Download TACTICS FOR GP background and precancerous diseases of the

TACTICS FOR GP background and
precancerous diseases of the cervix and
endometrium.
Assistent of department obstetrics and
gynecology for GP TMA, D.Y. Yuldasheva
About This Presentation
• In this presentation, you will learn about old
and new methods of cervical cancer
screening
• We hope that this presentation will help
women to take an active part in their health
Cervical Cancer Screening and
Prevention
• You can prevent cervical cancer with
screening.
• Screening is the search for diseases, such as
cancer, in people without symptoms.
• Screening has saved thousands of lives.
• You should get screened for cervical cancer
on a regular basis.
• Cervical cancer can be prevented!
How common is cervical cancer?
500,000 women worldwide are diagnosed with cervical
cancer annually
50-60 million women in the U.S. have a Pap test each
year
3-5 million women in the U.S. have an abnormal result
– usually due to precancer changes on the cervix
Approximately 9,500 new cervical cancers diagnosed in
the U.S. per year
Over 3,500 deaths from cervical cancer in the U.S. per
year
Most Cervical Cancer Can Be Prevented
New cancer diagnoses in the U.S.
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2006 Statistics:
Breast 212,920
Uterus (womb) 41,200
Ovary 20,180
Cervix 9,710
Vulva 3,740
Source: American Cancer Society.
Women’s Cancer Network:
www.wcn.org
• Confidential gynecologic (ovarian,
endometrial, cervical) and breast cancer risk
assessment
• Comprehensive women’s cancer information
including gynecologic, breast and colon
cancers
• Links to other sources of cancer information
What is cervical cancer?
• It is a cancer of the female reproductive tract
• It is the most common cause of cancer death
in the world where Pap tests are not available
• It is the easiest gynecologic cancer to prevent
through screening and early vaccination
Predisposing Factors
• Early age of first coitus
- Adolescent age group
- Time interval from menarche
- Active cellular proliferation of the
transformation zone
Predisposing Factors
• Multiple sexual partners
• Higher risk of HPV infection
• Likely to have first coitus at an early age
Epidemiologic studies: rare in celibate women
Predisposing Factors
• Contraceptive Pills
• Less likely to use barrier method
• Screening bias: more likely to be seen by a
physician regularly
• Associated with Adenocarcinoma
Predisposing Factors
• Male factor
• Multiple sexual partner
Cervical Intraepithelial Neoplasia
• “ Normal tissue sheds normal cells, abnormal
tissue sheds abnormal cells “
• Samples from the ENDOCERVIX and
ECTOCERVIX
History of the Conventional
Pap Smear
• Developed by Dr. George N.
Papanicolaou in 1940’s
• Most common cancer screening
test
• Critical aspect of annual
gynecologic examination
Ferris et al. Modern Colposcopy. 2004: 2-4, 49.
Photo accessed from http://www.cytology-iac.org/Cytopaths/1998/cytoFall98.htm
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Collection Devices
Spatula &
Endocervical Brush
Broom Device
Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.
All pictures accessed from http://www.clinilab.fr/cytopathologie.html
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Cervical Cytology Terminology
Normal1
ASCUS2
LSIL3
HSIL3
• Atypical squamous cells (ASC)4
– Atypical squamous cells of undetermined significance (ASC-US)
– Atypical squamous cells, cannot exclude high-grade squamous
intraepithelial lesions (ASC-H)
• Squamous intraepithelial lesions (SIL)4
– Low-grade SIL (LSIL): Mild dysplasia, cervical intraepithelial neoplasia 1
(CIN 1)
– High-grade SIL (HSIL): Moderate and severe dysplasia (CIN 2/3)
carcinoma in situ (CIS)
• Atypical glandular cells (AGC)4
1. Spitzer M, Johnson C. Philadelphia, Pa: WB Saunders Co; 2002:41–72. Reprinted with the permission of Elsevier.
2. Apgar BS, Zoschnick L. Am Fam Physician. 2003;68:1992–1998. Reprinted with the permission of the AAFP.
3. Cannistra SA, Niloff JM. N Engl J Med. 1996;334:1030–1038. Images reproduced courtesy of Dr. Graziella Abu-Jawdeh.
4. Solomon D, Davey D, Kurman R, et al, for the Forum Group Members and the Bethesda 2001 Workshop. JAMA. 2002;287:2114–2119.
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Cervical Intraepithelial Neoplasia (CIN)
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CIN 1 (histologic LSIL)
CIN 2 (histologic HSIL)
CIN 3 (histologic HSIL)
You will see less “CIN” as CIN is converted into
LSIL and HSIL
Screening targets
• CIN3 is a true precancer, 30-50% progress to
cancer over 30 years.
- Observation is unacceptable since it cannot be predicted which
CIN 3’s will invade.
• CIN 2 is a collection of CIN 3 and CIN 1
- 50% regression rate, low risk of invasion
- Observation acceptable, especially in young women
• CIN 1 is a transient or stable HPV infection with
minimal cancer risk: DO NOT TREAT!
How risk is managed
• High risk >>> treat
• Low risk >>> observe
• Intermediate risk >> manage by level of risk - Short interval rescreening.
- Molecular triage (HPV, genotyping, biomarker)
Definitions of high/low/intermediate risk are
arbitrary, based on balancing risks of
intervention vs. risks of cancer
Cervical Cancer Screening Guidelines
Summary
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Adults
– Annually with conventional paps and every 2 years with liquid-based cytology
– ≥30 with 3 consecutive negatives may change to every 2-3 years
• GUIDANCE BY HPV STATUS!!
Adolescents
– First screen 3 years after onset of sexual intercourse or at age 21
– Those who do not need screening should still get appropriate contraceptive services,
STD screening and other preventive health care
Exclusions:
• DES exposure
• Immunocompromised
• HIV
Cervical Cancer Screening Guidelines
Summary
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Women >70 years with:
– At least 3 consecutive documented, satisfactory negative smears1
– No abnormal/positive cytology within past ten years1
After hysterectomy
– If hysterectomy performed for benign disease and cervix was removed2
– Negative history of abnormal paps2
Exclusions2:
– History of cervical cancer
– DES exposure
– Immunocompromised
– Positive HPV DNA test
High-Risk HPV Testing
ACOG Guidelines
Two Indications:
• Primary screening after age 30
– If both Pap and HPV test negative
• Re-screen no more frequently than every 3 years
• Triage of minimally abnormal Paps
– ASC-US
• Only need to do colposcopy if HPV +
HPV & Cervical Cancer
HPV is the Underlying Cause of
Cervical Cancer
• NIH Consensus Conference on Cervical Cancer,
1996
• World Health Organization/European
Research Organization on Genital Infection
and Neoplasia, 1996
Human Papillomavirus (HPV)
• Over 100 types identified2
– 30–40 anogenital2,3
– 15-20 oncogenic types2,3
– 30-35 types sexually transmitted
• Disease Burden
– 20,000,000 current cases in US6
– 6,200,000 new annual cases5
– 80% of women will have acquired HPV
infection by age 505
– 50% of college students are infected4
1. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology. 4th ed. Philadelphia, Pa: Lippincott-Raven; 2001:2197–2229.
Picture reprinted with the permission of Lippincott-Raven.
2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934.
3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224.
4. Winer RL et al. Am J Epidemiol. 2003; 157:218-226.
5. Centers for Disease Control and Prevention. Rockville, Md: CDC National Prevention Information Network; 2004.
6. Cates W Jr, and the American Social Health Association Panel. Sex Transm Dis. 1999;26(suppl):S2–S7.
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Human Papillomavirus
 Cancer of cervix uteri
100%
 Cancer of anus (squamous cell)
90%
 Cancer of vulva, vagina
40%
 Cancer of penis
40%
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Cancer of oro-pharynx
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Cancer of mouth
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Cancer of oesophagus
.
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Cancer of skin
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Cancer of X,Y,Z….
.
15- 30%
3%
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Parkin DM et al. CA Cancer J Clin 2005; 55:74-108.
Natural History of HPV Infections
• HPV is sexually transmitted
• Asymptomatic
• No treatment for HPV infection
• Cervical changes and warts CAN be treated
• Transient or persistent
• HPV is a necessary cause of cervical cancer
• HPV is present in over 99.7% of cervical cancers
• High risk types (16, 18) associated with cancer and precancerous
lesions
• Low risk types (6, 11) are associated with external genital warts
and abnormal Pap tests
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Human Papillomavirus. ACOG Practice Bulletin No. 61. 2005; 105: 905-18.
Biology of HPV Infection: Low-Grade Lesions
Normal
Cervix
HPV Infection
(CIN* 1/Condyloma)
New infectious Viral
Particles
Infectious Viral Particles
Perinuclear Clearing
(Koilocytosis)
Episome
Episome
Basal Cell Layer
*CIN = cervical intraepithelial neoplasia
1. Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555–1564.
2. Doorbar J. J Clin Virol. 2005;32(suppl):S7–S15.
3. Bonnez W. American Society for Microbiology Press; 2002:557–596.
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Co-factors for HPV Infection
•Smoking
•HIV infection and other host immune factors
•Parity
•Oral contraceptive use
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Ferris et al. Modern Colposcopy. 2004.
HPV Prevalence and Cervical Cancer - Incidence by
1,2
30
30
25
25
20
20
15
15
10
10
5
5
0
0
Cancer incidence per 100,000
HPV Prevalence (%)
Age
15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54
Age (Years)
1. Sellors et al. CMAJ. 2000;163:503.
2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000.
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HPV and Anogenital Warts
• HPV 6 and 11 responsible for over 90%
of anogenital warts1
• Infectivity upon exposure is over 75%2
• Spontaneous regression can occur in up
to 30% women within 4 months3
• Treatment can be painful and
embarrassing4
– Topical and surgical therapies5
• Recurrence rates vary greatly5
– As low as 5% with podofilox or laser
treatment
– As high as 65% with other treatments
Images top left and top right: Reprinted with permission from NZ
DermNet (www.dermnetnz.org).
1. Jansen KU, Shaw AR. Annu Rev Med. 2004;55:319–331.
2. Soper DE. Novak’s Gynecology. 2002:453–470.
3. Lacey CJN. J Clin Virol. 2005;32(suppl):S82–S90.
4. Maw RD, Reitano M, Roy M. Int J STD AIDS. 1998;9:571–578.
5. Kodner CM, Nasraty S. Am Fam Physician. 2004;70:2335–2342.
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HPV Infections: Summary
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Most will acquire HPV at some time
Most will clear HPV, but some do not
Persistence of low-risk HPV can lead to anogenital warts
Persistence of high-risk HPV can lead to pre-cancer
CIN 3
Long persistence of high risk
HPV is necessary for the
accumulation of mutations that
lead to cancer
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HPV Vaccine
Gardasil ® (Merck)
• Quadrivalent vaccine against types 16, 18, 6, 11
• FDA approved for use in females 9-26 years of
age
• Prophylactic, not therapeutic
• Virus-like particles (VLP)
• Highly effective
• Safe, few serious adverse side effects
• Requires 3 injections
• Expensive
HPV Vaccine
ACOG Recommendations
Continued screening with Pap tests is mandatory
VACCINATE
• Females 9-26 years old, regardless of sexual activity
– Potential benefit diminishes with age & increasing number of sexual partners
Special populations
• Previous CIN, abnormal cervical cytology or genital warts
– Vaccine may be less effective
• Immunocompromised
– Vaccine may be less effective
HPV Vaccine
ACOG Recommendations
Continued screening with Pap tests is mandatory
NOT CURRENTLY RECOMMENDED
(Awaiting more evidence)
• Women over age 26
• Pregnant women (Category B)
– If pregnancy diagnosed during the vaccine schedule, give
remaining vaccine post-partum
• Men
HPV Vaccine
Important Considerations
Continued screening with Pap tests is mandatory
• Vaccine is most effective if administered before
sexual debut
– Vaccine may be less effective in sexually active women
• HPV testing prior to initiating vaccine is not
recommended
• Vaccine is not a treatment for current HPV infection,
genital warts, or CIN
Cervical Intraepithelial Neoplasia
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Management
Cryotherapy
Ablative procedures
LEEP / Conization
Hysterectomy
CLASSIFICATION OF HYPERPLASTIC
ENDOMETRIAL CONDITIONS (WHO, 1994).
• Simple non-atypical endometrial hyperplasia.
• Complex non-atypical endometrial
hyperplasia.
• Simple atypical endometrial hyperplasia.
• Complex atypical endometrial hyperplasia.
• Endometrial adenocarcinoma.
CLINICOPATHOLOGIC
CLASSIFICATION OF
ENDOMETRIAL HYPERPLASIAS.
• Background conditions:
• glandular hyperplasia, endometrial
polyps. Pre-cancerous diseases:
• adenomatosis (atypical hyperplasia).
Endometrial cancer.
CLINICAL PRESENTATIONS
• Menstrual irregularities (delay of menstruation
during 2 -3 months).
• Metrorrhagia .
• Infertility.
• Nervous system abnormalities (depression, sleep
disturbance, mood swings).
• Headache.
• General weakness, dizziness.
• Skin pallor.
DIAGNOSTICS
• Main diagnostics objectives.
• Detection of hyperplasia and clinical
interpretation of the results of histological
examination performed on the endometrium.
• Determination of hormone dependency of the
hyperplasia and evaluation of individual
hormonal balance in the patient.
Investigation methods
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History of disease .
Speculum examination.
Bimanual examination .
Cytological examination of the cervical matter.
Hysteroscopy .
Aspiration biopsy of endometrial tissue.
Fractional diagnostic curettage of uterine cavity.
Determination of blood hormone level: follicle-stimulating
hormone, luteinizing hormone, estradiol, progesterone.
Determination of thyroid gland functional activity.
• Administration of glucose tolerance test.
endometrial polyp
endometrial hyperplasia
Hysteroscopy
adenocarcinoma
Endometrium in the I and phase II Mc
endometrial hyperplasia
TREATMENT STAGES
• First stage – extirpation of transformed
endometrium in order to determine the type
of endometrial pathology by means of
morphological investigation and select the
appropriate therapeutic approach.
Second stage
• hormonal therapy aimed at suppression of
endometrial growth. The course of treatment
is 6 months, histological reanalysis should be
done after 6 months.
Gestagens
• Norcolut, orgametril, utrogestan, dufaston to be
taken from the 5th to the 25th day of the
menstrual cycle during 6 menstrual cycles.
• 12,5% solution of 17- oxyprogesteron capronat to
be administered i/m 500mg twice weekly.
• Depo-prover i.m. administration, 200-400mg
once weekly.
• GnRH agonists 3 – 6 injections: - goserelin 3,6 mg
s/c once per 28 days; - buserelin 3,75 i/m once
per 28 days; - buserelin nasal spray 900mg once
daily.
Third stage
• optimization of hormonal status for prevention
of hyperestrogemenia development.
• women of reproductive age: - hormonal
contraceptives containing gestagen with
pronounced antiproliferative effect (Janine,
Yarina, Jazz); - local administration of gestagens
(intrauterine system Myrena).
• In perimenopausal women : – menostasia with
administration of GnRH agonists (3 months)
combined with intake of gestagens during 6
months.
Fourth stage
• regular medical examinations during 5 years
following effective hormonal therapy and 6
months following surgical treatment.
INDICATIONS FOR SURGICAL
TREATMENT
• In reproductive age:
• 1. Complex endometrial hyperplasia without
atypia in cases when conservative therapy fails
to demonstrate its effectiveness during 3
months.
• 2. Simple atypical or complex non-atypical
hyperplasia in cases when therapy fails to
demonstrate its effectiveness during 6
months.
INDICATIONS FOR SURGICAL
TREATMENT
• In menopausal patients :
• 1. Complex endometrial hyperplasia with
atypia – in patients with confirmed diagnosis.
• 2. Simple atypical or complex non-atypical
hyperplasia in cases when therapy fails to
demonstrate its effectiveness during 3
months.
Types of surgical treatment:
• Hysteroscopic resection or endometrial
ablation;
• hysterectomy .