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HPV Infection ACHA May 2014 Why Talk About HPV Today? HPV is one of the “Now” diseases Recent new information HPV is the disease of the future We are seeing new HPV science every day In 10 years this will be a completely new and different lecture A Time of Transition To screening for anal cancer in certain populations To recognition of HPV role in Anal cancer Oropharyngeal cancer Esophageal cancer To expanded use and versions of vaccine for HPV infection Human Papillomaviruses dsDNA, circular (8 kb) non-enveloped Encode proteins that promote cell growth 100 types of HPV- divided generally by tissue tropism Cutaneous versus mucosal HPV causes the most commonly diagnosed STI’s High risk genotypes include 16 and 18 (cervical cancer), and many others Clinical Syndromes ◦ Warts ◦ Asymptomatic ◦ Soft, flesh-colored warts that develop weeksmonths after sexual contact ◦ Cytologic changes detected by Pap staining ◦ Dysplasia to cancer is 1-4 years if HPV 16, -18 or -31 Downloaded from: StudentConsult (on 20 February 2008 04:00 PM) © 2005 Elsevier Papillomavirus Epidemiology Non-enveloped** -- resists inactivation Transmitted by fomites Acquired by direct contact through small breaks in the skin or mucosa (sex, childbirth) Skin warts are common, mostly in children and young adults Worldwide, no seasonal incidence Papillomavirus pathogenesis HPV hides from immune responses Low levels of antigen for presentation Keratinocytes are immune privileged site HPV oncogenic potential HPV-16 and -18 cause cervical dysplasia 85% of cervical carcinomas contain integrated HPV DNA E6 and E7 genes are oncogenes -- when expressed, cells are more susceptible to mutations, chromosomal aberrations….cancer HPV-Cervical Involvement Estimated that prevalence of anogenital infection in US is 20 million Annual incidence of new cases is estimated to be 5.5 million Estimated that 75-80% of sexually active adults will have at least one HPV infection by age 50 Infections are most often transient – 58% clear infection within 18 months, persistence is a risk for development of cancer Human Papillomavirus—Prevalence of High-risk and Low-risk Types Among Females Aged 14–59 Years, National Health and Nutrition Examination Survey, 2003–2004 Prevalence, % 45 Low-risk HPV* 40 High-risk HPV 35 30 25 20 15 10 5 0 14–19 20–24 25–29 30–39 40–49 Age * HPV = human papillomavirus. NOTE: Error bars indicate 95% confidence intervals. Both high-risk and low-risk HPV types were detected in some females. SOURCE: Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, et al. Prevalence of HPV infection among females in the United States. JAMA. 2007;297(8):813-9. Copyright ©2007 American Medical Association. All rights reserved. 50–59 Lab Diagnosis Warts -- confirm by microscopy (hyperplasia and prickle cells) Pap smears PCR from cervical swabs to diagnose and type HPV No ELISAs or culturing Pap smear Normal Pap smear shows normal cervical cells Abnormal Pap smear Shows malformed cells, enlarged nuclei (due to transformation of cells) Where HPVs are Found: FIngernails4 Oral Cavity5 Anogenital area2,3 Fluid/secretions HPV can be spread via sexual contact and non-sexual routes such as vertical & horizontal transmission and autoinnoculation.1,2 Hands4 Cervix Vagina Vulva Anus Penis scrotum Coronal sulcus/Glans 1. Castellsague X et al. BMC ID 2009; 9:74. 2. Hernandez B et al. EID 2008;14(6):888-894. 3. Moscicki AB et al. AIDS 2003;17:311-20. 4. Sonnex C et al. STI 1999;75:317-319. 5. Sanchez-Vargas LO et al. Infect Agent Cancer 2010;5:25. HPV Involvement Elsewhere Skin: warts Anus: risk of cancer Similar to cervical pathway Head and neck: risk of cancers Prevalence of HPV across Anogenital Sites in a Cohort of 222 Heterosexual Men in the US1 100 90 80 70 60 50 40 30 20 10 0 71.2 63.1 24.8 21.3 16.6 5.4 9 Anal canal Any HPV 41.9 31.5 10.8 4.1 Perianal 46.9 36 13.1 5.9 Either or Both Anal Sites Glans, Shaft, or Scrotum Any Oncogenic Any Sitea Any Non-oncogenic • The prevalence of anal HPV infection was 25% • The prevalence of HPV infection at any of the 7 sites was 71% aPenile shaft, coronal sulcus/glans penis, urethra, scrotum, perianal region, anal canal & semen. 1. Nyitray A et al. JID 2008;197:1676-84. Acquisition of Any Anal HPV Infection in a Cohort of Women During a 12 Month Period1 Hawaii HPV Cohort Studya • 50% of sexually active females developed incident anal infections within 1 year. 9% 41% 50% (N= 431) aA • 9% had an anal HPV infection at baseline but no incident infections. Acquired new anal HPV Remained Anal HPV Baseline Anal HPV + longitudinal study of a cohort of sexually active women (N=431) recruited from 5 medical clinics in Hawaii who were able to read, understand, and sign an informed consent form and medical release form. Potentially eligible patients included those with appointments for new or annual gynecological examinations or for family-planning services who were not pregnant or postpartum within the past 6 months. At baseline and at 4-month intervals, interviews were conducted and cervical and optional anal cell specimens were obtained for detection of HPV DNA. 1 1.Shvetsov YB et al. Clin Infect Dis. 2009;48:536-46. Anal HPV in Women: Hawaii HPV Cohort Study1,2 Site of Infection Prevalence of HPV at Study Entry One Year Clearance Median Duration of HR HPV Anal1,a,b 42% 87% 5 months Cervical2,a, c 26% 70-80% ~8 months a These two groups are from the same cohort of sexually active women in Oahu, Hawaii. 431 women who consented for anal testing. 1 c N= 972 women from entire cohort for cervical testing. 2 b N= 1. Shvetsov YB et al. Clin Infect Diseases 2009;48:536–546. 2. Goodman MT et al. Cancer Res. 2008;68:8813–8824. Distribution of Certain HPV Types in AIN and Anal Cancer1a 80 70 60 50 AIN 1 AIN 2/3 Anal cancer 40 30 20 10 0 aMeta-analysis studies HPV 16 HPV 18 HPV 6 HPV 11 of 29 1.De Vuyst H et al. Int J Cancer 2009;124:1626-1636. Anal Intraepithelial Neoplasia (AIN): A Precursor to Anal Cancer HPV infection is associated with development of anal SIL.1 Anal cancer is analogous to cervical cancer. Both cancers arise in their respective transformation zones.1 Histology and molecular characteristics are similar to cervical cancer, for example, anal HSIL resembles cervical HSIL.1 AIN 2/3 is believed to be a precursor to invasive anal malignancy.1 1. Chang GJ et al. Clin Colon Rectal Surg. 2004;17:221–230. Anal Cancer A Disease Affecting Both Men and Women Women account for 60% of the cases of anal cancer.1 Risk of anal cancer is elevated among women with cervical and vulvar cancers.2 Oncogenic HPV infections may spread to the anal canal from the cervix and vulva.3 Although anal cancer occurs in both heterosexuals and men who have sex with men, MSM are at particularly high risk for anal HPVassociated disease.3,4 1.Cancer Facts and Figures 2010. American Cancer Society Web site. http://www.cancer.org. Accessed March 12, 2011. 2. Saleem AM et al. Obstetrics and Gynecology 2011;117:643-649. 3.Hoots BE et at. Int J Cancer 2009;124: 2375-2383. 4. Daling JR et al. Cancer 2004;101(2): 270-280. U.S. Anal Cancer Epidemiology: Increasing Incidence of Anal Cancer Incidence is increasing at ~2% per year.1 Anal cancer represents ~4% of all lower GI tract cancers in U.S.2 Age-adjusted rates from 1975 to 2007 doubled from 0.8 to 1.6 per 100,000.1 Rates are per 100,000 and are age-adjusted to the 2000 US STD population3 1. SEER Fast Stats http://seer.cancer.gov/faststats/Horner MJ et al. SEER Cancer Statistics Review 1975-2006. SEER Web site. http://seer.cancer.gov/sr/1975_2006/. Accessed December 1, 2010. 2. Clark MA Lancet Oncology ;Vol 5 2004 pp149-157. 3. Altekruse /SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/faststats/selections.php?series=cancer. U.S. Anal Cancer Epidemiology Estimated 5260 new cases of anal cancer in 4000 3260 3000 2000 the United States in 2010.1 ~3260 females (60%) ~2000 males (40%) Women Men 2000 1000 0 Estimated Cases in 2010 Lifetime Risk2: Based on rates from 2005-2007, 0.16% of men and women born today (1 in 610 men and women) will be diagnosed with cancer of the anus, anal canal, and anorectum at some time during their lifetime. 1.Cancer Facts and Figures 2010. American Cancer Society Web site http://www.cancer org/Research/CancerFactsFigures/cancer-facts-and-figures-2010. Accessed February 7,2011. 2. SEER Stat Fact Sheets: Anal Cancer. http://seer.cancer.gov/statfacts/html/anus.html. Accessed March 11, 2011. Risk Factors for Anal Cancer Strong Evidence1 Moderately strong evidence1 Cigarette smoking History of receptive anal intercourse Long-term use of corticosteroids HPV Infection (anogenital warts) HIV infection History of cervical, vulvar, or vaginal cancer More than 10 sexual partners History of STD Immunosuppression after solid-organ transplantation Populations in which risk factors are more prevalent have higher incidences of anal cancer.2 Anal intercourse is a risk factor but is not required for anal HPV infection or cancer development in men or women.3 1. Ryan DP NEJM 2000; 342(11):792-800. 2. Daling JR et al. Cancer 2004;101(2):270-280. 3. Goodman MT JID 2010;201:(9)1331-1339. Anal Cancer Symptoms and stage at presentation1,2 Signs and symptoms:1a Rectal bleeding (~45%) Pain or sensation of a rectal mass (~30%) Stage at presentation: While most anal cancers are detected at an early stage, many people are diagnosed when the disease is more advanced.2 There are currently no standard anal cancer screening recommendations for the general population.2 a Approximately 100 90 80 70 60 50 40 30 20 10 0 58 Stage at Presentation 22.2 6.7 In Situ twenty percent of individuals may have no rectal symptoms.1 1. Ryan DP et al. NEJM 2000;342:792-800. 2. Joseph DA Cancer 2008;113:2892-2900. Regional Distant Anal Cancer is a Similar Disease in Men and Women Anal Cancer in a Male Photographs Courtesy of M. Stoler, M.D. Anal Cancer in a Female Male and Female Genital Anatomy The close proximity of genital organs to one another supports the concept that HPV infection may affect the entire anogenital field, possibly resulting in multifocal/multicentric disease.1,2 Medical Illustration Copyright© 2011 Nucleus Medical Media, All rights reserved. www.nucleusinc.com. 1. Saleem AB et al. Obstet Gynecol 2011;117(3):643-649. 2. Moscicki AB et al. AIDS 2003;17:311-320. Penis Anal Intercourse is Not Required for the Development of Anal Cancer Percentages of men and women with anal cancer who reported no history of anal intercourse from selected studiesa. Study Females Males (sexual orientation n/a) Daling1b 66% 2004 [83/127] Daling2c 83% 74% 1987 [74/89] [43/58] aStudies N/A Heterosexual males NonHeterosexual Males 100% 12.5% [54/54] [6/48] N/A N/A included anal and rectal cancer cases. bBetween 1986 and 1998 in the Seattle area, men (n 119 patients) and women (n 187 patients) diagnosed with anal cancer were identified through the local Surveillance, Epidemiology, and End Results registry. Random-digit telephone dialing was used to ascertain control participants (n 1700) and identified participants were interviewed in person and provided blood samples. Archival tumor tissue was tested for human papillomavirus (HPV) DNA, and serum samples were tested for HPV type 16 (HPV-16).1 cPersons under 70 years of age were identified from records of population based cancer registries of 3 counties in whom anal cancer was diagnosed from Jan. 1978-Dec.1985. All histologic types of tumors were included. To elucidate risk factors for anal cancer, individuals were interviewed and blood specimens were obtained from 148 persons with anal cancer and from 166 controls with colon cancer. Interviewers were not blinded to the subjects' diagnoses or to hypotheses in general. 1. Daling JR et al. Cancer 2004;101:270-280. 2. Daling JR et al. NEJM 1987;317(16):973-977. Current Anal Screening Methods Ascertaining risk factors.1 Components of screening evaluations include:1 Pap tests using conventional methods or the liquid medium technique (Anal Paps) – HPV testing has an uncertain role in screening Digital Rectal Examinations High Resolution Anoscopy (HRA) Dysplasia screening presents an opportunity to screen for other anal STIs (sexually transmitted infections).1 1. Mathews Top HIV Meds 2003;11( 2):45-49. Treatment Options for Anal Disease AIN/Condyloma1 Intra-Anal Lesions1 Chemical therapy Cryotherapy Infrared Coagulation Laser therapy Electrocautery Anal Cancer2 Surgery Radiation Combined Radiation and Chemotherapy AIN=anal intraepithelial neoplasia 1.Palefsky JM et al. Obstet Gynecol Clin N Am. 2009;36:187–200. 2.Anal Cancer Treatment (PDQ®) - National Cancer Institute accessed February 8, 2011. Adverse Effects of Anal Cancer Treatment Late adverse effects of radiation therapy, such as anal ulcers, stenosis, and necrosis, may necessitate the need for a colostomy in 6 to 12% of patients.1 Patients treated with radiation or radiotherapy report acceptable overall long-term quality of life scores, but poor sexual function scores. A significant percentage report having difficulty with diarrhea, bowel control, and different aspects of sexual function.2 Radiation proctitis Radiation-related skin inflammation Photographs Courtesy of S. Goldstone, M.D 1.Ryan DP et al. NEJM 2000;342(11):792–800. 2.Das P et al. Cancer 2010;822-829. Post-radiation anal stenosis Oropharyngeal Cancer The majority of cases are linked to HPV Esophageal Cancer Data is variable, but the newer studies demonstrate HPV genome in about 50% of tumors Screening for Cervical Cancer A model of success for finding HPV related cancer of the cervix Broad acceptance Refined guidelines Proven effectiveness The likely path for other HPV cancers Like anal cancer Bethesda 2001 Workshop Cosponsors American Cancer Society* American College Health Association* American College of Obstetricians and Gynecologists* American Social Health Association* American Society of Cytopathology* American Society for Colposcopy and Cervical Pathology* American Society of Clinical Pathologists* American Society for Cytotechnology* Asociación Mexicana de Patologos Association of Reproductive Health Professionals Association of Women's Health, Obstetric and Neonatal Nurses Australian Society of Cytology British Society for Clinical Cytology Canadian Society of Cytology – Société Canadienne de Cytologie* Centers for Disease Control and Prevention Chinese Society of Cytopathology College of American Pathologists* Deutsche Gesellschaft für Zytologie Food and Drug Administration Gynecologic Oncology Group, ACOG* Health Care Financing Administration International Academy of Cytology International Society of Gynecological Pathologists Irish Association for Clinical Cytology* Japanese Society of Clinical Cytology Korean Society for Cytopathology Magyar Onkológusok Társasága-Cytodiagnosztikai Sectio National Committee for Clinical Laboratory Standards Nurse Practitioners in Women's Health Öesterreichische Gesellschaft fuer Zytologie* Papanicolaou Society of Cytopathology* Planned Parenthood Federation Romanian Society of Cytology Sociedad Argentina de Citologia Sociedad Chilena de Citologia Sociedad Española de Citologia* Sociedad Peruana de Citologia Sociedade Boliviana de Citologia Sociedade Brasileira de Citopatologia Società Italiana di Anatomia Patologica e Citopatologia Diagnostica Société Belge de Cytologie Clinique—Belgische Vereniging voor Klinische Cytologie* Société Française de Cytologie Clinique* Society of Gynecologic Oncologists* Suid Afrikaanse Vereniging vir Kliniese Sitologie—South African Society of Clinical Cytology* *Indicates that the society has endorsed the 2001 Bethesda System. SPECIMEN ADEQUACY Satisfactory for evaluation (note presence/absence of endocervical/ transformation zone component) Unsatisfactory for evaluation . . . (specify reason) Specimen rejected/not processed (specify reason) Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality because of (specify reason) GENERAL CATEGORIZATION Negative for intraepithelial lesion or malignancy Epithelial cell abnormality Other Epithelial Cell Abnormalities Squamous cell * Atypical squamous cells (ASC) - of undetermined significance (ASC-US) - cannot exclude HSIL (ASC-H) * Low-grade squamous intraepithelial lesion (LSIL) encompassing: human papillomavirus/mild dysplasia/cervical intraepithelial neoplasia (CIN) 1 * High-grade squamous intraepithelial lesion (HSIL) encompassing: moderate and severe dysplasia, carcinoma in situ; CIN 2 and CIN 3 * Squamous cell carcinoma ASCUS LGSIL HGSIL Glandular cell Atypical glandular cells (AGC) (specify endocervical, endometrial, or not otherwise specified) Atypical glandular cells, favor neoplastic (specify endocervical or not otherwise specified) Endocervical adenocarcinoma in situ (AIS) Adenocarcinoma Other (List not comprehensive) Endometrial cells in a woman ≥40 years of age Anal Pap A proposed screening system to obtain cells from the anal transitional zone for cytologic examination Standardization still not fully established Collection technique Expected quality performance measures Clinical utilization –target groups Preparation of patient Anal Anatomy Most of the anal canal is lined by squamous mucosa.1 The dentate line represents a border between more distal squamous mucosa and a transitional area of squamous and nonsquamous mucosa.1 Anal cancers arise from the transformation zone.2 Immature squamous metaplastic cells of the transformation zone are most susceptible to oncogenic HPV.2 Adapted from [Shia, J., An Update on Tumors of the Anal Canal. Arch Pathol Lab Med. 2010;134:1601–1611] with permission from Archives of Pathology & Laboratory Medicine. Copyright 2010. College of American Pathologists. 1. Ryan DP et al. NEJM. 2000;342(11):792-800. 2. Chang GJ et al. Clin Colon Rectal Surg. 2004;17:221–230. YouTube CAP Recognizes emerging role of anal cytology Requires use of 2001 Bethesda guidelines Recommends that ASCUS or higher receive high resolution anoscopy States role of HPV testing still not established but accepts that negative results can have high negative predictive value Anal Pap at McKinley Clinician collection Moisten Dacron swab with tap water Walk specimen through process Call reference lab to discuss No enema or douche in previous 24 hours No trauma/receptive anal sex in previous 24 hours Report will follow Bethesda terminology HPV reflex testing not automatic, make arrangements HRA High Resolution Anoscopy Very Similar to colposcopy Uses 3% acetic acid (not 5%) Suspicious areas biopsied Uses Bethesda classification Not generally covered by insurance for screening Colposcopy CDC There is no HPV test recommended for men Screening for anal cancer is not routinely recommended for men Some experts do perform the test (anal pap) for gay, bisexual and HIV positive men There is no test for “HPV status” in men There are no routine screening tests recommended for HPV related cancers in women other than for cervical cancer IDSA HIV infected men and women with human papillomavirus (HPV) infection are at increased risk for anal dysplasia and cancer. MSM, women with a history of receptive anal intercourse or abnormal cervical Pap test results, and all HIV-infected persons with genital warts should have anal Pap tests (weak recommendation, moderate quality evidence). Guidelines NY State DOH AIDS Institute For HIV positive patients Anal cytology for HIV positive men who have sex with men Also for HIV positive men or women with a history of anogenital condylomas Also for HIV positive women with abnormal cervical/vulvar histology Most Insurance Anthem (Blue Cross) and AETNA will not pay for anal pap or HRA Potential Expansion of Anal Pap Screening All HIV positive people All MSM with history of anogenital warts All MSM All women with history of anogenital warts All women with history of abnormal paps All sexually active people Horizon Oropharyngeal and esophageal cancers may follow the path of cervical cancer and anal cancer towards greater recognition The real question will be how to perform appropriate screening to these sites A recent patient request “I want an HPV test on my pharynx because I performed fellatio last week and now I am worried!” Her internet exploration: A dentist in Chicago promotes HPV testing in his office for all such patients Cost for initial visit: $1,000. Prevention-HPV vaccines Gardasil Quadrivalent recombinant protein vaccine L1 coat proteins from HPV 6, 11, 16, 18 Administered to females or males $360 for a 3-part vaccination Cervarix – bivalent (HPV 16 and 18 L1 coat proteins) HPV Vaccine Update CDC says HPV vaccine should now be routine for all boys age 11-12, and all boys age 13-21 should catch up US pediatricians recommend routine HPV vaccine age 11-12, and all boys age 13-21 should catch up In Conclusion New recommendations about HPV vaccine use New frontiers in anal cancer screening New understanding of oropharyngeal and esophageal cancers Role of HPV