LAUSR

Dear Editor, A 62-year-old woman was admitted to another hospital due to swelling of a cervical lymph node and was diagnosed to have an Epstein-Barr virus (EBV)–positive diffuse large B cell lymphoma, not otherwise specified (DLBCL, NOS). She was treated with R-CHOP therapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, and a complete response was achieved. Two years later, she was admitted to our hospital complaining of high fever. The whole-body computed tomography scans showed swelling of the cervical, subclavian, mediastinal, paraaortic, and inguinal lymph nodes. Her laboratory tests revealed the following: white blood cell count, 1.94 × 10/L; hemoglobin level, 86 g/ L; platelet count, 37 × 10/L; lactate dehydrogenase, 944 U/L; and C-reactive protein, 6.78 mg/dL. Serum concentrations of interferon (IFN)–γ, tumor necrosis factor (TNF)–α, and interleukin (IL)–6, IL-10, IL-12, and IL-18 were 18.5 IU/mL (normal, < 0.1 IU/mL), 15.4 pg/mL (normal, 0.75–1.66 pg/mL), 123 pg/mL (normal, < 4.0 pg/mL), 557 pg/mL (normal, < 5.0 pg/mL), < 7.8 pg/mL (normal, < 7.8 pg/mL), and 7950 pg/mL (normal, 81.5–170.5 pg/mL), respectively. A biopsied lymph node showed relapse of EBV-positive DLBCL, NOS (Fig. 1a). The tumor cells were histologically positive for EpsteinBarr-encoded RNA (Fig. 1b), IFN-γ (Fig. 1c), TNF-α (Fig. 1d), IL-6 (Fig. 1e), IL-10 (Fig. 1f), and IL-18 (Fig. 1g), and negative for IL-12. Bone marrow aspiration showed 2.2% abnormal lymphocytes and hemophagocytosis (Fig. 1h). These findings were consistent with lymphoma-associated hemophagocytic syndrome (LAHS). Her disease had become refractory to chemotherapy. She eventually died from progressive disease. Cytopenias in hemophagocytic syndrome (HPS) are caused mainly by hypercytokinemia or unbalanced cytokine levels through a mechanism that uncontrolled secretion of cytokines stimulates the proliferation and phagocytic activity of macrophages [1]. In patients with active HPS, serum levels of IFN-γ, TNF-α, and IL-6, IL-10, IL12, and IL-18 are markedly elevated, and this is closely associated with poor prognosis [2, 3]. In addition, high serum levels of IL-6, IL-10, and IL-18 and TNF-α have also been reported to correlate with poor prognosis in patients with non-Hodgkin lymphoma [4–7]. The development of LAHS has been mostly linked to T cell or natural killer (NK) cell lymphomas [8]. Neoplastic T/NK cel ls in T/NK cel l lymphoma–associa ted hemophagocytic syndrome (T/NK-LAHS), as well as the reactive T/NK cells in EBV–associated HPS, have been confirmed to be infected with clonal EBV, suggesting that clinical symptoms are ascribed to the cytokines produced by the EBV-infected T/NK cells [8, 9]. On the other hand, B cell lymphomas rarely complicate LAHS [8]. In B cell lymphoma–associated hemophagocytic syndrome (BLAHS), serologic testing suggested that some patients had remote infection with EBV [10], but there were no reports showing that neoplastic B cells indeed contain EBV genomes. In B-LAHS, some reports suggest that activated T-lymphocytes play a role in immune dysregulation and abnormal production of cytokines [10], but the source of these cytokines is unknown. To the best of our knowledge, this is the first case report of EBV-positive DLBCL, NOS with HPS, in which EBV-infected tumor cells stained positive for multiple cytokines (IFN-γ, TNF-α, IL-6, IL-10, and IL-18). These * Shoko Nakayama [email protected]