Navigating the Diagnostic Gray Zone: A Case Series on Mediastinal Gray Zone Lymphomas

Gray zone lymphomas (GZLs) are rare mature B-cell neoplasms characterized by overlapping morphologic and immunophenotypic features of classical Hodgkin lymphoma (CHL) and diffuse large B-cell lymphoma, particularly primary mediastinal B-cell lymphoma, posing significant diagnostic and therapeutic challenges. We present a case series of four patients illustrating the clinicopathologic spectrum of GZL, including mediastinal tumors with discordant CHL-like and B-cell phenotypes, a nonmediastinal systemic GZL, and a rare metachronous presentation demonstrating clonal evolution. These cases highlight marked lineage plasticity, frequent morphologic-immunophenotypic discordance, and the limitations of morphology-based diagnosis alone. Comprehensive immunophenotyping was critical for accurate classification and appropriate therapy selection. This case series underscores the importance of an integrated clinicopathologic approach to avoid misclassification and to guide optimal, biology-driven management of GZLs.