Anal and Guidelines for Human Papillomavirus in Men

Richard A. Ortoski, DO Christine S. Kell, PhD

The association between human papillomavirus (HPV) and and the similarities between the “transitional zones” within the cervix and anus have raised questions regarding the medical biology of anal cancer. In recent years, increased rates of HPV and anal cancer among men have encouraged the medical community to search for causes and ways to identify the less insidious precursor, anal intraepithelial neoplasia. The “alphabet soup” terminology describing anal cytologic findings obtained by Papanicolaou (Pap) tests and the anal histologic find - ings obtained from specimens need to be better under - stood as distinct entities. Risk factors for the development of anal cancer have been identified and should be discussed with patients—especially those infected with human immunodefi - ciency —who have a much higher than normal risk of anal cancer. The anal has been used by the Northwest Penn - sylvania Rural AIDS Alliance to detect potential precursors to cancer and degrees of anal dyplasia in patients with HIV infection. The Alliance has been instrumental in creating guidelines for anal Pap testing and encouraging other medical professionals and clinics to do the same, and these guidelines are provided herein. J Am Osteopath Assoc . 2011;111(3 suppl 2):S35-S43

he incidence of anal human papil - demonstrated that anal HPV infection is behavior, external assistant devices, Tlomavirus (HPV) and anal cancer not uncommon in heterosexual men agents to enhance sexual performance, is growing among men, in whom HPV who have not had sex with men. 2 In and numbers of partners—and sexual has been shown to be a major cause, if men with the precursor to anal cancer, partners are affected by each other’s not a necessary cofactor, in the devel - anal intraepithelial neoplasia (AIN), the sexual history. For all of these reasons, opment of anal cancer. 1 Anal intercourse prevalence of HPV infection is high. men who do not identify themselves as is a major in acquiring HPV This viral infection is the most common homosexual or as men who have sex infection, but at least one study has a sexually transmitted disease in the with men (MSM) may nonetheless be at United States. 3 Persistence of HPV is risk and should be screened and tested associated with clinically identifiable for and cancer. 2 In MSM lesions and high-grade dysplasia leading and heterosexual men who are immuno - to anogenital , all of which are compromised, including those infected From the departments of family medicine (Dr associated with specific types of HPV. with human immunodeficiency virus Ortoski) and microbiology (Dr Kell) at the Lake In the author’s (R.A.O.) clinical expe - (HIV), the incidence of anal dysplasia Erie College of Osteopathic Medicine in Erie, Penn - 4 sylvania. rience, the patterns of human sexual and cancer is even higher. Patients in Financial Disclosures: The authors have no behavior have been changing—with HIV clinics are offered anal Papanico - conflicts of interest or financial disclosures rele - changes in participant anatomy, risk laou (Pap) tests to screen for cellular vant to the article topic. Address correspondence to Ricahrd A. Ortoski, DO, Professor of Family Medicine, Lake Erie College of Osteopathic Medicine, 1858 W Grandview Blvd, Erie, PA 16509-1025. This supplement is supported by an independent educational grant from Merck & Co, Inc. E-mail: [email protected]

Ortoski and Kell • Anal Cancer and Screening Guidelines for HPV in Men JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S35

Downloaded From: http://jaoa.org/ by a Lake Erie College of Osteopathic Medicine User on 04/10/2018 changes that may indicate a trend toward medical, and surgical histories are unre - Anatomy Review anal cancer, and perhaps other men at markable for this complaint of rectal Understanding the basic anatomy and risk of anal cancer should also be bleeding. histologic characteristics of the anus and screened. During the , perianal area is essential in compre - Many clinicians are unfamiliar with the patient’s genitalia are found to be hending the pathologic possibilities of the the procedure and the purpose of anal without mass, discharge, lesions, or evi - region. Figure 1 has been adapted from a Pap testing. Appropriate triage and dence of a hernia, and his perianal area is common sketch found in the literature to referral for care of anal cytologic abnor - pink, warm, dry, and intact. With his illustrate the areas of concern. 5 Just as in malities should ideally be clearly defined permission, the performs a dig - cervical Pap test screening, in the anal Pap before implementation of anal Pap test ital rectal examination and palpates a test, the presence of both rectal glandular screening. As more laboratories are nondescript thickened area at the 12- columnar mucosal cells and anal squa - becoming familiar with this test, proce - o’clock position posteriorly and 2 cm into mous mucosal cells (reported simply as dural policies are being written. Industry the anus. No blood is grossly visible on columnar cells and squamous cells) veri - standards have been in the develop - the glove, and the guaiac test result is fies the accuracy of the area needed by mental stages during the timeframe of negative. Other areas of examination are confirming the sampling at the most prox - this article, and early concerns noted by found to be noncontributory. imal area, which is the transition zone, the author (R.A.O.) have inhibited the What are the presumptive diagnoses for f ull interpretation in screening for processing of anal Pap specimens. For in this man? What are the next steps in (SCC). 3 (Other example, clerical laboratory errors have his diagnostic workup? In the following sources have stated, however, that cyto - occurred because of laboratory workers’ sections, we describe the anatomy of the logic specimens without the presence of unfamiliarity with the test. Cervical anogenital area; highlight characteristics columnar cells should not be rejected cancer screening with cervical cytology is and for HPV; and provide a solely on this basis. 6) routine, but there is no equivalent widely thorough look at the , risk accepted procedure guidelines for men factors, diagnosis, and screening of anal Human Papillomavirus with possible exposure to HPV that can cancer. Case follow-up is provided at the Virologic Characteristics lead to dysplasia, and there are no uni - end of the present article. Human papillomavirus has been found versal guidelines on screening. Available in most types of anal cancers. It is a research, however, identifies HPV as a double-stranded DNA virus that repli - cofactor in the development of anogen - ital cancer. The information presented here will show that screening and testing methods for anal dysplasia are available and need to be communicated. Rectum: Columnar Cell Case Presentation Glandular Mucosa Dentate Line R.S., a 40-year-old man, presented to his Pectinate Line family physician with the chief complaint ͕ Transition Zone of rectal bleeding found on toilet tissue during the past week. He had penile and Anus: Anus: perianal condylomas 15 years ago, but Approximately 4 cm there has been no recurrence that he is Squamous Cell Mucosa aware of. His answers concerning his Anus Verge present illness reveal no history of anal ͕ Anal Margin trauma or penetration, rectal pain or dis - charge, perianal itch, or change in bowel movement habits or appearance. The patient has felt no mass or sores on his genitalia or perianal area and reports no dysuria, frequent urination, or penile dis - Figure 1. The anal canal is approximately 4 cm long from the anal verge (margin) to the transi - tional zone. The dentate line (also called the pectinate line) is located at the proximal end of the charge. He reports using condoms anus. The flat squamous cells of the anal canal end here. The transitional (transition, transformation) during every vaginal and anal penetra - zone has been considered synonymous with the dentate line owing to their proximity, but the tion during his past 2 relationships with transitional zone is actually just proximal to the dentate line, is considered part of the anus, and women, which occurred within the past contains cube-shaped cells called transitional cells. It is the junction between rectal columnar epithe - 2 years. He also has a 23-pack-per-year lium and anal squamous , similar to the cervical transitional zone. Above the transi - history of tobacco. His family, tional zone is the rectum with its columnar epithelium. Adapted from Netter. 5

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Downloaded From: http://jaoa.org/ by a Lake Erie College of Osteopathic Medicine User on 04/10/2018 cates in the nucleus of squamous epithe - revealed protection against other HPV- malignant , developing from lial cells, thus its association with cervical, related health concerns, it is conceivable the skin or anal lining. 3 anogenital, and oral areas. Hundreds of that both the quadrivalent and bivalent Not all HPV types have been asso - papillomavirus types are capable of vaccines will be shown to prevent cancers ciated with dyplasia. According to the infecting humans. Most cases of anal of the head and neck, penis, and anus CDC, oncogenic HPV types are believed cancer are linked to infection by HPV-16, due to HPV-16 or HPV-18. 8 The vacci - to be the causative agent in up to 90% of which is closely associated with cervical nation of boys to prevent anogenital and anal cancers. 14 Persistent HPV infection cancer. 7 The infection is initiated by a oral cancers and their transfer to females with any of these 13 high-risk types (ie, breach in the skin, permitting the virus as has been discussed as oncogenic HPV strains 16, 18, 31, 33, 35, entry and access to binding sites. Once a possibility, but as of 2010, many inves - 39, 45, 51, 52, 56, 58, 59, and 66) is the the virus binds, it is endocytosed into the tigators have concluded that there is no cofactor leading to the dysplastic changes host cell. Replication of the virus is closely economic benefit to doing so. 8 of AIN seen before anal invasive carci - associated with the differentiation state noma is diagnosed. 2 As with cervical of the host squamous epithelial cell. 7 Anal Cancer cancer, HPV is the principal cause of anal Statistics cancer. 10 A minority of anal cancer cases Vaccines The death of actress Farrah Fawcett in have not been shown to have a connec - An HPV quadrivalent (HPV4) 2009 gave anal cancer a higher public tion with any HPV infection, and no dis - was approved by the Food and Drug profile, but it still has a very low inci - cernible differences have been noted Administration for vaccination of females dence. About 0.16% of men and women between these cancers and HPV-associ - between the ages of 9 and 26 years. 8 The born today will have cancer of the anus, ated cancers in terms of patient age, adja - antigens included in the vaccine generate anal canal, or anorectum sometime cent dysplasia, ductal differentiation, or protective antibodies to HPV types 6, 11, during their life. 10 Approximately 5260 prognosis. 15 16, and 18; HPV-6 and HPV-11 are related men and women would have these can - Anal HPV infection was present in to genital condylomas in males and cers diagnosed in 2010. 10 24.8% of immunocompetent heterosexual females, and HPV-16 and HPV-18 cause How do those numbers stack up men in a recent study. 2 These most cervical cancers. The Centers for against those for other forms of cancer? have been transient, with a low incidence Disease Control and Prevention (CDC) For the same time frame, the estimates for of persistent infection. Immunosup - recommend that all females be vaccinated other common cancers were as follows: pressed patients, such as transplant recip - against HPV, starting at age 11 or 12 207,090 diagnosed cases of breast cancer ients and patients with HIV infection, years. The CDC also report studies in women, 11 217,730 diagnosed cases of have opposite results, with higher rates showing that the vaccine, working against prostate cancer in men, 12 and 222,520 of persistent HPV infection, and these HPV-16 and HPV-18, can protect against diagnosed cases of lung and bronchus persistent infections lead to a higher inci - cancers of the vagina and . 8 The cancer in men and women. 13 The major - dence of HPV-associated . 16 HPV4 vaccine is also licensed to be safe ity of anal cancer cases occur in women, The prevalence of HPV infection is and effective for preventing genital with 2010 diagnosis estimates of 2000 in highest in MSM, HIV-infected men, and condylomas in males aged 9 to 26 years, men and 3260 in women. 10 transplant recipients, all of whom are in but it has not been placed on the recom - the at-risk population. Even HIV-infected mendation schedule as a standard vac - Risk Factors and At-Risk men without a history of anal intercourse cine for males because of clinical trial find - Populations have a higher risk of AIN than do the ings suggesting that the best way to Before addressing risk factors, one needs general population. prevent HPV diseases in both males and to understand what the term anal cancer Most of the research data on HPV females is to vaccinate females. 8 comprises. Tumors that arise from the and anal cancer in men have been col - A bivalent HPV vaccine is also transitional or squamous mucosa of the lected in HIV-positive men, especially approved for use in the United States 8 anus are termed squamous cell carci - MSM assumed to be anal receptive. In and contains viruslike particle antigens noma (SCC). These terms, anal cancer and HIV-negative MSM, the identifiable risk for HPV-16 and HPV-18. Both HPV vac - SCC , are used interchangeably in most factors for anal cancer include HPV infec - cines are designed to lower the risk of studies 3 and will be used interchange - tion, a greater number of HPV types pre - cervical cancer in women. Surveillance ably in the present review as well. Other sent, the number of receptive Epidemiology and End Results estimated cancers are also categorized as anal can - partners, and injection drug use. 17 No that 12,200 women would be diagnosed cers because of their location; these association has been seen between age with cervical cancer in 2010 and that 4210 include cloacogenic carcinomas (subset of and AIN prevalence in HIV-negative women would die of the disease. 9 Vac - SCC), developing in the transitional zone; MSM. 17 cination is expected to decrease those , arising mostly from In the general population, other risk numbers substantially. the rectum; basal cell carcinomas, derived factors for anal cancer include a history Although no definitive studies have from the skin in the perianal area; and of anal intercourse, a history of perianal

Ortoski and Kell • Anal Cancer and Screening Guidelines for HPV in Men JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S37

Downloaded From: http://jaoa.org/ by a Lake Erie College of Osteopathic Medicine User on 04/10/2018 condylomas, chronic immunosuppres - of sexual intercourse just before diag - to rule out the diagnosis of sion (seen in patients taking immuno - nosis. A possible association with lack anal cancer. The physician would then suppressive medications, those who are of circumcision has also been seen. 2 perform a physical (including perianal) HIV positive, or those who have received Other possible risk factors related examination. Before performing a digital organ transplants), age older than 50 to sexual behavior include self-initiated rectal examination requiring lubrication, years, multiple sexual partners or partner-initiated anal massage with the physician should decide whether an (increasing the risk of HPV infection), an object, anal massage or insertion with anal Pap test is required, because the and smoking (increasing the risk of non - a finger, nonpenetrating sex (finger- lubricant may make it difficult to interpret clearing HPV infection). 3,18 In one study, vulvar, penile-vulvar, and oral-penile the Pap test results, as in cervical Pap cigarette smoking and lifetime number of contact associated with female genital screening. If digital rectal examination sexual partners were associated with an HPV infection), and oral-anal sex. 2 Non - reveals a macroscopic lesion or the anal increased prevalence of anal cancer. 19 sexual behavioral risk factors include Pap test reveals any abnormalities, high- Receptive anal intercourse is the hand carriage, as in hygiene care, from resolution anoscopy (HRA) is recom - most prominent risk factor for anal HPV the genitals to the anus 21 and transfer - mended. High-resolution anoscopy is infection, but infection can also be ence from objects of any kind used to similar to for cervical abnor - acquired from contact with other infected manage genital HPV infection. 22 malities; it involves using a microscope to genital areas, particularly the vulva in examine the anus for abnormalities, such women and the penis in men. Contact Clinical Manifestation as ulcerated areas, thickened areas, and of fingers and sex toys with infected With advanced anal cancer, patients may lesions containing abnormal vessels. fluids may also be associated with anal experience multiple symptoms. With These areas are then assessed, and biopsy HPV infection. 18 developing anal cancer, the number, type, specimens are obtained during the exam - When interviewing a patient, the and intensity of symptoms may vary. ination. This procedure is discussed later physician should always ask about the Patients with rectal bleeding commonly in the present article. patient’s sexual history, especially when assume the problem is due to hemor - the examination involves the anogenital rhoids. Those with rectal cancer may pre - Precursors of Anal Cancer area. When the examination involves the sent with rectal bleeding as the most In the general population, the good news anal area, the physician should ask ques - common initial symptom; it occurs in is that only a fraction of people with anal tions to discern whether objects, fingers, 45% of cases. 3 Thirty percent of patients HPV infection will experience a lasting or other body parts have been inserted with anal cancer present with a mass sen - case of AIN, and even fewer will go on to into the anus. This type of questioning is sation or with pain in the anal area, and have anal cancer. 18 Figure 2 illustrates the appropriate because it provides infor - 20% have no symptoms at all. 23-25 The progression of persistent HPV infection mation relevant to the patient’s health. pain or sensation of fullness may be con - in the cells of the cervix, which are com - The history should also identify MSM stant, and it may manifest with bowel parable to that in anal cells. 27 Figure 3 who may practice anal receptive inter - movement or with mechanical manipu - displays the cytologic and histologic course; such patients must be educated lation involving a partner or device “alphabet soup” that makes up the ter - about potential risk factors for acquiring during sexual activity. The sensation of minology within Pap (cytologic) and HPV infection amongst other infections. fullness may provoke the frequent urge to biopsy (histologic) reports. 7 In heterosexual patients, the causes empty the bowels. Other symptoms may High-grade squamous intraepithe - of anal HPV infection may not be as include perianal itching, anal discharge, lial lesions (HSILs) are the precursor of obvious. In all men, the incidence of HPV changes in bowel habits, or changes in invasive cancer in the cervix, and although infection has increased nearly 3-fold in the shape of stool. 18,26 the connection has not been proven, the past 30 years. 2 The prevalence of anal When listening to the patient’s med - mounting evidence indicates that anal HPV infection in heterosexual men ical history, the physician must note past HSILs are the comparable precursor for without a history of anal or oral sex with or present anorectal condylomas. The anal cancer, 1 and they are generally rec - a man has been shown to be 24.8%; 33.3% presence of HPV-causing condylomas ognized as such. The progression of HSILs of these infections are with oncogenic may suggest co-infection with oncogenic to invasive anal SCC is caused by many HPV types. Therefore, anal HPV infec - HPV types and require testing for cyto - interrelated factors: HIV seropositivity, tion in heterosexual men, even those logic changes. Patients with SCC in one low CD4+ T-cell count, HPV subtype without any visible or palpable signs of study had a history of anogenital condy - (oncogenic HPV-13), and higher levels of anal condylomas or masses—which are lomas, with rates of 50% in homosexual oncogenic subtypes in the anal canal. 28 usually caused by nononcogenic, high- men and less than 30% in women and Anal cancer is an increasing health risk, HPV types 20 —could be considered heterosexual men, significantly higher concern in the entire male population, common. Risk factors for heterosexual than rates found in the general population but especially in MSM, both HIV positive men include a large lifetime number of (ie, 1%-2%). 23-25 Any of the above symp - and HIV negative. 1 Men who have sex female sex partners and a high frequency toms or risk factors should encourage with men have a high risk of HSILs and

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Downloaded From: http://jaoa.org/ by a Lake Erie College of Osteopathic Medicine User on 04/10/2018 invasive anal cancer, 1 independent of 28,29 HIV status. Most MSM who have a Cytology LSIL HSIL history of receptive anal sex carry anal CIN 1 CIN 2 CIN 3 HPV, with rates of more than 60% in HIV-negative MSM and nearly 100% in Very Mild/ Moderate Severe In Situ Invasive HIV-positive MSM, leading to dysplastic Normal Mild Dysplasia Dysplasia Dysplasia Carcinoma Carcinoma changes. 1 Compared with HIV-negative MSM, HIV-positive MSM have a greater risk of anal squamous intraepithelial lesions. Lower CD4+ T-cell counts increase the risk of such lesions more than counts that are higher than 500 cells/mm 3 (within the possible low normal range in labora - tory reporting), but all HIV-positive MSM have a higher risk than HIV-negative HPV Infection, No Virus Virus Production Production MSM. 30 One study found a 60-fold High E6 and E7 increased risk of AIN in HIV-positive Viral DNA Integration MSM. 16 In another study with 357 HIV- Microinvasive Carcinoma positive MSM in San Francisco, 81% of subjects had AIN (grades 1-3), 52% had high-grade AIN (grade 2 or 3), and 98% Figure 2. Progression of persistent human papillovmavirus (HPV) infection in the cells of the cervix. From left to right, there is a progression from initially normal cells. The nucleus-to-cytoplasm were HPV positive. 16 ratio increases as cells progress through the stages of dysplasia and into cancer. Abbreviations: CIN, Also, HIV-positive men are at cervical intraepithelial neoplasia; HSIL, high-grade squamous intraepithelial lesion; LSIL, low- greater risk of developing HSIL than are grade squamous intraepithelial lesion. Reprinted with permission from Lowy and Schiller. 27 HIV-negative men, and the men’s cases have been shown to advance from low- grade squamous intraepithelial lesions (LSILs) to HSILs. 20 Continuous immuno - The standard of care for cervical cancer been projected to be cost-effective. 34 suppression by HIV is associated with a screening is the Pap test. Anal cytology Even though the cervical Pap test is progression from LSILs to HSILs or inva - (ie, the anal Pap test) has been recom - within the standard of care, its findings sive SCC. 31,32 This finding is also seen in mended by several research groups for may be nonspecific; in particular, atypical recipients of solid organ transplants who screening at-risk populations for anal squamous cells of undetermined signif - have been subjected to long-term cancer; this test is adapted from the prin - icance (ASCUS), with a US incidence . 33 Human papillo - ciples of cervical screening. 16 In specific ranging from 1% to 10.4%, have a low mavirus infections and HPV-associated populations, anal cytology has been pro - specificity, so colposcopy often reveals malignancies are seen at higher rates in jected as a cost-effective way to prevent normal nondysplastic findings. 1 These HIV-infected patients, regardless of the occurrence of anal cancer and cells have a higher incidence in the anal sexual practices. 31 There is increasing evi - manage its precursors. Specificity and canal—14% to 78% in HIV-positive and dence of the progression from HSILs to sensitivity findings comparing anal cyto - 12% in HIV-negative MSM. 1 The speci - anal cancer, but the time frame has not logic Pap test results and histologic ficity of anal ASCUS relative to patho - been verified. Anal Pap tests or cytologic biopsy results were similar to those com - logic abnormalities has been found to be examinations are the primary screening paring cervical cytologic and biopsy lower than that for cervical ASCUS. tests for identifying anal tissue dysplasia results. In one study, the positive pre - Therefore, some men with ASCUS will in persons at risk. Once abnormal cyto - dictive value of anal cytologic Pap test proceed to HRA with possible biopsy logic findings have been identified, the abnormalities for anal dysplasia was without having HSILs or AIN. The sen - use of HRA is recommended to identify 95.7%. 16 Anal cytologic abnormalities sitivity of ASCUS can be increased by dysplastic lesions as a tissue histologic seen with Pap tests appear to be highly considering the patient’s oncogenic HPV diagnosis. 16 predictive of anal dysplasia seen at his - status. 1 Two other studies showed that tologic biopsy. 16 Populations in whom more than 33% of patients with anal Pap Screening for Precursors anal Pap screening is recommended results reporting ASCUS or LSILs have The pathophysiologic characteristics of include HIV-infected patients with a his - high-grade findings at biopsy reports, anal cancer are similar to those of other tory of anal condylomata or dysplasia which support the need to perform HRA intraepithelial found on the or with CD4+ T-cell counts of less than with biopsy even in patients with LSILs, cervix, penis, oral tissue, and vulva. 16 200 cells/mm 3; this screening has also regardless of HIV status, when they are

Ortoski and Kell • Anal Cancer and Screening Guidelines for HPV in Men JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S39

Downloaded From: http://jaoa.org/ by a Lake Erie College of Osteopathic Medicine User on 04/10/2018 Anal Cytology (Anal Pap Test) Anal Histology (Anal Biopsy)

Term Definition Term Definition ■ ASCUS* Atypical Squamous Cells Undetermined Significance ■ ASCH* Atypical Squamous Cells suspicious for HSIL ■ ASIL Atypical Squamous Intraepithelial Lesion ■ AIN Anal Intraepithelial Neoplasia □ LSIL Low-grade Squamous Intraepithelial Lesion □ AIN 1 mild dysplasia □ HSIL High-grade Squamous Intraepithelial Lesion □ AIN 2 moderate dysplasia □ AIN 3 severe dysplasia/carcinoma in situ ■ SCC Squamous Cell Carcinoma ■ Invasive Anal Carcinoma

Figure 3. Distinguishing the cytologic terminology (ASCUS, ASCH, ASIL, of a tumor as identified histologically; dysplasia is abnormal tissue devel - LSIL, HSIL), as used in the cytology reports from anal Papanicolaou tests, opment. LSIL corresponds to AIN 1 and condylomata on biopsy; HSIL cor - from the histologic terminology (AIN), as used in biopsy reports, makes responds to AIN 2 or AIN 3 or carcinoma in situ counterpart on biopsy. understanding the “alphabet soup” much easier. Many studies and lit - *ASCUS and ASCH do not have all the characteristics of HSIL but are not erature items combine the 2 types of nomenclature in reporting. 25,27 Neo - classified as benign. plasia is the pathologic process that results in the formation and growth

higher risk for anal cancer. 34,35 anal cells because more research is also be screened. Anal Pap test screening Given all of the available data and thought to be needed to show that iden - has been proposed to be cost-effective in given that the anal Pap test is an uncom - tifying and removing abnormal cells pre - preventing anal cancer in HIV-positive plicated and quick procedure, the rates vent future development of anal cancer. and HIV-negative MSM when per - seen for anal cancer screening in the clin - The CDC have not recommended rou - formed every 1 to 2 years. 25 ical setting are low, as noted by Kreuter tine anal Pap test screening for anyone or Regarding HPV screening with the and Wieland 16 and the clinical experi - any sub-group. However, they do state anal Pap test, Figure 4 summarizes the ence of the author (R.A.O.), especially that “anal cytology screening of HIV- Cleveland Clinic recommendations for among MSM. Primary care physicians infected men who have sex with men … the timing of HPV testing and how should consider the potential benefits of might become useful preventive mea - results should be followed up (personal anal cancer screening in that select pop - sures. However, studies of screening and communication, Alan J. Taege, MD, ulation of patients and find ways to dis - treatment programs for anal HSILs need February 2011). cuss these benefits with patients, as they to be implemented before recommenda - discuss other screening advice. 16 Primary tions for anal cytology screening can be Guidelines for Anal Pap Test care physicians also need an appropriate made.” 36 The New York State Depart - Screening referral system for patients with ment of Public Health AIDS Institute has In 2008, the Northwest Pennsylvania abnormal cytologic findings and should published guidelines stating that Rural AIDS Alliance 37 attempted to create consider training in HRA. “screening for cellular dysplasia is pru - a program to screen men for HPV and The screening process for anal dent and recommended, particularly in anal cytologic changes. The challenges pathologic abnormalities begins with a persons at high risk for infection with included the following: laboratory con - thorough physical examination and an .” 6 cerns related to specimen acquisition, appropriate history. In our opinion, Chin-Hong and Palefsky 4 have pro - equipment, codes, and internal labora - patients who have negative examination posed an anal cancer screening program tory policy; state licensure problems findings but whose history places them based on the principles of cervical cancer involving who was licensed to read anal in an at-risk population should undergo screening used today. The program rec - Pap tests; and the lack of established poli - anal cancer screening with Pap testing. ommends that anal cancer screening be cies from other clinics to use for guid - Those with any abnormal Pap test find - performed in high-risk-populations: HIV- ance. Laboratories and pathologists are ings are then offered histologic confir - positive men and women, MSM, women now more knowledgeable about the tech - mation with HRA. This is a common with a history of vulvar or cervical cancer, nique and the rationale for anal Pap tests, strategy incorporated by many anal and organ transplant recipients. 4 Men - clerical staff have been educated about cancer screening programs. 25 tioned by Palefsky in a slide presenta - the test so that specimens are not dis - To our knowledge, there have been tion, which was given by personal com - carded for having the “wrong” source no universal, formal recommendations to munication with the author (R.A.O.), (ie, anus) on the laboratory requisition, use anal Pap tests to screen for abnormal those with perianal condylomas should and laboratory policies have been written

S40 • JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 Ortoski and Kell • Anal Cancer and Screening Guidelines for HPV in Men

Downloaded From: http://jaoa.org/ by a Lake Erie College of Osteopathic Medicine User on 04/10/2018 and updated to reflect the growing need Anal Cytology for anal Pap screening. (Anal Papanicolaou Test) HPV Test* Recommendation The Northwest Pennsylvania Rural New New Await results AIDS Alliance 37 of Clarion University of Negative Negative Annual screen Pennsylvania has enacted a policy regarding anal Pap test screening. Appro - Negative Positive 6 months rescreen priate screening for anal cancer should ASCUS Negative 6 months rescreen always include the baseline visual inspec - ASCUS Positive Refer for HR anoscopy tion of external genitalia, palpation, and LSIL or HSIL Negative or Positive Refer for HR digital rectal examination to identify such anoscopy abnormalities as , lesions that bleed, lesions of uncertain origin, lesions with hypo- or hyperpigmented plaques, and Figure 4. Cleveland Clinic recommendations for human papillomavirus (HPV) screening and follow- up. *Positive identifies at least 1 of 13 oncologic, high-risk types. Abbreviations: ASCUS, abnormal palpable internal lesions. Because atypical squamous cells of undetermined significance; HR, high-resolution; HSIL, high-grade squa - bleeding is the most common presenting mous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion. Adapted from Cleve - symptom of anal cancer, it is important land Clinic recommendations (personal communication, Alan J. Taege, MD, February 2011). to determine its cause. The digital rectal examination with lubrication must be performed after the anal Pap test with the HPV test because the lubrication 5. Dispose of the swab; cap and label the tion for HIV-positive women is not as interferes with the Pap test’s ability to specimen jar. clear and is without expert agreement, identify cells. they should probably undergo similar Obtaining specimens for HPV testing — screening. Obtaining specimen for anal cytology — To obtain an adequate anal specimen for 3. If the Pap test shows abnormal find - The anal Pap test involves collection and HPV testing, perform the following steps: ings—either ASCUS, LSIL, or HSIL— examination of cells with techniques sim - the patient should be further evalu - ilar to those used for cervical Pap tests. 1. Moisten a Dacron swab with water or ated with HRA and biopsy according Obtaining an adequate anal cytology use a brush from an HPV kit. to the algorithm shown in Figure 5 .38 specimen involves the following steps: 2. Insert the swab 1.5 to 2 inches into the 4. If AIN I (LSIL) is found at biopsy, rou - anal canal. tine follow-up should be performed 1. Moisten a Dacron swab with water. It 3. Rotate the swab firmly with lateral every 6 to 12 months. is important to use a Dacron swab, not pressure while slowly inserting and 5. For patients with AIN II or III (HSIL), a cotton swab, because cotton clings withdrawing in a tight spiral motion therapy is recommended. Observation to the specimen cells, making exami - for 15 to 20 seconds. with repeated evaluation is a option nation difficult. 38 4. Place the swab in liquid-based medium for patients with AIN I (LSIL). 2. Insert the swab 1.5 to 2 inches into the (eg, Digene specimen transport 6. Patients with a low CD4+ T-cell count anal canal 39 and proceed through the medium [Digene Corp, Gaithersburg, (<500 cells/mm 3) should be moni - dentate line and transitional zone Maryland] transport medium), leave it tored more frequently than noted between the squamous and columnar in the container, cap the container, and above. There is no recommendation epithelia. This transitional zone is sub - shake it vigorously for 10 seconds. for frequency, I (R.A.O.) suggest a fre - ject to infection with HPV or neoplastic quency of every 6 to 9 months. transformation by HPV. Precancerous Testing frequency and follow-up — lesions of the anal squamous epithe - Although there are no formal guidelines Completing laboratory requisitions — lium can develop and are classified as for the use of anal Pap test screening in The following are recommendations for low or high grade, according to the HIV-positive individuals, experts on anal the local laboratories that support the Bethesda criteria nomenclature. 39 Pap testing 40 recommend the following: Northwest Pennsylvania Rural AIDS 3. Rotate the swab firmly with lateral Alliance. They may be adapted to indi - pressure while slowly inserting and 1. When an HIV diagnosis is made, an vidual laboratory situations: withdrawing in a tight spiral motion anal Pap test should be offered as part for 15 to 20 seconds. of the initial evaluation for men and 1. Provide complete identifying patient 4. Place the swab in liquid-based medium women. information. (eg, ThinPrep CytoLyt solution 2. If the initial anal Pap test results are 2. Select ICD-9 diagnosis codes of 042 [Hologic Inc, Marlborough, Mas - reported as normal for HIV-positive (AIDS) or V08 (HIV infection) and sachusetts]) and swish the swab vig - MSM, the test should be repeated V69.2 (high-risk sexual behavior). orously for 15 to 20 seconds. annually. Although the recommenda - 3. Under “Tissue Pathology and Non-

Ortoski and Kell • Anal Cancer and Screening Guidelines for HPV in Men JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S41

Downloaded From: http://jaoa.org/ by a Lake Erie College of Osteopathic Medicine User on 04/10/2018 may reveal punctuation and mosaicism, which are signs of HPV infection. Vas - Screen cular changes, such as neovasculariza - tion, increased vascularization, vessel interruption, and vessel caliber variation, are suggestive of malignant tissue. 4,16,20 Normal ASCUS, LSIL, or HSIL The presence of any of these changes would necessitate biopsy for definitive histologic diagnosis. Repeat in 12 Anoscopy with biopsy We stated previously that all months when HIV abnormal findings at anal cytologic infected screening deserve further investigation with HRA. The converse—that normal cytologic findings do not warrant HRA— No lesion seen AIN 1 AIN 2, AIN 3 is not necessarily true. One study demon - strated that even with normal Pap find - ings, the probability of neoplasia is not Follow Treat low enough to rule out the need for HRA. 12 Therefore, for optimal care, HRA should also be recommended for patients Figure 5. Flow chart of a practical algorithm to follow in response to abnormal results of an anal at high risk for HPV or anal dysplasia, Pap test. 34 Abbreviations: AIN, anal intraepithelial neoplasia; ASCUS, abnormal atypical squamous including those with visible or palpable cells of undetermined significance; HIV, human immunodeficiency virus; HSIL, high-grade squa - lesions or prior HSILs. mous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion. Case Follow-Up R.S., the patient whose case was pre - GYN Cytology Test Offerings,” select Figure 5 illustrates a practical algo - sented at the beginning of this article, was the appropriate code for anal-rectal rithm for guiding follow-up when offered an anal Pap test, to which he cytology. abnormal results are received from an agreed. Because of the lubricant used for 4. In the test box identified as “Addi - anal Pap test. the digital rectal examination, the test was tional Tests,” write “high-risk HPV performed a few days after his initial visit and low-risk HPV.” Guidelines for HRA for rectal bleeding. Given the patient’s 5. Submit specimen to laboratory with When anal cytologic findings are history of perianal condyloma, an anal requisition form. abnormal, HRA should be performed to HPV test was also performed. The results, detect anal dysplasia. As with col - received 1 to 2 weeks later, were positive Grading and results of anal pap tests — poscopy, specialized training and equip - for the HPV high-risk group, and the The Bethesda 2001 system 39 categorizes ment are necessary. After a clear plastic cytologic results revealed LSIL. The cervical disease in increasing order of anoscope is placed approximately 2 patient was set up with a physician spe - severity. Because anal cytologic findings inches into the anus, allowing visualiza - cializing in HRA. Biopsy was performed, demonstrate similar histologic changes, tion of the dentate line and transitional and the histologic examination revealed they are graded the same way: zone, a 3% acetic acid solution is applied AIN III. The patient was scheduled for a to the surface of the perianal area, anal return visit to discuss options for man - 1. Negative: negative for intraepithelial canal, transformation zone, and distal aging this precursor to anal SCC. lesion or portion of the rectum. Using a standard 2. AIN: anal intraepithelial neoplasia, as gynecologic colposcope with a light Conclusion seen in histology source and binocular lenses having 20- to Physicians should become more familiar 3. ASCUS: atypical squamous cells of 30-fold magnification, the examiner looks with anal Pap tests and when, how, and undetermined significance for a white coating or plaque that reflects why to perform them. Changing pat - 4. ASC-H: atypical squamous cells sus - areas of dysplasia from HIV-infected terns of generally picious for HSIL cells. Lugol iodine solution is then may make HPV infection more common 5. LSIL: low-grade squamous intra- applied to identify intraanal lesions of in all men, leading to more challenging epithelial lesion dysplasia. The normal mucosal tissue pathologic conditions associated with 6. HSIL: high-grade squamous intra - stains dark brown; the dysplastic cells, the same pathogens. The known pre - epithelial lesion which do not absorb the solution, remain cursors to anal cancer need to be recog - 7. SCC: squamous cell carcinoma unstained and yellow. The abnormal cells nized, and screening should be per -

S42 • JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 Ortoski and Kell • Anal Cancer and Screening Guidelines for HPV in Men

Downloaded From: http://jaoa.org/ by a Lake Erie College of Osteopathic Medicine User on 04/10/2018 formed in those at risk for this pre - 10. SEER stat fact sheets: anal cancer. Surveillance, tent/CRI_2_2_3X_How_is_anal_cancer_found_47.asp Epidemiology, and End Results Web site. http://seer ?sitearea=. Accessed January 31, 2011. ventable disease. The knowledge pro - .cancer.gov/statfacts/html/anus.html. Accessed Jan - vided by anal Pap screening must be 27. Lowy D, Schiller J. Prophylactic human papillo - uary 31, 2011. mavirus vaccines. J Clin Invest . 2006;116(5):1167- used to reduce the occurrence of other 11. SEER stat fact sheets: breast. Surveillance, Epi - 1173. virus-associated malignancies. Investi - demiology, and End Results Web site. http://seer 28. Palefsky JM, Holly EA, Ralston ML, Jay N. Preva - .cancer.gov/statfacts/html/breast.html. Accessed lence and risk factors for human papillomavirus gation into the logistics and advantages January 31, 2011. of immunizing more people for HPV infection of the anal canal in human immuno- 12. SEER stat fact sheets: prostate. Surveillance, Epi - deficiency virus (HIV)-positive carcinomas. J Infect may also help prevent these malignan - demiology, and End Results Web site. http://seer Dis . 1998;177(2):361-367. .cancer.gov/statfacts/html/prost.html. Accessed Jan - cies. More longitudinal studies are 29. Peters RK, Mack TM. Patterns of anal carci - uary 31, 2011. needed to solidify and support what we noma by gender and marital status in Los Angeles 13. SEER stat fact sheets: lung and bronchus. Surveil - County. Br J Cancer . 1983;48(5):629-636. know today. lance, Epidemiology, and End Results Web site. 30. Palefsky JM, Holly EA, Ralston ML, Jay N, Berry http://seer.cancer.gov/statfacts/html/lungb.html. JM, Darragh TM. High incidence of anal high-grade Accessed January 31, 2011. Acknowledgment squamous intra-epithelial lesions among HIV-pos - We thank our contributor, Leah Magagnotti, 14. HPV and men fact sheet. Centers for Disease itive and HIV-negative homosexual and bisexual Control and Prevention Web site. http://www.cdc men. AIDS . 1998;12(5):495-503. RN, Clinic Nurse Manager of the Northwest .gov/std/HPV/STDFact-HPV-and-men.htm. Accessed 31. Critchlow CW, Surawicz CM, Holmes KK, et al. Pennsylvania Rural AIDS Alliance of Clarion January 31, 2011. Prospective study of high grade anal squamous University of Pennsylvania. One of her many 15. Williams GR, Lu QL, Love SB, Talbot IC, intraepithelial neoplasia in a cohort of homosexual roles and responsibilities is the creation and Northover JM. Properties of HPV-positive and HPV- men: influence of HIV infection, immunosuppres - maintenance of policies, including the policy negative anal carcinomas. J Pathol . 1996;180(4):378- sion and human papillomavirus infection. AIDS . 382. 1995;9(11):1255-1262. on anal Pap tests discussed in the present 16. Kreuter A, Wieland U. Human papillomavirus- 32. Melbye M, Sprogel P. Aetiological parallel article. associated diseases in HIV-infected men who have between anal cancer and cervical cancer. Lancet . sex with men [review]. Curr Opin Infect Dis . 1991;338(8768):657-659. 2009;22(2):109-114. References 33. Penn I. Incidence and treatment of neoplasia 1. Goldstone MD, Enyinna CS, Davis TW. Detec - 17. Chin-Hong PV, Vittinghoff E, Cranston RD, after transplantation. J Heart Lung Transplant . tion of oncogenic human papillomavirus and other Buchbinder S, Cohen D, Colfax G, et al. Age-specific 1993;12(6 Pt 2):S328-S336. predictors of anal high-grade dysplasia in men prevalence of anal human papillomavirus infec - tion in HIV-negative sexually active men who have 34. Goldie SJ, Kuntz KM, Weinstein MC, Freedberg who have sex with men with abnormal cytology. KA, Welton ML, Palefsky JM. The clinical effec - Dis Colon Rectum . 2009;52(1):31-39. sex with men: the EXPLORE Study. J Infect Dis . 2004:190(12):2070-2076. tiveness and cost-effectiveness of screening for 2. Nyitray A, Nielson CM, Harris RB, et al. Prevalence anal squamous intraepithelial lesions in homo - of and risk factor for anal human papillomavirus 18. Anal cancer. University of California, San Fran - sexual and bisexual HIV positive men. JAMA . infection in heterosexual men. J Infect Dis . 2008;197 cisco, Medical Center Web site. http://www.ucsf 1999;281(19):1822-1829. (12):1676-1684. health.org/conditions/oral_cancer. Accessed Jan - uary 31, 2011. 35. Panther LA, Wagner K, Proper J, et al. High 3. Ryan DP, Willett CG. Classification and epi - resolution anoscopy finding in men who have sex demiology of anal cancer. UpToDate . March 13, 19. Daling JR, Madeleine MM, Johnson LG, et al. with men: inaccuracy of anal cytology as a pre - 2008. Human papillomavirus, smoking and sexual prac - dictor of histologic high grade anal intraepithe - tices in the etiology of anal cancer. Cancer . 2004; lial neoplasia and the impart of HIV serostatus. 4. Chin-Hong PV, Palefsky JM. Human papillo - 101(2):270-280. mavirus-related malignancies with and without Clin Infect Dis . 2004;38(10):1490-1492. HIV: epidemiology, diagnosis and management. 20. Levine AM. Non-AIDS-defining cancers in the 36. Kaplan JE, Masur H, Holmes KK; USPHS; Infec - In: Volberding PA, Palefsky J, eds; Walsh CC, assist era of HAART [module]. In: HIV/AIDS Annual tious Disease Society of America. Guidelines for ed. Viral and Immunological Malignancies . Update 2008 . Reston, VA: Clinical Care Options; Preventing Opportunistic Infections Among HIV Hamilton, Ontario, Canada: BC Decker; 2006:224- 2008. http://www.clinicalcareoptions.com/HIV Infected Persons—2002: Recommendations of the 241. /Annual%20Updates/2008%20Annual%20Update/ US Public Health Service and the Infectious Dis - Modules/Cancers.aspx 5. Plate 374. In: Netter FH. Atlas of Human eases Society of America. MMWR Recomm Rep . Anatomy . 3rd ed. Teterboro, NJ: Icon Learning Sys - 21. Sonnex C, Strauss S, Gray JJ. Detection of human 2002;51(RR-8):1-52. papillomavirus DNA on the fingers of patients with tems; 2003. 37. Northwest Pennsylvania Rural AIDS Alliance. genital warts. Sex Transm Infect . 1999;75(5):317-319. 6. New York State Department of Health. HIV clin - Rectal Exam Policy . Clarion, PA: ical resource: human papillomavirus (HPV). http: 22. Ferenczy A, Bergeron C, Richart RM. Human Northwest Pennsylvania Rural AIDS Alliance; June //www.hivguidelines.org/Guidelines.aspx?pageID papillomavirus DNA in fomites on objects used for 9, 2008. the management of patients with genital human =257&guideLineID=1-2&vType=txt. Accessed 38. Palefsky J. Screening for anal and cervical dys - papillomavirus infections. Obstet Gynecol . 1989; February 20, 2008. plasia in HIV-infected patients. PRN Notebook . 74(6):950-954. 7. Howley PM, Lowy DR. Human papillomaviruses. 2001;6(3):24-31. 23. Singh R. Nime F, Mittleman A. Malignant In: Knipe DM, Howley PM, eds. Fields Virology . 5th 39. Solomon D, Davey D, Kurman R, et al; Forum ed. Philadelphia, PA: Lippincott Williams & Wilkins, epithelial tumors of the anal canal. Cancer . 1981;48(2):411-415. Group Members; Bethesda 2001 Workshop. The 2007:2299-2340. 2001 : terminology for reporting 8. HPV vaccines: questions and answers. Centers 24. Schneider TC, Schulte WJ. Management of car - results of cervical cytology. JAMA . 2002;287(16): for Disease Control and Prevention Web site. http: cinoma of anal canal. Surgery . 1981;90(4):729-734. 2114-2119. //www.cdc.gov/vaccines/vpd-vac/hpv/vac-faqs.htm. 25. Schraut WH, Wang CH, Dawson PJ, Block GE. 40. American Academy of HIV Medicine. Funda - Accessed January 31, 2011. Depth of invasion, location and size of cancer of the mentals of HIV Medicine . Washington, DC: Amer - 9. SEER stat fact sheets: cervix uteri. Surveillance, Epi - anus dictate operative treatment. Cancer . 1983;51 ican Academy of HIV Medicine; 2007:199-201. demiology, and End Results Web site. http://seer (7):1291-1296. .cancer.gov/statfacts/html/cervix.html. Accessed Jan - 26. What is Anal Cancer? American Cancer Society uary 31, 2011. Web site. http://www5.cancer.org/docroot/CRI/con -

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