Updates on Pap Smear Guidelines 2014 David Murphy, D.O. Indiana University Health Southern Indiana Physicians

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

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

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

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

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

HPV and the Development of Cancer

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. As many as 28% of women w LSIL cytology results have CIN 2 or 3, ~ 2/3 identified by colposcopy

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

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

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.

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 <21 and screened and abnormality detected, follow guidelines of 21 - 24

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)

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

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)

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

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

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

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.

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

>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

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 All women 25+ with HPV (+) ASCUS should undergo colposcopy

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%

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

Cytology testing alone at 12 month intervals is preferred, but reflex HPV testing is acceptable. For women w 2 consecutive negative results, return to routine screening is rec.

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

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+ Colposcopy finds at least CIN 2 53 – 66%; LEEP 84 -97%; 2% have invasive cancer

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.

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 Following w Paps and/or HR HPV alone is NOT appropriate

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 AGC-favor neoplasia: 27 -96% have bx confirmed invasive cancer, AIS, or CIN 2,3

Cervical adenoca assoc w predominately 18; endometrial, ovarian and fallopian tube cancer are not

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

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

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.

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 Colp not recommended for ASCUS or LSIL unless present on second of two annual f/u cytologies or ASC-H, HSIL or AGC

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 Goals of screening are ID and Tx of true cervical CA precursors

CIN 2+ in <25 When a histologic diagnosis of CIN 3 is present, or colposcopy is inadequate  treatment If colposcopic appearance worsens, or HSIL persists for 1 year  repeat biopsy If CIN 2+ persists for 2 years  treatment After 2 consecutive negative cytologies, an additional co-test 1 yr later is recommended, then repeat at 3 yrs CIN 3 is a definite cancer precursor, and therefore, should be treated regardless of age or fertility concerns.

CIN in Pregnant Patient Colposcopy should have exclusion of invasive cancer as its primary goal. Unless cancer is identified or suspected, treatment of CIN in pregnancy is CONTRAindicated. A diagnostic excisional procedure is recommended only if invasion is suspected. Initial evaluation of AGC is the same except NO ECC or endometrial biopsy Reassess with cytology and colposcopy no sooner than 6 weeks postpartum.

Additional References ACOG Practice Bulletin. Management of abnormal cervical screening test results and cervical cancer precursors. Number 140, December, 2013 USPSTF Web site (March, 2012 recommendations): http://www.uspreventiveservicetaskforce.org/uspstf11/cervcancer/cervcancerrs.htm#summary ASCCP website (algorithms): http://www.asccp.org/LinkClick.aspx?fileticket=uUGOqspsCBU%3d&tabid=5964