A clinicopathologic study of the spectrum of systemic forms of EBV‐associated T‐cell lymphoproliferative disorders of childhood: A single tertiary care pediatric institution experience in North America

Abstract

Background Systemic forms of EBV‐associated T‐cell lymphoproliferative disorders of childhood (S‐EBV‐T‐LPD) comprise three major forms: EBV‐positive hemophagocytic lymphohistiocytosis (EBV‐HLH), systemic EBV‐positive T‐cell lymphoma (S‐EBV‐TCL), and systemic chronic active EBV infection (S‐CAEBV). These disorders occur rarely in children in Western countries. Here, we described eight children of such entities. Design Eight cases (six clinical and two autopsy) with S‐EBV‐T‐LPD of childhood were retrospectively identified from 1990 to 2015. Clinicopathologic parameters including histomorphology, immunophenotype, EBV studies, and T‐cell receptor gene rearrangement studies were recorded. Results Patients include five females and three males of Hispanic, Asian, and Caucasian origins with an age range of 14 months to 9 years. Fever, hepatosplenomegaly, cytopenias, abnormal EBV serologies, and very high EBV viral loads were common findings. Histologic findings showed EBV+ T‐cell infiltrates with variable degrees of architectural distortion and cytologic atypia ranging from no to mild cytologic atypia to overt lymphoma and tissue hemophagocytosis. All showed aberrant CD4+ or CD8+ T cells with dim to absent CD5, CD7, and CD3, and bright CD2 and CD45 by flow cytometry or loss of CD5 by immunohistochemistry. TCR gene rearrangement studies showed monoclonal rearrangements in all clinical cases (6/6). Outcomes were poor with treatment consisting of chemotherapy per the HLH‐94 or HLH‐2004 protocols with or without bone marrow transplant. Conclusion In this large pediatric clinicopathologic study of S‐EBV‐T‐LPD of childhood in the United States, EBV‐HLH, S‐EBV‐TCL, and S‐CAEBV show many overlapping features. Diagnosis is challenging, and overall outcome is poor using current HLH‐directed therapies.

Systemic EBV-positive T-cell lymphoma of childhood

“…The liver in reported cases demonstrates infiltration of small lymphocytes in portal, lobular, and sinusoidal areas. Cholestasis, steatosis, hepatocyte necrosis, and hemophagocytosis can also be seen (Figure 2) (Coffey et al 2019;Quintanilla-Martinez et al 2000, Yoshii et al 2012. Eckel AM, Chisholm KM Atlas Genet Cytogenet Oncol Haematol.…”

“…Bone marrow biopsies tend to show histiocytic hyperplasia, prominent hemophagocytosis, and an interstitial lymphocytic infiltrate (Figure 1). (Coffey et al 2019;Quintanilla-Martinez et al 2000). Multiple reports describe lymph nodes as being largely unremarkable with preserved architecture and open sinuses, although occasional cases have been described to have partial or more complete destruction with paracortical expansion by a prominent infiltration of small to medium-size atypical lymphocytes and areas of necrosis (Coffey et al 2019;Hong et al 2013;Quintanilla-Martinez et al 2000;Zhu et al 2019).…”

“…For this particular diagnosis, it is important to distinguish this type of lymphoma from acute self-limited infectious mononucleosis with EBV-infected B cells, and the other EBVpositive lymphoproliferative disorders (LPD) which include aggressive NK-cell leukemia, extranodal NK/T-cell lymphoma, nasal type, and chronic active EBV infection (CAEBV) of T-and NK-cell type (cutaneous and systemic forms). It is frequently particularly challenging to differentiate systemic EBV-positive T-cell lymphoma of childhood from acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), and the differentiation is often not ultimately made in many cases (Coffey et al 2019;Smith et al 2014). It is also important to distinguish this entity from chronic active EBV infection of T-and NK-cell type, which can show a broad range of clinical manifestations, from indolent, localized forms such as hydroa vacciniforme-like lymphoproliferative disorder and severe mosquito bite allergy to more systemic disease manifestations characterized by symptoms similar to systemic EBV-positive T-cell lymphoma of childhood.…”

“…Systemic EBV-positive T-cell lymphoma of childhood is extremely rare but reports of this disease have most frequently been in Asians including individuals from Japan and China (Kikuta et al 1993;Su et al 1994;Suzuki et al 2004;Yoshii et al 2012;Zhu et al 2019). Additional reports have described the disorder in several individuals from Mexico, Central and South America, and occasional individuals whose ethnic origin is described as White, not further specified (Coffey et al 2019;Quintanilla-Martinez et al 2000). It occurs most often in children and young adults.…”

“…Similarly, fever, hepatosplenomegaly, and frequent lymphadenopathy are also present in reported cases arising from patients with CAEBV. (Coffey et al 2019;Kikuta et al 1993;Quintanilla-Martinez et al 2000;Zhu et al 2019). Patients in either group generally develop hemophagocytic lymphohistiocytosis, sepsis, and multiorgan dysfunction, which ultimately lead to death usually within days to weeks.…”