**2.1.1 Immunologic characterization of non-Hodgkin's lymphoma**

Although B-cell lymphomas are constantly more common around the world, T-cell lymphomas are proportionally more common in Asia than in western countries (Müller, et al., 2005). Despite a higher percentage of T-cell lymphomas in Asians compared with westerns, the absolute incidences of T-NHL in HTLV1 non endemic areas, and western countries are quite similar when calculated by age-adjusted incidence (Aoki, et al., 2008; Au, et al., 2005; Wang, Young, Win, & Taylor, 2005). In a Chinese (non endemic area for HTLV1) study T-cell lymphoma proportion was 28.1% (Wang, et al., 2005), and also in Taiwan which is not endemic for HTLV1, T/NK lymphoma incidence was 12.4% (Lee, Tsou, Tan, & Lu, 2005). In an Indian study T-cell lymphomas formed 16.2% of the total NHL (Naresh, Srinivas, & Soman, 2000). Previous Japanese studies have reported a higher proportion of Tcell lymphoma, accounting for approximately 32-38% of non-Hodgkin lymphoma (Kadin, Berard, Nanba, & Wakasa, 1983; Pathologists, 2000), but the recent findings in Japan show the decreased frequency of T/NK cell lineage (25%) (Aoki, et al., 2008). In endemic area for HTLV1 in Japan, T/NK-cell neoplasm accounted for a higher percentage of lymphoid neoplasm, in Kyushu (30%) and Okinawa (38%), compared with other areas of Japan (18– 20%) (Aoki, et al., 2008). In one study in 1997 in Korea, in comparison with data reported in 1992, the proportion of T-lineage lymphoma was markedly decreased (25%). At that time, the T-lineage of lymphoma accounted for 35.2% of malignant lymphomas (Y. H. Ko, et al., 1998). It may be due to an increase in the frequency of B-cell lymphoma and an actual decrease in T/NK-cell, but the real reason remains unclear (Y. H. Ko, et al., 1998).

### **2.1.2 Histological subtype of non-Hodgkin's lymphoma**

**Diffuse Large B Cell Lymphoma***.* Among B-cell lymphomas, diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin's Lymphoma representing approximately one third of all Non-Hodgkin's Lymphomas worldwide. This is one type of Non Hodgkin's Lymphoma in which the relative incidence does not seem to vary geographically (Mozaheb, et al., 2011). In almost all parts of the world this is the most frequent occurring non-Hodgkin's lymphoma (K. E. Hunt & Reichard, 2008). In some studies like a recent study in Mashhad, Iran (Mozaheb, et al., 2011) there was a higher rate of aggressive NHL specially, diffuse large B cell lymphoma which occurs more frequent than others. It may be related to the etiology of diffuse large B cell lymphoma such as immune deficient conditions and their treatments which in most instances caused aggressive non-Hodgkin's lymphoma, and we should consider that a comparative excess of DLBCL resulting in a deficit of follicular lymphoma. In addition genetic factors may have an important role in this difference.

Epidemiology of Lymphoid Malignancy in Asia 329

the increase in the relative frequency of Fl (1.6% vs 6.4%) over time suggests that the patterns of malignant lymphoma occurrence in the Republic of Korea might be gradually changing, probably due to westernization and other reasons which were mentioned

**INDIA** 

**Total (No)** 391 1165/1548 ----/598 447 1983 3025/2260 9567 10580 **NHL %** 92 94.7/94.7 ----/93 2831 82.6% 92.1% 94/7/92.7 84.4

**DLBCL %** 37.8 -/43.2 47.2/39 34 35.1 50.5 33/33 41.2 41.3 28 **FL %** 1.4 1.6/6.2 8.6/16.4 12.6 8.6 8.4 6.7/18.2 9.2 17 13 **MCL %** 2.2 -/1.5 ----/4 3.4 2.6 1.5 2.7/2.7 3.7 2

**lymphoma%** 2.2 -/0.6 6.1/5.6 8.2 11.7 5.5 8.4/4.2 8.7 3.6 3.7 **SLL/CLL %** 23.9 -/2.3 5.6 3.6 3.4 1.4/1.4 20

**lymphoma %** ----/12.4 0.9 30.6 1.5 5

**ATLL %** 1.4 -/0.1 rare rare 7.4/10 rare rare **HL %** 8 5.3/5.3 ----/7 13.9 7.9 4.4/7.3 15.6 8

In the analysis of 1983 cases of malignant lymphoma in Thailand shows that Bangkok has a significantly high frequency of FL, much higher than that the Central region. They suggest that the underlying reason for this observation is not known. Obviously, Metropolitan Bangkok has a more diverse population, migrated from various geographical locations, than people in the Central region (Sukpanichnant, 2004). A clinicopathological analysis of 598 Malignant Lymphomas in Taiwan during the period of 1995–2002 was retrieved, and their data showed a similar incidence of FL (16.4%) to that in Western countries (Lee, Tan, et

**Mantle cell Lymphoma (MCL)** in a case series has been between 2 and 10% of all NHL. The incidence rate is approximately similar around the world (table 1) and it is about 0.5 cases per 100000 person-year, with male to female ratio 2.3-2.5:1, and a median age at diagnosis is about 70 years. Relative association of MCL risk with *Borrelia burgdorferi* infection, family history of hematopoietic malignancies, and genetic variation in the interleukin 10 and tumor necrosis factor genes have been reported, but finding remain unconfirmed (Smedby &

Table 1. The Most Common subtypes of NHL in Various Geographic Locations

**CHINA** 

80.6/19.4 79/15.2 68.6/30.6 75/25 68/24,

2010 1991/1997 2000/2006 2000 2005 2004 2000/2008 1991 2001 2006

1.9 -/9.4 19.3/3.8 1.9 12 13.1 6.6/4.5 9.7 5.9 6

**THILAND** 

**JAPAN** 

**Asia** 

65.2/25.4 76/24 93/7 90/10

**UK** 

**USA** 

previously (Y. H. Ko, et al., 1998).

**IRAN** 

**B/T cell %** 75/25 81.7/18.3

**KOREA** 

**TIWAN** 

 **Country/ year** 

**Lymphoma** 

**MALT** 

**NK/T cell** 

al., 2005).

Hjalgrim., 2011).

**%** 

**Peripheral T cell lymphoma**

Moreover it can represent the progression/transformation (referred to as secondary) of a less aggressive lymphoma, such as follicular lymphoma, marginal zone B-cell lymphoma, or nodular lymphocyte–predominant Hodgkin's lymphoma (K. E. Hunt & Reichard, 2008). All lymphoid cancers are more frequent in males than females among all age groups and in our study Diffuse large B cell lymphoma occurs about twice among men (Mozaheb, et al., 2011). This pattern suggests that the underlying environmental or behavioral factors are also important and must be more common in men. The most common subtypes of NHL in Various Geographic Locations are showed in table 1.

**Follicular Lymphoma.** Incidence rates of follicular lymphoma (FL) inexplicably vary markedly between Asian and Western countries (Biagi & Seymour, 2002). Follicular lymphoma was found more frequently in North America and Europe compared to other geographic sites (Kim, et al., 1992). The lowest rates of follicular lymphoma have been reported among Asian population (Anderson, et al., 1998; Mozaheb, et al., 2011). In addition, the risk was lower for the first generation of migrants from China and Japan into the US in comparison with the subsequent migrant generations, and in Japanese-Americans in Hawaii it was reported to be relatively high compared with that for native Japanese and close to the rate of North American Caucasians (Yanagihara, Blaisdell, Hayashi, & Lukes, 1989). The percentage of follicular lymphoma in our study in Mashhad, IRAN, was the lowest observed in any site (1.4%) (Mozaheb, et al., 2011), it was near the incidence rate of NHL in a previous study in Korea (1.6) (Y. H. Ko, et al., 1998). Although the exact reason for this difference is unknown, the results of several studies suggest differences in genes and environmental factors such as diet habits, infections and smoking, which plays an important role in follicular lymphoma, are responsible. Some cytogenetic changes such as a higher incidence of bcl-2 translocations are seen within follicular lymphoma among individuals in the US than for Asian populations (Shih & Liang, 1991). It conclude that a significant gradient exists in the *bcl-2* frequency between these FL populations, and therefore suggest that the relatively low incidence of FL in Asian populations is caused not by a lower frequency of *bcl-2* rearrangements in healthy populations but by distinct molecular pathways developing in different geographic regions that nonetheless culminate in FL, which is morphologically similar but molecularly distinct (Biagi & Seymour, 2002).

In a previous study in Japan the incidence rate of FL was 6.7% (Pathologists, 2000), but in a recent study in Japan they found a relatively high rate of FL (19%) similar to that of western countries (11-30%) (Aoki, et al., 2008). They suggest the following reasons for the relatively high rate of occurrence of follicular lymphomas. First, there have been improvements in the recognition and diagnostic accuracy for this subtype due to the development of comprehensive diagnostic methods including flow cytometry, immunohistochemistry, chromosome testing, gene testing and FISH. Second, the patients in their recent study comprised only initial visit cases and did not include consultation cases, because typical follicular lymphoma tends to be diagnosed at the initial visit and not during consultation, previous studies of patients in large hospitals may not have included initial visit cases and thus underestimated the frequency of follicular lymphoma. The third reason is the westernization of the Japanese lifestyle that may have contributed to an increase in follicular lymphoma (Aoki, et al., 2008). The rate of follicular lymphoma for Japanese– Americans in Hawaii was reported to be relatively high compared to that of native Japanese and close to the rate of North American Caucasians. A similar trend in completely follicular lymphoma has been reported for Korea. In one study in 1997 compared with the data reported in 1991,

Moreover it can represent the progression/transformation (referred to as secondary) of a less aggressive lymphoma, such as follicular lymphoma, marginal zone B-cell lymphoma, or nodular lymphocyte–predominant Hodgkin's lymphoma (K. E. Hunt & Reichard, 2008). All lymphoid cancers are more frequent in males than females among all age groups and in our study Diffuse large B cell lymphoma occurs about twice among men (Mozaheb, et al., 2011). This pattern suggests that the underlying environmental or behavioral factors are also important and must be more common in men. The most common subtypes of NHL in

**Follicular Lymphoma.** Incidence rates of follicular lymphoma (FL) inexplicably vary markedly between Asian and Western countries (Biagi & Seymour, 2002). Follicular lymphoma was found more frequently in North America and Europe compared to other geographic sites (Kim, et al., 1992). The lowest rates of follicular lymphoma have been reported among Asian population (Anderson, et al., 1998; Mozaheb, et al., 2011). In addition, the risk was lower for the first generation of migrants from China and Japan into the US in comparison with the subsequent migrant generations, and in Japanese-Americans in Hawaii it was reported to be relatively high compared with that for native Japanese and close to the rate of North American Caucasians (Yanagihara, Blaisdell, Hayashi, & Lukes, 1989). The percentage of follicular lymphoma in our study in Mashhad, IRAN, was the lowest observed in any site (1.4%) (Mozaheb, et al., 2011), it was near the incidence rate of NHL in a previous study in Korea (1.6) (Y. H. Ko, et al., 1998). Although the exact reason for this difference is unknown, the results of several studies suggest differences in genes and environmental factors such as diet habits, infections and smoking, which plays an important role in follicular lymphoma, are responsible. Some cytogenetic changes such as a higher incidence of bcl-2 translocations are seen within follicular lymphoma among individuals in the US than for Asian populations (Shih & Liang, 1991). It conclude that a significant gradient exists in the *bcl-2* frequency between these FL populations, and therefore suggest that the relatively low incidence of FL in Asian populations is caused not by a lower frequency of *bcl-2* rearrangements in healthy populations but by distinct molecular pathways developing in different geographic regions that nonetheless culminate in FL,

which is morphologically similar but molecularly distinct (Biagi & Seymour, 2002).

In a previous study in Japan the incidence rate of FL was 6.7% (Pathologists, 2000), but in a recent study in Japan they found a relatively high rate of FL (19%) similar to that of western countries (11-30%) (Aoki, et al., 2008). They suggest the following reasons for the relatively high rate of occurrence of follicular lymphomas. First, there have been improvements in the recognition and diagnostic accuracy for this subtype due to the development of comprehensive diagnostic methods including flow cytometry, immunohistochemistry, chromosome testing, gene testing and FISH. Second, the patients in their recent study comprised only initial visit cases and did not include consultation cases, because typical follicular lymphoma tends to be diagnosed at the initial visit and not during consultation, previous studies of patients in large hospitals may not have included initial visit cases and thus underestimated the frequency of follicular lymphoma. The third reason is the westernization of the Japanese lifestyle that may have contributed to an increase in follicular lymphoma (Aoki, et al., 2008). The rate of follicular lymphoma for Japanese– Americans in Hawaii was reported to be relatively high compared to that of native Japanese and close to the rate of North American Caucasians. A similar trend in completely follicular lymphoma has been reported for Korea. In one study in 1997 compared with the data reported in 1991,

Various Geographic Locations are showed in table 1.

the increase in the relative frequency of Fl (1.6% vs 6.4%) over time suggests that the patterns of malignant lymphoma occurrence in the Republic of Korea might be gradually changing, probably due to westernization and other reasons which were mentioned previously (Y. H. Ko, et al., 1998).


Table 1. The Most Common subtypes of NHL in Various Geographic Locations

In the analysis of 1983 cases of malignant lymphoma in Thailand shows that Bangkok has a significantly high frequency of FL, much higher than that the Central region. They suggest that the underlying reason for this observation is not known. Obviously, Metropolitan Bangkok has a more diverse population, migrated from various geographical locations, than people in the Central region (Sukpanichnant, 2004). A clinicopathological analysis of 598 Malignant Lymphomas in Taiwan during the period of 1995–2002 was retrieved, and their data showed a similar incidence of FL (16.4%) to that in Western countries (Lee, Tan, et al., 2005).

**Mantle cell Lymphoma (MCL)** in a case series has been between 2 and 10% of all NHL. The incidence rate is approximately similar around the world (table 1) and it is about 0.5 cases per 100000 person-year, with male to female ratio 2.3-2.5:1, and a median age at diagnosis is about 70 years. Relative association of MCL risk with *Borrelia burgdorferi* infection, family history of hematopoietic malignancies, and genetic variation in the interleukin 10 and tumor necrosis factor genes have been reported, but finding remain unconfirmed (Smedby & Hjalgrim., 2011).

Epidemiology of Lymphoid Malignancy in Asia 331

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

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

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

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

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

in Europe and North America (Zucca, 2008).

closely related to EBV infection (Jaffe, 1999; Jaffe, et al., 1996).

(Pramoolsinsap, Kurathong, Atichartakarn, & Nitiyanand, 1993).

(Du, 2007).

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


Table 2. Major subtype of T cell lymphoma by region

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 environmental factors probably are more important than the genes.
