Subsets of salivary duct carcinoma defined by morphologic evidence of pleomorphic adenoma, PLAG1 or HMGA2 rearrangements, and common genetic alterations

Abstract

Background We hypothesized that histogenetic classification of salivary duct carcinoma (SDC) could account for de novo cases and those with morphologic or molecular evidence (PLAG1, HMGA2 rearrangement, amplification) of pleomorphic adenoma (PA). Methods SDCs (n=66) were reviewed for morphologic evidence of PA. PLAG1 and HMGA2 alterations were detected by fluorescence in situ hybridization (FISH). PLAG1 positive cases were tested for FGFR1 rearrangement (by FISH). Thirty-nine cases were analyzed by the Ion Ampliseq Cancer HotSpot panel v2 for mutations and copy number variation in 50 cancer-related genes. Results Based on combined morphologic and molecular evidence of PA, four subsets of SDC emerged: 1) carcinomas with morphologic evidence of PA, but intact PLAG1 and HMGA2 (n=22); 2) carcinomas with PLAG1 (n=18), or 3) HMGA2 alteration (n=12); and 4) de novo carcinomas, without morphologic or molecular evidence of PA (n=14). The median disease free survival was 37 months (95% confidence interval, 28.4 – 45.6 months). Disease free survival and other clinicopathologic parameters did not differ by above defined subsets. Combined HRAS/PIK3CA mutations were seen predominantly in de novo carcinomas (5/8 vs 2/31, p = 0.035). ERBB2 copy number gain was not seen in de novo carcinoma (0/8 vs. 12/31, p = 0.08). TP53 mutations were more common in SDC ex PA than in de novo cases (17/31 vs. 1/8, p = 0.033). Conclusion The genetic profile of SDC varies with the absence or presence of pre-existing PA and its cytogenetic signature. Most de novo SDCs harbor combined HRAS/PIK3CA mutations and no ERBB2 amplification.

Carcinoma Ex Pleomorphic Adenoma: Case Report and Options for Systemic Therapy

“…Alterations in PLAG1 and MYC, coded on chromosome 8, have been associated with cxpa [16][17][18] . Potential drivers in 12q include HMGA2 (formerly HMGIC) and MDM2 18,19 . In salivary tumours, p53 mutations are commonly identified, and that identification is consistent in cxpa 20 .…”

Salivary duct carcinoma: An aggressive salivary gland malignancy with opportunities for targeted therapy

“…Interestingly, a high proportion of SDC tumors are found within a benign pleomorphic adenoma; SDC tumors that are also classified as carcinoma ex pleomorphic adenoma may be frequent, with studies reporting evidence of prior pleomorphic adenoma in 20–70% of SDCs [7, 11, 27, 28]. An encapsulated, in situ form of SDC has also been described, characterized by lack of capsular invasion.…”

Salivary Duct Carcinoma: An Update on Morphologic Mimics and Diagnostic Use of Androgen Receptor Immunohistochemistry

“…Currently, based on apocrine morphology, ER-/PR-/ AR + immunoprofile, prevalence and type of mutations, and gene expression pattern apocrine SDC appears to resemble one subtype of breast carcinoma-"luminal AR-positive/molecular apocrine" [4,[25][26][27]. The practical value of such similarity is uncertain, as significant differences between the "luminal AR-positive/molecular apocrine" type of breast carcinomas and SDC remain (e.g., HMGA2 or PLAG1 rearrangements in a subset of SDCs ex pleomorphic adenoma) [26].…”

“…Salivary duct carcinoma de novo (with known intact PLAG1 and HMGA2) with anaplastic change and HRAS, PIK3CA, and TP53 deletion/frame shift mutations[26]. a About 90% of salivary duct carcinoma was represented by conventional component with cribriform and solid growth (left half of the image), while the minor component was represented by more bizarre discohesive cells with more prominent nuclear pleomorphism and hyperchromasia (right), H&E, 200x.…”

“…The practical value of such similarity is uncertain, as significant differences between the "luminal AR-positive/molecular apocrine" type of breast carcinomas and SDC remain (e.g., HMGA2 or PLAG1 rearrangements in a subset of SDCs ex pleomorphic adenoma) [26].…”