title: Cyclin D1 as a diagnostic immunomarker for endometrial stromal sarcoma with YWHAE-FAM22 rearrangement.
abstract: Endometrial stromal sarcoma (ESS) characterized by YWHAE-FAM22 genetic fusion is histologically higher grade and clinically more aggressive than ESS with JAZF1-SUZ12 or equivalent genetic rearrangements, hence it is clinically important to recognize this subset of ESS. To identify diagnostic immunomarkers for this biologically defined ESS subset, we compared gene expression profiles between YWHAE-FAM22 ESS and JAZF1-rearranged ESS. These studies showed consistent upregulation of cyclin D1 in YWHAE-FAM22 ESS compared with JAZF1-SUZ12 ESS. Immunohistochemically, the high-grade round cell component of all 12 YWHAE-FAM22 ESS demonstrated diffuse (≥70%) moderate to strong nuclear cyclin D1 staining, and this diffuse positivity was not seen in 34 ESSs with JAZF1 and equivalent genetic rearrangements or in 21 low-grade ESS with no demonstrable genetic rearrangements. In a series of 243 non-ESS pure uterine mesenchymal and mixed epithelial-mesenchymal tumors, only 2 of 8 undifferentiated endometrial sarcomas with nuclear uniformity and 1 of 80 uterine leiomyosarcomas demonstrate diffuse cyclin D1 immunoreactivity. Both cyclin D1-positive undifferentiated endometrial sarcomas showed diffuse strong CD10 staining, which is consistently absent in the high-grade round cell component of YWHAE-FAM22 ESS. The low-grade spindle cell component of YWHAE-FAM22 ESS showed a spatially heterogenous cyclin D1 staining pattern that was weaker and less diffuse overall. Our findings indicate that cyclin D1 is a sensitive and specific diagnostic immunomarker for YWHAE-FAM22 ESS. When evaluating high-grade uterine sarcomas, cyclin D1 can be included in the immunohistochemical panel as an indicator of YWHAE-FAM22 ESS.
authors.affiliation: Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.forename: Rola H
authors.initials: RH
authors.lastname: Ali
authors.forename: Marjan
authors.initials: M
authors.lastname: Rouzbahman
authors.forename: Adrian
authors.initials: A
authors.lastname: Marino-Enriquez
authors.forename: Meijun
authors.initials: M
authors.lastname: Zhu
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Guo
authors.forename: Alayne L
authors.initials: AL
authors.lastname: Brunner
authors.forename: Sarah
authors.initials: S
authors.lastname: Chiang
authors.forename: Samuel
authors.initials: S
authors.lastname: Leung
authors.forename: Nataliya
authors.initials: N
authors.lastname: Nelnyk
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: C
authors.initials: C
authors.lastname: Blake Gilks
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.forename: Esther
authors.initials: E
authors.lastname: Oliva
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Marisa R
authors.initials: MR
authors.lastname: Nucci
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007890:Leiomyosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D018203:Sarcoma, Endometrial Stromal / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis; D014157:Transcription Factors; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C430461:SUZ12 protein, human; D014157:Transcription Factors; C576541:YWHAE-FAM22 fusion protein, human; D019938:Cyclin D1; D063151:Polycomb Repressive Complex 2