WOMEN WITH CERVICAL HUMAN PAPILLOMA virus (HPV) infection are at increased risk of developing cervical intraepithelial neoplasia that may progress to invasive cervical cancer.1 Human immunodeficiency virus (HIV)-infected women have a higher relative risk of cervical cancer than uninfected women, and invasive cervical cancer is an acquired immunodeficiency virus (AIDS)-defining malignancy.2,3 Similarly, prior studies have shown a high prevalence of anal squamous intraepithelial lesions among HIV-infected men and an increased incidence and relative risk of anal cancer among people with AIDS.4–6 Men with AIDS have an increased risk of developing anal cancer for multiple reasons. First, men who have sex with men (MSM) have an increased risk of anal cancer associated with the practice of receptive anal intercourse.7 Also, both HIV and HPV are sexually transmitted viruses and thus coinfection is common. Lastly, the immunosuppression associated with HIV infection results in an increased risk of HPV-related anal cancer, as is the case in immunosuppressed organ transplant recipients.8 Because highly active antiretroviral therapy (HAART) has been available since 1996, we sought to determine how the availability of HAART influenced rates of anal cancer among patients with AIDS.
AIDS and Cancer Registry Linkage Methods
We performed a linkage between the AIDS and cancer registries for San Diego County in August 2003 as part of a multicenter study sponsored by the National Cancer Institute.2,4 We obtained approval from the University of California Irvine Institutional Review Board before study initiation (IRB 97*503). Both the AIDS and cancer registries are population-based, striving to record all incident cases of cancer or AIDS, respectively, in San Diego County. We linked cancer registry data from 1988 to 2000 with AIDS registry data from 1981 through July 2003. The linkage identified 2055 patients as having both AIDS and cancer diagnoses; these patients were selected from 153,444 cancer registry patients and 11,867 AIDS registry patients.
Anal Cancer Case Definitions
We defined squamous cell cancer of the anus as topographic code C21 with histology code 8050 to 8089,9 thus excluding carcinoma of the rectum and carcinoma with nonsquamous histology such as non-Hodgkin lymphoma or Kaposi’s sarcoma. Of the 2055 patients with AIDS and cancer, 39 had anal squamous cell cancer. By reviewing cancer registry abstracts of all male anal cancer cases in San Diego diagnosed between 1988 and 2000, we identified three additional cases of anal cancer in men with AIDS and five cases of anal cancer in men with HIV infection. In addition, we examined the death certificate diagnoses of all anal male cancer cases in San Diego diagnosed between 1988 and 2000 and did not find any additional AIDS cases.
To characterize the 42 men with AIDS and anal cancer, we determined their age, race, HIV-related characteristics (CD4 cell count, HIV-exposure category, and duration of HIV infection), stage of cancer, treatment (surgery, radiation, and/or chemotherapy), and outcomes (vital status, survival, and cause of death listed first on the death certificate). We did not have CD4 cell counts for the three men from the cancer registry and did not know the duration of HIV infection for two of these three men. We defined the pre-HAART period as 1991–1995 and the post-HAART period as 1996–2000. We chose these 5-year time periods because there were no anal cancer cases in men with AIDS before 1992 and HAART became commercially available in 1996.
We used the Mann-Whitney U test to compare CD4 cell counts and Student t test to compare duration of known HIV infection in the pre-HAART versus post-HAART periods. In calculating the duration of known HIV infection, we excluded men who were diagnosed with anal cancer before their HIV diagnoses. Using the Fisher exact test, we compared the frequency of in situ disease in the pre-HAART versus post-HAART period. We used the Kaplan-Meier method to determine the median survival. We used SPSS 11.5 statistical software (SPSS Inc., Chicago, IL).
We performed the calculations shown subsequently for all cases of anal cancer and for invasive cases only. We determined the annual age-specific incidence of squamous cell anal cancer for men with AIDS aged 25 to 64 years in San Diego County for 1991–2000 and the corresponding rates for all San Diego men aged 25 to 64 years. We then excluded men who were identified through the registry linkage as having AIDS and men who were recorded as HIV-infected on their cancer registry abstract to determine the annual age-specific incidence of anal cancer among men without known HIV/AIDS in San Diego County between 1991 and 2000. We used the age range of 25 to 64 years because there were no cases in patients with AIDS outside of this age range, and the majority of men with AIDS fall in this age range; younger men are at low risk for developing anal cancer. Spearman’s rank correlation was used to evaluate trends in the annual incidence of anal cancer among patients with AIDS, anal cancer among men in San Diego, and anal cancer among men without known HIV/AIDS in San Diego. We then determined an average annual age-specific incidence in men with AIDS and men without known HIV/AIDS for the pre- and post-HAART periods. For all of the rates here, we calculated exact (Poisson) 95% confidence intervals.10 Lastly, we calculated the relative risk by dividing the average annual age-specific incidence among the men with AIDS by the average annual age-specific incidence among the men without known HIV/AIDS and estimated 95% confidence intervals (log-normal approximation).
All 42 patients with squamous cell carcinoma of the anus were men. The median age was 42 years (range, 25–63 years). Thirty-three (79%) were white, 7 (17%) were Latino, and 2 (5%) were black.
Ninety percent (N = 38) of the 42 patients were MSM; 9 of the 38 MSM reported injection drug use as well as sex with men as an HIV exposure. Two (5%) reported injection drug use without other HIV exposures. Another two (5%) did not have their risk factor recorded, although both had a history of Kaposi’s sarcoma implicating homosexual sex as an HIV exposure.11 Among the 37 men known to have been diagnosed with HIV before or simultaneous with their anal cancer diagnoses, the median duration of known HIV infection before the diagnosis of anal cancer was 76 months (range, 0–175 months). The median duration of HIV infection was 22 months among men diagnosed in the pre-HAART period versus 84 months among men diagnosed in the post-HAART period (P <0.01). Among the three men who were diagnosed with HIV after their anal cancer diagnoses, the duration of time between anal cancer diagnosis and HIV diagnosis ranged from 2 weeks to 13 months.
The median most recent CD4 cell count was 120/MCL (range, 2–551) with a median of 57/MCL among patients diagnosed with anal cancer pre-HAART versus 160/MCL in patients diagnosed with anal cancer post-HAART (P <0.09). The median lowest CD4 cell count was 63/MCL (range, 2–368) with a median of 57/MCL in patients diagnosed with anal cancer pre-HAART versus 86/MCL in patients diagnosed with anal cancer post-HAART (P <0.42).
Stage, Treatment, and Outcomes of Anal Cancer
Twelve (29%) anal cancer cases were in situ, whereas 30 (71%) were invasive. Four (44%) of nine cases in the pre-HAART period were in situ, whereas 8 (24%) of 33 cases diagnosed in the post-HAART period were in situ (P <0.41).
Thirty men (71%) received surgical treatment. Seventeen (40%) received both radiation therapy and chemotherapy. One (2%) received radiation therapy without chemotherapy and one (2%) received chemotherapy without radiation. Twenty-three (55%) did not receive radiation or chemotherapy.
The median survival was 37 months (range, 2–104 months). Twenty-one (50%) patients were alive at most recent follow up. The median follow-up time was 22 months (range, 2–104 months). Among the 21 deceased, 8 (38%) died of HIV/AIDS, 6 (29%) died of anal cancer, and 7 (33%) died of other or unknown causes.
Annual Incidence of Anal Cancer Among Men With AIDS in San Diego County, 1991–2000
None of the 42 cases of anal cancer among men with AIDS were diagnosed before 1992. Nine (21%) were diagnosed in the pre-HAART period and 33 (79%) were diagnosed in the post-HAART period. The number of cases of squamous cell anal cancer among patients with AIDS increased each year between 1996 and 2000 (3 in 1996, 5 in 1997, 6 in 1998, 8 in 1999, and 11 in 2000; Table 1). The incidence of anal cancer in men with AIDS increased from zero per 100,000 men with AIDS aged 25 to 64 years in 1991 to 274 per 100,000 in the year 2000 (r = .70, P <0.03) (Fig. 1). The incidence of invasive anal cancer also rose from zero per 100,000 men with AIDS aged 25 to 64 years in 1991 to 224 per 100,000 in the year 2000 (r = .70, P <0.03) (Fig. 2).
Annual Incidence of Anal Cancer Among Men in San Diego County, 1991–2000
The number of male cases of squamous cell anal cancer in the San Diego County cancer registry among men aged 25 to 64 years increased from 3 in 1991 to 16 in the year 2000 (Table 1), and the age-specific incidence of anal cancer among all men in San Diego increased from 0.5 per 100,000 in 1991 to 2.1 per 100,000 in the year 2000 (r = 0.77, P <0.01). The incidence of invasive anal cancer also rose from 0.5 per 100,000 men aged 25 to 64 years in 1991 to 1.6 per 100,000 in the year 2000 (r = .75, P <0.01).
Annual Incidence of Anal Cancer Among Men Without Known HIV/AIDS in San Diego County, 1991–2000
After exclusion of men who were identified through the linkage as having AIDS and men who were recorded as HIV-infected on their cancer registry abstract, the age-specific incidence of squamous cell anal cancer among men in San Diego without known HIV/AIDS did not demonstrate a trend (r = −.15, P <0.69) (Table 1). There also was no trend for the incidence of invasive anal cancer among men without HIV/AIDS (r = −.44, P <0.20).
Average Annual Incidence and Relative Risk of Anal Cancer Pre- and Post-HAART
Among men with AIDS, the average annual incidence of anal cancer pre-HAART was 88 per 100,000 men aged 25 to 64 years and 190 per 100,000 post-HAART (Table 2). The relative risk of anal cancer among men with AIDS aged 25 to 64 years as compared with men without known HIV/AIDS of the same age was 149 pre-HAART and 367 post-HAART. For invasive anal cancer among men with AIDS, the average annual incidence of anal cancer pre-HAART was 49 per 100,000 men aged 25 to 64 years and 144 per 100,000 post-HAART, and the relative risk of anal cancer among men with AIDS aged 25 to 64 years as compared with men without known HIV/AIDS of the same age was 98 pre-HAART and 352 post-HAART.
We used a linkage between the San Diego County AIDS and cancer registries to determine whether the availability of HAART coincided with a change in the incidence of squamous cell anal cancer among patients with AIDS. The annual incidence of invasive anal cancer increased from zero per 100,000 men with AIDS aged 25 to 64 years in 1991 to 224 per 100,000 in the year 2000 (Fig. 2). Pre-HAART, the average annual incidence of invasive anal cancer was 49 per 100,000 men with AIDS aged 25 to 64 years versus 144 per 100,000 post-HAART. The relative risk of invasive anal cancer among men with AIDS compared with men without known HIV/AIDS was 98 pre-HAART and 352 post-HAART (Table 2). The increased incidence of anal cancer among men with AIDS resulted in an increase in the age-specific rate of anal cancer among men in San Diego County.
Patients diagnosed with anal cancer during the post-HAART period had a longer duration of diagnosed HIV infection (84 months vs. 22 months pre-HAART). HPV-associated anal cancer has a latency period of 5 to 40 years in individuals without HIV infection, although immunosuppression may accelerate the development of malignancy.12 Although three of our 42 cases were diagnosed with anal cancer before their HIV diagnoses, it is likely that these men were HIV-infected but had not undergone serologic testing at the time of their anal cancer diagnoses. Because MSM with HPV are at increased risk for anal cancer even without HIV infection or AIDS,7,13 anal dysplasia may have developed before HIV infection or at least before the development of AIDS-related immunosuppression. It is possible that the use of HAART increases longevity and thus the time at risk for the development of anal cancer.
The median CD4 cell counts were low among our cases in both the pre- and post-HAART period consistent with either lack of HAART or absence of response to HAART. However, we identified most cases from the AIDS registry in which the majority of patients will have CD4 cell counts under 200/MCL. Previous studies have shown that low CD4 cell counts are associated with an increased risk of high-grade anal squamous intraepithelial lesions.14,15 Based on those findings, one would expect that the improved CD4 cell counts associated with HAART would result in less squamous intraepithelial lesions and thus less anal cancer. However, studies have shown no correlation between successful antiretroviral therapy and regression or decreased prevalence of squamous intraepithelial lesions.16–18 HAART has dramatically decreased rates of the AIDS-defining malignancy Kaposi’s sarcoma.19 However, anal cancer is more similar to another AIDS-defining malignancy, cervical cancer, in its pathogenesis. Early reports suggest that HAART may not reduce rates of AIDS-related cervical cancer and may even increase its incidence.19,20 Improved survival with the use of HAART and the resultant increased time to develop anal cancer may outweigh any potential decreased risk conferred by increased CD4 cell counts with HAART.
Similar to the increasing incidence among people with AIDS, the age-specific rate of squamous cell anal cancer among all men in San Diego increased from 0.5 per 100,000 in 1991 to 2.1 per 100,000 in the year 2000. However, when we exclude men with known HIV/AIDS, there is no clear trend for this rate (Table 1). This finding suggests that HIV-infected men contribute greatly to the general rise in anal cancer rates in San Diego County men. A previous report hypothesized that increased rates of anal cancer among men in San Francisco in the 1990s might be related to the increased prevalence of HIV infection among MSM in that region, and our data provides evidence that increasing rates of anal cancer are related to the HIV epidemic.21,22
Our post-HAART anal cancer (invasive and in situ) average annual incidence of 190 per 100,000 men with AIDS aged 25 to 64 years (95% confidence interval [CI], 131–266) and relative risk of 367 (95% CI, 209–646) in men with AIDS compared with men without HIV/AIDS (Table 2) are higher than previous estimates. Previous studies have reported the relative risk of anal cancer in MSM as approximately 12 to 337,13 and the relative risk of anal cancer in MSM with AIDS in the pre-HAART era as 84.4 Frisch et al reported a relative risk of 60 for in situ anal cancer and 38 for invasive anal cancer for men with AIDS.2 It is possible that the exclusion of cases of known HIV from the denominator of the relative risk escalated the relative risk, but given that men with HIV without AIDS may have an increased risk of anal cancer, we felt justified in excluding them.4,6 Similarly, the inclusion of the AIDS cases from the cancer registry may have increased the rate of anal cancer among men with AIDS, but we included them because they were definite cases of anal cancer in men with AIDS. The relative risk of anal cancer among men with AIDS increased between the pre- and the post-HAART periods.
Knowledge of the changing size of the AIDS population is necessary to interpret the rates of anal cancer among men with AIDS. During the period under study, the AIDS population denominator has increased every year (Table 1), whereas AIDS incidence reached its peak in 1993, the first year of implementation of the expanded AIDS surveillance case definition.3 Three cases of anal cancer occurred in men with AIDS in 1992, resulting in a spike in the age-specific rate of squamous cell anal cancer among men with AIDS. However, there were no recorded cases of anal cancer in people with AIDS before 1992. Furthermore, the age-specific incidence of squamous cell anal cancer among men with AIDS declined to a low of 77 per 100,000 in the following years. Thus, small numbers and use of the more restrictive pre-1993 AIDS case definition may have resulted in an elevated rate in 1992.
Although the increase in anal cancer incidence among people with AIDS phenomenon could be related to more screening for anal cancer, the percentage of in situ cases did not change significantly between the pre-HAART and post-HAART periods. Furthermore, excluding in situ cases did not change the trend. If the increase in rates was the result of screening, one would expect more early-stage tumors in the post-HAART era. Nevertheless, we cannot exclude an effect of increased screening and/or diagnosis as an explanation of our findings. There has been greater physician awareness in recent years of anal cancer morbidity in MSM. This awareness may have resulted in the performance of more screening cytologic examinations and perhaps a lower threshold for biopsy of anal lesions. To our knowledge, there was no organized screening program in San Diego County until July 2000, near the end of the period under study. However, HIV specialist providers might have read about anal cancer screening and initiated it outside of an organized program.
It may be difficult for a pathologist to distinguish between severe dysplasia and carcinoma in situ and not every case of carcinoma in situ will necessarily progress to invasive cancer. Although it is possible physicians might not report anal carcinoma in situ for the reasons mentioned here, the cancer registry considers it reportable and routinely reviews pathology reports from hospitals and independent pathology services to obtain cases not reported by physicians. Because of the concerns regarding the diagnosis and reporting of carcinoma in situ, we report both total rates (including carcinoma in situ) and rates for invasive cancer only.
There is always the possibility of incomplete reporting to either the cancer registry or the AIDS registry as evidenced by the three additional cases of anal cancer in men with AIDS found in the cancer registry. However, lack of reporting to either registry would likely result in an underestimate of the increased incidence because of failure of cases to match. By examining cancer registry abstracts and death certificates for HIV/AIDS diagnoses, we sought to find cases not in the AIDS registry such as individuals with HIV infection who have not progressed to AIDS or AIDS cases not reported to the AIDS registry.
There are limitations to our study. The number of cases is small. However, we use information collected over more than a decade from both the cancer and AIDS registries, which are both population-based. Because the cancer registry does not routinely collect information regarding HIV status in patients with anal cancer, we do not know the HIV status of men with anal cancer who are in the cancer registry but either did not match with AIDS registry or did not have their HIV status recorded on the cancer registry abstract or death certificate. The cancer registry also does not routinely collect information regarding other factors related to the risk of anal cancer such as homosexual orientation, smoking, or HPV infection, all of which are more common in people with HIV infection.23 Lastly, our study defines 1996–2000 as the post-HAART period because HAART became widely available in the United States in 1996; we do not know whether any of the men diagnosed in the post-HAART period actually received HAART.
Our findings suggest that squamous cell anal cancer will be an increasing source of morbidity and mortality among patients with AIDS post-HAART. We propose that invasive anal cancer, like cervical cancer, should be considered an AIDS-defining illness because HIV-related immunosuppression increases the prevalence of anal dysplasia and the risk of anal cancer and may adversely affect the clinical course and treatment of anal cancer.24 Researchers have suggested annual anal cytologic examinations may be indicated in HIV-infected individuals to diagnose and treat dysplasia before the development of invasive cancer.25 An increasing risk of anal cancer among men with AIDS would provide an argument for the benefits of screening. We recommend further clinical research regarding the prevention, early diagnosis, treatment, and outcomes of anal cancer among the HIV-infected as well as basic research on whether HAART alters the biologic and immunologic milieu to promote anal carcinogenesis.
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