Fulminant EBV-driven CD8 T-cell lymphoproliferative disorder following primary acute EBV infection: a unique spectrum of T-cell malignancy

Abstract

Fulminant Epstein-Barr virus (EBV)-driven clonal T-cell lymphoproliferative disorder (T-LPD) is rare and most patients are of Asian origin. The disease usually develops shortly after primary acute EBV infection and the mechanism remains poorly understood. Here we report such a rare case in a 28-year-old Caucasian female with systemic lupus erythematosus (SLE). Immunophenotypic and molecular studies revealed that the proliferating lymphoid cells displayed a CD8(+) T-cell phenotype with clonal rearrangement of the T-cell receptor gamma gene. Epstein-Barr virus-encoded RNA was also observed in the clonal lymphoid cells by in situ hybridization. The patient subsequently developed fatal virus-associated hemophagocytic syndrome one month after the primary acute EBV infection. The case represents the first report of fulminant EBV-driven CD8(+) T-LPD occurring in an immunocompromised Caucasian SLE patient. This study, along with studies of similar Asian cases reported in the literature, suggests that dysregulated immunity due to either acquired or genetically determined susceptibility may result in an abnormal response to primary EBV infection and contribute to the pathogenesis of EBV-mediated fatal T-LPD.

Keywords: Epstein-Barr virus; Fatal infectious mononuleosis; T-cell lymphoproliferative disorder; hemophagocytosis; systemic lupus erythematosus; virus-associated hemophagocytic syndrome.

Figure 1

Histological and immunohistochemical features of fulminant EBV-driven CD8⁺ T-LPD in the peri-cystic duct lymph node. A. H&E section shows complete effacement of the nodal architecture by atypical lymphoid cells (400×). B. The atypical lymphoid cells demonstrate slightly irregular hyperchromatic nuclei and some with prominent nucleoli (1000×). The atypical lymphoid cells show strong CD3, but not CD20 immunoreactivity (C, D). E and F. The atypical lymphoid cells show partial loss of immunoreactivity to CD5 and CD7, respectively. G. The atypical lymphoid cells show strong reactivity with EBV-encoded RNA by in situ hybridization. H. The atypical lymphoid cells show a high proliferative index (immunostain with Ki-67).

Figure 2

Histological and immunohistochemical features of EBV-driven CD8+ fulminant T-cell lymphoproliferative disorder and hemophagocytosis in the bone marrow and lymph node. A. The bone marrow aspirate smear shows a small cluster of neoplastic cells with basophilic cytoplasm and conspicuous nucleoli (Wright stain, 1000×). B. The bone marrow biopsy demonstrates interstitial distribution of neoplastic cells that are difficult to differentiate from immature myeloid cells (H&E stain, 1000×). C. CD3 immunostain highlights neoplastic T-cells. D. The tumor cells show strong reactivity with EBV-encoded RNA by in situ hybridization. E and F. The lymph node is effaced by proliferation of histiocytes with extensive hemaphagocytosis (H&E, 400× and 1000×, respectively).

Figure 3

Phenotypic and molecular features of EBV-driven CD8+ fulminant T-cell lymphoproliferative disorder by flow cytometry and molecular studies. A. The CD8⁺ neoplastic lymphocytes (red) are larger than normal CD4⁺ T-cells (blue) and express low intensity CD3 and high intensity CD8 expression. B. Clonal rearrangement of the TCR gamma gene is confirmed by PCR followed by capillary electrophoresis on the peri-cystic duct lymph node.