Lymphotropic Viruses EBV, KSHV and HTLV in Latin America: Epidemiology and Associated Malignancies. A Literature-Based Study by the RIAL-CYTED

The Epstein–Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) and human T-lymphotropic virus (HTLV-1) are lymphomagenic viruses with region-specific induced morbidity. The RIAL-CYTED aims to increase the knowledge of lymphoma in Latin America (LA), and, as such, we systematically analyzed the literature to better understand our risk for virus-induced lymphoma. We observed that high endemicity regions for certain lymphomas, e.g., Mexico and Peru, have a high incidence of EBV-positive lymphomas of T/NK cell origin. Peru also carries the highest frequency of EBV-positive classical Hodgkin lymphoma (HL) and EBV-positive diffuse large B cell lymphoma, not otherwise specified (NOS), than any other LA country. Adult T cell lymphoma is endemic to the North of Brazil and Chile. While only few cases of KSHV-positive lymphomas were found, in spite of the close correlation of Kaposi sarcoma and the prevalence of pathogenic types of KSHV. Both EBV-associated HL and Burkitt lymphoma mainly affect young children, unlike in developed countries, in which adolescents and young adults are the most affected, correlating with an early EBV seroconversion for LA population despite of lack of infectious mononucleosis symptoms. High endemicity of KSHV and HTLV infection was observed among Amerindian populations, with differences between Amazonian and Andean populations.


Hodgkin Lymphoma
There are several series of lymphomas reported in this region, particularly at the end of last century, which, however, were only classified as Hodgkin and non-Hodgkin (NHL), and which obviously did not follow the latest WHO classification. HL has a bimodal age distribution, there is an early peak occurring in adolescents and young adults, and a late peak after 50 years of age in industrialized countries. Developing countries also exhibit a bimodal distribution of the disease, but the early peak starts before adolescence [121]. In the US, pediatric HL shows the highest incidence in adolescents between 15-19 years of age, while developing countries present similar incidences than the US for adolescents, but also exhibit a marked augmented incidence in young children [122,123]. In developing countries, classical HL (cHL) with an early onset (14 yrs or younger) shows high EBV association, more often of the mixed cellularity (HL-MC) subtype. A strong male to female predominance is also observed, particularly in the group younger than 5 yrs, in which the ratio is 5:1. HL in adolescents and young adults displays lower EBV association, nodular sclerosis subtype (HL-NS) predominance and affects male and females almost equally [122].
We found 36 studies of HL in LA, including pediatric and adult series from 12 countries. Pediatric series from Argentina exhibited a profile compatible with early cHL (i.e., younger ages, EBV positivity of~50% and HL-MC as the predominant subtype) [20,[25][26][27], while adult HL displayed a 31% of EBV-association, with similar frequencies of both NS and MC subtypes [22]. On the other hand, in the Southeast of Brazil, EBV positivity was 40-50%, HL-NS was the predominant subtype, and there was a smooth peak between adolescents and young adults [38,[41][42][43][44][45]47,52,58,60,[66][67][68][69][70]73], which may suggest a transition state in the epidemiology of the disease presentation between the ones observed in developing and developed areas. Indeed, one study in the most affluent Brazilian State (Sao Paulo) reviewed 817 cases of cHL over 54 years , describing that EBV-positive cases showed a decrease from 87% to 46% during the time of the study, with a remarkable decrease in young adults (85% to 32%) [32]. Nevertheless, HL-NS was still the predominant subtype in all periods. On the contrary, HL in the North of Brazil exhibits high EBV association (87%), HL-MC and young age predominance [61]. These results support the hypothesis that the socioeconomic level may determine the presentation features of this neoplasm, also highlighting the role of EBV as an HL driver that is also influenced by socioeconomic factors. Figure  There is only one large pediatric cohort of 42 cases published from Mexico, with a median age of 5 yrs at diagnosis, and in which a male predominance (2.5:1) was observed [78]. EBV positivity was found in 76.1% of the cases and the HL-MC subtype was the most predominant (71.4%). Other studies from Mexico mostly include young and older adults, with scarce inclusion of children and adolescents, and in which EBV association frequencies vary between 61% and 77%. In those studies, a predominance of HL-MC and HL-NS subtypes was observed [82,[87][88][89]118]. In these Mexican studies, a high EBV association was also observed for the lymphocyte depleted (HL-LD) subtype, with 91.2% positive cases [87][88][89].
In line with the above-described data, a 94% of EBV association was observed in pediatric HL in Peru [108], while in Colombia, EBV association varied from 60% in adults to 84% in children [93,94]. Another study from Honduras that included 11 children younger than 15 yo also found 100% EBV positivity [115]. Series of studies from the Caribbean and continental Central American countries: Puerto Rico, Ecuador, Costa Rica and the Dominican Republic found intermediate EBV association frequencies (50%, 55%, 36-40% and 64%, respectively) [90,91,110,[116][117][118], which are closer to the frequencies observed in the more developed Argentina. These frequencies should be confirmed with more samples and up-to-date techniques.

Burkitt Lymphoma
BL is a highly aggressive B cell lymphoma, characterized by the translocation of the MYC oncogene to the immunoglobulin loci. It affects mostly children and is also more predominant in males [124]. EBV-associated BL conforms almost 100% of endemic BL and around 20% of sporadic cases of North America and Europe. Other regions of the world, especially developing populations, exhibit intermediate frequencies, such as 50-70% in North Africa and Russia [3,125]. Pediatric BL in Argentina has an EBV association frequency closer to the sporadic subtype (25-47%), and the highest incidence of EBV-positive cases is in children younger than 5 yo [14,16,24,28]. As with HL, the frequency of EBV positive cases increase with latitude in Brazil, being ~60% in the South East [37,55,56,62-64], and 73-87% in North East [72,74]. A study including an extensive number of BL cases from five Brazilian geographic regions confirmed this trend, disclosing EBV association frequencies from 29% in the South to 76% in the North [53,54]. This pattern appears to represent a socio-geographic gradient, which might reflect social development, as well as other unknown environmental, ethnic or genetic factors [63]. A Brazilian study of 14 population-based cancer registries showed that the global age-adjusted incidence rate for pediatric BL does not differ significantly from the expected for a sporadic BL region. However, the incidence was elevated for BL children aged 1-4 years [126]. Given the association of EBV positive BL with young age, it is tempting to ascribe this elevated risk to the early EBV seroconversion, which is characteristic of the natural history of EBV infection in our geographic region [127]. Indeed, an EBV-associated BL inverse correlation with age has been shown in other studies from Brazil [56] and Argentina [14]. Unfortunately, we could not find reports on BL series from the Andean and Caribbean regions of LA, which, most probably, does not represent a low frequency of this lymphoma there. Although there are studies including BL from Mexico, they do not address EBV infection, and there is only one case report from a 63 yo male with an EBV positive intraoral BL [128].

Burkitt Lymphoma
BL is a highly aggressive B cell lymphoma, characterized by the translocation of the MYC oncogene to the immunoglobulin loci. It affects mostly children and is also more predominant in males [124]. EBV-associated BL conforms almost 100% of endemic BL and around 20% of sporadic cases of North America and Europe. Other regions of the world, especially developing populations, exhibit intermediate frequencies, such as 50-70% in North Africa and Russia [3,125]. Pediatric BL in Argentina has an EBV association frequency closer to the sporadic subtype (25-47%), and the highest incidence of EBV-positive cases is in children younger than 5 yo [14,16,24,28]. As with HL, the frequency of EBV positive cases increase with latitude in Brazil, being~60% in the South East [37,55,56,62-64], and 73-87% in North East [72,74]. A study including an extensive number of BL cases from five Brazilian geographic regions confirmed this trend, disclosing EBV association frequencies from 29% in the South to 76% in the North [53,54]. This pattern appears to represent a socio-geographic gradient, which might reflect social development, as well as other unknown environmental, ethnic or genetic factors [63]. A Brazilian study of 14 population-based cancer registries showed that the global age-adjusted incidence rate for pediatric BL does not differ significantly from the expected for a sporadic BL region. However, the incidence was elevated for BL children aged 1-4 years [126]. Given the association of EBV positive BL with young age, it is tempting to ascribe this elevated risk to the early EBV seroconversion, which is characteristic of the natural history of EBV infection in our geographic region [127]. Indeed, an EBV-associated BL inverse correlation with age has been shown in other studies from Brazil [56] and Argentina [14]. Unfortunately, we could not find reports on BL series from the Andean and Caribbean regions of LA, which, most probably, does not represent a low frequency of this lymphoma there. Although there are studies including BL from Mexico, they do not address EBV infection, and there is only one case report from a 63 yo male with an EBV positive intraoral BL [128].

Diffuse Large B Cell Lymphoma
DLBCL is a highly aggressive neoplasm that can arise in almost any location of the body. It is very rare in pediatric patients and young adults, but is one of the most common NHLs in older individuals. Due to the median age of presentation of 70 yrs, it is usually associated with underlying immunosuppression. In the former 2008 WHO classification [129], EBV-positive DLBCL of the elderly (>50 years) was recognized as a provisional entity among the DLBCL subtypes. This provisional entity represented 5-11% of the DLBCL among immunocompetent East Asian patients [130], while in Western populations, the frequency was lower than 5% [81,131]. The reported series from LA have shown slightly higher EBV association frequencies (7% México, 9% Brazil, 13% Argentina and 14-28% Peru) [10][11][12]34,81,95,100,101] than the observed in Western countries [81]. LA patients are also younger than the ones described in other series [11,81]. Peru is particularly interesting, since it has the highest incidence of positive EBV DLBCLs, in addition to the incidence of DLBCL being the highest reported, accounting for up to 45% of all lymphomas [100,101,132]. In a Peruvian study of five cases, DLBCL of the gastrointestinal tract was consistently associated with EBV infection in elderly patients [98]. Remarkably, a series of cases of DLBCL of the palatine tonsils from Salvador de Bahia Brazil did not find an association with EBV [40]. Figure 1E,F shows an example of an EBV positive DLBCL.
In the 2016 WHO classification of lymphoid neoplasms, the age factor was eliminated from the association of EBV with DLBCL, leading to the substitution of the modifier "elderly" with "not otherwise specified" (EBV-positive DLBCL, NOS) [9]. Therefore, new studies free from the restraint of the age limit are needed, to better characterize the magnitude of this association, as well as the prognostic impact of EBV positivity in LA patients. DLBCL are also distinguished by their phenotype as germinal center or activated, with the former exhibiting an overall better survival rate. No differences were found in a series of Argentinian cases with respect to EBV positivity in these two subtypes of DLBCL [11,95].

T and NK Lymphoproliferative Disorders
Although EBV tropism is mainly of B cells and in healthy individuals exclusively localizes in B cells [133], the revised 2016 WHO classification recognizes the chronic active EBV infection (CAEBV) of T/NK cell type, the aggressive NK-cell leukemia, the systemic T-cell lymphoma of childhood and the extranodal NK/T-cell lymphoma, nasal type (ENKTCL), as well as a new provisional entity, the primary EBV-positive nodal T/NK-cell lymphoma [9,134]. These neoplasms represent a broad spectrum of diseases that occur with higher incidence in Asian populations, and, in which, CAEBV, the aggressive NK leukemia and the systemic T-cell lymphoma are more prevalent in children and adolescents, while ENKTCL mainly affects adults [9,134]. How the virus infects T or NK cells is still a matter of debate, but exists some evidence of a preferential tropism for T cells for the EBV-2 subtype [135,136].
CAEBV corresponds to a group of reactive LPDs associated with a heightened EBV infection lasting longer than IM, and with the potential to progress to a systemic lymphoma. The clinical picture is diverse and includes the indolent, localized cutaneous form hydroa vacciniform-like LPD (HVL-LPD), renamed by the revised 2016 WHO classification [9]. Several series of patients with HVL-LPD have been described in LA indicating a high incidence of this disease, mainly in countries with a large Amerindian population component, such as Mexico [77,84], Bolivia [84], Peru [97,103,105] and Ecuador [109]. In Brazil, two HVL-LPD cases were reported in children from Amazon indigenous tribes, supporting the ethnic bias of this disease [31,39]. In these series of patients, the association with EBV was virtually 100%. These studies have also greatly contributed to illustrate the clinical and pathological features of this disease in LA as an LPD with 70% of cases being of T-cell origin and 30% of NK origin. This scenario is more similar to Asian CAEBV, since, in the US, CAEBV is very rare, and also presents as a B cell LPD [137]. Although cellular and viral monoclonality has been proven in the majority of T-cell cases, the disease is today considered an LPD, with a high risk to progress into a systemic lymphoma [77], to reflect the diverse clinical spectrum of the disease presentation, from self-limited HV to HV-like lymphoma, and also to allow for more adequate therapeutic approaches, since patients respond well to immunomodulatory agents as first line of treatment [77,103,105].
Extranodal NK/T cell lymphoma (ENKTCL) is an EBV-positive lymphoma more commonly derived from NK cells. Similar to CAEBV lymphoproliferations, this type of lymphoma has been described mainly in East Asia and LA, in which the ethnic composition includes a high proportion of Amerindians. EBV infection is also confirmed in virtually all cases. Series of cases have been reported from México [83], Peru [104,106], Chile [104,106,112,113] and Guatemala [120]. In Brazil, ENKTCL usually occurs as isolated cases [71]. Recently, a large series was reported that included 122 cases with mostly adults (only three children) from all five Brazilian regions [46]. In this Brazilian cohort, the clinico-pathological characteristics of the neoplasm were similar to the ones described in patients from East Asia and other American countries, in which the disease is considered endemic. No ethnic data was recorded for the patients included in the study. In a Brazilian unicentric study that included lymphomas involving the midline facial region, 16 were of T/NK cell origin and nine were of B cell origin (n = 25). Remarkably, no ethnic differences were found between the patients with T/NK or B cell presentation [71]. Figure 2 shows an example of an ENKTCL.
Cancers 2020, 12, x FOR PEER REVIEW 11 of 58 approaches, since patients respond well to immunomodulatory agents as first line of treatment [77,103,105]. Extranodal NK/T cell lymphoma (ENKTCL) is an EBV-positive lymphoma more commonly derived from NK cells. Similar to CAEBV lymphoproliferations, this type of lymphoma has been described mainly in East Asia and LA, in which the ethnic composition includes a high proportion of Amerindians. EBV infection is also confirmed in virtually all cases. Series of cases have been reported from México [83], Peru [104,106], Chile [104,106,112,113] and Guatemala [120]. In Brazil, ENKTCL usually occurs as isolated cases [71]. Recently, a large series was reported that included 122 cases with mostly adults (only three children) from all five Brazilian regions [46]. In this Brazilian cohort, the clinico-pathological characteristics of the neoplasm were similar to the ones described in patients from East Asia and other American countries, in which the disease is considered endemic. No ethnic data was recorded for the patients included in the study. In a Brazilian unicentric study that included lymphomas involving the midline facial region, 16 were of T/NK cell origin and nine were of B cell origin (n = 25). Remarkably, no ethnic differences were found between the patients with T/NK or B cell presentation [71]. Figure 2 shows an example of an ENKTCL.

Kaposi Sarcoma Human Herpesvirus
KSHV is a gamma-2 herpesvirus closely related to EBV, also called human herpesvirus 8 or HHV8. KSHV is the etiological agent of Kaposi sarcoma (KS), multicentric Castleman disease (MCD) and primary effusion lymphoma (PEL). The revised WHO classification of hematopoietic and lymphoid tissues also included two entities associated with KSHV, the HHV8-positive diffuse large B-cell lymphoma, NOS and the HHV8-positive germinotropic lymphoproliferative disorder. KSHVassociated neoplasms usually develop in severely immunocompromised patients, and, as such, KS is, in many countries, an AIDS defining marker. The incidence of KS has sharply diminished after the introduction of anti-retroviral therapy, but has since stabilized in many countries [138]. In regions in which the virus is endemic, such as in Sub-Saharan Africa, HIV negative KS (classic KS or cKS) is one of the most common neoplasms in men [139].
MCD and PEL are extremely rare neoplasms. There are two main presentations of Castleman disease (CD), one in which reactive B cells only affect a single group of close lymph nodes, denoted as unicentric (UCD) and MCD, in which more than one group of lymph nodes are reactive. CD is also classified according to its microscopic morphology as hyaline-vascular (usually UCD), and plasma cell and plasmablastic (usually MCD). CD is not a true lymphoma, but rather a polyclonal B cell

Kaposi Sarcoma Human Herpesvirus
KSHV is a gamma-2 herpesvirus closely related to EBV, also called human herpesvirus 8 or HHV8. KSHV is the etiological agent of Kaposi sarcoma (KS), multicentric Castleman disease (MCD) and primary effusion lymphoma (PEL). The revised WHO classification of hematopoietic and lymphoid tissues also included two entities associated with KSHV, the HHV8-positive diffuse large B-cell lymphoma, NOS and the HHV8-positive germinotropic lymphoproliferative disorder. KSHV-associated neoplasms usually develop in severely immunocompromised patients, and, as such, KS is, in many countries, an AIDS defining marker. The incidence of KS has sharply diminished after the introduction of anti-retroviral therapy, but has since stabilized in many countries [138]. In regions in which the virus is endemic, such as in Sub-Saharan Africa, HIV negative KS (classic KS or cKS) is one of the most common neoplasms in men [139].
MCD and PEL are extremely rare neoplasms. There are two main presentations of Castleman disease (CD), one in which reactive B cells only affect a single group of close lymph nodes, denoted as unicentric (UCD) and MCD, in which more than one group of lymph nodes are reactive. CD is also classified according to its microscopic morphology as hyaline-vascular (usually UCD), and plasma cell and plasmablastic (usually MCD). CD is not a true lymphoma, but rather a polyclonal B cell expansion and is thus considered an LPD. MCD is associated with HIV and KSHV co-infection, and if HIV is uncontrolled, MCD can have an aggressive clinical course and progress to an entity with cellular and viral monoclonality, in which it resembles a DLBCL [140]. On the contrary, PEL is an aggressive monoclonal B cell lymphoma with a poor clinical outcome, regardless of a down the line HIV control. PEL usually presents with lymphoid effusions in cavities, such as the pleura, peritoneum and pericardium. Post-transplant LPD and germinotropic LPD are also very rare and recently recognized [141,142], therefore, we could not find studies about them. Of interest is that in about 80% of PELs arising in AIDS patients, the tumor cells are co-infected with KSHV and EBV, a characteristic in common with germinotropic LPD [140].

KSHV Prevalence and Morbidity in Latin America
To our knowledge, there is no routine screening for KSHV infection in blood banks in LA countries, nor in the rest of the world, and the World Health Organization and the World Federation of Hemophilia do not recommend it [143]. Thus, one problem when assessing the incidence of KSHV infection is that there is not a reference standard assay, and comparative studies have often demonstrated great disparity [144]. Therefore, comparing different studies may be inaccurate. Blood donor-based studies from Brazil illustrate this point (see Table 2), while some studies from Sao Paulo report a prevalence of 3.8-4.6% [145][146][147], another found 26% [148]; albeit, 1.1% positives were found among health workers and 20.4% in HIV/AIDS patients from the same city [149]. A screening of blood donors from the Amazonian region also found a high prevalence of 31.3% [150]. Pediatric studies found 7.6% positivity in Sao Paulo, 6.8% in Campinas and 12% in children of low-income families from Belem Pará [151][152][153]. Figure 3 summarizes studies about the KSHV prevalence among LA countries.
Cancers 2020, 12, x FOR PEER REVIEW 12 of 58 expansion and is thus considered an LPD. MCD is associated with HIV and KSHV co-infection, and if HIV is uncontrolled, MCD can have an aggressive clinical course and progress to an entity with cellular and viral monoclonality, in which it resembles a DLBCL [140]. On the contrary, PEL is an aggressive monoclonal B cell lymphoma with a poor clinical outcome, regardless of a down the line HIV control. PEL usually presents with lymphoid effusions in cavities, such as the pleura, peritoneum and pericardium. Post-transplant LPD and germinotropic LPD are also very rare and recently recognized [141,142], therefore, we could not find studies about them. Of interest is that in about 80% of PELs arising in AIDS patients, the tumor cells are co-infected with KSHV and EBV, a characteristic in common with germinotropic LPD [140].

KSHV Prevalence and Morbidity in Latin America
To our knowledge, there is no routine screening for KSHV infection in blood banks in LA countries, nor in the rest of the world, and the World Health Organization and the World Federation of Hemophilia do not recommend it [143]. Thus, one problem when assessing the incidence of KSHV infection is that there is not a reference standard assay, and comparative studies have often demonstrated great disparity [144]. Therefore, comparing different studies may be inaccurate. Blood donor-based studies from Brazil illustrate this point (see Table 2), while some studies from Sao Paulo report a prevalence of 3.8-4.6% [145][146][147], another found 26% [148]; albeit, 1.1% positives were found among health workers and 20.4% in HIV/AIDS patients from the same city [149]. A screening of blood donors from the Amazonian region also found a high prevalence of 31.3% [150]. Pediatric studies found 7.6% positivity in Sao Paulo, 6.8% in Campinas and 12% in children of low-income families from Belem Pará [151][152][153]. Figure 3 summarizes studies about the KSHV prevalence among LA countries.    Argentina reports a prevalence of 3.6-7.4% [146,[161][162][163], higher for San Salvador Jujuy in the North West of the country (12.3%), a region with a high population of immigrants and indigenous [161]. Higher prevalence for females than males was reported in two Brazilian studies, one pediatric (14.9:1) and one adult (3.7:1) [145,151], while in San Salvador Jujuy, the opposite was observed, with a male to female ratio of 3:1. More limited studies from Colombia (n = 25), Chile (n = 300) and Peru (n = 128) found 4%, 2.6% and 56.2% positivity, respectively [146,168,180]. In Peru, high endemicity was also challenged by a different study, in which the MSM high risk group was analyzed (n = 497), finding a seropositivity of 42.4% [181]. However, Peru is among the few countries from LA with multiple reports of cKS [182,183], including a large cohort of 126 cases that included pediatric cKS [184]. There are not large prevalence studies from Mexico, Central America and the Caribbean countries, a small screening of blood donors from Cuba (n = 171) found 1.2% KSHV positives [176]. Mexico reports KS as the most common neoplasm in AIDS patients, particularly before HAART [185,186]. For KSHV studies based on risk groups, see Table 3. Brazil [149,150,[188][189][190][191][192] 13.9-52.6% X = 21.8% n = 2358 Honduras [193] 31.8% n = 22 Peru [181] 66.5% n = 197 Argentina [194] 17.4% n = 144 Prevalence of KSHV infection in specific risk groups, percentages and the number of tested individuals (n) are given. When more than one study was found, the range of positives and the average (X) are also given. FSW: female sex workers, MSM: men that have sex with men.
LA harbors distinct ethnic groups differentially distributed among different geographic regions in each country. Most urban populations are formed by mestizos and a minority of Caucasians, while some rural regions concentrate pure Amerindians or Afro-descendants. KSHV hyper endemicity is reported among LA indigenous populations and a hyper-endemicity area (30-100% prevalence) is reported among tribes inhabiting the South American lowlands of the Amazonas and the savannah ( Figure 4 maps the prevalence of KSHV among Amerindian populations). For instance, Amazonian Amerindians from Ecuador were found 24% (the Siona, n = 41) to 100% (the Huaorani, n = 38) seropositive [195], while in Brazil different studies have found 56.8-79.1% among Amerindians from the Pará state (n = 339-1270) [150,[196][197][198] and 50-83% (n = 110) among Amerindian tribes from transitional zones in central Brazil from Amazonian to the savannah. On the other hand, 0-14% positivity has been found in Amerindians from the South of Brazil (n = 85) [198]. Chacó Amerindians (n = 55) from Bolivia were 22% positive and 45% were positive in Paraguay [198].
One of the DLBCL was also positive to EBV infection [164]. On the other hand, a screening of a series of cases of B cell lymphomas arising in HIV/AIDS patients (n = 49) did not find any KSHV positive supporting the rarity of these kind of neoplasms [199]. Peru reported two cases of UCD hyaline that were KSHV positive by IHC [169]. We found only one PEL and three MCD reported from Mexico [170,172,173], and two PEL and one MCD from Cuba [179,187]. Figure 5 shows KSHV positive PEL and MCD.  Although our main aim was to document the incidence of lymphomas mediated by tumor viruses in LA, there are no such studies for KSHV in many LA countries, with most studies being about the prevalence of KS in HIV/AIDS patients. Additionally, because many of the reports are from the 1980s and 1990s, the studies only addressed the overall frequency of lymphomas, and lymphomas were only classified as Burkitt, Hodgkin and non-Hodgkin. Thus, both MCD and PEL seem more common after HAART, but they may have been under-diagnosed in early studies. Furthermore, KSHV-associated neoplasms most often are reported based on their histological and clinical characteristics, lacking confirmatory tests for viral infection. KSHV-associated lymphomas are reported from Brazil, Argentina and Peru. We found five cases of MCD in Brazil, mostly of the plasmablastic variety, and one mixed plasmablastic and hyaline [154][155][156][157][158]. Although KSHV infection was not assessed in all cases, four cases were in HIV infected individuals and in three cases MCD co-presented with KS. There was also a case of PEL in an HIV positive patient [159], and a multiple myeloma patient with a bone marrow KSHV PCR positive [160]. We found three KSHV positive MCD from Argentina, two PEL and two KSHV positive DLBCL, all in HIV positive patients [13,[165][166][167]. One of the DLBCL was also positive to EBV infection [164]. On the other hand, a screening of a series of cases of B cell lymphomas arising in HIV/AIDS patients (n = 49) did not find any KSHV positive supporting the rarity of these kind of neoplasms [199]. Peru reported two cases of UCD hyaline that were KSHV positive by IHC [169]. We found only one PEL and three MCD reported from Mexico [170,172,173], and two PEL and one MCD from Cuba [179,187]. Figure 5 shows KSHV positive PEL and MCD. There are five major KSHV genotypes described (A, B, C, D and E), mainly based on the hypervariable regions of the oncogenic K1 gene. Interestingly, in the series of studies from LA, while genotypes A, B and C [167,177,190,[200][201][202] were described in neoplasms or HIV positive cases, subtype E has been the sole genotype found in Amerindians from Ecuador, Brazil and French Guiana [190,195,197,[203][204][205]. Genotypes A and C are prevalent in Europe and North America, while genotype B is more prevalent in individuals with African ancestry [195]. Thus, one plausible explanation for the low incidence of KSHV-induced neoplasms (including cKS) among South American Amerindians is a low oncogenicity of the KSHV genotype E. Indeed, only two KS reported in Peru shared genotype E [204], while KSHV A and B genotypes have been isolated from Brazilian and Argentinian patients with European ancestry [201,206]. To our knowledge, the tumorigenic activity of the genotype E K1 has not been tested in vitro or in animal models, and it is not clear why KSHV would become more attenuated in South American Amerindians, but not in other populations with an equally prevalent KSHV infection, such as those from Uganda or Zambia.

Human T-Cell Lymphotropic Virus
HTLV belongs to the family Retroviridae, genus Deltaretrovirus, and, as such, its genome consists of two identical copies of positive sense single stranded RNA that during its life cycle is converted into double stranded DNA and inserted into the DNA of the human host cell. This integrated form is referred to as the provirus, and HTLV predominantly exists in the host as a cellassociated provirus. Indeed, infected cells hardly produce any virus and plasma viral load is usually undetectable. There are two main types of HTLV infecting humans, HTLV-1 that preferentially infects CD4+, but also CD8+ T-lymphocytes, and HTLV-2 that preferentially infects CD8+ T-lymphocytes. Two other HTLV types have been described in Africa, but today, it is not clear whether HTLV-3 and HTLV-4 can be transmitted from human to human or are exclusively zoonotic, and no clinical disease has been associated with these two novel isolates thus far [207]. There are five major KSHV genotypes described (A, B, C, D and E), mainly based on the hypervariable regions of the oncogenic K1 gene. Interestingly, in the series of studies from LA, while genotypes A, B and C [167,177,190,[200][201][202] were described in neoplasms or HIV positive cases, subtype E has been the sole genotype found in Amerindians from Ecuador, Brazil and French Guiana [190,195,197,[203][204][205]. Genotypes A and C are prevalent in Europe and North America, while genotype B is more prevalent in individuals with African ancestry [195]. Thus, one plausible explanation for the low incidence of KSHV-induced neoplasms (including cKS) among South American Amerindians is a low oncogenicity of the KSHV genotype E. Indeed, only two KS reported in Peru shared genotype E [204], while KSHV A and B genotypes have been isolated from Brazilian and Argentinian patients with European ancestry [201,206]. To our knowledge, the tumorigenic activity of the genotype E K1 has not been tested in vitro or in animal models, and it is not clear why KSHV would become more attenuated in South American Amerindians, but not in other populations with an equally prevalent KSHV infection, such as those from Uganda or Zambia.

Human T-Cell Lymphotropic Virus
HTLV belongs to the family Retroviridae, genus Deltaretrovirus, and, as such, its genome consists of two identical copies of positive sense single stranded RNA that during its life cycle is converted into double stranded DNA and inserted into the DNA of the human host cell. This integrated form is referred to as the provirus, and HTLV predominantly exists in the host as a cell-associated provirus. Indeed, infected cells hardly produce any virus and plasma viral load is usually undetectable. There are two main types of HTLV infecting humans, HTLV-1 that preferentially infects CD4+, but also CD8+ T-lymphocytes, and HTLV-2 that preferentially infects CD8+ T-lymphocytes. Two other HTLV types have been described in Africa, but today, it is not clear whether HTLV-3 and HTLV-4 can be transmitted Cancers 2020, 12, 2166 20 of 63 from human to human or are exclusively zoonotic, and no clinical disease has been associated with these two novel isolates thus far [207].
HTLV-1 and -2 are very similar in terms of genome structure and replication patterns, but they are strikingly different in terms of clinical impact and geographical distribution. HTLV-1 is present throughout the world with regions of high endemicity together with low prevalence in neighboring zones. Major endemic regions include Southwest of Japan, LA and some areas of West Africa [208,209]. Ten to twenty million people are estimated to be infected with HTLV-1. However, the world prevalence of HTLV-1 is largely unknown, since most published studies are performed on blood donors and there are not population-based studies. The epidemiology and pathogenic potential of HTLV-2 infection are less well characterized. HTLV-2 is present in many world areas, and high HTLV-2 seroprevalence has been reported in indigenous populations in Africa and Amerindians from Central and South America, as well as among IVDU in Europe and North America [209]. Moreover, six genotypes have been found for HTLV-1 based on the genomic sequences of the long terminal repeats, A (also called the Cosmopolitan strain, because of its worldwide distribution) to G (the rest of them with a somehow more restricted geographical distribution) and five for HTLV-2, A to E [210].
HTLV-1 infection has been associated with adult T cell leukemia/lymphoma (ATLL) and a subacute myelopathy known as tropical spastic paraparesis or HTLV-1-associated myelopathy (TSP/HAM). Although most HTLV-1 carriers are asymptomatic, about 5% of them will develop clinical complications, including TSP/HAM and ATLL. Both diseases are severe and produce progressive incapacitation or death. In addition to ATLL and TSP/HAM, infection by HTLV-1 also leads to a broad spectrum of inflammatory diseases with significant morbidity, such as uveitis, arthritis, myositis, infective dermatitis, Strongyloides stercoralis infection and crusted scabies [209,211]. The mechanisms leading to them are currently unknown. On the contrary, and in spite of sharing 60% of genetic homology, no disease has been consistently associated with HTLV-2 infection, although sporadic cases of subacute myelopathy or hematological malignancies have been reported [209].

HTLV Prevalence and Morbidity in Latin America
When assessing the viral prevalence, we found that the majority of studies are based on immunological methods that do not discriminate between HTLV-1 and HTLV-2 (referred to as HTLV). The Caribbean basin is usually considered endemic to HTLV infection, perhaps because early 1980s studies documented several cases of ATLL from black immigrants from the Caribbean islands [212,213]. There are several studies from Cuba and Dominican Republic that tried to confirm that high endemicity and morbidity. Surprisingly, three sero-epidemiological studies carried on Cuban blood donors found 0.25%, 0.27% and 0.99% HTLV positivity, even though they included a significant number of black Cubans [214][215][216]. Dominican Republic and Puerto Rico report 2.5% and 0.2% positivity in blood donors, respectively [217][218][219]. Higher prevalence has been reported for risk groups. A retrospective study from 1996 to 2007 from two sentinel hospitals from Havana and Matanzas Cuba that registered all lymphoid neoplasms, reported only five ATLL cases [220]. On the contrary, in spite of multiple reports about TSP/HAM in Dominican Republic and Puerto Rico [218,[221][222][223], we could not find a single ATLL case. Although it is not clear which is the most prevalent subtype, HTLV-1 is almost exclusively the one reported [216,220,224,225]. Thus, the low incidence of ATLL may be due to the low prevalence of HTLV infection, or the scarcity of other needed co-factors. For a summary of data see Table 4. Peru [257] Case report Undisclosed HTLV-1+ Acute liver failure as presentation of ATLL.    Brazil [335] Case report EIA HTLV-1+ ATLL in a patient with Strongyloides stercoralis. Zero to 0.39% HTLV positivity and no ATLL were found from Mexico [226,228,342,343]. Interestingly, in those studies in which subtypes were identified, HTLV-2 was the only or the most prevalent one [344][345][346][347]. In agreement, HTLV-2 was highly prevalent in IVDUs (22%) [346]. From Central American countries, 5% HTLV-1 positivity has been found in the metropolitan areas of Panama City and Colon [229], and 0.24% and 0.68% HTLV-1 positive cases in Nicaragua and Costa Rica, respectively [235,348]. Honduras exhibited significant differences between regions, namely a 0.3-1.1% prevalence reported in the Central capital of Tegucigalpa and in the North West of the country, compared to a higher prevalence observed in coastal cities, particularly among black natives (17.7%) and non-mestizos (8.1%) [232,233,349]. High prevalence of 8.3-9% has also been reported among indigenous populations of Panama, all carrying HTLV-2. Although multiple cases of TSP/HAM have been reported, mostly associated with HTLV-1 infection [349][350][351][352][353], only five ATLL cases have been reported in Central American countries, one associated with HTLV-1 infection and the others of an unknown etiology [230,231,234].
Screening for HTLV infection in blood banks is mandatory in several South American countries; Brazil has done it since 1993, Peru since 1998, Uruguay since 2000, Argentina since 2005, Chile since 2009 and Colombia since 2014. This has allowed for studies based on a large number of samples, and for a more factual estimation of HTLV prevalence. In Caracas, Venezuela a 0.2% HTLV positivity and a rate HTLV-1: HTLV-2 of 11:1 was observed [236]. Other similar studies also found low HTLV positivity in Maracay (0.58%) and in Caracas (1%), but higher in the Amazon region (13%) [237,238]. A study that included all Colombian departments found an overall seropositivity of 0.3%, with most departments below 1% and Chocó being the only exception with 6.28% [239]. Similar studies from several blood banks from Medellin observed 0.06-0.176% positivity, mainly for HTLV-1 [243,244]. We also found two studies conducted on blood donors from Peru, Arequipa (0.9% HTLV-1 positive) and Abancay (3.4%, unknown subtype), and one in pregnant women from Lima (1.7% HTLV-1 positive) [253,254,256]. Concerning Chile, 0.12-0.24% HTLV positivity was described, showing higher prevalence in the central region of Valdivia than in Concepcion in the South; together with an almost 3:1 female to male ratio and a 7:1 HTLV-1 to HTLV-2 ratio [265,274]. A 0.13% HTLV positivity was found in Uruguay, ranging from 0.2% in the North to 0.09% in the South [277]. Those studies that were not based on archival data taken from blood donors reported an HTLV seropositivity of 0.42% in continental Ecuador, 1.57% in the Galapagos Island [252] and 2.4-3.5% for Afro-descendants from the Esmeralda province [250,251], 4.3% HTLV-1 in Bolivia [354] and 0% HTLV positives [276] to 2.5% HTLV-2 in Paraguay [355]. Figure 6 summarizes studies about the HTLV prevalence among LA countries.
There are multiple reports of ATLL in South America, mostly describing a disease with similar features to Japan ATLL, but in younger individuals. In Colombia, 19 HTLV positive ATLL cases have been reported, 12 confirmed as HTLV-1, while, in the others, the HTLV subtype was not investigated [246][247][248][249]. On the other hand, about 200 of TSP/HAM cases have been documented, with half of them confirmed to be in HTLV infected individuals [249,[447][448][449][450][451]. It is also notable that many cases come from the Tumaco district, in which TSP/HAM was originally described and in which a 5.3% HTLV-1 positivity has been reported among adults [241]. Furthermore, 12 ATLL cases from Peru and an additional case of a Peruvian immigrant in Uruguay were described, all of them being fatal [257][258][259][261][262][263]279]. These ATLLs displayed common features, since half of them had gastrointestinal tract compromise, and half of them occurred in individuals younger than 50 yr, including a 20 yr female. There were also seven DLBCL developing in HTLV-1 seropositive patients, but in which, the presence of the provirus was not assessed [260]. The tumor cell also harbored EBV in three of these DLBCLs. As an HTLV endemic country, Peru reports large cohorts of TSP/HAM reflecting a common disease [452][453][454][455], and also cases in which HTLV infection correlates with infective dermatitis [456], including children in which neurological disorders co-exists with infective dermatitis [457] and Strongyloides stercoralis [458,459]. Fifty-four cases of ATLL have been reported from Chile [266][267][268][269][270][271][272]275]. Highlights are the early presentation, with medians of 50 yrs and 51 yrs for the largest cohorts [266,268], and an onset concomitant with or proceeded by TSP/HAM. It is also interesting to point out that all reported cases in large cohorts are of Caucasian origin (49/49) [266,268,270]. Barrientos A, et al. found HTLV positivity by PCR in 16/88 (18.2%) cases of hematological malignancies (15 HTLV-1 and 1 HTLV-2), including two of myeloid origin. The median age of diagnosis was 33 yrs (2-92 yrs), with 50% of HTLV positive patients being 30 yrs or younger. No ATLL assignation was given in this study [273]. Multiple cases of TSP/HAM are also reported from Chile [460][461][462][463], but, contrary to ATLL, TSP/HAM occurs in Caucasians, in mestizo and Chilean Amerindians. There were no reports of other HTLV-associated diseases. In Argentina, ATLL cases have been described in the highly endemic Jujuy, with five cases with confirmed diagnoses [298]. There are seven other ATLL cases reported (two originating in brothers) [300,301]. In addition, TSP/HAM cases have been described in Aymara Amerindians, also in Jujuy [464], and also in Caucasian patients from other non-endemic regions [465][466][467][468]. Figure 7 shows an example of an ATLL with a CD4+CD25+FOXP3+ regulatory T cell phenotype.
Cancers 2020, 12, x FOR PEER REVIEW 28 of 58 Amerindians. There were no reports of other HTLV-associated diseases. In Argentina, ATLL cases have been described in the highly endemic Jujuy, with five cases with confirmed diagnoses [298]. There are seven other ATLL cases reported (two originating in brothers) [300,301]. In addition, TSP/HAM cases have been described in Aymara Amerindians, also in Jujuy [464], and also in Caucasian patients from other non-endemic regions [465][466][467][468]. Figure 7 shows an example of an ATLL with a CD4+CD25+FOXP3+ regulatory T cell phenotype. The number of ATLL and TSP/HAM cases reported from Brazil is in agreement with a country of high HTLV endemicity. For instance, ATLL cases have been reported in the urban areas of North East Brazil, by and large in the Bahía state that presents the largest prevalence of HTLV-1 infection [326,327,333,335,336,[469][470][471]. Characteristics of these ATLL are that they displayed cutaneous involvement [323,324], or were associated with infective dermatitis (IDH) [336], hyalohyphomycosis [333], Strongyloides stercoralis [335] or Hodgkin-like features [332]. Remarkably, ATLL has also been described in 31 pediatric patients [472]. In the South of Brazil, most reports are from Rio de Janeiro, where ATLL features often included a primary cutaneous type presentation [330,340,394,406], 9% (of 195 patients) co-presented with TSP/HAM [340], and eight cases were in pediatric patients [328]. There are at least 27 articles describing TSP/HAM cases that also support a common disease. TSP/HAM incidence was increased in HTLV-1 and HIV positive individuals (18-30%) versus those who were only HTLV positive (1.93%) [473,474], and pediatric cases of TSP/HAM have also been reported [472]. HTLV infection was also associated with IDH [475] and other dermatologic [476][477][478][479][480], oral [481], ocular [482] and neurologic [483] complications. Although there are multiple reports of TSP/HAM from Venezuela, Ecuador, Uruguay and Paraguay, we could not find a single report of ATLL in these countries. The number of ATLL and TSP/HAM cases reported from Brazil is in agreement with a country of high HTLV endemicity. For instance, ATLL cases have been reported in the urban areas of North East Brazil, by and large in the Bahía state that presents the largest prevalence of HTLV-1 infection [326,327,333,335,336,[469][470][471]. Characteristics of these ATLL are that they displayed cutaneous involvement [323,324], or were associated with infective dermatitis (IDH) [336], hyalohyphomycosis [333], Strongyloides stercoralis [335] or Hodgkin-like features [332]. Remarkably, ATLL has also been described in 31 pediatric patients [472]. In the South of Brazil, most reports are from Rio de Janeiro, where ATLL features often included a primary cutaneous type presentation [330,340,394,406], 9% (of 195 patients) co-presented with TSP/HAM [340], and eight cases were in pediatric patients [328]. There are at least 27 articles describing TSP/HAM cases that also support a common disease. TSP/HAM incidence was increased in HTLV-1 and HIV positive individuals (18-30%) versus those who were only HTLV positive (1.93%) [473,474], and pediatric cases of TSP/HAM have also been reported [472]. HTLV infection was also associated with IDH [475] and other dermatologic [476][477][478][479][480], oral [481], ocular [482] and neurologic [483] complications.
Although there are multiple reports of TSP/HAM from Venezuela, Ecuador, Uruguay and Paraguay, we could not find a single report of ATLL in these countries.

Discussion
The association between EBV infection and lymphoma varies worldwide. The most compelling observation is the higher incidence of EBV-positive cHL in LA than in industrialized countries, and also the relationship between the age at which EBV primo-infection occurs and the onset of cHL. In underdeveloped and developing LA populations, earlier exposure to EBV in the face of a relatively underdeveloped immune response might be a predisposing factor for EBV-positive cHL. Socioeconomic improvement in Brazil turned into a decreased incidence from 87% to 46% in a 54 year period [32]. A similar picture emerges for EBV-positive BL, since this disease shows features of endemic BL in particularly underdeveloped regions, for instance, 56], while it resembles more the sporadic form in the South of Brazil, Chile and Argentina [114]. Fewer driver mutations, especially among genes with roles in apoptosis, were demonstrated in EBV-positive BL from USA and Uganda, suggesting a specific BL phenotype, irrespective of geographic origin [494]. Particular pathogenic mechanisms may predispose against EBV-positive cHL and EBV-positive BL, such as ethnicity, endemic infectious agents, low age of seroconversion or differences in socioeconomic development.
EBV-associated T and NK LPDs represent a broad spectrum of diseases that occurs with higher incidence in Asian and LA populations. The incidence of these lymphomas in LA should grant EBV1 and EBV2 prevalence studies, particularly for Mexico and Peru, in which this lymphoma is highly prevalent. NKT LPDs often emerge within CAEBV disease in which infection of T-or NK-cells apparently occurred during primary infection. Genetic alterations are rare in CAEBV, but mutations in DDX3X, KMT2D, BCOR, BCORL1, TET2 and KM6A have been identified [495]. Likewise, LA has shown slightly higher EBV association frequencies in DLBCL, particularly in Peru. Peru has also reported cases of systemic EBV-positive T-cell lymphoma of childhood [99]. Gene expression profiling shows that EBV-positive DLBCL NOS, is molecularly distinct from EBV-negative DLBCL in Western developed populations, with NFκB p50, STAT-3 and CD30 more commonly expressed in EBV-positive DLBCLs [496]. No genetic study has been conducted in DLBCL of Hispanic patients so far.
ENKTL represents around 23% of all T-cell lymphomas in LA (up to 40% in Mexico and 66% in Guatemala), compared with 4% to 5% in Europe and the United States. The clinical presentation is similar in all geographic regions; however, patients in LA tend to present with more advanced clinical stages [497]. In the ENKTCL arising in East Asia, genetic analyses have shown that activating mutations of the JAK-STAT pathway, such as in JAK3 (5-35%), STAT3 (6-27%) and STAT5B (2-6%) genes are characteristic of this lymphoma [498,499]. Other mutations include the RNA helicase DDX3X, the tumor suppressor gene TP53, as well as genes encoding proteins involved in epigenetic pathways (MLL2, ASXL3, ARID1A and EP300) [134]. In a study of 71 ENKTCL cases from three different centers in LA (42 from Mexico, 17 from Peru and 12 from Argentina), mutations affecting the JAK-STAT signaling pathway were identified in 27% of cases, being STAT3 the most frequently mutated gene (22%). Mutations in BCOR, DDX3X and TP53 were also identified, but with different frequencies than in Asian cohorts [500]. These data indicate that ENKTCL shows a similar mutational landscape in LA and Asia.
With respect to KSHV, available reports based on healthy populations and risk groups make it possible to infer an LA prevalence higher than in the US and non-Mediterranean Europe but lower than endemic regions of Africa and the Mediterranean. With the exception of Chile, LA exhibits global frequencies above 3%, and particularly above 10% for Cuba, Colombia, Argentina (San Salvador Jujuy), Ecuadorian Afro-descendants and Peru. Indeed, large KS series (e.g., ≥ 50 cases) from Cuba, Colombia and Peru have been published [184,501,502], including a series of cases of cKS published before the HIV/AIDS era, and of pediatric KS [503]. KS has also been documented as the third most common neoplasm in Peru [504].
In Amerindian tribes in which the KSHV genotype E is endemic, viral transmission starts very early, with 35 to 65% seropositives by age 10 [150,196,197,505], supporting casual contacts between family members as an important via of viral dissemination. Indeed, close contacts of KS patients have higher KSHV prevalence than the general population (Table 3). A similar scenario is found for HTLV, with seroprevalences increasing with age [442,506]. A study of 104 mothers with TSP/HAM showed that 19-31% of their children were already HTLV seropositive [454], supporting an early mechanism of vertical transmission, such as breast feeding, which could explain the pediatric presentation of ATLL and TSP/HAM in LA HTLV endemic zones. On the contrary, among non-endemic populations, the high prevalence among MSM and FSW supports sexual transmission as an important route for KSHV dissemination (Table 5). However, the latter is not as clear for HTLV infection, since those studies based on people attending STD clinics (0.6-2.8%), FSW (below 5% in most studies) and MSM (2% and below) reported lower frequencies than those observed for KSHV. An important exception is HTLV transmission among IVDUs that is consistently high (7.8-20.7%) in LA countries, with a notable higher prevalence of HTLV-2, and also in blood transfused individuals (0.4-10%), supporting contaminated blood as an important source for viral transmission. It is worth mentioning a study from Venezuela, in which three of five organ recipients from an HTLV-1 positive multi-donor became seropositive [507].
While ATLL among Amerindians is very rare, TSP/HAM is commonly reported. TSP/HAM was first described in the Southern Pacific of Colombia in 1981 as a chronic non-hereditary spastic paraparesis, initially termed Pacific spastic paraparesis [508], later also observed in the Caribbean islands of Martinique and Jamaica and in HTLV endemic regions of Japan. TSP/HAM seems to be highly prevalent in LA, particularly for Afro-descendants, but also for mestizo and Caucasian populations [223,249,351,448,449,[452][453][454][455]461,464,472,509]. Likewise, infective dermatitis, strongyloidiasis and many other dermatological, oral, ocular and neurological complications are usually found co-presenting with ATLL or TSP/HAM, or independent of those diseases in HTLV endemic regions of Peru, Chile and Brazil. Infective dermatitis and strongyloidiasis sometimes precede TSP/HAM or ATLL [248,325,456]. It is also worth mentioning that extensive series of pediatric TSP/HAM have been reported from Salvador de Bahia and Rio de Janeiro in Brazil and in Peru [457,472]. All these studies pointed out that South America represents a major endemic area for HTLV infection and associated diseases. Remarkably, Mexico did not report HTLV positive ATLL or TSP/HAM.
Reports of ATLL series were found only for Brazil and Chile (see Table 4), which makes it difficult to identify the unique features of the disease presentation in our population. Furthermore, most case reports lack molecular and serological methods to confirm HTLV infection. Nevertheless, during the review process those cases in which the neoplasm co-presented with TSP/HAM, infective dermatitis or strongyloidiasis, or with the characteristic flower cell, were assumed to be bona fide ATLL. However, absence of confirmatory tests may miss early ATLL, for instance, in the smoldering stage, in which there is no significant lymphocytosis. Still, there do not seem to be major clinical differences between the ATLL cases in LA and those from Japan, or from other parts of the world [340]. Perhaps the most distinctive feature is an early presentation. Iwanaga et al. reported that in Brazil the median age of presentation is 44 yrs, while in Japan it is 68 yrs [510], and, in spite of being named as an adult disease, there are pediatric cases of ATLL in Brazil [323,325,328,340,471]. The Chilean ATLL cohort also had a younger disease presentation than Japan, with a median age of 50 yrs [266]. Most studies also support a poor prognosis for ATLL, the study of 195 cases from Brazil found an overall survival of 9.2 months [340].

Conclusions
We observed a high incidence of EBV-positive lymphomas of T/NK cell origin for Mexico and Peru and of BL for North Brazil. Peru also carries the highest frequency of EBV-positive HL and DLBCL than any other LA country. The presentation of HL and BL was also earlier than for industrialized countries, coinciding with an early EBV primo-infection, in spite of there being no evidence of infectious mononucleosis in the region. High prevalence of KSHV and HTLV was found among Amerindian populations, with different distributions between low-land (e.g., the Amazons) and high-land (e.g., the Andes) tribes. In spite of this, there were only scarce reports of MCD, PEL and ATLL. However, Peru reports KS as its third most common neoplasm.