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Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord-Stromal Tumors: A Contemporary Review.

ABSTRACT: Non-epithelial ovarian tumors are heterogeneous and account for approximately 10% of ovarian malignancies. The most common subtypes of non-epithelial ovarian tumors arise from germ cells or sex cord and stromal cells of the gonads. These tumors are usually detected at an early stage, and management includes surgical staging and debulking. When indicated for advanced disease, most respond to chemotherapy; however, options for patients with refractory disease are limited, and regimens can be associated with significant toxicities, including permanent organ dysfunction, secondary malignancies, and death. Targeted therapies that potentially decrease chemotherapy-related adverse effects and improve outcomes for patients with chemotherapy-refractory disease are needed. Here, we review the molecular landscape of non-epithelial ovarian tumors for the purpose of informing rational clinical trial design. Recent genomic discoveries have uncovered recurring somatic alterations and germline mutations in subtypes of non-epithelial ovarian tumors. Though there is a paucity of efficacy data on targeted therapies, such as kinase inhibitors, antibody-drug conjugates, immunotherapy, and hormonal therapy, exceptional responses to some compounds have been reported. The rarity and complexity of non-epithelial ovarian tumors warrant collaboration and efficient clinical trial design, including high-quality molecular characterization, to guide future efforts.

SUBMITTER: Maoz A

PROVIDER: S-EPMC7353025 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord-Stromal Tumors: A Contemporary Review.

Maoz Asaf A Matsuo Koji K Ciccone Marcia A MA Matsuzaki Shinya S Klar Maximilian M Roman Lynda D LD Sood Anil K AK Gershenson David M DM

Cancers 20200529 6

Non-epithelial ovarian tumors are heterogeneous and account for approximately 10% of ovarian malignancies. The most common subtypes of non-epithelial ovarian tumors arise from germ cells or sex cord and stromal cells of the gonads. These tumors are usually detected at an early stage, and management includes surgical staging and debulking. When indicated for advanced disease, most respond to chemotherapy; however, options for patients with refractory disease are limited, and regimens can be assoc ...[more]

PMID: 32485873

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Project description:BackgroundMalignant ovarian sex-cord stromal tumors (MOSCSTs) are rare neoplasms that account for approximately 5-7% of all ovarian malignancies. The majority (70%) of patients had an early stage; thus, surgery is the predominant treatment. Patients were relatively young at the onset of the tumor. Moreover, the prognosis of patients with this tumor is better than that of malignant epithelial ovarian tumors and tends to recur late with an indolent clinical course. Thus, patients may be more inclined to conservative surgical procedures. There is, however, no objective criterion for selecting a suitable surgical procedure. Clinically, surgical extent depended on the preoperative evaluations, age, and willingness of patients, and gynecologists were relatively subjective when choosing surgery. The prognosis of patients with different surgical extents is still controversial. The review aimed to summarize the impacts of different surgical extents on oncological prognosis and fertility outcomes.MethodsThe literature search was performed in PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), and publications between January 2011 and December 2021 in English including clinical cohort studies and case reports were eligible for inclusion.ResultsWe finally identified 12 large-sample retrospective studies and 18 cases of MOSCSTs. The primary surgical procedures include fertility-spring surgery (FSS), total hysterectomy with unilateral or bilateral salpingo-oophorectomy (TAH-USO/BSO), FSS with complete staging procedure, complete staging surgery (CSS), and debulking surgery. FSS includes cystectomy (CYS), unilateral salpingo-oophorectomy (USO) or bilateral salpingo-oophorectomy (BSO) with uterine preservation that allows for potential future assisted reproductive approaches. Complete staging procedure includes peritoneal cytologic examinations, inspections of peritoneal surfaces, random peritoneal biopsies and omentectomy. FSS with complete staging procedure means surgical procedure with uterine preservation and complete staging procedure. And, generally, CSS means TAH-BSO with complete staging procedure.ConclusionIt can be concluded that USO can be done in young, fertility-desired patients with tumors confined to the ovary but avoid CYS. FSS with complete staging procedure is feasible among stage IC-III patients who have fertility desire. Patients can choose to have a complete surgery once their family is complete or without fertility requirements. CSS is recommended for patients with risk factors such as high stage, poor differentiation, and large tumor size and without fertility desire. A close follow-up is essential.

Project description:Sertoli-Leydig cell tumors are characterized by the presence of somatic DICER1 hotspot mutations. In this study, we sought to define the association between DICER1 hotspot mutations and different morphologic subtypes of ovarian Sertoli-Leydig cell tumors. Furthermore, we aimed to assess whether DICER1 hotspot mutations occur in other ovarian sex cord-stromal tumors, testicular sex cord-stromal tumors, or other female genital tract tumors with rhabdomyosarcomatous differentiation. We subjected a series of ovarian Sertoli-Leydig cell tumors (n=32), Sertoli cell tumors (n=5) and gynandroblastomas (n=5), testicular sex cord-stromal tumors (n=15) and a diverse group of female genital tract tumors with rhabdomyosarcomatous morphology (n=10) to DICER1 hotspot mutation analysis using Sanger sequencing. We also tested two gynandroblastomas for the presence of FOXL2 hotspot mutations (p.C134W; c.402C>G). Twenty of 32 (63%) Sertoli-Leydig cell tumors harbored a DICER1 hotspot mutation, of which 80% had the p.E1705K mutation. No association was found between DICER1 mutation status and the presence of heterologous or retiform differentiation in Sertoli-Leydig cell tumors. DICER1 mutations were found at similar frequencies in gynandroblastoma (2/5; 40%) and ovarian Sertoli cell tumors (5/8; 63%; P>0.1), and all mutated tumors harbored a p.E1705K mutation. DICER1 hotspot mutations were also identified in a single cervical rhabdomyosarcoma and in the rhabdomyosarcomatous component of a uterine carcinosarcoma. No DICER1 mutations were detected in testicular sex cord-stromal tumors. Two DICER1 wild-type gynandroblastomas harbored a p.C134W FOXL2 hotspot mutation in both tumor components. In this study we confirmed that DICER1 hotspot mutations occur in over half of ovarian Sertoli-Leydig cell tumors, and are unrelated to tumor differentiation. We also widened the spectrum of ovarian sex cord-stromal tumors with sertoliform differentiation, in which DICER1 mutations are known to occur, to include Sertoli cell tumors and gynandroblastomas. Our results suggest that DICER1 mutations may not have a role in testicular sex cord-stromal tumorigenesis.

Dataset Information

Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord-Stromal Tumors: A Contemporary Review.

Publications

Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord-Stromal Tumors: A Contemporary Review.

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