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Anal Neoplasia in Persons with HIV Infection

Immunodeficiency and the development of various forms of neoplasia are clearly associated. Non-Hodgkin's lymphoma occurs commonly in congenital immunodeficiency states such as the Wiskott-Aldrich syndrome, common variable immunodeficiency, and ataxia-telangiectasia. Organ transplant recipients treated with immunosuppressive therapies to prevent graft rejection are at high risk for the development of non-Hodgkin's lymphoma, Kaposi's sarcoma, and anal and cervical malignancies. Non-Hodgkin's lymphoma and Kaposi's sarcoma also occur with greater frequency in persons with immunodeficiency caused by infection with HIV.

Recently, numerous observations have suggested that HIV-induced immunodeficiency may also be associated with the development of neoplasia in the cervical and anal mucosa, probably as a consequence of coinfection with human papillomavirus (HPV). Cervical intraepithelial neoplasia (dysplasia, squamous intraepithelial lesion, carcinoma in situ) and detectable HPV infection have been shown to be more common and intractable in HIV-infected women than in non-HIV-infected women with similar demographic characteristics. In HIV-infected women, invasive cervical cancer appears to be more aggressive than in comparable non-HIV-infected women, less responsive to standard therapies, and consequently associated with a poorer prognosis.

Similarly, anal intraepithelial neoplasia and HPV infection are also more common, severe, and difficult to treat in HIV-infected men than in similar non-HIV-infected men. Cervical and anal neoplasia may become more common manifestations of HIV disease as patients with profound immunodeficiency, who earlier in the epidemic would have succumbed to opportunistic infections, now survive longer on increasingly effective antiretroviral, prophylactic, and antimicrobial therapies. A prolonged, severely immunodeficient state provides a milieu for development of diseases with long latency, such as anogenital carcinomas.

This review addresses current knowledge on the relation between HPV infection and pathogenesis of anal neoplasia, considers the epidemiological and clinical aspects of HPV infection and anal neoplasia in people with HIV infection, and discusses strategies for diagnosis and treatment.

HPV Infection, Immunodeficiency, and Anal Neoplasia

The association between HPV infection and the development of anogenital neoplasia is widely appreciated, although the mechanisms involved are incompletely understood. However, the actions of several HPV gene products and their possible roles in the process of malignant transformation have recently been described.

The E6 and E7 genes of HPV appear to be critical in the process of malignant transformation. These genes are transcriptionally active in cervical cancers and derived cell lines in which the viral genome is integrated in the host genome; it is speculated that integration disrupts normal control of E6 and E7 gene expression.1 E6 and E7 bind to p53 and the Rb protein, respectively.2,3 These cellular proteins, products of so-called tumor suppressor genes or antioncogenes, are believed to function as essential growth regulators in the normal cell. Loss of the normal quantity or function of these proteins has been associated with malignant transformation and the development of retinoblastoma, colorectal cancer, and other tumors. It has been hypothesized that binding by E6 and E7 inactivates the tumor suppressor functions of p53 and/or Rb protein, leading to malignant transformation.

Additional observations suggesting a role for HPV in the development of anal and cervical neoplasia have come from prospective natural history studies of asymptomatic women infected with various HPV genotypes. For example, an important recent report described a cohort of 241 women with negative cervical cytologic tests on first visit to a sexually transmitted diseases clinic.4 The cumulative incidence of cervical intraepithelial neoplasia (CIN grade 2 or 3) after two years of observation was 28% among the 110 women with cervical HPV infection detected by DNA probe analysis on their first visit. The comparable figure for women without detectable cervical HPV infection was 3%. The risk was highest among those with HPV type 16 or 18 infection (adjusted relative risk compared with that in women without HPV infection, 11; 95% confidence interval, 4.6 to 26).

HPV is presumed to play an etiologic role in anal neoplasia similar to that described above for cervical neoplasia. Epidemiologic investigations of anal cancer incidence have identified many risk factors associated with both cervical neoplasia and HPV infection, including history of anal or genital condyloma and history of other sexually transmitted diseases. In addition, male homosexuality and the practice of receptive anal intercourse have been associated with anal cancer risk, emphasizing this mode of acquisition of HPV.5,6 In a manner similar to investigations performed on cervical cancer specimens, anal cancer specimens have been found to contain antigens, DNA, and mRNA of HPV.7,8 These observations have been confirmed by amplification of HPV DNA from anal cancer specimens using polymerase chain reaction (PCR).9

Anogenital neoplasia also has a recognized association with chronic immunodeficiency. Studies of cohorts of immunosuppressed organ transplant recipients have demonstrated a 100-fold increase in the incidence of vulvar and anal carcinomas, and a 144-fold increase in the incidence of cervical carcinoma, compared with controls.10,11

The high incidence of anogenital cancer in immunosuppressed transplant recipients is believed to be a consequence of the high prevalence of detectable anogenital HPV infection seen in these patients, coupled with and perhaps resulting from, impaired immunologic response to the infection. The prevalence of detectable HPV infection is 5 to 17 times greater in immunosuppressed transplant recipients than in the general population,12 and cell-mediated immunity is believed to be the primary mechanism by which activity of HPV is controlled.13

Anal Intraepithelial Neoplasia: Epidemiology and Clinical Aspects

In a manner analogous to studies of cervical neoplasia, a number of studies have demonstrated a relation between HIV-induced immunodeficiency, HPV infection, and the development of anal neoplasia. Most of these studies have focused on anal intraepithelial neoplasia (AIN), variously called dysplasia, squamous intraepithelial lesion, carcinoma in situ, or preinvasive cancer. The findings of these studies, which have been reasonably consistent, are described in Table 1.


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  		Table 1. Summary of Findings from Studies of Anal Neoplasia in Persons with HIV Infection

 


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  		Table 2. Relative Risk* of Anal Cancer Among Never-Married Men

 

A more detailed review of several recent studies illustrates these points. Palefsky et al. characterized the prevalence of and risk factors for anal HPV infection and cytologic abnormalities by studying 37 HIV-infected and 28 non-HIV-infected participants in the San Francisco General Hospital Cohort Study.14 Risk factors for detectable anal HPV infection identified in multivariate analysis included HIV seropositivity with CD4 count less than 200 cells/mm3 (p = 0.03) and history of smoking (p = 0.03). Risk factors for abnormal anal cytology included HIV seropositivity with CD4 count less than 200 cells/mm3 (p = 0.006) and current smoking (p = 0.03).

Carter et al., in a study of 210 men recruited from a central London genitourinary medicine clinic, found anal intraepithelial neoplasia to be more common in biopsy specimens from HIV-infected patients than from non-HIV-infected patients (relative risk, 1.58; 95% confidence interval, 1.01 to 2.48).15 In addition, patients with anal warts, which are known to be associated with HPV infection, were more likely to have anal intraepithelial neoplasia than those without warts (relative risk, 4.70, 95% confidence interval, 1.81 to 12.20).

An important study by Williams et al. examined the relation between anal and cervical HPV infection, HIV infection, and anal and cervical cytologic abnormalities in 114 women.16 They found that anal and cervical HPV infection and cytologic abnormalities were significantly more common in HIV-infected women than in non-HIV-infected women, and that anal cytologic abnormalities were actually more common than cervical cytologic abnormalities. They further noted that cytologic abnormalities and detection of HPV infection by the dot blot hybridization technique (less sensitive than PCR) were associated with lower CD4 counts, suggesting that greater impairment in immune system function may lead to greater proliferation and easier detection of HPV in infected tissues.

Invasive Anal Cancer: Epidemiology and Clinical Aspects

Less has been published on the clinical features of invasive anal cancer in HIV-infected persons. Epidemiologic evidence has shown the incidence of invasive anal cancer to be increasing among men at risk for HIV infection. Between 1986 and 1987, the odds ratio for detection of anal or anorectal cancer in young unmarried men was 2.6 relative to the period between 1973 and 1978 (prior to the HIV epidemic).17 A subsequent analysis of the same data by these authors revealed that the relative risk of anal cancer among never-married men increased significantly compared with ever-married men in urban areas (Table 2).18 The authors speculated that this increased risk for anal cancer may be due to the influence of HIV infection during the second period of their analysis.

Lorenz et al.19 reviewed the surgical experience with anal carcinoma in HIV-infected men at the University of California, San Francisco. They noted poor treatment outcomes and short survival in their patients, similar to the experience described with HIV-associated cervical cancer. Reports of single cases have described varying outcomes with standard therapeutic approaches, suggesting that HIV-infected patients can benefit from standard therapies for anal cancer when immune system function is relatively intact.20,21

Holland and Swift retrospectively compared the anal cancer treatment outcomes of 7 HIV-seropositive patients and 55 patients whose HIV serostatus was negative or unknown.22 The HIV-infected patients required more treatment delays and hospitalizations due to treatment-related toxicities. Relapses were more common, and the mean time to failure of treatment was shorter in HIV-infected patients.

Screening for Anal Neoplasia in Persons with HIV Infection

Although anogenital HPV infection and intraepithelial neoplasia are common in persons with HIV-induced immunodeficiency, information on the natural history of these conditions is limited. Nevertheless, experts in this field hypothesize that such lesions are precancerous and likely to evolve into invasive cancer. Early detection of preinvasive or minimally invasive anal cancers can provide the opportunity to cure these diseases, as has been demonstrated by the success of screening programs using cervical Pap smears in the general female population. Recommendations on screening for anal neoplasia in persons with HIV infection are presented in Table 3.

As is true for cervical neoplasia, the anal Pap smear (Table 4) may be useful as a screening tool in patients with HIV infection who are at high risk for anal HPV infection and neoplasia. Preliminary studies have suggested that anal Pap smears have a sensitivity of 50% to 75% (with histopathology being the "gold standard"), similar to that of cervical Pap smears.23-25 However, other investigators have reported that anal cytology is relatively insensitive, and that colposcopy and biopsy are generally required to adequately assess anal dysplasia.26 In addition, the grading of anal Pap smears has not correlated well with the histopathologic grade of simultaneously biopsied lesions, with the Pap smear generally underestimating the grade of neoplasia.27

There is currently no information available on which to base recommendations on the optimal type or frequency of screening for anal neoplasia in persons with HIV infection. The use of tests for detection of HPV infection as a means of further refining screening and diagnosis of anal neoplasia has not received sufficient study to allow for general recommendations to be made. The screening strategy presented in Table 3 is based on screening for cervical neoplasia and is analogous to it.

At Pacific Oaks Medical Group in Palm Springs, Calif., a primary care and multispecialty group focusing on care of persons with HIV infection, we are developing a screening strategy for anal neoplasia. HIV-infected outpatients are offered Pap smears if they have any history of anal condyloma or current anorectal symptoms, or if they have CD4 counts less than 200/mm3 and are currently smoking tobacco. Those found to have mild or moderate cytologic atypia (AIN-1, AIN-2) are scheduled for follow-up screening at 6- to-12 month intervals. Those with severe cytologic atypia (AIN-3, carcinoma in situ) undergo anoscopy with four-quadrant biopsies for more definitive assessment. Outcome information is being collected to determine the value of this strategy.


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  		Table 3. Screening for Anal Neoplasia in Persons with HIV Infection

 


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  		Table 4. Anal Pap Smear Technique

 


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  		Table 5. Standard Treatment Approaches for Anal Neoplasia

 

Anal neoplasia must be ruled out in anyone with HIV infection who presents with anorectal complaints. Investigation of any abnormal discharge, bleeding, bowel irregularity, pruritus, dysuria, or pelvic pain should include screening for anal neoplasia.

Therapy for Anal Neoplasia

A person with HIV infection who develops anal neoplasia should receive the standard therapy for the specific stage of disease. These standard treatment approaches are outlined in Table 5. At present, there is no information to suggest that persons with HIV and HPV infection can benefit from other than standard therapies for anal neoplasia. However, general health status and stage of HIV disease must be considered when planning therapy.

Appropriate therapy for AIN has yet to be defined, because the natural history and implications of this condition are uncertain. At the University of California, San Francisco, the current approach is to treat only high-grade anal lesions (AIN-2, AIN-3). This approach is based on experience accumulated in natural history studies of cervical intraepithelial neoplasia, which suggest that the majority of low-grade lesions regress spontaneously.27

Experience at San Francisco General Hospital and the University of California, San Francisco, suggests that patients with mild or moderate immunodeficiency can tolerate standard combined modality therapy (external beam radiotherapy with concomitant chemotherapy) for invasive anal carcinoma.22 However, radiotherapy should be directed to a treatment field smaller than the full pelvic field used in non-HIV-infected patients with anal cancer, because of the increase in mucosal toxicity and myelotoxicity seen in radiotherapy of patients with HIV disease.

Summary

Prolonged, severe immunodeficiency provides the necessary milieu for the emergence of anogenital neoplasia related to HPV infection. Cervical and anal neoplasia are likely to become more common manifestations of HIV disease as patients with profound immunodeficiency, who would have succumbed to opportunistic infections earlier in the epidemic, are now surviving for extended periods because of increasingly effective antiretroviral, prophylactic, and antimicrobial therapies. The screening and treatment strategies described above for use in HIV-infected patients with anogenital neoplasia are currently being investigated and refined.

— Donald W. Northfelt, MD, FACP

Dr. Northfelt is an AIDS oncologist and AIDS primary care physician, Pacific Oaks Medical Group, Palm Springs, Calif. He was formerly Assistant Clinical Professor, UCSF. The author wishes to thank Joel M. Palefsky, MD, CM, and Patrick S. Swift, MD, for helpful comments.

Published in AIDS Clinical Care August 1, 1996

Citation(s):

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2. Dyson N et al. The human papillomavirus-16 E7 oncoprotein is able to bind the retinoblastoma gene product. Science 1989 Feb 17 243 934-937.

3. Werness BA et al. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 1990 Apr 6 248 76-79.

4. Koutsky L et al. A cohort study of the risk of intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Engl J Med 1992 Oct 29 327 1272-1278.

5. Daling JR et al. Sexual practices, sexually transmitted diseases, and the incidence of anal cancer. N Engl J Med 1987 Oct 15 317 973-977.

6. Holly EA et al. Anal cancer incidence, genital warts, anal fissure or fistula, hemorrhoids, and smoking. J Natl Cancer Inst 1989 Nov 15 81 1726-1731.

7. Gal AA et al. Papillomavirus antigens in anorectal condyloma and carcinoma in homosexual men. JAMA 1987 Jan 16 257 337-340.

8. Gal AA et al. In situ hybridization analysis of human papillomavirus in anal squamous cell carcinoma. Mod Pathol 1989 Sep 2 439-443.

9. Palefsky JM et al. Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Res 1991 Feb 1 51 1014-1019.

10. Penn I. Cancers of the anogenital region in renal transplant recipients: analysis of 65 cases. Cancer 1986 Aug 1 58 611-616.

11. Penn I. Tumors of the immunocompromised patient. Annu Rev Med 1988 39 63-73.

12. Sillman FH and Sedlis A. Anogenital papillomavirus infection and neoplasia in immunodeficient women. Obstet Gynecol Clin North Am 1987 Jun 14 537-558.

13. Majewski S et al. Partial defects of cell-mediated immunity in patients with epidermodysplasia verruciformis. J Am Acad Dermatol 1986 Nov 15 966-973.

14. Palefsky JM et al. Risk factors for anal human papillomavirus infection and anal cytologic abnormalities in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr 1994 Jun 7 599-606.

15. Carter PS et al. Human immunodeficiency virus infection and genital warts as risk factors for anal intraepithelial neoplasia in homosexual men. Br J Surg 1995 Apr 82 473-474.

16. Williams AB et al. Anal and cervical human papillomavirus infection and risk of anal and cervical epithelial abnormalities in human immunodeficiency virus-infected women. Obstet Gynecol 1994 Feb 83 205-211.

17. Rabkin CS et al. Cancer trends associated with increasing AIDS (abstract). VI International Conference on AIDS, San Francisco 1990 1 295-.

18. Melbye M et al. Changing patterns of anal cancer incidence in the United States, 1940-1989. Am J Epidemiol 1994 Apr 15 139 772-780.

19. Lorenz HP et al. Squamous cell carcinoma of the anus and HIV infection. Dis Colon Rectum 1991 Apr 34 336-338.

20. Svensson C et al. Carcinoma of the anal canal in a patient with AIDS. Acta Oncol 1991 30 986-987.

21. Nasti G et al. Anal cancer in patients with HIV infection: a report of two cases without evidence of immunological dysfunction. AIDS 1994 Oct 8 1507-1508.

22. Holland JM and Swift PS. Tolerance of patients with human immunodeficiency virus and anal carcinoma to treatment with combined chemotherapy and radiation therapy. Radiology 1994 Oct 193 251-254.

23. Palefsky JM et al. Natural history of anal cytologic abnormalities and papillomavirus infection among homosexual men with group IV HIV disease. J Acquir Immune Defic Syndr 1992 Dec 5 1258-1265.

24. Melbye M and Sprogel P. Aetiological parallel between anal cancer and cervical cancer. Lancet 1991 Sep 14 338 657-659.

25. Sonnex C et al. Anal human papillomavirus infection: a comparative study of cytology, colposcopy, and DNA hybridisation as methods of detection. Genitourin Med 1991 Feb 67 21-25.

26. Surawicz CM et al. Anal dysplasia in homosexual men: role of anoscopy and biopsy. Gastroenterology 1993 Sep 105 658-666.

27. Palefsky JM. Anal human papillomavirus infection and anal cancer in HIV-positive individuals: an emerging problem. AIDS 1994 Mar 8 283-295.

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Copyright © 1996. Massachusetts Medical Society. All rights reserved.