Discussion

Secretory carcinoma, previously termed mammary analogue secretory carcinoma, is a relatively rare low-grade malignancy of the salivary gland, accounting for ~5% of the salivary gland tumors. It is characteristically defined by the ETV6::NTRK3 gene fusion resulting from a t(12;15)(p13;q25) translocation. Approximately 75% of cases arise in the parotid gland, with the remainder arising from the oral cavity, submandibular gland, and minor salivary glands. Secretory carcinomas usually occur in adults with a relatively equal sex distribution. It is generally an indolent malignancy with ~15% risk of local recurrence and ~20% risk of metastasis to lymph nodes. Distant metastases are uncommon and rare instances of high-grade transformation have been observed.

Salivary gland neoplasms can be classified as monophasic or biphasic depending on their cellular components. Biphasic tumors, such as pleomorphic adenoma, adenoid cystic carcinoma, and myoepithelial epithelial carcinoma, originate from both luminal cells (acinar/ductal epithelial cells) and abluminal cells (myoepithelial/basal cells). Monophasic tumors, such as secretory carcinoma, myoepithelioma, salivary duct carcinoma, and acinic cell carcinoma, have only one cell of origin. Given the lack of myoepithelial/basal cells, secretory carcinoma is negative for p40, p63, and calponin. However, biphasic tumors can show an attenuated basal cell layer, especially in scant cell block specimens, and may present a challenge in FNA specimens.

Prior to being recognized as a separate entity, secretory carcinoma was classified as acinic cell carcinoma due to their many shared cytomorphologic features. Ancillary studies are useful in distinguishing these two entities. By immunohistochemistry, secretory carcinoma is positive for mammaglobin, S100, SOX10, and GATA3, and negative for DOG1, whereas acinic cell carcinoma is positive for DOG1 (apical membranous staining pattern around lumina) and demonstrates characteristic PAS-positive diastase-resistant cytoplasmic zymogen granules. Molecular studies with demonstration of the hallmark ETV6::NTRK3 fusion confirms the diagnosis of secretory carcinoma.

ETV6::NTRK3 fusion is also a defining molecular feature in infantile fibrosarcoma, secretory carcinoma of breast, and cellular congenital mesoblastic nephroma. Identification of this gene fusion is increasingly significant with ongoing development of selective TRK inhibitors.

Other salivary gland neoplasms harbor recurrent molecular alterations which serve as useful diagnostic markers that can be demonstrated by molecular studies, such as fluorescent in situ hybridization (FISH) or next generation sequencing (NGS). Pleomorphic adenomas demonstrate rearrangements involving PLAG1 encoded on 8q12 or the less common HMGA2 encoded on 12q14.3. Mucoepidermoid carcinomas most commonly harbor CRTC1::MAML2 fusions resulting from the t(11;19)(q21;p13) translocation. Approximately half of all adenoid cystic carcinomas have a t(6;9)(q22-23;p23-24) translocation resulting in a MYB::NFIB fusion. The very rare low-grade salivary gland neoplasm hyalinizing clear cell carcinoma is characterized by a EWSR1::ATF1 fusion secondary to a t(12;22)(q13;q12) translocation.

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