title: Microcystic Stromal Tumor: A Distinctive Ovarian Sex Cord-Stromal Neoplasm Characterized by FOXL2, SF-1, WT-1, Cyclin D1, and β-catenin Nuclear Expression and CTNNB1 Mutations.
abstract: Since our first description of the microcystic stromal tumor (MST) of the ovary, a rare and distinctive neoplasm with a definitional, usually striking microcystic pattern and a CD10+/vimentin+/inhibin-/calretinin- immunophenotype, 3 examples with β-catenin nuclear localization, and CTNNB1 mutation have been reported. We undertook a detailed immunohistochemical study and molecular analysis of CTNNB1 and FOXL2 of 15 cases of MST to further characterize this neoplasm and establish its histogenesis. Diffuse nuclear staining for FOXL2, WT-1, cyclin D1, and β-catenin was present in all tumors tested, and 12/15 were positive for steroidogenic factor-1 (SF-1). Heterozygous missense point mutations in exon 3 of CTNNB1 were detected in 8 of 14 cases, resulting in amino acid changes at codons 32, 34, 35, and 37. There was no correlation between CTNNB1 exon 3 mutation status and tumor immunophenotype. All 14 cases tested showed wild-type FOXL2. Our study establishes that MST of the ovary exhibits a characteristic FOXL2/SF-1/WT-1/cyclin D1/nuclear β-catenin-positive immunohistochemical profile, which may be useful in diagnosis and in the exclusion of histologic mimics. The presence of diffuse nuclear FOXL2 and WT-1 immunostaining in all cases and SF-1 in most supports the classification of MST within the sex cord-stromal category. Aberrant nuclear β-catenin expression, detected in all MSTs, appears to be the result of stabilizing CTNNB1 mutations in 57% of cases, providing further evidence that dysregulation of the Wnt/B-catenin pathway is involved in the tumorigenesis of MST and may involve activation of β-catenin with upregulation of cyclin D1.
authors.affiliation: *Department of Laboratory Medicine, Pathology, and Medical Genetics, Royal Jubilee Hospital, Victoria †Department of Pathology, University of British Columbia §Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC ‡Department of Laboratory Medicine and Pathology, University of Alberta and Royal Alexandra Hospital, Edmonton, AB, Canada ∥James Homer Wright Pathology Laboratories of the Massachusetts General Hospital, and the Department of Pathology, Harvard Medical School, Boston, MA ¶Department of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, United Kingdom.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Irving
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.forename: Stephen
authors.initials: S
authors.lastname: Yip
authors.forename: Esther
authors.initials: E
authors.lastname: Oliva
authors.forename: W Glenn
authors.initials: WG
authors.lastname: McCluggage
authors.forename: Robert H
authors.initials: RH
authors.lastname: Young
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D019938:Cyclin D1 / Q000032:analysis*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000032:analysis*; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000032:analysis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D000072260:RNA Splicing Factors; D018312:Sex Cord-Gonadal Stromal Tumors / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D014157:Transcription Factors / Q000032:analysis*; D025721:WT1 Proteins / Q000032:analysis*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000032:analysis / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; D004268:DNA-Binding Proteins; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D000072260:RNA Splicing Factors; C107467:SF1 protein, human; D014157:Transcription Factors; D025721:WT1 Proteins; C583751:WT1 protein, human; D051176:beta Catenin; D019938:Cyclin D1