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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 The histogenesis and cell lineage of small cell carcinoma of the ovary of hypercalcaemic type (SCCOHT) is unknown. We aim to provide evidence that this may be a primitive germ cell neoplasm arising from a teratoma. Methods/ Results Following the identification of two cases of SCCOHT associated with germ cell tumours (one dermoid cyst, one immature teratoma with a focus of yolk sac tumour), we undertook a literature review to look for any prior reports of SCCOHT in association with other neoplasms or elements. This revealed two cases associated with immature teratomas, one arising in an ovary where a cystectomy had previously been undertaken for a teratoma and another arising in association with a mucinous borderline tumour. Mucinous elements have also been reported in SCCOHT, this type of epithelium potentially being of teratomatous derivation. We stained whole tissue sections of 9 cases of SCCOHT and a tissue microarray (TMA) containing 34 different SCCOHT with germ cell markers SALL4, OCT3/4, alpha fetoprotein (AFP) and glypican 3. All except one of the whole tissue sections and approximately half of the TMA cases were positive with SALL4 while all cases were OCT3/4, AFP and glypican 3 negative, except for focal glypican 3 staining in an occasional case. Conclusions Our findings provide additional evidence to that proposed by others that SCCOHT is a primitive germ cell neoplasm arising from a teratoma. This article is protected by copyright. All rights reserved.

The introduction of new sequencing technologies has resulted in the discovery of commonly mutated genes in uncommon cancers, including non-epithelial ovarian neoplasms and other rare gynaecological tumours, such as cervical embryonal rhabdomyosarcoma. In some of these neoplasms, mutations in certain genes are both frequent and specific enough for the genomic mutations and sometimes their associated protein loss or overexpression to be used as an aid to diagnosis. In this review, we contrast previous gene identification methods with newer ones, and discuss how the new sequencing technologies (collectively referred to as 'next-generation sequencing') have permitted the identification of specific molecular events that characterize several rare gynaecological neoplasms. We highlight the value of using sequencing to complement traditional pathological methods when diagnosing certain tumours, and provide practical advice to pathologists dealing with these neoplasms. We focus on adult granulosa cell tumours (somatic monoallelic mutations in FOXL2), Sertoli-Leydig cell tumours, gynaecological embryonal rhabdomyosarcomas (germline and somatic mutations in DICER1), and small-cell carcinoma of the ovary, hypercalcaemic type (biallelic mutations in SMARCA4). The new genetic findings provided by next-generation sequencing in these uncommon neoplasms have brought these disorders back into focus, and point the way towards new diagnostic, preventive and therapeutic avenues.