The incidence of pediatric BL is very high in the central African countries of Uganda and Cameroon [24, 25]. The rates are low in the Far East and India, where nearly all children are infected by EBV before five years of age. In Europe, North America, and most of the Middle East, rates of BL are intermediate between those of central Africa and Asia [35, 36, 37, 38, 39, 40, 41]. BL of the Middle East is a pediatric neoplasm with few cases reported in adults [8, 9, 10, 19, 21]. Data from Sulaimani, Qatar, and Bahrain indicate that nearly half of EBV seroconversion in the Middle East may occur between four and 15 years old [15, 16, 17]. Three Middle East studies, including ours, show that tumors have a high frequency of EBER positivity [8, 9, 10]. In North America, Japan, Korea, and parts of Europe, BL is more common in adults than children [4, 5, 27, 32, 36, 37]. In these countries, much of the EBV seroconversion is in adolescents and young adults, and the frequency of EBER-positive tumors is low.
The variations in regional EBV exposure and evidence for tumor EBV latency confuse our understanding of the relationship between EBV and BL. EBV is an upper respiratory virus that enters the nasopharynx and infects epithelium and lymphocytes, with B cells being the primary target .
The early EBV infection stimulates lymphoblastic proliferation. The lymphoblasts enter the germinal centers and undergo somatic hypermutations in heavy and light chain genes [2, 45]. Random translocations between the chromosome 8 MYC oncogene and the chromosome 14 heavy chain or an alternative light chain locus complicate these hypermutations. The MYC translocation is considered an essential carcinogenic event [2, 45]. The EBV-stimulated lymphoblastic proliferation usually becomes quiescent, and approximately 2% of cells enter a type 3 latency as memory B cells. In a type 3 latency, cells produce nuclear EBER but have little expression of other viral components, and viral replication is limited [2, 45, 46]. If infected memory B cells encounter their cognate antigen, they can transform into proliferating mature B cells, and if they bear the MYC translocation, they can become BL [2, 45].
The age of exposure to EBV affects latency and the risk of tumor development, with early childhood exposure in much of the world being associated with a low risk of BL . The endemic BL is an exception, and the very high risk of lymphoma is attributed to coexisting malaria that stimulates B cells. This stimulation augments the frequency of somatic hypermutations and MYC translocations, with higher translocation rates increasing the risk of BL [2, 45].
The relationship of BL to germinal center MYC translocations means that virtually any antigenic stimulus could promote tumor development [2, 45]. Even in countries with a late age of EBV infection, overall seropositivity is at least 70–80%. The nearly universal nature of the infection and the low rates of BL outside of endemic regions questions the role of EBV in the development of the tumor. The Middle East populations have a bottom-heavy structure, with 30–45% of individuals being under 20 years of age . Large numbers of children in families tend to encourage the childhood spread of EBV. Yet, many infections appear delayed until late childhood, and Middle Eastern rates of pediatric BL are not different from much of Europe. The difference is the adult BL that is not diagnosed with any frequency in the Middle East .
While pediatric BL has a generally uniform histologic and clinical appearance, BL in adults can present challenges that may not be adequately addressed in current Middle East pathology practices. The WHO classification of lymphoid neoplasms was introduced into the region around 2010, and the complexity of the classification can be difficult for a general pathologist anywhere . BL is defined as a high proliferation rate mature B-cell lymphoma with an isolated MYC translocation [2, 5]. The distinction between BL and diffuse large B-cell lymphoma can be a problem in children and adults, and high-grade B-cell lymphomas of adults histologically and clinically overlap with BL [2, 5, 48]. To make matters even more complex, data on molecular profiling indicate that BL may not always have a MYC abnormality and that the germinal center CD10 and BCL6 positive phenotype, by itself, might be sufficient for the diagnosis .
Analyzing international data provokes as many questions as it provides answers. Detailed information is available through IICC-3 on virtually all pediatric cancers . For adults, the WHO Globocan website records international data for non-Hodgkin lymphoma, but there is no separation into subtypes . This is a problem for BL. Most adult BL occurs in immunocompetent patients, and increased adult BL rates may be related to the aging of populations having late exposure to EBV . But in Europe, North America, Japan, and Korea, it is notable that the higher frequency in adults is associated with a parallel increase in pediatric EBER-negative BL.
BL is an important adult tumor, having a frequency approaching mantle cell lymphoma . The absence of details in Globocan requires investigators to depend upon regional publications. US studies using the SEER database are representative of the general population . In many other countries, the studies are hospital-based and may not embody the entire nation.
Recent investigations of BL emphasize molecular mechanisms related to MYC activity and rarely include an analysis of EBV latency . There also seems to be a declining interest in the relationship between the spread of EBV and lymphoma, although, outside of endemic regions, high rates of early childhood EBV infection are associated with low rates of EBV-positive BL [2, 3, 4]. When infections are more frequent in adolescents and young adults, rates of BL are moderately high, and the frequency of tumor EBV latency is low. These are clear relationships that deserve an explanation.
In Sulaimani, several childhood and adult EBV-related tumors are recognized. These include nasopharyngeal carcinoma, NK/T-cell lymphoma of nasal type, and EBV-related large B cell lymphoma. As a group, they comprise less than 0.1% of our cancers. EBV-positive post-transplant lymphoproliferative disease occurs in approximately 1% of our kidney transplants, a frequency similar to the US [50, 51]. All of these tumors are occurring in a population that has a high EBV seroconversion rate that reaches its peak in mid to late adolescence.
BL in the Middle East has an incidence that resembles countries with high indices of development. We believe this BL is a sporadic disease. There is no identifiable promoting influence coexisting with EBV. The indigenous populations of most of the Middle East, including Iraq, have been malaria-free since the late 1990s, and non-Hodgkin lymphomas associated with other infections such as human herpes virus-8, Helicobacter pylori, and hepatitis B and C are uncommon or no more common than in Europe or North America [9, 52].
If there is a link with Europe, we should probably be identifying more BL in adults. The reason that adult BL is rare in the Middle East is uncertain. It may be related to a high rate of EBV exposure but with a delayed plateau until late adolescence. This seems to be the third pattern of EBV infection between the early childhood exposure of countries with low developmental indices and the adolescent and young adult exposure of countries with high socioeconomic development. It is notable that until adulthood, rates of Middle Eastern BL resemble those of Southern Europe more than any other region of the world.
The determination of the Sulaimania EBV seropositivity used de-identified clinical specimens initially obtained for other diagnostic purposes. This is a limitation to any generalization about seropositivity in the region. Nevertheless, the limitation is shared with other major studies of population EBV exposure that also analyzed stored clinical specimens or blood donations [12, 15, 16, 22, 26, 29, 30, 31, 32, 46]. The social strata of patients seeking medical attention may be different than the general population, and socio-economic factors can influence infection [12, 14]. A study of EBV infection rates in a general population would raise issues of harm and confidentiality and be difficult to design short of a large project using stored specimens as a general health survey . This leaves the analysis of previously clinical specimens the most available, although less than ideal, method for inferring viral exposure.