EBV-positive diffuse large B-cell lymphoma, not otherwise specified masking Richter syndrome

Excerpt

A 63-year-old man presented with a 6-week history of fever (37.5–39.5 °C) and abdominal pain. He had been in his usual state of health with no history of tumor or immunosuppressive condition. Blood tests revealed thrombocytopenia (platelets 43 × 10⁹/L; normal, 100–300 × 10⁹/L), anemia (hemoglobin 74 g/L; normal, 120–160 g/L), elevated lactate dehydrogenase (399 U/L; normal, 140–240 U/L), 67.4% circulating lymphocytes (6.4 × 10⁹/L; normal, 1.1–3.2 × 10⁹/L), and an Epstein–Barr virus (EBV) DNA load of 7.62 × 10⁴ copies/mL. Abdominal computed tomography revealed enlarged retroperitoneal lymph nodes and a splenic space-occupying lesion. Histological analysis of the retroperitoneal lymph node core biopsy showed effacement of normal architecture with a diffuse infiltration pattern, predominantly composed of immunoblasts. Neoplastic cells were positive for CD20, CD79a, Bcl-6, MUM-1, MYC and Bcl-2 markers, and negative for CD3, CD10, CD5, CD30 and cyclin D1. In situ hybridization (ISH) revealed that the lymphoma was EBV-encoded RNA (EBER)-positive and polymerase chain reaction (PCR)-based clonality studies showed that the tumor cells were monoclonal for immunoglobulin heavy chain (IgH). 18-Fluorodeoxyglucose positron emission tomography/computed tomography scanning (¹⁸F-FDG PET/CT) showed cervical, mediastinal, abdominal and retroperitoneal lymph nodes, spleen, left adrenal gland, left perirenal fascia and left anterior renal space involvement. The patient was diagnosed with EBV-positive diffuse large B-cell lymphoma, not otherwise specified (EBV + DLBCL, NOS) stage IV. However, flow cytometry of bone marrow and peripheral blood confirmed the presence of a large population of lymphocytes (71% of events) with most demonstrating CD19, CD20, CD200, CD5, CD22, CD23 and immunoglobulin lambda light chain restrictive expression, which met criteria for a diagnosis of chronic lymphocytic leukemia (CLL). To clarify the diagnosis, an excisional biopsy of left cervical lymph node (diameter 1.5 cm) was performed and, interestingly, two different components were observed. Approximately 80% of the regions showed a diffuse infiltrate of large cells with immunoblastic features just like the morphology seen in the retroperitoneal core biopsy, whereas 20% of the regions were made up of small neoplastic cells (Figs. 1, 2a, b). The large cells expressed CD20, CD79a, Bcl-6, Mum-1, CD30 (10–20%), Bcl-2 (weak), MYC and lacked CD3, CD10, CD5 (Fig. 2), CD23 (Fig. 2), Cyclin D1, SOX11, P53, PD-1 and PD-L1 (Supplementary Fig. 1a, b). However, the small cells expressed CD20, CD79a, Bcl-6 (weak), Bcl-2 (strong), MYC (5–10%), CD5 (Fig. 2), CD23 (Fig. 2) and lacked CD3, CD10, Mum-1, CD30, Cyclin D1, SOX11, P53, PD-1 and PD-L1 (Supplementary Fig. 1c, d). EBER was detected in the large cells but not in the small cells (Fig. 2). The proliferative index (Ki-67) was around 80% in the large cells and 2% in the small cells (Fig. 2). PCR results for IgH and IgK gene rearrangement showed an identical band size when analyzing the two components separately (Supplementary material). Therefore, a diagnosis of Richter syndrome (RS, CLL transforming to EBV + DLBCL) was made. The patient completed 2 cycles of R-CHOP (rituximab, cyclophosphamide, pharmorubicin, vincristine, prednisone), but did not respond to treatment and finally died of respiratory failure 4 months after the diagnosis.

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