Fulminant EBV+ T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome

Abstract

This study describes the clinicopathologic features of 5 patients who developed a fulminant Epstein-Barr virus (EBV)-positive clonal T-cell lymphoproliferative disorder (LPD) after acute EBV infection. One additional patient developed a similar disorder in the setting of long-standing chronic active EBV infection. Detailed immunophenotyping, in situ hybridization for EBV early RNA-1 (EBER1) and polymerase chain reaction (PCR) analyses for immunoglobulin (Ig) heavy chain and T-cell receptor (TCR)-gamma gene rearrangements were performed on paraffin-embedded tissue from all patients. In addition, EBV strain typing and detection of the characteristic 30-bp deletion of the latent membrane protein-1 (LMP-1) gene were performed by PCR. Controls included 8 cases of uncomplicated infectious mononucleosis (IM). Patients included 4 males and 2 females with a median age of 18 years (2-37 years). Three patients were Mexican, 2 were white, and 1 was of Asian descent. All presented with fever, hepatosplenomegaly, and pancytopenia; 5 were previously healthy, but had a clinical history of a recent viral-like upper respiratory illness (1 week to 2 months), and 1 patient had documented chronic active EBV infection for 7 years. Serologic data for EBV were incomplete but titers were either negative or only modestly elevated in 3 cases. In 1 case serology was consistent with severe chronic active EBV infection. In the remaining 2 cases serologic studies were not performed. All patients died within 7 days to 8 months of presentation with T-cell LPD. On histologic examination, the liver and spleen showed prominent sinusoidal and portal lymphoid infiltrates of CD3+, βF1+, EBER1+ T cells lacking significant cytologic atypia. Two cases were CD4+, 2 cases were CD8+, and 2 cases had admixed CD4+ and CD8+ cells without clear subset predominance. All were TIA-1+, CD56−. Only rare B cells were noted. Marked erythrophagocytosis was present. Molecular analysis revealed identical T-cell clones in 2 or more sites (liver, spleen, lymph node) in 5 cases. All patients carried type A EBV; 4 cases had wild-type EBV-LMP, and 2 showed the 30-bp deletion. This fulminant T-cell LPD after acute/chronic EBV infection is characterized by hepatosplenomegaly, often without significant lymphadenopathy, fever, liver failure, pancytopenia, and erythrophagocytosis indicative of a hemophagocytic syndrome. EBV serology may be misleading, with lack of elevated titers. The presence of an EBER1+ T-cell infiltrate with scant B cells should alert one to this diagnosis. Although cytologic atypia is minimal, studies for T-cell clonality confirm the diagnosis.

Hepatic cytotoxic T‐cell infiltrates in patients with peripheral T‐cell proliferative diseases/lymphomas: Clinicopathological and molecular analysis

“…Epstein-Barr virus infection is associated with several human malignancies including Burkitt's lymphoma, Hodgkin's disease, post-transplantation lymphoproliferative disorders, fulminant EBV-positive T-cell lymphoproliferative disorder following chronic active EBV infection (CAEBV), nasopharyngeal carcinoma, gastric carcinoma, smooth muscle tumor in immunosuppressed patients, thymic carcinoma, and various types of peripheral T-cell and NK/T-cell proliferative disease/ lymphoma. 1,2,[11][12][13][14][15][16][17][18][19][20][21][43][44][45][46][47][48][49][50][51] In this study we found EBV genome and expression of EBER in the hepatic T-cell infiltrates of 61.4% and 38.6% of the patients, respectively. Expression of EBER was more commonly found in patients from groups C and D. The EBV serological study showed significantly high titers of anti-VCA-IgG and anti-EA-IgG in patients compared to our previous controls, 1 although the titer of the two groups overlapped to a considerable extent.…”

“…Mature NK/T-cell neoplasms are highly associated with Epstein-Barr virus (EBV) infection, and it is likely that EBV plays an important role in tumorigenesis. 1,2,[6][7][8] The EBV-associated lymphoproliferative disorders of the T cell include EBV-associated hepatitis, 10 fulminant (fatal) EBVpositive T-cell lymphoproliferative disorder following acute and chronic EBV infection, [11][12][13][14] hepatic peripheral T-cell lymphoma, 2,15 extranodal NK/T-cell lymphoma, nasal-type, [16][17][18] enteropathy-type intestinal T-cell lymphoma, 19 nonhepatosplenic g / d T-cell lymphomas of various sites, 20 and angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified. 21 Peripheral T-cell proliferative diseases/lymphomas can manifest with nodal and extranodal involvement.…”

Small‐cell predominant extranodal NK/T cell lymphoma, nasal type: clinicopathological analysis of a series of cases diagnosed in a Western population

“…These clinical findings, in conjunction with markedly elevated antibody titres to EBV-associated antigens, were consistent with chronic active EBV (CAEBV) infection. [14][15][16][17][18] Patients with sinonasal disease presented with symptoms of chronic rhinosinusitis and nasal obstruction and congestion, with or without deviated nasal septum. In one patient, the tumour was diagnosed from a biopsy of tissue taken during surgery for septal repair.…”

Two cases of chronic active Epstein–Barr virus infection in which EBV‐specific cytotoxic T lymphocyte was induced after allogeneic bone marrow transplantation

“…Recently, diagnostic criteria have been proposed (7,17). Although the pathogenesis and etiology were unclear, it has been reported that the clonal expansion of EBV-infected T or NK cells might be associated with the development of CAEBV (5,6,8,9,18). However, oligoclonal expansion of EBV-infected lymphocyte has been reported, so it is not clear whether CAEBV is truly a monoclonal disorder or not (10).…”