Narrative review: this or that?-uncommon challenges in mediastinal pathology.

Background and Objective: Accurate diagnosis of mediastinal tumors is of critical importance to establish appropriate therapy. However, these lesions are relatively uncommon and may be challenging to evaluate, particularly in small biopsy specimens. Thymomas and thymic carcinomas are the most common primary malignant tumors of the mediastinum, but the site can be affected by many other neoplasms that can pose significant difficulty in diagnosis. The objective of this article is to bring awareness to these rarer tumors and offer a diagnostic approach using ancillary techniques guided by clinical and morphological features. Methods: We discuss and review six challenging cases of mediastinal tumors with overlapping morphologic features. We discuss their unique morphologic, immunophenotypic, and relevant molecular characteristics to support their definitive diagnosis, based on current literature. Sources were obtained via PubMed search and include original studies and review articles published in the English language between 1990 and 2025. Search terms include the diagnostic entities discussed in the article. Key Content and Findings: Judicious use of immunohistochemistry and molecular studies is necessary to accurately diagnose mediastinal neoplasms with overlapping histologic features, such as those seen in the cases discussed. Conclusions: Diagnosis of uncommon mediastinal lesions may be challenging, particularly in small biopsies, as morphological features may be shared among different entities. Awareness of these rare entities, their clinical characteristics and presentation, and differential diagnosis can guide in the selection of appropriate immunohistochemical panels, molecular markers, and molecular diagnostics when appropriate to support the diagnoses.