[MOL] Risk Factors for Hodgkin's Disease [01931] Medicine On Line


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[MOL] Risk Factors for Hodgkin's Disease



Hodgkin's Disease


Paul H. Levine, M.D.*

Hodgkin's disease is a form of cancer involving the lymphatic system. In 1994, there were an estimated 7,900 new cases (4,400 men and 3,500 women) and 1,550 deaths (900 men and 650 women) (Ries et al., 1994). From 1973 to 1991, mortality rates from Hodgkin's disease declined more than 50 percent, largely because of more effective therapy (mortality rates for 1987-91 were 0.7/100,000 men and 0.4/100,000 women). In the United States, Hodgkin's disease is relatively rare in children. However, two incidence peaks occur, between the ages of 15 and 34 and after age 45, which suggest different etiologies in these two age groups (MacMahon, 1957).

The patterns of this disease differ from one country to another. In developing countries, for example, childhood Hodgkin's disease is far more common than the adult manifestation (Correa and O'Conor, 1971), indicating the importance of environmental factors in the cause of this disease. Italy, Switzerland, Canada, and the United States experienced the highest incidence rates in the world for this relatively rare cancer (Parkin et al., 1992). The world standardized rate for U.S. white males was 3.4/100,000. The rate for U.S. black males was nearly half that for white males. For both races, rates for females were lower than those for males. In general, developed countries, particularly Scandinavian countries and the United States, have the highest incidence of Hodgkin's disease among 15- to 34-year-olds. There is a notable and unexplained exception in Japan, where only the older age group (greater than 45) is affected.

There are several histopathologic subtypes of the disease that not only hold great prognostic importance but also suggest different causality. Childhood Hodgkin's disease in developing countries is usually of the mixed cellularity or lymphocyte depletion histopathologic subtype associated with a higher frequency of Reed-Sternberg cells. This important morphologic feature of Hodgkin's disease generally correlates with poor prognosis. The nodular sclerosis form of Hodgkin's disease is seen most frequently in young women in developed countries and is usually associated with a good prognosis, though a subclass designated lymphocyte-depleted nodular sclerosis has a poorer prognosis than other nodular sclerosis cases (Axtell et al., 1972). Current information suggests that many cases of lymphocyte- predominant Hodgkin's disease are B-cell tumors and may be a different entity from other forms of Hodgkin's disease (Wright, 1989). In general, the prognosis is better in those cases with greater numbers of lymphocytes and fewer Reed-Sternberg cells. Stage of disease is another important factor determining prog nosis; patients with stage I and stage II Hodgkin's disease, the more limited forms, are more likely to be cured by therapy than those with more advanced stage III and stage IV disease.

Infection

In the early descriptions of Hodgkin's disease, clinicians noted the frequent appearance of fever and enlarged cervical lymph nodes, which suggested an infectious etiology for this disease. Subsequent reports noted the appearance of clusters of Hodgkin's disease (Vianna et al., 1971; Grufferman, 1982), and several studies have suggested that siblings of patients with Hodgkin's disease are at higher risk of developing this malignancy (Grufferman, 1982). There is considerable disagreement, however, as to whether these clusters are biologically meaningful or an artifact of reporting of coincidental occurrences (National Conference on Clustering of Health Events, 1990). Additional reports suggesting an infectious etiology include geographic patterns (Cole et al., 1968), noting a higher mortality rate in the Northern United States than in the South for young adult Hodgkin's disease. This pattern was not apparent for Hodgkin's disease in the older population, again indicating different etiologies for these two age groups. A number of investigators have noted parallels to other illnesses known or suspected of having an infectious etiology. Polio, for example, which affects younger people in developing countries more often than in developed countries, parallels the incidence pattern of Hodgkin's disease in developing versus developed countries. In addition, multiple sclerosis, where the risk of disease is related to place of birth, has also been noted to have a geographic pattern similar to that of Hodgkin's disease (Newell, 1970).

The two viruses that have been linked most specifically to Hodgkin's disease are Epstein-Barr virus (EBV) and the more recently discovered human herpesvirus-6 (HHV-6). Of particular interest is the association between Hodgkin's disease and infectious mononucleosis, a disease known to be caused by EBV and, rarely, other herpes viruses, including HHV-6. Several studies have shown that young adults developing infectious mononucleosis have a significantly higher risk of developing Hodgkin's disease within five years of their infectious mononucleosis (Grufferman, 1982). Whether this is a direct result of the infection with EBV or whether it is a result of the depressed immunity known to accompany infectious mononucleosis (Lantorp et al., 1972; Mangi et al., 1974) is unknown, but it is apparent that five years after the occurrence of infectious mononucleosis, the risk of developing Hodgkin's disease returns to normal.

Infection with EBV at an early age is rarely accompanied by significant clinical signs or symptoms but, as with most herpes viruses, the first infection at a later age produces a much more severe clinical illness. Therefore, infectious mononucleosis is largely a disease of individuals in upper socioeconomic groups who escape early infection; it is also of interest that, in the United States, Hodgkin's disease in the younger age groups is largely a disease of upper socioeconomic status (Gutensohn, 1982). Laboratory data first linking EBV (then called herpes-type virus) to the mixed cellularity and lymphocyte depletion forms of Hodgkin's disease was first reported in 1970 in the United States (Levine et al., 1970, 1971) and was partly confirmed in Sweden (Johanssen et al., 1970), where a different histologic classification was used. Although an etiologic role for EBV was suspected because of the relationship of antibody titers to stage of disease and to histologic subtype in patients before therapy (Levine et al., 1971), more convincing data were developed with a prospective serologic study (Mueller et al., 1989) and the detection of EBV in the Reed-Sternberg cells of biopsies taken from patients with Hodgkin's disease (Weiss et al., 1989). The relationship between EBV and Hodgkin's disease has been clarified even further by recent reports detecting EBV in the lymph node biopsies of children and older adults (but less frequently in young adults) (Jarrett et al., 1992) and the identification of EBV tumor-associated gene products in Hodgkin's disease tumor cells (Pallesen et al., 1991). Because infectious mononucleosis is known to have more than one causative agent, it is possible that Hodgkin's disease also can result from more than one infectious agent. Evidence for a role for HHV-6 was described (Clark et al., 1990; Torelli et al., 1991), but longitudinal studies suggest that the antibody titers to HHV-6 reflect a response to therapy, unlike EBV, and therefore an etiologic role is less likely (Levine et al., 1992; Levine et al., in press [b]).

Occupation

The strongest occupational link to Hodgkin's disease was first noted by Acheson, who reported an increased incidence in woodworkers (1967). Support for this finding occurred in a series of studies summarized by Grufferman (1982). Phenoxyacetic herbicides have been associated with Hodgkin's disease in one study (Hardell et al., 1981), but this report is unconfirmed, and the significance of this association has been questioned (Hoar et al., 1986).

Other Factors

Genetic susceptibility does not appear to be of major importance in Hodgkin's disease (Fraumeni and Li, 1969). The evidence for a genetic predisposition to Hodgkin's disease is primarily limited to the association with ataxia telangiectasia (AT), a genetically determined abnormality of the immune system, but because other lymphomas are even more prominent in AT patients (Spector et al., 1982), the association is probably the result of the immunosuppressed state and not of a specific genetic predisposition to Hodgkin's disease. Certain genetic markers have been associated with Hodgkin's disease (Forbes and Morris, 1970), and familial occurrences, though rare, have been described (Grufferman, 1982; Chakravarti, 1986). It has been estimated that most of these cases are the result of genetic susceptibility (Chakravarti, 1986; Levine, in press [b]). Other reported associations, such as tonsillectomy and amphetamine usage, have not been confirmed as contributing to the etiology of Hodgkin's disease (Grufferman, 1982; Mueller et al., 1987).

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