**2.1.3 Extra-nodal non-Hodgkin Lymphoma**

Non-Hodgkin lymphoma arises in lymphatic cell in other organs except lymphatic tissues, called extra-nodal lymphoma. Some authors believe that, specific local factors may play an etiologic role in the development of lymphomas at certain extra-nodal sites e.g., Helicobacter pylori infection is associated with primary gastric lymphoma, but not with lymphoma at other sites (Parsonnet, et al., 1994b; Wotherspoon, et al., 1993). There are geographical and ethnic differences in the incidence of extra-nodal lymphomas (Newton, Ferlay, Beral, & Devesa, 1997).

The frequency of primary extra-nodal NHL in Asia Varied from 28.5 to 45% (Shih & Liang, 1991), it is similar to Europe, but slightly more common than united states: Denmark 37% (d'Amore, et al., 1991), India 22% (Advani, et al., 1990), Hawaii-Japanese 34% (Yanagihara, et al., 1989), Lebanon 44% (P. Salem, et al., 1986), Chinese Hong Kong 28% (Ho, Todd, Loke, Ng, & Khoo, 1984), USA 25% (Freeman, Berg, & Cutler, 1972), Italy 48%, East Germany 47% (Newton, et al., 1997).

The incidence of extra-nodal NHL in Western countries has increased substantially in the last 40 years. This may be due to improved diagnostic procedures (particularly in gastrointestinal and brain lymphomas) and changes in classification systems, but the change is real and the AIDS epidemic in the 1980s does not completely explain this rise (Groves, Linet, Travis, & Devesa, 2000). The etiology of extra-nodal lymphomas appears to be multifactorial and includes immune suppression, infections both viral and bacterial, and exposure to pesticides and other environmental agents (Zucca, 2008). True geographic

**T cell lymphomas** are very complicated, based on WHO classification, there are various subtypes, and different types of them are different in various area of the world and some are extremely rare, occurring in a few patients per year throughout the world. Major T cell NHL types were reported in the international study in about 1300 patients 22 sites in different countries. Based on this study the most common subtype of T cell lymphoma in North American (NA) was PTCL (unspecified), in Europe was Angioimmunoblastic T cell lymphoma (AITL), and in Asia was Natural Killer T cell lymphoma (NKTCL) and ATLL (Foss, et al., 2011). This variation may reflect exposure or genetic susceptibility to pathogenic agents such as EBV and HTLV1 in Asian countries. Table 2 showed the major T cell subtype

% PTCL AITL Anaplastic NKT CL ATLL NA **34.4** 16 23.8 5.1 2 Europe 34.3 **28.7** 15.8 4.3 1 Asia 22.4 17.9 5.8 22.4 **25** 

Generally speaking an increasing incidence in lymphoma reported from western countries is also seen in Asia, albeit at a lower rate (Shih & Liang, 1991).Essential differences in the incidence and distribution of major NHL subtypes among different geographic areas were seen which seems to be related to host, racial and environmental differences (Atichartakarn, et al., 1982), but these differences gradually changes in recent reports, this shows that the

Non-Hodgkin lymphoma arises in lymphatic cell in other organs except lymphatic tissues, called extra-nodal lymphoma. Some authors believe that, specific local factors may play an etiologic role in the development of lymphomas at certain extra-nodal sites e.g., Helicobacter pylori infection is associated with primary gastric lymphoma, but not with lymphoma at other sites (Parsonnet, et al., 1994b; Wotherspoon, et al., 1993). There are geographical and ethnic differences in the incidence of extra-nodal lymphomas (Newton,

The frequency of primary extra-nodal NHL in Asia Varied from 28.5 to 45% (Shih & Liang, 1991), it is similar to Europe, but slightly more common than united states: Denmark 37% (d'Amore, et al., 1991), India 22% (Advani, et al., 1990), Hawaii-Japanese 34% (Yanagihara, et al., 1989), Lebanon 44% (P. Salem, et al., 1986), Chinese Hong Kong 28% (Ho, Todd, Loke, Ng, & Khoo, 1984), USA 25% (Freeman, Berg, & Cutler, 1972), Italy 48%, East Germany 47%

The incidence of extra-nodal NHL in Western countries has increased substantially in the last 40 years. This may be due to improved diagnostic procedures (particularly in gastrointestinal and brain lymphomas) and changes in classification systems, but the change is real and the AIDS epidemic in the 1980s does not completely explain this rise (Groves, Linet, Travis, & Devesa, 2000). The etiology of extra-nodal lymphomas appears to be multifactorial and includes immune suppression, infections both viral and bacterial, and exposure to pesticides and other environmental agents (Zucca, 2008). True geographic

of NHL in different area (Vose, et al., 2008).

Table 2. Major subtype of T cell lymphoma by region

**2.1.3 Extra-nodal non-Hodgkin Lymphoma** 

Ferlay, Beral, & Devesa, 1997).

(Newton, et al., 1997).

environmental factors probably are more important than the genes.

differences are, however, present for example, the incidence of Epstein–Barr virus and human T-cell lymphotropic virus 1-associated with T-cell lymphomas is higher in Asia than in Europe and North America (Zucca, 2008).

One study, which was done in 39 centers in 14 countries (USA, Europe, Asian) reported the most frequent extra-nodal sites of lymphoma are stomach and skin, followed by small intestine and tonsil (Newton, et al., 1997). In recent study extra-nodal lymphoma in Japan, was seen in 27% of cases, but in previous Japanese series it was 60% (Izumo, 1996). DLBCL was the most common type of extra-nodal lymphoma lesion primarily biopsied/resected (60%). The ear–nose–throat region (7.2%), gastrointestinal tract (6.0%), soft tissue (2.8%) and skin (2.6%) was reported in Japanese study (Aoki, et al., 2008). A clinical analysis in Republic Korea revealed that the rate of extra-nodal lymphoma exceeded that of lymph node lymphoma (63.3% vs. 36.7%) (Y.-H. Ko, et al., 1998). As in other Far East countries, Korea has a relatively high rate of angiocentric lymphomas, which more than 70% of them arise in the nose and paranasal sinus. EBV was positive in 80% of nasal and paranasal angiocentric lymphomas. (Ko & Lee, 1994, 1996). In a study in Thailand, extra-nodal involvement was found in 1072 of 1826 cases (58.7%) of NHL. The frequency of B-cell NHL in cases of NHL involving extra-nodal sites was 72.9%, whereas the frequency of nodal Bcell NHL was 78.0%. Thus, a higher frequency of T-cell NHL involving extra-nodal sites and a higher frequency of B-cell NHL involving lymph nodes were significant when compared to the overall NHL (*P* <0.05). In the Thailand study, among the extra-nodal sites involved in NHL, the upper aerodigestive tract (including the tonsils, sinonasal region, oral cavity, and nasopharynx) was the most common site. The second most common site was the gastrointestinal tract, including the stomach and intestine (Sukpanichnant, 2004). These studies shows that extra-nodal NK/T cell lymphoma is more prevalent in far east and is closely related to EBV infection (Jaffe, 1999; Jaffe, et al., 1996).

Immunoproliferative small intestinal disease (IPSID) or α heavy chain disease is mostly found in young adults of low socioeconomic class in developing countries or in indigent immigrant population within western countries. Relatively high incidence rates of small intestinal lymphoma have been reported before in the Middle east, Mediterranean region, South and central Africa, Mexico, and South America, but is rare in Southeast Asia (Pramoolsinsap, Kurathong, Atichartakarn, & Nitiyanand, 1993).

IPSID was one of the most common small intestinal malignancy in the Middle East (Azar, 1962). Early infectious stress in infancy and chronic antigenic stimulation along with genetic factors are probably important in the pathogenesis of IPSID (Khojasteh, Haghshenass, & Haghighi, 1983). It showed that Campylobacter jejune were present in 5/7 cases of IPSID in one study and 12/27 (47%) cases in other and 14/87 (16%) cases of other intestinal lymphoma. Eradication of the organism with antibiotics lead to complete remission of IPSID (Du, 2007).

In one series of 161 patients with IPSID in Shiraz (Iran), they observed a dramatic decrease in the incidence of the disease over the past decade. After the Islamic revolution in Iran, improving sanitation in villages was one of the priorities of the many health strategies in Iran. Access to sanitary drinking water in rural areas increased from 35% before 1988 to 80% a decade later. Vaccination programs increased dramatically after the Islamic revolution, reaching more than 90% of children. Local health facilities increased significantly during the first two decades after the revolution. They suggest that improvement of health in general

Epidemiology of Lymphoid Malignancy in Asia 333

mechanisms. Also a correlation between the duration of gluten exposure and the incidence of lymphoma has been found. The relative risk of lymphoma is reduced by a gluten free diet (Jafroodi, Zargari, & Hoda, 2009). In a US cohort study, an increased risk of NHL was reported in patients with celiac disease (SMR = 9.1, 95% CI: 4.7-13.0). Similarly, a relative

The incidence of CD is increasing among certain populations in Africa (Saharawui population), Asia (India), and the Middle East (Cummins & Roberts Thomson, 2009). In Asian populations, including the Japanese, CD and the associated NHL have been supposed to be quite rare, and studies concerning the frequency of CD or its relationship with NHL are scarce. A Japanese case report describes a Japanese middle-aged man with intestinal diffuse large B-cell lymphoma associated with CD. Following multi-combined chemotherapy, the patient's lymphoma has received complete response, and his GI symptoms have improved with a gluten free diet (Makishima, et al., 2006). Also an Iranian case report describes a child with Hodgkin's disease and sever atopic dermatitis associated with CD (Arellano, et al., 2009). These cases suggest that the possibility of CD and its association with lymphoid malignancy should be kept in mind, even in Asian populations.

Epidemiological studies pointed towards a viral and bacterial etiology on NHL. In this part

**Epstein-Barr virus (EBV).** The *Epstein-Barr virus* has a worldwide distribution, which greater than 80% of people over the age of 30 are infected. Once *EBV* infection has occurred, it remains for the lifetime of the individual (Serraino, et al., 2005). Infection with this virus usually occurs in children, but can also occur in adolescence or adulthood. *EBV*  asymptomatically establishes persistent infections however, due to effective immune control, only a minority of infected carriers develop spontaneous *EBV*-associated lymphoma (Heller, Steinherz, Portlock, & Munz, 2007). Infection by *EBV* is more common in developing countries where sanitation, hygiene, and cooking are not as sterile as nations

*EBV* has a unique set of genes that causes a growth activation of the B-cells that are infected. Sometime the growth activating genes may cause the infected B-cell to transform into cancer in certain people. The most common type of lymphoma caused by EBV are T-cell lymphoma, Post-transplant lymphoma, AIDS associated lymphoma, Burkitt's lymphoma (BL), and Hodgkin's lymphoma. These *EBV*-associated neoplasms are characterized by peculiar

In the endemic areas of Africa, BL is the leading childhood cancer, occurring as many as 4-5 cases per 100000. In areas where *EBV* infection occurs at a very early age and malaria is holoendemic, the incidence of association with BL is highest. In African countries in the lymphoma belt there is a very high association between BL and *EBV* (90%). However, in France and the US, the rare cases of BL are only associated with *EBV* in 10-15% of all

Induced immunosuppretion, necessary for the transplant to be accepted, leads to a loss of control over *EBV* infection. The lymphoma that is developed contains parts of the latent *EBV* genome. About half of NHL tumors accompanying *HIV1* infections are *EBV* positive.

geographic distributions and distinctive epidemiologic features (Serraino, et al., 2005) .

we discuss about some of them which are more important.

such as the USA (Evans & Kaslow, 1997).

reported cases (Frimpong-Boateng).

risk of 5.8 (95% CI: 1.58-14.86) was observed in a UK cohort (Alexander, et al., 2007).

**2.2.2 Infectious agents** 

and decreasing childhood gastroenteritides in particular has resulted in a decrease in the incidence of IPSID. This report highlights the almost complete disappearance of a malignant disease from a region where it was once very common. This changes probably related to changes in environmental factors, decreasing exposure to infectious agents (Lankarani, et al., 2005). Other preliminary recent epidemiological data has also shown a decrease in the incidence of this disease in endemic areas; therefore, environmental factors are suspected to play an important role in its pathogenesis (P. A. Salem & Estephan, 2005).
