Download Cervical Cancer

Cervical Cancer: An update on
the guidelines for screening
Shikha Bose M.D.
Prof. of Pathology
Cedars Sinai Medical Center &
David Geffen School of Medicine, UCLA
Global Cancer Congress Sept. 20, 2014
Worldwide Cervical cancer

Cervical cancer is a considerable problem
 555,100 new cases
 80% of these will be in low/middle income
countries

Third leading cause of cancer death in
women
 309,800 deaths annually
 73,000 deaths in India (1/4)
Cervical cancer incidence rates
Global Cancer facts & Figures 2007, ACS
HPV & Cervical CA
HPV: Cause of Cervical CA
HPV is a 55 nm non-enveloped double stranded
circular DNA virus belonging to the
Papillomaviridae family
HPV cause papillomas
Infects keratinocytes of
 Skin:
 hands and feet
 Mucosa
 throat
 genital area.
HPV



Harald zur Hausen - 2008
Nobel Prize for Medicine
Was first discovered in the 1950s
Stefania Ginsburg-Jablonska,
Polish dermatologist, Univ. of
Warsaw first discovered the
association between HPV & skin
cancer in 1972
Harald zur Hausen, a German
scientist and virologist was the
first to show that HPV causes
Cervical Ca and identified HPV16
and HPV18 as the responsible
strains.
Anogenital HPV
 Most
common STD (6.2 million new infections/yr in
US)
 Warts present in 1% of sexually active people
 Subclinical infection >15%
 1 in 2 will acquire genital HPV in their lifetime
 Worldwide
age standardized prevalence of current
HPV infection: 10.5%
 Varies between different regions: 1.4% (Spain) to
25% (Nigeria)
HPV
 >100
types; 40 infect anogenital mucosa
 Low risk (LR)- HPV 6, 11
 Condyloma acuminata (~ 500,000/yr)
 Juvenile respiratory papillomatosis
 Rare progression to cancer
 High risk (HR) – at least 15 known
 HPV 16, 18 – Commonly associated with cancer
HPV and Cancer
Cancer Type
Annual
Incidence/death (US)*
HPV associated
Cervical
Vulvar
11,070/3,870
3,870/870
≥95%
50%
Anal
Penile
Oral &
Oropharyngeal
Esophageal
5,070/680
1,250/290
35,310/7,590
70-90%
~50%
~20-30%
16,470/14,280
~22%
*Estimated numbers for 2008 per NCI/ACS
Origin of cervical cancer
At the squamocolumnar junction
Natural history of HPV infection
Moscicki et al. Updating the Natural History of Human Papillomavirus and Anogenital Cancers. Vaccine Volume 30, Supplement 5
2012 F24 - F33. http://dx.doi.org/10.1016/j.vaccine.2012.05.089
HR HPV genotypes & Cervical CA
 HPV
16 – 50-60% of
 HPV 18 – 10-20%
 HPV 31, 45 – 10%
 Remaining 11 subtypes – 10%
 MOST
infections are subclinical
 MINORITY produce SIL
 Small fraction of SIL lead to CA
Natural history of CIN and Cervical Ca
Viral Persistence
HPV
Infection
CIN 1
Normal
Cervix
CA
CIN 2
CIN 3
15
30
45
CERVICAL CANCER
SCREENING
The Papanicolaou (Pap) Test



George Papanicolaou
First announced the test in
1928 at a conference in
Michigan.
1943 published “Diagnosis
of Uterine Cancer by the
Vaginal Smear”
Best screening tool introduced
for any cancer
The Pap Test
 The
Pap test, when combined with a regular
screening program & appropriate follow-up,
can reduce cervical cancer deaths by up to 80%.
 In the US of women with invasive cervical
cancer:
 >50% have never had a Pap smear
 10-20% have not had a Pap smear in the preceding 5 yrs
 25% had an abnormal Pap smear, but did not get
appropriate follow-up (woman did not return for care, or
clinician did not perform recommended tests or
treatment)
The Pap Test: Limitations
Good quality cytology-based screening
programs require highly trained personnel,
specialized equipment and screening at
regular intervals
 Low sensitivity 50-60% (Specificity – 95%)

• High false negative associated with
• patient compliance
• sample collection
• subjective assessments
Limitations of the Pap Test
 Good
quality cytology-based screening
programs require highly trained personnel
and specialized equipment
 Low sensitivity 50-60% (Specificity – 95%)
• High false negative
• Increased liability
• Requires screening at regular intervals
 Subjective
assessments
Newer modalities for Screening
 Liquid
based cytology
 Computer - assisted screening
 Adjunctive molecular testing
Liquid based Pap Test






Currently ThinPrep© (Hologic, Marlborough, MA) and
SurePath© (Becton‐ Dickinson/TriPath, Burlington, NC) are
the predominant LB Pap test types used in the US.
Provide a more representative sampling
Decrease pre‐analytic problems: transfer of sample, excess
blood/inflammation, and air‐drying.
Allows additional tests for HPV, STI (Chlamydia, Gonorrhea
and Trichomonads) from the same vial.
Allowed the incorporation of computer imaging technology.
Meta‐analyses do not indicate an overall increase in HSIL
detection.
Arbyn M, Bergeron C, Klinkhamer P et al. Obstet Gynecol 111:167, 2008
Computer imaging technology

Two FDAs approved devices to assist in cervical
cytology screening:
 The B.D. FocalPoint™ Slide Profiler Intelligent Pap
Imaging™ system
 incorporates initial computer evaluation followed by manual
rescreening of the most likely abnormal cases; the least abnormal
cases require no review.
 The Hologic ThinPrep™ Imaging System
 involves automated pre‐screening and presentation of digitized
images of the most abnormal 22 fields of view (FOV) to a reviewer,
thus allowing a dual review: one full review from the ThinPrep
Imager and another from an experienced cytotechnologist
HPV testing

Advantages:
 Highly reproducible
 Easily monitored
 Objective outcome

1999: FDA approved HPV
testing for ASC-US Paps

2003: FDA approved for
primary screening in women
>30yrs
Testing for low-risk HPV types has NO role in routine cervical cancer
screening or for the evaluation of women with abnormal cervical
cytology.
The sensitivity of HPV testing is not 100%. A subset of carcinomas,
both squamous and glandular, and other tumor types may not be
detected by HPV testing.
FDA approved HPV assays
Hybrid Capture 2
Cobas HPV test
(Digene Corporation /
Qiagen group)
(Roche Molecular Systems,
Inc)
13
14
Same as Cervista
except 66
Pooled: 31, 33, 35,
39, 45, 51, 52, 56, 58,
59, 66, 68
HPV16
HPV18
Invader technology
In situ Hybridization
Real time PCR
Absent
Present
Absent
Present
Absent
Present (β globin)
Cervista
(Hologic Inc.)
HRHPV types 14
Probes
A5/6 - 51,56,66
A7-18,39,45,59,68
A9 16,31,33,35,52,58
Test type
Cross
reactivity
Internal
control
Summary of Screening Recommendations
Population
(age in yrs)
Recommended
screening
method
<21
No screening
21-29
Cytology x 3 yrs
Management of screening results
Comments
HPV testing should
not be used for
screening or
ASCUS triage
ASCUS+ HPV+
≥ LSIL
Colpo
CytologyASCUS+ HPV- Rescreen x 3 yrs
HPV testing should
not be used for
screening but is
used for ASCUS
triage
The American Congress of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical
Management Guidelines for Obstetrician-Gynecologists: Screening for Cervical Cancer. November,
2012
Summary of Screening Recommendations
Population
(age in yrs)
Recommended
screening
method
Management of screening results
Comments
30-65
Cytology + HPV
(Co-test) x 5 yrs
(preferred)
ASCUS+ HPV+/≥ LSIL: Colpo
Cytology- HPV+
HPV testing is
done with the Pap
test (Co-test) and
is not
recommended
alone for most
clinical settings
1. Co-test x 12 mo
2. HPV16 or HPV16/18 test
Pos: Colpo
Neg: Co-test in 12 mo
Cytology- HPV-/ASCUS+HPV-:
Rescreen x 5 yrs
Cytology x 3 yrs
(acceptable)
ASCUS+ HPV+/≥ LSIL : Colpo
Cytology-/ASCUS+ HPV-: Rescreen
x 3 yrs
Summary of Screening Recommendations
Population
(age in yrs)
Recommended
Management of
screening method screening results
Comments
>65
No screening
≥ CIN2:
routine screening x 20 yrs
After
hysterectomy
No screening
No cervix &
no history of
≥ CIN2 past 20 yrs or
Cervical ca
HPV
vaccinated
Age specific recommendations (same as unvaccinated)
The American Congress of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical
Management Guidelines for Obstetrician-Gynecologists: Screening for Cervical Cancer. November,
2012
Co-testing: HPV+Pap test
Sensitivity :
• of HPV - 95% v. Pap - 55%
• of HPV + cytology - 100%
• referral rate - 7.9%
Specificity:
• of HPV 94% v. Pap - 97%
Cumulative incidence of CIN 3+ when baseline
Pap- HPV- :
• 0.047% at 3 years
• 0.16% at 5 years
Katki HA, et al.: Lancet Oncol 12 (7): 663-72, 2011
Primary Cervical Ca Screening with
HPV DNA Test

FDA approved in 2014
 Roche Cobas HPV Test
 Thin Prep Pap Test PreserveCyt Solution
 Endocervical brush/spatula
 Roche Cobas HPV Test
 Originally FDA approval in 2011 for Co-test and Reflex test
 pcr-based target DNA amplification and hybridization for
detection of 14 HR HPV (HPV 16, HPV18 and 12 other HR HPV) in a
single reaction
FDA APPROVAL DOES NOT CHANGE CURRENT PRACTICE GUIDLINES
HPV for primary screening


Meta analysis of 4 European randomised trials comparing HPVbased with cytology-based Cx Ca screening (Swedescreen,
POBASCAM, ARTISTIC & NTCC10) of >175 000 women
HPV-based screening resulted in:
 60–70% reduction in invasive Cx Ca incidence
 significant decreased incidence of invasive Cx Ca on longer follow-up
 observed cumulative incidence of invasive cervical cancer was lower
5·5 years after a negative HPV test than 3·5 years after a negative
cytology test, indicating that 5-year screen intervals with HPV-based
testing are safer than 3-year intervals with conventional cytology
 enhanced detection of CIN2/3 in screened women, therefore enabling
early treatment and reduction of invasive cervical cancer risk
ATHENA trial


Prospective study of 40,901 women aged 25 years
and older who underwent routine cervical exams
Colposcopy and cervical tissue biopsy was performed
on women with:
 positive Pap test
 positive HPV test
 subset with negative Pap and HPV tests (~900 women).
 Used to calculate verification biased adjustment (VBA)


All biopsy results were compared with the Pap and
cobas HPV Test results.
3 years of follow-up
Provisional proposal for follow up
Cobas HPV test
HPV -
Follow up
x 3 yrs
12 HR HPV
31, 33, 35, 39, 45, 51,
52, 56, 58, 59, 66, 68
HPV
16/18+
12 HR HPV +
Pap Test
Normal
Follow up
x 12 mos
HPV 16
HPV 18
Colposcopy
Abnormal
≥ASC
Colposcopy