Cervical Cancer Screening and HPV Leslie Ablard, M.D.

Cervical Cancer Incidence/Prevalence Signs & Symptoms 3rd most common GYN cancer in developed world 11,270 new cases in 2009 4,070 deaths in 2009 Most common GYN cancer in developing countries 500,000 new cases annually 240,000 deaths annually Signs & Symptoms Abnormal Vaginal Bleeding Postcoital Bleeding Vaginal Discharge (watery, mucoid, purulent, malodorous)

Cervical Cancer Risk Factors Early onset of sexual activity Multiple sexual partners High-risk sexual partner History of sexually transmitted diseases Smoking (not adenocarcinoma) High parity Immunosuppression Low socioeconomic status Prolonged use of oral contraceptives Hx of vaginal or vulvar cancer Vast majority of cases are caused by persistent high risk HPV infection Most common Histologies Squamous Cell Carcinoma Adenocarcinoma Adenosquamous

Human Papillomavirus Lifetime cumulative risk of acquiring HPV in sexually active persons = 80% Spectrum of HPV Condyloma Acuminata Cervical Dysplasia Cervical Cancer > 150 different types of the virus 15 High Risk Types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82) 16, 18  > 70% all cervical cancers 6, 11  90% genital warts HPV Vaccine – Gardasil ® Active against 16, 18, 6, 11 FDA approved in US for girls & boys ages 9-26

Human Papillomavirus 6.2 million new infections per year 20 million active infections (prevalence) 330,000 cases of CIN 2, 3 11, 400 cases of cervical cancer LEEP/Cone doubles risk of PTL and IUGR

Human Papillomavirus HPV 16, 18 Association with abnormal pap tests Rate 16 18 Total/yr ASC 5.1% 13% 6% 581,000 LSIL 2.6% 24% 10% 530,000 HSIL 0.7% 61% 7% 285,100

Human Papillomavirus External Genital Warts 500,000-1,000,000 new cases per year 240,000 initial office visits per year 1% of sexually active US population between 18-49 yrs old 1/3 of all STI dollars annually

Human Papillomavirus HPV associated cancer deaths Site Total Cancers AF (%) Attributable Cases Cervix 11,150 100% Penis 1,280 40% 512 Vulva/Vagina 5,630 2,252 Anus 4,650 90% 4,185 Airway 24,540 26% 6,380 Total 47,250 12% 24,479

HPV ACIP recommendations Females with abnormal pap results or genital warts should be given one of the two vaccines if they are in the indicated age group to prevent from types she has not been exposed to previously

ACOG Bulletin 109 Cervical cancer is one of the most preventable cancers In the past 30 yrs, Pap test has reduced cervical cancer deaths by over 80% New ACOG screening guidelines published in December 2009

Natural History of Cervical CA Persistent infection with HPV is a prerequisite for the development of cervical cancer and its precursors At least 80% of women acquire genital HPV infection at some point in their lifetime HPV most common in teenagers and women in their early 20s, prevalence decreases with age Most HPV infected women will not develop significant cervical abnormalities

Natural History of Cervical CA Most HPV infections become undetectable in an average of 8-24 months Most CIN lesions resolve spontaneously in adolescents and young women HPV in older women is more likely to reflect persistent infection acquired in the past HPV type and persistence of infection are the most important determinants of progression

Clearance of HPV @ 48 months – 50% CIN 2,3 @ 60 months- 60% CIN 2,3 @ 1 yr- 60% clear 35% persistent 3% HGSIL

When should Pap screening Begin? New Recommendations: Begin at age 21 Prior guidelines begin at age 21 or 3 yrs after onset of intercourse Why the change? HPV infection and minor cytological abnormalities common in young women Most are cleared in 1-2 yrs Cervical cancer is extremely uncommon less than age 25

Invasive Cervical Cancer in Adolescents- SEER Registry 0.1% of cervical cancer occurs before age 21 yrs British data suggests that those cancers that occur aren’t detected through screening 1-2 cases/ 1,000,000 girls age 15-19 Audit of UK cervical cancers found no benefit of screening women 20-24 yrs old US ONLY COUNTRY TO DO ANNUAL PAPS

Consequences of Screening Adolescents Treatment for lesions destined to resolve without therapy Treatment for CIN (LEEP) increases risk of Preterm Birth (OR 1.7) LBW (OR 1.8) PPROM (OR 2.7) DOUBLES RISK!!!

Frequency of Cervical Cytology Screening Every 2 yrs for women age 21-29 Every 3 yrs for women age 30 or greater (after 3 consecutive negative paps or with concurrent neg HR HPV) Exceptions to extended screening HIV Twice first yr, annually thereafter Immunocompromised DES exposed History of CIN 2,3 or cancer Annual screening for 20 yrs after initial post-treatment suvelliance

Screening Interval Why change? Supported by both empirical data and mathematical modeling studies 31,728 women age 30-64 yrs in National Breast Cervical Cancer Early Detection Program Rate of CIN decreased with increasing number of sequential negative Paps If 3 consecutive negative Pap tests, prevalence of CIN 3 was 0.019% with no cases of cancer

When to discontinue screening Age 65 or age 70 in women with 3 consecutive negative Paps and no abnormal Paps in the past 10 yrs ACOG guidelines accept either USPSTF (65) or ACS (70) age cutoff If screening is discontinued, risk factors should be reassessed during the annual examination

When to discontinue screening Why the change? In well screened older women with HSIL rates are low and cervical cancer is rare Most cases of cervical CA in US women older than 65 yrs are in inadequately screened women Cervical cancer develops slowly and risk factors decrease with age

Consequences of screening older women False-positive cytology due to vaginal atrophy Additional procedures Anxiety Unnecessary expense Difficulty in getting satisfactory samples Vaginal atrophy Cervical stenosis

Discontinue Screening Following Hysterectomy? Discontinue screening in women with no history of CIN 2,3 Most abnormal test results are falsely positive In one study, only 1.1% had cytological abnormalities, no VaIN 3 or cancer Continued screening is not cost-effective, causes anxiety, and leads to over treatment HAVE TO DOCUMENT NO CIN 2,3 ON PATH

What is a Pap Smear? “Papanicolaou test” - 1941 Dr. Babes & Dr. Papanikolaou 80% decrease in rates of cervical cancer in developed countries over last 30 yrs due to widespread screening A sample cervix cells from transformation zone. junction of endocervix and ectocervix Use of spatula +/- cytobrush, broom stick 2 types – conventional, liquid-based Send for cytologic interpretation

How to perform a Pap smear… Conventional smear direct application of cells to a slide Liquid Based smear 90% of all Pap smears in US Transfer cells to a liquid preservative. Liquid processed in laboratory and transferred to a slide

Bethesda System (2001) Classification Specimen Adequacy Is the transformation zone present ?? Negative for intraepithelial lesion or malignancy (NIL,NILM, NIELM) Squamous Cell Atypical squamous cells Undetermined Significance (ASC-US) Not exclude High Grade (ASC-H) Low Grade Squamous Intraepithelial lesion (LSIL) – encompasses CIN I High Grade Squamous Intraepithelial lesion (HSIL) – encompasses CIN II & III Squamous Cell Carcinoma Glandular Cell Atypical Glandular cells (AG) Atypical Endocervical Cells Atypical Endometrial Cells Atypical Glandular Cells Not Otherwised Specified (AG-NOS) Favors Neoplasm Adenocarinoma In Situ (AIS) Adenocarcinoma

Management of Abnormal Paps ASC-US Reflex HPV testing if age > 21 If positive for high risk HPV (HRHPV)  Colposcopy If negative  Repeat Pap and HPV in 1 year Adolescents (<21)  Repeat Pap/HPV in 12 months HGSIL at 12 months - Colpo If ASC or greater in 12 additional months (total 24 months)- Colpo Pregnancy with HR HPV- acceptable to defer pap/colpo post partum

Management of Abnormal Paps ASC-H Refer to colposcopy If CIN 2,3- treat If no CIN 2,3 Cytology 6, 12 months OR HPV at 12 months ASCUS or greater or HPV + - Colpo

Management of Abnormal Paps LSIL Adolescents (<21)  Repeat Pap in 12 months- If ASCUS or greater total 24 months- Colpo Pregnancy- acceptable to defer pap/colpo post partum Everyone else  Colposcopy Non pregnant and NO lesion – ECC Preferred Unsatisfactory -ECC Preferred Satisfactory with Lesion -ECC Acceptable No CIN 2,3- Cytology at 6,12 months OR HPV at 12 mo ACUS or +HPV- Colpo CIN 2,3- Treat per guidelines

Management of Abnormal Paps HSIL LEEP or Refer to colposcopy No CIN 2,3 Unsatisfactory- Diagnostic Excisional Procedure (LEEP) Satisfactory Colpo and cytology for 6 months x 1 yr Diagnostic Excisional Procedure (LEEP) CIN 2,3 Treat per guidelines Adolescents - Persists for 24 months- LEEP

Management of Cervical Dysplasia Glandular Cells; Atypical Glandular Cells Subtype: Atypical Endometrial Cells Endometrial biopsy (EMB), endometrial currettage (ECC) If no endometrial pathology  Colposcopy Rest of Subtypes (AGC-NOS, endocervical, favor neoplasm) Colposcopy EMB if over 35 or at risk for Endometrial Cancer ECC HPV DNA testing Adenocarcinoma in situ Colposcopy, EMB & ECC Diagnostic Excisional Procedure / Total Hysterectomy?

Basic Components of Colposcopy Prepare your patient Obtain informed consent and answer her questions Assure her you will attempt to minimize pain (often a consuming worry) Make sure to know the pregnancy status of your patient Ibuprofen 800 mg may be offered prior to procedure or the night before and morning of the procedure, although its efficacy is questionable

Basic Components of Colposcopy Quickly examine the vulva for obvious condylomata or other lesions Warm the speculum with water or water soluble lubricants and insert the speculum Examine the cervix Is the cervix inflamed or infected-looking An active cervicitis confounds colposcopic detail Do cultures if necessary Repeat Pap only if this is critical information Even a correctly performed Pap smear may irritate the cervix and often causes bleeding Gently blot (not wipe) away any excess mucous using normal saline Look for leukoplakia and abnormal vessels

Basic Components of Colposcopy Generously place 3-5% acetic acid on the cervix- (Acetowhite correlates with high nuclear density) Mild acetowhite epithelium < Intensely acetowhite No blood vessel pattern < Punctation < Mosaic Diffuse vague borders < Sharply demarcated borders Follows normal contours of the cervix < "humped up" Normal iodine reaction (dark) < Iodine-negative epithelium (yellow) Leukoplakia - usually a very good (condylomata) or a very bad sign Atypical vessels - a hallmark of cancer

Transformation Zone Nearly all cervical neoplasia occurs in the TZ This is even true of the adenocarcinomas, which are often associated with adjacent high-grade squamous disease This is because it is the reserve cells undergoing metaplasia that are vulnerable to various carcinogens such as HPV Metaplasia is at peak activity during adolescence and first pregnancy, it is understandable that early age on sexual activity and first pregnancy are known risk factors for cervical cancer Given a particular lesion, the more severe disease tends to be cephalad in the TZ, where the epithelium is least mature In order that a colposcopic exam may be deemed “satisfactory” or “adequate,” the TZ must be seen in its entirety, all the way up to the columnar epithelium, 360°, which means that all areas involved in squamous metaplasia have been visualized

Basic Components of Colposcopy “Satisfactory” and “Adequate” Entire TZ visualized All lesions seen in their entirety Tools to help Endocervical Speculum Small Q-tip If not-----ECC

Lugol’s or Schiller’s Test Stains Glycogen May be used by the beginning colposcopist or at any time when further clarification of potential biopsy sites is necessary Iodine staining does not interfere with histology Lugol's solution is often very helpful on the vagina and proximal vulva (non- keratinized skin) It can be used to thoroughly and simultaneously examine the entire vagina for glycogen-deficient areas, which correlate with HPV and/or dysplasia in non-glandular mucosa It is often reserved for difficult cases when a non-cervical source of cervical Pap smear atypism is suspected (as in "normal cervical colposcopy" with dysplasia on Pap smear or normal ECC histology)

Summary Historically we have over-screened and over- treated women ACOG 2009 guidelines are based on sound mathematical and epidemediologic data HPV type and Persistence is the greatest predictor of the progression of dysplasia Colposcopy beginners rule- Biopsy everybody

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