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PAP Smears, HPV and Colposcopy Lisa Abel ARNP, WHNP-BC Anatomy of the Cervix Ectocervix: Covered by stratified squamous epithelium Squamous epithelium is divided into layers (superficial, intermediate, parabasal, basal). It is modified by estrogen and progesterone. The superficial layer is the most differentiated layer and periodically undergoes proliferation, maturation and desquamation. These cells are glycogenated. Under colposcopy the surface appears pink and translucent in appearance Endocervix: Portion of the cervical canal covered by columnar epithelium The internal os is the opening of the cervix into the uterus and the external os is the opening of the cervix into the vagina Columnar epithelium is a singular layer of mucus secreting cells Columnar epithelium have cleft like folds and not really a gland Under colposcopy they appear as grapelike structures Squamocolumnar Junction (SCJ): This is where the columnar cells meet the squamous cells. There is an original or native SCJ and a new SCJ. The new SCJ is the current junction and the original is its location at birth. The location of the SCJ will vary depending on age and hormonal changes. It is closest to the os before puberty and in menopause. Transformation Zone (TZ): The area between the original SCJ and the new SCJ. There may be nabothian cysts and epithelial cells in various stages. Squamous metaplasia is the transformation of columnar cells to stratified squamous cells. During this transformation, the cells are very vulnerable. It is effected by hormone changes. PAP Smear Basics: Screening test for cervical cancer Ideally a Pap smear has cells from both the ectocervix and the endocervix Collection tools – Cervix broom, spatula, endocervical brush Liquid based solution – put collection sample in solution ASAP Try to collect Pap smear off of menses and no vaginal medication or sexual intercourse for 48 hours before collection If vaginal bleeding present, note in chart Pap collection Equipement Endocervical brush, Spatula, Cervix broom, liquid-based container Pap Smear Screening Guidelines: 1,2 Initial Pap at age 21 regardless of age of first intercourse Age 21 – 29: cytology every 3 years. HPV testing only for an abnormal Pap. Age 30 – 65: cytology and HPV testing every 5 years (preferred) or cytology alone every 3 years Age > 65: stop screening if history of adequate negative Pap smears and no history of CIN 2+ in past 20 years After hysterectomy: stop screening if cervix is absent and no history of CIN 2+ Always use your judgment, some women are at an increase risk of cervical cancer and more frequent screening may be necessary Collection Tips: Set up your area beforehand to avoid contamination of counter top, light source If you need to lubricate the speculum, K-Y Jelly is usually fine in small amounts but warm water is the best If this is a first Pap smear, explain the procedure before proceeding and have the woman take a deep breathe in as your inserting the speculum and then exhale For menopausal women, the vagina may be dry so be sure to lubricate the speculum. If the sample comes back inadequate because of insufficient cells, use vaginal estrogen (if not contraindicated) for 2 to 3 weeks before attempting another sample The Bethesda System (TBS): Classification system for Pap Smears Within normal Limits - negative ASCUS (Atypical Squamous Cells of Undetermined Significance) ASC-H (Atypical Squamous Cells, cannot rule out High Grade SIL) LGSIL (Low Grade Squamous Intraepithelial Lesion) HGSIL (High Grade Intraepithelial Lesion) AGC (Atypical Glandular Cells) Unsatisfactory 3 Human Papillomavirus (HPV): 3 What is it? A non-enveloped double stranded circular DNA viral molecule that infects and replicates in epithelial cells. Why do we worry about HPV? Almost all Cervical cancers are caused by HPV. 80% of sexually active individuals are infected sometime in their lifetime with HPV. Other risk factors for cervical cancer include multiple sexual partners, young age of initial sexual experience, smoking, multiparity, immunosuppressive What do we know about HPV? 2,3,4 HPV is the most common STD with 14.1 million new cases diagnosed each year. HPV infection occurs at the basal cell layer of stratified squamous epithelial cells. Infection stimulates cellular proliferation. HPV is spread through skin to skin contact. In adults this is usually with sexual contact. All skin and mucus membranes are vulnerable to this virus. 90% of HPV infections are transient and become undetectable in 1 – 2 years Evidence suggest that HPV infections are uninfected by age of exposure and most should clear spontaneously There are high risk and low risk types of HPV. High risk types are oncogenic. The virus can stay dormant for several years and then suddenly activate How Does HPV Cause Cervical Cancer? The virus takes advantage of the cell’s replication machinery to reproduce its genome HPV oncogenes E6 and E7 inactivate cellular tumor suppressor proteins p53 and retinoblastoma protein (pRb) The normal function of p53 is to respond to damage of the DNA by activating the transcription of genes involved in cell repair or destruction pRb inactivates the transcription factor E2F-DP which is required to initiate the transcription of genes involved in DNA replication Working together, p53 and pRb prevent damage cells from dividing and prevent malignant changes The HPV Life Cycle: HPV is composed of eight genes (E1, E2, E4, E5, E6, E7, L1 and L2). These are expressed at different times during the HPV life cycle and categorized by early or late. HPV infects epithelial tissues through micro-abrasions such as skin abrasions or during sexual intercourse. For the virus to replicate it needs to reach the basal layer. The viral genome then enters the host cell’s nucleus and E1 and E2 genes replicate the virus genome. Next they build messenger RNA which hold a copy of the DNA material (transcription). Soon there are many copies of the virus genome. The host cells divide and differentiate – transcription cascade takes place. E4 and E5 genes assist in the virus genome production and controlling the rate of the epidermal growth. E6 and E7 interfere with the human genes p53 and Rb which facilitate normal cell division. HPV Life Cycle (continued) E6 binds with p53 and stops it from repairing cell damage or destroying the cell. E7 binds with Rb and stops it from accumulating necessary proteins and from preventing cell division if the proteins are not accumulated. Ultimately the damaged cell continues to divide and could lead to cancer. Lastly, L1 and L2 help create proteins to build new viruses. Sources: Panse S, Davidson College, Yim et al, Apgar et al HPV testing: 1,5 HPV testing can be done off a liquid-based Pap smear It is testing for the high risk (oncogenic) types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 66) The advantage of the HPV test is to detect the prevalence of CIN 2 and 3 in the population. A Pap test alone only detects 50 – 60% of CIN 2/3 but with HPV testing 90 – 95% are detected. There is no need to test for low risk HPV types Types of HPV Tests: 5 The first HPV test that became available was the Hybrid Capture 2 (HC2) – Digene Corporation. It had no internal control so cross contamination between low risk HPV types and high risk HPV types could occur. There are 3 newer tests: Cervista - DNA (Hologic, Inc), Cobas – DNA (Roche Molecular Systems, Inc) and Aptima - mRNA, E6 and E7 oncogenes (Gen-probe Inc) HPV Genotyping: 2,5 Detecting HPV type 16 and 18 The 3 newer HPV tests can do this HPV 16 accounts for 55% - 60% of cervical cancers HPV 18 accounts for 10% - 15% of cervical cancers 25% - 35% of cervical cancer caused by other HPV genotypes HPV Vaccine: 6,7 Gardasil (Merck): non-infectious recombinant quadrivalent vaccine with purified virus-like particles of the major L1 protein of HPV types 6,11, 16, and 18. It is approved for girls and women ages 9 to 26 years. It is also approved for boys and men. Given in 3 doses at 0, 2 and 6 months. Cervarix (GlaxoSmithKline): non-infectious recombinant bivalent vaccine with purified virus-like particles of L1 protein 16 and 18. It is approved for girls and women ages 9 to 25 years. Given in 3 doses at 0, 1 and 6 months. Safety profile is good for both. Time will tell if boosters will be needed. Colposcopy: A colposcopy is a diagnostic test. The colposcope allows you to better visualize the cervix. It focuses similar to a microscope and has three magnifications. During colposcopy, biopsies may be taken to determine the extent of the abnormalities. The cervical biopsy often feels like a quick pinch. The endocervical curette causes cramping while the specimen is being obtained. Equipment: Punch biopsy forceps Endocervical curette Endocervical speculum Scopettes Small cotton tipped swabs Acetic acid 3 – 5% (white vinegar is 5%) Lugol’s solution - especially helpful when looking for vaginal lesions Monsels Silver nitrate sticks Anesthetic spray Graves speculum Specimen container Colposcopy Equipment Colposcopy Equipment Tischler punch biopsy, Endocervical curette with basket, Endocervical speculum Colposcopy Procedure Choose the appropriate size of speculum to adequately view the cervix Gently remove any excess mucus. Move the colposcope into place. It may be helpful to view the cervix before applying the acetic acid. You can also look for any abnormal vessels with the green filter. Apply acetic acid to cervix. I like to use scopettes saturated in acetic acid and place them in the vagina for at least a minute. Use Lugol’s solution if need to further assess area (Do not use if allergy to Iodine). Be sure to visualize area on multiple magnifications. Look for acetowhite changes. This reaction occurs either from dehydration of the cells or from a chemical reaction. If you have difficulty visualizing the SCJ, use an endocervical speculum. Take any cervical biopsies and an endocervical curette (ECC) if appropriate. Never use an endocervical curette on a pregnant patient. Use Monsels or silver nitrate to stop any bleeding Documentation: Draw location of acetowhite changes and describe changes; make notation of SCJ and TZ location and any vessels Document where biopsies were taken. Areas on the cervix are noted by the face of a clock. Note whether the colposcopy exam was adequate – to be adequate, the entire SCJ needs to be seen. Reporting of Cervical Biopsy: Atypia, reactive atypia Cervical lntraepithelial Neoplasia (CIN I, CIN II, CIN III), carcinoma in situ – the grading depends on how deep the abnormal cells have invaded the cervical epithelium. Squamous cell carcinoma Adenocarcinoma, AIS Treatment Options for Cervical Intraepithelial Neoplasia: CIN 2, 3 Treatment options include an excision or an ablation procedure LEEP – loop electrosurgical excision procedure LLETZ – large loop excision of the transformation zone Cone biopsy / cold cone biopsy Laser ablation Cryotherapy is rarely used anymore. It should never be used for CIN 3. The goal of treatment is to remove the dysplasia and leave no residual disease behind. This is called having “negative” margins. You want both ectocervix and endocervix margins to be free of disease. Cervical Cancer: 8 According to the National Cancer Institute, there were 12,340 new cases of cervical cancer and 4,030 deaths in 2013. Cervical cancer is classified by stages. Class 0 would be CIS and AIS and have a good prognosis. Treatment Options for Cervical Cancer: Treatment depends on the extent of disease, age at diagnosis and whether preserving fertility is desired. In young women a cone biopsy maybe done for CIS and AIS Treatment can include hysterectomy, chemotherapy and radiation Prevention of Cervical Cancer: Educate on the importance of regular screening Pap smears Encourage and offer the HPV vaccine Discuss HPV and how it is transmitted Educate on the risks factors for cervical cancer Case Study #1: Jennifer is a 39 year old G2 P2 who had her first abnormal Pap smear. The results were ASCUS positive HR HPV. Should she have a colposcopy? She had an adequate colposcopy. A cervical biopsy at 4 o'clock was CIN I – II. An ECC was negative. Should she have any treatment? If yes, what would be the treatment options? She had a LEEP. The results were CIN II. The CIN II involves both the inked apparent ectocervical margin and endocervical margin. Her first follow up Pap smear 6 months later was negative. According to the new guidelines, what else should have been done at this visit? Case Study #2: Susan is a 35 year old G 0 who presents for her annual exam. Her Pap smear results are negative but no endocervical component is present. The HPV testing is positive. What would be the next plan of care for her? Case Study #3: Mary is a 56 year old G0 who was referred by her PCP for colposcopy. Her Pap results were HGSIL and she has no previous abnormal Pap smear history. Mary believes her previous Pap was 2 years ago in her home country. At her first visit her BP was 198/110. She was sent to urgent care. After multiple phone calls and a certified letter, she returned 5 months later. Her colposcopy was inadequate because the entire SCJ could not be seen. On colposcopy, from 3 – 9 o'clock there were stark AA changes and course vessels. The impression on colposcopy was HGSIL/CIS. The cervical biopsy was squamous cell carcinoma. What is the next plan for her? Case Study #4: Megan is a 23 year old G 0 with a 2 year history of abnormal Pap smears. Her initial abnormal Pap smear was LGSIL positive HR HPV 10/2011. A adequate colposcopy was done in 11/2011. A cervical biopsy was CIN I and the ECC was negative. A follow up Pap was done 6/2012 and the result was ASCUS positive HR HPV. It was decided to follow up with a repeat Pap smear. Megan did not come back for a Pap smear until 12/2013. The result was AGUS, favor endocervical origin. Does she need colposcopy? A colposcopy was done which was adequate. A cervical biopsy was CIN I and the ECC was negative. What is the appropriate follow up plan? Case Study #5: Diane is a 44 year old G3 P3002 who presents for an annual exam. Her Pap smear was HGSIL. The colposcopy was difficult because of her weight of 284 lbs. The colposcopy was adequate and there were AA changes at 12 o'clock. My impression was CIN I but the biopsy was CIN III. An ECC was negative. A LEEP was done which took 45 minutes. The pathology was CIN III with deep endocervical involvement. There was no invasive carcinoma. The plan of care is a TAH References 1. American Society for Colposcopy and Cervical Pathology. Cervical cancer screening recommendations, 2012. ASCCP. http://www.ascp.org/Guidelines/ Screening-Guidelines. Accessed January 3, 2014. 2. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol. 2012;137,516-542.doi:10.1309/AJCPTGD94VRSJCG(2012). 3. Centers for Disease Control. Self-study STD modules for clinicians; Genital Human Papillomavirus (HPV) infection. CDC. http://www2a.cdc.gov/stdtraining/self-study/hpv/default.htm. Published June 15, 2012. Updated 3/2013. Accessed January 6, 2014. 4. Adams HP, Carnright, EL. HPV infection and cervical cancer prevention. Clinician Reviews. 2013;23,9:42-50. 5. Torres M, Fraile L, Eshevarria JM et al. Human Papillomavirus genotyping: Automation and application in routine laboratory testing. Virol J. 2012;6:144-150. doi: 10.2174/1874357901206010144. 6. Gardasil (Merck) Package Insert 7. Cervarix (GlaxoSmithKline) Package Insert References 8. National Cancer Institute. Cervical cancer. National Cancer Institute. http://www.cancerx.gov/cancertopics/types/cervical. Accessed January 10, 2014. 9. Centers for Disease Control. HPV vaccine. CDC. http://www.CDC.gov/vaccines/vpdvac/hpv/vac-faqs.htm. Published April 6, 2011. Accessed January 10, 2014. 10. Panese S. Life Cycle of the Human Papilloma Virus. Bright Hub Inc. http://www.brighthub.com/ science/genetics/articles/24048.asp. Updated November 4, 2009. Accessed January 2, 2014. 11. Department of Biology. HPV life cycle. Davidson College. http://www.bio.davidson.edu/people/sosarafova/assets/Bio337. Published 2006. Accessed January 10, 2014. 12. Massad LS, Einstein MH, Huh WK, et al. 2012 Updated consensus guidelines for the management of abnormal cervical cancer screening tests and cervical precursors. J Low Genit Tract Dis. 2013;17,5: S1-S27. 13. Yim EK, Park JS. The role of HPV E6 and E7 oncoproteins in HPV associated cervical carcinogenesis. Cancer Res Treat. 2005; 37(6):319-324. doi:10.4143/crt.2005.37.6.319. 14. Apgar BS, Brotzman GL, Spitzer M, eds. Colposcopy Principles and Practice: An Integrated Textbook and Atlas. Philadelphia, PA: WB Saunders Co; 2002. 15. American Society for Colposcopy and Cervical Pathology. 2012 Updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. ASCCP. http://www.asccp.org/Guidelines-2/Management-Guidelines. Accessed January 3, 2014. 16. National Cancer Institute. What you need to know about cervical cancer. National Cancer Institute. http://www.cancer.gov/cancertopics/wyntk/cervix. Accessed January 10, 2014.
