Populations from different ethnic groups have variable susceptibility to EBV infection, as is demonstrated by geographical variations in the prevalence of EBV-related cancers. The relative incidence of T or NK/T cell lymphomas, especially EBV-associated nasal or nasal type NK/T cell lymphoma, is much higher in Asians than in Western populations (6
). In Korea, T or NK/T cell lymphomas comprise 25% of NHLs (13
), which is in line with reports from other Far Eastern countries. In the present study, T and NK cell lymphoproliferative diseases accounted for 64% of EBV-associated disease and 47.5% of T or NK cell lymphomas were associated with EBV. If we exclude those EBV-positive T and NK cell lymphomas, the incidence of NK and T cell lymphoma in Korea is similar to that of Western countries, accounting for 10-15% of NHLs (17
), which again emphasizes the role of EBV in the pathogenesis of NK and T cell lymphomas in Asia.
B-cell tropism of EBV through the EBV-specific receptor CD21 (CR2), which is expressed on B cells and developing T cells but not on mature peripheral T cells, is well known (18
). In individuals with a normal immune system, sustained T-cell infection by EBV occurs only rarely, raising the possibility that the infection of T lymphocytes and their subsequent unregulated growth is caused, at least in part, by a defect in immune surveillance (7
). It has been suggested that a genetically determined susceptibility, possibly based on certain HLA types, results in an abnormal response to primary EBV infection in certain parts of Asia. A study of Chinese and natives of New Guinea has shown that this ethnic group has a high prevalence of HLA A11, a type that is associated with a mutation of EBNA-4 that abrogates cytotoxic T-cell recognition of EBV (19
). By contrast, A11 is rare among Europeans, in whom cytotoxic T cells recognizing the EBNA-4 peptide dominate the immune response to EBV. These variations in HLA phenotype may provide a basis for the higher frequency of EBV-positive tumors - including nasal T/NK cell lymphomas - among Asians. In addition, a recent study from Japan has shown that patients with nasal type EBV-associated NK/T cell lymphomas have a low frequency of the HLA-A*0201 allele, suggesting the importance of this allele in cytotoxic T lymphocyte responses (21
CAEBV infection is a peculiar disease showing an abnormal immune response to primary EBV infection and characterized by recurrent infectious mononucleosis-like symptoms in childhood. Patients with CAEBV infections usually show clonal proliferation of T or NK cell and some of them develop overt NK cell or T cell lymphoma/leukemia in their teens and twenties (22
). In the present study, ANKL and PTCL were mainly diseases of adults, but a few instances of EBV-associated PTCLs and ANKLs developed in patients in their twenties. Considering the natural course of chronic active EBV infection, these ANKL and PTCL occurring in young adults were probably transformed from chronic active EBV infections.
Patients with NK/T cell lymphomas, ANKL, and PTCL had major age peaks in their forties, forties, and sixties, respectively. It is not known what proportion of those EBV-associated diseases occurring in adults is a de novo disease unrelated with chronic (active) EBV infection. In Korea, the primary infection rate with EBV is 90% in those aged 7-9 yr and 100% in those between 10 and 15 yr (23
). Almost all adult individuals are serologically positive. Therefore, EBV-associated diseases of adult onset seem to be derived from reactivation of chronic latent EBV infections or new EBV infection. In this study, we failed to find the past history suggesting chronic EBV infection from the medical record in most patients. Only one patient with a nasal-type NK/T cell lymphoma had mosquito-bite hypersensitivity when he was young. After childhood, he was relatively healthy without specific symptoms related to chronic EBV infection. Because mosquito-bite hypersensitivity is a cutaneous manifestation associated with latent EBV infection of the NK cells (7
), this supports the idea that adult-onset nasal NK/T cell lymphoma may develop with a background of chronic latent EBV infection. Given the age that most patients develop NK/T cell lymphomas, transformation of EBV-infected NK cells into NK/T cell lymphoma cells may require a long latent period for the accumulation of genetic mutations sufficient for neoplastic transformation. Prospective epidemiologic studies are clearly needed to clarify the natural history of adult-onset EBV-associated malignancy.
In this study, some patients with adult-onset EBV-associated LPD showed associated illnesses that could have caused immunological dysfunctions provoking the reactivation of latent EBV infection and neoplastic transformation of EBV-infected cells. Four of six adult patients with acute EBV-HLH were associated with HCV hepatitis and chronic arthritis, or postpartum status. Three of seven patients with EBV-associated PTCL had a history of medication for rheumatoid arthritis, HCV hepatitis, and prostate carcinoma. Common association with HCV in these patients suggests an apparently ineffective antiviral T-cell response. Likewise, in the patients with DLBCL, 19 of the 29 patients were older than 60 yr and 5 of the 29 adult EBV-positive DLBCL patients had histories of HCV hepatitis, hepatitis B virus (HBV) hepatitis, tuberculosis, or HD, which suggests that decreased immunity in elderly patients may also contribute to the pathogenesis of adult EBV-positive DLBCL (24
It is intriguing that the five patients with chronic EBV infection were associated with B-cell LPDs of various histological spectra. Three of four such patients presented with recurrent tonsillitis-like symptoms with monoclonal or oligoclonal B cell proliferation. Two of them expressed EBNA-2 as well as LMP-1, which indicates a type III latency of EBV infection usually identified in immunocompromised patients and which indicates an innate defect in the immune surveillance of EBV infection. The prognosis of those patients with B-LPD was excellent, as it was for those with EBV-associated large B cell lymphomas and for adult patients with HD. With additional genetic changes, these proliferating B cells in children with an immune defect to eradicate EBV may convert to HD or DLBCL, although the exact relationship between B-cell LPDs in children with chronic EBV infection and EBV-associated large B cell lymphomas or HD arising among adult patients remains to be clarified.
In summary, EBV infection in Koreans induced predominantly T or NK cell LPDs; among these, NK/T cell lymphomas were the most common. A high prevalence of EBV infection in early childhood associated with the failure of innate immune responses to eradicate the virus resulted in the development of EBV-associated LPD throughout life. As shown in , primary infections in early childhood may be complicated by the development of Burkitt's lymphoma and acute EBV-HLH as well as CAEBV infections; some of these transformed to ANKLs and PTCLs in young adults. In the middle-aged patients, some with chronic latent infections developed NK/T cell lymphomas and ANKL. In old patients, decreased immunity and environmental cofactors may provoke the development of PTCL and DLBCL.
The relation between EBV infection and development of EBV-associated lymphoproliferative disease by age group.