Etiologyrisk Factors

Evidence suggests that Hodgkin lymphoma represents several disease entities over the age spectrum, with different etiological factors for different age groups. Children acquire Hodgkin lymphoma at an earlier age in developing countries than in developed countries, and commonly show Epstein-Barr virus (EBV) genomic sequences in their Reed-Sternberg cells [5, 6]. The incidence of Hodgkin lymphoma in developed countries peaks in the adolescent and young adult years, and again in older adults [7]. This reflects the bimodal peak first noted by McMahon [2]. The increased risk of developing Hodgkin lymphoma at an early age has been linked to a higher socioeconomic status and standard of living during childhood, including factors such as low housing density, high

Figure 8.5

Average annual percent change (AAPC) in the incidence of non-Hodgkin lymphoma and Hodgkin lymphoma; United States SEER 1975-2000

Figure 8.6

Average annual percent change in the incidence of Hodgkin lymphoma by gender; United States SEER 1975-2000

maternal education, and few older siblings. These conditions may contribute to a delay in exposure to common childhood infections and a subsequent delay in maturation of cell immunity [8]. Yet in the younger (<10 years) and older (>45 years) age groups, the association with higher socioeconomic status is reversed [9]. Among the histologic subtypes of Hodgkin lymphoma, the nodular sclerosing subtype has a more favorable prognosis [10].

While the etiology of Hodgkin lymphoma remains unknown, it has long been thought that an infectious agent plays a role in the cause of the disease. There is growing evidence that the EBV contributes to the etiology of many cases of Hodgkin lymphoma [11]. This relationship, suggested by past medical history of infectious mononucleosis and serologic studies in patients with Hodgkin lymphoma, has been confirmed by immunohistochemistry and molecular biology. Approximately 40-50% of Hodgkin lymphoma cases are associated with the EBV in developed countries [12, 13]. The presence of the EBV genome in Reed-Stern-berg cells is associated with the mixed-cellularity subtype [4]. As this subtype occurs infrequently in adolescents and young adults, childhood and older adult cases are more likely to be associated with EBV. Young adults are more commonly diagnosed with nodular sclerosis Hodgkin lymphoma, which is rarely associated with EBV, perhaps signifying a separate disease entity. This variance in EBV incidence, histological subtypes, and the difference in gender ratios between young adults and children and older adults suggests that Hodgkin lymphoma has different etiologies in different age groups. The exact cause of non-EBV-associated Hodg-kin lymphoma remains to be elucidated. Whereas the risk for Hodgkin lymphoma appears to be greater in young children from poorer socioeconomic conditions, the converse is seen for adolescents (Table 8.2). While the evidence points to EBV as a cofactor in the development of Hodgkin lymphoma, the exact relationship of the infection to the subsequent development of a tumor is not completely delineated.

The incidence of Hodgkin lymphoma is greatly increased in children with certain immunodeficiency disorders, specifically ataxia-telangiectasia, Wiskott-Aldrich syndrome, and Bloom syndrome. Given the broad spectrum of underlying genetic defects associated with these disorders and their association with the mixed-cellularity subtype, severely impaired immunity may be a likely etiology with consequent enhanced susceptibility to EBV.

Genetic susceptibility is also a factor for adolescents and young adults. The risk of developing Hodgkin lymphoma is significantly higher for those with relatives with the disease; the risk is higher for males than for females, and for siblings than for parents or offspring [14]. Familial clustering of Hodgkin lymphoma sug gests a genetic predisposition. Identical twins of young adults with Hodgkin lymphoma are 100 times more likely to develop Hodgkin lymphoma than fraternal twins, supporting a genetic component to the development of Hodgkin lymphoma in young adulthood [15].

Adults with Hodgkin lymphoma are more likely to have children who develop the disease at a younger age, particulary during adolescence and young adulthood [16].

In patients with human immunodeficiency virus (HIV) infection, there is an increase in the incidence of both Hodgkin and non-Hodkgin lymphoma [17, 18]. Other risks associated with the development of Hodgkin lymphoma in this age group are a history of autoimmune disorder, a family history of cancer/ hematopoietic disorder, and Jewish ethnicity [15, 16].

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