Cervical Cancer Screening


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  • Cervical dysplasia and cancer arise at transformation zone
  • Can include sources of error in need longer lecture
  • Risk factors previous ASC-US, previous unexplained glandular abnormality, HPV positive for high risk type in last 12 months, inability to clearly visualize endocervical canal, immunosuppression, blood or inflammation
  • Increased risk: immunosuppression, HIV, DES exposure, previous CIN II/III or cervical cancer
  • Cervical Cancer Screening

    1. 1. WEEK OF 9/21-9/24 DOMMR
    2. 2. Objectives Discuss the epidemiology of cervical cancer and methods of screening  Will focus specifically on the Pap Smear as a screening method Review the Bethesda Classification System for reporting cervical cytology Discuss when cervical cancer screening should start, how frequent it should be done, and how long to continue Review the interpretation of cytology seen on pap smears
    3. 3. Cervical Cancer - Epidemiology • A disease of sexually active women • Risk factors: – HPV infection – Cigarette smoking – Immunosuppression – Three or more lifetime sexual partners or 1st intercourse before Age 18 – Maternal DES (diethylstilbesterol) exposure during pregnancy – A previous abnormal Pap smear • 2nd most common female cancer worldwide • Most often a disease of adult women, rarely seen in adolescents • Most common in developing countries • In 2008, 11,070 new cases of invasive cervical cancer in the US – 3870 expected cancer related deaths
    4. 4. Cervical Cancer • Cervical intraepithelial neoplasia (CIN) is the pre- invasive dysplasia of cervical epithelial cells • Precursor of malignant disease • Categorized by depth and atypicality of cells in the cervical epithelium (CIN 1-3) • Slow malignant transformation leads to a long latency period • Some low grade lesions may regress spontaneously – Rates of regression as high as 75% at 5 yrs in adults and up to 91% at 3 yrs in adolescents
    5. 5. Cervical Cancer Screening • The Pap smear introduced in 1941 by George Papanicolau who initially used this method to study the estrous cycle of guinea pigs • Used to identify abnormal cells taken from the transformation zone (junction of ecto- and endocervix) • Between 50-60 million pap smears done annually in the US – 3.5 million are read as abnormal – 2.5 million undergo diagnostic colposcopy • An Australian study showed that a 15yr female has a 77% lifetime risk of undergoing at least one colposcopy • Thin layer (or liquid-based) cervical cytology is also used in the US as another screening method – SurePath, ThinPrep
    6. 6. Pap Smear • A screening test (used for asymptomatic patients), not diagnostic (to confirm a disease) • Cannot be used for a definitive diagnosis or to initiate treatment • Functions to screen for cellular abnormalities associated with an increased risk for cervical cancer • Goal is to distinguish between lesions likely to progress to carcinoma verses those that aren’t • Sensitivity and specificity are widely variable • Liquid based cytology has theoretical advantages (lower incidence of inappropriate fixation and drying artifact) but never proven to have better accuracy
    7. 7. Pap Smear • The pap smear has never been evaluated in a randomized controlled trials • Only observational studies have given any evidence of improving mortality from cervical cancer – Screening implemented in Finland, Sweden, Iceland, but not Norway • Before screening – all with similar rates of cervical cancer • After screening – all countries but Norway saw a decrease in incidence of cervical cancer • In the US, invasive cervical cancer is more likely from failure to perform appropriate screening rather than inaccuracies in screening – >50% of women with cervical cancer have never had screening and another 10% have not had a pap smear in the last 5 yrs
    8. 8. Pap Smear • Pap smear obtains cytologic results, but not able to assess tissue structure – Diagnosis of CIN or cervical carcinoma requires a tissue sample, which is obtained by biopsy • Bethesda system standardized terminology for reporting cervical cytology – First introduced in 1988, revised in 2001 – Now reports on the adequacy of the specimen – ASCUS category changed to ASC (ASC-US, ASC-H) – AGUS category changed to AGC – Now tells origin of cell and further subcategorizes
    9. 9. Bethesda Classification System • Atypical Squamous Cells (ASC) • Unspecified (ASC-US) - includes unspecified and favors benign/inflammation • Cannot exclude HSIL (ASC-H) • Low-grade squamous intraepithelial lesion (low-grade SIL) • Cellular changes associated with HPV • Mild (slight) dysplasia/CIN 1 • High-grade squamous intraepithelial lesion (high-grade SIL) • Moderate dysplasia/CIN 2 • Severe dysplasia/CIN 3 • Carcinoma in situ/CIN 3 • Atypical Glandular Cells of Uncertain Significance (AGC) • AGC distinguishes cell origin: endocervical, endometrial, or NOS • Further differentiated into: favors neoplasm, Adenocarcinoma in situ (AIS), or adenocarcinoma
    10. 10. Bethesda classification • 2001 revision now subcategorizes ASC into ASC-H and ASC-US – ASC-H comprises 5-10% of ASC overall – Subclassification hopefully allows physicians to more rapidly evaluate a patient who may have CIN 2, 3 • There is some correlation between pap smear cytology results and biopsy results – i.e. LSIL cytology would yield CIN 1 histology – Of patients with LSIL, 45%CIN 1, 33% had no identifiable pathology, 16% had CIN 2, 3 • Most common cytologic abnormality is ASC-US, seen in 3-4% of pap smears – LSIL seen in 2% of pap smears, HSIL in 0.5-1% of pap smears
    11. 11. Atypical Glandular Cells • Important to differentiate AGC (atypical glandular cells) from ASC (atypical squamous cells) • AGC is a significant marker for neoplasia • AGC associated with premalignant or malignant lesion 10-40% of the time • All with AGC should be referred for colposcopy • Women >35yrs should also have endometrial biopsy
    12. 12. Pap Smears When should screening start?  At age 21 or 3 yrs after first sexual intercourse (whichever comes first) How often should I screen for cervical cancer?  Originally, annual screening was implemented in the US  More recently this frequency has been reconsidered
    13. 13. Frequency of pap smear screening • “Protection from cervical cancer remained high up to 3 yrs after a negative pap smear” • “Rates of severe cervical cytology (CIN 2 or worse) within 2 yrs of a normal pap smear was negligible (1 case per 4895 person-yrs of follow up)” • “Duration of protection from a negative pap smear was greater with older age” – 55-69yrs – q 5yr screening was strongly protective and annual screening had little advantage – Same results were not seen in women 20-39yrs • “Using Markov model after 3yrs of negative pap smears, comparing annual vs triennial screening would detect:” – 3 more cases of cervical cancer per 100,000 women age 30-44 – 1 more case per 100,000 women age 45-59 – No extra cases in women age 60-64
    14. 14. When should screening end? • More controversy on when you should stop screening – should we be screening after the age of 65yrs? • Highest mortality from cervical cancer seen in older women who have never been screened. Yet, it is rare to see high grade lesions in older women who have been screened • Mortality increase after age 65, but benefit of screening declines with age
    15. 15. When should screening end? • No current screening guidelines • The decision is individualized • Dependent on: – Life expectancy – Prior screening results – HPV status – Current sexual activity • Generally, a women > 65yrs with 3 negative pap smears in the last 10 yrs, with no other risk factors needs no further screening
    16. 16. What if my patient had a hysterectomy? Small risk of cervical cancer in patients with prior hysterectomy in which cervix was taken out Certain groups at higher risk:  Intact cervix post hysterectomy  Hysterectomy done because of uterine or cervical cancer  Exposure to DES in utero
    17. 17. So what are the recommendations? Cervical cancer screening guidelines from:  USPSTF, ACS, ACOG Regarding what type of screening:  ACS and ACOG allow liquid base cytology and/or routine HPV testing (for women >30yrs)  USPSTF makes no recommendation on alternate screening tests due to insufficient evidence
    18. 18. Age to initiate screening Age to discontinue screening Screening interval for cervical cytology Post hysterecto my for benign disease ACS (2002) 3 years after onset of sexual intercourse, or by age 21 Women may choose, if 70 years and 3 negative tests and no positive tests within last 10 years Annual for conventional cytology: every 2 years for liquid-based cytology; for age >30, every 2 to 3 years after 3 normal consecutive smears and no increased risk Not Indicated ACOG (2003) 3 years after onset of sexual intercourse, or by age 21 Inconclusive evidence Annual for age <30; for age >30, every 2 to 3 years after 3 normal consecutive smears, no history CIN 2 or 3, and no increased risk Women may decline testing USPSTF (2003) 3 years after onset of sexual intercourse, or by age 21 Age 65, if not at high risk At least every 3 years Not indicated Around the world, starting age for screening ranges from 18-30 while end age ranges from 58-70 (or indefinitely in Germany)
    19. 19. The Cervical Cytology Report • Specimen type (pap smear, liquid based cytology) • Specimen adequacy – Satisfactory • Includes 8000-12,000 squamous cells and at least 10 well- preserved endocervical cells (or squamous metaplastic cells) – This indicates adequate sampling of the transition zone – Endocervical cells not present • Repeat in 12 months or 6 months if certain risk factors – Unsatisfactory • More than 75% of the cells are uninterpretable • Should always be repeated in 2-4 months • Interpretation of result
    20. 20. ASC Slightly enlarged nucleus, small perinuclear halo
    21. 21. ASC: ASC-US • Most common abnormality on pap smear • Often associated with spontaneously, resolving, self- limited disease • Reflexive HPV testing (**Preferred**) – If positive, immediate referral to colposcopy – If negative, repeat cervical cytology in 12 months • Repeat Cytology at 6 and 12 months – If normal, continue routine screening – If abnormal, immediate referral to colposcopy • Immediate referral for colposcopy
    22. 22. ASC-US – Special Populations • Adolescents (<20yrs) – High prevalence of HPV infection, very low risk of invasive cervical cancer • Reflex HPV testing would lead to a high rate of colposcopy – Should have follow up cytology at 12 months • HSIL  colposcopy • LSIL or less  repeat cytology at 12 months  if ASC-US remains at 24 months or now higher grade  colposcopy • Pregnancy – Never do endocervical curettage (ECC) – Can see increase in squamous metaplasia with pregnancy • Infection/reactive changes, postmenopausal, immunosuppression: no difference
    23. 23. ASC-H Refer for colposcopy and ECC No HPV testing indicated initially If colposcopy shows CIN 1  follow up cytology in 6 and 12 months or HPV testing  If cytology shows again shows ASC-US (or greater) or HPV is positive  colposcopy
    24. 24. LSIL Dysplastic nuclear changes, binucleation
    25. 25. LSIL Premenopausal  12-16% risk of CIN 2, 3  Colposcopy/biopsy is preferred method of follow up  Reflex HPV testing is not helpful  77% of women with LSIL will have a positive HPV, so colposcopy referrals would not be reduced  These women get treated the same as someone with ASC-US with positive HPV testing  colposcopy
    26. 26. LSIL – Special Populations • Adolescents – Likely ASC-US representing transient HPV infection – Initial colposcopy deferred (risk of invasive cervical cancer is near zero) – Repeat cytology in 12 months • If HSIL  colposcopy • If ASC-US  repeat in 12 months  ASC-US or higher grade lesion  colposcopy • Pregnant – Colposcopy (can be deferred 6 months post-partum) – No ECC • Post menopausal – 3 options – Immediate colposcopy – Reflex HPV testing – low rate of HPV in this population vs adolescents so HPV testing can reduce rate of colposcopy – Repeat cytology in 6 and 12 months
    27. 27. HSIL Enlarged nucleus, less cytoplasm (increased N:C ratio). Irregular nuclear membrane
    28. 28. HSIL • Over 50% will have CIN 2 or greater, 2% have invasive cancer • Recommend either: • Colposcopy of entire cervix and vagina with biopsy of all visible lesions and ECC • Unsatisfactory colposcopy • Need diagnostic excisional procedure • Loop electrosurgical excision procedure (LEEP), conization • Diagnostic excisional procedure • CIN 1 or less – Will require further evaluation given the high prevalence of CIN 2 or greater in HSIL – Diagnostic excisional procedure, repeat cytology and colposcopy at 6 and 12 months, review cytology, colposcopy and biopsy reports • CIN 2, 3 • Need excisional procedure
    29. 29. HSIL – Special Populations • Adolescents – Colposcopy with ECC – If CIN I or less  colposcopy with ECC q 6 months for the next 2 years • Pregnant – Colposcopy – CIN 2 or greater  biopsy but not ECC – Often see spontaneous regression of CIN 2, 3 lesions
    30. 30. Review • When should testing begin? • At age 21 or 3yrs after onset of sexual intercourse • Annual screening until 3 consecutive negative pap smears. Then. . . – If <30yrs, repeat annually – If >30yrs, repeat 3 yrs – More frequently if at increased risk • Screening can end if >65 and have had 3 negative pap smears in the last 10yrs – Possible exceptions: favorable life expectancy who are sexually active with a new partner
    31. 31. Review Cervical Cytology Report includes:  Specimen type, specimen adequacy, interpretation of result  ASC (ASC-US, ASC-H)  LSIL  HSIL  AGC
    32. 32. Review ASC-US  Usually do reflex HPV testing next, although can repeat cytology or do colposcopy ASC-H  Referral for colposcopy and ECC LSIL  Generally go straight to colposcopy unless an adolescent, who would get HPV testing first HSIL  Straight to colposcopy  Consider diagnostic excisional procedure
    33. 33. Follow up of Patient 22y F who is currently sexually active with a new partner in the last month. Her last pap smear was 2 years ago and was normal. Pap smear done at this visit showed ASC-US Reflex HPV testing was negative Will repeat cytology in 12 months
    34. 34. Follow Up of Patient 63y F with history of HTN and hypothyroidism who presents for routine exam. Last pap smear was 3 years ago and was normal, although she has had a positive pap-smear with ASC-US in the past. Pap smear done at this visit showed HSIL Will refer for colposcopy