Epidemiology

The increased frequency of squamous cell neoplasia in HIV-infected individuals has been documented in a number of studies. The single AIDS-defining disease among the HPV-related tumors is that of invasive cervical carcinoma, though there is controversy as to whether this malignancy is increased in frequency in the setting of HIV infection. However, it is very clear that intraepithelial neoplasia of both the uterine cervix and the anus is increased. Homosexual HIV-infected men have a particularly high incidence of squamous cell abnormalities and a markedly increased risk of anal cancer.²⁵² Whether the incidence of invasive cancer is greater in the HIV-infected as compared with the HIV-seronegative homosexual male cohort, also remains controversial. Indirect evidence that immune suppression augments this cancer risk comes from an analysis of AIDS and cancer registries. In a study by Frisch and colleagues, the incidence of in situ and invasive cancers was significantly higher in the 5 years following an AIDS defining illness than in the 5 years preceding it.²⁵³ Among women, cervical, vulvar/vaginal, and anal cancers were increased, while among men, anal, penile, tonsillar and conjunctival cancers were increased.

Pathology and Pathogenesis

The association of specific subtypes of HPV with a potential for epidermal cell transformation has been long established, and the frequency of HPV-16, -18, and -19, is reported to be increased in HIV-infected individuals.²⁵⁴ The frequency of multiple subtypes of HPV has also been assessed and found to be markedly increased in the HIV-infected population (73% of HIV-1-infected homosexual men, as compared with 23% of uninfected homosexual men).^254,255 The incidence of high-grade intraepithelial neoplasia of the anus has been estimated to be as high as 48% among HIV-1-positive homosexual men over a 4-year interval and was associated with the presence of multiple HPV subtypes, persistent anal infection, and high-level infection with oncogenic HPV subtypes.²⁵⁶ Screening for intraepithelial neoplasia among HIV-1-infected homosexual men has demonstrated a prevalence of high-grade anal intraepithelial neoplasia (or carcinoma in situ) of 36% compared with 7% of HIV-1-negative homosexual men.²⁵⁷ Most often, these lesions on the anus and uterine cervix are not solitary sites but rather represent one of multiple areas of dysplasia and are therefore difficult to satisfactorily treat,²⁵⁸ particularly on the anus. Patients with a history of high-grade intraepithelial neoplasia may often have recurrence following attempts at excision, cryotherapy, or topical treatment because of the ubiquitous nature of the HPV infection locally and the tendency of that virus to continue to have effects on local tissue.

A critical issue in evaluating the magnitude of this problem is the risk of progression of intraepithelial neoplasia to frank invasive cancer. This issue remains ill defined and highly controversial. If the risk is estimated at 1% or above, cost-benefit analyses have indicated that ongoing screening is justified.²⁵⁹ The lack of large increases in the frequency of invasive anogenital cancer among HIV risk groups suggests that the risk is relatively small. However, the potential for frank invasion is not zero, and therefore, vigilance among patients with HIV disease is warranted.

The risk of some opportunistic neoplasms is clearly diminished in the context of aggressive therapy for HIV and suppression of HIV replication. There have been conflicting reports of whether HPV-related tumors are among those responsive to improved anti-HIV therapy. Some reports have indicated that some individuals may experience improvement in HPV-related neoplasia,²⁶⁰ while others indicate otherwise.²⁶¹ At present, the complete suppression of HIV should not be regarded as fail-safe defense against the development of HPV-related tumors.

Clinical Presentation

HPV disease may present anywhere along the continuum of condyloma acuminatum to invasive anal cancer. Patients who have anal dysplasia may or may not have symptoms associated with it. Common practice among patients with a history of high-grade anal dysplasia is to perform an anoscopic examination and possible biopsy, even if the diagnostic lesion is on the anal verge, to assess for possible invasive disease out of the external examination field. Some centers are initiating anal Papanicolaou (Pap) evaluation for HIV-infected individuals, but this approach is highly controversial.

For women with HIV infection, the standard practices and recommendations for cervical screening are to be followed, with increased vigilance for those with severe immunosuppression. For HIV-infected women with CD4 counts of < 200 cells/mm³, the recommendation is for Pap smears to be performed semiannually.

Treatment

Treatment guidelines for dysplasia and carcinoma of the uterine cervix are well defined and should be followed in the setting of HIV infection. Management of anal disease is less clear.

For patients with invasive carcinoma of the anus, treatment guidelines recommending a combination of chemotherapy and radiation therapy should be followed; this treatment has been reasonably well tolerated in the HIV-infected population.^262–264 There is a distinct increased sensitivity to mucosal injury with radiation in HIV disease, and therefore, close interaction of the medical and radiation oncologist is essential. If patients have very advanced HIV disease failing antiretrovirals, a conservative approach to management of the malignancy may be warranted, but this requires case-by-case assessment.

The ambiguity of risk for invasion if high-grade intraepithelial neoplasia or carcinoma in situ is diagnosed has led to considerable variability in treatment practices for these patients. Our practice has been to surgically remove any lesions identifiable to the eye but not to attempt wide excisions. For those patients with recurrent anal warts or with tissue discoloration seen with HPV disease, imiquimod cream has been useful and is generally well tolerated. For lesions within the anal canal, satisfactory topical therapy is not available, and vigilant monitoring is the general approach.

Lesions on other sites are generally approached with similar principles. For invasive disease, resect, and use standard guidelines for care. For noninvasive disease, excise overt lesions locally, and attempt topical therapies such as imiquimod or 5-fluorouracil.