The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder

Abstract

Epstein Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (EBV-HLH) is a form of acquired, infection-related HLH which typically represents a fulminant presentation of an acute EBV infection of CD8+ T cells with 30-50% mortality rate. Systemic EBV-positive lymphoproliferative disease of childhood (SE-LPD) is a rare T cell lymphoproliferative disorder predominantly arising in the setting of acute EBV infection, often presenting with HLH. Since both entities have been associated with clonal T cell populations, the discrimination between these diseases is often ambiguous. We report a unique case of a 21 years old female who presented with clinical and laboratory findings of florid HLH in the setting of markedly elevated EBV titers (>1 million) and an aberrant T cell population shown to be clonal by flow cytometry, karyotype, and molecular studies. This case raises the differential of EBV-HLH versus SE-LPD. Review of the literature identified 74 cases of reported EBV-HLH and 21 cases of SE-LPD with associated HLH in 25 studies. Of those cases with available outcome data, 62 of 92 cases (67%) were fatal. Of 60 cases in which molecular clonality was demonstrated, 37 (62%) were fatal, while all 14 cases (100%) demonstrating karyotypic abnormalities were fatal. Given the karyotypic findings in this sentinel case, a diagnosis of SE-LPD was rendered. The overlapping clinical and pathologic findings suggest that EBV-HLH and SE-LPD are a biologic continuum, rather than discrete entities. The most clinically useful marker of mortality was an abnormal karyotype rather than other standards of clonality assessment.

Keywords: EBV-related HLH; EBV-related T cell lymphoma; Systemic EBV-positive lymphoproliferative disease of childhood; atypical T cell population; clonal EBV-related HLH.

Figure 1

Images of the diagnostic marrow. A. CD68+ immunohistochemical stain highlighting intramedullary histiocytes with intact intracytoplasmic nucleated cells (1000×). B. Wright stain aspirate smear with erythrophagocytosis and frequent intermediate sized lymphocytes with irregular nuclear contours (1000×).

Figure 2

Flow cytometry histograms. A. Four panels showing a discrete population (10.29% of total events, indicated in blue) with greater side scatter (and forward scatter, not shown) compared to background CD3+ T lymphocytes (red) with the following atypical immunophenotype: CD5-, CD7 dim, CD8+, CD4-, and CD2 bright. B. Histograms showing isotype controls (left) and clonality of the neoplastic population by Vbeta3 (right).

Figure 3

Karyogram showing inv (7) (p13q32) in 10 of 20 metaphases examined.

Figure 4

T-cell receptor gamma studies showing a distinct clonal band on V10 studies.