Vaginal Cytology and Other Vaginal Issues

Vaginal cytology and other vaginal issues

Barbara S. Apgar MD, MS Professor of Family Medicine Michigan Medicine Ann Arbor, Michigan Why examine the vagina?

 Abnormal cervical cytology Following hysterectomy with history of CIN 2,3 or cancer. Abnormal cytology with negative cervical colposcopy. Persistent abnormal cytology/HPV after treatment for HSIL (CIN 2,3).

 Abnormal vaginal cytology Inappropriate screening after TAH for benign disease Women with HSIL/CIN 2,3 who subsequently undergo TAH will still require vaginal cytology screening for at least 20 years after treatment. Images

• Used with permission of Apgar B, Brotzman G, Spitzer M. From Colposcopy Text and Atlas: Elsevier Publishing 2004, 2008 • Used with permission of Candace Tedeschi, NP • Used with permission of ASCCP. A Common Clinical Dilemma: Management of Abnormal Vaginal Cytology and Human Papillomavirus Test Results. J Lower Genital Tract Dis 2016; 20(2):119-125. Important Citations

• Kahn MJ, Massad LS, Kinney W et al. A Common Clinical Dilemma: Management of Abnormal Vaginal Cytology and Human Papillomavirus Test Results. J Lower Genital Tract Dis 2016;20(2):119-125. – Published simultaneously in Gynecologic Oncology and J Lower Genital Tract Disease.

• Moyer VA. Preventive Services Task Force. Screening for cervical cancer. USPSTF Recommendation Statement. Ann Int Med 2012;156:880-891. Why examine the vagina?

• DES-exposure in utero • 4 quadrant sampling of the cervix and upper 1/3 of vagina.

• Lesion in the vagina on speculum or bimanual exam

• Multifocal disease of the cervix, vagina, vulva, anorectal Multifocal disease

Apgar B, Brotzman G, Spitzer M Challenges of vaginal colposcopy

• Unlike the cervix, the vagina is not easily visualized in a static colposcopy.

• There are multiple folds and areas covered with the speculum requiring the colposcopist to manipulate the speculum to view all the vaginal walls and fornix. – Only half of the vagina is seen if a speculum is used

• Manipulate the speculum to see full extent of vagina – Rotate the speculum to see 360 degrees – Slowly withdraw the speculum and visualize the vagina in front of the speculum Vaginal colposcopy

• More difficult and time consuming than examining cervix. • Use largest speculum that is comfortable. • Examine cervix first. • May need various instruments for visualization.

Candice Tedeschi NP Acetowhite effects in the vagina (area visualized in front of the speculum)

• 3-5% acetic acid should be applied to the entire vaginal mucosa, waiting a minimum of 1-2 minutes for acetowhite changes to appear. • Effects less pronounced than cervix: may be disappointing. – Postmenopausal women

Candice Tedeschi NP Vaginal Colposcopy

. Hook helpful for examining vaginal rugae and lateral vaginal angles (“dog ears”) after hysterectomy . Moistened large cotton swab with dilute acetic acid . Narrow endocervical speculum . Vaginal cuff is most common place for VaIN Candice Tedeschi NP after TAH Lugol’s iodine staining

• Apply Lugol’s iodine to confirm presence or absence of abnormal epithelium • Ask about iodine allergy • Apply and wipe off excess • Stain entire length but most abnormal areas will be in upper 1/3 of vagina so stain this first

VaIN: Candice Tedeschi NP Lugol’s Solution

• Non-glycogenated epithelium will be non- staining • Nonspecific test. – could be benign or cancer but directs attention on where to biopsy

Candice Tedeschi, RN, NP

VaIN 3 after hysterectomy for cervical cancer • If no lesion seen on cervix to explain abnormal cytology - look at vagina • Lugol’s can delineate lesions otherwise missed at colposcopy

HSIL (VaIN 3)

Candice Tedeschi NP Don’t forget the vagina!

Perhaps the most common cause of non- correlating colposcopy

JT Cox Examining the vagina

• Will get more experience and proficiency at manipulating speculum, focusing colposcope and applying dilute acetic acid/Lugol’s at the same time

• Look for non-staining yellow lesions or dense acetowhite lesions that have sharp borders - more likely to be significant dysplastic lesions.

• If abnormalities are seen, stop and biopsy. Vaginal Biopsy

• Generally no need for anesthesia in upper vagina: Test !!! – Middle and lower vagina more sensitive • Need needle extender or dental syringe with long needle to reach middle to upper vagina • Biopsy all but most obvious low-grade lesions • Use sharp biopsy punch • May need hook to pull rugae down • Small biopsies 1.5-3mm depth (no glands) • Bleeding usually minimal – Monsels, silver nitrate or pressure Needle extenders can be as long as dental syringes

Barbara Apgar, MD Syringe Needle extender Needle

Barbara Apgar, MD Vaginal Cancer 1- 4% of cancers of female genital tract

• NCI estimates in 2013 – 2890 new cases vaginal cancers – 840 deaths • Vaginal cancer incidence rate 0.4-0.6 per 100,000 – Cervical cancer incidence rate 7.7 per 100,000 • SEER data: 729 cases of vaginal cancer each year from 2004-2008 – 500 attributable to HPV

Morb Mortal Wkly Rep 2012;61:258-261 NCI Incidence of Mortality 2013 SEER.cancer.gov/faststats; June 5, 2011 Vaginal cancer

• It is not recommended to screen the general population for vaginal cancer.

• May be detected by vaginal cytology or HPV testing.

• Mean age of diagnosis is 69 years, 2 decades later than mean age of cervical cancer at 48 years.

• Women who have had cervical cancer are at significantly increased risk of developing vaginal CA Vaginal Neoplasia: Risk Factors

• Risk factors similar to cervical cancer – Persistent high risk HPV infection (type 16 most common) – Immunosuppression – Current HSIL (CIN 3) or prior cervical cancer – Age first intercourse < age 17 years – > 5 lifetime sexual partners – Smoking – DES exposure in utero

Zeligs KP et al, Obstet Gynecol 2013;122:1223 Smith JS et al. Obstet Gynecol 2009;113:917 Daling JR et al. Gynecol Oncol 2002;84:263-270 Vaginal Cancer Cell Types

• Primary cancer of vagina is rare – About 1% of all gyn malignancies • Squamous cell (most common) • Adenocarcinoma • Melanoma • Sarcoma • Metastatic disease most common— endometrium, cervix, ovary

Gunderson C et al. JLGTD 2013:17:409-13 Vaginal Cancer

• 85% squamous origin – Primary – Direct spread or metastasis

Apgar, Spitzer, Brotzman: Colposcopy Principles and Practice Vaginal cancer: Squamous origin

• Colposcopic features – Atypical vessels - bizarre, wide intracapillary distance – Ulcerations – Irregular topography – Friability Apgar, Brotzman, Spitzer: Colposcopy Principles and Practice Vaginal Carcinoma: Squamous origin

• Symptoms – Often asymptomatic – Vaginal bleeding – Vaginal discharge - malodorous, blood tinged

• Oncogenic HPV

Gunderson C et al. JLGTD 2013:17:409-13 Apgar, Brotzman, Spitzer: Colposcopy Principles and Practice Vaginal Cancer: Adenocarcinoma origin • 5-10% adenocarcinoma • Mostly clear cell adenocarcinoma - associated with DES exposure in utero

Candice Tedeschi, NP Evidence Summary for VaIN, Vaginal Cancer

• hrHPV positivity found in 99-100% of LSIL (VaIN 1), 90-96% of HSIL (VaIN 2,3), 54-75% of vaginal cancers. – HPV 16 most common hrHPV type in VaIN and vaginal cancers. •Next common types were HPV 18, 31, 33, 52 but prevalence much lower then HPV 16. – HPV infection a necessary co-factor for most Evidence Summary for VaIN, Vaginal Cancer

• Accuracy of vaginal cytology for prediction of HSIL/VaIN and vaginal cancer is limited by few available studies.

• Sensitivity was 84% in one prospective study.

• PPV of cytology for HSIL (VaIN 2,3) and vaginal cancer ranges from 0-14%. Evidence Summary for VaIN, Vaginal Cancer

• No FDA hrHPV approved test for screening for VaIN or vaginal cancer. – Women who had inappropriate screening after TAH for benign disease often have hrHPV or cotesting results that requires interpretation and management.

• HPV of the vagina is as common as HPV infection of the cervix. – Prevalence of hrHPV was not significantly different in women with TAH and those with intact uterus. – Sensitivity 82-90% for prediction of VaIN persistence/ progression and 92-100% for prediction of HSIL (VaIN 2,3).

Castle PE et al. J Infec Dis 2004;190:458-69. Castle et al. J Infect Dis 2006; 194:1702-5. Evidence Summary VaIN 2,3

• Age range for VaIN 35-55 years • Age range for vaginal cancer 15-20 years later – 50% cases > age 70 (more difficult to assess) •Compare mean age cervical cancer is 48 years • True incidence VaIN unknown – 0.2-0.3 cases/100,000 (old studies)

Shah C et al. Obstet Gynecol 2009;113:1038-45 Gunderson CC et al. Am J Obstet Gynecol 2013; 208: 410. e1-6 CDC. HPV –associated cancer diagnosis by age. Available at: http://www.cdc.gov/ cancer/hpv/statistics/age.htm VaIN Terminology

• LSIL (VaIN 1) - benign proliferation of HPV • HSIL (VaIN 2,3) - true cancer precursor analogous to HSIL (CIN 2/3)

• Risk of VaIN 3 becoming cancerous is less than CIN 3 Risk factors for VaIN

• Age – HSIL/VaIN 2/3 found more often in women > 50 years compared with LSIL/VaIN 1 (mean age = 45 years). Age of Diagnosis for VAIN

Perrptta M et al. JLGTD 2013;17:1:23-27 How is VaIN diagnosed?

• Most diagnosed on colposcopy for abnormal cytology (>80%) • Colposcopy of the vagina after diagnosis of other anogenital lesions • Lesion found on speculum exam • >90% asymptomatic but postcoital bleeding or unusual vaginal discharge may be present

Dodge et al. Gyn Oncology 2001;83:363-369 Sillman et al. Am J Obstet Gynecol 1997:176:93-9 Zeligs K et al. Obstet and Gynecol 2013;122:1223 VAIN 1 Characteristics of VaIN VAIN 3 . Color . Varying shades of acetowhite . All VaIN will appear acetowhite . Margins/surface contour . Flat to slightly raised . Vessel pattern . Absent in low grade . Punctation more common than Vain 1 VAIN 3 mosaic in VaIN 2,3 . Lugol’s pattern . Identifies lesions in rugae . Most lesions occur in upper 1/3 of vagina

Indraccolo U et al. JLGTD;16(2):75-79

Candice Tedeschi NP Colposcopy of VaIN 1

• Benign manifestation of HPV infection • Raised and textured lesion • Acetowhite • MULTIFOCAL –check other areas

Candice Tedeschi NP Colposcopy of VaIN 1

• Condyloma acuminata • Flat lesions can also exist • 30% women with vulvar condyloma have vaginal condyloma

Apgar B, Brotzman G, Spitzer M Colposcopy of LSIL/VaIN 1

Apgar B, Brotzman G, Spitzer M HSIL (VaIN 2/3)

• Precancerous lesion analogous to HSIL (CIN 2/3) • Natural history data is scarce. – Estimated progression rate to vaginal cancer ranges from 0-9% in 5 different studies (included VaIN 1) – Much lower than 30% progressive rate of CIN 3 to cervical cancer. • Found more often in women older than 50 years Colposcopy of HSIL (VaIN 3)

• True cancer precursor • Focal or multifocal • Mosaic rarely seen, usually punctuation, absent atypical vessels • Biopsy lesions not obviously low grade

Candice Tedeschi NP Colposcopy of VaIN 3 Margins/contour – Well circumscribed – Straight margins – Elevated or flat – Peeling edges Color – Acetic acid effect may take longer to develop and be more subtle especially in postmenopausal women – Dense acetowhite – Absent Lugol’s staining Apgar, Brotzman, Spitzer; Colposcopy-Principles and Practice Colposcopy of VaIN 3 • Vascular pattern – Develops late in neoplastic process – Fine to coarse punctation – Mosaic rare – Coarse caliber vessels suspicious for cancer • Leukoplakia

Candice Tedeschi NP VAIN 3

Candice Tedeschi NP hrHPV testing is not FDA approved for use on specimens obtained from vagina Given the high prevalence of hrHPV in HSIL (VaIN 3) and vaginal cancer, the NPV of a hrHPV test is very high. Reassuring there is low risk of vaginal cancer.

PPV of hrHPV is more problematic. Few studies have reported hrHPV testing in women without histologically-confirmed VaIN. Expected to be low. Who are at low risk for vaginal cancer?

Asymptomatic healthy women with negative cotesting are at extremely low risk and do not require future testing if they have - TAH for benign disease No history of HSIL/CIN 3 or cervical cancer Need caution to avoid overscreening or overevaluating women for a rare condition Are there screening guidelines for vaginal cancer? • Research and professional guidelines recommend against screening – women post TAH for benign disease – women post TAH for cancers other than cervical (endometrial) • There are no large clinical trials or rigorous epidemiologic studies of vaginal cancer screening on which to base recommendations. – No ASCCP consensus management guidelines. • Expert authors applied cervical guidelines to management of abnormal vaginal screening tests 55 year old postmenopausal woman had a LEEP 3 years ago for HSIL (CIN 3) She recently had a hysterectomy for fibroids.

What would you advise her about vaginal cancer screening? Apgar B, Brotzman G, Spitzer M Are there screening guidelines for vaginal cancer?

Women with HSIL/CIN 2,3 who subsequently undergo TAH will still require vaginal cytology screening for at least 20 years after treatment. Disease recurrence

• Women post-treatment for HSIL or cancer are at higher risk for vaginal cancer than women post-TAH for benign disease. – Most disease recurrence occurs within the first 2-3 years post-treatment. •Risk decreases substantially after repetitive negative screening tests.

• Authors decided that women post-treatment for HSIL or cancer can be managed similarly as low-risk women after they had negative post-treatment surveillance tests and are back to “routine surveillance” for at least 20 years.

Kahn MJ, Massad LS, Kinney W et al. A Common Clinical Dilemma: Management of Abnormal Vaginal Cytology and Human Papillomavirus Test Results. J Lower Genital Tract Dis 2016;20(2):119- 125. The ASCCP vaginal guideline

• Applies to women without history of HSIL/CIN 2,3 or cancer who had a TAH for benign reasons and were inappropriately screened using cytology or cotesting.

• Applies to women with a history of HSIL/CIN 2,3 or cancer who have completed the recommended surveillance after treatment and are now in follow-up for at least 20 years.

Kahn MJ, Massad LS, Kinney W et al. Management of Abnormal Vaginal Cytology and Human Papillomavirus Test Results. J Lower Genital Tract Dis 2016;20(2):119-125. Management of Women with Biopsy-confirmed Cervical Intraepithelial Neoplasia - Grade 2 and 3 (CIN2,3) *

Inadequate Colposcopy or *Management options Adequate Colposcopy will vary in special Recurrent CIN2,3 or circumstances or if the Endocervical sampling is CIN2,3 woman is pregnant or ages 21-24 †If CIN2,3 is identified at the margins of an † excisional procedure Either Excision or Diagnostic Excisional or post-procedure Ablation of T-zone * Procedure † ECC, cytology and ECC at 4-6mo is preferred, but repeat excision is acceptable and hysterectomy is acceptable if re- excision is not feasible. Cotesting at 12 and 24 months

2x Negative Any test abnormal Results

Repeat cotesting in 3 years Colposcopy With endocervical sampling Routine screening

© Copyright, 2013, American Society for Colposcopy and Cervical Pathology. All rights reserved. Proposed algorithm to identify women at highest risk • Who should undergo colposcopy and biopsy of vaginal lesions? – Women with HSIL, ASC-H, or AGC vaginal cytology. – Women with persistent hrHPV infection for one year or longer. – Women with persistent ASC-US or LSIL for one year or longer.

Kahn MJ, Massad LS, Kinney W et al. Management of Abnormal Vaginal Cytology and Human Papillomavirus Test Results. J Lower Genital Tract Dis 2016;20(2):119-125. ASC-US/LSIL on vaginal cytology

• Non-specific equivocal result similar to cervical ASC-US. – Requires some type of triage test to lead to the next step in management (vaginal colposcopy). • LSIL indicative of HPV infection is likely to test hrHPV +. • Vaginal colposcopy can be deferred and vaginal cotesting repeated in one year. – If persistently abnormal or hrHPV +, colposcopy is recommended with biopsy of any lesions.

Kahn MJ, Massad LS, Kinney W et al. Management of Abnormal Vaginal Cytology and Human Papillomavirus Test Results. J Lower Genital Tract Dis 2016;20(2):119-125. Alternative approach to repeating cotesting in one year for ASC-/LSIL

• Most HPV + vaginal cancers are HPV 16/18+ and genotyping can be done. • Immediate colposcopy – If HPV 16/18 + ASC-US/LSIL • Observation for up to 2 years – If HPV 16/18 + but negative cytology – If HPV 16/18 – (+ HPV others) and ASC-US/LSIL

Kahn MJ, Massad LS, Kinney W et al. Management of Abnormal Vaginal Cytology and Human Papillomavirus Test Results. J Lower Genital Tract Dis 2016;20(2):119-125. Follow-up of vaginal cytology results for ASC-US/LSIL

• If cotesting is negative/negative can return to routine screening. – Cessation of screening if TAH for benign reasons. – Continued surveillance for 20 years if they have had HSIL or cancer.

• If cotesting unavailable, cytology can be repeated in one year. – If any abnormality is reported (> ASC-US), colposcopy should be performed. – There is lower sensitivity/NPV of cytology compared with cotesting. • 2 negative cytology results should be documented before returning to routine screening or cessation of screening.

Kahn MJ, Massad LS, Kinney W et al. Management of Abnormal Vaginal Cytology and Human Papillomavirus Test Results. J Lower Genital Tract Dis 2016;20(2):119-125. HSIL vaginal cytology

• HSIL vaginal cytology is rare. • Should prompt vaginal colposcopy with biopsy of any suspicious-appearing lesions. – If vaginal colposcopy is negative • Repeat vaginal cytology in 6-12 months. • No evidence to guide management of AGC or ASC-H after TAH. – Same management as HSIL vaginal cytology

Kahn MJ, Massad LS, Kinney W et al. Management of Abnormal Vaginal Cytology and Human Papillomavirus Test Results. J Lower Genital Tract Dis 2016;20(2):119-125. Negative vaginal cytology and + hrHPV test

• Repeat cytology or cotesting in one year. – Any abnormality should prompt vaginal colposcopy.

• Applies to women appropriately undergoing vaginal surveillance. – Surveillance should continue for at least 20 years after treatment for HSIL or cancer even after negative/negative cotesting. • ASCCP guidelines do not specifically indicate the interval for surveillance after the 1st 5 years posttreatment. – Authors propose that asymptomatic women with negative/negative cotesting undergo surveillance tests at 3-year intervals. – Does not apply to women with abnormal vaginal cytology who have symptoms (bleeding or visible vaginal lesions).

Any questions?

Thanks! Images

• Moyer VA. Preventive Services Task Force. Screening for cervical cancer. USPSTF Recommendation Statement. Ann Int Med 2012;156:880-891.