Lymphomas Diagnosed Primarily on Serous Effusion Cytology: Cytology Rises to the Challenge!

Abstract Background: Lymphomas involving serous effusions as the initial clinical presentation are uncommon and pose significant diagnostic challenges because of their overlapping cytomorphologic features with reactive lymphocyte-rich effusions. Early diagnosis is crucial, particularly when tissue biopsy is difficult or inconclusive. Aim: This study aimed to evaluate the cytomorphologic spectrum of previously undiagnosed lymphoproliferative disorders presenting in serous effusions and to assess the complementary role of immunocytochemistry (ICC) and flow cytometry (FCM) in their diagnosis and subtyping. Materials and Methods: A retrospective descriptive study was conducted at a tertiary cancer center over 10 years (January 2015–December 2024). Eighteen cases with an upfront diagnosis of lymphoma on pleural or ascitic fluid cytology were included. Cytomorphologic evaluation was performed on May–Grünwald–Giemsa and Papanicolaou-stained smears. Cell block-based ICC and multiparametric FCM were performed whenever indicated. Final diagnoses were established by integrating cytomorphology, immunophenotypic findings, and clinical correlation according to the fifth edition of the World Health Organization Classification of Haematolymphoid Tumours. Results: Among 12,092 serous effusion samples processed, 18 cases (0.15%) represented previously undiagnosed lymphomas diagnosed primarily on effusion cytology. The median age was 16 years (range: 8–55 years), with a male predominance (13 males and 5 females). Pleural effusions accounted for 83.3% of cases, and mediastinal mass was the most common presentation (83.3%). T-lymphoblastic lymphoma was the predominant subtype (12/18, 66.7%), followed by diffuse large B-cell lymphoma (3/18, 16.7%), high-grade B-cell lymphoma, unclassifiable (2/18, 11.1%), and Burkitt lymphoma (1/18, 5.6%). ICC was particularly useful for diagnosing B-cell lymphomas, whereas FCM played a complementary role in T-lymphoblastic lymphoma and Burkitt lymphoma. Five mediastinal biopsies were nondiagnostic because of hemorrhagic specimens, highlighting the diagnostic value of effusion cytology when tissue sampling was inadequate or not feasible. Conclusion: Serous effusion cytology, combined with ICC and FCM, is a valuable minimally invasive approach for the early diagnosis and subtyping of lymphomas presenting without prior tissue diagnosis. An integrated interpretation of cytomorphology, immunophenotyping, and clinical findings can facilitate timely diagnosis and appropriate clinical management, particularly in patients in whom tissue biopsy is difficult, delayed, or nondiagnostic.