Epstein-Barr Virus: Main Pathogenic Agent in Hodgkin Lymphoma Associated Hemophagocytic Syndrome?.

Hemophagocytic syndrome (HPS) is characterized by an uncontrolled proliferation of macrophages displaying extensive phagocytosis of hematopoietic cells that can be associated with non Hodgkin lymphomas. However, Hodgkin lymphoma associated with hemophagocytic syndrome (HL-HPS) has rarely been published. We report here a large series of 34 patients presenting HL-HPS. Histological analysis and Epstein-Barr Virus (EBV) studies were performed. The 34 patients were enrolled from 1992 to 2006. HPS diagnosis was based on usual clinico-biological criteria. Bone marrow aspiration or biopsy were performed in all cases and confirmed HPS, showing hemophagocytic features in scattered macrophages. HL was documented on histological material in all 34 patients. The biopsies were performed on different localizations: lymph nodes (n=18), bone marrow (n=27), liver (n=2) and tonsil (n=1). All histological slides were reviewed and classified according to the World Health Organization (WHO) Lymphoma classification. The presence of EBV in the tumour cells was detected using EBER RNA in situ hybridization and the expression of viral proteins LMP-1, EBNA-2 by immunoperoxidase. Patients were 26 men and 8 women (sex ratio M/F = 3.3). The median age was 45 years (range 19–84). HIV status was negative in 26 patients and positive in 8 patients. All patients were in clinical stage IVB. HL subtypes (18 lymph nodes) were Mixed Cellularity (n=12, 67%), Nodular Sclerosis (n=2, 11%) and Lymphocyte Depleted (n=4, 22%). Extra nodal tissues were highly infiltrated by tumour cells in all cases. The presence of EBV in tumour cells was detected in 32 out of the 34 patients (94%). In all EBV positive cases, high levels of LMP-1 without EBNA2 expression were detected, defining a latency II. This study reports the largest series to date of HL-HPS. The features of HL-HPS are particular by the high proportion of mixed cellularity subtypes (67%) in contrast to the frequency of nodular sclerosis subtypes observed in the general population of non overt immunosuppressed patients, and by the striking high proportion of EBV associated HL (32 out of the 34 patients, 94%). Our findings suggest not only a pathogenic role of EBV, but also a defective immune system in the control of EBV infection in HL-HPS patients.The high predominance of male in our population of HPS-HL (sex ratio M/F = 4.3 after exclusion of HIV positive patients) and the strong association with EBV could suggest X-linked immune defect in these patients.