**3.2.1 Environment**

**Infections.** Systemic analysis of epidemiological data pointed towards an infectious agent as a potential cause for Hodgkin's lymphoma. Recognition of an association of infectious

Filipino, and Asian Indian in the US and in Asia reports HL incidence rates were quite low in all Asian subgroups but approximately double in US Asian. The consistently low rates of HL in Asians suggest genetic resistance to the disease development, possibly associated with HLA type. In addition environmental and lifestyle differences between the USA and Asia are important. In some study from Eastern Asia and among Chinese immigrants in North America indicate increasing incidence trends for HL being associated with westernization (Caporaso, Goldin, Anderson, & Landgren, 2009). International and interethnic differences and risk factor patterns in case-control data, implicate environmental

Incidence rate of HL are usually grater in male than in female (Correa & O'Conor, 1971). In western countries the young adult peak largely consist of nodular sclerosis tumors, whereas the rise at older ages are largely mixed cellularity and lymphocytic-depleted histology (Spitz, et al., 1986). Hodgkin's lymphoma tends to be more common in young adult with higher socio-economic classes (Correa & O'Conor, 1971). Pattern of low social class determinants in children and older adult with HL, the age groups at risk for mixed cellularity (MC), support involvement of underling infectious agent given intense exposure, and EBV is a likely candidate based on its high prevalence in these groups (Glaser & Jarrett, 1996). Based on different studies the most common subtype of HL in the most Asian countries such as Iran, Korea, Thailand, Japan is mixed cellularity and relative paucity of NS subtype, particularly in males (Glaser & Hsu, 2002), which seems to be related to the etiologic factors (environment and/or inheritance) of disease. Subtypes of HL in different

> **Thailand No (%)**

**NS** 10 (31.2) 26 (31.7) 58 (36.9) 29 (69) 70 (42.4) Up to 08 60 **MC** 16 (50) 38 (46.3) 64 (40.8) 2 (4.7) 51 (31) <10 15 **LD** 3 (9.3) 6 (7.3) 14 (8.9) 0 8 (5) 1 rare **LP** 1 (3.1) 4 (2.6) 18 (11.5) 2 (4.7) 18 (11) 6 10 **NLPHD** 2 (6.3) 8 (9.8) 3 (1.9) 3 (7.1) 8 (5) 5 5

A shift from MC-dominant histologic subtype of HL was observed over 20-year period within Japan, particularly in young adults (Aozasa, Ueda, Tamai, & Tsujimura, 1986). As NS and MC have been shown to have different environmental cofactors, including socioeconomic status and degree of *EBV* tumor-cell presence, geographic variation in HL is likely to reflect change in socioeconomically determined exposures whenever possible.

The differences in descriptive epidemiology of Hodgkin's lymphoma between children, young adults and older adults may reflect differences in etiology between these age groups.

**Infections.** Systemic analysis of epidemiological data pointed towards an infectious agent as a potential cause for Hodgkin's lymphoma. Recognition of an association of infectious

**Taiwan Japans** 

**No (%)** 

**US %** 

**UK %** 

influences in the etiology of HL (Glaser & Hsu, 2002).

countries are showed in table 4.

**No (%)** 

**Korea No (%)** 

Table 4. Subtypes of Hodgkin's disease in various countries

**HL Iran** 

**3.2 Etiologic epidemiology** 

**3.2.1 Environment** 

mononucleosis with Hodgkin's disease predate the discovery of **EBV** (Richard F. Ambinder, 2007). Investigators have reported that EBV infectious mononucleosis is associated with a lifelong "immunologic scar" (Sauce, et al., 2007). The statistical analysis suggested that HL tended to occur 2.9 years after infectious mononucleosis (R.F. Ambinder, 2007). Remarkably, the change in lymphocyte cell population is sustained over years or longer (Richard F. Ambinder, 2007). There are new insights into infectious mononucleosis and disturbances in cellular immunity, new insight relating to the role that viruses may play in molecular pathogenesis of HL, an emerging appreciation of the increased incidence of HL in *HIV* and its relationship to immune suppression (Richard F. Ambinder, 2007). A role for suppression T cell suggested in the 1970s, and increasing evidence shows a role for this cells in suppressing antitumor immune responses (Hjalgrim, et al., 2007).

In western countries, about 50% of all cases of classical HL are *EBV* positive, means the virus is carried within the tumor cells. Detection of *EBV* in tumors in these region are least common in young adult disease. In some parts of Latin America, Africa, and Asia, the percentage is much higher with the percentage in children approaching 90- 100% (Glaser, et al., 1997; Zarate Osorno, Roman, Kingma, Meneses Garcia, & Jaffe, 1995). The MC subtype harboring *EBV* DNA in up to 70% of cases and the NS subtype being positive in 15-30% of cases (Brousset, et al., 1991). Also detection of *EBV* in HL in most Asian countries are less in young adults and are more detectable in children and older ages. Because of these differences infectious cofactors other than *EBV* have been suggested, but no consensus in support of any other particular association have emerge (Wilson, et al., 2007).

As we mentioned *EBV* induce immune suppression, and in an *EBV* positive person, MC subtype is more common (like *HIV* positive), therefore in MC subtype of HL, which is more common in Asian countries, immunodeficiency has more important role in comparison with other subtypes.

**HIV.** Hodgkin's lymphoma in the setting of *HIV* has distinctive features and is usually associated with EBV infection (Glaser, et al., 2003). HL in patients with *HIV* tends to present at an advanced stage with associated B symptoms and extra-nodal involvement and is most often a mixed cellularity subtype. Model fitting suggested that for persons with AIDS with moderate immunosuppretion at the onset of AIDS, HL risk was 15-fold higher than in the general population. Lower CD4 counts were associated with less risk, the risk fall as CD4 count fall (R.F. Ambinder, 2007).

#### **3.2.2 Inheritance**

The risk of developing HL among family member of patients affected by HL increase from three-to nine-fold (Haim, Cohen, & Robinson, 1982). One study showed a significant association between HL and parental consanguinity and pointed to the possible etiologic role of recessive inheritance (Abramson, Pridan, Sacks, Avitzour, & Peritz, 1978).

The relative risk for HL among first degree relatives of cases compared with controls was 3.1. Relative risks were higher in males compared with females, and in siblings of cases compared with parents and offspring. Identifying inherited susceptibility genes is an important step towards defining the pathway leading to development of HL and

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understanding its etiology. There are many studies of somatic mutations in HL tumor cells, but although there are associations with HLA types, specific germline genes causing susceptibility have not yet been identified. On the other hand it is not known whether or how extrinsic risk factors interact with genetic susceptibility (Goldin, et al., 2005).

Oza et al. in the single study of HL-HLA relationship found that HLA-DPB1\*0301 inreased risk of HL in all ethnic groups, while HLA-DPB1\*0401 was associated with a lowered risk of HL in Japanese and Chinese and an elevated risk for US whites and Israelis (Oza, et al., 1994). Therefore; HLA-DPB1\*1401, or factors related to it, could explain some of the lower incidence of HL in certain Asian ethnic groups, although environmental factors involves as well and indicate that HL etiology is complex.
