Serous fluids, primarily pleural, peritoneal, and pericardial, present a wide spectrum of neoplastic and non-neoplastic conditions. Malignant effusions are often attributed to metastatic carcinoma, melanoma, sarcoma, and hematolymphoid malignancies. The most frequent origins of metastatic carcinomas to effusions include lung, breast, gastrointestinal, and female genital tracts.¹ Primary malignancies are quite rare, with malignant mesothelioma the most common, usually originating from the pleura and peritoneum.²

The International System for Reporting Serous Fluid Cytopathology (TIS) provides a standardized reporting system with five distinct diagnostic categories: nondiagnostic (ND), negative for malignancy (NFM), atypia of undetermined significance (AUS), suspicious for malignancy (SFM), and malignant (MAL). Malignant effusions may indicate an initial diagnosis of an occult primary malignancy or early recurrence, with tumor distribution varying by site, origin, and sex. Lung cancer often metastasizes to the pleura in men, while ovarian cancer spreads to the peritoneum in women. Changes in the incidence of other malignancies in serous fluids reflect advances in detection and treatment of certain tumors and variations in patient demographics.¹

The cytologic evaluation of serous effusions remains a highly valuable diagnostic modality with high diagnostic sensitivity in the initial evaluation of the etiology of effusions.³ particularly in the context of preexisting malignancies or unknown primary tumors. The incidence of malignancy was significantly higher in females than males in both pleural and peritoneal fluids.¹ Key cytologic features of metastatic adenocarcinoma include a second distinctive population of cells arranged in round, 3-D clusters with smooth contours, papillary clusters, glandular acini, and single or signet ring cells. The tumor cells exhibit an increased nuclear to cytoplasmic ratio, enlarged and pleomorphic nuclei, coarse chromatin, and prominent nucleoli. Nuclear abnormalities may be subtle in certain cases, such as gastric carcinoma or lobular breast carcinoma. Intracellular mucin, often seen as intracytoplasmic vacuoles, and extracellular mucin may also be present.^2,4 Distinguishing benign and reactive conditions, such as reactive mesothelial cells, from malignancy, including malignant mesothelioma and metastatic carcinoma, can be challenging based on cytology alone due to overlapping cytologic features. Ancillary studies, such as IHC, molecular testing, flow cytometry, and fluorescence in situ hybridization (FISH), are often required to differentiate mesothelial from epithelial origins and identify the primary tumor site in patients with multiple malignancies or an unknown primary.^5,6

Metastatic carcinomas are the most frequently encountered malignancies in serous effusions. Cytologic evaluation, complemented by ancillary techniques and the integration of clinical and radiologic findings, is essential for identifying the primary site, staging, detecting recurrence, and guiding treatment strategies, particularly when serous effusions represent the first indication of occult malignancy. Additionally, cytology slides and cell block preparations enable both prognostic and predictive molecular and biomarker testing, providing valuable insights to guide clinical management. This multimodal approach enhances diagnostic accuracy and informs comprehensive management, ultimately improving patient outcomes.