Answer: Parotid clear cell carcinoma, NOS

Histology: The tumor is comprised of interconnecting nests of monotonous cells portioned by a pauci-cellular fibrotic stroma. The cytoplasmic qualities vary from eosinophilic to clear. The nuclei are uniformly small, dark and without nucleoli. Mitotic figures are not identified. The fibrous septa show varying degrees of hyalinization. A special stain is negative for mucin production. By immunohistochemistry, the tumor cells are strongly positive for AE1/AE3, CK5/6 and p63; and they are negative for calponin, S100, RCC and PAX8. A chromosomal translocation resulting in an EWSR1-ATF1 fusion is detected by genetic analysis.

Discussion: Clear cell carcinoma, not otherwise specified (current WHO classification), formerly designated as hyalinizing clear cell carcinoma, is a low grade carcinoma of salivary gland origin characterized by optical clearing of the tumor cells. Although diagnostic terminology draws attention to its hyalinized stromal component, this feature is developed to varying degrees among tumors and even within the same tumor. As many other salivary gland tumors exhibit cytoplasmic clearing, hyalinizing clear cell carcinoma is generally a diagnosis by exclusion. For example, absence of cytoplasmic mucin (mucicarmine stain) helps exclude a clear cell predominant mucoepidermoid carcinoma. Most problematic of all is the distinction of clear cell carcinoma from a clear cell variant of a myoepithelial neoplasm. This distinction usually requires immunohistochemical analysis. Unlike most myoepithelial neoplasms, hyalinizing clear cell carcinomas tend to be negative or only weakly positive for S100 and smooth muscle actin. Rather than myoepithelial differentiation, clear cell carcinomas tend to show expression along squamous lines. These tumors are consistently positive for p63 and CK5/6 by immunohistochemistry; and, at the ultrastructural level, exhibit tight junctions, desmosomal attachments and basal lamina.

Recently, a novel fusion of EWSR1-ATF1 has been detected in almost all clear cell carcinomas. Detection of the EWSR1-ATF1 alteration can be very helpful in establishing the diagnosis, particularly when a tumor may deviate from the more classic description of its histologic appearance (e.g. absence of stromal hyalinization). The current case is a case in point. Here, the diagnosis is elusive on microscopic grounds due to the fact that cytoplasmic clearing is not well developed throughout the entire tumor. Despite the absence of prominent cytoplasmic clearing, the tumor was found to harbor the EWSR1-ATF1 translocation.

Clear cell carcinomas are low grade neoplasms. This low grade character is certainly reflected at the microscopic level. Despite their squamoid appearance, the tumor cells lack the malignant features of a true squamous cell carcinoma. Clinically, clear cell carcinomas rarely metastasize to regional lymph nodes, and they do not behave in an aggressive clinical fashion.