The absence of metastatic breast cancer and the concern of an atypical mesothelial proliferation were communicated to the clinician. The follow up revealed a left pleural thickening by computed tomography at an outside hospital. The definitive diagnosis of mesothelioma was made by a surgical pleural biopsy showing the presence of tissue invasion.

Although the cytomorphologic atypia in this pleural effusion specimen was only mild, metastatic breast cancer was initially considered because metastatic breast carcinoma in effusions commonly demonstrates a so-called cannonball pattern of large three dimensional cell clusters and paradoxical bland cytomorphology. The immunoprofile excluded breast carcinoma and proved a mesothelial lineage.

Distinguishing reactive mesothelial cells from malignant mesothelioma is extremely challenging by cytologic examination alone. Hjerpe et al summarized the cytomorphologic criteria indicating malignant mesothelioma including a highly cellular specimen with numerous tissue fragments, cell size larger than normal mesothelial cells in each cellular component, and nuclear criteria of malignancy, among others. [1]However, in reality most cytopathologists would be very reluctant to make a diagnosis of malignant mesothelioma by effusion cytomorphology in a patient without a past history or clinical suspicion. Of course, a clinical history of asbestos exposure, imaging finding of pleural thickening, and unilateral pleural effusion along with an atypical population of mesothelial cells would further raise the concern for malignant mesothelioma. This case was originally signed out as “Atypical Mesothelial Proliferation” due to lack of the previously mentioned clinical history and the specimen was sent for ancillary testing.

Ancillary testing is becoming increasingly helpful in differentiating malignant from reactive mesothelial cells. Some authors advocate using an IHC staining panel of negative Desmin and positive EMA in helping the diagnosis of malignant mesothelioma; however, the results are not consistently useful. Currently, BAP1 IHC and p16 FISH are considered the two most reliable markers for malignant mesothelioma in cytology specimens. [2, 3] BAP1 is a tumor suppressor gene that is lost in malignant mesotheliomas. Loss of BAP1 can be a useful adjunct to support the diagnosis of malignant mesothelioma; however, intact BAP1 does not exclude malignancy. [2, 4] McGregor et al found patchy loss of BAP1 in benign lesions and caution over interpretation in small samples. [5]  p16 is a cell cycle suppressor. Deletion of p16 is not pathognomonic for malignant mesotheliomas, but fairly specific if the mesothelial lineage is determined.  Loss of p16 has not been found in benign effusions.[6]  Like BAP1, a negative result does not rule out the possibility of malignant mesothelioma. [2] These two tests, along with an appropriate clinical history and morphologic features increase the cytologic diagnostic accuracy for malignant mesotheliomas. This patient’s pleural effusion specimen showed intact BAP1 and loss of p16 by FISH, supporting a diagnosis of malignant mesothelioma.