Clinicopathologic Analysis of 34 Japanese Patients With EBV-Associated Reactive Lymphoid Hyperplasias

The 5th edition of the WHO classification of haematolymphoid tumours introduces the concept of hyperplasias arising in immune deficiency and dysregulation (IDD), which are frequently associated with Epstein-Barr virus (EBV). These lesions can be histologically classified as follicular hyperplasia (FH), infectious mononucleosis-like hyperplasia (IMH), or plasmacytic hyperplasia. Although EBV-associated reactive lymphoid hyperplasia (EBV-RLH) has been recognized in various IDD settings, comprehensive clinicopathologic analyses remain limited. We analyzed 34 Japanese patients with EBV-RLH. The IDD settings primarily included autoimmune diseases (with or without immunosuppressive therapy), chemotherapy for prior malignancies, aging, post-hematopoietic stem cell transplantation, and HIV infection. No patient exhibited histologic transformation or died due to EBV-RLH. Three patients had concurrent hematologic malignancies, and 12 had immune dysregulation related to prior chemotherapy. Histologically, 20 cases showed FH, 6 IMH, and 8 nonspecific patterns. EBER-positive cells were distributed in both interfollicular areas and germinal centers (GCs) in 27 cases (79%) and confined to interfollicular areas in 7. Six cases exhibited intensive aggregation of EBER-positive cells in one or a few GCs. Double staining confirmed that most EBER-positive cells expressed CD79a but not CD3. IGH and TCRG PCR analyses were successful in 24 cases: 21 were negative for both rearrangements, and 3 showed clonal rearrangements (1 double, 1 IGH-only, and 1 TCRG-only). EBV-RLH generally followed an indolent course; however, it may coexist with hematologic malignancies or develop after multichemotherapy. Careful histopathologic evaluation is essential to avoid overlooking concurrent malignancy or unnecessary treatment.