title: Comprehensive screening for MED12 mutations in gynaecological mesenchymal tumours identified morphologically distinctive mixed epithelial and stromal tumours.
abstract: OBJECTIVE
  MED12 exon 2 mutations have been identified in most uterine leiomyomas and mammary fibroepithelial tumours. MED12 has not been genotyped in most other gynaecological mesenchymal tumours. The purpose of this study was to determine the prevalence of MED12 mutations in uncommon gynaecological mesenchymal tumours.
  
  
  RESULTS
  Sixty-eight uncommon gynaecological mesenchymal tumours were genotyped for MED12 exon 2, including 27 Müllerian adenosarcomas (including three tentatively diagnosed as 'variant adenosarcomas'), six cellular angiofibromas, six aggressive angiomyxomas, five angiomyofibroblastomas, five superficial myofibroblastomas, five atypical polypoid adenomyomas, and 14 endometrial stromal sarcomas. Immunohistochemistry for CD10, myogenic markers, hormone receptors, MDM2, and CDK4, and fluorescence in-situ hybridization (FISH) for JAZF1, PHF1 and YWHAE rearrangement, were performed on selected cases. The three 'variant adenosarcomas' harboured MED12 exon 2 mutations (including p.L36R hotspot mutation, recurrent p.L39_A50del, and a novel splice site mutation). Three endometrial stromal sarcomas with JAZF1-SUZ12 or JAZF1-PHF1 fusion harboured unprecedented mutations (p.D54G in two, and p.Q48* in one). All remaining tumours were wild-type. The three MED12-mutated 'variant adenosarcomas' showed distinctive morphological features, including 'fibromyomatous' cytomorphology, a close association with adenomyosis, clustered thick-walled vessels, focal conspicuous hyalinization, and intralymphovascular tumour growth. Features of conventional adenosarcomas, including nuclear atypia, mitotic activity, periglandular condensation, and phyllodes-like architecture, were inconspicuous. All three cases showed immunoreactivity for desmin and hormone receptors, while being negative for MDM2 and CDK4; they showed no JAZF1, PHF1 or YWHAE rearrangement. Despite deep myoinvasion, these tumours followed an indolent clinical course.
  
  
  CONCLUSIONS
  These MED12-mutated adenosarcoma-like tumours might represent a distinct entity that requires more studies for its identification. MED12 exon 2 mutations seemed to have no significant role in other uncommon gynaecological mesenchymal tumours.
authors.affiliation: Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chang-Tsu
authors.initials: CT
authors.lastname: Yuan
authors.affiliation: Department of Pathology, Far-Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Wen-Chih
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Pathology, British Columbia Cancer Agency, Vancouver, British Columbia.|University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Ming-Chieh
authors.initials: MC
authors.lastname: Lin
authors.affiliation: Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Chen-Hui
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Chien
authors.initials: YC
authors.lastname: Kao
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
authors.affiliation: Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Kuan-Ting
authors.initials: KT
authors.lastname: Kuo
authors.affiliation: Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Jen-Chieh
authors.identifier: http://orcid.org/0000-0001-7739-5934
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D005833:Genital Neoplasms, Female / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D061346:Laser Capture Microdissection; D056892:Mediator Complex / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D018204:Neoplasms, Connective and Soft Tissue / Q000235:genetics*; D016133:Polymerase Chain Reaction; D055815:Young Adult
chemical_list: C460107:MED12 protein, human; D056892:Mediator Complex
keywords: MED12; adenosarcoma; endometrial stromal sarcoma; gynaecological mesenchymal tumour