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Etiology of Human Papilloma Virus Infections and the Development of Anal Squamous Intraepithelial Lesions
Etiology of Human Papilloma Virus Infections and the Development of Anal Squamous Intraepithelial Lesions Mark Lane Welton, MD The human papilloma virus is the most common sexually transmitted infection. Long standing infections may develop when the virus is able to elude immune surveillance. In a minority of patients this may lead to chronic inflammation and an increased risk of developing anal malignancy. This risk is particularly pronounced in immunocompromised patients. Semin Colon Rectal Surg 15:193-195 © 2004 Elsevier Inc. All rights reserved. KEYWORDS human papilloma virus, dysplasia, squamous intraepithelial lesions
T
he human papilloma virus (HPV) is the most common sexually transmitted infection.1,2 However, the immune system effectively clears the majority of the infections. Ten to 46% of patients will develop subclinical disease and only 1% will develop clinically apparent disease.3,4 The development of anal dysplasia and cancer is a prolonged multistep process initiated by the virus gaining access to the basal and parabasal cells through a variety of pathways. An erosion or disruption in the normal mucosal barrier may exist secondary to anoreceptive intercourse, sexually transmitted diseases (ulcers from syphilis, gonorrhea), or trauma from a bowel movement. The squamous metaplastic tissue that occurs above the dentate line represents a transformation of the epithelium from a fully developed columnar epithelium to a relatively “immature” or incompletely developed squamous epithelium overlying a columnar epithelium. This epithelium is felt to be particularly susceptible to HPV infection.5 Once the virus has passed through the broken barrier, the viral DNA can access the nucleus. If high-risk serotypes gain access to tissues that are replicating (wound repair or metaplasia), the infection can become widespread and persistent, lasting for decades and leading to an increased risk of cancer. The virus must elude immune surveillance to become established. The observed increased incidence of anal cancers in kidney transplant and HIV(⫹) patients implicate a blunted cell-mediated immune response as a important component of the virus establishing a prolonged presence within the cell.
Department of Surgery, Stanford University School of Medicine, Stanford, California. Address reprint requests to: Mark Lane Welton, MD, Associate Professor, Chief, Colon and Rectal Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California 94305-5655. E-mail: [email protected].
1043-1489/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.scrs.2005.03.001
This is supported by studies of cervical dysplasia where patients with established high-risk lesions were found to have a decreased ability to mount a T-helper cell type 1 (Th1 IL-2) response in contrast to those patients found to have low-risk lesions.6,7 Strong evidence supports the HPV as an infectious cause of anogenital cancer.8 HPV are DNA papovaviruses with an 8-kb genome. The viruses may produce warty lesions, as seen with HPV serotypes 6 and 11, and these have little oncogenic potential.9,10 In contrast, the HPV serotypes 16, 18, 31, 33, and 35 may cause lesions invisible to the naked eye and may harbor a malignant threat.11-13 These oncogenic viruses appear to interfere with cell-cycle control mechanisms, resulting in cellular proliferation in the latency phase.5,14 The increase in proliferation results from the loss of inhibition of the cell cycle through the actions of two “early region” viral genes E6 and E7. Control of the cell cycle is compromised by E7, which binds directly to the retinoblastoma (Rb) tumor suppressor protein products p105-, p107-, and p130-related proteins. This leads to a complicated cascade of events involving E2F transcriptions factors, cyclin complexes, and other regulatory proteins releasing the cell to progress through G1 into S phase.15 The events related to cell-cycle release by E7 allow for immortalization but alone are not sufficient for transformation of the infected cell. It appears that accumulation of genetic errors is necessary for transformation, which is consistent with the clinical scenario of a long-standing low-grade infection preceding the development of malignancy.16 The genetic errors may accumulate as a result of the E6 protein which binds to p53 with E6-associated protein (E6AP), resulting in degradation of p53 through the ubiquitin pathway.15,17 The p53 protein is an important cell-cycle regulat193
M.L. Welton
194 ing protein that leads to cell-cycle arrest and apoptosis when genetic errors have accumulated, allowing for DNA repair and thus avoiding the replication of errors. The E2 protein allows the HPV genome to attach to the host chromatin possibly allowing the HPV DNA to “hide,” avoiding intracellular detection mechanisms and assuring replication in a steady state with each cell division.5,18-20 In healthy uninfected epithelium, division occurs in the basal layers and maturation results in pyknotic condensed cells that slough from the tissue surface. In infected tissues, the viral DNA replication process is reactivated, leading to the presence of specific proteins and viral particles that can be detected in the upper cell layers. There are many other known and potential actions of E6, E7, E2, and other viral genes,5 but, in summary, through the combined effect of E7, E6, and E2, cells with genetic errors may proliferate, accumulate, and involve the entire thickness of the epithelium and this may result in carcinogenesis. As the infection with oncogenic viruses persists, the anal tissues may progress through low-grade to high-grade dysplasia and cancer. The changes that occur are similar to those seen in the cervix. In the cervix, there is increased proliferation and angiogenesis, and decreased apoptosis. The mechanisms responsible for the increased proliferation and decreased apoptosis are outlined in the above discussion. The mechanisms involved in increased angiogenesis are less well defined. Similar changes in proliferative rates, apoptosis, and angiogenesis have been described in the anus as high-grade dysplasia and cancer develop.21 The angiogenic changes have long been recognized in the cervix as an important step in the progression of dysplasia. Cancer may not develop in the absence of sufficient angiogenesis and the term the “angiogenic switch” has been coined to emphasize how important this step is in the progression to cancer. Culposcopy, a magnified view of the cervix, allows for direct visualization of these vascular changes. Various patterns of angiogenic changes characteristic of HSIL or LSIL may be identified with the aid of acetic acid and Lugol’s solution. Gynecologists are trained to recognize these vascular patterns and target their therapeutic destruction accordingly. As noted above, increased angiogenesis is a key event in the development of anal cancer.21 Fortunately, these angiogenic changes can also be visualized (with acetic acid and Lugol’s solution) in the perianal skin, anus, and distal rectum through an operative microscope, culposcope, or loops.13 This can be performed in the office and/or operating room and the targeted destruction is safe and may lead to a decrease in the incidence of anal cancer as was seen when cervical Pap smears and targeted destruction was introduced.22 Thus, screening programs in high-risk populations should be considered. The association of men who have sex with men (MSM) and anal cancer is clear23-25 but the association of HIV with the development and progression of anal cancer has been hard to separate from other confounding factors. Initial studies failed to show a correlation26,27 but more recent studies suggest an association.28-32 The major difference between these studies is the time periods over which the data were accumulated.
The earlier data reflect the anal cancer rates in the preHAART (highly active antiretroviral therapy) era. HPV is an indolent infection that leads to cancer in a minority of patients who have generally suffered from a long-term infection. In the pre-HAART era, patients did not live long enough to develop anal cancer in that they died due to the complications of HIV infection. More recently, with HAART therapy, patients are living longer and we are beginning to see the consequences with a rise in anal cancer and dysplasia in patients who are HIV-positive. This is true of both MSM and heterosexual men and women who do not report anoreceptive intercourse. A French study of HIV-positive patients with HPV revealed HIV-positive patients had fewer Langerhans cells, were more likely to suffer condyloma recurrence, and more commonly developed HSIL and anal cancer than HIVnegative patients.33 Studies from Seattle and San Francisco suggest that HIV-positive patients are more likely to have HSIL and are more likely to progress from LSIL to HSIL over a 2-year time period; both of these findings were increased in the patients with a lower CD4 count (⬍200 cells/mm).28-30 Low CD4 counts are a surrogate measure for immunosuppression from the HIV infection and it is therefore suggested that HIV infection is associated with an increased risk of progression of anal disease. Women who were HIV-positive had parallel changes to those seen in MSM.31,32 It is of particular interest that the rates of anal HPV infection exceeded the rates of cervical HPV infection in both HIV-positive and -negative patients.32 In contrast to the permissive role suggested by the above articles, HIV status did not correlate with risk for developing anal cancer in HIV-positive men and women in a recent cancer registry report of anal cancer rates from 1995 to 1998 when pre-AIDS era data were compared with post-AIDS era data.34 Despite this article, it appears that data are accumulating to suggest that, as men and women live longer in the HAART era, indolent HPV infection will result in an increased risk for the development of anal cancer and this effect will be most significant in the more immunocompromised patients. In summary, exposure to HPV is common but clinical and subclinical infections are less so. Nonetheless, infection in the immunocompromised host may place the individual at risk for anal malignancy and screening and surveillance techniques should be considered.
References 1. O’Mahony C, Law C, Gollnick HP, et al: New patient-applied therapy for anogenital warts is rated favourably by patients. Int J STD AIDS 12(9):565-570, 2001 2. Koutsky L: Epidemiology of genital human papillomavirus infection. Am J Med 102(5A):3-8, 1997 3. van der Snoek EM, Niesters HG, Mulder PG, et al: Human papillomavirus infection in men who have sex with men participating in a Dutch gay-cohort study. Sex Transm Dis 30(8):639-644, 2003 4. Bauer HM, Ting Y, Greer CE, et al: Genital human papillomavirus infection in female university students as determined by a PCR-based method. JAMA 265(4):472-477, 1991 5. Bosch FX, Lorincz A, Munoz N, et al: The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 55(4):244265, 2002
HPV and anal squamous intraepithelial lesions 6. Hildesheim A, Schiffman MH, Tsukui T, et al: Immune activation in cervical neoplasia: cross-sectional association between plasma soluble interleukin 2 receptor levels and disease. Cancer Epidemiol Biomarkers Prev 6(10):807-813, 1997 7. Tsukui T, Hildesheim A, Schiffman MH, et al: Interleukin 2 production in vitro by peripheral lymphocytes in response to human papillomavirus-derived peptides: correlation with cervical pathology. Cancer Res 56(17):3967-3974, 1996 8. Strickler HD, Schiffman MH: Is human papillomavirus an infectious cause of non-cervical anogenital tract cancers? BMJ 315(7109):620621, 1997 9. Pecoraro G, Morgan D, Defendi V: Differential effects of human papillomavirus type 6, 16, and 18 DNAs on immortalization and transformation of human cervical epithelial cells. Proc Natl Acad Sci USA 86(2):563-567, 1989 10. Woodworth CD, Doniger J, DiPaolo JA: Immortalization of human foreskin keratinocytes by various human papillomavirus DNAs corresponds to their association with cervical carcinoma. J Virol 63(1):159164, 1989 11. Palefsky JM, Gonzales J, Greenblatt RM, et al: Anal intraepithelial neoplasia and anal papillomavirus infection among homosexual males with group IV HIV disease. JAMA 263(21):2911-2916, 1990 12. Palefsky JM, Holly EA, Gonzales J, et al: Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Res 51(3):1014-1019, 1991 13. Jay N, Berry JM, Hogeboom CJ, et al: Colposcopic appearance of anal squamous intraepithelial lesions: relationship to histopathology. Dis Colon Rectum 40(8):919-928, 1997 14. McGlennen RC: Human papillomavirus oncogenesis. Clin Lab Med 20(2):383-406, 2000 15. zur Hausen H: Immortalization of human cells and their malignant conversion by high risk human papillomavirus genotypes. Semin Cancer Biol 9(6):405-11, 1999 16. Martin F, Bower M: Anal intraepithelial neoplasia in HIV positive people. Sex Transm Infect 77(5):327-331, 2001 17. Werness BA, Levine AJ, Howley PM: Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248(4951):76-79, 1990 18. Chow LT, Broker TR: Papillomavirus DNA replication. Intervirology 37(3-4):150-158, 1994 19. Dollard SC, Wilson JL, Demeter LM, et al: Production of human papillomavirus and modulation of the infectious program in epithelial raft cultures. OFF. Genes Dev 6(7):1131-1142, 1992 20. Flores ER, Lambert PF: Evidence for a switch in the mode of human papillomavirus type 16 DNA replication during the viral life cycle. J Virol 71(10):7167-7179, 1997
195 21. Litle VR, Leavenworth JD, Darragh TM, et al: Angiogenesis, proliferation, and apoptosis in anal high-grade squamous intraepithelial lesions. Dis Colon Rectum 43(3):346-352, 2000 22. Chang GJ, Berry JM, Jay N, et al: Surgical treatment of high-grade anal squamous intraepithelial lesions: a prospective study. Dis Colon Rectum 45(4):453-458, 2002 23. Holly EA, Whittemore AS, Aston DA, et al: Anal cancer incidence: genital warts, anal fissure or fistula, hemorrhoids, and smoking. J Natl Cancer Inst 81(22):1726-1731, 1989 24. Daling JR, Weiss NS, Hislop TG, et al: Sexual practices, sexually transmitted diseases, and the incidence of anal cancer. N Engl J Med 317(16):973-977, 1987 25. Scholefield JH, Sonnex C, Talbot IC, et al: Anal and cervical intraepithelial neoplasia: possible parallel. Lancet 2(8666):765-769, 1989 26. Rabkin CS, Yellin F: Cancer incidence in a population with a high prevalence of infection with human immunodeficiency virus type 1. J Natl Cancer Inst 86(22):1711-17116, 1994 27. Koblin BA, Hessol NA, Zauber AG, et al: Increased incidence of cancer among homosexual men, New York City and San Francisco, 19781990. Am J Epidemiol 144(10):916-923, 1996 28. Critchlow CW, Surawicz CM, Holmes KK, et al: Prospective study of high grade anal squamous intraepithelial neoplasia in a cohort of homosexual men: influence of HIV infection, immunosuppression and human papillomavirus infection. AIDS 9(11):1255-1262, 1995 29. Palefsky JM, Holly EA, Ralston ML, et al: Anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual and bisexual men: prevalence and risk factors. J Acquir Immune Defic Syndr Hum Retrovirol 17(4):320-326, 1998 30. Palefsky JM, Holly EA, Hogeboom CJ, et al: Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol 17(4):314319, 1998 31. Palefsky JM, Holly EA, Ralston ML, et al: Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women. J Infect Dis 183(3):383-391, 2001 32. Holly EA, Ralston ML, Darragh TM, et al: Prevalence and risk factors for anal squamous intraepithelial lesions in women. J Natl Cancer Inst 93(11):843-849, 2001 33. Sobhani I, Vuagnat A, Walker F, et al: Prevalence of high-grade dysplasia and cancer in the anal canal in human papillomavirus-infected individuals. Gastroenterology 120(4):857-866, 2001 34. Frisch M, Biggar RJ, Goedert JJ: Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 92(18): 1500-1510, 2000
T
he human papilloma virus (HPV) is the most common sexually transmitted infection.1,2 However, the immune system effectively clears the majority of the infections. Ten to 46% of patients will develop subclinical disease and only 1% will develop clinically apparent disease.3,4 The development of anal dysplasia and cancer is a prolonged multistep process initiated by the virus gaining access to the basal and parabasal cells through a variety of pathways. An erosion or disruption in the normal mucosal barrier may exist secondary to anoreceptive intercourse, sexually transmitted diseases (ulcers from syphilis, gonorrhea), or trauma from a bowel movement. The squamous metaplastic tissue that occurs above the dentate line represents a transformation of the epithelium from a fully developed columnar epithelium to a relatively “immature” or incompletely developed squamous epithelium overlying a columnar epithelium. This epithelium is felt to be particularly susceptible to HPV infection.5 Once the virus has passed through the broken barrier, the viral DNA can access the nucleus. If high-risk serotypes gain access to tissues that are replicating (wound repair or metaplasia), the infection can become widespread and persistent, lasting for decades and leading to an increased risk of cancer. The virus must elude immune surveillance to become established. The observed increased incidence of anal cancers in kidney transplant and HIV(⫹) patients implicate a blunted cell-mediated immune response as a important component of the virus establishing a prolonged presence within the cell.
Department of Surgery, Stanford University School of Medicine, Stanford, California. Address reprint requests to: Mark Lane Welton, MD, Associate Professor, Chief, Colon and Rectal Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California 94305-5655. E-mail: [email protected].
1043-1489/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.scrs.2005.03.001
This is supported by studies of cervical dysplasia where patients with established high-risk lesions were found to have a decreased ability to mount a T-helper cell type 1 (Th1 IL-2) response in contrast to those patients found to have low-risk lesions.6,7 Strong evidence supports the HPV as an infectious cause of anogenital cancer.8 HPV are DNA papovaviruses with an 8-kb genome. The viruses may produce warty lesions, as seen with HPV serotypes 6 and 11, and these have little oncogenic potential.9,10 In contrast, the HPV serotypes 16, 18, 31, 33, and 35 may cause lesions invisible to the naked eye and may harbor a malignant threat.11-13 These oncogenic viruses appear to interfere with cell-cycle control mechanisms, resulting in cellular proliferation in the latency phase.5,14 The increase in proliferation results from the loss of inhibition of the cell cycle through the actions of two “early region” viral genes E6 and E7. Control of the cell cycle is compromised by E7, which binds directly to the retinoblastoma (Rb) tumor suppressor protein products p105-, p107-, and p130-related proteins. This leads to a complicated cascade of events involving E2F transcriptions factors, cyclin complexes, and other regulatory proteins releasing the cell to progress through G1 into S phase.15 The events related to cell-cycle release by E7 allow for immortalization but alone are not sufficient for transformation of the infected cell. It appears that accumulation of genetic errors is necessary for transformation, which is consistent with the clinical scenario of a long-standing low-grade infection preceding the development of malignancy.16 The genetic errors may accumulate as a result of the E6 protein which binds to p53 with E6-associated protein (E6AP), resulting in degradation of p53 through the ubiquitin pathway.15,17 The p53 protein is an important cell-cycle regulat193
M.L. Welton
194 ing protein that leads to cell-cycle arrest and apoptosis when genetic errors have accumulated, allowing for DNA repair and thus avoiding the replication of errors. The E2 protein allows the HPV genome to attach to the host chromatin possibly allowing the HPV DNA to “hide,” avoiding intracellular detection mechanisms and assuring replication in a steady state with each cell division.5,18-20 In healthy uninfected epithelium, division occurs in the basal layers and maturation results in pyknotic condensed cells that slough from the tissue surface. In infected tissues, the viral DNA replication process is reactivated, leading to the presence of specific proteins and viral particles that can be detected in the upper cell layers. There are many other known and potential actions of E6, E7, E2, and other viral genes,5 but, in summary, through the combined effect of E7, E6, and E2, cells with genetic errors may proliferate, accumulate, and involve the entire thickness of the epithelium and this may result in carcinogenesis. As the infection with oncogenic viruses persists, the anal tissues may progress through low-grade to high-grade dysplasia and cancer. The changes that occur are similar to those seen in the cervix. In the cervix, there is increased proliferation and angiogenesis, and decreased apoptosis. The mechanisms responsible for the increased proliferation and decreased apoptosis are outlined in the above discussion. The mechanisms involved in increased angiogenesis are less well defined. Similar changes in proliferative rates, apoptosis, and angiogenesis have been described in the anus as high-grade dysplasia and cancer develop.21 The angiogenic changes have long been recognized in the cervix as an important step in the progression of dysplasia. Cancer may not develop in the absence of sufficient angiogenesis and the term the “angiogenic switch” has been coined to emphasize how important this step is in the progression to cancer. Culposcopy, a magnified view of the cervix, allows for direct visualization of these vascular changes. Various patterns of angiogenic changes characteristic of HSIL or LSIL may be identified with the aid of acetic acid and Lugol’s solution. Gynecologists are trained to recognize these vascular patterns and target their therapeutic destruction accordingly. As noted above, increased angiogenesis is a key event in the development of anal cancer.21 Fortunately, these angiogenic changes can also be visualized (with acetic acid and Lugol’s solution) in the perianal skin, anus, and distal rectum through an operative microscope, culposcope, or loops.13 This can be performed in the office and/or operating room and the targeted destruction is safe and may lead to a decrease in the incidence of anal cancer as was seen when cervical Pap smears and targeted destruction was introduced.22 Thus, screening programs in high-risk populations should be considered. The association of men who have sex with men (MSM) and anal cancer is clear23-25 but the association of HIV with the development and progression of anal cancer has been hard to separate from other confounding factors. Initial studies failed to show a correlation26,27 but more recent studies suggest an association.28-32 The major difference between these studies is the time periods over which the data were accumulated.
The earlier data reflect the anal cancer rates in the preHAART (highly active antiretroviral therapy) era. HPV is an indolent infection that leads to cancer in a minority of patients who have generally suffered from a long-term infection. In the pre-HAART era, patients did not live long enough to develop anal cancer in that they died due to the complications of HIV infection. More recently, with HAART therapy, patients are living longer and we are beginning to see the consequences with a rise in anal cancer and dysplasia in patients who are HIV-positive. This is true of both MSM and heterosexual men and women who do not report anoreceptive intercourse. A French study of HIV-positive patients with HPV revealed HIV-positive patients had fewer Langerhans cells, were more likely to suffer condyloma recurrence, and more commonly developed HSIL and anal cancer than HIVnegative patients.33 Studies from Seattle and San Francisco suggest that HIV-positive patients are more likely to have HSIL and are more likely to progress from LSIL to HSIL over a 2-year time period; both of these findings were increased in the patients with a lower CD4 count (⬍200 cells/mm).28-30 Low CD4 counts are a surrogate measure for immunosuppression from the HIV infection and it is therefore suggested that HIV infection is associated with an increased risk of progression of anal disease. Women who were HIV-positive had parallel changes to those seen in MSM.31,32 It is of particular interest that the rates of anal HPV infection exceeded the rates of cervical HPV infection in both HIV-positive and -negative patients.32 In contrast to the permissive role suggested by the above articles, HIV status did not correlate with risk for developing anal cancer in HIV-positive men and women in a recent cancer registry report of anal cancer rates from 1995 to 1998 when pre-AIDS era data were compared with post-AIDS era data.34 Despite this article, it appears that data are accumulating to suggest that, as men and women live longer in the HAART era, indolent HPV infection will result in an increased risk for the development of anal cancer and this effect will be most significant in the more immunocompromised patients. In summary, exposure to HPV is common but clinical and subclinical infections are less so. Nonetheless, infection in the immunocompromised host may place the individual at risk for anal malignancy and screening and surveillance techniques should be considered.
References 1. O’Mahony C, Law C, Gollnick HP, et al: New patient-applied therapy for anogenital warts is rated favourably by patients. Int J STD AIDS 12(9):565-570, 2001 2. Koutsky L: Epidemiology of genital human papillomavirus infection. Am J Med 102(5A):3-8, 1997 3. van der Snoek EM, Niesters HG, Mulder PG, et al: Human papillomavirus infection in men who have sex with men participating in a Dutch gay-cohort study. Sex Transm Dis 30(8):639-644, 2003 4. Bauer HM, Ting Y, Greer CE, et al: Genital human papillomavirus infection in female university students as determined by a PCR-based method. JAMA 265(4):472-477, 1991 5. Bosch FX, Lorincz A, Munoz N, et al: The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 55(4):244265, 2002
HPV and anal squamous intraepithelial lesions 6. Hildesheim A, Schiffman MH, Tsukui T, et al: Immune activation in cervical neoplasia: cross-sectional association between plasma soluble interleukin 2 receptor levels and disease. Cancer Epidemiol Biomarkers Prev 6(10):807-813, 1997 7. Tsukui T, Hildesheim A, Schiffman MH, et al: Interleukin 2 production in vitro by peripheral lymphocytes in response to human papillomavirus-derived peptides: correlation with cervical pathology. Cancer Res 56(17):3967-3974, 1996 8. Strickler HD, Schiffman MH: Is human papillomavirus an infectious cause of non-cervical anogenital tract cancers? BMJ 315(7109):620621, 1997 9. Pecoraro G, Morgan D, Defendi V: Differential effects of human papillomavirus type 6, 16, and 18 DNAs on immortalization and transformation of human cervical epithelial cells. Proc Natl Acad Sci USA 86(2):563-567, 1989 10. Woodworth CD, Doniger J, DiPaolo JA: Immortalization of human foreskin keratinocytes by various human papillomavirus DNAs corresponds to their association with cervical carcinoma. J Virol 63(1):159164, 1989 11. Palefsky JM, Gonzales J, Greenblatt RM, et al: Anal intraepithelial neoplasia and anal papillomavirus infection among homosexual males with group IV HIV disease. JAMA 263(21):2911-2916, 1990 12. Palefsky JM, Holly EA, Gonzales J, et al: Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Res 51(3):1014-1019, 1991 13. Jay N, Berry JM, Hogeboom CJ, et al: Colposcopic appearance of anal squamous intraepithelial lesions: relationship to histopathology. Dis Colon Rectum 40(8):919-928, 1997 14. McGlennen RC: Human papillomavirus oncogenesis. Clin Lab Med 20(2):383-406, 2000 15. zur Hausen H: Immortalization of human cells and their malignant conversion by high risk human papillomavirus genotypes. Semin Cancer Biol 9(6):405-11, 1999 16. Martin F, Bower M: Anal intraepithelial neoplasia in HIV positive people. Sex Transm Infect 77(5):327-331, 2001 17. Werness BA, Levine AJ, Howley PM: Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248(4951):76-79, 1990 18. Chow LT, Broker TR: Papillomavirus DNA replication. Intervirology 37(3-4):150-158, 1994 19. Dollard SC, Wilson JL, Demeter LM, et al: Production of human papillomavirus and modulation of the infectious program in epithelial raft cultures. OFF. Genes Dev 6(7):1131-1142, 1992 20. Flores ER, Lambert PF: Evidence for a switch in the mode of human papillomavirus type 16 DNA replication during the viral life cycle. J Virol 71(10):7167-7179, 1997
195 21. Litle VR, Leavenworth JD, Darragh TM, et al: Angiogenesis, proliferation, and apoptosis in anal high-grade squamous intraepithelial lesions. Dis Colon Rectum 43(3):346-352, 2000 22. Chang GJ, Berry JM, Jay N, et al: Surgical treatment of high-grade anal squamous intraepithelial lesions: a prospective study. Dis Colon Rectum 45(4):453-458, 2002 23. Holly EA, Whittemore AS, Aston DA, et al: Anal cancer incidence: genital warts, anal fissure or fistula, hemorrhoids, and smoking. J Natl Cancer Inst 81(22):1726-1731, 1989 24. Daling JR, Weiss NS, Hislop TG, et al: Sexual practices, sexually transmitted diseases, and the incidence of anal cancer. N Engl J Med 317(16):973-977, 1987 25. Scholefield JH, Sonnex C, Talbot IC, et al: Anal and cervical intraepithelial neoplasia: possible parallel. Lancet 2(8666):765-769, 1989 26. Rabkin CS, Yellin F: Cancer incidence in a population with a high prevalence of infection with human immunodeficiency virus type 1. J Natl Cancer Inst 86(22):1711-17116, 1994 27. Koblin BA, Hessol NA, Zauber AG, et al: Increased incidence of cancer among homosexual men, New York City and San Francisco, 19781990. Am J Epidemiol 144(10):916-923, 1996 28. Critchlow CW, Surawicz CM, Holmes KK, et al: Prospective study of high grade anal squamous intraepithelial neoplasia in a cohort of homosexual men: influence of HIV infection, immunosuppression and human papillomavirus infection. AIDS 9(11):1255-1262, 1995 29. Palefsky JM, Holly EA, Ralston ML, et al: Anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual and bisexual men: prevalence and risk factors. J Acquir Immune Defic Syndr Hum Retrovirol 17(4):320-326, 1998 30. Palefsky JM, Holly EA, Hogeboom CJ, et al: Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol 17(4):314319, 1998 31. Palefsky JM, Holly EA, Ralston ML, et al: Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women. J Infect Dis 183(3):383-391, 2001 32. Holly EA, Ralston ML, Darragh TM, et al: Prevalence and risk factors for anal squamous intraepithelial lesions in women. J Natl Cancer Inst 93(11):843-849, 2001 33. Sobhani I, Vuagnat A, Walker F, et al: Prevalence of high-grade dysplasia and cancer in the anal canal in human papillomavirus-infected individuals. Gastroenterology 120(4):857-866, 2001 34. Frisch M, Biggar RJ, Goedert JJ: Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 92(18): 1500-1510, 2000