Mediastinal Gray Zone Lymphomas: Diagnostic Challenges, Clinicopathologic Overlap, and Emerging Management Strategies

Background: Mediastinal gray zone lymphoma (MGZL) is a rare B-cell lymphoma which shares clinicopathologic and molecular features between primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (CHL). Although included as provisional disease entity back in 2008 WHO classification after initial description in 1998, the concept of MGZL has since evolved, with latest WHO-HEMA5 and ICC limiting the entity to EBV-negative mediastinal lesion. Methods: This review summarizes the historical evolution, epidemiology, clinicopathologic characteristics, immunophenotypic and genetic features, diagnostic challenges, and therapeutic strategies for MGZL. Data from retrospective series, prospective cohorts, and recent molecular studies are synthesized to provide a comprehensive perspective. Results: MGZL generally affects young adults, especially males, and presents with bulky mediastinal disease. Transitional morphology, pleomorphic Reed–Sternberg–like cells, and variable B-cell and activation markers make its diagnosis challenging. Molecular studies have shown that they share changes with PMBL and CHL such as 9p24. 1 (JAK2/PD-L1/PD-L2); however, specific alterations, including HOXA5 hypomethylation and MYC gains, argue for its designation as a separate entity. Therapeutically, DA-EPOCH-R is one of the most effective regimens, but prognosis is still worse than PMBL or CHL, 5-year OS ~40–60%. Salvage chemotherapy and autologous transplantation are frequently necessary for relapsed/refractory disease. Novel therapies, especially brentuximab vedotin and PD-1 inhibitors, appear to be effective, especially in combination. Conclusion: MGZL continues to be a diagnostically challenging, and therapeutically complex lymphoma with an inferior prognosis compared to related entities. Advancements in molecular profiling and immunotherapy suggest the promise of personalized therapy. Yet, prospective clinical trials and international cooperation are urgently needed to develop guidelines for therapy of this rare lymphoma.