title: Claudin-4 expression distinguishes SWI/SNF complex-deficient undifferentiated carcinomas from sarcomas.
abstract: Inactivation of SWI/SNF (switch/sucrose non-fermentable) chromatin remodeling complex subunits is a feature shared by select carcinomas and sarcomas with epithelioid morphology and variable keratin expression, making the distinction between carcinoma and sarcoma challenging in some cases. The tight junction-associated protein claudin-4 is a marker of epithelial differentiation that is expressed in nearly all carcinomas. Claudin-4 expression has been reported in the glandular component of biphasic synovial sarcoma but has not been systematically evaluated in other sarcoma types. In this study we assessed claudin-4 expression in SWI/SNF complex-deficient neoplasms showing loss of SMARCB1 (INI1), SMARCA4 (BRG1), or ARID1A and other sarcomas with epithelioid morphology. Immunohistochemistry for claudin-4 was performed on 130 neoplasms, including 90 soft tissue tumors with epithelioid morphology and/or SMARCB1 deficiency (20 epithelioid sarcomas (10 conventional, 10 proximal-type); 10 epithelioid angiosarcomas; 10 epithelioid hemangioendotheliomas; 15 epithelioid malignant peripheral nerve sheath tumors; 10 malignant rhabdoid tumors; 15 myoepithelial carcinomas; 10 biphasic synovial sarcomas), 10 ovarian clear cell carcinomas, 10 ovarian small cell carcinomas of hypercalcemic type, and 20 SWI/SNF complex-deficient undifferentiated carcinomas (14 SMARCB1 deficient and 6 SMARCA4 deficient, including rhabdoid carcinomas of various sites and sinonasal carcinomas). Membranous expression of claudin-4 (≥5% of cells) was observed in all biphasic synovial sarcomas (epithelial component only), all ovarian clear cell carcinomas, and 16 (80%) SWI/SNF complex-deficient undifferentiated carcinomas. All other soft tissue tumors were negative for claudin-4, with the exception of two myoepithelial carcinomas and one malignant rhabdoid tumor. Interestingly, none of the ovarian small cell carcinomas of hypercalcemic type expressed claudin-4. In summary, expression of claudin-4 is highly specific for true epithelial differentiation and may be useful to distinguish SWI/SNF complex-deficient undifferentiated carcinomas from sarcomas with epithelioid morphology. The lack of claudin-4 expression in ovarian small cell carcinomas of hypercalcemic type suggests that these tumors may be better regarded as sarcomas rather than carcinomas.
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: Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Christopher Dm
authors.initials: CD
authors.lastname: Fletcher
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
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002277:Carcinoma / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D062506:Claudin-4 / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009687:Nuclear Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D000071796:SMARCB1 Protein / Q000378:metabolism; D012509:Sarcoma / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C112476:ARID1A protein, human; D014408:Biomarkers, Tumor; D002868:Chromosomal Proteins, Non-Histone; D062506:Claudin-4; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000071796:SMARCB1 Protein; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases