HPV and Cervical Cancer Screening Peter Valenzuela, MD, MBA, FAAFP Assistant Dean for Clinical Affairs Assistant Professor/Dept. of Family Medicine

Objectives Discuss key aspects of HPV including: Types Transmission Course Detection Vaccine Describe cervical cancer screening guidelines Provide an introduction to colposcopy using cervical images

Background Human papillomavirus (HPV) is the most common sexually transmitted infection in the U.S. Over half of sexually active men and women are infected with HPV at some point in their lives 6.2 million people in the U.S. become infected annually

Economic Impact Approximately $3.5 billion spent on cervical HPV-related disease in the U.S. annually This image is Figure 13 at: http://www.merckmedicus.com/pp/us/hcp/diseasemodules/hpvd/epidemiology.jsp

Types There are over 100 different types of HPV Over 40 types infect mucosal surfaces of the ano-genital area High risk (cancer-associated)-16,18,31,33,35,39,45,51,52,56,58,59,68,82 Low risk (non-oncogenic)- 6,11,40,42,43,44,54,61,72,73,81

Types High Risk Low Risk HPV 16 most common (found in almost half of all cervical CA) HPV 18 accounts for 10%-12% of cervical CA Low Risk HPV 6 & 11 most commonly found in genital warts

Transmission Usually transmitted through direct skin-to-skin Can occur from mother to baby in delivery Detected on inanimate objects, but transmission via this route is unknown This image is Figure 14 at: http://www.merckmedicus.com/pp/us/hcp/diseasemodules/hpvd/epidemiology.jsp

Risk Factors for HPV Infection Young age (less than 25 years old) Increasing number of sex partners Early age at first intercourse (16 years old or younger) Male partner has (or has had) multiple sex partners

Course Typical duration of new infection is 8 months 70% of women become HPV negative within 1 year 91% become HPV negative within 2 years 10% of women infected with HPV will develop persistent HPV infections Even the majority of infections with high-risk HPV types generally clear within 2 years, failing to persist or progress to cervical cancer. This suggests that HPV infection alone is not sufficient for cervical cancer; rather, an interaction between high-risk HPV types and other host or environmental cofactors (e.g. smoking, oral contraceptive use) appears to play a role in disease progression The peak prevalence of CIN 1 occurs at approximately 28 years of age, CIN 2/3 at 42 years of age, and cervical cancer at approximately 50 years of age. This suggests that there may be a sequenced evolution of stages for cervical cancer over time, beginning with infection with high-risk HPV types, viral persistence, and progression from CIN 1 through CIN 3, ultimately to invasive cervical cancer [Baseman & Koutsky, 2005]. However, some studies contradict the hypothesis that stages of HPV-related disease are sequential; for example, development of CIN 2/3 may occur in the absence of known previous CIN 1 [Schiffman, 2003]. This image is Figure 19 at: http://www.merckmedicus.com/pp/us/hcp/diseasemodules/hpvd/natural-history.jsp

Detection HPV DNA test (Hybrid Capture II) Can be analyzed from the residual fluid of a liquid-based cytology specimen Detects high risk HPV types, but does not identify individual type Indications for use Routine adjunct to Pap in women 30 and over Management of ASCUS

Prevention of HPV Quadrivalent HPV vaccine (Gardasil) Protects against HPV 6,11,16,18 3 IM injections over six-month period ($360 for series) Indicated in females 9-26 years old Ideally before onset of sexual activity

Cervical Cancer Screening This is table 12 at: http://www.merckmedicus.com/pp/us/hcp/diseasemodules/hpvd/screening.jsp  

Cervical Dysplasia Classification Bethesda System- developed by the CDC and NIH to standardize method CIN Grading System BETHESDA CIN GRADING ASCUS Atypia LGSIL CIN I HGSIL CIN II HGSIL Carcinoma In Situ CIN III Staging Since the Pap smear was introduced in 1943, a number of methods have been developed to classify the results. The two methods commonly used today are the Bethesda System and the CIN Grading System. The Bethesda System was developed by the CDC and NIH in order to have a comprehensive and standardized method of classifying Pap smear results. It uses the term squamous intraepithelial lesion (SIL) to describe abnormal changes in the cells on the surface of the cervix. Squamous refers to thin, flat cells that lie on the outer surface of the cervix. An intraepithelial lesion occurs when normal cells on the cervical surface are replaced by a layer of abnormal cells, and these changes are classified as high grade or low grade. Bethesda System ASCUS (atypical squamous cells of undetermined significance) - Borderline, some abnormal cells LGSIL (low-grade squamous intraepithelial lesions) - Mild dysplasia and cellular changes associated with HPV HGSIL (high-grade squamous intraepithelial lesions)- Moderate to severe dysplasia, precancerous lesions, and carcinoma in-situ (preinvasive cancer that involves only the surface cells) Squamous cell carcinoma Cervical intraepithelial neoplasia (CIN) refers to new abnormal cell growth. Intraepithelial refers to the surface layers of the cells. The CIN System grades the degree of cell abnormality numerically, CIN I is the lowest and CIN III is the highest. CIN Grading System Atypia - correlates with ASCUS CIN I - mild dysplasia and correlates with LGSIL CIN II - moderate dysplasia and correlates with HGSIL CIN III - severe dysplasia and correlates with HGSIL Carcinoma in-situ Cervical cancer

Management of an Abnormal Pap This is the first image on page 22 of the CDC brochure and may be found at: http://www.cdc.gov/std/HPV/common-infection/CDC_HPV_ClinicianBro_LR.pdf

Management of an Abnormal Pap This is the second image on page22 of the CDC brochure and may be found at: http://www.cdc.gov/std/HPV/common-infection/CDC_HPV_ClinicianBro_LR.pdf

Colposcopy This image can be found at: http://medicalimages.allrefer.com/large/colposcopy-directed-biopsy.jpg Indications: Grossly visible or palpable abnormality of the cervix Abnormal cervical cytology Positive screening test for cervical neoplasia such as spectroscopy, cervicography, speculoscopy Cervical cytology unsatisfactory due to unexplained inflammation History of in-utero diethylstilbestrol (DES) exposure Unexplained cervico-vaginal discharge Unexplained abnormal lower genital tract bleeding History of lower genital tract neoplasia (cervical, vaginal, vulvar) Post-treatment surveillance ASCCP

Colposcopy Ectopy Nabothian Cyst This image can be found at: http://www.asccp.org/edu/practice/cervix/colposcopy/benign.shtml This image can be found at: http://www.asccp.org/edu/practice/cervix/colposcopy/benign.shtml Ectopy-Most pronounced in adolescence and the first pregnancy when squamous metaplasia is most active. It is also common with the use of oral contraceptives. It is an entirely normal finding, and does not warrant any kind of diagnostic or therapeutic response Nabothian cysts: Single or multiple, the translucent cysts appear yellow and can be as large as several centimeters. Formation occurs secondary to blockage of mucin secreting endocervical crypts by overlying metaplastic squamous epithelium. Nabothian cysts are always located within the transformation zone. Prominent large vessels are often noted overlying the attenuated epithelial surface of the cyst. On close inspection, the vessels arborize normally and are not atypical (disorganized) in appearance. Nabothian cysts are normal. They do not require any treatment.

Colposcopy Leukoplakia This image can be found at: http://www.asccp.org/edu/practice/cervix/colposcopy/benign.shtml Keratosis or leukoplakia: Lesions that appear white on visual inspection of the cervix prior to the application of acetic acid are termed keratosis or leukoplakia. Microscopy of these lesions reveals a thick hyperkeratotic or parakeratotic surface. Located within or outside of the transformation zone, keratotic lesions are raised and bright white. Leukoplakia is a nonspecific finding and may arise secondary to trauma such as with diaghram or pessary use, human papilloma virus infection or even invasive keratinizing squamous carcinoma. Biopsy is necessary to establish the exact diagnosis. Coarse” vascular patterns (punctation, mosaicism, or both) characterized by: Larger and varied caliber of vessels Larger and variable intercapillary distances “Umbilicated” mosaic patterns, with punctation in the middle of the “tiles” suggests CIN 3 / carcinoma-in-situ. Vascular patterns can be striking and visible even at lower magnification Vascular patterns change as acetic acid effects develop, then fade: keep watching! Prominent and dilated vessels may blunt acetowhite change; Don’t miss the HSIL or invasive cancer because the examining eye is drawn to acetowhite change and away from the less-white HSIL or cancer!

Colposcopy Punctation This is image 7.3 at: http://screening.iarc.fr/colpochap.php?lang=1&chap=7.php Punctation- stippled appearance of capillaries appear as fine-to-coarse red spots after acetic acid

Colposcopy Mosaicism CIN I This is image 7.16 at: http://screening.iarc.fr/colpochap.php?lang=1&chap=7.php Mosaicism-linear, tile-like patterns, abnormal change made of small blood vessel appearing in linear form.

Colposcopy CIN II CIN III This is image 7.19 at: http://screening.iarc.fr/colpochap.php?lang=1&chap=7.php This is image 7.23 at: http://screening.iarc.fr/colpochap.php?lang=1&chap=7.php

Colposcopy Strawberry Cervix Common indicator of cervicitis Trichomoniasis is usually the culprit This image can be found at: http://www.asccp.org/edu/practice/cervix/colposcopy/benign.shtml Always keep in mind that cervicitis may make Pap interpretation more difficult and less accurate, and make colposcopic assessment more difficult. Cervicitis secondary to trichomoniasis results in coalescent erythematous patches giving a reverse punctation also called a “strawberry cervix”. The mucopurulent cervicitis of chlamydia and gonorrhea is associated with prominent vascularity and hypertrophy of the cervical ectropion. Many authorities recommend diagnostic tests and any indicated treatment before biopsy when any cervicitis (STD) or severe vaginitis is strongly suspected.

Summary Discuss key aspects of HPV including: Types Transmission Course Detection Vaccine Describe cervical cancer screening guidelines Provide an introduction to colposcopy using cervical images

References Centers for Disease control and Prevention http://www.cdc.gov/std/hpv/hpv-clinicians-brochure.htm American Society for Colposcopy and Cervical Pathology http://www.asccp.org/edu/practice/cervix.shtml American College of Obstetricians and Gynecologists http://www.acog.org/

References Pfenninger and Fowler’s Procedures for Primary Care, 2nd Ed. 2003 Colposcopy and Treatment of Cervical Intraepithelial Neoplasia: A Beginner’s Mannual. Edited by Edited by J.W. Sellors and R. Sankaranarayanan HPV Disease www.merckmedicus Women’s Health Channel www.womenshealthchannel.com