Human Papillomavirus (HPV) What? 7/31/2015

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1 Theresa M. Schwartz, RN, MS, FNP, ANP C, Anal Dysplasia Specialist Rochester Colon and Rectal Surgeons Purpose of Talk Discussion of anal Human Papillomavirus (HPV) infection and etiology of High Grade Anal Intraepithelial Neoplasia (AIN) / Dysplasia, a precancerous condition Description of office screening, diagnosis of High Grade Intraepithelial Neoplasia / Dysplasia utilizing High Resolution Anoscopy (HRA) and treatment utilizing Infrared Photocoagulation (IRC) ablation Explanation of research, political and cultural issues involved in changing the standard of medical care. Human Papillomavirus (HPV) What? The most commonly diagnosed STD in the world. Over 150 HPV types; 40 specific for anogenital squamous epithelium Types 16, (73% of tumors), 18 (7% of tumors), 31, 33, and others are oncogenic squamocellular carcinoma (SCC) High risk HPV types associated with cervical, anal, vulvar, penile and oropharyngeal cancers History of genital condyloma acuminata is associated with cancer risk Daling, JR, Madeleine, MM, Johnson, LG, Schwartz, SM, Shera, KA, Wurscher, JA, Carter, JJ, Porter, PL, Galloway, DA (2004) Cancer 101(2)

2 Human Papillomavirus How? Penetrative intercourse Digital / vaginal Digital / anal Oral / anal Skin to skin contact not body fluid transmission Fomites Limited protection of condoms Behaviors HPV is an equal opportunity virus (M,F). The rectum is an equal opportunity sex organ. Men who have sex with men (MSM) do not have the corner on the anal sex behavior, nor do all MSM have anal sex. People are at risk because of practices other than anal receptive sex because of skin to skin transmission, women wiping front to back, etc. Assessment and discussion of anal sex practices is helpful. HPV Genetics Why? HPV oncoproteins (E6 and E7) bind to and degrade host cell tumor supressors (p53 and Rb), causing them to be functionally inactivated. Jones, D, Munger, K. (1997) Analysis of the p53 mediated GI growth arrest pathway in cells expressing the human Papillomavirus type 16 E7 oncoprotein. Journal of Virology, 71, accessed

3 Estimated Prevalence of Genital HPV Infection Among Men and Women ages Years of Age in the US Koutsky, L. (1997) Epidemiology of Genital Human Papillomavirus Infection. The American Journal of Medicine. 5 May (5A): 3-8. Human Papillomavirus Who? 75% of the US population Many young people clear HPV within 2 years. Reinfection can occur. Immunosuppression (due to disease or medications), HIV, tobacco smoking promote persistence of HPV infection. Palefsky, J (2004) Inf Dis; Dec million people in the US are currently infected with HPV. 14 million people are diagnosed with HPV each year. 360,000 people develop warts each year. cdc.gov/std/hpv accessed Human Papillomavirus Who? 80% of those with 2 sex partners 100% of those with more than two lifetime partners 57% of HIV MSM are HPV+; 27% with high risk strains. 90% of HIV + MSM are HPV+. HIV + and HIV MSM have the same types of HPV Palefsky, J Inf Dis; Dec 14, 2004 Estimated lifetime probability of acquiring HPV in the US with at least one opposite sex partner is 85% for women and 91% for men. Chesson, H, Dunne, E, 2015 et al Sexually Transmitted Diseases 41(11) 3

4 Human Papillomavirus When? Papilloma viruses were identified in the 1930s. HPV related cancers have been increasing since the 1960s. HPV can remain in a body cavity for up to years before cancer develops in HIV negative people. First, Do No Harm. What is the possibility that not changing exam gloves between the vaginal and rectal exams has spread HPV from one body cavity of women to another? Anal Cancer Who? Risk factors for anal cancer: Human papilloma virus infection and: HIV infection Chronic immunosuppression not due to HIV Multiple sexual partners Receptive anal intercourse Female gender History of cervical, vulvar, or vaginal carcinoma Smoking Crohn s disease accessed

5 Incidence of Anal Cancer 2015 Increasing at a rate of 2% per year Estimated 7,271 anal cancers and 1010 deaths for This is almost three times the death rate of testicular cancer (380) 11,000 cervical cancers are diagnosed each year More anal cancers in women 4,630 and 610 deaths American Cancer Society Incidence of Anal Cancer The incidence of squamous cell cancer of the anus (SCAA) has increased by 160% in men and 78% in women between 1973 and Daling, JR, Madeleine, MM, Johnson, LG, Schwartz, SM, Shera, KA, Wurscher, JA, Carter, JJ, Porter, PL, Galloway, DA (2004) Cancer 101(2) Incidence of HPV Related Cancers Anal cancer incidence: nearly identical in MSM (before HIV) = 36 /100,000 1 to cervical cancer in women (before cervical cytology screening) = 35 / 100,000 2 General population incidence of anal cancer = 7 9/100,000, with higher incidence in women 3 Cervical cancer incidence is 8 / 100, Daling, JR, Weiss, NS, Hislop, TG, et al. NEJM, Palefsky, JM, Holly, EA, Ralston, ML, et al. JAIDS, Palefsky, JM AIDS, Qualters, Jr., Lee, NC, Smith, RA, Aubert, RE. MMWR,

6 Why More Anal Cancer in Women? In absolute numbers, seven times more women than gay/bisexual men engage in unprotected receptive anal intercourse. Halperin, DT, 1(999). Heterosexual anal intercourse, cultural factors, and HIV infection and other health risks, Part 1. AIDS Patient Care STDS. Dec. 13(12): Rates of HPV Associated Cancers and Median Age at Diagnosis Among Men in the United States, Rates of HPV associated cancers and median age at diagnosis among men in the United States,

7 Rates of HPV Associated Cancers and Median Age at Diagnosis Among Women in the United States, Rates of HPV associated cancers and median age at diagnosis among women in the United States, Anal Cancer in HIV Negative Immunosuppressed Patients Six patients with multifocal high grade anal dysplasia who elected observation instead of treatment. Three patients progressed to anal cancer at a median of five years after initial diagnosis. All 3 were treated with CRT, but one developed metastatic disease and died two years after diagnosis of anal carcinoma. Scholefield JH, Castle MT, Watson NF (2005) Malignant transformation of high grade anal intraepithelial neoplasia. British Journal of Surgery; 92:

8 Anal Cancer in HIV Infected People The risk of developing non AIDS defining cancers is higher when the CD4 cell count is less than 500/microliter for one year or more. Antiretroviral Treatment of Adult HIV Infection: 2008 Recommendations of the International AIDS Society USA Panel. JAMA, August 6, 2008, vol. 300,5, p Incidence of Anal SCC in HIV Infected People In a retrospective series of 32 HIV positive patients treated in NYC for anal SCC, six patients died of their SCC despite treatment. In the same cohort, the median time from HIV diagnosis to SCC was 12 years. Wexler, A., Berson, A., Goldstone, S et al (2007). Invasive anal squamous cell carcinoma in the HIVpositive patient: Outcome in the era of highly active antiretroviral therapy. Doseases of Colon & Rectum, March 12. HPV Prevention Vaccines Gardasil9 (Merck) vaccine approved for use in females ages 9 through 26 males ages 9 through 15. It is approved for the prevention of cervical, vulvar, vaginal and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52 and 58, and for the prevention of genital warts caused by HPV types 6 or accessed

9 Explicit Photo Warning!! Penile Condylomata 9

10 Anal Condylomata Oral Condylomata Chesson, HW, Blanford, TM, Gift, TL et alperspect Sex Reprod Health, 2004: 36:

11 Cost of Cervical Cancer Screening $ 6 billion annually for the treatment of low grade cervical SILs Annual cervical Pap after two negatives, 6 months apart = $14,800 per QALY (quality adjusted life year) saved. Semiannual cervical Pap = $27,600 per QALY saved. zgoldie, SJ, Weinstein, MC et al (1999). The costs, clinical benefits, and cost effectiveness of screening for cervical cancer in HIV infected women. Annals of Internal Medicine 130 (2), Cost Effectiveness of Screening for Anal Dysplasia $16,600 per QALY saved, for screening, diagnosis and treatment of high grade anal dysplasia. Goldie, SJ, Kuntz, KM, et al. (1999) The clinical effectiveness and cost effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV positive men. JAMA, May 19, (19). Dysplasia Screening Guidelines for the screening the cervix of are concise and clear in HIV+ women. Guidelines also exist for evaluation of anus. The general public believes that they are routinely screened for HPV, as for other STDs. 11

12 Anal Pap Tests Similar to Cervical Paps Fluid based cytology method using commercial methods used at your lab Do prior to Digital Rectal Exam Dacron swab, moistened only with water Part the anoderm, insert about 1 2 inches Rotate (do not twirl) 360 degrees both ways for 10 sec. Stir into fluid for at least 30 seconds Press against container to extract fluid Palefsky JM, Holly EA, Hogeboom CJ, Berry JM, Jay N, & Darragh TM (1991), J of AIDS, 14: Sensitivity of Anal Paps In HIV positive men the sensitivity of abnormal cytology to detect high grade anal neoplasia was 87%, and in HIV negative MSM it was 55%. Among HIV negative men, 9 of 20 cases of highgrade anal neoplasia would have been missed because cytology was negative. Berry, JM, Palefsky, JM, Jay, N, Cheng, SC, Darragh, TM, Chin Hong, PV (2009) Performance characteristics of anal cytology and human papillomavirus testing in patients with highresolution anoscopy guided biopsy of high grade anal intraepithelial neoplasia. Dis Colon Rectum Feb;52(2):

13 Bethesda Staging System (2001) CIN/AIN Atypical squamous cells Of undetermined significance (ASCUS) Cannot exclude HSIL (ASC-H) Squamous intraepithelial lesion (SIL) Low grade SIL (LSIL) Mild dysplasia = CIN/AIN 1 (HPV cellular changes) High grade SIL (HSIL) Moderate dysplasia = CIN/ AIN 2 Severe dysplasia = CIN/AIN 3 Squamous cell carcinoma in-situ Microinvasive squamous cell carcinoma (SCC) Invasive squamous cell carcinoma Wright et al (2002) JAMA 287; Cytology and Histology Terminology Anal Pap and tissue samples NIH Squamous Intraepithelial Lesions 13

14 Anal Pap: HSIL Follow up of Cytologic Dysplasia If anal Paps are performed for screening, those reported as ASCUS or higher should be referred for High Resolution Anoscopy (HRA), because of anatomical differences between the anus and cervix. Normal Paps have been reported in patients with anal carcinoma in situ (CIS). Treatment Algorithm Anal Pap Test and High Resolution Anoscopy +/- Biopsy No lesion seen AIN 1 AIN 2 or 3 CIS Repeat in 12 months, HIV + Repeat in 2-3 years, HIV - Follow every 6-12 months Treat 14

15 Anal Dysplasia Screening Visit Procedure History and risk factor assessment Patient education and informed consent Examination of perianal, perineal, and genital regions Obtain Pap and cultures (if indicated) Digital rectal exam with tetracaine/water based lubricant mixture HRA with biopsies as indicated by history, findings Hemostasis Follow up, pending biopsy results Digital Rectal Exam Should be done as part of the annual CPE Using a water soluble gel; may use local anesthetic Provides an opportunity to examine perianal skin Palpable mass on DRE warrants urgent evaluation by colorectal surgeon HRA is not necessary to diagnose tumors Note sphincter tone and any pain on DRE Anal canal condylomata are often palpable High Resolution Anoscopy (HRA) Analogous to cervical colposcopy Uses a colposcope Clear plastic anoscope Tetracaine 2% gel Acetowash with 3% for 1 2 minute(s) to locate SCJ Lugol s iodine to assess for stigmata of dysplasia In vivo microscopic evaluation Baby Tischlers biopsy forceps for sample retrieval CPT for HRA without biopsy 46601; with bx Jay N, Berry JM, Hogeboom CJ et al. (1997) Colposcopic appearance of anal squamous intraepithelial lesions: Relationship to histopathology. Dis Colon Rectum, 40:

16 Patients are thinking about. You re going to do what to me?!? Whether or not they have cancer Whether they will eventually get cancer People they have known with colostomies Who they got HPV from Whether or not they can trust their current partner or need to end the relationship Whether and how to disclose HPV to future intimate partners I have to do this screening forever?!? Past anal sexual abuse, PTSD 16

17 (1) Healthy Lugol s +; (2) LSIL Lugol s +; (3) HSIL Lugol s - 17

18 Flat plaque LGSIL X16 (Jay N et al. Dis Colon Rectum 1997;40:923) Punctation (Jay N et al. Dis Colon Rectum 1997;40:923) Mosaicism (Jay N et al. Dis Colon Rectum 1997;40:923) 18

19 Management of Biopsy Proven Anal Dysplasia Biopsies reported as moderate or high grade dysplasia (AIN 2 or 3 or CIS) are ablated by Infrared Photocoagulation (IRC). CPT code Treatment of Anal Intraepithelial Neoplasia Infrared Photocoagulation uses infrared light in preset (1.5 sec) pulses. Electrocautery uses heat to destroy tissue, necessitating evacuation of smoke. Works well for small lesions. Surgical excision / fulguration prolonged recovery, stenosis, incontinence, frequent recurrences. IRC2100 TM Infrared Coagulator Light guide Redfield Corporation, Rochelle Park, N.J. 19

20 Treatment Changes HSIL Char dessicating Char debrided bluntly Bulging submucosal veins Thrombosed submucosal veins Post treatment Follow Up: Low Resolution Anoscopy Recommended follow up in three months to grossly rule out significant recurrence Welch Allyn hand held scope Or clear plastic anoscope with an external light source Low Resolution Anoscopy CPT Cure Rate of Individual Lesions: Goldstone Practice 165 lesions treated the first time 46 lesions persisted (28%) 119 lesions cured (72%) 39 of these lesions were treated a second time 11 lesions persisted (28%) 28 lesions cured (72%) Goldstone, S.E., Kawalek, A.Z., Huyett, J.W. (2004) Infrared Coagulator: A useful tool for treating anal squamous intraepithelial lesions. Diseases of the Colon & Rectum, 48 (5),

21 Additional Findings No patient developed infection, bleeding or anal stricture No patient required anything more than mild oral narcotic analgesia No patient developed SCC Cranston Results (Pittsburgh) Series of 68 HIV infected MSM with average CD4 of 436, range Patients received evaluation and treatment with IRC between 2003 and Treatment efficacy was 64% Cranston, RD, Hirschowitz, SL, Moe, AA (2008) A retrospective clinical study of the treatment of highgrade anal dysplasia by infrared coagulation in a population of HIV positive men who have sex with men. International Journal of ATD & AIDS; 19: Rochester Experience HIV + patients (60% AC and 40% SMH) 65% had biopsy proven anal dysplasia (AIN 1 3) 42% of patients had HGSIL (AIN 2,3 or CIS) Three patients had carcinoma in situ (CIS) Paps were only 53.4% sensitive for any dysplasia Paps were only 7.7% sensitive for detecting HGSIL Correlation between Paps and HGSIL was 0.18 No patients had invasive anal cancer Mallari AO, Schwartz TM, Luque AL, Polashenski PS, Rauh SM, Corales RB. (2013) Anal Cancer Screening in HIV Infected Patients: Is It Time to Screen Them All? Diseases of the Colon & Rectum.55(12),

22 Unpublished Rochester Experience Over 2,000 patients screened and treated as appropriate. No patients developed invasive anal SCC who have presented for screening in accordance with standard of care guidelines. Treatment of Anal Dysplasia IRC is a safe office based modality for treating anal HSIL. While recurrence rates are high, they are comparable to results seen in the cervix. Successive treatments led to decreased recurrence rates, but patients should continue to be followed for disease. Other Treatments for Condylomata Aldara cream: 5% imiquimod, a biologic response modifier, used 3 times per week. Zyclara cream: 3.75% imiquimod, used daily for two week cycles. Veregen ointment 15% = catechins a botanical drug, as defined by the FDA, from green tea extract, used 3 times daily. All are FDA approved for topical treatment of anal / genital condylomata, for external use only 22

23 General Perspectives Prevention methodologies requiring sequential screenings is a new concept for many patients, especially male. No more stigmatizing than cervical cancer. Analogous to dentistry or checking one s cholesterol. Standards continue to evolve. Question: Do we need more data to demonstrate the need for anal HPV screening? There has never been a randomized control trial for standard cervical Pap screening, nor would it be ethical to conduct such a study today. The efficacy of Pap screening in preventing cervical malignancies rests exclusively on decades of epidemiological data for validation.. New York State, Department of Health, AIDS Institute Guidelines: Anal Dysplasia and Cancer, Neoplastic Complications of HIV Infection, July, 2007 NYS DOH AIDS Institute Guidelines, Neoplastic Complications of HIV Infection July, 2007 Answer: No! Given that 1) It is unlikely that a 10 year clinical trial demonstrating the efficacy of obtaining anal cytology in any HIV infected population will ever be performed and 2) HPV initiated carcinomas are clearly preventable malignancies, this committee recommends obtaining routine anal cytology in populations that are clearly at risk. NYS DOH AIDS Institute Guidelines, Neoplastic Complications of HIV Infection July, 20N New York State, Department of Health, AIDS Institute Guidelines: Anal Dysplasia and Cancer, Neoplastic Complications of HIV Infection, July,

24 ANCHOR Study Anal Cancer/HSIL Outcome Research Study 15,000 patients will be screened 1. At least 35 years of age 2. HIV positive 3. Never received HPV vaccine 4. Never had cancer of the anus, vulva, vagina, cervix 5,000 patients will be enrolled and randomized to either the Active Monitoring (no treatment) or Treatment group. Over the 8 year study period, an estimated 50 patients will develop anal cancer. Summary Preventive management of HPV related conditions reduces treatment morbidity compared to extensive treatment of advanced, invasive disease. Anal Paps and biopsies allow for assessment for dysplasia. Treatment decisions should follow. Prompt, localized treatment of precancerous lesions can prevent the need for surgery, chemotherapy, radiation therapy and related morbidity. Community Norms and Standards Effect of current conservative culture and politic on sexual health in general, the HIV positive and sexual minorities Stigma associated with anal sex Public not aware of prevalence of HPV, or the consequences of infection. Evidence based scientific climate is different than when cervical screening was introduced. 24

25 Summary of Recommendations HPV as Precursor to Anal SILs Pap Screening for HIV Negative Pap Screening for HIV Positive HRA and / or biopsy recommended Treatment of SILs recommended American Cancer Yes Yes Yes Yes Yes Society NYS DOH AIDS Inst. Yes No Yes Yes Yes CDC Yes No Yes Yes Yes American Society of Colo Rectal Surgeons Yes Yes Yes Yes Yes Case Study # 1 52 yo white female, HIV negative History of anal sex X2 at age 33 Cervical dysplasia 1992 & 2005; normal Pap 06 Treated for genital condylomata by GYN Anal warts on routine colonoscopy, treated by rectal surgeon with TCA, Referred for anal Pap, 8 06 = LGSIL HRA 9 06 ; one of two biopsies = SCC in situ IRC ablation performed Used internal Aldara with decrease of int. condyloma Repeat HRA and biopsies 1 07 = LGSIL Repeat HRA and biopsies 5 07 = AIN3, ablated 7 07 Since 10 07: negative Paps and biopsies Died Fall of 2014 from ovarian cancer. Case Study # 2 43 yo HIV + MSM Referred for routine screening anal Pap 9 07 Anal Pap 9 07 = Rare ASCUS Biopsies done the same day = CIS 25

26 Case Study # 3 44 yo HIV + MSM Anal Pap = CIS Biopsies revealed AIN 3 x2 and CIS x2 IRC ablation of the CIS and later AIN 3 Repeat HRA and biopsies all AIN 2 Half treated 4 08 and the other half Patient cannot tolerate internal Imiquimod use. Seen regularly for ablation. Using Imiquimod tampons Case Study # 4 43 yo HIV + MSM Pap = LGSIL 5/07 Treated for AIN 2, 3 New perianal skin lesion biopsied CIS, no definite invasion To OR for conventional mapping, reported as AIN 2 3 Did not use Imiquimod as advised. Developed perianal minimally invasive SCC, which cleared with daily Imiquimod use (off label use). Case Study # 5 41 yo MSM 8 07 surgery for internal anal condylomata 9 07 repeat surgery for internal condylomata Seen by ID for immune system eval seem by me. Subsequent results: Pap = LGSIL, Bx = AIN1. Does not tolerate Imiquimod to present: had 10 ablative procedures, followed by one visit with no visible condylomata, which then returned. Used Imiquimod tampons (off label use) No condylomata since

27 Impact on Practices of. Family practitioners / Pediatricians Adolescent / Family Planning / school sites HIV specialists Colorectal surgeons OB / GYN STD testing / treating clinics GLBT focused practices Parents of non infected children Research Needs Generalizeable protocols regarding epidemiology, screening and detection Primary care screening Effective suppressive therapy Self treatment methods Pharmacologic or immunologic therapy for AIN, CIS Conclusions Routine cervical Pap screening is a general primary care function Anal Pap screening can be done in any primary care setting and demonstrates a need for referral AIN detection and treatment exists Education of and advocacy for patients are essential Need to develop additional treatment centers Further research and development will impact the health of our patients 27

28 Resources screening prevention treatmentrochester ny.php s.html_ucsf Anal Dysplasia Practice at Rochester Colon Rectal Surgeons Theresa M. Schwartz, NP Appointment line Clinic hours: Tuesdays, Wednesdays, and Thursdays 9:00 AM to 5:00 PM Questions? Thank you! 28

29 Key Messages for Persons with HPV Infection General Anogenital HPV infection is very common. It usually infects the anogenital area but can infect other areas including the mouth and throat. Most sexually active people get HPV at some time in their lives, although most never know it. Partners who have been together tend to share HPV, and it is not possible to determine which partner transmitted the original infection. Having HPV does not mean that a person or his/her partner is having sex outside the relationship. Most persons who acquire HPV clear the infection spontaneously and have no associated health problems. When the HPV infection does not clear, genital warts, precancers, and cancers of the cervix, anus, penis, vulva, vagina, head, and neck might develop. The types of HPV that cause genital warts are different from the types that can cause cancer. Many types of HPV are sexually transmitted through anogenital contact, mainly during vaginal and anal sex. HPV also might be transmitted during genital-to-genital contact without penetration and oral sex. In rare cases, a pregnant woman can transmit HPV to an infant during delivery.

30 HPV Screening Screening is a vital component in preventing HPV-associated cancers. The importance of screening has proved extremely effective in decreasing the prevalence cervical cancer, another HPV-associated cancer. In the United States, incidence rates for cervical cancer fell by 57% between 1975 to 2007, with a similar decline in deaths from the disease. This translates to a difference of nearly 10,000 lives saved per year, adjusted for the growing size of the population. The primary reason for the decline is better screening practices and methods, including regular check-ups and cervical pap smears. HPV-associated cancers in other sites, such as the anus, remain on the rise in part due to a lack of widespread screening protocols. In the United States, sexually active women are recommended to have cervical Pap smears and digital rectal exams (DREs) during regular gynecological visits to test for HPV-associated lesions and other abnormalities. There is a growing trend in the medical community to call DREs digital anorectal exams (DAREs) to emphasize that the clinician is checking the anus as well. Experts believe this exam is an effective method for detecting anal cancer. Men are not regularly tested for HPV-related cell abnormalities.hpv, if unresolved by the body s immune system and left untreated, can eventually cause anal, penile and head and neck cancer in men. Men who have sex with men (MSM) are among those who are most at risk for acquiring anal HPV infection, although men who have sex with women (MSW) can also develop anal HPV infection. More recently, the medical community is improving efforts to screen MSM for anal HPV, but these efforts are inconsistent and vary among different practitioners and municipalities. People at risk should be examined using DAREs, anal Pap smears, or high-resolution anoscopies (HRA), which is a procedure using a high resolution magnifying instrument called an anoscope to identify abnormal cells (similar to a colposcope used to identify cervical abnormalities). If you believe you are at risk for anal HPV infection or have anything that seems abnormal, you should ask your doctor if he or she can implement appropriate screening procedures. Ask your doctor about these procedures. Do not expect your doctor to suggest these for you. If diagnosed with an abnormal cervical or anal pap smear, additional tests can be performed to determine whether the patient has a high-risk or low-risk lesion. These include a laboratory HPV DNA test to determine of the range of HPV strains the infected individual has been exposed to. Post-diagnosis, men and women who have an HPV infection should carefully monitor their body and obtain regular check-ups. Anal Cancer and Screening While cervical cancer rates have fallen dramatically in the past three decades, HPV-associated cancers in other sites remain on the rise. Cervical cancer has decreased significantly in the United States primarily due to improved early detection of, and treatment for, precancerous lesions (dysplasia). The incidence of anal and oral cancers, however, continues to increase across the U.S. population. One reason is that the medical community has yet to agree to routinely perform optimal early screening and treatment protocols for these sites. While there is no easy procedure to check for HPV-associated oral precancer and cancer, there are numerous tools to check for precancer and cancer in the anus. Widespread practice of effective protocols for early detection and early intervention of HPV-caused anal disease could prevent many individuals from ever developing this cancer, just like it has for cervical cancer. Anal cancer is often missed or misdiagnosed, many times as hemorrhoids. According to University of California San Francisco s anal cancer website, the possibility of cancer is often overlooked and symptomatic patients are told that they are suffering from hemorrhoids and are not examined with a simple digital anorectal exam (DARE). A DARE is when a health professional manually examines one s anus and rectum. If you are experiencing symptoms such as lumps near the anus, anal bleeding, anal discharges, or changes in bowel movements, you should inform your health care provider, especially if you are at higher risk for anal cancer. Sometimes patients are embarrassed and do not let their providers know they are having symptoms. In patients with anal cancer but with no symptoms, something abnormal may still be felt with a DRE/DAE. If a mass, a thickening, an area of hardness, a lump, an area of localized tenderness or an ulcer is found, then the patient must be referred to clinicians experienced in managing anorectal problems who can evaluate and biopsy the suspicious areas. If you are diagnosed with what is believed to be a hemorrhoid and it has not resolved for several weeks despite all recommended treatments, please discuss it with your physician and have it formally reevaluated again. Ask whether a DRE/DAE is appropriate. If you have anal cancer, this may help to prevent misdiagnosis as a hemorrhoid and obtain appropriate treatment faster. For people who are at-risk for anal cancer, in addition to regular DREs/DAEs, it is recommended to have an anal pap smear (also called anal cytology) or highresolution anoscopy (HRA), where available. An anal pap smear is identical to the technology used for cervical pap smears. HRA is a procedure using a highresolution magnifying instrument called an anoscope to identify abnormal cells. A list of providers can be found here. Patients can also check with their local gastroenterologist to get information about HRA providers in their area. More Information American Cancer Society: University of California, San Francisco, Department of Medicine:

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32 UCLA Newsroom HIV plus HPV leads to increased anal cancer risk in men Laura Perry December 02, 2013 Human papillomavirus, or HPV, which can cause cervical cancer in women, is also known to cause anal cancer in both women and men. Now, a study led by researchers at the UCLA School of Nursing has found that older HIV-positive men who have sex with men are at higher risk of becoming infected with the HPVs that most often cause anal cancer. The researchers also report that smoking increases the risk of infection with specific types of HPV among both HIVinfected and uninfected older men by up to 20 percent. This is the first large U.S. study of a group of HIV-infected and uninfected men between the ages of 40 and 69 who have sex with men. Study participants were examined twice a year for up to 25 years. "Invasive anal cancer is a health crisis for gay, bisexual and other men who have sex with men," said Dorothy J. Wiley, associate professor at the UCLA School of Nursing and lead author of the study, which was published Nov. 20 in the journal PLOS ONE. "Right now, invasive anal cancer rates among HIV-infected men who have sex with men surpass rates for seven of the top 10 cancers in men." The study, which involved more than 1,200 participants, was performed at four sites in the United States. Nearly 49 percent of the men were HIV-positive. During semi-annual visits, all the men were examined for demographic, sexual, behavioral and HIV-infection characteristics and were tested for HPV. The researchers found that HPV infections were common among all the men in the study and that the proportion of men affected by HPV remained consistently high across the age range. However, HIV-infected men between the ages of 40 and 69 showed a higher risk for HPV infection than HIV-uninfected men. The study also found that for HIV-positive men, taking antiretroviral therapies as prescribed appeared to lower their risk for the HPV infections that cause cancers. Avoiding tobacco use also lowered the risk of HPV infections among all the men. "This study highlights the benefit of adhering to HIV treatment, which among HIV-infected men who have sex with men, is important for cancer-prevention strategies," Wiley said. The next step in this research is to begin looking at ways to develop better, more effective HPV infection prevention strategies, including vaccination for age-eligible males and screening and treatment programs for high-risk men who have sex with men to prevent invasive cancers. "Right now, we perform colonoscopies to prevent colon cancer, where 53 men per 100,000 are diagnosed annually," Wiley said. "Unfortunately, we do not provide screening tests routinely for anal cancer for men who have sex with en, where the numbers are much higher 78 men per 100,000." The study was funded by the National Cancer Institute and the National Institute of Allergy and Infectious Diseases. In addition to Wiley, researchers included Dr. Roger Detels, Otoniel Martinez-Maza, Hilary Hsu, Katherine DeAzambuja, Kristofer Chua and Shehnaz K. Hussain from UCLA; Xiuhong Li, Gypsyamber D'Souza and Eric Seaberg from Johns Hopkins University; Dr. Ross D. Cranston of the University of Pittsburgh; and Stephen Young of the University of New Mexico. Laura Perry lperry@sonnet.ucla.edu

33 UCSF Department Of Medicine Anal Cancer Info Screening of 2 file:///c:/users/shubbard.thenpa/appdata/local/microsoft/windows... 7/31/2015 8:15 AM UCSF navigation bar Department of Medicine Education Patient Care Research Divisions Giving Administration Search NAL ANCER NFO Home Natural History of HPV Screening & Diagnosis Principles Screening Anatomy Examination Results Treatment Anal Cancer Current Research & Clinical Trials HRA Providers About Us Contact Us Screening Obtaining an Anorectal Cytology Specimen The reason to do an anal Pap smear is to look for evidence of HPV-related cellular changes. When someone becomes infected with HPV and the infection persists, the cells that are infected with HPV may not appear normal. HPV infected cells also may divide and multiply more than normal uninfected cells. There are also other changes that interfere with normal cellular processes at a molecular level in such a way as to allow the development of lesions or growths. In some cases warts or condyloma grow, in other cases flat lesions occur, with thickening of the tissues and sometimes increased blood vessels, which are usually hallmarks of the precancerous kind of lesions. And in some cases with HPV, there are no visible changes seen at all. By obtaining a sample of cells from the anus, we can get an idea of whether HPV has caused any changes and if so, how severe these changes might be. Most importantly, we can determine whether or not further examination is necessary. The anal Pap smear is a blind sampling of the anal canal and similar to a cervical Pap smear, is best looked at as a general indicator of whether the cells are normal or abnormal. If abnormal cells are present, then further examination is required to determine the exact nature of the abnormality. As mentioned earlier, HPV infection is the principal cause of AIN, CIN, and anal and cervical cancer. So, why not do tests to look for HPV? One of the reasons not to do HPV screening is that in groups of patients known to be at increased risk for anal cancer, such as HIV-positive men who have sex with men (MSM) with a history of receptive anal intercourse, the likelihood of finding HPV is nearly 100%; even 60% of HIV-negative MSM with a history of receptive anal intercourse have been shown to have HPV. The point is that HPV infection is so widespread that knowing someone has HPV doesn't help discriminate who needs to be treated. Going back to cervical cancer screening, HPV testing is only recommended for women with ASC-US Pap smears and if high-risk types of HPV are found then women are referred for colposcopy or examination of the cervix using a microscope. Screening Obtaining an Anorectal Cytology Specimen What are the possible results from anal cytology and what do they mean? Remember not all people infected with HPV will have problems and we want to focus our attention on the ones in whom HPV has led to potentially precancerous changes. The best way to do that is by sampling the cells of the anus with a Pap smear. An anal Pap smear is performed to screen for anal HSIL (the correct terminology is to obtain a sample for anorectal cytology) in the following manner. 1. Patients are asked not to douche or have an enema or insert anything into their anus for 24 hours prior to an anal cytology exam. 2. Lubricants should not be used prior to obtaining a cytology sample because the lubricant may interfere with the processing and interpretation of the sample. 3. We usually obtain the sample with the patient lying on their left side, but other positions are acceptable. 4. The buttocks are retracted to visualize the anal opening and a Dacron or polyester tipped swab moistened in tap water is inserted for approximately 2 to 3 inches into the anus. The swab can be felt to pass through the internal sphincter so the sample is obtained from the junction of the anus and rectum, which is where most of the HPV-related lesions are found. This area is slightly above the region that corresponds anatomically to the dentate line. 5. The swab is rotated 360 degrees with firm lateral pressure applied to the end of the swab, such that it is bowed slightly and then it is slowly withdrawn over a period of 15 to 30 seconds from the anus, continuing to rotate the swab in a circular fashion. The lateral pressure ensures that the mucosal surface, rather than rectal contents are sampled. 6. The swab is either smeared directly onto a glass slide and fixed as a conventional Pap smear by placing it into alcohol, or the swab is placed in a preservative vial and vigorously agitated to disperse the cells for liquid based cytology. 7. Regardless of method used, the sample must be fixed quickly within 15 seconds in order to avoid drying artifact, which occurs easily and makes interpretation difficult. 8. The slides are stained using the Papanicolau stain, hence the term Pap smear, and then are examined by the pathologist. What are the Possible Results from Anal Cytology and What Do They Mean? As shown in this illustration, with increasing severity of SIL, of either the cervix or anus, the proportion of the epithelium replaced by immature cells with large

34 UCSF Department Of Medicine Anal Cancer Info Screening of 2 file:///c:/users/shubbard.thenpa/appdata/local/microsoft/windows... 7/31/2015 8:15 AM nuclear-cytoplasmic ratios increases. Invasive cancer probably arises from one or more foci of high-grade squamous intraepithelial lesions (HSIL), which is depicted in the drawing by epithelial cells crossing the basement membrane. All epithelial cells sit on a basement membrane and below the basement membrane are connective tissue, blood vessels, nerves, and the muscles of the anus. Cancer arises when abnormal HSIL cells develop additional genetic changes, which then turns them into cancer cells that have the ability to invade across the basement membrane into normal tissues. Adapted and used with permission of Joel Palefsky, MD Examination of an anal cytology specimen will yield one of the following results: 1. Insufficient: not enough cells were obtained for the pathologist to evaluate to make an interpretation: a new sample should be obtained. Some of the reasons why the specimen may have been inadequate include having an enema or sex within 24 hours prior to collecting the specimen or the swab may not have been inserted deep enough or rotated with enough pressure to dislodge cells from the lining of the anus. 2. Negative for intraepithelial lesions: the sample had an adequate number of cells to be examined and they were normal in appearance with no evidence of HPV-related changes. It is still possible to have HSIL, because the swab may not have sampled an area of HSIL if it was very small or hidden deep in a fold and sometimes the lesions just don't shed cells. 3. ASC-US (atypical squamous cell-undetermined significance): also known as atypia, which means that the cells were somewhat abnormal in appearance but not so much so as to be formally classified as a SIL. Based on our natural history studies, we currently recommend that patients with ASC-US on anal cytology be examined with a digital rectal examination (DRE) and using high-resolution anoscopy (HRA). HRA will be described below and is a more effective way of visually inspecting the anus for the presence of any lesions. 4. ASC-H (atypical squamous cells-cannot exclude HSIL): this is another form of atypia in which the cells appear more abnormal and in some ways similar to HSIL, but the changes are not definitive enough to make a diagnosis of HSIL. Similar to the recommendations for ASC-US, patients with this type of atypia should be examined with DRE and HRA and are probably more likely to have either LSIL or HSIL found. 5. LSIL (low-grade squamous intraepithelial lesion): also known as mild dysplasia or AIN 1, these changes include anal warts, which are also known as condyloma. As mentioned above, since cytology is not the best way to determine the exact level of abnormality, patients with LSIL on cytology should be examined with DRE and HRA to look for evidence of HSIL or anal cancer. More than half of patients with LSIL on cytology will have HSIL found during HRA. 6. HSIL (high-grade squamous intraepithelial lesion): often subdivided into moderate or severe dysplasia, which are also known as AIN 2 or 3. Most patients with HSIL on anal cytology will have a lesion visible on HRA that when biopsied will also show HSIL. As with lower grades of abnormality, patients should undergo DRE and HRA to be sure that anal cancer is not present. Remember the swab is sampling only the cells on the surface, and as seen in the diagram, cancer develops when cells invade more deeply. This means that these cells may not be sampled with a Pap smear. Also since we believe that HSIL is a potentially precancerous lesion, then patients should be examined to determine how best to eliminate these areas as a means of preventing invasive anal cancer from developing. 7. HSIL with features suggestive of invasion: the pathologist detects very abnormal cells that appear like cancer cells. As mentioned, patients should be examined as above with a DRE and HRA with biopsies. A biopsy is when samples of the most abnormal areas are cut out, so the pathologist can see the relationship of the cells to one another and evaluate the tissue underneath to see whether there are cells invading across the basement membrane as shown in the diagram above, which is how cancer is diagnosed. 8. Squamous cell cancer (invasive anal cancer): this is the type of cancer that develops in the anus and is very different from colon or rectal cancer, although many people, including some health care providers, will incorrectly use the term rectal cancer for anal cancer. The anus is the opening to the rectum and is composed of skin type cells called squamous cells, which are susceptible to HPV, which in a very small percentage of all those infected develops into cancer. In contrast, cancers of the rectum and colon are called adenocarcinomas. They develop from the gland-like cells of the colon and rectum, which are different than the skin cells of the anus and do not become infected with HPV. Rectal or colon cancer is a type of cancer in which an increased tendency to develop it can be inherited from your parents; there is no inherited risk for anal cancer. Home Education Patient Care Research Divisions Giving Webmaster Copyright 2015 The Regents of the University of California

35 UCSF Department Of Medicine Anal Cancer Info Treatment of Non-... of 2 file:///c:/users/shubbard.thenpa/appdata/local/microsoft/windows... 7/31/2015 8:17 AM UCSF navigation bar Department of Medicine Education Patient Care Research Divisions Giving Administration Search NAL ANCER NFO Home Natural History of HPV Screening & Diagnosis Treatment LSIL & Warts HSIL Therapies Surgery Anal Cancer Current Research & Clinical Trials HRA Providers About Us Contact Us Treatment of Non-Cancerous HPV Treatment of anal HPV-associated disease depends on the diagnosis, location, and size or amount of disease. Most clinicians treat grossly evident genital warts, or those that can be seen with the naked eye. Treatment of cervical, vaginal, and vulvar high-grade squamous intraepithelial lesions (HSIL), the precancerous lesions, is routine in clinical practice. There are also common clinical practices for treatment and follow-up of non-warty cervical, vaginal, and vulvar low-grade squamous intraepithelial lesions (LSIL), the benign lesions. However, there are no current standards of care for non-warty anal low-grade (LG) or the precancerous high-grade anal intraepithelial lesions (HGAIN). There are arguments both in favor and against treatment of anal warts, LGAIN and HGAIN disease. Because LGAIN (including warts) is benign, and usually regresses on its own, it may be unnecessary to treat. However, many patients and clinicians prefer to remove warts rather than waiting for them to go away on their own. Treatment of HGAIN may be unnecessary because most HGAIN does not progress to cancer, and much of it also regresses without treatment, nor it been proven to be the definitive cancer precursor lesion. However, it is also argued that since some HSIL does progress to cancer, the prevention of cancer overrides these concerns. In our practice we accept the limitations of current knowledge, and hypothesize that treatment of the precancerous lesions (HSIL) will result in a decreased incidence of anal cancer. There is considerable overlap in the treatment of warts, LGAIN and HGAIN. However, there are principles for treatment that are specific to each, and the way each type presents or looks may be somewhat different. Therefore treatment guidelines will be presented first, followed by a description of the treatments that may be relevant to either warts, LGAIN or HGAIN. Treatment of anal warts, LGAIN or HGAIN can take a long time and may require many visits over several months. It will also require long-term follow up to be certain that the disease has not recurred and to evaluate for any new developments. It is common, especially in people who are immune-compromised, to have ongoing HPV and to develop HGAIN within a few years of developing LGAIN or warts. As such continued evaluation is recommended. It is important for patients to work with their providers in developing both a treatment and follow-up plan. One aspect of treatment which is in the hands of the person being treated is smoking. Tobacco has been implicated in the development of all HPV disease, although the evidence is sometimes confused by other risk factors. In practice, we strongly believe that people who smoke are harder to treat successfully, and that smoking cessation can contribute to faster treatment and less recurrence. In addition to the cancer producing elements of tobacco, it also suppresses the immune system which contributes to the development and persistence of HPV and its associated diseases. Treating your warts or HSIL may be the excuse you were looking for to quit smoking now! Every local community and hospital has many programs to help you quit. There are also many web-based programs. American Lung Association American Cancer Society Smokenders Efficacy of Treatment There has been very little published which evaluates the efficacy of treatments for anal or perianal HGAIN disease. A small prospective study of surgical intervention for HGAIN showed it to be effective in HIV negative men (n=8) but 23 of 29 HIV seropositive men had persistence or recurrence of HSIL 1. Laser therapy has been used intra-operatively for both perianal HSIL 2 and internally 3,4. Efficacy (measured by recurrence) ranged from 20-91% depending on the location, level of disease and type of treatment. None of these were randomized controlled studies. Several small non-randomized studies indicate that imiquimod has reduced anal, perianal or vulvar HSIL 5. Imiquimod has been used to decrease lesions in size and number so that surgical ablation is possible 6 and in preventing recurrence of condyloma post-surgery 7. But imiquimod currently is approved solely for treatment of external genital warts and using it internally or for treatment of HSIL is off-label. Another topical agent, Efudex TM (5% fluorouracil cream, also known as 5fU) has been reported as effective when used on the peri-anus 8 and intra-anally 9 for HGAIN. Efudex has been used intra-vaginally to treat both HSIL and LSIL. As a primary treatment (comparing daily Efudex for six weeks vs. biweekly for up to 10 weeks), 71% had complete or partial response 10. Intra-vaginal application of Efudex TM following surgical ablation has been shown to reduce recurrences in women treated for cervical HSIL (28% versus 47%) 11. Treatment efficacy is determined by successful regression of lesions and to a lesser extent, the length of time the patient remains free of disease post-treatment. However, the paucity of efficacy studies, and specifically randomized placebo designed studies, hinders our ability to manage anal LGAIN and HGAIN. Treatment Guidelines for Anal Warts, LGAIN and HGAIN It is important to understand that in treatment of any HPV-associated disease, the underlying cause itself is not treated. In other

36 UCSF Department Of Medicine Anal Cancer Info Treatment of Non-... of 2 file:///c:/users/shubbard.thenpa/appdata/local/microsoft/windows... 7/31/2015 8:17 AM words the HPV virus, which causes the problem, cannot be treated. Only the disease that the HPV causes, i.e., warts or lesions, either LGAIN or HGAIN, can be treated. Some treatments may affect the amount of HPV that the body sheds but we do not currently have any treatments that can rid the body of the HPV. However, in most cases we can effectively treat anything that the HPV causes. A careful examination will determine whether or not the warts or lesions are located inside the anus, outside (or perianal), or both. Although some lesions will be clinically apparent without any special equipment, many lesions will only be seen with the aid of magnification, lighting and the application of acetic acid (vinegar). This exam can be done with a colposcope, a microscope that was specially designed to provide magnification and lighting for cervical exams but has been shown to be just as valuable in examining the anus and surrounding areas. This exam is now called High-Resolution Anoscopy (HRA). The examination will determine what lesions need to be treated. Sometimes only HGAIN will be treated in order to minimize the amount of treatment needed. Areas of HGAIN can be located using HRA and diagnosis of any lesions so identified can be confirmed by biopsy. HPV only affects squamous epithelium, which includes the anus and perianal areas, as well as the cervix, vagina and vulva in women. or penis in men. HPV does not extend beyond the anus into the colon. The colon is a different tissue type, which is not infected by HPV. Therefore it is not necessary to have a colonoscopy in order to determine if warts are further inside the colon. Treatment of warts, LGAIN or HGAIN can be a long and frustrating process. This is especially true in the primary outbreak of warts. It takes the immune system time to "figure out" how to cope with this new virus. Once the immune system has learned to control the virus, there are generally few recurrences for most people. This means the HPV will be latent and will not cause any outbreaks unless the immune system stops suppressing it. This can happen if you become immune-compromised (for example, becoming HIV positive, or needing steroid therapy for asthma or auto-immune diseases such as Lupus, or following an organ transplant). There are times when it will not be possible or desirable to treat the lesions. Untreated, these lesions may regress on their own, may persist unchanged, or may increase in size and quantity. This cannot be predicted by any factors. Not everyone will respond to every type of treatment and it may take several types of treatment before there is finally a response. This can take many months. People who are immune-compromised from HIV or other reasons, may have frequent recurrences of warts and HSIL. In some cases, the lesions will never be completely eradicated. However, whatever is treated will be gone and that lesion cannot progress to cancer. So even treatment that is not 100% effective may still help prevent progression to cancer. Once it is determined whether the patient has LGAIN (which includes warts), HGAIN, or both, as well as the location and extent of the lesions, a treatment plan will be suggested which may include a single type of treatment or a combination of treatments. The goal of treatment will be to ablate (get rid of) all the lesions that can be seen. Once this is accomplished, the clinician will determine a follow-up plan to look for recurrences or just to be certain that the patient remains healthy and free of any further disease. Home Education Patient Care Research Divisions Giving Webmaster Copyright 2015 The Regents of the University of California