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Multimodal molecular analysis of an atypical small cell carcinoma of the ovary, hypercalcemic type.

ABSTRACT: A 12-yr-old normocalcemic female treated for a ruptured ovarian juvenile granulosa cell tumor at an outside hospital presented for exploratory laparotomy and gross surgical debulking of pelvic recurrence. Morphologically, the tumor was composed of sheets and nests of small blue cells forming cysts of various sizes and focal mucinous differentiation. Epithelial membrane antigen (EMA), patchy inhibin, and strong and diffuse p53 immunoreactivity were also observed. A revised diagnosis of mixed sex cord stromal tumor with heterologous elements was favored because of the inhibin immunoreactivity. Targeted next-generation sequencing of the tumor revealed a SMARCA4 c.1141C>T, p.Arg381Ter (NM_001128849.1) nonsense mutation and an in-frame 18-bp TP53 deletion (c.594_611del18, p.Gly199_Glu204del, NM_001126112.2). Cytogenetic analysis revealed a normal 46,XX karyotype, and OncoScan single-nucleotide polymorphism array analysis demonstrated copy-neutral loss of heterozygosity (CN-LOH) of 19p13.3-19p13.2 and mosaic CN-LOH of 17p13.3-p11.2 encompassing the SMARCA4 and TP53 loci, respectively. Subsequent germline SMARCA4 sequencing confirmed a heterozygous SMARCA4 p.Arg381Ter mutation. In lieu of the molecular findings, the diagnosis was amended to small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The patient was treated aggressively with paclitaxel, carboplatin, and bevacizumab. She received an autologous stem cell transplant but died 5 mo after SCCOHT diagnosis secondary to complications of the transplant. This case expands the morphologic, immunophenotypic, and genomic spectrum of SCCOHT and highlights how multimodal molecular analysis can assist with the diagnosis and clinical management of SCCOHT patients.

SUBMITTER: David MP

PROVIDER: S-EPMC6169825 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Multimodal molecular analysis of an atypical small cell carcinoma of the ovary, hypercalcemic type.

David Marjorie P MP Venkatramani Rajkumar R Lopez-Terrada Dolores H DH Roy Angshumoy A Patil Ninad N Fisher Kevin E KE

Cold Spring Harbor molecular case studies 20181001 5

A 12-yr-old normocalcemic female treated for a ruptured ovarian juvenile granulosa cell tumor at an outside hospital presented for exploratory laparotomy and gross surgical debulking of pelvic recurrence. Morphologically, the tumor was composed of sheets and nests of small blue cells forming cysts of various sizes and focal mucinous differentiation. Epithelial membrane antigen (EMA), patchy inhibin, and strong and diffuse p53 immunoreactivity were also observed. A revised diagnosis of mixed sex ...[more]

PMID: 30275002

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Project description:BackgroundSmall-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare aggressive ovarian malignancy mainly affecting children, adolescents, and young adults. Since the discovery of mutations in the SMARCA4 gene in 2014, SCCOHT has become the subject of extensive investigation. However, international uniform treatment guidelines for SCCOHT are lacking and the outcome remains poor. The aim of this systematic review is to generate an overview of all reported patients with SCCOHT from 1990 onwards, describing the clinical presentation, genetic characteristics, treatment, and outcome.MethodsA systematic search was performed in the databases Embase, Medline, Web of Science, and Cochrane for studies that focus on SCCOHT. Patient characteristics and treatment data were extracted from the included studies. Survival was estimated using Kaplan-Meier's methodology. To assess the difference between survival, the log-rank test was used. To quantify the effect of the FIGO stage, the Cox proportional hazard regression model was estimated. The chi-squared test was used to study the association between the FIGO stage and the surgical procedures.ResultsSixty-seven studies describing a total of 306 patients were included. The median patient age was 25 years (range 1-60 years). The patients mostly presented with non-specific symptoms such as abdominal pain and sometimes showed hypercalcemia and elevated CA-125. A great diversity in the diagnostic work-up and therapeutic approaches was reported. The chemotherapy regimens were very diverse, all containing a platinum-based (cisplatin or carboplatin) backbone. Survival was strongly associated with the FIGO stage at diagnosis.ConclusionsSCCOHT is a rare and aggressive ovarian cancer, with a poor prognosis, and information on adequate treatment for this cancer is lacking. The testing of mutations in SMARCA4 is crucial for an accurate diagnosis and may lead to new treatment options. Harmonization and international collaboration to obtain high-quality data on diagnostic investigations, treatment, and outcome are warranted to be able to develop international treatment guidelines to improve the survival chances of young women with SCCOHT.

Dataset Information

Multimodal molecular analysis of an atypical small cell carcinoma of the ovary, hypercalcemic type.

Publications

Multimodal molecular analysis of an atypical small cell carcinoma of the ovary, hypercalcemic type.

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