CIN in the uterine cervix. This fact accounts
for the necessity of routine colposcopic examinations of women with bacterial and viral
infections which will help prevent cancer of the uterine cervix.
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P094
HIGH-GRADE CIN IN WOMEN UNDER 30 YEARS OLD
Gomes F., Lourenço C., Paredes E., Ramalho G.
Centro Hospitalar de V. N. Gaia, V. N. de Gaia, Portugal
The authors present the casuistic (n=19) related to high-grade intraepitelial lesions in women
under 30 years.
The study reports t the period between January 2001 and December 2002.
This group of patients was refered to our hospital (colposcopy) by Family Doctors, after
detection of an abnormal cytology.
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P095
THE ROLE OF COLPOSCOPY IN CERVICAL CANCER
PREVENTION
Stojovsk M, Milanova E, Naumov J, Janevska M
Clinic of gynecology and obsterics
Objective: This study is focused on the meaning of the colposcopical examination to improve
the precancerous cervical lesions.We have tried to show the role of the experience of the
doctor to control all the cervical lesions: low squamous intraepithelial lesions (LSIL), and
high squamous intraepithelial lesions (HSIL).
Material and methods: In our report we did about 80 colposcopy examinations.Cervical
biopsy was criterion standard.The histology results showed presence of HPV.patients with
initial citology diagnosies were included for colposcopic examination.The abnormal
colposcopical examination was showed by the colposcopical gradus by Coppleson and Pixly
with degree of comparison gradus1 (G1), gradus 2 (G2), and gradus 3 (G3).
Results: From 80 examinations, 34 (42,5%) were G1, 17 (21%) were G2, and 29 (36%) were
G3.Colposcopy exam with G1 found were hysthologicaly proved as HSIL at 2 and LSIL at 32
of them.G2 founds hysthologicaly diagnosies were 7 with LSIL and 10 with
HSIL.Colposcopical gradus G3 we introduced at 20 HSIL and at 9 LSIL.
Conclusion: We found out that our colposcopy exams colaborate with heavines of cervical
precancerose.We showed that colposcopcal gradus G1 is often to LSIL and G3.G2 found is
typical for both hystological exams.
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P096
BAX PROTEIN AND PHOSPHORYLATED HISTONE H3 IN
CERVICAL SMEARS ARE ASSOCIATED WITH PROGRESSION OF
CERVICAL INTRAEPITHELIAL NEOPLASIA.
Anton Milan (2), Horky Marcel (1), Kuchticková Sarka (1) and Vojtesek Borivoj (2)
(1) Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Komenského
námestí 2, 662 43 Brno, Czech Republic ; (2) Masaryk Memorial Cancer Institute, Zlutý kopec 7, 656
53 Brno, Czech Republic.
Objective: Bax protein, a product of an anti-apoptotic gene, has been found in tumors
resistant to chemotherapy. Histones bind in a sequence-independent manner to form
chromatin. The amino-terminal tails of histones are targets for both phosphorylation and
acetylation events. These modifications are thought to fundamentally regulate chromatin
structure to accommodate transcription, DNA replication, mitosis and DNA repair.
Regeneration of squamous and columnar epithelia is accompanied by marked cellular atypia,
nuclear and nucleolar pleomorphism which could be confused with neoplasia. The aim of the
study was to detect phosphorylated and acetylated forms of H3 (histone-3) in cytological
smears.
Methods: Smears from women whose ages ranged from 20 to 56 yrs, undergoing routine
Papanicolaou tests were selected. The smears were evaluated for abnormal cells according to
the traditional nomenclature. The specimens comprised 10 squamous metaplasia, 11 epithelial
repair, 9 CIN I, 12 CIN II, and 14 CIN III. The smears were stained with polyclonal
antibodies against Bax and phosphorylated H3.
Results: We found that nuclear positivity for phosphorylated form of H3 in CIN II (23%) and
CIN III (25%) was higher in comparison with repair (11%) and metaplasia (8%). Bax
positivity was only shown perinuclearly in CIN II (28%) and CIN III (34%).
Conclusion: We revealed a marked association of histone H3 modification with the
progression of CIN in comparison to cervical repair and metaplasia. Our results are in
agreement with recent findings that staining of cells with anti-phospho-histone H3 antibodies
therefore provides a highly specific marker for mitosis.Bax protein , present in the smears of
CIN II and CIN III, proved a potential resistance of neoplastic cells to apoptosis.
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