Year: 2003
Type: letter
Abstract: Since the seminal description of Hodgkin's disease (HD) epidemiology by MacMahon in 1966,1 the young-adult form of this lymphoma has been postulated to have an infectious component to its etiology. In early studies, Epstein-Barr virus (EBV) was implicated by serologic evidence and associations with a history of infectious mononucleosis.2 Subsequent research supported these hypotheses by associating risk of young-adult HD with correlates of delayed exposure to common childhood illnesses and with abnormal anti-EBV antibody patterns in sera obtained before diagnosis.3, 4, 5 Later studies using methods to detect gene products of EBV within tumor cells, considered evidence of etiologic involvement, led to an unexpected conundrum: EBV is not detected in tumors of most young adults with HD.6, 7 This apparent paradox renewed interest in the possibility that elevated anti-EBV antibody titers in young-adult HD patients are markers for another etiologic virus.5 As reported recently in this journal, Gallagher et al.8 have searched for herpesviruses in HD tumors, using 2 PCR assays shown to detect all known viruses in this family. They did not find any evidence, however, and their null results have led them to call for consideration of other virus families or indirect effects of infection in HD etiology. Perhaps relevant to this controversy is the relatively obscure finding of an apparent elevated risk of HD in persons with intravenous (i.v.) exposure to blood or blood products but presumed to be HIV-negative. As part of a hospital-based study in Los Angeles, Dworsky and Henderson described HD diagnosed in 1969–71 in 7 young-adult heroin addicts frequenting a common shooting gallery.9 Although this cluster was not subjected to formal statistical evaluation, its occurrence among the 85 Los Angeles young-adult study cases, otherwise characterized by the anticipated risk profiles of white race and relatively high social class, makes the finding unusual.10 In 2000, Serraino et al.11 reported that a 1982–97 cohort of French and Italian HIV-negative i.v. drug users included 2 cases of young-adult HD when 0.361 were expected (SIR = 5.6; 95% CI = 0.5–20.4). A linkage of Swedish transfusion recipients to the cancer registry found 1 32-year-old with HD vs. 0.29 expected (SIR = 3.47; 95% CI = 0.1–19.3) but the expected number of HD cases among hospitalized but non-transfused patients (4 vs. 5.6; SIR = 0.72; 95% CI = 0.2–1.9).12 Among 1,701 hemophiliacs enrolled in the National Cancer Institute Multicenter Hemophilia Study, 1 HIV-negative HD case was identified against 0.12 expected (SIR = 8.2), although this finding also was not significant statistically.13 More recently, Wilde et al.14 found 8 HIV-negative cases of HD in a UK cohort of 7,250 hemophiliacs followed between 1978 and 1999 (SIR = 2.7; 95% CI = 1.2–5.2), although ages at HD diagnosis were not specified. Some of these observations could reflect the effects of undetected HIV infection, which is well-established to lead to a substantially elevated risk of HD in all exposure groups.15, 16, 17 The composition of the Los Angeles HD cluster, in which 5 of 7 i.v. drug users were black and 3 of 7 had the mixed cellularity histologic subtype, partially resembles the current epidemiologic profile of HIV-associated HD.15 Nevertheless, these patients were diagnosed nearly a decade before the first identification of HIV/AIDS in the US and represent a proportion of all the study cases (7/104 = 7%) similar to the 7% we have observed for HIV-associated HD in the San Francisco Bay Area at the height of the HIV epidemic in the 1990s (unpublished data). For the cohort of French and Italian i.v. drug users, the short follow-up time (mean of 2 years) suggests that the 2 HIV-negative HD patients could have subsequently seroconverted, given the tendency for HIV-associated HD to develop relatively early in the course of HIV infection.15 Seroconversion, however, does not appear to have occurred as of 2002 (personal communication, Diego Serraino). For the UK cohort of hemophiliacs, HIV testing was not complete until 1985; however, an excess of HD in known HIV-negative cohort members was also noted for the time period 1985–99 (5 cases observed vs. 0.48 expected, p < 0.001).14 If these cases of HD in persons with i.v. exposure to blood products are in fact not attributable to HIV, then they may help inform the question of viral etiologies for HD. Intravenous drug users and, to a lesser extent hemophiliacs and other blood transfusion recipients, are exposed to a multitude of blood-borne pathogens;18 thus, an elevated risk of HD in those who are HIV-negative might reflect exposure to a novel pathogenic virus or group of viruses. Recent serologic studies of hepatitis-C virus, a lymphotropic flavivirus, have produced only weak evidence for an association with HD.19, 20, 21 A study of hepatitis-G virus, a similar flavivirus, has reported a higher seroprevalence in HIV-negative HD cases than in controls.22 Given the challenge of envisioning a pathogen whose behavior fits the assumptions of both typical young-adult HD (ubiquitous agent with a mild and self-limited infection) and HD in i.v. drug users or hemophiliacs (agent with high oncogenicity in blood-borne exposure), one might postulate that more than 1 type of virus could be involved. In addition, perturbations of immune function associated with I.V. receipt of blood and blood products may contribute to HD development. Intravenous heroin users are subject to drug-related disruption of immune function, including decreased synthesis of nitric oxide, which regulates and affects immune responses to tumor and other antigens, and altered levels of T-lymphocytes (CD3, CD4, CD8), B-lymphocytes and NK cells.23, 24, 25, 26 Transfusions of blood and blood products can produce similar immunosuppressive effects.27 Thus, chronic immune dysregulation from these exposures could increase risk of HD via poor immunologic control of infection with viruses, known or novel, having the potential to contribute to the development of HD. The Los Angeles cluster is consistent with the effects of reactivated EBV infection, as the high proportion of patients with the mixed cellularity subtype is a feature of EBV-positive HD.6 The HD patient in the Swedish transfusion cohort had similar EBV-associated HD characteristics of mixed cellularity subtype and late-stage disease at diagnosis.12 In theory, linkage of a large cohort of HIV-negative i.v. drug users, hemophiliacs or transfusion recipients to cancer diagnoses could help discriminate among these possibilities by permitting identification of HD cases in whom novel or previously unassociated pathogens might be sought. In practice, establishment of such a cohort is unlikely in the era of HIV. HIV-positive HD patients also represent a potentially informative population for this purpose, as the moderate associated immunosuppression preceding HD development in this group, like that linked to i.v. heroin use and transfusions, may be modulating the activity of responses not only to EBV but also to other viruses that play a direct or complementary role in HD pathogenesis or etiology in young adults.17 With the availability of highly active antiretroviral therapies, which lengthen survival in the HIV-infected population,28 the numbers of HD patients for such studies may be rising. Yours sincerely, Sally L. Glaser*, Christina A. Clarke*, Lyndsey A. Darrow*, * Northern California Cancer Center, Union City, CA, USA.
Source: International Journal of Cancer
DOI: 10.1002/ijc.11005
Institution: Cancer Prevention Institute of California
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2004592225