Pericardial effusion is a recognized complication of mediastinal lymphoma, particularly with bulky disease. However, establishing malignancy as the underlying etiology can be challenging when repeated fluid analysis and tissue sampling are nondiagnostic. We present a case of recurrent, hemodynamically significant pericardial effusion in which multiple negative diagnostic studies delayed the diagnosis of an aggressive mediastinal lymphoma.

Case Presentation: A 26-year-old man with a remote history of resected unifocal Langerhans cell histiocytosis presented with chest pressure and bilateral cervical lymphadenopathy. He was found to have a large pericardial effusion with tamponade physiology requiring urgent pericardiocentesis. Despite drainage, the effusion repeatedly reaccumulated, necessitating two subsequent pericardial window procedures.

An extensive evaluation across multiple hospitalizations including pericardial fluid cytology and flow cytometry, pericardial and pleural biopsies, and repeated cervical lymph node sampling with cytology, flow cytometry, and FISH was negative or nondiagnostic for malignancy. Inflammatory pericarditis was considered, and colchicine was initiated without improvement.

The patient was subsequently readmitted with recurrent pericardial effusion. Cardiac MRI revealed a 15 × 11-cm anterior mediastinal mass encroaching on the right atrium, and PET imaging demonstrated extensive hypermetabolic cervical, supraclavicular, mediastinal, hilar, axillary, and pericardial adenopathy. Prior lymph node pathology demonstrating inflammatory lymphadenitis with a T-cell and histiocytic infiltrate, along with leukopenia and rash, raised concern for Kikuchi disease. Erdheim-Chester disease was also considered given his history and recurrent pericardial involvement. He was treated empirically with prednisone.

Following steroid taper, he was readmitted with persistent bulky mediastinal disease, progressive pericardial and cardiophrenic adenopathy, and a recurrent circumferential pericardial effusion measuring up to 4.5 cm. Repeat pericardiocentesis yielded 550 mL of serous fluid. Given progressive radiographic disease despite repeatedly nondiagnostic studies, CT-guided core biopsy of the anterior mediastinal mass was pursued. Pathology demonstrated an aggressive CD30+/CD20+ mediastinal B-cell lymphoid malignancy with overlapping features of mediastinal gray zone lymphoma and classical Hodgkin lymphoma. He was initiated on dose-adjusted R-EPOCH. Following treatment, the pericardial effusion decreased to a small residual collection without further need for drainage.

Discussion: This case illustrates the diagnostic challenge of malignancy presenting as recurrent pericardial effusion despite repeatedly negative cytology and tissue sampling. Although negative studies appropriately broadened the differential toward inflammatory and histiocytic disorders, the patient's recurrent effusions, failure of anti-inflammatory therapy, progressive adenopathy, and bulky mediastinal mass remained discordant with a benign inflammatory process.

For patients with recurrent admissions, the longitudinal clinical trajectory can be as important as an individual diagnostic result. Negative pericardial cytology or limited lymph node sampling does not definitively exclude lymphoma, particularly when diagnostic tissue architecture is not adequately captured. When recurrent pericardial disease remains unexplained and imaging demonstrates progressive adenopathy or a suspicious mediastinal mass, the working diagnosis should be reassessed and repeat tissue acquisition from the highest-yield target pursued. This case emphasizes the importance of recognizing discordance between negative diagnostic testing and a progressively malignant clinical phenotype to avoid diagnostic delay.