Context.— Plasmablastic lymphoma (PBL) is a rare aggressive lymphoma, usually positive for CD138 and frequently occurring in the oral cavity of human immunodeficiency virus (HIV) patients. Up to 10% of cases are negative for CD138 and diagnostically very challenging. Objective.— To investigate the appropriate approach to diagnose CD138− plasmablastic lymphoma and avoid misdiagnosis. Design.— We studied 21 cases of CD138− PBL from multiple large institutes in the United States and 21 cases from literature. Results.— CD138− PBLs were positive for different B/plasma cell markers at various percentages: MUM1 (94.4%; 34 of 36), OCT2 (70.6%; 12 of 17), immunoglobulin light chains (68.8%; 22 of 32), CD38 (68.4%; 13 of 19), CD79a (34.2%; 13 of 38), and PAX5 (15.6%; 5 of 32), suggesting that MUM1, OCT2, immunoglobulin light chains, and CD38 are useful markers to help establish the lineage. A total of 83% of cases (30 of 36) were extraoral lesions. Extraoral lesions showed much lower Epstein-Barr virus (EBV) infection rates (16 of 30; 53.3%) and had worse prognosis. MYC was positive in 80% (8 of 10) of EBV+ cases and 40% (2 of 5) EBV− cases, indicating the importance of MYC in pathogenesis, especially in EBV+ cases. Conclusions.— Our study emphasizes that CD138− PBLs tend to be extraoral lesions, with much lower EBV infection rates, and diagnostically very challenging. Accurate diagnosis requires a thorough investigation and workup by using appropriate markers.
