The hereditary nature of small cell carcinoma of the ovary, hypercalcemic type: two new familial cases

Abstract

Small cell carcinoma of the ovary, hypercalcemic type, (SCCOHT) is the most common undifferentiated ovarian cancer in women aged under 40 years. SCCOHT is a monogenic disease, characterized by germline and somatic SMARCA4 mutations. Recent studies have stressed its morphological and clinical similarity to malignant rhabdoid tumours, which are usually caused by mutations in the related gene, SMARCB1. While familial tumours are rare, the incidence of germline mutations is relatively high, with up to 43% of SCCOHTs and 35% of rhabdoid tumours caused by germline mutations in SMARCA4 and SMARCB1, respectively. We report two new familial cases of SCCOHT. Affected members in both families and the associated tumours were found to carry SMARCA4 germline and somatic mutations, respectively, leading to loss of SMARCA4 protein expression in the tumours. Despite the rarity of familial SCCOHT, the high incidence of germline mutations is important to note, as without a family history of the disease, the hereditary nature of SCCOHT may be missed, especially if the mutation was inherited from the father or acquired de novo. The similarity between SCCOHT and rhabdoid tumours should be recognized, as infant carriers of SMARCA4 mutations may be at risk for these tumours in addition to SCCOHT.

Keywords: Hereditary; Mutation; Ovarian cancer; Rhabdoid; SCCOHT; SMARCA4.

Fig. 1

Family 1. a Pedigree of family 1. b Mutations found by Sanger sequencing in affected patients. Top: Germline mutation found in both patients; middle: representative chromatogram from patient III:1 showing somatic LOH found in tumours of both patients; bottom: cDNA sequencing across mutation, showing that splice mutation leads to skipping of exon 19. Loss of expression was seen in both SCCOHT tumors and representative SMARCA4 immunohistochemistry is shown in two tumors—c in the SCCOHT from patient III:3, with complete loss of SMARCA4 staining and positive internal controls and d: in the lung tumor from patient II:4. In d immunohistochemistry for SMARCA4 shows loss of nuclear SMARCA4 staining in pleomorphic tumor cells, but retained staining in small round lymphocytic nuclei (internal positive control). Original magnification 600×. TAH/BSO, total abdominal hysterectomy/bilateral salpingo-oophorectomy

Fig. 2

Family 2. a Pedigree of family 2. b Mutations found by Sanger sequencing in affected patients. Top germline mutation found in both patients; middle LOH seen in tumour from patient II:3; bottom somatic LOH found in tumours of both patients. c Representative SMARCA4 immunohistochemistry in tumour of patient III:2. Loss of expression was seen in both patients. Pr Ca, Prostate cancer