**2.2.2 Infectious agents**

Epidemiological studies pointed towards a viral and bacterial etiology on NHL. In this part we discuss about some of them which are more important.

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

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

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 reported cases (Frimpong-Boateng).

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.

Epidemiology of Lymphoid Malignancy in Asia 335

**southern Japan** Up to 30% General population **Iran (Mashhad)** 1653 2.1 General population **Lebanon** 3529 0.06 Blood donors **Taiwan** 3700000 0.06 Blood donors **Korea** 9281 0.13 Blood donors **Jamaica** 3-6% General population **Caribbean** 6% General population **Curacao** 2524 1.92% General population **Papua New Guinea** 1221 0-14.6% General population **Argentina** 2082 1.9% General population **U.S** 1700000 0.01 Blood donors **Italy** 14598 0.03 Blood donors **Germany** 100852 0 Blood donors **U.K** 570609 0.001 Blood donors

Adult T-cell lymphoma leukemia (ATL) is an aggressive lymphoproliferative malignancy, with short survival in its acute form and an incidence of less than 5% in *HTLV-1*-infected people (Shimoyama, 1991). The cumulative incidence of ATL among Japanese HTLV1 carrier is about 2.5% (3-5% in male and 1-2% in female). Although women are more infected with HTLV1, but ATL is more common in men, it shows that other factors also should be responsible. At first ATL was described in Japan and later in the Caribbean region and South America (Uchiyama, Yodoi, Sagawa, Takatsuki, & Uchino, 1977). In the United States and Europe, ATL was diagnosed in immigrants from regions of endemicity. ATL occurs at least 20 to 30 years after the onset of *HTLV-1* infection and is more common in adult males. Individuals infected in childhood may be at a higher risk of developing ATL (Pawson, et al., 1998). The occurrence of ATL in the fourth decade predominates in Brazil and in Jamaica (Proietti, Carneiro-Proietti, Catalan-Soares, & Murphy, 2005), but in Japan, the fifth decade of life is predominant for the occurrence of ATL (Shimoyama, 1991). Possibly, local factors

*Helicobacter pylori* **(***H. pylori***).** *Helicobacter pylori* colonizes gastric mucosa, leading to chronic Gastric infection, and induce peptic ulcer disease and gastric carcinoma, also may cause Bcell lymphomas, particularly mucosa-associated lymphoid tissue (MALT) tumors in the stomach, with the association being strongest in early lesion (Chiu & Weisenburger, 2003; Zucca, et al., 2000). In developing countries, where over 90% of the population may be infected, *H. pylori* infection usually occurs during childhood with chronic infection continuing throughout adulthood (Pounder & Ng, 1995). In contrast, although in developed countries the overall prevalence generally remains lower than in developing countries, the prevalence is low among children and rises with age in adults. *H. pylori* has been detected in more than 90% of patients with low-grade gastric MALT lymphoma, and in 40-75% of high-

Direct fecal oral transmission is predominant in industrialized countries whereas other transmission routes such as contamination of water may be more important in developing

**country Sample size Prevalence of HTLV1 Group** 

Table 3. Prevalence of *HTLV1* in different countries

play a role in disease pathogenesis.

grade gastric lymphomas (Boot & Jong, 2002).

**rural Miyazaki,** 

These lymphoma are grouped into several categories: small non-cleaved-cell lymphoma, diffuse large cell lymphoma, anaplastic large cell lymphoma, and body-cavity based lymphoma (Gaidano, et al., 1996).

Several studies showed the association of Asian T cell lymphoma and evidence of *EBV* infections. Asian T-cell lymphomas are different from Western T-cell lymphoma, and are also associated with increased levels of cytokine production, including tumor necrosis factor (Dutcher, 2003). Aggressive NK-cell LGL leukemia is usually a rapidly progressive disorder associated with EBV, with a higher prevalence in Asia and South America (Sokol & Loughran, 2006).

**Human T-Cell Lymphotrophic virus-1 (HTLV1).** HTLV1, the first human retrovirus to be discovered, is estimated to infect 10-20 million people worldwide (De Thé & Bomford, 1993). Infection with *HTLV1* is strongly related to adult T-cell leukemia/ Lymphoma (Hinuma, et al., 1981) and *HTLV1* associated myelopathy (Morgan, Mora, Rodgers-Johnson, & Char, 1989). *HTLV1* is primarily transmitted by breast feeding, blood transfusion, Sharing of needles and sexual transmission. The predominance of vertical transmission results in clustering cases in familial or geographically discrete groups. It is endemic in southern Japan, the Caribbean, the Melanesian island, Papua New Guinea, the Middle East, central and southern Africa, and South America. In these endemic areas, seroprevalences range are different from about one percent in Mashhad in southeast Iran (1-3%) (Abbaszadegan, et al., 2003; Tarhini, et al., 2009) to 30 percent in rural Miyazaki in southern Japan. In table 3 we can see the prevalence rate of *HTLV1* in different countries.

Population *HTLV-I* seroprevalence increases with age and is twice as high in females. In Jamaica 174% of women over 70 and 91% of men over 70 were seropositive. In Japan, *HTLV-I* seroprevalence in persons over 80 was 50% in females and 30% in males. This gender difference usually emerges after 30 years of age and may be related to more efficient transmission of the virus from males to females in the sexually active years (Yamaguchi, 1994). Seroprevalence tends to increase with age and women are nearly twice as likely to be infected as men (Mueller, Okayama, Stuver, & Tachibana, 1996).

*HTLV1* shows little genomic variability during the course of infection and between patients in the same geographic area. Mother/child and spouse pairs from Okinawa (Japan) have been shown to be infected with highly conserved viruses upon direct sequencing of viral genome (Kakuda, Ikematsu, Chong, Hayashi, & Kashiwagi, 2002). Studies in France (Gessain, Gallo, & Franchini, 1992) the Solomon Islands (Nerurkar, Song, Saitou, Melland, & Yanagihara, 1993) and Zaire (LIU, et al., 1994) have shown similarly low genomic variability based upon the less accurate sequencing of PCR products. Therefore, small strain variation is recognized between geographic areas. Risk of infection is higher (fourfold increase) in breast fed infants than in those who are bottle fed (HIRATA, et al., 1992). A longer duration of breast feeding increase transmission risk (Li, et al., 2004). Another important risk factor is provirus load in breast milk.

The infection is usually asymptomatic in the beginning and the disease typically manifests later in life; therefore silent transmission occurs. Since there are no prospects of vaccines and screening of blood banks and prenatal care settings are not universal, transmission is active in many areas such as parts of Africa, South and Central America, the Caribbean region, Asia, and Melanesia (Goncalves, et al., 2010).

These lymphoma are grouped into several categories: small non-cleaved-cell lymphoma, diffuse large cell lymphoma, anaplastic large cell lymphoma, and body-cavity based

Several studies showed the association of Asian T cell lymphoma and evidence of *EBV* infections. Asian T-cell lymphomas are different from Western T-cell lymphoma, and are also associated with increased levels of cytokine production, including tumor necrosis factor (Dutcher, 2003). Aggressive NK-cell LGL leukemia is usually a rapidly progressive disorder associated with EBV, with a higher prevalence in Asia and South America (Sokol &

**Human T-Cell Lymphotrophic virus-1 (HTLV1).** HTLV1, the first human retrovirus to be discovered, is estimated to infect 10-20 million people worldwide (De Thé & Bomford, 1993). Infection with *HTLV1* is strongly related to adult T-cell leukemia/ Lymphoma (Hinuma, et al., 1981) and *HTLV1* associated myelopathy (Morgan, Mora, Rodgers-Johnson, & Char, 1989). *HTLV1* is primarily transmitted by breast feeding, blood transfusion, Sharing of needles and sexual transmission. The predominance of vertical transmission results in clustering cases in familial or geographically discrete groups. It is endemic in southern Japan, the Caribbean, the Melanesian island, Papua New Guinea, the Middle East, central and southern Africa, and South America. In these endemic areas, seroprevalences range are different from about one percent in Mashhad in southeast Iran (1-3%) (Abbaszadegan, et al., 2003; Tarhini, et al., 2009) to 30 percent in rural Miyazaki in southern Japan. In table 3 we

Population *HTLV-I* seroprevalence increases with age and is twice as high in females. In Jamaica 174% of women over 70 and 91% of men over 70 were seropositive. In Japan, *HTLV-I* seroprevalence in persons over 80 was 50% in females and 30% in males. This gender difference usually emerges after 30 years of age and may be related to more efficient transmission of the virus from males to females in the sexually active years (Yamaguchi, 1994). Seroprevalence tends to increase with age and women are nearly twice as likely to be

*HTLV1* shows little genomic variability during the course of infection and between patients in the same geographic area. Mother/child and spouse pairs from Okinawa (Japan) have been shown to be infected with highly conserved viruses upon direct sequencing of viral genome (Kakuda, Ikematsu, Chong, Hayashi, & Kashiwagi, 2002). Studies in France (Gessain, Gallo, & Franchini, 1992) the Solomon Islands (Nerurkar, Song, Saitou, Melland, & Yanagihara, 1993) and Zaire (LIU, et al., 1994) have shown similarly low genomic variability based upon the less accurate sequencing of PCR products. Therefore, small strain variation is recognized between geographic areas. Risk of infection is higher (fourfold increase) in breast fed infants than in those who are bottle fed (HIRATA, et al., 1992). A longer duration of breast feeding increase transmission risk (Li, et al., 2004). Another important risk factor is

The infection is usually asymptomatic in the beginning and the disease typically manifests later in life; therefore silent transmission occurs. Since there are no prospects of vaccines and screening of blood banks and prenatal care settings are not universal, transmission is active in many areas such as parts of Africa, South and Central America, the Caribbean region,

can see the prevalence rate of *HTLV1* in different countries.

infected as men (Mueller, Okayama, Stuver, & Tachibana, 1996).

lymphoma (Gaidano, et al., 1996).

Loughran, 2006).

provirus load in breast milk.

Asia, and Melanesia (Goncalves, et al., 2010).


Table 3. Prevalence of *HTLV1* in different countries

Adult T-cell lymphoma leukemia (ATL) is an aggressive lymphoproliferative malignancy, with short survival in its acute form and an incidence of less than 5% in *HTLV-1*-infected people (Shimoyama, 1991). The cumulative incidence of ATL among Japanese HTLV1 carrier is about 2.5% (3-5% in male and 1-2% in female). Although women are more infected with HTLV1, but ATL is more common in men, it shows that other factors also should be responsible. At first ATL was described in Japan and later in the Caribbean region and South America (Uchiyama, Yodoi, Sagawa, Takatsuki, & Uchino, 1977). In the United States and Europe, ATL was diagnosed in immigrants from regions of endemicity. ATL occurs at least 20 to 30 years after the onset of *HTLV-1* infection and is more common in adult males. Individuals infected in childhood may be at a higher risk of developing ATL (Pawson, et al., 1998). The occurrence of ATL in the fourth decade predominates in Brazil and in Jamaica (Proietti, Carneiro-Proietti, Catalan-Soares, & Murphy, 2005), but in Japan, the fifth decade of life is predominant for the occurrence of ATL (Shimoyama, 1991). Possibly, local factors play a role in disease pathogenesis.

*Helicobacter pylori* **(***H. pylori***).** *Helicobacter pylori* colonizes gastric mucosa, leading to chronic Gastric infection, and induce peptic ulcer disease and gastric carcinoma, also may cause Bcell lymphomas, particularly mucosa-associated lymphoid tissue (MALT) tumors in the stomach, with the association being strongest in early lesion (Chiu & Weisenburger, 2003; Zucca, et al., 2000). In developing countries, where over 90% of the population may be infected, *H. pylori* infection usually occurs during childhood with chronic infection continuing throughout adulthood (Pounder & Ng, 1995). In contrast, although in developed countries the overall prevalence generally remains lower than in developing countries, the prevalence is low among children and rises with age in adults. *H. pylori* has been detected in more than 90% of patients with low-grade gastric MALT lymphoma, and in 40-75% of highgrade gastric lymphomas (Boot & Jong, 2002).

Direct fecal oral transmission is predominant in industrialized countries whereas other transmission routes such as contamination of water may be more important in developing

Epidemiology of Lymphoid Malignancy in Asia 337

other viruses, which may result in opportunistic infection and replication of oncogenic viruses (Coté, et al., 1997). In AIDS patients NHL has been reported in approximately 2-3% of patients with AIDS, but AIDS accounts only for a small fraction of all NHL (Biggar & Rabkin, 1992; Rabkin & Yellin, 1994). In an international collaboration on *HIV* and cancer, incidence data from 23 prospective studies were used to compare incidence rates of NHL in *HIV-*infected persons in 1997–1999 with those in 1992–1996 (Coutinho, 2000). The incidence rates for NHL declined from 6.2 per 1,000 person-years to 3.6 per 1,000 person-years. Grulich *et al.* (Grulich, et al., 2001) reported a significantly lower relative risk of NHL in persons with *HIV* in the period of highly active antiretroviral therapy (HAART) availability than in the period immediately prior (RR = 0.58, 95% CI: 0.36–0.92) *(Alexander, et al., 2007).* In one study in Japan the incidence of AIDS-related lymphoma detected at autopsy was higher in Japan (27%) than in the US (12%). However, histological subtypes of AIDS-related lymphoma in Japan seem to be similar to those in western countries and DLBCL is also the most common subtype of AIDS-related lymphoma in Japan. A large number of AIDSrelated lymphoma cases were categorized into EBV-associated opportunistic lymphoma in Japan. The incidences detected by autopsy did not differ statistically between the pre-HAART era and the HAART era (*P* = 0.31), and the histological subtype of DLBCL was stable in both the pre-HAART era (78%) and the HAART era (77%) . In contrast, they found an increase in patients with BL from 2% in the pre-HAART era to13% in the HAART era. (Hishima, et al., 2006). Despite the high rate of human immunodeficiency virus infection in Thailand, only 5 cases of documented AIDS-associated lymphoma were noted in one study (5 of 389 NHL; 1.3%). Similarly, Kaposi's sarcoma is not common in AIDS patients in Thailand. The underlying reason for this unique feature of AIDS-related lymphoma in Thailand is not known and further investigation is needed (Sukpanichnant, et al., 1998). In one study in India the proportional incidence ratio (PIR) for NHL was significantly increased in *HIV* era (PIR in males = 17.1, 95%CI 13.33-21.84, females = 10.3, 95%CI 6.10- 17.41), and their finding was similar to that reported by other studies (Dhir, et al., 2008). In one study in Singapore when comparing the age-standardized rates for males and female in 1998 – 2002 which are 8.2 and 5.0 per 100,000 respectively compared with 7.5 and 4.4 per 100,000 in 1993-1997 and 3.1 and 1.9 per 100,000 in 1968-1972, this may be partly due to *HIV*/AIDS, changes in pathological classification and improved diagnostic capabilities (Seow & Registry, 2004). Except for one study in Thailand, *HIV*/AIDS lead to increase

incidence rate of lymphoma in both eastern and western countries.

et al., 1997).

**Human herpesvirus-8** (HHV-8). Human herpesvirus-8, is endemic in regions of the Mediterranean and Africa (Kamiyama, et al., 2004), but the seroprevalence of *HHV-8* which has been studied in Malaysia, India, Sri Lanka, Thailand, Trinidad, Jamaica and the USA, in both healthy individuals and those infected with *HIV*, was found to be low in these countries in both the healthy and the *HIV*-infected populations (Ablashi, et al., 1999). *HHV-8* is generally accepted to be associated with development of primary effusion lymphoma (PEL), a rare B-cell lymphoma that almost exclusively affects *HIV*-positive patients (Ascoli, et al., 2002). However this lymphoma is often associated with both *HHV-8* and *EBV*, limiting the understanding of the pathogenic role of *HHV-8* (Ascoli, et al., 2002). Within B-cell lymphomas, however, *HHV-8* infection was associated significantly and positively with risk of lymphoplasmacytic lymphoma (OR = 4.47, 95% CI: 1.34–14.85) or low-grade B-cell lymphoma and lymphoma not otherwise specified (OR = 5.82, 95% CI: 1.07-31.73) (Feuillard,

countries. The bacteria is transmitted within families in early childhood (Farinha & Gascoyne, 2005). Parsonnet *et al.* (Parsonnet, et al., 1994a) and Vineis *et al.* (Vineis, et al., 1999) reported a significant positive association between *H. pylori* infection and risk of gastric NHL but not non-gastric NHL. Greater than 60% of MALT lymphomas regress with *H. pylori* eradication following treatment with antibiotics (R. Hunt, Sumanac, & Huang, 2001). Because the US prevalence of *H. pylori* infection is low and declining, *H. pylori* most likely did not play a significant role in the overall rising trend of NHL incidence in the US (Alexander, et al., 2007)*.* H. pylori infection is more common in Asian countries, therefore as we can see in table 1, MALT lymphoma in most Asian countries are more common than western countries.

**Hepatitis C Virus** (HCV)**.** Hepatitis C virus infection has been reported to be a prevalent disease since the second half of the 20th century (Strickland, 2006). Infection in different parts of Asia is similar, with an average seroprevalence of hepatitis C antibody less than 2.5% in the general population. The major routes of *HCV* transmission in Asia have been through blood transfusions and intravenous drug use, similar to the other countries. Other possible routes of transmission are medical intervention, tattooing, acupuncture, vertical and sexual transmission, accidental needle-stick and household contact. It is believed that *HCV* is still spreading in some areas of Asia because of the lack of routine screening of donated blood (Kao & Chen, 2000). *HCV* has been linked to lymphomagenesis in people with and without type II mixed cryoglobulinemia (Saadoun, Landau, Calabrese, & Cacoub, 2007). Increasing evidence indicates that the association between *HCV* infection and lymphoma may be due to viral infection related chronic antigenic stimulation. The chronic inflammation pathway would be consistent with the association between *HCV* and several types of lymphomas and with the regression of some lymphoma after eradicating the *HCV* infection (Hermine, et al., 2002; Vallisa, et al., 2005)*.* One study showed that the association between *HCV* infection and risk of NHL subtypes included mostly countries with low background *HCV* prevalence. This study showed increased risks of DLBCL, marginal zone lymphoma and lymphoplasmacytic lymphoma associated with *HCV* infection (De Sanjose, et al., 2008). Another study revealed that there is no association between NHL and *HCV* infection (King, Wilkes, & DIAZ ARIAS, 1998). Prevalence of *HCV* in series of patients with NHL in studies from different countries was various, it was more common in Italy and Japan (Armstrong, et al., 2006). Based on these studies there are marked regional differences in the prevalence of *hepatitis C* infection in non-Hodgkin lymphoma. It seems that other factors including genetics, race, hormonal, and immunologic factors are required for malignant transformation. Several studies showed the frequency was higher in older women. Lymphoma associated with *HCV* infection more frequently present as primary extra-nodal lymphoma, especially in the liver, spleen and salivary glands (Armstrong, et al., 2006).

**Human Immunodeficiency Virus (HIV).** The relationship between human immunodeficiency *virus*/acquired immunodeficiency syndrome (HIV/AIDS) and the risk of developing NHL has been observed with strong positive associations in numerous studies. (Hooper, Holman, Clarke, & Chorba, 2001; Ragni, et al., 1993). The relative risk of NHL among persons infected with *HIV* has been reported to be over 100, (Coté, et al., 1997; Goedert, et al., 1998) with the greatest risk for B-cell lymphomas and high-grade histology (Coté, et al., 1997; A. Swerdlow, 2003). Chronic antigenic stimulation and immune deficiency may be responsible for the increased risk of *NHL* among *HIV*-infected persons. *HIV* may act by inducing immunodysregulation, affecting genes responsible for cell regulation and failing to control

countries. The bacteria is transmitted within families in early childhood (Farinha & Gascoyne, 2005). Parsonnet *et al.* (Parsonnet, et al., 1994a) and Vineis *et al.* (Vineis, et al., 1999) reported a significant positive association between *H. pylori* infection and risk of gastric NHL but not non-gastric NHL. Greater than 60% of MALT lymphomas regress with *H. pylori* eradication following treatment with antibiotics (R. Hunt, Sumanac, & Huang, 2001). Because the US prevalence of *H. pylori* infection is low and declining, *H. pylori* most likely did not play a significant role in the overall rising trend of NHL incidence in the US (Alexander, et al., 2007)*.* H. pylori infection is more common in Asian countries, therefore as we can see in table 1, MALT lymphoma in most Asian countries are more common than

**Hepatitis C Virus** (HCV)**.** Hepatitis C virus infection has been reported to be a prevalent disease since the second half of the 20th century (Strickland, 2006). Infection in different parts of Asia is similar, with an average seroprevalence of hepatitis C antibody less than 2.5% in the general population. The major routes of *HCV* transmission in Asia have been through blood transfusions and intravenous drug use, similar to the other countries. Other possible routes of transmission are medical intervention, tattooing, acupuncture, vertical and sexual transmission, accidental needle-stick and household contact. It is believed that *HCV* is still spreading in some areas of Asia because of the lack of routine screening of donated blood (Kao & Chen, 2000). *HCV* has been linked to lymphomagenesis in people with and without type II mixed cryoglobulinemia (Saadoun, Landau, Calabrese, & Cacoub, 2007). Increasing evidence indicates that the association between *HCV* infection and lymphoma may be due to viral infection related chronic antigenic stimulation. The chronic inflammation pathway would be consistent with the association between *HCV* and several types of lymphomas and with the regression of some lymphoma after eradicating the *HCV* infection (Hermine, et al., 2002; Vallisa, et al., 2005)*.* One study showed that the association between *HCV* infection and risk of NHL subtypes included mostly countries with low background *HCV* prevalence. This study showed increased risks of DLBCL, marginal zone lymphoma and lymphoplasmacytic lymphoma associated with *HCV* infection (De Sanjose, et al., 2008). Another study revealed that there is no association between NHL and *HCV* infection (King, Wilkes, & DIAZ ARIAS, 1998). Prevalence of *HCV* in series of patients with NHL in studies from different countries was various, it was more common in Italy and Japan (Armstrong, et al., 2006). Based on these studies there are marked regional differences in the prevalence of *hepatitis C* infection in non-Hodgkin lymphoma. It seems that other factors including genetics, race, hormonal, and immunologic factors are required for malignant transformation. Several studies showed the frequency was higher in older women. Lymphoma associated with *HCV* infection more frequently present as primary extra-nodal lymphoma, especially in the liver, spleen and salivary glands (Armstrong, et al., 2006).

**Human Immunodeficiency Virus (HIV).** The relationship between human immunodeficiency *virus*/acquired immunodeficiency syndrome (HIV/AIDS) and the risk of developing NHL has been observed with strong positive associations in numerous studies. (Hooper, Holman, Clarke, & Chorba, 2001; Ragni, et al., 1993). The relative risk of NHL among persons infected with *HIV* has been reported to be over 100, (Coté, et al., 1997; Goedert, et al., 1998) with the greatest risk for B-cell lymphomas and high-grade histology (Coté, et al., 1997; A. Swerdlow, 2003). Chronic antigenic stimulation and immune deficiency may be responsible for the increased risk of *NHL* among *HIV*-infected persons. *HIV* may act by inducing immunodysregulation, affecting genes responsible for cell regulation and failing to control

western countries.

other viruses, which may result in opportunistic infection and replication of oncogenic viruses (Coté, et al., 1997). In AIDS patients NHL has been reported in approximately 2-3% of patients with AIDS, but AIDS accounts only for a small fraction of all NHL (Biggar & Rabkin, 1992; Rabkin & Yellin, 1994). In an international collaboration on *HIV* and cancer, incidence data from 23 prospective studies were used to compare incidence rates of NHL in *HIV-*infected persons in 1997–1999 with those in 1992–1996 (Coutinho, 2000). The incidence rates for NHL declined from 6.2 per 1,000 person-years to 3.6 per 1,000 person-years. Grulich *et al.* (Grulich, et al., 2001) reported a significantly lower relative risk of NHL in persons with *HIV* in the period of highly active antiretroviral therapy (HAART) availability than in the period immediately prior (RR = 0.58, 95% CI: 0.36–0.92) *(Alexander, et al., 2007).*

In one study in Japan the incidence of AIDS-related lymphoma detected at autopsy was higher in Japan (27%) than in the US (12%). However, histological subtypes of AIDS-related lymphoma in Japan seem to be similar to those in western countries and DLBCL is also the most common subtype of AIDS-related lymphoma in Japan. A large number of AIDSrelated lymphoma cases were categorized into EBV-associated opportunistic lymphoma in Japan. The incidences detected by autopsy did not differ statistically between the pre-HAART era and the HAART era (*P* = 0.31), and the histological subtype of DLBCL was stable in both the pre-HAART era (78%) and the HAART era (77%) . In contrast, they found an increase in patients with BL from 2% in the pre-HAART era to13% in the HAART era. (Hishima, et al., 2006). Despite the high rate of human immunodeficiency virus infection in Thailand, only 5 cases of documented AIDS-associated lymphoma were noted in one study (5 of 389 NHL; 1.3%). Similarly, Kaposi's sarcoma is not common in AIDS patients in Thailand. The underlying reason for this unique feature of AIDS-related lymphoma in Thailand is not known and further investigation is needed (Sukpanichnant, et al., 1998). In one study in India the proportional incidence ratio (PIR) for NHL was significantly increased in *HIV* era (PIR in males = 17.1, 95%CI 13.33-21.84, females = 10.3, 95%CI 6.10- 17.41), and their finding was similar to that reported by other studies (Dhir, et al., 2008). In one study in Singapore when comparing the age-standardized rates for males and female in 1998 – 2002 which are 8.2 and 5.0 per 100,000 respectively compared with 7.5 and 4.4 per 100,000 in 1993-1997 and 3.1 and 1.9 per 100,000 in 1968-1972, this may be partly due to *HIV*/AIDS, changes in pathological classification and improved diagnostic capabilities (Seow & Registry, 2004). Except for one study in Thailand, *HIV*/AIDS lead to increase incidence rate of lymphoma in both eastern and western countries.

**Human herpesvirus-8** (HHV-8). Human herpesvirus-8, is endemic in regions of the Mediterranean and Africa (Kamiyama, et al., 2004), but the seroprevalence of *HHV-8* which has been studied in Malaysia, India, Sri Lanka, Thailand, Trinidad, Jamaica and the USA, in both healthy individuals and those infected with *HIV*, was found to be low in these countries in both the healthy and the *HIV*-infected populations (Ablashi, et al., 1999). *HHV-8* is generally accepted to be associated with development of primary effusion lymphoma (PEL), a rare B-cell lymphoma that almost exclusively affects *HIV*-positive patients (Ascoli, et al., 2002). However this lymphoma is often associated with both *HHV-8* and *EBV*, limiting the understanding of the pathogenic role of *HHV-8* (Ascoli, et al., 2002). Within B-cell lymphomas, however, *HHV-8* infection was associated significantly and positively with risk of lymphoplasmacytic lymphoma (OR = 4.47, 95% CI: 1.34–14.85) or low-grade B-cell lymphoma and lymphoma not otherwise specified (OR = 5.82, 95% CI: 1.07-31.73) (Feuillard, et al., 1997).

Epidemiology of Lymphoid Malignancy in Asia 339

omega-3 fatty acids from fish was not associated with reduced risk of NHL in one cohort study (Purdue, Bassani, Klar, Sloan, & Kreiger, 2004). Several but not all studies have reported positive association with red meat intake. Data are limited, and results have not been consistent, for estimates of associations with specific types of red meat or with preparation or cooking methods (Chang, et al., 2006; Ward, et al., 1994). Saturated fat intake was associated positively (Chang, et al., 2006), however vegetable consumption was associated inversely, with NHL risk in most studies (Chang, et al., 2005; Mozaheb & Aledawood, 2011). Biological mechanisms for these dietary factors have not been established*.* Neither obesity nor physical activity has been associated consistently with NHL

Certain workers have a slightly increased risk of developing NHL, including farmers; pesticide applicator; miller; meat worker; wood and forestry worker; chemists; painters; mechanics; printers; and worker in the petroleum, rubber, plastics, and synthetics industries (Alexander, et al., 2007). Some of these occupations are more common in Asian countries such as farmers, pesticide applicator, wood worker, worker in petroleum; on the other hand exposure is more because of low educational program in these places. Also There is significant relationship between hair dye use and NHL risk (Altekruse, Jane Henley, &

Hodgkin lymphoma is a neoplastic disease of the lymphoid tissue characterized by the present of multinucleated giant cell of B-cell origin, known as Red-Stenberg cell, in background of numerous reactive lymphocyte (Classical, 2009). HL is less common in Asians, especially at the young adult ages. There is incidence variation by age, social class, geographic location in HL. Thus, the comparison of HL rates in Asian and western countries could inform the relative

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

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,

importance of environmental factors and genetic to disease etiology.

respectively (RiesLAG, HankeyBF, & HarrasA, 1994).

(Alexander, et al., 2007).

**3. Hodgkin's Lymphoma** 

**3.1 Descriptive epidemiology** 

Thun, 1999).

**Simian Virus 40 (SV40).** Simian Virus 40 is the most well characterized member of the Polyomaviridae family, and is closely related to two human polyomaviruses (Poulin & DeCaprio, 2006).It induces an inapparent infections in immunocompetent hosts, but can produces pathologic effects in immunocompromised individuals through the destruction of infected cells (Imperiale, 2000).*Simian virus 40*, an agent that infects *Asian* ma- caques, contaminated the early poliovirus vaccines used in the United States, Europe, and other region during the mass immunization program for poliovirus in the late 1950 and early 1960 (Strickler, et al., 2003). The Norwegian study shows that between 1953 and 1997, the incidence rate of lymphoproliferative diseases increased about 3-fold in both males and females (Thu, et al., 2006), and the other study report that *polyomavirus SV40* is significantly associated with non-Hodgkin lymphoma in *HIV-1*-infected and *HIV-1-*uninfected patients and might have a role in the development of these hematological malignancies (Vilchez, et al., 2002). These observations suggest that *polyomavirus SV40* might be causing infections in human beings long after the use of the contaminated vaccines. There is no documented study around it in Asian countries.
