Rare non-epithelial ovarian neoplasms: Pathology, genetics and treatment.

Rare non-epithelial ovarian neoplasms have posed management challenges for many years. Their rarity means that most specialist practitioners will see one such case every several years, and most generalists may never see a case. The first step in management is to establish the correct diagnosis and this may necessitate specialist pathology review. Here, we review recent developments in the pathology, genetics and treatment of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and sex cord-stromal tumours. Pathologically, these tumours often display morphological overlap with other neoplasms; for example, SCCOHT overlaps with many other "small round blue cell" tumours. Specific immunohistochemical stains, while useful, may not always be definitive. The discovery of somatic mutations in FOXL2 (adult granulosa cell tumours) and germline and somatic mutations in DICER1 (Sertoli-Leydig cell tumours) and SMARCA4 (SCCOHT) has demonstrated the value of molecular investigation as an adjunct to traditional histopathological approaches. In addition, the presence of germline mutations in a significant proportion of some of these neoplasms points to the need for genetic counselling and testing, offering the prospect of prevention and early diagnosis. Treatment of these rare tumours, as a group, should be on the basis of sound oncological principles, given that level 1 evidence will almost always be lacking. The rationale for experimental therapies must be clearly established. In view of the complex issues involved in the management of these conditions, expert opinion in pathology, genetics and treatment may be essential to offer the patient and her family the best chance of a good outcome.

Risk reduction for small cell cancer of the ovary, hypercalcemic type in prepubertal patient: A clinical and bioethical perspective.

Loss of heterozygosity in the SMARCA4 gene is a hallmark feature of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), an aggressive ovarian cancer occurring in young adults and adolescents with an average age of 23 years and a median survival of less than fifteen months following diagnosis. Patients with germline pathogenic variants of SMARCA4 have a genetic predisposition to developing this aggressive ovarian cancer, a condition called rhabdoid tumor predisposition syndrome type 2 (RTPS2). Given the limited efficacy of surveillance imaging for ovarian neoplasm and the absence of an identified biomarker for the progression of this disease, asymptomatic patients who are found to possess pathogenic variants of the SMARCA4 gene following genetic testing are advised to consider risk-reducing bilateral salpingo-oophorectomy to eliminate the risk of SCCOHT. Given the reproductive impacts of this procedure, bioethical consultation must be considered when counseling patients with RTPS2, particularly for those who have not completed their desired course of family planning. In this report, we describe the bioethical considerations and outcomes for the case of a 6-year-old female with a pathogenic variant of SMARCA4 who underwent risk-reducing bilateral salpingo-oophorectomy (RRBSO). To our knowledge, this is the first time that this procedure has been reported in a prepubertal individual for cancer prevention in a patient with RTPS2.

Case Report: A Durable Response to Camrelizumab and Apatinib Combination Therapy in a Heavily Treated Small Cell Carcinoma of the Ovary, Hypercalcemic Type.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive malignancy with a poor prognosis. Most patients experience recurrence even after surgery and chemotherapy, and there are no standard treatment options for recurrent disease. Here, we report the case of a 36-year-old woman with SCCOHT who underwent primary cytoreductive surgery without adjuvant chemotherapy and remained disease-free for 9 months. She then developed retroperitoneal lymph node metastasis and was treated with two cycles of bleomycin/etoposide/cisplatin chemotherapy. However, the disease progressed and the patient received four cycles of liposomal doxorubicin/ifosfamide chemotherapy, followed by local radiation to the enlarged retroperitoneal lymph nodes. She achieved partial remission for 13 months, after which the disease progressed again. Tumor tissues and blood samples were sent for next-generation sequencing. The results indicated a somatic SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutation, microsatellite stability, and a tumor mutation burden of 1.0 muts/Mb without any germline mutations. An anti-PD-1 antibody, camrelizumab, and an antiangiogenic agent, apatinib, were administered, and the patient achieved partial remission for 28 months. Our study provides the first clinical evidence that the combination therapy of camrelizumab and apatinib could be an effective treatment for recurrent SCCOHT.

Successful pregnancy following chemotherapy in a survivor of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT): A case report and review of literature.

•Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare neoplasm that mostly affects young women.•The chances of future fertility in women are limited due to the aggressive nature of SCCOHT and need for adjuvant therapy.•We report the case of a 26y woman with stage IA SCCOHT who had a successful pregnancy following surgery and chemotherapy.

SWI/SNF Complex Mutations in Gynecologic Cancers: Molecular Mechanisms and Models.

The SWI/SNF (mating type SWItch/Sucrose NonFermentable) chromatin remodeling complexes interact with histones and transcription factors to modulate chromatin structure and control gene expression. These evolutionarily conserved multisubunit protein complexes are involved in regulating many biological functions, such as differentiation and cell proliferation. Genomic studies have revealed frequent mutations of genes encoding multiple subunits of the SWI/SNF complexes in a wide spectrum of cancer types, including gynecologic cancers. These SWI/SNF mutations occur at different stages of tumor development and are restricted to unique histologic types of gynecologic cancers. Thus, SWI/SNF mutations have to function in the appropriate tissue and cell context to promote gynecologic cancer initiation and progression. In this review, we summarize the current knowledge of SWI/SNF mutations in the development of gynecologic cancers to provide insights into both molecular pathogenesis and possible treatment implications for these diseases.

The dilemma of early preventive oophorectomy in familial small cell carcinoma of the ovary of hypercalcemic type.

•New pathogenic familial SMARCA4 variant, c.3081+1G>T.•Prophylactic surgery in healthy carrier of germline SMARCA4 mutation.•Long term hormone therapy in a 13-year-old girl.

Identification of Driver Mutations in Rare Cancers: The Role of SMARCA4 in Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT).

Cancer is a complex genetic disease that can arise through the stepwise accumulation of mutations in oncogenes and tumor suppressor genes in a variety of different tissues. While the varied landscapes of mutations driving common cancer types such as lung, breast, and colorectal cancer have been comprehensively charted, the genetic underpinnings of many rare cancers remain poorly defined. Study of rare cancers faces unique methodological challenges, but collaborative enterprises that incorporate next generation sequencing, reach across disciplines (i.e., pathology, genetic epidemiology, genomics, functional biology, and preclinical modeling), engage advocacy groups, tumor registries, and clinical specialists are adding increasing resolution to the genomic landscapes of rare cancers. Here we describe the approaches and methods used to identify SMARCA4 mutations, which drive development of the rare ovarian cancer, small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), and point to the broader relevance of this paradigm for future research in rare cancers.

Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and understudied cancer with a dismal prognosis. SCCOHT's infrequency has hindered empirical study of its biology and clinical management. However, we and others have recently identified inactivating mutations in the SWI/SNF chromatin remodeling gene SMARCA4 with concomitant loss of SMARCA4 protein in the majority of SCCOHT tumors.(1-4) Here we summarize these findings and report SMARCA4 status by targeted sequencing and/or immunohistochemistry (IHC) in an additional 12 SCCOHT tumors, 3 matched germlines, and the cell line SCCOHT-1. We also report the identification of a homozygous inactivating mutation in the gene SMARCB1 in one SCCOHT tumor with wild-type SMARCA4, suggesting that SMARCB1 inactivation may also play a role in the pathogenesis of SCCOHT. To date, SMARCA4 mutations and protein loss have been reported in the majority of 69 SCCOHT cases (including 2 cell lines). These data firmly establish SMARCA4 as a tumor suppressor whose loss promotes the development of SCCOHT, setting the stage for rapid advancement in the biological understanding, diagnosis, and treatment of this rare tumor type.