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Ovarian Sex Cord-Stromal Tumors Review Int J Gynecol Cancer: first published as 10.1136/ijgc-2020-002018 on 7 January 2021. Downloaded from Ovarian sex cord- stromal tumors: an update INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Original research Editorials Joint statement Society statement on clinical features, molecular changes, Meeting summary Review articles Consensus statement Clinical trial Case study Video articles Educational video lecture and management Images Pathology archives Corners of the world Commentary Letters ijgc.bmj.com Rehab Al Harbi,1 Iain A McNeish,2 Mona El- Bahrawy1,3 1Department of Metabolism, ABSTRACT cord tumors with annular tubules, arise from primi- Digestion, and Reproduction, 7 Sex cord stromal- tumors are rare tumors of the ovary that tive sex cord cells. Mixed sex cord- stromal tumors Imperial College London, include Sertoli–Leydig cell tumors and sex cord- London, UK include numerous tumor subtypes of variable histological 2Department of Surgery and features and biological behavior. Surgery is the main stromal tumors that have not otherwise been spec- 7 Cancer, Imperial College therapeutic modality for the management of these ified. London, London, UK tumors, while chemotherapy and hormonal therapy may Sex cord- stromal tumors may present with an 3 Department of Pathology, be used in some patients with progressive and recurrent adnexal mass, abdominal distention, and abdom- Faculty of Medicine, University tumors. Several studies investigated molecular changes inal pain.1 Unlike epithelial and germ cell tumors, of Alexandria, Alexandria, Egypt in the different tumor types. Understanding molecular some sex cord- stromal tumors have clinical signs of changes underlying the development and progression of hormone production, including menstrual changes, Correspondence to sex cord-stromal tumors provides valuable information 1 Professor Mona El-Bahra wy, for diagnostic and prognostic biomarkers and potential precocious puberty, hirsutism, and/or virilization. Metabolism, Digestion, and therapeutic targets for these tumors. In this review, we The most important prognostic factors for sex cord- Reproduction, Imperial College provide an update on the clinical presentation, molecular stromal tumors are the International Federation of London Faculty of Medicine, changes, and management of sex cord-stromal tumors. Gynecology and Obstetrics (FIGO) stage and tumor London, W12 0NN, UK; m. rupture.4 elbahrawy@ imperial. ac.uk INTRODUCTION Received 7 September 2020 Sex cord- stromal tumors are rare tumors of the ovary PURE STROMAL TUMORS Revised 24 November 2020 that usually occur in the first two to three decades of Fibromas Accepted 30 November 2020 life1 2 and represent approximately 7% of all primary Published Online First Fibromas are relatively common tumors and account malignant ovarian tumors,3 with the exception of 7 January 2021 for 4% of all ovarian tumors.8 These solid, typically adult granulosa cell tumors, which are characterized benign, tumors arise from spindle shaped stromal http://ijgc.bmj.com/ by later onset with a peak incidence between 50 and cells that form collagen.9 These hormonally inac- 55 years of age.1 Sex cord- stromal tumors are usually tive tumors occur most often in perimenopausal and diagnosed at an early stage, and may have late recur- postmenopausal women.9 Fibromas are commonly rence, as late as 30 years, after the initial diagnosis unilateral; however, bilateral cases may occur and and treatment.4 The longest period of recurrence of may be associated with Gorlin syndrome.10 Gorlin granulosa cell tumors after initial diagnosis reported 5 syndrome, also called nevoid basal cell carcinoma was 41 years. Sex cord- stromal tumors constitute on September 27, 2021 by guest. Protected copyright. syndrome or basal cell nevus syndrome, is a rare a heterogeneous group of benign and malignant hereditary disease and it is inherited in an auto- neoplasms and are formed by distinct cell types that somal dominant manner.11 It affects multiple organ arise from stromal cells or primitive sex cord cells.6 7 systems of the human body and is associated with an increased risk of developing several types of benign and malignant tumors.11 This syndrome is caused by CLASSIFICATION OF SEX CORD-STROMAL a germline mutation in the human homolog of the ► http:// dx. doi. org/ 10. 1136/ TUMORS ijgc- 2020- 002329 patched (PTCH1) gene, which is located on chromo- These tumors are classified into three main groups, some 9.12 13 However, It is still unclear whether this according to the World Health Organization, as germline mutation is also involved in the development presented in Table 1, and include pure stromal 14 © IGCS and ESGO 2021. No of sporadic ovarian fibromas. Molecular cytoge- commercial re-use. See rights tumors, pure sex cord tumors, and mixed sex cord- netics analysis by fluorescence in situ hybridization 7 and permissions. Published by stromal tumors. Pure stromal tumors arise from has shown the presence of trisomy 12 in fibromas.15 BMJ. mesenchymal cells of the ovarian stroma, and include To cite: Al Harbi R, fibromas, thecomas, sclerosing stromal tumors, Thecomas McNeish IA, El- Bahrawy M. microcystic stromal tumors, Leydig cell tumors, and Thecomas are very rare tumors and represent Int J Gynecol Cancer steroid cell tumors.7 Pure sex cord tumors, such as approximately 0.5–1% of all ovarian tumors.16 They 2021;31:161–168. granulosa cell tumors, Sertoli cell tumors, and sex can occur at any age and can be seen in women Al Harbi R, et al. Int J Gynecol Cancer 2021;31:161–168. doi:10.1136/ijgc-2020-002018 161 Review Int J Gynecol Cancer: first published as 10.1136/ijgc-2020-002018 on 7 January 2021. Downloaded from Sclerosing Stromal Tumors Table 1 World Health Organization classification of ovarian sex cord- stromal tumors Sclerosing stromal tumors represent less than approximately 5% of all sex cord-stromal tumors,7 and 70% are diagnosed in young Tumor type women aged 14–29.19 These tumors are usually unilateral and Pure stromal tumors hormonally inactive. However, sclerosing stromal tumors may 8 Fibroma 4% of all ovarian tumors present with hormonal manifestations, primarily androgenic ones, 20 Cellular fibroma and they occur more frequently during pregnancy. On immu- nostaining, sclerosing stromal tumors show strong TFE3 expres- Thecoma 0.5–1% of all ovarian tumors16 sion, which is a transcription factor binding to the immunoglobulin heavy chain enhancer 3.21 A study using whole exome, targeted Luteinized thecoma capture, and RNA sequencing identified recurrent gene fusions of associated with sclerosing peritonitis FHL2- GLI2 in 65% and other GLI2 rearrangements in 15% of scle- rosing stromal tumors, but none of these fusion genes has been Fibrosarcoma reported in other types of sex cord- stromal tumors.22 FHL2- GLI2 Signet ring stromal tumor fusions activate the sonic hedgehog pathway in sclerosing stromal Sclerosing stromal tumor 5% of all sex cord stromal tumors and could, therefore, serve as an oncogenic driver of scle- tumors7 rosing stromal tumor.22 Microcystic stromal tumor Microcystic Stromal Tumors Leydig cell tumor Microcystic stromal tumors are very rare and present in patients Ster oid cell tumor between the ages of 20 and 60.23 On immunostaining, microcystic Ster oid cell tumor, stromal tumors have shown the expression of CD10, vimentin, and malignant Wilms tumor 1, while sex cord- stromal markers (α-inhibin and Pure sex cord tumors calretinin) and epithelial membrane antigen are negative.24 Nuclear 25 Adult granulosa cell tumor 95% of all granulosa cell expression of β‐catenin occurs in microcystic stromal tumors. tumors68 The somatic exon 3 missense CTNNB1 mutation is a hallmark of 25 Juvenile granulosa cell 5% of all granulosa cell most ovarian microcystic stromal tumors. The CTNNB1 gene tumor tumors68 encodes the β‐catenin protein, and this mutation leads to the loss Sertoli cell tumor of a phosphorylation site in the β-catenin protein. Also, microcystic stromal tumors may be associated with familial adenomatous poly- Sex cord tumors with 1.4% of all sex cord- stromal posis, which is an autosomal dominant inherited disease caused annular tubules tumors81 by germline mutations of the adenomatous polyposis coli gene on Mixed sex cord stromal tumors chromosome 5 (q21-22).26 A case study of the molecular anal- Sertoli–Leydig cell tumors <0.5% of all ovarian ysis of microcystic stromal tumors by Zhang et al identified two 84 http://ijgc.bmj.com/ tumors missense mutations, one in exon 1 of the KRAS gene and the other Well differentiated in exon 15 of the adenomatous polyposis coli gene.27 Moderately differentiated With heterologous elements PURE SEX CORD TUMORS Poorly differentiated Granulosa Cell Tumors Granulosa cell tumors are the most common subtype of sex cord- on September 27, 2021 by guest. Protected copyright. With heterologous stromal tumors, accounting for 2–5% of all ovarian tumors.28 29 elements Granulosa cell tumors originate from normally proliferating gran- Retiform ulosa cells of late preovulatory follicles, with which they share With heterologous similar biochemical, morphological, and hormonal characteristics, elements including the expression of inhibin, estrogen, and Müllerian inhib- Sex cord- stromal tumor, iting substance.28 30 These hormones account for some of the clin- not otherwise specified ical manifestations and provide valuable tumor markers for moni- toring disease progression and treatment efficacy.28 30 31 Inhibin is a glycoprotein hormone produced by ovarian granulosa
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