1 New York State Department of Health, Bureau of HIV/AIDS Epidemiology, Albany, NY.
2 New York State Department of Health, Bureau of Chronic Disease Epidemiology and Surveillance, Albany, NY.
3 New York City Department of Health, Office of AIDS Surveillance, New York, NY.
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ABSTRACT |
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acquired immunodeficiency syndrome; HIV; lymphoma; AIDS-related; lung neoplasms; registries; risk factors
Abbreviations: AIDS, acquired immunodeficiency syndrome; CNS, central nervous system; HIV, human immunodeficiency virus; IDU, injection drug user; MSM, men who have sex with men; NHL, non-Hodgkin's lymphoma; NYS, New York State; RR, relative risk; SIR, standardized incidence ratio
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INTRODUCTION |
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MATERIALS AND METHODS |
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Subjects and coding
Analysis of cancer incidence was restricted to AIDS and cancer cases diagnosed between 1981 and 1994 because these were the date ranges that were available. NYS residents aged 1569 years were abstracted from the matched data set. Malignant disorders were grouped into types or sites of cancer by using the International Classification of Diseases, Ninth Revision codes (19). Although 57 separate sites or types of cancer were identified, analysis was limited to cancers with frequencies of four or more. Cancers were classified as AIDS defining if they were included in the 1993 AIDS case definition (6
) or as non-AIDS defining if they were invasive malignancies not included in the AIDS case definition. Noninvasive neoplasms (International Classification of Diseases, Ninth Revision, codes 210234) are also presented, although they are underreported to the cancer registry, and the results may be attenuated.
Data analysis
This study was limited to cancers diagnosed between 60 months before and 60 months after an AIDS diagnosis. This time interval was selected to make our results comparable with those of other published studies. The time interval before AIDS was also selected because there is evidence that the median duration of HIV infection before AIDS is at least 5 years (2022
). While cancers that occur in a patient prior to AIDS are, strictly speaking, HIV, not AIDS, related, we denote this period prior to an AIDS diagnosis as the pre-AIDS period. For the post-AIDS period, the median duration of survival post-AIDS diagnosis has been reported within the range of 326 (21
) and 222 months (23
). While these findings indicate that a short post-AIDS follow-up period may be sufficient to capture the majority of cancers that occur in AIDS patients after AIDS diagnosis, we have chosen to use an extended post-AIDS period to capture as many observations of cancer as possible in this time interval. Examining the NYS data, we found a small number of cancers occurring up to 5 years after AIDS diagnosis, and we chose to include these observations in the analysis. The calculation of person-time for the period at risk for cancer was defined as beginning in 1981 or 5 years prior to an AIDS diagnosis, whichever occurred later, and ending 5 years post-AIDS diagnosis, at the date of death, or on December 31, 1994, whichever occurred earliest. The observed number of cancers by type or site among people with AIDS was compared with the expected number of cases by calculating standardized incidence ratios (SIRs). Expected incident cases at the time of AIDS diagnosis or after AIDS diagnosis were calculated by multiplying NYS age-, sex-, region-, and race-specific cancer incidence rates from the NYS Cancer Registry by the corresponding person-years at risk for these time periods. However, calculation of the expected number of cancer cases preceding AIDS was complicated because HIV-infected subjects who develop cancer might die before progression to AIDS and therefore would never be recorded in the AIDS registry. In our study, the cohort that was matched to the cancer registry was diagnosed with AIDS; therefore, they survived until AIDS diagnosis. All of the cancer cases observed in this cohort diagnosed before AIDS survived to an AIDS diagnosis. Since the observed cancer cases survived until AIDS diagnosis, the expected cancer cases must be adjusted to reflect survival to AIDS diagnosis. Therefore, the joint probability of developing cancer and of surviving cancer was applied to the person-year distribution, and NYS cancer incidence rates and Surveillance, Epidemiology, and End Results differential survival rates for specific malignancies were used to calculate the expected number of cancer cases prior to AIDS diagnosis (24
). All SIRs discussed in the results are adjusted. To calculate confidence intervals around the SIR, either the normal or the Poisson distribution was used, depending on the number of expected cases. If the number of expected cases was equal to or greater than 25, the normal distribution was used; otherwise, the Poisson distribution was used.
For determination of whether cancer risk increases with time, as the immune status of the HIV-infected patient declines, the time period between a cancer and AIDS diagnosis was divided into four intervals: early pre-AIDS diagnosis (-60 to -25 months), late pre-AIDS diagnosis (-24 to -7 months), at AIDS diagnosis (-6 to 3 months), and post-AIDS diagnosis (460 months) (figure 1). The trend in relative risk was analyzed over three time periods (the at AIDS time period was excluded) by using the Poisson trend statistic (25).
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To explore the association between risk factors and malignant disease, SIRs were calculated for groups defined by HIV exposure group (men who have sex with men (MSM) combined with MSM and intravenous drug user (IDU), heterosexual contact with HIV/AIDS patients, IDUs, patients infected via transfusion or transplantation, and unknown or other HIV exposure).
All statistical analyses were performed by using the Statistical Analysis System (26).
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RESULTS |
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Non-AIDS-related cancers and post-AIDS relative risks
For all non-AIDS-related cancers combined, the relative risk was 3.1 for men and 2.9 for women, and significantly elevated relative risks were found for several sites and types of cancer in both men and women (table 4). Cancers with significant relative risks for men and women were liver (relative risk (RR) = 3.6 and 9.2, respectively); trachea, bronchus, and lung (RR = 3.0 and 7.1, respectively); skin, excluding Kaposi's sarcoma (RR = 44.6 and 12.0, respectively); brain and CNS (RR = 4.0 and 6.2, respectively); Hodgkin's disease (RR = 5.3 and 7.2, respectively); and multiple myeloma (RR = 3.5 and 9.2, respectively). We also found significantly elevated relative risks for the rectum, rectosigmoid, and anus (RR = 4.0) and connective tissue (RR = 9.9) in men and for gum and other mouth (RR = 13.5), esophagus (RR = 8.7), stomach (RR = 5.4), larynx (RR = 10.6), and leukemias (RR = 5.2) in women.
Non-AIDS-related cancers and relative risk trend
Significant increases in relative risk over time were found for several sites in men and women. For some of the sites with significant trends, the changes in relative risks over time were not linear. For men, cancers with significant trends were digestive system (p = 0.002); Hodgkin's disease (p = 0.0135); rectum, rectosigmoid, and anus (p = 0.0164); trachea, bronchus, and lung (p = 0.0046); brain and CNS (p = 0.0018); melanoma of the skin (p = 0.0478); skin, excluding Kaposi's sarcoma (p < 0.0000); leukemias (p = 0.0087); and connective tissue cancers (p < 0.0000) (table 5). The only site of non-AIDS-related cancer found to increase significantly over time in women was the digestive system (p = 0.0176) (table 6).
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Non-AIDS-related cancers with SIRs lower than those of the general population
In men, prostate (SIR = 0.7) and bladder (SIR = 0.5) cancers both had SIRs below 1.0 (table 2). These sites had relative risks below 1.0 during all periods relative to AIDS diagnosis, including the AIDS period (table 5). For women, breast cancer had an SIR of 0.8 (95 percent confidence interval: 0.58, 1.04) (table 3). Relative risks for breast cancer in the early pre-AIDS and post-AIDS periods were below 1.0, with the post-AIDS period being especially low (RR = 0.2) (table 6).
Non-AIDS-related cancer risk by HIV exposure group
Cancers with significantly elevated overall SIRs were evaluated by HIV exposure group. All results are displayed in table 7. Results for groups with five or more observations are presented as follows.
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Hodgkin's disease. Male homosexual contact (SIR = 8.7) and intravenous drug use (SIR = 7.8) had comparable risks, while the SIR for heterosexual contact was 31.3. For female heterosexual contact, there was a higher standardized incidence ratio (SIR = 12.3) than for injection drug use (SIR = 9.4).
Trachea, bronchus, and lung. There was a higher SIR for male injection drug use (SIR = 4.6) than for male homosexual contact (SIR = 2.6). For female injection drug use, there was an elevated standardized incidence ratio (SIR = 9.8) compared with female heterosexual contact (SIR = 6.4).
Brain and CNS. In men, the SIR for homosexual contact was 4.7, which was higher than that for intravenous drug use (SIR = 2.7), while for women, the SIR for heterosexual contact was 23.8.
Connective tissue. Among men who acquired HIV infection through homosexual contact, the risk was increased 10.5-fold.
Oral cavity and pharynx. The SIRs for male and female intravenous drug use were 1.9 and 8.2, respectively.
Digestive system. For male intravenous drug use, there was an elevated SIR of 1.8, and the SIR for female heterosexual contact (SIR = 3.1) was higher than that for female intravenous drug user (SIR = 2.4).
Invasive cervix. The SIR for heterosexual contact was higher (SIR = 10.7) than that for intravenous drug use (SIR = 8.7).
In situ cervix. The SIRs for heterosexual contact (SIR = 5.4) and intravenous drug use (SIR = 5.3) were comparable.
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DISCUSSION |
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Hodgkin's disease
Hodgkin's disease is one of the most common non-AIDS-related cancers found in this cohort. The overall SIRs (male, 8.0; female, 6.4; both, 7.8) in our study are consistent with studies from San Francisco (male, 8.8) (9), the United States and Puerto Rico (both 8.8) (2
), and Italy (male, 9.3; female, 7.7) (4
), but are lower than those in the paper by Grulich et al. (5
) (both 18.3). The post-AIDS relative risks (male, 5.3; female, 7.2; both, 5.4) are also similar to those in the paper by Goedert et al. (2
) (both 7.6), but are much lower than those found by Franceschi et al. (4
) (both 20.4) and Grulich et al. (5
) (both 29.9). A significant, but nonlinear, increase in relative risk over time was found in male AIDS patients in this study (p = 0.0135). Goedert et al. (2
) previously found a significant increase in relative risk over time for both sexes; therefore, our study contributes to the evidence that the risk of Hodgkin's disease increases as males with HIV disease advance in their immunodeficiency.
Rectal and anal cancer
There is strong evidence of a relation between HIV-related immunodeficiency, human papilloma virus infection, and development of anal cancer (2934
). Carcinomas of the anus and anal intraepithelial neoplasia occur at increased rates among homosexual men with HIV. The incidence among MSM was elevated in 19731979, which preceded the HIV epidemic (35
). In our study, elevated overall SIRs for rectal and anal cancer were found (male, 3.3; female, 3.0), while post-AIDS relative risks were significant for men (RR = 4.0) but not for women. We also detected an elevated relative risk in male AIDS patients with declining immune status (p = 0.0164). Several other studies have also found an increased incidence of anal cancer in men but not in women (10
, 36
, 37
).
Lung cancer
Lung cancer is the second most common cancer in both men and women in the general population. In our study, we found a significant overall SIR (male, 3.3; female, 7.5; both, 3.7), similar to a report by Grulich et al. (5) (both 3.8). Post-AIDS relative risks were also significantly elevated (male, 3.0; female, 7.1; both, 3.3), and this is also similar to the post-AIDS result from Grulich et al. (5
) (both 3.9). A significant (p = 0.0046) increase in the trend in relative risk was also found in men.
This study found a significantly increased risk of lung cancer with advancing immunodeficiency. However, this result may be confounded, since it is widely known that lung cancer is related to tobacco use, and it is likely that HIV-infected patients smoke more cigarettes per day than do persons in the general population.
Brain and CNS cancer
In recent years, incidence of brain and CNS cancer has risen strikingly, and CNS lymphoma in people with AIDS is thought to represent much of the recent increase (3840). In our study, we found elevated SIRs (male, 3.1; female, 3.4; both, 3.2), which is higher than the findings in the study by Goedert et al. (2) (both 2.0). Our analysis also revealed elevated post-AIDS relative risks (male, 4.0; female, 6.2; both, 4.3), which are higher than those in the study by Goedert et al. (5
) (both 3.5) and a significant, but nonlinear, trend in relative risks over time for men (p = 0.0018). The trend in the paper by Goedert et al. was significant (both p = 0.006) and linear. Other studies that have examined the relation between brain and CNS cancer and HIV illness have had mixed results (41
43
), and brain and CNS cancer has not been clearly linked to immunodeficiency. The etiology of CNS lymphoma among persons with and those without AIDS remains unknown, and infectious viral agents such as Epstein-Barr virus might contribute to lymphoma.
Skin cancer
For skin cancer, we found relatively high SIRs (male, 20.9; female, 7.5), even higher relative risks in the post-AIDS period (male, 44.6; female, 12.0), and an increased risk over time in men (p < 0.0001). The two most common forms of skin cancer, basal and squamous cell carcinomas, are not reportable to the registry. Consequently, most nonmelanomatous skin cancers reported to the registry are sarcomas, followed by adenocarcinomas. It is possible that Kaposi's sarcoma cases might have been misclassified as non-Kaposi's sarcoma skin cancers.
Connective tissue
Cancer of connective tissues occurred in statistically significant excess among men. The overall SIR was 5.6, the post-AIDS relative risk was 9.9, and the p value was less than 0.0001. Grulich et al. (5) have also found an elevated SIR of 9.2 for both sexes combined.
Noninvasive neoplasms
An increased risk for in situ cancers was found in this study (tables 2 and 3). We present findings from our data to allow comparison with other published data; however, there are serious potential biases relating to the interpretation of in situ cancer results. Reporting of in situ cancers is incomplete in the cancer registry. This is especially true for in situ cervical cancer. In fact, most state cancer registries have dropped in situ cervical cancer from their reportable list. Thus, rates for in situ cancers based on registry data would be artificially low, and the number of expected cases would also be low, so the SIRs would not be accurate and would tend to be elevated among a population with an increased likelihood of hospitalization.
Non-AIDS-related cancers with SIRs lower than the general population
While the focus of the analysis is ascertaining cancers with elevated SIRs, we found a few sites with SIRs below 1.0. In men, prostate (SIR = 0.7) and bladder (SIR = 0.5) cancers had SIRs below 1.0 (table 2). These sites had relative risks below 1.0 during all periods relative to AIDS diagnosis. In women, breast cancer relative risks during the early pre-AIDS and post-AIDS periods were below 1.0, with the post-AIDS period especially low (RR = 0.2) (table 6).
Risk factors
A person's risk of developing a specific cancer is affected by various factors, including age, sex, race, and exposure to environmental agents. As yet, there is only limited information about which characteristics and exposures of HIV-infected people promote the development of cancer. The association between risk factors for acquiring HIV infection and selected malignant disease in people with AIDS was examined in this study. Sex between men and intravenous drug use are the major behavioral risk factors for men in our study cohort. For six cancer types or sites (rectum, rectosigmoid, and anus; connective tissue; Hodgkin's disease; brain and CNS; oral cavity and pharynx; and trachea, bronchus, and lung), our study contains sufficient observations to detect meaningful differences between these two risk groups for men and six cancer types or sites for women (invasive cervix; in situ cervix; Hodgkin's disease; trachea, bronchus, and lung; oral cavity and pharynx; and digestive system).
Rectum, rectosigmoid, and anus
Our study confirms that the risk of anal cancer among homosexual men with HIV infection is higher than that in the general population.
Trachea, bronchus, and lung
Both male (SIR = 4.6) and female (SIR = 9.8) IDUs had increased SIRs for trachea, bronchus, and lung cancer compared with other risk groups. This finding is not surprising, since IDUs are known to be heavy smokers, which may confound the relation between HIV and trachea, bronchus, and lung cancer.
Brain and CNS
SIRs varied by route of HIV acquisition in men, MSM (SIR = 4.7), and IDUs (SIR = 2.7), although the confidence intervals overlap for these point estimates. While differences by risk group are noteworthy, it is likely that route of HIV infection is a proxy for other risks, such as coinfection with Epstein-Barr virus, hepatitis B or C, or human herpes virus 8. Women infected heterosexually had a relative risk of 23.8.
Connective tissue
In this study, risk of this cancer appeared almost exclusively among HIV-infected men with homosexual contact, and therefore, this may be a result of misdiagnosis of Kaposi's sarcoma as hemangiosarcoma.
Hodgkin's disease
The relative risk for the MSM risk group, 8.7, is comparable with that in the study by Reynolds et al. (9) (RR = 8.8). The relative risk for male IDUs, 7.8, is similar to the that of 8.1 for males and females in the study by Franceschi et al. (4
). Heterosexually infected men had a greatly elevated relative risk (RR = 31.3), which was significantly higher than that for the intravenous drug use risk group.
Oral cavity and pharynx
SIRs were elevated for IDUs (1.9) but not for any other risk group.
Limitations
There are several potential biases in this study. First, it is possible that cancers with a higher incidence were detected because of intensive medical scrutiny among AIDS patients. Second, this cohort is the result of a match between two registries. If records are erroneously matched, the measures of association may be inaccurate. Third, in this study, Surveillance, Epidemiology, and End Results differential survival rates were applied to expected frequencies of cancer that occurred preceding AIDS. These adjusted relative risks for pre-AIDS expected cancers were then used to calculate the pre-AIDS relative risk and overall SIRs. However, this adjustment was approximate and could have resulted in overestimates of the early pre-AIDS prevalence and expected cancer cases.
Another potential limitation relates to the method we used to calculate post-AIDS relative risk. For types and sites of cancer that did not contribute a large number of observed cases in the 60-month post-AIDS period, the relative risks for this period will be attenuated due to the large number of expected cases that are derived with no or few corresponding observed cases.
This analysis was conducted on heterogeneous case definition data, with 1993 and 1987 AIDS definition cases analyzed together. Patients classified as 1987 definition cases are at a more advanced stage of HIV infection compared with 1993 definition cases, as indicated by significant differences in survival probabilities between the two groups (44, 45
). A final potential limitation is that pulmonary and neurologic complications of HIV illness may have been misdiagnosed as tumors at these sites.
In a large, heterogeneous cohort of AIDS patients, we have confirmed that cancer occurs in excess for AIDS-related cancers, and for non-AIDS-related cancers, our results support previous findings for Hodgkin's disease, rectal and anal cancer, and brain and CNS system cancer. This analysis has contributed to the knowledge of the relation between AIDS and cancer by analyzing incidence by gender and risk group. Our analysis revealed an increasing relative risk of trachea, bronchus, and lung cancer in men over time and an increase in risk of cancer of connective tissues for MSM.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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