May 2021 – Surgical Pathology

The correct answer is: DOG1.

The entity shown above is high-grade acinic cell carcinoma, a malignant epithelial neoplasm of serous acinar cells and other cell types. This tumor often features a combination of architectural patterns, including solid, microcystic, papillary cystic, and follicular. Most of the cells seen in this case were serous acinar cells, but acinic cell carcinoma can also contain intercalated duct cells, vacuolated cells, and clear cells. Acinic cell carcinoma generally has a good prognosis, with a 5-year survival rate of 90%, and complete surgical excision is the treatment of choice. However, as in our patient, local recurrence can occur in approximately 35% of cases. 

Immunohistochemistry specific for acinic cell carcinoma include DOG1 and NR4A3. DOG1 has a delicate membrane reaction, and NR4A3 has highly specific and strong nuclear staining. In fact, the most common oncogenic driver of acinic cell carcinoma is the overexpression of NR4A3, which can result from the t(4;9)(q13;q31) translocation. This translocation (which occurs in 80% of cases) moves the enhancer region from the SCCP gene to upstream of NR4A3, resulting in its overexpression. Another newly identified mechanism of NR4A3 overexpression is a result of the upregulation of the MYB gene, which mostly occurs in high-grade acinic cell carcinoma. Acinic cell carcinoma can also show patchy PAS+ and diastase-resistant zymogen granules.

Positive staining for mammoglobin occurs in secretory carcinoma. This entity can have a variety of architectural patterns (cystic to microcystic) and intraluminal secretions, as in acinic cell carcinoma, but typically the cytology is very uniform and the cytoplasm is much more pale. Acinic cell carcinoma is mammoglobin negative.

Positive staining for synaptophysin occurs in neuroendocrine carcinoma. Like our high-grade acinic cell carcinoma, this entity often forms sheets and nests. However, acinic cell carcinoma lacks the cytologic features that we would expect from a neuroendocrine tumor and is negative for synaptophysin. Positive staining for p63 occurs in adenoid cystic carcinoma and mucoepidermoid carcinoma. Like our high-grade acinic cell carcinoma, adenoid cystic carcinoma is very basaloid and can show cribriform or solid architecture, but we would expect to see myoepithelial cells with angulated nuclei, which are not present. Mucoepidermoid carcinoma can display a microcystic pattern, like our tumor, but would be composed of a mix of squamous, mucinous, and intermediate cells, not serous acinar cells. 

References

• Haller, F., Bieg, M., Will, R. et al. Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands. Nat Commun. 2019;10(1):368.
• Haller, F., Skálová, A., Ihrler, S., et al. Nuclear NR4A3 Immunostaining Is a Specific and Sensitive Novel Marker for Acinic Cell Carcinoma of the Salivary Glands. Am J Surg Pathol. 2019;43(9):1264-1272. 
• Lee, D. Y., Brayer, K. J., Mitani, Y., et al. Oncogenic Orphan Nuclear Receptor NR4A3 Interacts and Cooperates with MYB in Acinic Cell Carcinoma. Cancers. 2020;12(9):2433.
• Thompson L. D. Salivary gland acinic cell carcinoma. Ear, nose, & throat journal. 2010;89(11):530–532.