Analcancerhelp.info

Management of Anal Cancer in 2010 Part 1:
Overview, Screening, and Diagnosis
1 Medical Resident, School of Medicine and Biomedical Sciences, State University of New York atBuffalo Director, Gastrointestinal, Radiation Medicine, Roswell Park Cancer Institute Professor of Oncology, Roswell Park Cancer Institute, Buffalo, New York ABSTRACT: Although anal cancer is a rare disease, its incidence is increasing in men and women
worldwide. The most important risk factors are behaviors that predispose individuals to human
papillomavirus (HPV) infection or immunosuppression. Anal cancer is generally preceded by
high-grade anal intraepithelial neoplasia (HGAIN), which is most prevalent in human
immunodeficiency virus (HIV)-positive men who have sex with men. There is a general consensus
that high-risk individuals may benefit from screening. Meta-analysis suggests that 80% of anal
cancers could be avoided by vaccination against HPV 16/18. Nearly half of all patients with anal
cancer present with rectal bleeding. Pain or sensation of a rectal mass is experienced in 30% of
patients, whereas 20% have no tumor-specific symptoms. According to the Surveillance
Epidemiology and End Results (SEER) database, 50% of patients with anal cancer have disease
localized to the anus, 29% have regional lymph node involvement or direct spread beyond the
primary, and 12% have metastatic disease, while 9% have an unknown stage. Clinical staging of
anal carcinoma requires a digital rectal exam and a computed tomography scan of the chest,
abdomen, and pelvis. Suspicious inguinal lymph nodes should be subject to pathologic
confirmation by fine-needle aspiration. The 5-year relative survival rates are 80.1% for localized
anal cancer, 60.7% for regional disease, and 29.4% for metastatic disease. Part 2 of this two-part
review will address the treatment of anal cancer, highlighting studies of chemoradiation.
The treatment of anal squamous cell cancer with definitive chemoradiation is cemented as thegold-standard therapy for localized anal cancer, mainly due to its sphincter-saving andcolostomy-sparing potential. Over the course of the past 2 decades, several studies have addresseddifferent chemoradiation regimens in hopes of improving on the standard Nigro protocol of fluorouracil(Drug information on fluorouracil), mitomycin(Drug information on mitomycin), and radiation. Whilethese studies failed to reveal any superiority of alternative regimens to the Nigro protocol, importantconclusions were derived regarding the continuity of radiation as well as the role of induction(pre-chemoradiation) and maintenance chemotherapy (post-chemoradiation) in patients with analcancer.
Before we continue with a consideration of treatment, some background on anal cancer is in order. Part1 of this review will provide an overview of anal cancer epidemiology, risk factors, screening, http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/1553005 prevention, and diagnosis. Part 2, which will appear in the next issue of ONCOLOGY, will focus ontreatment, highlighting the current status of chemoradiation for anal cancer and potential areas for futureimprovement.
Epidemiology
Anal cancer affected an estimated 5,290 patients (2,100 men and 3,190 women), and led toapproximately 710 deaths in 2009.[1] Although it is a rare disease, the incidence of anal cancer isincreasing in men and women worldwide.[2-6] The incidence rates according to the SurveillanceEpidemiology and End Results (SEER) database are 1.4 per 100,000 in men and 1.7 per 100,000 inwomen.[1] Women have a higher incidence rate than men for age groups over 50 years, whereas mendominate for the ages of 20 to 49 years. Over the period 1973 to 2000, black men had the sharpestincrease in anal cancer incidence rates, followed by white men, white women, and black women indecreasing order.
The median age at diagnosis of anal cancer ranges from 60 to 65 years. The overall 5-year survival ratesfor anal cancer are 60% in men and 78% in women, based on SEER data analysis for the modern era oftherapy, 1994 to 2000. During the same period, the 5-year overall survival of black men decreased to28%, presumably due to complicating human immunodeficiency virus (HIV) infection.[2] Risk Factors for Anal Cancer
The risk factors associated with anal cancer are summarized in Table 1.[1-30] The most important risksare behavioral factors that predispose individuals to human papillomavirus (HPV) infection orimmunosuppression.
Behavioral Risk Factors
Specific sexual practices have been associated with an increased risk of anal cancer. The risk of analcancer appears to be the highest among men having sex with men[7-10] (odds ratio [OR] = 17.3; 95%confidence interval [CI] = 8.2–36.1).[9] These risks are increased in the setting of men having sex withmen who are HIV-positive (relative risk [RR] = 59.5). It is now recognized that the increased risk ofanal cancer in this population is due to the increased HPV infection rate rather than isolated HIVinfection.
Risk factors common to both men and women are receptive anal intercourse, lifetime number of sexualpartners, cigarette smoking, and a history of genital warts.[9] For women, additional risk factors includehistory of high-grade vulvar intraepithelial neoplasia, and vulvar cancer or cervical cancer.[7,9,11-14] http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/1553005 Squamous cell cancer of the anal region is similar to that of the uterine cervix, vagina, and vulva,[15]and shares the common association with high-risk HPV infection.[10,12,16-21] While the prevalence ofcervical HPV infection in women declines after age 30 years, anal HPV in HIV-negative men who havesex with men (MSM) remains high and constant throughout life.[22,23] The prevalence of anal HPV infection is greater than cervical HPV infection in women who areHIV-positive or have a high risk of HIV infection.[24-26] In a population of healthy Hawaiian women,anal HPV infection was as common as cervical HPV.[27] In immunocompetent heterosexual men,anogenital and anal HPV infections were documented in 65.4% and 24.8% of patients,respectively.[28,29] History of multiple sexual partners in homosexual or heterosexual individuals or ofunprotected anal intercourse were predictive of greater risk of developing anal intraepithelial neoplasia(AIN) and invasive anal cancer.[30] Several subtypes of HPV are linked to anal cancer and its precursor lesions. HPV 16 has the highestdegree of association and, to a lesser extent, types 18, 31, 33, 35 and others have been connected. Theprevalence of high-risk HPV is about 85% in patients with squamous cell cancer of the anal canal,depending on the sensitivity of the assay[15,31,32] and the geographic variations.[33] In one series,high-risk HPV was identified in 90% of anal squamous cell carcinomas in women and 63% of suchcancers in men.[31] HPV-negative anal cancers were similar to HPV-positive anal cancers in terms ofpatient age, adjacent dysplasia, ductal differentiation, and prognosis.[34] Immunosuppression and HIV
Immunosuppression probably impairs the body’s ability to clear HPV after sexual exposure.[35-38]Patients undergoing organ transplantation have a 10- to 100-fold risk of anal cancer compared to thegeneral population.[39-44] The rate of high-grade squamous intraepithelial neoplasia is higher inHIV-positive patients than HIV-negative patients and is inversely related to the CD4 lymphocytecount.[45,46] However, HIV-related immunosuppression has not been clearly established as anindependent risk factor for anal cancer.
Since the introduction of highly active antiretroviral therapy (HAART), HIV patients are living longerand consequently, have an increased lifetime risk of developing anal cancer.[47] Although there havebeen reductions in the incidence of Kaposi’s sarcoma and lymphoma, no significant change has beenseen in the incidence of anal carcinoma.[48] In a study matching a cancer database to AIDS databases,the relative risk of developing anal cancer among HIV-positive men with a history of homosexualcontact was 59.5, while the relative risk for anal cancer was 6.8 in HIV-positive women in comparisonto the general population.[49] Benign Lesions and Anal Cancer
Benign lesions in the anal canal such as fistulas or fissures do not appear to predispose to cancer.[30]Similarly, inflammatory bowel disease does not appear to predispose to anal squamous cellcancer.[50,51] A Danish population-based cohort study of 6,334 patients with ulcerative colitis and2,723 patients with Crohn’s disease who were followed for 10 years showed no increased risk of analcancer.[52] Screening and Prevention
Screening of High-Risk Individuals
http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/1553005 Anal cancer is generally preceded by high-grade anal intraepithelial neoplasia (HGAIN), a precursorlesion analogous to cervical intraepithelial neoplasia (CIN) in carcinoma of the cervix.[53-56] HGAINprogresses to anal cancer at a rate of about 1% per year.[56,57] The prevalence of HGAIN is highest inHIV-positive MSM (52%–44%), followed by HIV-negative MSM (24%) and HIV-positive women(9%). By contrast, HIV-negative women have an estimated incidence of 1%.[58-64] No randomizedtrials or ecologic studies (ie, epidemiologic investigations in which the unit of analysis is a populationrather than an individual) have shown any improved outcome with screening for anal cancer.[65]However, there is a general consensus that high-risk individuals may benefit from screening.
In 2007, the New York State Department of Health AIDS Institute issued guidelines recommendingtargeted anal cancer screening for HIV-infected patients, MSM, women with abnormal vulvar orcervical cytology, and patients with a history of anogenital warts. Screening involves a digital rectalexam, anal pap smear (cytology), and high-resolution anoscopy (HRA)-directed biopsy. One studyreported a sensitivity of 95% and a specificity of 64% for physican-performed anal cytology, whereaspatient-collected cytology had a sensitivity 75% and a specificity of 50%.[66] This suggests thatcytology alone may not be enough to screen for high-risk patients in view of its low negative-predictivevalue. HRA-directed biopsy, first described by Jay et al, is now the gold standard for diagnosis ofHGAIN.[59,67] Treatment of HGAIN involves local administration of an agent such as trichloroacetic acid, which canbe applied by either the patient or the physician.[68] Other physician-applied ablative techniques includeelectrocautery, photodynamic therapy, and surgery.[69-73] HGAIN can recur in up to 25% of patientswho are HIV-negative and up to 80% of patients who are HIV-positive, indicating the need for closefollow-up and repeated ablations.[69] It should be noted that HRA screening is limited to select centersand may not be available for population-based screening. Furthermore, the impact of HRA screening onoverall outcome is yet to be determined. In centers where HRA is not available, screening should focuson digital anal examination and screening anal Pap smears.
HPV Vaccination
Vaccination of girls against oncogenic HPV is now being recommended for the prevention of cervicalcancer. A recent meta-analysis indicated that 80% of anal cancers could be avoided by vaccinationagainst HPV 16/18.[74] Vaccination of boys along with girls has been recommended by some.[75]Prospective studies are needed to further assess the role of prophylactic vaccination in preventing analcancer.
Symptoms and Stage at Presentation
Almost half of all patients with anal cancer will present with rectal bleeding. Pain or sensation of a rectalmass is experienced in 30% of patients, while 20% have no tumor-specific symptoms.[76-78] Cancerextends beyond the anal canal into the rectum and/or perineal skin in about half of all cases. Anovaginalseptum invasion occurs in about 10% of female cases.[79] Anal cancer metastasizes via the lymphatic system and less often by hematogenous spread. The distalanal canal below the dentate line drains into the inguinal and femoral lymph nodes, whereas theproximal anal canal drains into the perirectal lymph node. The staging of anal cancer is summarized in Table 2.
http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/1553005 The SEER database shows that 50% of patients with anal cancer have disease localized to the anus, 29%have regional lymph node involvement or direct spread beyond the primary, and 12% have metastaticdisease, while 9% have an unknown stage.[see http://www.seer.cancer.gov/statfacts/html/anus.html] Diagnostic Tests
Clinical staging of anal carcinoma requires a digital rectal exam and a CT scan of the chest, abdomen,and pelvis. Any suspicious inguinal lymph node should be subject to pathologic confirmation byfine-needle aspiration (FNA). The role of PET scanning in anal cancer has not been adequatelystudied.[80,81] PET is superior to CT in visualizing the primary tumor, with a detection rate of 91% to98% compared to CT rates of only 58% to 76%.[80-82] Surgical series have shown that up to 44% ofmetastases occur in lymph nodes smaller than 5 mm that are not considered to be involved by CTimaging criteria.[83] PET assessment relies more on metabolic activity than on simple size and mayhave an advantage in addressing smaller lymph nodes. Several reports suggest that 17% to 20% ofpatients will be found to have previously undetected lymph node involvement on baseline PET.
However, these metabolically positive cases of lymph node involvement on PET scan were notconfirmed by FNA, and therefore, false-positivity cannot be ruled out. Thus, PET is not routinelyindicated in the staging of anal cancer. MRI may be useful in distinguishing tumors from normal pelvicstructures, especially in the setting of disease recurrence.
Along with anal examination and staging, a gynecologic exam including cervical cancer screening isrecommended for women with anal cancer. HIV testing is recommended in the setting of associated riskfactors or a history of multiple sexual partners. CD4 levels should be measured in HIV-positive patientsfor prognostic evaluation.
Endoanal ultrasound, although not routinely done, helps in evaluating the depth of invasion of theprimary tumor and the involvement of adjacent nodes.[84-87] Prognosis
The 5-year relative survival rates are 80.1% for localized anal cancer, 60.7% for regional disease, and29.4% for metastatic disease.[see http://www.seer.cancer.gov/statfacts/html/anus.html] Extra-pelvicmetastases are associated with the worst prognosis.[2,88] Nodal involvement, T stage, and male gender predict for a higher risk of local and distant relapse, ahigher colostomy rate, and a worse overall survival following treatment with chemoradiation.[89,90-92]In HIV-positive patients, high viral load, low CD4+ counts, and AIDS are poor prognostic factors interms of local tumor control, survival, and impaired tolerance of radiation and chemotherapy.[93,94] This article will conclude in the April 30th issue of ONCOLOGY. Part 2 will address the treatment ofanal cancer, including questions about chemoradiation and neoadjuvant chemotherapy, how duration of http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/1553005 therapy affects tumor control, and the management of HIV-positive patients. Commentaries by Drs.
Derek R. McHaffie and Kevin R. Kozak; and Drs. Clifford D. Fuller and Charles R. Thomas, Jr, willaccompany part 2. Financial Disclosure: The authors have no significant financial interest or other relationship with the
manufacturers of any products or providers of any service mentioned in this article.
References
1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2009. CA Cancer J Clin 59:225-249, 2009.
2. Johnson LG, Madeleine MM, Newcomer LM, et al: Anal cancer incidence and survival: thesurveillance, epidemiology, and end results experience, 1973-2000. Cancer 101:281-288, 2004.
3. Chiao EY, Krown SE, Stier EA, et al: A population-based analysis of temporal trends in the incidenceof squamous anal canal cancer in relation to the HIV epidemic. J Acquir Immune Defic Syndr40:451-455, 2005.
4. Frisch M, Melbye M, Moller H: Trends in incidence of anal cancer in Denmark. BMJ 306:419-422,1993.
5. Brewster DH, Bhatti LA: Increasing incidence of squamous cell carcinoma of the anus in Scotland,1975-2002. Br J Cancer 95:87-90, 2006.
6. Goldman S, Glimelius B, Nilsson B, et al: Incidence of anal epidermoid carcinoma in Sweden1970-1984. Acta Chir Scand 155:191-197, 1989.
7. Daling JR, Weiss NS, Hislop TG, et al: Sexual practices, sexually transmitted diseases, and theincidence of anal cancer. N Engl J Med 317:973-977, 1987.
8. Daling JR, Sherman KJ, Hislop TG, et al: Cigarette smoking and the risk of anogenital cancer. Am JEpidemiol 135:180-189, 1992.
9. Daling JR, Madeleine MM, Johnson LG, et al: Human papillomavirus, smoking, and sexual practicesin the etiology of anal cancer. Cancer 101:270-280, 2004.
10. Frisch M, Glimelius B, van den Brule AJ, et al: Sexually transmitted infection as a cause of analcancer. N Engl J Med 337:1350-1358, 1997.
11. Ogunbiyi OA, Scholefield JH, Robertson G, et al: Anal human papillomavirus infection andsquamous neoplasia in patients with invasive vulvar cancer. Obstet Gynecol 83:212-216, 1994.
12. Melbye M, Sprogel P: Aetiological parallel between anal cancer and cervical cancer. Lancet338:657-659, 1991.
http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/1553005 13. Jiménez W, Paszat L, Kupets R, et al: Presumed previous human papillomavirus (HPV) relatedgynecological cancer in women diagnosed with anal cancer in the province of Ontario. Gynecol Oncol114:395-398, 2009.
14. Rabkin CS, Biggar RJ, Melbye M, et al: Second primary cancers following anal and cervicalcarcinoma: Evidence of shared etiologic factors. Am J Epidemiol 136:54-58, 1992.
15. Zbar AP, Fenger C, Efron J, et al: The pathology and molecular biology of anal intraepithelialneoplasia: Comparisons with cervical and vulvar intraepithelial carcinoma. Int J Colorectal Dis17:203-215, 2002.
16. Palefsky JM: Human papillomavirus infection and anogenital neoplasia in human immunodeficiencyvirus-positive men and women. J Natl Cancer Inst Monogr (23):15-20, 1998.
17. Chin-Hong PV, Palefsky JM: Human papillomavirus anogenital disease in HIV-infected individuals.
Dermatol Ther 18:67-76, 2005.
18. Panther LA, Schlecht HP, Dezube BJ: Spectrum of human papillomavirus-related dysplasia andcarcinoma of the anus in HIV-infected patients. AIDS Read 15:79-82, 85-76, 88, 91, 2005.
19. Tilston P: Anal human papillomavirus and anal cancer. J Clin Pathol 50:625-634, 1997.
20. Duggan MA, Boras VF, Inoue M, et al: Human papillomavirus DNA determination of analcondylomata, dysplasias, and squamous carcinomas with in situ hybridization. Am J Clin Pathol92:16-21, 1989.
21. Palefsky JM, Holly EA, Gonzales J, et al: Detection of human papillomavirus DNA in analintraepithelial neoplasia and anal cancer. Cancer Res 51:1014-1019, 1991.
22. Schiffman MH: Recent progress in defining the epidemiology of human papillomavirus infectionand cervical neoplasia. J Natl Cancer Inst 84:394-398, 1992.
23. Chin-Hong PV, Vittinghoff E, Cranston RD, et al: Age-related prevalence of anal cancer precursorsin homosexual men: The EXPLORE study. J Natl Cancer Inst 97:896-905, 2005.
24. Palefsky JM, Holly EA, Ralston ML, et al: Prevalence and risk factors for anal humanpapillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negativewomen. J Infect Dis 183:383-391, 2001.
25. Melbye M, Smith E, Wohlfahrt J, et al: Anal and cervical abnormality in women--prediction byhuman papillomavirus tests. Int J Cancer 68:559-564, 1996.
26. Williams AB, Darragh TM, Vranizan K, et al: Anal and cervical human papillomavirus infection andrisk of anal and cervical epithelial abnormalities in human immunodeficiency virus-infected women. Obstet Gynecol 83:205-211, 1994.
27. Hernandez BY, McDuffie K, Zhu X, et al: Anal human papillomavirus infection in women and itsrelationship with cervical infection. Cancer Epidemiol Biomarkers Prev 14:2550-2556, 2005.
http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/1553005 28. Nielson CM, Harris RB, Dunne EF, et al: Risk factors for anogenital human papillomavirus infectionin men. J Infect Dis 196:1137-1145, 2007.
29. Nyitray A, Nielson CM, Harris RB, et al: Prevalence of and risk factors for anal humanpapillomavirus infection in heterosexual men. J Infect Dis 197:1676-1684, 2008.
30. Frisch M: On the etiology of anal squamous carcinoma. Dan Med Bull 49:194-209, 2002.
31. Frisch M, Fenger C, van den Brule AJ, et al: Variants of squamous cell carcinoma of the anal canaland perianal skin and their relation to human papillomaviruses. Cancer Res 59:753-757, 1999.
32. Bjorge T, Engeland A, Luostarinen T, et al: Human papillomavirus infection as a risk factor for analand perianal skin cancer in a prospective study. Br J Cancer 87:61-64, 2002.
33. Scholefield JH, Kerr IB, Shepherd NA, et al: Human papillomavirus type 16 DNA in anal cancersfrom six different countries. Gut 32:674-676, 1991.
34. Williams GR, Lu QL, Love SB, et al: Properties of HPV-positive and HPV-negative analcarcinomas. J Pathol 180:378-382, 1996.
35. Ryan DP, Compton CC, Mayer RJ: Carcinoma of the anal canal. N Engl J Med 342:792-800, 2000.
36. Sillman F, Stanek A, Sedlis A, et al: The relationship between human papillomavirus and lowergenital intraepithelial neoplasia in immunosuppressed women. Am J Obstet Gynecol 150:300-308, 1984.
37. Sillman FH, Fruchter RG, Chen YS, et al: Vaginal intraepithelial neoplasia: Risk factors forpersistence, recurrence, and invasion and its management. Am J Obstet Gynecol 176:93-99, 1997.
38. Goncalves MA, Donadi EA: Immune cellular response to HPV: Current concepts. Braz J Infect Dis8:1-9, 2004.
39. Sillman FH, Sentovich S, Shaffer D: Ano-genital neoplasia in renal transplant patients. AnnTransplant 2:59-66, 1997.
40. Adami J, Gabel H, Lindelof B, et al: Cancer risk following organ transplantation: A nationwidecohort study in Sweden. Br J Cancer 89:1221-1227, 2003.
41. Penn I: Cancers of the anogenital region in renal transplant recipients. Analysis of 65 cases. Cancer58:611-616, 1986.
42. Arends MJ, Benton EC, McLaren KM, et al: Renal allograft recipients with high susceptibility tocutaneous malignancy have an increased prevalence of human papillomavirus DNA in skin tumours anda greater risk of anogenital malignancy. Br J Cancer 75:722-728, 1997.
43. Albright JB, Bonatti H, Stauffer J, et al: Colorectal and anal neoplasms following livertransplantation. Colorectal Dis Mar 26 2009 (epub ahead of print).
44. Patel HS, Silver AR, Northover JM: Anal cancer in renal transplant patients. Int J Colorectal Dis22:1-5, 2007.
http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/1553005 45. Critchlow CW, Surawicz CM, Holmes KK, et al: Prospective study of high grade anal squamousintraepithelial neoplasia in a cohort of homosexual men: Influence of HIV infection,immunosuppression and human papillomavirus infection. AIDS 9:1255-1262, 1995.
46. Palefsky JM, Holly EA, Hogeboom CJ, et al: Virologic, immunologic, and clinical parameters in theincidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negativehomosexual men. J Acquir Immune Defic Syndr Hum Retrovirol 17:314-319, 1998.
47. Palefsky JM: Anal squamous intraepithelial lesions: relation to HIV and human papillomavirusinfection. J Acquir Immune Defic Syndr 21(suppl 1):S42-S48, 1999.
48. Hessol NA, Pipkin S, Schwarcz S, et al: The impact of highly active antiretroviral therapy onnon-AIDS-defining cancers among adults with AIDS. Am J Epidemiol 165:1143-1153, 2007.
49. Patel P, Hanson DL, Sullivan PS, et al: Incidence of types of cancer among HIV-infected personscompared with the general population in the United States, 1992-2003. Ann Intern Med 148:728-736,2008.
50. Preston DM, Fowler EF, Lennard-Jones JE, et al: Carcinoma of the anus in Crohns disease. Br JSurg 70:346-347, 1983.
51. Slater G, Greenstein A, Aufses AH Jr: Anal carcinoma in patients with Crohns disease. Ann Surg199:348-350, 1984.
52. Frisch M, Johansen C: Anal carcinoma in inflammatory bowel disease. Br J Cancer 83:89-90, 2000.
53. Watson AJ, Smith BB, Whitehead MR, et al: Malignant progression of anal intra-epithelialneoplasia. ANZ J Surg 76:715-717, 2006.
54. Scholefield JH, Castle MT, Watson NF: Malignant transformation of high-grade anal intraepithelialneoplasia. Br J Surg 92:1133-1136, 2005.
55. Abbasakoor F, Boulos PB: Anal intraepithelial neoplasia. Br J Surg 92:277-290, 2005.
56. Fenger C: Anal neoplasia and its precursors: Facts and controversies. Semin Diagn Pathol8:190-201, 1991.
57. Klencke BJ, Palefsky JM: Anal cancer: An HIV-associated cancer. Hematol Oncol Clin North Am17:859-872, 2003.
58. Palefsky JM, Holly EA, Efirdc JT, et al: Anal intraepithelial neoplasia in the highly activeantiretroviral therapy era among HIV-positive men who have sex with men. AIDS 19:1407-1414, 2005.
59. Berry JM, Palefsky JM, Jay N, et al: Performance characteristics of anal cytology and humanpapillomavirus testing in patients with high-resolution anoscopy-guided biopsy of high-grade analintraepithelial neoplasia. Dis Colon Rectum 52:239-247, 2009.
60. Hessol NA, Holly EA, Efird JT, et al: Anal intraepithelial neoplasia in a multisite study ofHIV-infected and high-risk HIV-uninfected women. AIDS 23:59-70, 2009.
http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/1553005 61. Goldstone SE, Winkler B, Ufford LJ, et al: High prevalence of anal squamous intraepithelial lesionsand squamous-cell carcinoma in men who have sex with men as seen in a surgical practice. Dis ColonRectum 44:690-698, 2001.
62. Panther LA, Wagner K, Proper J, et al: High resolution anoscopy findings for men who have sexwith men: Inaccuracy of anal cytology as a predictor of histologic high-grade anal intraepithelialneoplasia and the impact of HIV serostatus. Clin Infect Dis 38:1490-1492, 2004.
63. Fox PA, Seet JE, Stebbing J, et al: The value of anal cytology and human papillomavirus typing inthe detection of anal intraepithelial neoplasia: A review of cases from an anoscopy clinic. Sex TransmInfect 81:142-146, 2005.
64. Cranston RD, Hart SD, Gornbein JA, et al: The prevalence, and predictive value, of abnormal analcytology to diagnose anal dysplasia in a population of HIV-positive men who have sex with men. Int JSTD AIDS 18:77-80, 2007.
65. Chiao EY, Giordano TP, Palefsky JM, et al: Screening HIV-infected individuals for anal cancerprecursor lesions: A systematic review. Clin Infect Dis 43:223-233, 2006.
66. Chin-Hong PV, Berry JM, Cheng SC, et al: Comparison of patient- and clinician-collected analcytology samples to screen for human papillomavirus-associated anal intraepithelial neoplasia in menwho have sex with men. Ann Intern Med 149:300-306, 2008.
67. Jay N, Berry JM, Hogeboom CJ, et al: Colposcopic appearance of anal squamous intraepitheliallesions: Relationship to histopathology. Dis Colon Rectum 40:919-928, 1997.
68. Wieland U, Brockmeyer NH, Weissenborn SJ, et al: Imiquimod treatment of anal intraepithelialneoplasia in HIV-positive men. Arch Dermatol 142:1438-1444, 2006.
69. Chang GJ, Berry JM, Jay N, et al: Surgical treatment of high-grade anal squamous intraepitheliallesions: A prospective study. Dis Colon Rectum 45:453-458, 2002.
70. Runfola MA, Weber TK, Rodriguez-Bigas MA, et al: Photodynamic therapy for residual neoplasmsof the perianal skin. Dis Colon Rectum 43:499-502, 2000.
71. Pineda CE, Berry JM, Jay N, et al: High-resolution anoscopy targeted surgical destruction of analhigh-grade squamous intraepithelial lesions: A ten-year experience. Dis Colon Rectum 51:829-837 (incldiscussion), 2008.
72. Goldstone SE, Hundert JS, Huyett JW: Infrared coagulator ablation of high-grade anal squamousintraepithelial lesions in HIV-negative males who have sex with males. Dis Colon Rectum 50:565-575,2007.
73. Cranston RD, Hirschowitz SL, Cortina G, et al: A retrospective clinical study of the treatment ofhigh-grade anal dysplasia by infrared coagulation in a population of HIV-positive men who have sexwith men. Int J STD AIDS 19:118-120, 2008.
74. De Vuyst H, Clifford GM, Nascimento MC, et al: Prevalence and type distribution of humanpapillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: Ameta-analysis. Int J Cancer 124:1626-1636, 2009.
http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/1553005 75. Gillison ML, Chaturvedi AK, Lowy DR: HPV prophylactic vaccines and the potential prevention ofnoncervical cancers in both men and women. Cancer 113(10 suppl):3036-3046, 2008.
76. Singh R, Nime F, Mittelman A: Malignant epithelial tumors of the anal canal. Cancer 48:411-415,1981.
77. Schneider TC, Schulte WJ: Management of carcinoma of anal canal. Surgery 90:729-734, 1981.
78. Schraut WH, Wang CH, Dawson PJ, et al: Depth of invasion, location, and size of cancer of the anusdictate operative treatment. Cancer 51:1291-1296, 1983.
79. DeVita VTL, Theodore S, Rosenberg SA (eds): Devita, Hellman and Rosenbergs Cancer: Principles& Practice of Oncology, 8th ed, vol 1. Philadelphia, Lippincott Williams & Wilkins, 2008.
80. Cotter SE, Grigsby PW, Siegel BA, et al: FDG-PET/CT in the evaluation of anal carcinoma. Int JRadiat Oncol Biol Phys 65:720-725, 2006.
81. Nguyen BT, Joon DL, Khoo V, et al: Assessing the impact of FDG-PET in the management of analcancer. Radiother Oncol 87:376-382, 2008.
82. Scherrer A, Reboul F, Martin D, et al: CT of malignant anal canal tumors. Radiographics10:433-453, 1990.
83. Wade DS, Herrera L, Castillo NB, et al: Metastases to the lymph nodes in epidermoid carcinoma ofthe anal canal studied by a clearing technique. Surg Gynecol Obstet 169:238-242, 1989.
84. Giovannini M, Bardou VJ, Barclay R, et al: Anal carcinoma: Prognostic value of endorectalultrasound (ERUS). Results of a prospective multicenter study. Endoscopy 33:231-236, 2001.
85. Tarantino D, Bernstein MA: Endoanal ultrasound in the staging and management of squamous-cellcarcinoma of the anal canal: Potential implications of a new ultrasound staging system. Dis ColonRectum 45:16-22, 2002.
86. Goldman S, Norming U, Svensson C, et al: Transanorectal ultrasonography in the staging of analepidermoid carcinoma. Int J Colorectal Dis 6:152-157, 1991.
87. Roseau G, Palazzo L, Colardelle P, et al: Endoscopic ultrasonography in the staging and follow-upof epidermoid carcinoma of the anal canal. Gastrointest Endosc 40:447-450, 1994.
88. Tanum G, Tveit K, Karlsen KO, et al: Chemotherapy and radiation therapy for anal carcinoma.
Survival and late morbidity. Cancer 67:2462-2466, 1991.
89. Ajani JA, Winter KA, Gunderson LL, et al: US intergroup anal carcinoma trial: Tumor diameterpredicts for colostomy. J Clin Oncol 27:1116-1121, 2009.
90. Goldman S, Auer G, Erhardt K, et al: Prognostic significance of clinical stage, histologic grade, andnuclear DNA content in squamous-cell carcinoma of the anus. Dis Colon Rectum 30:444-448, 1987.
http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/1553005 91. Bartelink H, Roelofsen F, Eschwege F, et al: Concomitant radiotherapy and chemotherapy issuperior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase IIIrandomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy andGastrointestinal Cooperative Groups. J Clin Oncol 15:2040-2049, 1997.
92. Newman G, Calverley DC, Acker BD, et al: The management of carcinoma of the anal canal byexternal beam radiotherapy, experience in Vancouver 1971-1988. Radiother Oncol 25:196-202, 1992.
93. Hoffman R, Welton ML, Klencke B, et al: The significance of pretreatment CD4 count on theoutcome and treatment tolerance of HIV-positive patients with anal cancer. Int J Radiat Oncol Biol Phys44:127-131, 1999.
94. Place RJ, Gregorcyk SG, Huber PJ, et al: Outcome analysis of HIV-positive patients with analsquamous cell carcinoma. Dis Colon Rectum 44:506-512, 2001.
a Tx = primary tumor cannot be assessed;T0 = no evidence of primary tumor; T1 = tumor size 2 cm orless in greatest dimension; T2 = tumor > 2 cm but < 5 cm; T3 = tumor > 5 cm; T4 = tumor of any sizeinvading adjacent organs.
b Nx = regional lymph nodes cannot be assessed; N0 = no regional lymph node metastastsis; N1 =metastasis in perirectal lymph node; N2 = metastasis in unilateral internal iliac or unilateral inguinallymph node; N3 = metastasis in perirectal and inguinal lymph node and/or bilateral inguinal lymph nodeand/or bilateral internal iliac lymph nodes.
c Mx = distant metastasis cannot be assessed; M0 = no distant metastasis; M1 = distant metastasis.
http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/1553005

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