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.

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases

“…Besides MRTs, a role of SMARCA4 has been described for a variety of tumor entities including non-small cell lung cancer or thoracic sarcomas [ 28 , 39 ]. In small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), loss of the SMARCA4 protein has been proposed to be the main driving event in tumorigenesis [ 46 ]. In other tumor types, such as Burkitt lymphoma or medulloblastoma (MB), heterozygous missense mutations in SMARCA4 have been identified, but their role in tumor development remains elusive [ 23 , 26 , 38 , 41 ].…”

Ovarian carcinoma in children with constitutional mutation of SMARCA4: single-family report and literature review

“…Despite individualized and diverse approaches for treatment, recurrence and progression of cancer have been observed in children diagnosed with SCCOHT. Novel therapies targeting the SCCOHT vulnerabilities [such as EZH2 and HDAC, bromodomain and extraterminal motif containing protein inhibitors (BETi), tyrosine kinase, and PD-1 inhibitors] have been successfully tested, mainly in preclinical studies, but prospective multicenter protocols are highly needed in this particularly rare disease [18]. To this purpose, in 2018, the International SCCOHT Consortium was formed.…”

“…The administration of such aggressive treatments can only be justified by proper histopathological diagnosis [17]. However, pathologists often struggle with these tumors due to overlapping morphology and immunohistochemistry in this group of cancers [18].…”

Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group

“…whole-body MRI, NGS technology) detailed surveillance guidelines for RTPS have been provided among others by Teplick Very recently an excellent status paper on the current evidence, practical clinical approach for genetic testing and surveillance as well as research issues in SCCOHT has been published. We would like to point the reader to this manuscript for into-depth information and advice [56].…”