title: Subsets of salivary duct carcinoma defined by morphologic evidence of pleomorphic adenoma, PLAG1 or HMGA2 rearrangements, and common genetic alterations.
abstract: BACKGROUND
  The authors hypothesized that histogenetic classification of salivary duct carcinoma (SDC) could account for de novo tumors and those with morphologic or molecular evidence (pleomorphic adenoma gene 1 [PLAG1], high-mobility group AT hook 2 [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 tumors were tested by FISH for fibroblast growth factor receptor 1 (FGFR1) rearrangement. Thirty-nine tumors were analyzed using a commercial panel for mutations and copy number variations in 50 cancer-related genes.
  
  
  RESULTS
  On the basis of combined morphologic and molecular evidence of PA, 4 subsets of SDC emerged: 1) carcinomas with morphologic evidence of PA but intact PLAG1 and HMGA2 (n = 22); 2) carcinomas with PLAG1 alteration (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 for the subsets defined above. Combined Harvey rat sarcoma viral oncogene homolog/phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit α (HRAS/PIK3CA) mutations were observed predominantly in de novo carcinomas (5 of 8 vs 2 of 31 tumors; P = .035). Erb-B2 receptor tyrosine kinase 2 (ERBB2) copy number gain was not observed in de novo carcinomas (0 of 8 vs 12 of 31 tumors; P = .08). Tumor protein 53 (TP53) mutations were more common in SDC ex pleomorphic adenomas than in de novo carcinomas (17 of 31 vs 1 of 8 tumors; P = .033).
  
  
  CONCLUSIONS
  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. Cancer 2016;122:3136-44. © 2016 American Cancer Society.
authors.affiliation: Depatment of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. chioseasi@upmc.edu.
authors.forename: Simion I
authors.initials: SI
authors.lastname: Chiosea
authors.affiliation: Department of Pathology, Southern California Permanente Medical Group, Woodland Hills, California.
authors.forename: Lester D R
authors.identifier: http://orcid.org/0000-0003-3714-1432
authors.initials: LD
authors.lastname: Thompson
authors.affiliation: Department of Pathology, University Health Network, Toronto, Ontario, Canada.
authors.forename: Ilan
authors.initials: I
authors.lastname: Weinreb
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Bauman
authors.affiliation: Depatment of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Alyssa M
authors.initials: AM
authors.lastname: Mahaffey
authors.affiliation: Depatment of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Caitlyn
authors.initials: C
authors.lastname: Miller
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Robert L
authors.identifier: http://orcid.org/0000-0001-6605-2071
authors.initials: RL
authors.lastname: Ferris
authors.affiliation: Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: William E
authors.initials: WE
authors.lastname: Gooding
mesh_terms: D008949:Adenoma, Pleomorphic / Q000175:diagnosis* / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D044584:Carcinoma, Ductal / Q000145:classification / Q000175:diagnosis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D003937:Diagnosis, Differential; D005260:Female; D005500:Follow-Up Studies; D015321:Gene Rearrangement; D014644:Genetic Variation / Q000235:genetics*; D025743:HMGA2 Protein / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D012468:Salivary Gland Neoplasms / Q000145:classification / Q000175:diagnosis* / Q000235:genetics; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D025743:HMGA2 Protein; C104382:PLAG1 protein, human
keywords: malignant transformation; next-generation sequencing; pleomorphic adenoma; salivary; salivary duct carcinoma