Introduction: Metastatic melanoma (MM) is an uncommon finding in serous effusion specimens with a highly variable cytomorphology. Methods: We reviewed specimens submitted over a 19-year period to determine (a) the range of cytologic findings in effusion specimens from melanoma patients and (b) the cytologic presentation and immunoprofile of MM in effusion specimens. Results: Of 123 serous effusion specimens from patients with clinical notes of melanoma, 59% were reported negative for malignancy, 16% were reported with a non-melanoma malignancy, 19% MM, and 6% atypical, MM not excluded. Pleural fluids were twice as likely to be reported as MM than peritoneal samples. Review of 44 cases with confirmed MM showed the most common cytologic pattern was epithelioid. Most (88%) cases contained mainly dispersed plasmacytoid cells, but many (61%) also contained malignant cells arranged in loose groups. Rare cases also had spindle cells, giant bizarre cells, small lymphoid-like cells, or cells with large hard-edged vacuoles, mimicking other metastatic malignancies. MM cases containing predominantly plasmacytoid cells often mimicked reactive mesothelial cells. As well as being composed of cells of similar size, features such as bi- and multinucleation, round nuclei, mild anisokaryosis, nucleoli, and loose groups were common to both. Features seen more commonly in MM than reactive cells included large nucleoli (95%) and intranuclear cytoplasmic inclusions (41%), binucleate “bug-eyed demons,” and small punctate vacuoles on the air-dried preparations. Pigment was identified in 36% of cases. Immunohistochemistry (IHC) is a valuable aid in confirming the cell type. The sensitivity for the most commonly used melanoma markers was as follows: S100 84% (21/25), pan-melanoma 100% (19/19), HMB45 92% (11/12), Melan A 92% (11/12), SOX10 91% (10/11). No staining was reported for calretinin (0/21), AE1/AE3 (0/11), EMA (0/16), Ber-Ep4 (0/13). Discussion: Effusion specimens from patients with a history of melanoma are frequently (40%) malignant but almost as likely to be reported as a nonmelanoma malignancy as MM. The cytology of MM may mimic a wide range of other metastatic malignancies but also often closely resembles reactive mesothelial cells. It is important to be aware of this latter pattern so that IHC markers can be applied.

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