Occult Malignancy Presenting as Pericardial Effusion: The Diagnostic Contribution of Pericardial Fluid Cytology

Background/Objectives: Pericardial effusion may occur in patients with established cancer but may also represent the first manifestation of an occult malignancy. This study evaluated the diagnostic contribution of pericardial fluid cytology and pathological assessment according to previous oncological status, with particular emphasis on previously unrecognized malignancy. Methods: We conducted a retrospective observational study of patients hospitalized with pericardial disease between January 2021 and December 2025 at a tertiary cardiovascular center. The final cohort comprised 234 clinical episodes in 209 patients. Clinical, laboratory, imaging, procedural, cytological, and histopathological data were analyzed in relation to previous oncological status and malignant pericardial involvement. Results: Pathological assessment was available in 95/234 episodes (40.6%), with neoplastic involvement identified in 21/95 (22.1%). Neoplastic findings occurred in 13/33 (39.4%) evaluable episodes with known malignancy and 8/62 (12.9%) without a previous cancer diagnosis (odds ratio, 4.39; 95% confidence interval, 1.59–12.11; p = 0.004). Conversely, 20/33 (60.6%) evaluable episodes in patients with known cancer showed no neoplastic involvement. In all eight patients without previously known malignancy, pericardial fluid cytology provided the first pathological evidence of cancer; six (75%) had findings suggestive of a pulmonary origin. All presented with large effusions and hemodynamic compromise. Conclusions: Pericardial pathological assessment provides diagnostic information beyond previous oncological status. It can distinguish malignant from non-neoplastic pericardial involvement in patients with established cancer while also revealing occult malignancy when pericardial disease is its first presentation.