**3.1 Descriptive epidemiology**

The epidemiology of Hodgkin's lymphoma is complex. Hodgkin Lymphoma demonstrates different histologic findings, clinical presentation, and outcome. Hodgkin's lymphoma is relatively uncommon, but at young adult ages it is one of the most common malignancies. Increasingly there is a great difference in incidence between developing and western developed countries. In developing countries, the disorder appear predominantly during childhood and its incidence decreases with age (Thomas, Re, Zander, Wolf, & Diehl, 2002). The annual age adjusted incidence rates of 2.8 and 2.4 per 100,000 in the USA and UK respectively (RiesLAG, HankeyBF, & HarrasA, 1994).

Hodgkin's lymphoma has been reported to be rare in Asians. One study in the US from 2000 to 2007, 16,710 cases of HL reported that black and Asians had low incidence (black/white incidence rate ratio (IRR) 0.86, P<0.01; Asian/White IRR 0.43, P<0.01). The bimodal pattern of incidence was less prominent for black males. Asian and black presented at a mean age of 38 years compared to 42 years for Whites (P<.001) (Pareen, Alison, Neha, & Christopher, 2010).There are few studies in exploring the relative contributions of environmental and hereditary etiology of Hodgkin's lymphoma, and individual risk factors in an Asian population. The other study which compared HL incidence rate in Japanese, Chinese,

Epidemiology of Lymphoid Malignancy in Asia 341

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

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

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

**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

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,

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

suppressing antitumor immune responses (Hjalgrim, et al., 2007).

al., 2007).

other subtypes.

**3.2.2 Inheritance** 

1978).

count fall (R.F. Ambinder, 2007).

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

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 countries are showed in table 4.


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

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.

### **3.2 Etiologic epidemiology**

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.
