The Classical Kaposis Sarcoma Working Group
J. J. Goedert, E. E. Brown, Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD; F. Vitale, N. Romano, Dipartimento di Igiene e Microbiologia "Giuseppe DAlessandro," Universitá degli studi di Palermo, Palermo, Italy; C. Lauria, L. Gafá, Lega Italiana per la lotta contro i tumori-sez. Ragusa, Ragusa, Italy; D. Serraino, Dipartimento di Epidemiologia, Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; M. Tamburini, M. Montella, Servizio di Epidemiologia e Prevenzione, Istituto Tumori "Fondazione G. Pascale," Napoli, Italy; A. Messina, Dipartimento di Scienze Biomediche, Universitá degli studi di Catania, Catania, Italy; G. Rezza, Laboratorio di Epidemiologia e Biostatistica, Istituto Superiore di Sanità, Rome.
Correspondence to: James J. Goedert, M.D., National Cancer Institute, 6120 Executive Blvd., Suite 8012, Rockville, MD 20892 (e-mail: goedertj{at}mail.nih.gov).
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ABSTRACT |
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INTRODUCTION |
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KSHV now is known to be the primary cause of all types of KS (7), but classical KS occurs in only a small fraction of KSHV-infected people. In the Mediterranean area, classical KS develops annually in only 0.03% of the KSHV-infected men older than age 50 years and in 0.01%0.02% of the KSHV-infected women older than age 50 years (8). Thus, there must be strong cofactors affecting the risk of classical KS after KSHV infection. No highly pathogenic strain of KSHV has been identified (9). Genetic susceptibility is plausible, and the risk of classical KS was increased twofold with human leukocyte antigen (HLA) type DR5 in Sardinians (10). Evidence from Greek patients with classical KS suggests underlying immune activation is associated with this disease (11).
The current study is, to our knowledge, the first study to search generally for risk factors by comparing classical KS case patients to KHSV-infected control subjects.
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METHODS |
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We reviewed all cases of KS reported to the population-based cancer registries in Ragusa (Eastern Sicily) and Campania (Naples) and to the major referral centers in Sicily (the University of Palermo and the University of Catania) and Rome (San Gallicano Hospital and the Istituto Dermatopatico dellImmacolata). Case patients were ineligible if they had AIDS; resided outside of Sicily, Lazio (including Rome), or Campania (including Naples); or lacked histologic confirmation [morphology code M9140/3 of the International Classification of Disease-Oncology (12)]. Project staff contacted each case patient by telephone to introduce the study.
Control Subject Selection
For our study, KSHV-seropositive control subjects of the same age and sex and from the same communities as the case patients were identified through and with the assistance of collaborating local, primary care physicians. Every person in Italy is assigned to a local, primary care physician. In Sicily, control subjects were obtained from the primary care physicians who had had a KS case patient. In Naples, control subjects were obtained from a large primary care group practice in the health districts of the cancer registry. In Rome, control subjects were obtained both from primary care physicians who had reported a KS case patient and from group practices representative of their communities.
Of all patients on the local physicians rosters, up to 20 times as many potential control subjects as case patients were selected at random from each sex and age (±5 years or 80 years of age) stratum. We anticipated 10%15% KSHV seroprevalence among potential control subjects. Thus, a 20 : 1 ratio of potential control subjects to case patients was expected to yield twice as many KSHV-seropositive control subjects as case patients. At special sessions at each local physicians office, the study was explained to each potential control subject and, with written informed consent, blood was drawn for KSHV serology. Project staff contacted the KSHV-seropositive subjects to recruit them for the full study.
Institutional Review, Informed Consent, and Data and Specimen Collection
Institutional review boards at each institution reviewed and approved the protocol, forms, and process for obtaining written informed consent. KSHV test results were available on request but not routinely reported to individuals. Current understanding of KSHV, its distribution, and its relationship to KS was provided to all participants. Each participant was seen in a private setting, where a trained interviewer obtained written informed consent, questionnaire data, and laboratory specimens. The face-to-face interview questionnaire included demographic, occupational, sexual, and medical history, skin hygiene, alcohol use, and cigarette smoking. Smokers were those who reported smoking at least one cigarette per day for at least 1 year. On completion, the interviewer scored the cooperation of the respondent and the quality of the data on a four-point subjective scale. Four respondents (one case patient and three control subjects) were deemed to have provided unreliable data because of dementia or inebriation. Because exclusion of these four interviews had no substantive effect on the results, all collected data are presented herein.
KSHV Antibody Screening
Antibodies against KSHV antigens were detected in a 1 : 120 dilution of a patients serum by an immunofluorescence assay, using the BCBL-1 cell line with and without induction by phorbol 12-tetradecanoate 13-acetate (TPA) (13). All samples that tested KSHV-positive were blinded and retested, along with random samples that initially tested negative. Samples that produced disparate results (<4%) were retested again, and that result was considered final. All positive sera were also retested at the same dilution with the Molt4 cell line to exclude nonspecific cellular reactivity. Serum from control subjects that had antibody reactivity both with and without TPA induction was considered seropositive and included in the study. Serum from each case patient was tested likewise, and all sera were KSHV seropositive, except for serum from one case patient who lacked detectable antibodies without TPA induction.
Statistical Methods
Frequency distributions of questionnaire variables were used to compare classical KS case patients with KSHV-seropositive control subjects, first using contingency tables. Totals in the tables do not always sum to 141 KS case patients and 192 control subjects because of missing data. Continuous data were split at medians or in levels of approximately equal size. Corticosteroid medications were used by four routes (topical, inhalation, injection, and oral) examined by any use and by duration of use. Nonusers of corticosteroid medication were compared with high users (defined as those who used corticosteroid medication by at least three routes or orally for at least 2 years) and with low users (defined as all other corticosteroid users). Medication dose and brand could not be evaluated. Risk of classical KS, adjusted by sex, was estimated by the odds ratio (OR) and 95% confidence interval (CI) calculated by logistic regression. Statistically significant differences between sex strata were determined by the BreslowDay test for homogeneity. Statistical significance of trends was tested with a 1-df MantelHaenszel 2 test. To examine the effect of KS survival on the association between smoking and KS risk, male KS case patients were stratified by time since diagnosis (<1, 15, and >5 years) and compared with male control subjects of similar age in each stratum. Logistic regression was used to evaluate the independence and mutual contributions of multiple variables by using liberal entry (P<.20) and stay (P<.20) criteria. The 95% CIs for logistic regression parameter estimates and linear combinations of these estimates were calculated from the variancecovariance matrix. All statistical tests were two-sided.
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RESULTS |
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Cigarette smoking was associated with a statistically significantly reduced risk of KS (OR = 0.25, 95% CI = 0.14 to 0.45). Among men, 59% of the case patients and 86% of the control subjects were current or former smokers. Among men, more intensive smoking (packs per day) and especially more cumulative smoking (pack-years) were associated with an even lower risk (Ptrend<.001 for each; Table 3). The risk for KS decreased approximately 20% (OR = 0.81, 95% CI = 0.74 to 0.89) for each 10 pack-years reported. With more than 40 pack-years, the OR for KS was 0.14 (95% CI = 0.07 to 0.30) (Table 3
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KS risk was not associated with drinking beer or liquor (OR = 1.03, 95% CI = 0.64 to 1.67) or wine (OR = 1.37, 95% CI = 0.76 to 2.47) at least monthly. Risk of KS also was not associated with the intensity and cumulative amounts of beer, liquor, and wine consumption (data not shown).
KS was not associated with histories of sexually transmitted diseases, arthritis, colitis, diabetes, cirrhosis, cardiovascular disease, or renal disease (Table 4). With allergies, the risk of KS was statistically significantly elevated among men (OR = 2.78, 95% CI = 1.39 to 5.54) and statistically nonsignificantly reduced among women (OR = 0.36, 95% CI = 0.11 to 1.18; interaction with sex P = .002). An elevated risk of KS was associated with a history of asthma (OR = 2.34, 95% CI = 1.12 to 4.91). Statistically nonsignificant elevated risks for KS from sparse data were associated with a history of gout (OR = 2.13, 95% CI = 0.74 to 6.15) and benign prostate disease (OR = 2.16, 95% CI = 0.59 to 7.90). History of non-KS cancers was not statistically significantly associated with reduced KS risk among case patients (OR = 0.77, 95% CI = 0.34 to 1.73). Among the case patients, four reported a non-KS, nonmelanoma skin cancer; three reported uterine cancer; and one each reported breast cancer, bladder cancer, and leukemia. Malignancies among the control subjects included three each of uterine, breast, colorectal, and bladder cancers; two each of lung and prostate cancers; and one each of gastric cancer and leukemia. No case patient or control subject had received an organ transplant.
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DISCUSSION |
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Previously, HIV-infected homosexual men in the United States who smoked were found to have a reduced risk of AIDS-associated KS that was statistically significant, albeit of lesser magnitude (OR = 0.4), than what we found (14). In Uganda, tobacco use was not associated with AIDS-associated or endemic KS (15,16).
If the prevalence of smoking is indeed low among KS patients, then smoking-related diseases should be reduced in this population. In support of this hypothesis is a striking absence of lung cancer among classical KS patients from Israel, Sweden, and New York (1719). In the American population, patients with predominantly classical KS (diagnosed after age 70 years or before 1980) had a markedly reduced risk of lung cancer (OR = 0.27, 95% CI = 0.06 to 0.80; Rabkin CR and Goedert JJ: unpublished data from the Surveillance, Epidemiology, and End Results [SEER]1 U.S. cancer registries).
Smoking has myriad effects that could influence the risk of KS. Hoover et al. (14) postulated that an effect of smoking on inflammatory cytokines might lower the risk of AIDS-associated KS. This is an attractive hypothesis, given that inflammatory cytokines and growth factors have potent effects on the recruitment of KSHV-infected cells into tissue sites and induction of KSHV replication leading to local dissemination of the infection (20,21). Some cytokines and growth factors are altered in smokers or in vitro by smoke extracts (2224), although the interactions are complex and not well defined. Perhaps activation of these immunologic and inflammatory pathways also are related to the apparently higher risk of KS that we observed for people with asthma and men with allergies.
Casecontrol studies are subject to bias. Of greatest concern for our study is the possibility of participation bias; that is, if control subjects who smoked were disproportionately enrolled. We sought an unbiased sample of control subjects from the rosters of the local physicians, but we cannot rule out the possibility that smokers might have been more willing than nonsmokers to be tested for KSHV antibodies and to enroll as control subjects. The prevalence of smokers in Italy has been well quantified by stratified random sampling and face-to-face interviews. In 1995, 76% of men and 19% of women ages 6574 years reported that they were current or former smokers (25). The prevalence of smokers among our control subjects was lower than expected among females (15%) but higher than expected among males (86%). Hypothetically, if there were no smokers among the 25 men who did not enroll as control subjects, our male smoking prevalence would have been 71%, and the risk of KS for smokers would have been reduced twofold (OR = 0.52, 95% CI = 0.32 to 0.86) rather than the fourfold that we estimated from the participants.
Survival bias is inevitable in a prevalent casecontrol study, because an exposure such as smoking may differentially affect survival and the risk of disease development. The lower risk of KS among smokers, particularly long-term heavy smokers, did not differ between case patients with incident KS who were recently diagnosed and those who had survived the disease for more than 5 years (Table 3). Although based on only 17 case patients with incident KS, this suggests, but by no means proves, that survival bias had little effect on our results. What cannot be excluded is recall bias among case patients, especially for variables such as use of topical corticosteroid medication. Overall, however, recall bias appears to have been small, as illustrated by the similar past medical histories of case patients and control subjects (Table 4
).
Skin hygiene or skin disease may affect the risk of classical KS. Based on Zieglers proposal (26) that endemic KS results from localized immune deficiency in the extremities resulting from chronic exposure of the skin to volcanic soil, Montella et al. (27) noted that risk of classical KS was twofold higher among people born near Mount Vesuvius than among people born in neighboring areas. In Uganda, delayed-type hypersensitivity skin reactions were diminished in the legs and feet compared with the arms of endemic KS patients (28). Our finding that KS risk was increased with use of topical corticosteroid medication supports the hypothesis that inflammatory or immunologic events in the skin are critical to the development of classical KS. Because the risk was not clearly related to duration of medication use, the dermatitis and not its treatment may be the link to KS. The KS risks that we observed for asthmatics and for men with allergies, which were a bit ambiguous but not confounded by use of nontopical corticosteroid medications, suggest an intrinsic proclivity for developing KS.
Prolonged working or walking in river or lake water was associated with increased risks of AIDS-associated and endemic KS in Uganda (15,16). We could not evaluate prolonged exposure to dirty water in Italy, but we found no differences between case patients and control subjects in frequent or prolonged dirt on the skin. We did, however, find a higher KS risk with infrequent bathing or showering. This association with bathing was not statistically significant in univariate analysis. However, as skin hygiene was an a priori hypothesis, bathing frequency was included in the multivariable model and was found to have a statistically significant 1.85-fold association with KS risk.
Finally, although KSHV can be transmitted to children, perhaps via saliva (29,30), and among adults, probably via sexual activity (31,32), our case patients and control subjects had nearly identical histories of household crowding, birth order, and sexual activity. Thus, the route of and age at KSHV infection may not have strong effects on the risk of classical KS.
In summary, we found that the risk of classical KS was increased approximately fourfold for nonsmokers, an observation that requires corroboration in another population. Our findings should in no way be interpreted as an endorsement of smoking, because the many serious complications of smoking far outweigh its effect on classical KS, which remains a rare outcome of KSHV infection even among male nonsmokers. Understanding how smoking affects KS risk may lead to a better understanding of the pathogenesis of this malignancy and to interventions for its prevention.
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APPENDIX |
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NOTES |
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Funded by the Intramural Research Program of the National Cancer Institute (contract N02-CP-91027 with Research Triangle Institute); Associazione Italiana Ricerca sul Cancro; Programma Ricerche AIDS, ItalyU.S. Collaborative Project, Istituto Superiore di Sanità, Italy (Dr. Giovanni Rezza); Cooperativa Medici e Salute, Pomigliano dArco (Dr. Michele De Cicco); and Progetto Nazionale AIDS, Italian Ministry of Health, Istituto Superiore di Sanità, Rome (grant number 20C.15, Dr. Diego Serraino). The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing the report. No funding was provided by any industry or commercial enterprise.
We thank the following organizations and laboratory and field staff members: Registro Tumori ASL-NA4 and Cooperativa Medici e Salute, Pomigliano diArco (Napoli, Italy) for case registration; Domenica Tassielli and Giuseppe Ippolito (Rome, Italy) for study facilitation; Carla Del Carpio, Guido Tantillo, and Maria Manno, Ospedale dei BambiniARNAS Servizio Analisi Chimico-Cliniche (Palermo, Italy) and Maurizio Musso and Ferdinando Porretto, Casa di Cura "La Maddalena" (Palermo) for flow cytometry; Mario Arico and M. Rita Bongiorno, Universita di PalermoClinica Dermatologica, and Salvatore Amato, Ospedale CivicoARNAS Servizio di Dermatologia (Palermo) for case ascertainment; Giuseppe Arena and Salvatore Fornaro for phlebotomy and Caterina Martorana, Maria Grazia Ruggeri, Eliana Cavalieri, and Mirella Mazza (all in eastern Sicily) for data collection; the Brinch-Battaglia clinical pathology laboratory (Ragusa, Italy); the Director, secretary, and drivers of Agenzia Siciliana Trasporti (Ragusa and Palermo); and the Directors of histopathology laboratories and histopathology departments (Ragusa, Vittoria, Catania, Enna, Caltagirone,Taormina, and Trapani, Italy); Maryanne Ardini (Washington, DC) for study management; Daniel Ringer (Rockville, MD) for specimen processing and shipping advice; and Susan Wilson (Rockville, MD) and Liliana Preiss (Buenos Aires, Argentina) for computer programming. We are especially grateful to the research participants and the nearly 100 local primary care physicians for providing population control subjects, without whom this study would not have been possible.
1 Editors note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.
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