Blaise A Clarke1,2, Leora Witkowski3,4, Tuyet N Ton Nu5, Patricia A Shaw6,7, C Blake Gilks8,9,10, David Huntsman8,9,10, Anthony N Karnezis8,9,10, Neil Sebire11,12, Janez Lamovec13, Lawrence M Roth14, Colin J R Stewart15,16, Martin Hasselblatt17, William D Foulkes3,4,18, W Glenn McCluggage19. 1. Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON, Canada. blaise.clarke@uhn.ca. 2. Toronto General Hospital, Toronto, ON, Canada. blaise.clarke@uhn.ca. 3. Department of Human Genetics, McGill University, Montreal, QC, Canada. 4. Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, QC, Canada. 5. Department of Pathology, McGill University Health Centre, Montreal, QC, Canada. 6. Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON, Canada. 7. Toronto General Hospital, Toronto, ON, Canada. 8. Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada. 9. Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada. 10. Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada. 11. Department of Histopathology, Great Ormond Street Hospital, London, UK. 12. Institute of Child Health, University College London, London, UK. 13. Department of Pathology, Institute of Oncology, Ljubljana, Slovenia. 14. Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA. 15. School for Women's and Infants' Health, University of Western Australia, Perth, WA, Australia. 16. KEMH, Perth, WA, Australia. 17. Institute of Neuropathology, University Hospital Münster, Münster, Germany. 18. Department of Medical Genetics, Research Institute, McGill University Health Centre, Montreal, QC, Canada. 19. Department of Pathology, Belfast Health and Social Care Trust, Royal Group of Hospitals Trust, Royal Group of Hospitals, Belfast, UK.
Abstract
AIMS: 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. METHODS AND 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.
AIMS: 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. METHODS AND 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.
Authors: Madhuchhanda Roy; Darya G Buehler; Ranran Zhang; Michael L Schwalbe; Rebecca M Baus; M Shahriar Salamat; Ricardo V Lloyd; Jason N Rosenbaum Journal: Endocr Pathol Date: 2019-03 Impact factor: 3.943
Authors: Jennifer L Sauter; Rondell P Graham; Brandon T Larsen; Sarah M Jenkins; Anja C Roden; Jennifer M Boland Journal: Mod Pathol Date: 2017-06-23 Impact factor: 7.842
Authors: Marjorie P David; Rajkumar Venkatramani; Dolores H Lopez-Terrada; Angshumoy Roy; Ninad Patil; Kevin E Fisher Journal: Cold Spring Harb Mol Case Stud Date: 2018-10-01
Authors: Marc Tischkowitz; Sidong Huang; Susana Banerjee; Jennifer Hague; William P D Hendricks; David G Huntsman; Jessica D Lang; Krystal A Orlando; Amit M Oza; Patricia Pautier; Isabelle Ray-Coquard; Jeffrey M Trent; Michael Witcher; Leora Witkowski; W Glenn McCluggage; Douglas A Levine; William D Foulkes; Bernard E Weissman Journal: Clin Cancer Res Date: 2020-03-10 Impact factor: 13.801
Authors: Rosalba De Nola; Edoardo Di Naro; Luca Maria Schonauer; Giuseppe Lucarelli; Michele Battaglia; Maria Grazia Fiore; Salvatore Andrea Mastrolia; Giuseppe Loverro Journal: Medicine (Baltimore) Date: 2018-01 Impact factor: 1.889