Small-Cell Carcinoma of the Ovary, Hypercalcemic Type-Genetics, New Treatment Targets, and Current Management Guidelines

Abstract

Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive ovarian malignancy. In almost all cases, it is associated with somatic and often germline pathogenic variants in SMARCA4, which encodes for the SMARCA4 protein (BRG1), a subunit of the SWI/SNF chromatin remodeling complex. Approximately 20% of human cancers possess pathogenic variants in at least one SWI/SNF subunit. Because of their role in regulating many important cellular processes including transcriptional control, DNA repair, differentiation, cell division, and DNA replication, SWI/SNF complexes with mutant subunits are thought to contribute to cancer initiation and progression. Fewer than 500 cases of SCCOHT have been reported in the literature and approximately 60% are associated with hypercalcemia. SCCOHT primarily affects females under 40 years of age who usually present with symptoms related to a pelvic mass. SCCOHT is an aggressive cancer, with long-term survival rates of 30% in early-stage cases. Although various treatment approaches have been proposed, there is no consensus on surveillance and therapeutic strategy. An international group of multidisciplinary clinicians and researchers recently formed the International SCCOHT Consortium to evaluate current knowledge and propose consensus surveillance and therapeutic recommendations, with the aim of improving outcomes. Here, we present an overview of the genetics of this cancer, provide updates on new treatment targets, and propose management guidelines for this challenging cancer.

Figure 1.

SCCOHT is composed of predominantly diffuse arrangement of cells with follicle-like structures (A). On higher power, the tumor cells have hyperchromatic nuclei and scant cytoplasm (B). Large cell variant of SCCOHT composed of tumor cells with abundant eosinophilic cytoplasm (C). There is loss of nuclear immunoreactivity with SMARCA4 (BRG1) with a positive internal control in the form of nuclear staining of endothelial cells (D).

Figure 2.

Graphic summary of SCCOHT therapeutic candidates and their corresponding drugs. Agents that are being tested in clinical trials available to SCCOHT patients are underlined. See Table 2 for more details.