title: Abnormal p53 and p16 staining patterns distinguish uterine leiomyosarcoma from inflammatory myofibroblastic tumour.
abstract: OBJECTIVE
  Uterine myxoid leiomyosarcoma may show relatively bland histological appearances, despite its aggressive behaviour. Distinguishing uterine leiomyosarcoma from the more indolent inflammatory myofibroblastic tumour (IMT), which is amenable to targeted therapies, can be challenging. A significant subset of leiomyosarcomas harbour TP53 and/or CDKN2A genomic alterations. Here, we examined the diagnostic value of p53 and p16 immunohistochemistry in the distinction of uterine conventional and myxoid leiomyosarcoma from IMT, in correlation with targeted sequencing of TP53 and CDKN2A.
  
  
  RESULTS
  We performed p53 and p16 immunohistochemistry in 49 tumours, including 23 uterine leiomyosarcomas (12 myxoid, 11 conventional) and 26 IMT (12 uterine, 14 extrauterine). TP53 and CDKN2A coding regions were sequenced in 20 cases (four myxoid, 11 conventional uterine leiomyosarcomas; four uterine, one extrauterine IMT). Abnormal p53 staining patterns (strong/diffuse or null) were observed in six of 12 (50%) myxoid and six of 11 (55%) conventional leiomyosarcomas but none of the IMT (P < 0.0001), correlating with TP53 mutation/deletion (P = 0.0001). P16 loss was detected in five of 10 (50%) myxoid and two of 11 (18%) conventional leiomyosarcomas, but none of the IMT (P = 0.0005), correlating with CDKN2A deletion (P = 0.014). Strong/diffuse p16 staining in six of 21 (29%) leiomyosarcomas and three of 26 (12%) IMT did not correlate with CDKN2A alterations.
  
  
  CONCLUSIONS
  Abnormal p53 staining and p16 loss are observed frequently in uterine leiomyosarcomas, with 100% specificity and 70% sensitivity against IMT, and correlating with genomic alterations. Conversely, IMT shows normal p53 and p16 staining, highlighting the use of these markers in the differential diagnosis of uterine mesenchymal neoplasms.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Inga-Marie
authors.initials: IM
authors.lastname: Schaefer
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Quade
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Marisa R
authors.initials: MR
authors.lastname: Nucci
authors.affiliation: Department of Pathology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Carlos
authors.identifier: http://orcid.org/0000-0003-1420-7291
authors.initials: C
authors.lastname: Parra-Herran
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000032:analysis / Q000096:biosynthesis; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007890:Leiomyosarcoma / Q000175:diagnosis*; D012680:Sensitivity and Specificity; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis; D014594:Uterine Neoplasms / Q000175:diagnosis*
chemical_list: D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: immunohistochemistry; inflammatory myofibroblastic tumour; leiomyosarcoma; myxoid leiomyosarcoma; targeted sequencing