Epithelial-Myoepithelial Carcinoma: Frequent Morphologic and Molecular Evidence of Preexisting Pleomorphic Adenoma, Common HRAS Mutations in PLAG1-intact and HMGA2-intact Cases, and Occasional TP53, FBXW7, and SMARCB1 Alterations in High-grade Cases

Am J Surg Pathol. 2018 Jan;42(1):18-27. doi: 10.1097/PAS.0000000000000933.

Abstract

We hypothesized that there is a relationship between the preexisting pleomorphic adenoma [PA]), histologic grade of epithelial-myoepithelial carcinomas (EMCAs), and genetic alterations. EMCAs (n=39) were analyzed for morphologic and molecular evidence of preexisting PA (PLAG1, HMGA2 status by fluorescence in situ hybridization, FISH, and FGFR1-PLAG1 fusion by next-generation sequencing, NGS). Twenty-three EMCAs were further analyzed by NGS for mutations and copy number variation in 50 cancer-related genes. On the basis of combined morphologic and molecular evidence of PA, the following subsets of EMCA emerged: (a) EMCAs with morphologic evidence of preexisting PA, but intact PLAG1 and HMGA2 (12/39, 31%), (b) Carcinomas with PLAG1 alterations (9/39, 23%), or (c) HMGA2 alterations (10/39, 26%), and (d) de novo carcinomas, without morphologic or molecular evidence of PA (8/39, 21%). Twelve high-grade EMCAs (12/39, 31%) occurred across all subsets. The median disease-free survival was 80 months (95% confidence interval, 77-84 mo). Disease-free survival and other clinicopathologic parameters did not differ by the above defined subsets. HRAS mutations were more common in EMCAs with intact PLAG1 and HMGA2 (7/9 vs. 1/14, P<0.001). Other genetic abnormalities (TP53 [n=2], FBXW7 [n=1], SMARCB1 deletion [n=1]) were seen only in high-grade EMCAs with intact PLAG1 and HMGA2. We conclude that most EMCAs arose ex PA (31/39, 80%) and the genetic profile of EMCA varies with the absence or presence of preexisting PA and its cytogenetic signature. Progression to higher grade EMCA with intact PLAG1 and HMGA2 correlates with the presence of TP53, FBXW7 mutations, or SMARCB1 deletion.

MeSH terms

  • Adenoma, Pleomorphic / diagnosis
  • Adenoma, Pleomorphic / genetics
  • Adenoma, Pleomorphic / pathology*
  • Adenoma, Pleomorphic / surgery
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics*
  • DNA-Binding Proteins / genetics
  • Disease-Free Survival
  • F-Box-WD Repeat-Containing Protein 7 / genetics
  • Female
  • Follow-Up Studies
  • HMGA2 Protein / genetics
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • Middle Aged
  • Mutation*
  • Myoepithelioma / diagnosis
  • Myoepithelioma / genetics
  • Myoepithelioma / pathology*
  • Myoepithelioma / surgery
  • Neoplasm Grading
  • Neoplasms, Glandular and Epithelial / diagnosis
  • Neoplasms, Glandular and Epithelial / genetics
  • Neoplasms, Glandular and Epithelial / pathology*
  • Neoplasms, Glandular and Epithelial / surgery
  • Proto-Oncogene Proteins p21(ras) / genetics
  • SMARCB1 Protein / genetics
  • Salivary Gland Neoplasms / diagnosis
  • Salivary Gland Neoplasms / genetics
  • Salivary Gland Neoplasms / pathology*
  • Salivary Gland Neoplasms / surgery
  • Sequence Analysis, DNA
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • HMGA2 Protein
  • PLAG1 protein, human
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)