12q Amplification Characterizes a Distinctive Salivary Gland Tumor with Bizarre Myoepithelial Atypia

Background: Over the past two decades, an increased understanding of molecular alterations has greatly refined salivary gland tumor classification. Many tumors that were previously difficult or impossible to classify have been recognized to represent emerging entities based on shared histologic, immunophenotypic and molecular characteristics. While initial attention was given to carcinomas, more recently molecular discoveries have shed light on salivary gland adenomas as well. We present a series of biphasic salivary gland tumors characterized by striking bizarre myoepithelial atypia, unified at the genetic level by evidence of 12q amplification. Methods: Salivary gland tumors demonstrating bizarre but degenerative-appearing atypia were identified. Immunohistochemistry, MDM2 and HMGA2 fluorescence in situ hybridization (FISH), and/or targeted next-generation sequencing (NGS) were attempted on the cases. Results: Seven cases were identified. The tumors arose in the parotid gland (3 of 7), oral cavity (3 of 7) and submandibular gland (1 of 7). The patients were 5 women and 2 men, ranging from 53 to 83 years (mean, 65.7 years). Histologically, the tumors appeared well-circumscribed and partially encapsulated. They were highly cellular and solid, with no chondromyxoid stromal component. The tumors were biphasic, with a population of eosinophilic ducts in a background of basaloid cells with variable clear cell change and spindling. The most striking feature in all cases was the presence of scattered cells with bizarrely atypical nuclei with smudgy chromatin. These bizarre cells maintained low nuclear:cytoplasmic ratios and lacked mitotic activity. The biphasic nature of the tumors was demonstrated by the basaloid cells staining with S100, p63 and p40, while the ducts were positive for CD117 and AE1/AE3 (strong). The bizarre cells had a myoepithelial immunophenotype. The Ki67 index ranged from 1 to 10%, with most of the markedly atypical cells not labeling. DNA NGS was successful in 4 cases, demonstrating 12q copy number increase and 5q copy number loss in all 4 cases. RNA sequencing was able to identify increased MDM2 and HMGA2 expression in one additional case, while amplification of MDM2 and/or HMGA2 was also demonstrated in 6 of 7 cases by FISH. In summary, all 7 cases exhibited evidence of 12q amplification by at least one technique. Conclusion: Salivary gland neoplasms with bizarre myoepithelial atypia are consistently associated with evidence of 12q amplification. Although this histologic alteration may be alarming, the smudgy nature of the chromatin and paucity of mitotic activity and Ki67 labeling suggest that this finding may not necessarily be indicative of malignancy.