Loss of SMARCA4 (BRG1) protein expression as determined by immunohistochemistry in small-cell carcinoma of the ovary, hypercalcaemic type distinguishes these tumours from their mimics.
OBJECTIVE
Molecular investigation of small-cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) has revealed that it is a monogenetic tumour characterized by alteration of SMARCA4 (BRG1), encoding a member of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complex. A large majority of cases show loss of expression of the corresponding SMARCA4/BRG1 protein. Furthermore, three cases of SCCOHT with retained SMARCA4 protein expression showed loss of SMARCB1/INI1 expression. The aim of this study was to assess the sensitivity and specificity of loss of SMARCA4 expression as a diagnostic test for SCCOHT.


RESULTS
We performed SMARCA4 and SMARCB1 staining in 245 tumours, many of which were potentially in the differential diagnosis of SCCOHT. We also stained 56 cases of SCCOHT for SMARCA4 and 37 of these for SMARCB1. Fifty-four of the SCCOHT cases showed complete absence of SMARCA4 expression. The two cases with retained expression showed molecular alteration of SMARCA4. Of the 217 other neoplasms with interpretable staining, all retained SMARCA4 expression. Although the majority showed diffuse, strong nuclear expression, a heterogeneous, typically weak staining pattern was present in 13% of cases. All 37 cases of SCCOHT tested and all other neoplasms, apart from three malignant rhabdoid tumours, showed retained nuclear SMARCB1 expression. Loss of SMARCA4 expression had a sensitivity of 96.55% and specificity of 100%.


CONCLUSIONS
Loss of SMARCA4 expression is sensitive and specific for SCCOHT. Although some mimics show heterogeneous expression, there is retention of nuclear staining in at least a part of the tumour; therefore, only complete loss of staining should be regarded as being supportive of SCCOHT.
Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON, Canada. blaise.clarke@uhn.ca.|Toronto General Hospital, Toronto, ON, Canada. blaise.clarke@uhn.ca.
Blaise A
BA
Clarke
Department of Human Genetics, McGill University, Montreal, QC, Canada.|Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, QC, Canada.
Leora
L
Witkowski
Department of Pathology, McGill University Health Centre, Montreal, QC, Canada.
Tuyet N
TN
Ton Nu
Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON, Canada.|Toronto General Hospital, Toronto, ON, Canada.
Patricia A
PA
Shaw
Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada.|Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada.
C Blake
CB
Gilks
Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada.|Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada.
David
D
Huntsman
Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada.|Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada.
Anthony N
AN
Karnezis
Department of Histopathology, Great Ormond Street Hospital, London, UK.|Institute of Child Health, University College London, London, UK.
Neil
N
Sebire
Department of Pathology, Institute of Oncology, Ljubljana, Slovenia.
Janez
J
Lamovec
Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA.
Lawrence M
LM
Roth
School for Women's and Infants' Health, University of Western Australia, Perth, WA, Australia.|KEMH, Perth, WA, Australia.
Colin J R
CJ
Stewart
Institute of Neuropathology, University Hospital Münster, Münster, Germany.
Martin
M
Hasselblatt
Department of Human Genetics, McGill University, Montreal, QC, Canada.|Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, QC, Canada.|Department of Medical Genetics, Research Institute, McGill University Health Centre, Montreal, QC, Canada.
William D
WD
Foulkes
Department of Pathology, Belfast Health and Social Care Trust, Royal Group of Hospitals Trust, Royal Group of Hospitals, Belfast, UK.
W Glenn
WG
McCluggage
D014408:Biomarkers, Tumor / Q000032:analysis*; D000077216:Carcinoma, Ovarian Epithelial; D018288:Carcinoma, Small Cell / Q000175:diagnosis*; D004265:DNA Helicases / Q000032:analysis / Q000096:biosynthesis*; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009375:Neoplasms, Glandular and Epithelial / Q000175:diagnosis*; D009687:Nuclear Proteins / Q000032:analysis / Q000096:biosynthesis*; D010051:Ovarian Neoplasms / Q000175:diagnosis*; D012680:Sensitivity and Specificity; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000032:analysis / Q000096:biosynthesis*
D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases
SMARCA4; SMARCB1; differential diagnosis; immunohistochemistry; ovary; small-cell carcinoma of ovary (hypercalcaemic type)