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David Murphy, D.O. Indiana University Health Southern Indiana Physicians

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Objectives Review current recommendations Develop an algorithm for the appropriate use of screening cytology and HPV testing Discuss and incorporate into practice the newest ASCCP/ACOG consensus guidelines for management of cytologic abnormalities or (+) HPV testing

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Essential Changes From Prior Management Guidelines Cytology reported as negative, but lacking endocervical cells can be managed without early repeat Cytology reported as unsatisfactory requires repeat even if HPV negative Genotyping triages HPV (+) women with 16 or 18 to earlier colposcopy ASCUS- immediate colposcopy is not an option. Serial cytology at 12 months, and then if negative, cytology every 3 years

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Essential Changes (continued) HPV (-) and ASCUS results should be followed with co-testing q 3 years, rather than 5 years. HPV (-) and ASCUS results do not allow exit from screening at age 65. More strategies incorporate co-testing to reduce follow-up visits. Women aged 21 24 are managed conservatively

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Risk Factors for Cervical Cancer HPV infection (16/18) Early onset of sexual activity (4) Hx of genital warts Cigarette smoking HIV seropositive Immunosuppresive therapy

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HPV and Cervical Cancer Oncogenic (high risk) HPV types account for >99% of cervical cancer 70% of invasive cervical cancer is due to HPV 16 (60%) and 18 (10%) Nononcogenic (low risk) 6/11 Cause of genital warts No role for low risk hpv screening in cancer prevention

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HPV and the Development of Cancer

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HPV Most young women have an effective immune response that clears the infection in an avg of 8 months. CIN 1 is a manifestation of acute HPV and has a high rate of regression to normal cells CIN 2 is a mix of low-grade and high-grade lesions CIN 3 and AIS are cancer precursors HSIL is associated with a persistent and transforming infection and cancer risk.

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Colposcopy With directed bx remains the standard for disease detection Technique of choice for treatment decisions Endocervical sampling

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Screening Today When to start? When to stop? How often? HR HPV testing Continue in patients after hysterectomy? No change in women vaccinated against HPV

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Principles in Interpreting Guidelines Strategies developed based on risk where similar risk should have the same management. Clinical judgment is necessary in application to individual patients. Current strategies cannot eliminate the risk of developing cancer. Attempts to eliminate often result in unanticipated harm from excessive evaluation and treatment.

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Start screening at age 21 0.1% of cervical cancer cases 1-2 cases/1 million females age 15-19 US and UK studies demonstrated that earlier screening did NOT decrease cervical cancer rates in this population. Barnholtz-Sloan, 2009; Sasieni, 2009 If

Screening 21 - 29 Every 3 years Co-testing with HPV should NOT be performed (HPV frequent in this population and >90% will spontaneously clear within 2 yrs)

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Screening 30 - 65 Every 5 yrs Co-testing of HPV 16/18

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Risk Factors for Continued Annual Screening Hx of CIN2/3/cervical cancer within the past 20 yrs HIV infection or immunosuppression (transplant recipients) DES exposure in utero (last used in US >40 yrs ago)

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When to stop? Age 65 and not at high risk for cervical cancer (USPSTF, ACOG, ASCCP) Discontinuation of screening assumes adequate prior negative screening Three consecutive negative cytology results or 2 negative cytology results with (-) co-testing within the prior 10 yrs with one within 5 yrs No prior hx of cervical cancer, CIN2/3. If any present, continue screening for 20 yrs

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When to stop? After hysterectomy (with cervix removal) if no CIN 2/3 or cervical cancer If CIN 2+, and cervix removed, continue screening of vaginal cuff for 20 yrs, even if > 65 If hysterectomy and cervix not removed, continue screening as recommended for age

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High Risk HPV Testing Use as a co-test in women 30 and older Do not use at all in women < 30 Not a screening test for STDs Do not use as a test to determine whether to give HPV vaccine

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Unsatisfactory Cytology Repeat cytology in 2 4 months is recommended, with a negative or unknown HPV result Triage using reflex HPV testing not recommended Treatment to resolve atrophy or obscuring inflammation is acceptable If 30+ with (+) HPV co-test, repeat cytology in 2-4 months or colposcopy is acceptable. Colposcopy if 2 consecutive unsatisfactory cytology results.

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Negative Cytology but EC/TZ Absent/Insufficient 21 29: routine screening is recommended; HPV testing is unacceptable 30+: HPV testing preferred. Repeat cytology in 3 years if not performed. If HPV (-) return to routine. If HPV 16 or 18 (+), colposcopy, if (-) then repeat cytology in 1 yr Not associated with an increased incidence of cervical disease after treatment of high grade disease

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>30 Cytology Negative, (+) HPV Repeat cytology in 1 year is acceptable If repeat is (+) HPV, or ASCUS or worse, then colposcopy. If repeat cytology (-) and HPV (-), then repeat 3 yrs Risk of CIN 2+ is small with single HPV (+) and negative cytology. Reflex testing of 16/18 if HPV (+) is acceptable

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Women >25 with ASCUS Reflex HPV testing is preferred. If neg, then recheck 3 years with co-testing (+) HPV- colposcopy with ECC. If no CIN identified, then recheck pap w co-testing in 12 months If ASCUS and no HPV results, repeat cytology at 1 year is acceptable If >65, considered abnormal and should be rechecked in 12 months

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ASCUS with (-)HPV and 3 year f/u Risk of CIN 3 if ASCUS and HPV (-): 0.28% (Stoler 2011) 5 year f/u (no treatment): CIN 3 0.54% (Katki 2011) Normal cytology control (no HPV testing): risk of CIN 3 at 5 year f/u is 0.36%

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ASCUS new recommendations ASCUS and HPV (-) co-testing in 3 years ASCUS and HPV (+) colposcopy ASCH manage like HSIL colposcopy

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Low-Grade Squamous Intraepithelial Lesions (LSIL) Major determinant in treatment is age 21 24 HPV status in 25+ Routine co-testing in 30+ Here is where reflex co-testing is acceptable Reflex testing is NOT recommended in 21 - 24

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HSIL in 25+ Immediate LEEP or colposcopy is acceptable, except in special populations. Diagnostic excisional procedure is recommended when colposcopy is inadequate EXCEPT pregnancy ~60% have CIN 2+ on colposcopically directed bx and 2% have cervical cancer 5 yr cancer risk is 8%among women aged 30+

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ASC-H or HSIL 21 - 24 Colposcopy When CIN 2+ not identified, observation for up to 24 months using BOTH colposcopy and cytology testing at 6 month intervals is recommended. If HSIL persists without identification of CIN 2+, a diagnostic excision procedure is recommended.

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Atypical Glandular Cells Colposcopy with ECC, regardless of HPV Endometrial biopsy in 35+, or other risk of endometrial hyperplasia May be associated with benign disease (e.g., polyps, reactive changes), BUT can be due to adenocarcinoma of the cervix, endometrium, fallopian tube, or ovary 9 38% have significant neoplasia (CIN 2, AIS, or cancer) 3 17% have invasive cancer

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Subsequent Management of AGC AGC-NOS: if CIN 2+ not identified, co-testing at 12 and 24 months recommended. If both co-test results are neg, repeat co-testing in 3 yrs AGC favor neoplasia or endocervical AIS: if invasive disease not identified at initial colposcopy diagnostic excisional procedure recommended

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Endometrial Cells with Cervical cytology No further evaluation in asymptomatic premenopausal women If postmenopausal, endometrial assessment is recommended regardless of symptoms. No further evaluation with benign glandular cells following hysterectomy

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25+ and colposcopy demonstrates CIN 1 or less Co-testing at 1 yr. If both neg, then age-appropriate retesting in 3 years recommended. If CIN persists for at least 2 years, either continued f/u or treatment is acceptable. A diagnostic excision procedure is recommended if colposcopic exam is inadequate

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25+ after colposcopic evaluation of ASC-H or HSIL If CIN 2 not present on histology, then either diagnostic excisional procedure or observation with co-testing at 12 and 24 months are acceptable. If any result is abnormal repeat colposcopy If repeat HSIL at either 1 or 2 yr visit diagnostic excisional procedure.

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21 24 with CIN 1 on Biopsy Repeat cytology at 12 month intervals until 2 consecutive negative cytology results If f/u after an ASC-H or HSIL cytology result, observation for up to 24 months using BOTH cytology and colposcopy at 6 month intervals If colposcopy is inadequate, or CIN 2+ identified on ECC, a diagnostic excisional procedure is recommended

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Biopsy Confirmed CIN 2+ Adequate colposcopy: both excision and ablation are acceptable, except in special circumstances. Ablation is unacceptable if inadequate colposcopy or CIN 2+ on ECC Observation of CIN 2+ with sequential cytology and colposcopy is unacceptable, except spec. circs Prevalence of CIN 3 peaks between 25 30 and progression to cancer usually takes at least 10 years longer

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CIN 2+ in