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Epithelial-Myoepithelial Carcinoma

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Epithelial-Myoepithelial Carcinoma ORIGINAL ARTICLE 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 Soufiane El Hallani, MD, PhD,* Aaron M. Udager, MD, PhD,† Diana Bell, MD,‡ Isabel Fonseca, MD,§ Lester D.R. Thompson, MD,∥ Adel Assaad, MD,¶ Abbas Agaimy, MD,# Alyssa M. Luvison, BS,* Caitlyn Miller, BS,* Raja R. Seethala, MD,* and Simion Chiosea, MD* cytogenetic signature. Progression to higher grade EMCA with Abstract: We hypothesized that there is a relationship between intact PLAG1 and HMGA2 correlates with the presence of TP53, the preexisting pleomorphic adenoma [PA]), histologic grade FBXW7 mutations, or SMARCB1 deletion. of epithelial-myoepithelial carcinomas (EMCAs), and genetic alterations. EMCAs (n = 39) were analyzed for morphologic and Key Words: epithelial-myoepithelial carcinoma, carcinoma ex molecular evidence of preexisting PA (PLAG1, HMGA2 status pleomorphic adenoma, PLAG1, HMGA2 fl by uorescence in situ hybridization, FISH, and FGFR1-PLAG1 (Am J Surg Pathol 2018;42:18–27) 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 pithelial-myoepithelial carcinoma (EMCA) is a salivary combined morphologic and molecular evidence of PA, the following tumor with dual cell population: luminal ductal cells and subsets of EMCA emerged: (a) EMCAs with morphologic evidence E outer myoepithelial cells, classically with clear cytoplasm.1–4 of preexisting PA, but intact PLAG1 and HMGA2 (12/39, 31%), EMCA was initially described by Donath et al4 and was (b) Carcinomas with PLAG1 alterations (9/39, 23%), or (c) HMGA2 previously referred to as adenomyoepithelioma, clear cell alterations (10/39, 26%), and (d) de novo carcinomas, without adenoma, or carcinoma. Although rare cases of high-grade morphologic or molecular evidence of PA (8/39, 21%). Twelve high- EMCA have been reported,3,5–8 most commonly, EMCAs grade EMCAs (12/39, 31%) occurred across all subsets. The median are low-grade tumors and have to be distinguished from disease-free survival was 80 months (95% confidence interval, 77-84 pleomorphic adenoma (PA). Infiltrative growth, sharp mo). Disease-free survival and other clinicopathologic parameters demarcation from hypocellular hyalinized stroma, re- did not differ by the above defined subsets. HRAS mutations were traction (split) artifact between the ductal and abluminal more common in EMCAs with intact PLAG1 and HMGA2 (7/9 vs. myoepithelial cells are characteristic of EMCA. Such 1/14, P < 0.001). Other genetic abnormalities (TP53 [n = 2], FBXW7 histologic findings form distinct areas when EMCA arises in [n = 1], SMARCB1 deletion [n = 1]) were seen only in high-grade a PA and help to distinguish EMCA from a merely cellular EMCAs with intact PLAG1 and HMGA2. We conclude that most PA. Although, in practice, EMCA often has to be EMCAs arose ex PA (31/39, 80%) and the genetic profile of distinguished from PA, the prevalence of preexisting PA in EMCA varies with the absence or presence of preexisting PA and its EMCA is unknown. PA was the first benign human epithelial neoplasm From the *Department of Pathology, University of Pittsburgh Medical to be shown to harbor recurrent cytogenetic abnormalities, Center, Pittsburgh, PA; †Department of Pathology, Michigan Med- that is, rearrangements involving Pleomorphic Adenoma Gene 1 icine, Ann Arbor, MI; ‡Department of Pathology, The University of 9,10 Texas MD Anderson Cancer Center, Houston, TX; §Pathological (PLAG1)andHigh Mobility Group A2 (HMGA2). It has Anatomy Institute, Faculdade de Medicina, Universidade de Lisboa been recognized that there are several cytogenetically defined & Serviço de Anatomia Patológica, Instituto Português de Oncologia groups of PA, including those with PLAG1 or HMGA2 Francisco Gentil, Lisboa, Portugal; ∥Department of Pathology, rearrangements (in up to 40%). PLAG1 and HMGA2 status, Southern California Permanente Medical Group, Woodland Hills, CA; therefore, may complement morphology in identifying carci- ¶Department of Pathology, Virginia Mason Hospital, Seattle, WA; 11–13 and #Institute of Pathology, University Hospital, Erlangen, Germany. nomas ex PA. Conflicts of Interest and Source of Funding: The authors have disclosed The genetic events leading to an EMCA likely that they have no significant relationships with, or financial interest depend on the precursor lesion (ie, PA or intercalated in, any commercial companies pertaining to this article. duct hyperplasia14) and may involve alterations of Correspondence: Simion Chiosea, MD, UPMC, Presbyterian University Hospital, A610-2, 200 Lothrop St, Pittsburgh, PA 15213 TP53 and Harvey rat sarcoma viral oncogene homolog (e-mail: [email protected]). (HRAS). Up to 33% of EMCAs may harbor HRAS Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. codon 61 mutations.15,16 18 | www.ajsp.com Am J Surg Pathol Volume 42, Number 1, January 2018 Copyright r 2018 Wolters Kluwer Health, Inc. All rights reserved. Am J Surg Pathol Volume 42, Number 1, January 2018 Salivary Epithelial-Myoepithelial Carcinoma Here, we aimed to determine the prevalence of Clara, CA). Subsequently, the multiplexed barcoded libraries preexisting PA in a series of EMCAs, characterize the were enriched by clonal amplification using emulsion PCR frequency of PLAG1 and HMGA2 abnormalities, correlate on templated Ion Sphere Particles and loaded on Ion 318 PLAG1 and HMGA2 status with clinicopathologic features, Chip. Massively parallel sequencing was carried out on an and, finally, to characterize the relationship between the Ion Torrent Personal Genome Machine sequencer (Life presence of preexisting PA and mutations and copy number Technologies, Carlsbad, CA) using the Ion Personal Genome variations in 50 cancer-related genes. Machine Sequencing 200 Kit version 2 according to the manufacturer’s instructions. After a successful sequencing MATERIALS AND METHODS reaction, the raw signal data were analyzed using Ion Torrent platform-optimized Torrent Suite version 4.0.2 (Life Tech- Patients and Histologic Review nologies). The short sequence reads were aligned to the hu- This study was approved by the Institutional Review man genome reference sequence (GRCh37/hg19). Variant Board (IRB991206). Tumors were categorized as follows: calling was performed using Variant Caller version 4.0 plugin conventional (low grade by definition) EMCA, oncocytic, (integrated with Torrent Suite) that generated a list of de- and apocrine variants,3,17 EMCA ex PA, and high-grade tected sequence variations in a variant calling file (VCF EMCA. Conventional EMCAs were characterized by dual version 4.1; http://www.1000genomes.org/wiki/analysis/ cell population with about 1:1 ratio of outer myoepithelial variant%20call%20format/vcf-variant-call-format-version- cells to inner luminal ductal cells. High-grade EMCA was 41). The variant calls were annotated, filtered and priori- defined by areas with the predominance (overgrowth) of tized using SeqReporter,19 an in-house knowledgebase and either myoepithelial or epithelial components with necrosis the following publically available databases; COSMIC v68 and nuclear pleomorphism.5,6 Chondroid or myxoid stroma (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/ with benign ductal elements and hyalinized (to variable ), dbSNP build 137 (http://www.ncbi.nlm.nih.gov/SNP/), extent) hypocellular nodules were both accepted as mor- in silico prediction scores (PolyPhen-2 and SIFT) from phologic evidence for preexisting PA. Clinicopathologic dbNSFP light version 1.3.20 Sequence variants with at features of 13 cases were previously reported by Fonseca least 300× depth of coverage and mutant allele frequency et al2 and 6 cases were included in prior studies by our of > 5% of the total reads were included for analysis. Copy group.3,8,16,17 Tumors were staged according to the 7th number variations and gene fusions were identified by edition of the American Joint Committee on Cancer.18 NGS as described previously.21,22 Immunohistochemistry Statistical Analyses Immunohistochemical staining for SMARCB1/INI- Demographic and clinical comparison among subsets of 1 was performed with antibody from BD Transduction EMCA was conducted with the Wilcoxon test for continuous 2 Laboratories, clone 25/BAF47, San Jose, CA. data and the Fisher exact test or a χ test for discrete data. Disease-free survival (DFS) was analyzed with a log rank test. Fluorescence In Situ Hybridization A P-value of <0.05 was considered significant. PLAG1 and HMGA2 rearrangements were detected by break-apart fluorescence in situ hybridization (FISH) probes RESULTS (Empire Genomics, Buffalo, NY). Hyperploidy or amplifica- The clinicopathologic parameters of 39 patients with tion (centromeric enumeration probes were not used) was EMCA are summarized in Tables 1 and 2. Two thirds defined as presence of > 2 signals in > 75% of cells. To detect copy number alterations of the SMARCB1 (INI-1) gene locus, FISH was performed using the ZytoLight SPEC SMARCB1/ TABLE 1. Clinicopathologic Features of Patients With EMCA 22q12 Dual Color Probe, which is a mixture of a green Sex, Female (n/N [%]) 25/39 (64) fluorochrome direct labeled SPEC SMARCB1 probe hybrid- Age (mean [range]) (y) 66 (19-87) izing to the human SMARCB1 gene in the chromosomal Anatomic site (n [%]) fl Parotid gland 22 (57) region 22q11.23 and
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