All shades of gray in the mediastinum: do we have bright ideas about how to diagnose and treat mediastinal gray zone lymphoma in the era of targeted agents?

Mediastinal gray zone lymphoma (MGZL) is defined in the international World Health Organization classification as a B-cell lymphoma with overlapping clinical, morphological, immunophenotypic, and molecular features between primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (CHL), particularly nodular sclerosis CHL (NSCHL). Recent molecular studies have highlighted the similarities between these 3 entities, relying on immune escape, JAK-STAT, and nuclear factor-κB pathway alterations without specific features related to MGZL. These studies shed light on the different pathobiology of extramediastinal cases, leading to the conclusion that these cases are generally better classified as diffuse large B-cell lymphoma (DLBCL)-not otherwise specified. The absence of Epstein-Barr virus (EBV) on the biopsy is also a desirable criterion, leading to the differential diagnosis of EBV-positive DLBCL. Most studies reporting clinical and treatment data suggest that more intensive induction regimens provide greater disease control compared to standard regimens. Given the paucity of dedicated clinical trials, it remains unknown if, and when, the evolving therapeutic options of PMBL and NSCHL will become available to those with MGZL, offering novel immune-based treatments to these patients with a higher risk of primary chemorefractory disease.