Usually, Warthin tumor and mucoepidermoid carcinoma (MEC) are not considered in the same differential diagnosis. Warthin tumor accounts for 25-32% of benign parotid gland tumors, is associated with smoking, and can occur bilaterally. This neoplasm has a 2:1 male predominance with a mean age of 59.5 years and does not have a clear genetic association. However, this benign tumor can have squamous and mucinous metaplasia, especially in the context of prior trauma including inflammation, infarction, or following a fine needle aspiration biopsy. Patients with Warthin tumor are managed with clinical follow up and only undergo excision if the procedure is desired by the patient or if the tumor is slowly enlarging and causing discomfort. On the other hand, MEC is a rare malignant salivary gland neoplasm. It occurs over a wide age range with an average age of 46.2 years, and has a slight female predominance. MEC displays a wide morphologic spectrum and is composed of varying proportions of mucous, squamoid, and intermediate cells with columnar, clear cell, and oncocytic/apocrine changes. A large proportion of MEC shows a CRTC1/CRTC3-MAML2 fusion, which is specific for MEC. A small subset of MEC can appear bland and have “Warthin-like” morphologic features. However, patients with MEC are managed much differently and may undergo resection with possible neck dissection or radiation. The morphologic distinction between Warthin tumor and Warthin-like MEC can be challenging. Similar to Warthin tumor, Warthin-like MEC has oncocytic epithelial cells and a prominent stroma. However, unlike the bilayered epithelium overlying lymphoid stroma as seen in classic Warthin tumor, the epithelial cells in MEC are more disorganized, have multiloculated cysts, and mucinous cells. To confirm Warthin-like MEC, MAML2 FISH testing can performed on the cell block to confirm the diagnosis of MEC, as in the presented case.

A recent study evaluated 57 cases of salivary gland FNA and reported the detection of gene rearrangements based on FISH testing from the cell block material in 15 cases. These findings support that FISH testing performed on cytology cell block material can be a useful diagnostic tool in challenging salivary gland FNA. The cell blocks, made from 3-5 FNA biopsy passes, provide sufficient diagnostic tissue for this test to be feasible. Testing for MAML2 FISH should be considered when a young patient, non-smoker, appears to have a Warthin tumor, or if there are any mucous and areas that deviate from the classic Warthin tumor appearance.

The differential diagnosis for this case also includes oncocytic cystadenoma, oncocytoma, acinic cell carcinoma, metastatic renal cell carcinoma, and salivary duct carcinoma. Diffuse p63 nuclear staining could be a helpful marker for the differentiation of oncocytic MEC from most of its mimickers. The benign oncocytic tumors including oncocytic cystadenoma and oncocytoma lack evidence of infiltrative growth. Oncocytic cystadenoma is characterized by papillary proliferations lined by a single or two layers of epithelial cells. Oncocytomas are solid tumors and have peripheral p63 staining only. Acinic cell carcinoma, metastatic renal cell carcinoma, and salivary duct carcinoma are generally negative for p63 staining. Acinic cell carcinoma is composed of serous acinar cells and the cytoplasmic granules are highlighted by PAS-positive diastase resistant histochemical stain. Metastatic renal cell carcinoma displays an infiltrative growth and is characterized by a pseudoalveolar pattern with prominent admixed vasculature, some nuclear pleomorphism, clear cytoplasm, and prominent intercellular membranes. And lastly, salivary duct carcinoma morphologically resembles high grade ductal carcinoma in situ of the breast and characteristically expresses androgen receptor on immunohistochemistry.

In summary, mucoepidermoid carcinoma displays a wide morphologic spectrum and can show significant overlap with Warthin tumor. FISH testing for MAML2 rearrangement is diagnostic of mucoepidermoid carcinoma and can be performed on cytology cell blocks.