Cancer incidence in a cohort of human immunodeficiency virus seroconverters†
Presented in part at the American Society of Clinical Oncology meeting, Philadelphia, Pennsylvania, May 1996.
In addition to Kaposi's sarcoma and non-Hodgkin's lymphomas, it has been postulated that human immunodeficiency virus (HIV) infection may increase the risk of other cancers. The aim of the current study was to compare incidence rates of cancer among individuals who seroconverted for HIV infection with the rates in the general population of Italy.
This study is part of an ongoing cohort investigation conducted by the HIV Italian Seroconversion Study Group. The study has enrolled 1255 individuals (906 males and 349 females) between the ages of 20 and 49 years who are at risk for HIV infection and have had a documented negative HIV test followed by a positive test. For each individual, the midpoint in time between the negative and positive tests was used to estimate the seroconversion date. The person-years at risk for cancer were then computed from the midpoint date to the last follow-up date or to death, and the number of cases of cancer observed in the cohort was compared with the expected number, based on rates among the general population of the same age and gender. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were computed.
A total of 58 cases of cancer were observed in the cohort. In comparison with rates in the general population, Kaposi's sarcoma was 1051 times more frequent, and non-Hodgkin's lymphomas were 157 times more frequent. Hodgkin's disease was observed in 3 men (i.e., 38 times more often in the cohort of HIV seroconverters [95% CI, 8-111]), in particular among homosexual men (SIR = 103). One woman developed stomach carcinoma.
The findings of the current incidence study are in agreement with previous studies showing excesses of Kaposi's sarcoma and non-Hodgkin's lymphomas in HIV-positive individuals. In addition, the findings suggest an association of HIV infection with Hodgkin's disease. Whether Hodgkin's disease in HIV-infected individuals should be considered an AIDS-defining illness is a question that is worthy of attention. Cancer 1997; 79:1004-8. © 1997 American Cancer Society.
Four types of cancer are currently included among the conditions for defining acquired immunodeficiency syndrome (AIDS): Kaposi's sarcoma, primary brain lymphoma, B-cell high grade non-Hodgkin's lymphomas, and cervical invasive carcinoma.1 Some clinical and epidemiologic studies have suggested that human immunodeficiency virus (HIV) infection may increase the risk of the development of not only these types of cancer, but also others, in particular Hodgkin's disease.2-4 However, this issue has remained controversial. The potential association between HIV infection and Hodgkin's disease has important implications, both from a clinical point of view and for the definition of AIDS-associated diseases, and thus needs to be verified.
In the current investigation, data from a cohort of intravenous drug users, heterosexuals, and homosexuals with known dates of HIV seroconversion and person-years at risk for cancer were used to quantify the potential excess of both AIDS and non-AIDS-defining cancers in HIV-infected individuals.
MATERIALS AND METHODS
This study is part of an ongoing incidence cohort study being conducted in Italy by 16 clinical centers. The design of the study has been described in detail elsewhere.5, 6 After informed consent was obtained, individuals who had had a documented HIV-seronegative test followed by a positive confirming one were included in the study. The maximum accepted lag between these tests was 2 years, and the midpoint between the two dates was used to estimate the seroconversion period. Person-years at risk for cancer were computed from HIV seroconversion to the last follow-up date or to death. To reduce the number of individuals lost to follow-up, which was performed every 6 months and included full clinical examination, a linkage with the Italian National AIDS Registry was carried out, while further information on the vital status was ascertained through the census bureau of the town of the patient's residence.
To make a homogenous comparison with cancer incidence rates in the Italian general population of young adults and with similar studies conducted in the United States,7, 8 the current analysis was restricted to men and women whose age at seroconversion was between 20 and 49 years. Information was collected on sociodemographic characteristics, HIV exposure category, and the diagnosis of diseases at follow-up visits. All cancer diagnoses were histologically confirmed by a pathologist collaborating with the HIV Italian Seroconversion Study Group.
For each type of cancer observed among the members of the HIV seroconverter cohort, the expected number was computed by indirect standardization,9 using data from three population-based cancer registries. Because cancer registration in Italy is not conducted throughout the entire country, these registries were chosen to represent better the general population of the 16 participating centers (i.e., the Lombardy Registry in northern Italy, the Tuscan Registry in central Italy, and the Ragusa Registry in southern Italy).10 The average annual age specific and gender specific incidence rates from these registries were multiplied by the number of person-years of observation in the cohort. Confidence intervals (CI) for these standardized incidence ratios (SIR) were determined using the Poisson distribution for the observed cases.11
By December 1995, 1255 individuals (906 males and 349 females) had been enrolled in the study. Overall, 7075.4 person-years of observation were accumulated in the 3 HIV transmission categories (Table 1). Fifty-eight cases of cancer were diagnosed in this period: 39 of Kaposi's sarcoma, 15 of non-Hodgkin's lymphomas (including 2 primary lymphomas of the brain), 3 of Hodgkin's disease, and 1 of stomach carcinoma (Table 2).
Table 1. Distribution of 1255 Individuals Aged 20-49 Years Who Seroconverted for HIV Infection, According to Gender, HIV Transmission Category, and Person-Years at Risk: Italy, 1980-1995
|HIV transmission categories|| || || || || || || || || |
| Intravenous drug users||525||58||3161.9||206||59||1134.4||731||58||4296.3|
| Homosexual and bisexual men||315||35||1725.4||--||--||--||315||25||1725.4|
Table 2. Observed and Expected Number of Cancer Diagnoses Among 1255 Individuals Aged 20-49 Years Who Seroconverted for HIV Infection: Italy, 1980-1995
|Gender|| || || || || || || || || || || || || || || |
|Male||37|| ||0.0360|| ||11|| ||0.0751|| ||3|| ||0.0590|| ||0|| ||0.0913|
| SIR|| ||1027.8|| || || ||146.4|| || || ||50.9|| || || ||0|| |
| 95% CI|| ||733.9-1397.8|| || || ||73.1-262.1|| || || ||10.5-148.6|| || || || || |
| Female||2|| ||0.0011|| ||4|| ||0.0203|| ||0|| ||0.0203|| ||1|| ||0.0240|
| SIR|| ||1793.9|| || || ||197.5|| || || ||0|| || || ||41.7|| |
| 95% CI|| ||217.1-6475.9|| || || ||53.7-505.6|| || || || || || || ||1.1-232.4|| |
|Total||39|| ||0.03711|| ||15|| ||0.0954|| ||3|| ||0.0792|| ||1|| ||0.1153|
| SIR|| || ||1050.8|| || ||157.3|| || || || ||37.9|| || ||8.7|| |
Among the AIDS-defining cancers, Kaposi's sarcoma occurred approximately 1000 times more frequently in the cohort of HIV seroconverters than in the general population, and non-Hodgkin's lymphomas about 150 times more frequently. This excess risk was observed for both genders (SIR = 1028 in males and SIR = 1794 in females for Kaposi's sarcoma; SIR = 146 in males and SIR = 198 in females for non-Hodgkin's lymphomas) (Table 2). Homosexual men showed the highest risk for Kaposi's sarcoma (SIR = 2520, 95% CI: 1701-3604), whereas the risk for non-Hodgkin's lymphomas appeared to be similar across HIV exposure categories (not shown in Tables).
Regarding the two types of cancer not fulfilling the AIDS definition criteria and diagnosed in the cohort of HIV seroconverters, Hodgkin's disease was observed nearly 40 times more frequently than expected (SIR = 38, 95% CI: 8-111) (Table 2). All three cases of Hodgkin's disease were diagnosed in men (two in homosexuals and one in an intravenous drug user), and two of the three cases were of the mixed cellularity histologic subtype. The SIR was particularly high among homosexuals (SIR = 103, 95% CI: 12-370) (not shown in Tables). One woman developed stomach carcinoma, as compared with the expected 0.1 patients.
An increased incidence of AIDS-associated Kaposi's sarcoma and non-Hodgkin's lymphomas among young adults of both genders has been consistently reported in the United States, whereas temporal patterns of Hodgkin's disease have not appeared to be influenced by the AIDS epidemic.7, 8, 12, 13 In Europe, epidemiologic investigations on the incidence of AIDS-associated cancers have been rare,14 although an increased mortality for AIDS-associated cancers has been reported since 1991.15 The findings of the present incidence study are consistent with those reported in the United States,7, 8, 12, 13, 16 and they confirm, for the first time in Europe, a risk 1000 times higher for Kaposi's sarcoma and a risk more than 100 times greater for non-Hodgkin's lymphomas in HIV-infected individuals, including women.
An increased incidence among HIV-infected individuals of several neoplasms not included among the AIDS-defining conditions, such as colorectal and skin cancer,14, 16 has been hypothesized. Among the 1255 HIV seroconverters constituting this study group, the diagnosis of non-AIDS-defining neoplasms was limited to three cases of Hodgkin's disease and one case of stomach carcinoma. These data therefore suggest that the spectrum of neoplasms associated with HIV infection is limited, although a higher number of person-years at risk could be necessary to investigate this association fully.
The most interesting finding of our study was the suggestion of a significantly increased frequency of Hodgkin's disease, as reported in other cohort investigations.2, 14, 17 This is among the first studies on cancer and its relation to HIV infection that has been conducted among individuals with a known date of HIV seroconversion, allowing for the precise calculation of the time period during which HIV-infected individuals were at risk for cancer. Clinicopathologic studies of Hodgkin's disease have consistently shown a predominance of the mixed cellularity subtype in HIV-infected individuals,3, 18-20 and this histologic picture was confirmed in two of the three cases of Hodgkin's disease in this study.
Some limitations of this study, however, should be noted. First of all, the elevated SIR for Hodgkin's disease was based on only three observed cases, and histologic misclassification of Hodgkin's disease and non-Hodgkin's lymphomas may have occurred.21, 22 However, in the current study, all the cancer diagnoses were performed by experienced pathologists associated with the HIV Italian Seroconversion Study Group. The comparison of cancer incidence rates among individuals belonging to groups at risk for AIDS with an external population is a well-established methodology,2, 9, 11 although it has some drawbacks. In the current study, the 16 participating centers were located in cities without cancer registries, and therefore comparison was made with the closest cancer registry. It is unlikely, however, that the computation of the expected number of diagnoses of cancer was substantially affected by this fact, because population-based cancer registries use procedures that are internationally standardized.10 In this regard, it should be noted that the magnitude of the association between HIV infection, Kaposi's sarcoma, and non-Hodgkin's lymphomas that emerged in this study is similar to that reported in studies conducted the United States.2, 14
In conclusion, the results of this study confirm previous findings that the risks of Kaposi's sarcoma and non-Hodgkin's lymphomas are elevated in HIV-infected individuals, and they also suggest an association with Hodgkin's disease. Whether the evidence presented herein is sufficient to consider Hodgkin's disease (or the mixed cellularity histologic subtype) an AIDS-defining illness remains an open question that deserves serious attention.
The authors thank Dr. Silvia Franceschi for her useful comments, Mr. Mark Kanieff for revising the English revision, and Mr. Ernesto Costabile for technical support.