Fatal Non-Transplant-Related Epstein-Barr Virus–Associated Atypical Lymphoid Proliferations in Infants and Children: A Clinicopathologic Study

Most Epstein-Barr virus (EBV)–related infections in infants and children are asymptomatic or self-limited mild viral illnesses, but rare cases of a rapidly fatal disorder have been described. Failure of the cellular response to control EBV-related lymphoid proliferation leads to severe disease with multiple complications, including a fatal outcome or development of an EBV-driven, clonal lymphoid neoplasm. In this report we characterize 3 cases of fatal, nontransplant, or immunodeficiency-related EBV infection in very young children with immunophenotypic and molecular evidence of B/natural killer (NK)-T cell clonal expansion. An immunohistochemical staining panel included testing for B-cell antigen (CD20), and T/NK cell antigens including CD2, CD3, CD4, CD8, CD56, CD57, and TIA-1. T-cell and B-cell PCR clonality testing was performed on paraffin tissue specimens to identify clonal populations. The ages of these 3 patients ranged from 22 months to 4 years. Initial clinical presentations included pneumonia, abnormal liver function tests and fever, and lymphadenopathy. The 3 patients died within 17 to 72 days of presentation, and autopsy was performed on 1 patient. All cases demonstrated prominent atypical lymphoid or lymphohistiocytic infiltrates, and necrosis was present in 2 of the 3 cases. The atypical lymphocytes were positive for CD3 (cytoplasmic), CD2, CD8, TIA-1, and CD57 and negative for CD4. We molecularly identified B-cell clones in the 2 tested patients, who also showed evidence of hemophagocytosis. Fatal EBV infection is characterized by a morphologic spectrum with atypical lymphoid infiltrates and variable necrosis. Our molecular studies of these patients suggest a clonally-derived expansive process, most likely driven by EBV infection. Our results also suggest that development of clonality is associated with an aggressive clinical course and may be useful in predicting greater risk for fatal outcome. A high index of suspicion, coupled with appropriate serologic and molecular testing, aids in early recognition and diagnosis of these lymphoproliferative processes.