EBV-positive systemic T-cell lymphoma has been clinically recognized as EBV-associated hemophagocytic lymphohistiocytosis or EBV-associated hemophagocytic syndrome, severe CAEBV infection, and fatal IM. Even though this disease entity is rare, there have been many sporadic reports describing fulminant T-cell LPD following acute EBV infection and CAEBV infection in Asian countries especially Japan and Taiwan [15
]. The patients were mainly children or young adults, with cases occurring in elderly patients hard to find in the literature.
In this study, we compared the clinicopathological features and immunohistochemical and molecular findings of five elderly patients and eight children or young adult patients. Although the study has limitations because of the small number of elderly patients, the data suggested some differences in the clinicopathological features. The cases in the children and young adult group usually presented with chronic intermittent or acute onset of fever, general malaise, and hepatosplenomegaly. The bone marrow or liver was the initial site of involvement and generalized lymphadenopathy was unusual. Laboratory tests showed pancytopenia and liver function abnormalities. The elderly patients more commonly presented with generalized lymphadenopathy. Hemophagocytosis or the involvement of bone marrow by tumor cells was not common at initial presentation.
Regarding the underlying disease, a hydroa vacciniforme-like skin lesion was seen in one patient and chronic active EBV infection in three patients in the children and young adults group. Therefore, about 50% of the systemic T-cell lymphomas in the children and young adult group seem to develop through a prodromal period of chronic EBV infection. This incidence of preceding chronic EBV infection is higher than those reported previously by Quintanilla-Martinez et al. [23
]. Our five elderly patients had no history of either CAEBV infection or hydroa vacciniforme-like eruptions. Instead, three of five patients were hepatitis B virus carriers or had chronic hepatitis C virus infection. Although the patients had no proven immune defects, the common association with hepatitis virus in these patients suggests an apparently ineffective antiviral T-cell response.
It is intriguing that IgA nephropathy was present in the girl with the hydroa vacciniforme-like skin lesions and subsequent development of T-cell lymphoma. A previous study demonstrated the EBV genome in seven of 12 patients with IgA nephropathy (58%) and suggested that EBV contributes to glomerular mesangial injury [9
The histological features of 13 cases showed broad cytological appearances ranging from a reactive appearance to overt lymphoma, and there were no significant differences between the children and the elderly patients. Grade 1 histology was identified in two cases that revealed monoclonality according to TCR gene rearrangement and numerous EBV-positive cells by in situ hybridization. The differential diagnosis between reactive change and lymphoma was difficult on morphologic grounds alone. EBER in situ hybridization is essential to avoid misdiagnosis.
We analyzed EBV-related antibodies in eight patients. In primary EBV infection in healthy hosts, IgM antibodies to VCA rise first, followed by VCA IgG and EBV-EA. EBV IgM and EBV-EA will eventually disappear, and lastly, an antibody to EBNA arises at least 1 month after the onset of symptoms [30
]. EBV IgG and EBNA will remain for life. In many people, detection of antibody to the early antigen is a sign of active infection. In the absence of EBNA, EBV-EA indicates primary infection. Considering this principle, the serologic profiles of the members of the children and young adult group were more compatible with primary and active EBV infection while those of the elderly patients were compatible with past infection. However, high viral loads and acute onset of disease in cases 1 and 3 in the elderly group indicate active EBV infection. A recent study demonstrated low frequencies of EBV-specific CD8+ T cells in patients with chronic active EBV infection [29
]. Failure to produce an antibody against EBV in elderly patients seems to be associated with underlying antiviral T-cell dysfunction.
The immunophenotype of the proliferating cells in the children and young adults group in our study were predominantly CD8-positive cytotoxic αβ T cells. Only one case developed from a CAEBV infection and consisted of mixed CD4+ and CD8+ cells with a predominance of CD4+ cells. The elderly group showed similar results, with a case with a γδ T-cell phenotype. Sporadic reports of fulminant EBV+ T-cell LPD showed a predominantly CD8+ phenotype with a few mixed CD4 and CD8 phenotype cells [2
]. However, other studies could not find any subset predominance in EBV-infected cells. Quintanilla-Martinez et al. [23
] reported six cases of fulminant EBV-positive clonal T-cell LPD after acute or chronic EBV infection. The cells in two cases were CD4+, two CD8+, and two had admixed CD4+ and CD8+ cells. All were CD56-negative. In a recent retrospective study of 43 children and young adult patients with EBV-associated T/NK-cell lymphoproliferative disorders (severe chronic active EBV infection), eight cases were compatible with fulminant or subacute EBV+ T-cell LPD following CAEBV infection, one case with a CD8+ phenotype, two with a CD4+ phenotype, three with an admixture of CD8+ and CD4+ cells, and two showed a CD4−/CD8− phenotype. Six cases had αβ T cells and two γδ T cells [16
]. Kasahara et al. analyzed the frequency of EBV-infected cells in circulating lymphocyte subpopulations from four patients with acute EBV-HLH and four with CAEBV infection [12
], and they showed that EBV-infected cells in the acute phase of EBV-HLH were mainly an activated CD8+ T-cell population, whereas the EBV-infected populations in CAEBV infection were heterogeneous, including CD4, CD8, B, and NK cells.
In conclusion, fulminant EBV+ systemic T-cell lymphoma of elderly patients is a rare disease that shares similar clinical and pathologic findings with those seen in children and young adults, but which has some differences in clinical features. Although those elderly patients showed no obvious immune defect, a common association with chronic hepatitis virus infection suggests an underlying derangement of T-cell immunity and failure to eradicate infected virus. In these patients, additional factors related to senility may play a role in the disruption of homeostasis between the virus and the host’s immune system, eventually leading to neoplastic transformation of EBV-infected T lymphocytes.