Small Cell Carcinoma Of Ovary Research Articles

Small cell ovarian carcinoma hypercalcemic type and endometrial adenocarcinoma in a 49-year-old patient: a very rare case

Background: Small cell ovarian carcinoma hypercalcemic type (SCCOHT) is a rare ovarian malignancy with less than 400 cases worldwide. However, it affects mainly young women and has poor prognosis. The incidence of concurrent endometrial and ovarian cancer is as low as 10%, and has not been described, to our knowledge, with SCCOHT. Case Report: This is a rare case of a 49-year-old female who presented with abdominal pain, constipation, asymptomatic hypercalcemia, a large palpable abdominal mass, and was diagnosed with SCCOHT with concurrent Grade I endometrial adenocarcinoma endometroid type. Conclusion: This is an interesting case due to the concurrent endometrial cancer, the size of the tumor, and the age of the patient and aims to increase clinical suspicion around SCCOHT. The importance of the MDT should be highlighted, especially for this type of tumors which can be a diagnostic and treatment challenge.

Primary Ovarian Small Cell Carcinoma of Pulmonary Type: Analysis of 6 Cases and Review of 31 Cases in the Literatures

ObjectivePrimary ovarian small cell carcinoma of pulmonary type (SCCOPT) is a rare ovarian tumor with a poor prognosis. The platinum-based chemotherapy is the standard treatment. However, there is little research on the clinical characteristics of SCCOPT and the potential benefits of other treatments due to its low incidence. The study aims to investigate clinicopathological characteristics and treatment of SCCOPT. MethodsWe summarized the clinical, imaging, laboratorical and pathological characteristics of 37 SCCOPT cases, in which 6 cases were admitted to the Gansu Provincial Hospital from the year of 2008 to 2022 and 31 cases reported in 17 English and 3 Chinese literatures. ResultsThe median age of the studied SCCOPT cases (n=37) was 56.00 (range, 22–80) years. Almost 80% of them had a stage III or IV tumor. All patients underwent an operation and postoperative chemotherapy. Nevertheless, all cases had a poor prognosis, with a median overall survival time of 12 months. Immunohistochemically, the SCCOPT of all patients showed positive expressions of epithelial markers, such as CD56 and sex-determining region of Y chromosome-related high-mobility-group box 2 (SOX-2), and negative expressions of estrogen receptor, progesterone receptor, vimentin, Leu-7, and somatostatin receptor 2. The tumor of above 80% cases expressed synaptophysin. Only a few cases expressed neuron-specific enolase, chromogranin A, and thyroid transcription factor-1. ConclusionsSCCOPT had a poor prognosis. SOX-2 could be a biomarker to be used to diagnose SCCOPT.

Smallcell ovarian carcinoma of the hypercalcemic type: Report of three cases and literature review

The small-cell carcinoma of hypercalcemic type (SCOCHT) of the ovary is a rare and highly aggressive tumor. Due to the rarity of the disease, there is no consensus on its optimal therapy, and the treatment options are usually combines surgery, chemotherapy, and radiotherapy. Herein, we report the clinical presentation, management, and outcome of three cases of SCCOHT treated at Salah Azaiez Institution in Tunisia. The literature on this rare disease is also reviewed.

Abstract LB-232: Derazantinib (ARQ 087) pharmacodynamics: Alterations in FGF19/21/23 and phosphate in patients with cholangiocarcinoma

Abstract Background: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play important roles in cell proliferation, cell differentiation, cell migration, cell survival, protein synthesis, and angiogenesis. The FGFR family consist of four genes encoding tyrosine kinase receptors (FGFR1, FGFR2, FGFR3, and FGFR4). Dysregulation of FGFR signaling has been implicated in a number of developmental syndromes as well as cancers, e.g., intrahepatic cholangiocarcinoma (iCCA), squamous non-small cell lung cancer, small cell lung cancer, gastric, liver, breast, ovarian, endometrial, and bladder carcinomas, fueling significant interest in FGFRs as targets for therapeutic intervention. In human cancers, FGFRs have been found to be dysregulated by multiple mechanisms, including aberrant expression, mutations, chromosomal rearrangements, and amplifications. Members of the FGF19 ligand subfamily, FGFs 19, 21 and 23, are involved in the regulation of bile acid synthesis, glucose and lipid metabolism, and phosphate homeostasis, respectively. Unlike other FGFR ligands that act locally, the FGF19 subfamily circulate throughout the body, and can act as endocrine hormones at organs distant from their site of synthesis. The wide circulation of FGFs 19, 21, 23 makes them excellent potential biomarkers for FGFR inhibition. Study Design: 29 patients (18 women, 11 men, median age 58.7 years, all white) with FGFR2 gene positive fusion iCCA were enrolled and treated with derazantinib (dose range 300-400mg QD) at eight sites in the United States and Italy between August 2014 and October 2017 as part of clinical trial ARQ 087-101 [NCT01752920]. Patients' plasma samples were collected (on Day 1, 8, 15, 22 of Cycle 1 and Day 1 of Cycles 2-6) and analyzed for levels of FGF & phosphate. FGF levels were quantified using commercially available ELISA kits for FGF-19 and 21 (R&D Systems, Minneapolis, MN), and FGF-23 (EMD-Millipore, Billerica, MA). Results: Preliminary data analysis showed clear increase in mean FGF19, 23, and phosphate levels in iCCa patients treated with derazantinib. On Cycle 2 Day 1, phosphate levels on average increased by 40% over baseline. FGF19 and FGF23 increased by 300% and 140%, respectively. Final results and any additional findings will be presented at the meeting. Conclusions: The changes in FGF19, FGF23, and phosphate observed during treatment suggest that at the recommended phase II dose of derazantinib (300 mg QD), clinical signs of target engagement are detectable. Additional data to demonstrate potential correlation between FGFs/phosphate levels and clinical outcomes, including response and toxicity will be presented. DeLIVERr, a pivotal study of derazantinib in patients with FGFR2 gene fusion positive iCCA is ongoing (NCT03230318). Citation Format: Terence Hall, Vincenzo Mazzaferro, Bassel El-Rayes, Christian Cotsoglou, William P. Harris, Nevana Damjanov, Gianluca Masi, Lorenza Rimassa, Nicola Personeni, Vittorina Zagonel, Kyriakos P. Papadopoulos, Sherrie Bhoori, Michele Droz-Dit-Busset, Walid Shaib, Maria Lamar, Julia Kazakin, Brian Schwartz, Yunxia Wang, Ronald E. Savage. Derazantinib (ARQ 087) pharmacodynamics: Alterations in FGF19/21/23 and phosphate in patients with cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-232.

Small cell ovarian carcinoma of the pulmonary type: a rare case

Small cell ovarian carcinoma of the pulmonary type: a rare case

Ovarian Small Cell Carcinoma: A Rare Case Report and Review of Literature

Ovarian small cell carcinoma is a rare and highly malignant tumor with poor prognosis. It usually presents in younger females with features of hypercalcemia. The exact histogenesis of the tumor is unclear and it may present as an undifferentiated tumor. In such cases, immunohistochemistry (IHC) plays an important role to confirm the diagnosis. Limited treatment options are available and mainly include radical surgery followed by adjuvant therapy in advanced stages. The current report was a rare case of small cell carcinoma of ovary presenting no symptoms of hypercalcemia diagnosed on histopathological examination and IHC findings.

Pathology of Neuroendocrine Tumours of the Female Genital Tract.

Neuroendocrine tumours are uncommon or rare at all sites in the female genital tract. The 2014 World Health Organisation (WHO) Classification of neuroendocrine tumours of the endometrium, cervix, vagina and vulva has been updated with adoption of the terms low-grade neuroendocrine tumour and high-grade neuroendocrine carcinoma. In the endometrium and cervix, high-grade neoplasms are much more prevalent than low-grade and are more common in the cervix than the corpus. In the ovary, low-grade tumours are more common than high-grade carcinomas and the term carcinoid tumour is still used in WHO 2014. The term ovarian small-cell carcinoma of pulmonary type is included in WHO 2014 for a tumour which in other organs is termed high small-cell neuroendocrine carcinoma. Neuroendocrine tumours at various sites within the female genital tract often occur in association with other neoplasms and more uncommonly in pure form.

Abstract 3093: Expression of DLL3 in metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas as potential indications for rovalpituzumab tesirine (Rova-T; SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody drug conjugate (ADC)

Abstract Expression of DLL3 was examined in additional tumor types, as it was found to be highly expressed in tumor-initiating cells (TIC) in small cell lung cancer (SCLC), where a DLL3-targeted antibody drug conjugate (ADC), rovalpituzumab tesirine (Rova-T; SC16LD6.5; Saunders et al. 2015 Sci Transl Med 7:302ra136)) exerted clinically meaningful anti-tumor effects in a phase I trial (Spigel et al. 2016 Lancet Oncology; In Press). DLL3 expression was profiled by qRT-PCR, ELISA and immunohistochemistry in multiple tumor types. Patient-derived xenografts (PDX) from melanoma and ovarian small cell carcinoma were established and used for efficacy studies to determine the ability of Rova-T to impact tumor growth and TIC frequency. DLL3 expression was seen in metastatic melanoma (55%), low grade gliomas (90%), glioblastoma (70%), medullary thyroid cancer (65%), carcinoids (33%), dispersed neuroendocrine tumors in the pancreas (9%), bladder (57%) and prostate (24%), testicular cancer (90%), and lung adenocarcinomas with neuroendocrine features (80%). Unlike SCLC, where DLL3 does not predict clinical outcome on standard therapies, DLL3 expression negatively correlates with overall survival in melanoma and small cell bladder cancer. In mice bearing DLL3 positive melanoma PDX, treatment with a single dose of Rova-T resulted in effective and durable responses (>100 days), which correlated with a significant impact on TIC frequency. Similarly, in mice bearing DLL3-positive ovarian small cell PDX, a single dose of Rova-T resulted in effective and durable responses (>100 days). Our results show that DLL3 is expressed in many neuroendocrine tumors (lung, ovarian, prostate, bladder, etc), metastatic melanoma, medullary thyroid cancer, low-grade gliomas and glioblastoma. Given pre-clinical results showing efficacy of Rova-T in melanoma and ovarian small cell carcinoma, as well as encouraging clinical data with Rova-T in patients with recurrent/refractory SCLC, clinical evaluation of Rova-T in DLL3-positive melanoma, glioblastoma, medullary thyroid cancer and other high-grade neuroendocrine carcinomas is warranted. A “basket” trial enrolling patients with DLL3-positive solid tumors is now recruiting patients (NCT02709889). Citation Format: Laura R. Saunders, Samuel A. Williams, Sheila Bheddah, Kumiko Isse, Sarah Fong, Marybeth A. Pysz, Himisha Beltran, Loredana Puca, Verena Sailer, Juan M. Mosquera, Yu Yin, Jiaoti Huang, Andrew J. Armstrong, Jorge Garcia, Cristina Magi-Galluzzi, Vadim Koshkin, Petros Grivas, Farhad Kosari, John Cheville, Justin C. Moser, Thomas J. Flotte, Thorvardur Halfdanarson, Aaron Mansfield, Konstantinos N. Leventakos, Julian R. Molina, Douglas W. Ball, Barry D. Nelkin, Jill E. Shea, Courtney L. Scaife, Scott J. Dylla. Expression of DLL3 in metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas as potential indications for rovalpituzumab tesirine (Rova-T; SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody drug conjugate (ADC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3093. doi:10.1158/1538-7445.AM2017-3093

Case 2 – Ovarian small cell carcinoma: a case report and review of the literature

Ovarian small cell carcinoma is a rare tumor associated with poor prognosis. Although combination chemotherapy remains the cornerstone of treatment due to the rarity of these tumors, there is no evidencebased consensus for a standard treatment, although in the majority of cases platinum-based regimens are used. A case of small cell carcinoma of the ovary, hypercalcemic-type (SCCOHT), in a 22 year-old patient is reported.

Claudin-4 expression distinguishes SWI/SNF complex-deficient undifferentiated carcinomas from sarcomas

Inactivation of SWI/SNF (switch/sucrose non-fermentable) chromatin remodeling complex subunits is a feature shared by select carcinomas and sarcomas with epithelioid morphology and variable keratin expression, making the distinction between carcinoma and sarcoma challenging in some cases. The tight junction-associated protein claudin-4 is a marker of epithelial differentiation that is expressed in nearly all carcinomas. Claudin-4 expression has been reported in the glandular component of biphasic synovial sarcoma but has not been systematically evaluated in other sarcoma types. In this study we assessed claudin-4 expression in SWI/SNF complex-deficient neoplasms showing loss of SMARCB1 (INI1), SMARCA4 (BRG1), or ARID1A and other sarcomas with epithelioid morphology. Immunohistochemistry for claudin-4 was performed on 130 neoplasms, including 90 soft tissue tumors with epithelioid morphology and/or SMARCB1 deficiency (20 epithelioid sarcomas (10 conventional, 10 proximal-type); 10 epithelioid angiosarcomas; 10 epithelioid hemangioendotheliomas; 15 epithelioid malignant peripheral nerve sheath tumors; 10 malignant rhabdoid tumors; 15 myoepithelial carcinomas; 10 biphasic synovial sarcomas), 10 ovarian clear cell carcinomas, 10 ovarian small cell carcinomas of hypercalcemic type, and 20 SWI/SNF complex-deficient undifferentiated carcinomas (14 SMARCB1 deficient and 6 SMARCA4 deficient, including rhabdoid carcinomas of various sites and sinonasal carcinomas). Membranous expression of claudin-4 (≥5% of cells) was observed in all biphasic synovial sarcomas (epithelial component only), all ovarian clear cell carcinomas, and 16 (80%) SWI/SNF complex-deficient undifferentiated carcinomas. All other soft tissue tumors were negative for claudin-4, with the exception of two myoepithelial carcinomas and one malignant rhabdoid tumor. Interestingly, none of the ovarian small cell carcinomas of hypercalcemic type expressed claudin-4. In summary, expression of claudin-4 is highly specific for true epithelial differentiation and may be useful to distinguish SWI/SNF complex-deficient undifferentiated carcinomas from sarcomas with epithelioid morphology. The lack of claudin-4 expression in ovarian small cell carcinomas of hypercalcemic type suggests that these tumors may be better regarded as sarcomas rather than carcinomas.

Valor de la determinación inmunohistoquímica de SMARCA4/BRG1 en el diagnóstico del carcinoma de ovario de célula pequeña variante hipercalcémica. Presentación de dos casos

Small cell carcinoma of ovary-hypercalcemic type is an undifferentiated carcinoma. We describe two cases in women aged 32 and 29. Both presented with large masses and complete surgical extirpation was impossible. Histologically, the images were similar, with diffuse cell proliferation, accompanied by the presence of follicle-like spaces. In both cases it was necessary to make a differential diagnosis with entities such as adult or juvenile granulosa cell tumour, small cell carcinoma of pulmonary type, dysgerminoma and even peripheral neuroectodermal tumour. The absence of SMARCA4/BRG1 immunostaining proved very useful in the diagnosis of hypercalcemic small cell ovarian carcinoma.

ANNA-1 Paraneoplastic Encephalomyelitis Presenting as Rapidly Progressing Dementia in a Man With Undiagnosed Small Cell Lung Cancer

ANNA-1 Paraneoplastic Encephalomyelitis Presenting as Rapidly Progressing Dementia in a Man With Undiagnosed Small Cell Lung Cancer

Prophylactic BSO in an Adolescent Patient With a SMARCA4 Mutation and a Family History of Small Cell Ovarian Carcinoma [8P

INTRODUCTION: Small cell carcinoma of the ovary hypercalcemic type is a rare malignancy that affects young women. Mutations in the SMARCA4 gene have been implicated as the main factor underlying oncogenesis and correlate strongly with disease presence. Several germline mutations with multiple affected family members have been described, although little is known about disease penetrance. METHODS: We describe our experience with a young asymptomatic patient found to have a SMARCA4 mutation and strong family history. RESULTS: A 15 year old female with two half-sisters diagnosed with SMARCA4 positive SCCOHT tested positive for the SMARCA4 gene mutation during screening of family members. The patient ultimately opted for prophylactic bilateral salpingo-oophorectomy. She underwent both genetic and reproductive endocrinology consultations preoperatively, but elected to forgo oocyte preservation. She is currently being treated with hormone replacement therapy. CONCLUSION: With recent advances in our understanding of the genetic basis of SCCOHT, identifying germline SMARCA4 mutation carriers at an early age will become more common. Management of these patients is challenging, given young age of disease onset, highly lethal course, and unknown gene penetrance. Prophylactic salpingo-oophorectomy is a reasonable therapeutic option, but requires aggressive management of subsequent surgical menopause and threatened fertility.

Abstract IA16: SWI/SNF (BAF) complex mutations in cancer

Abstract Data emerging over the last several years implicate the SWI/SNF (BAF) chromatin remodeling complex as a major tumor suppressor as frequent inactivating mutations in at least eight SWI/SNF subunits have been identified in a variety of cancers. These include inactivating mutations of the gene encoding the ARID1A (BAF250a) subunit in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers; and of the BRG1 (SMARCA4) subunit in non-small cell lung cancers, medulloblastomas and ovarian small cell carcinomas. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription. My laboratory began studying the SWI/SNF complex when the SNF5 (SMARCB1/INI1/BAF47) subunit was first identified as a tumor suppressor over a decade ago when it was found to be recurrently and specifically inactivated in a highly aggressive type of pediatric cancer called malignant rhabdoid tumor. We now study the complex using mouse models, cell lines and primary human tumor samples. Our goals are to elucidate the normal function of the complex, identify the mechanisms by which subunit mutations drive cancer formation, and utilize this insight to identify and develop novel therapeutic approaches. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented. Citation Format: Charles W. M. Roberts. SWI/SNF (BAF) complex mutations in cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA16.

Loss of SMARCA4 Expression Is Both Sensitive and Specific for the Diagnosis of Small Cell Carcinoma of Ovary, Hypercalcemic Type.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare ovarian neoplasm that occurs in young women and has a poor prognosis. The histologic diagnosis of SCCOHT can be challenging due to its rarity and relatively nonspecific histologic features, which range from the classic, first-described small cell morphology to a pattern in which there are large cells with abundant eosinophilic cytoplasm. Many entities can be in the differential diagnosis and to date, immunohistochemical stains have shown no distinctive profile and have been of limited aid. SMARCA4 (also known as BRG1) mutations have recently been reported at high frequency in these tumors. SMARCA4 is an important component of the SWI/SNF complex that regulates gene expression through alteration of nucleosome conformation. Studies to date have suggested that immunohistochemical loss of expression of SMARCA4 is associated with the presence of a SMARCA4 mutation in most cases. In this study, the sensitivity and specificity of the immunohistochemical loss of SMARCA4 expression for the diagnosis of SCCOHT is examined in the context of the differential diagnosis with other primary or metastatic ovarian tumors. All but one of the SCCOHT showed loss of SMARCA4 expression (16/17; 94%), while of 279 other tumors tested, only two tumors (one clear cell carcinoma and one ovarian melanoma) showed loss of SMARCA4 expression. We conclude that SMARCA4 immunohistochemistry is highly sensitive and specific for a diagnosis of SCCOHT and is of clinical utility in the differential diagnosis of poorly differentiated ovarian tumors.

Abstract IA12: SWI/SNF (BAF) complex mutations in cancer

Abstract Data emerging over the last several years implicate the SWI/SNF (BAF) chromatin remodeling complex as a major tumor suppressor as frequent inactivating mutations in at least eight SWI/SNF subunits have been identified in a variety of cancers. These include inactivating mutations of the gene encoding the ARID1A (BAF250a) subunit in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers; and of the BRG1 (SMARCA4) subunit in non-small cell lung cancers, medulloblastomas and ovarian small cell carcinomas. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription. My laboratory began studying the SWI/SNF complex when the SNF5 (SMARCB1/INI1/BAF47) subunit was first identified as a tumor suppressor over a decade ago when it was found to be recurrently and specifically inactivated in a highly aggressive type of pediatric cancer called malignant rhabdoid tumor. We now study the complex using mouse models, cell lines and primary human tumor samples. Our goals are to elucidate the normal function of the complex, identify the mechanisms by which subunit mutations drive cancer formation, and utilize this insight to identify and develop novel therapeutic approaches. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented. Citation Format: Charles W. M. Roberts. SWI/SNF (BAF) complex mutations in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA12.

Abstract IA06: SWI/SNF chromatin remodeling complex mutations in cancer: Mechanisms and potential therapeutic insights

Abstract Data emerging over the last several years implicate the SWI/SNF (BAF) chromatin remodeling complex as a major tumor suppressor as frequent inactivating mutations in at least eight SWI/SNF subunits have been identified in a variety of cancers. These include inactivating mutations of the gene encoding the ARID1A (BAF250a) subunit in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers; and of the BRG1 (SMARCA4) subunit in non-small cell lung cancers, medulloblastomas and ovarian small cell carcinomas. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription. My laboratory began studying the SWI/SNF complex when the SNF5 (SMARCB1/INI1/BAF47) subunit was first identified as a tumor suppressor over a decade ago when it was found to be recurrently and specifically inactivated in a highly aggressive type of pediatric cancer called malignant rhabdoid tumor. We now study the complex using mouse models, cell lines and primary human tumor samples. Our goals are to elucidate the normal function of the complex, identify the mechanisms by which subunit mutations drive cancer formation, and utilize this insight to identify and develop novel therapeutic approaches. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented. Citation Format: Charles W.M. Roberts. SWI/SNF chromatin remodeling complex mutations in cancer: Mechanisms and potential therapeutic insights. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA06.

Unusual malignant neoplasms of ovary in children: two cases report.

Sex cord tumors with annular tubules are known to originate from the sex cord of embryonic gonads that synthesize Sertoli cells, Leydig cells, granulosa cells, and theca cells of the ovarian stroma, while ovarian small cell carcinoma of the hypercalcemic type is a type of neuroendocrine tumor. Both these tumors are uncommon, potentially malignant neoplasms in children. We report the case of a sex cord tumor with annular tubules in an 11-year-old girl and a case of small cell carcinoma of the hypercalcemic type in a 10-year-old girl. We also discuss the prognosis and management of these tumors.

Small cell carcinoma of ovary, hypercalcemic type: analysis of clinicopathologic characteristics and the diagnostic utility of loss expression of SMARCA4 protein

To study the clinicopathologic features of small cell carcinoma of ovary, hypercalcemic type (SCCOHT) and to evaluate the diagnostic significance of loss of SMARCA4 expression. The clinicopathologic characteristics of 5 cases of SCCOHT were reviewed. The expression of SMARCA4 protein was detected by immunohistochemistry in the cases of SCCOHT and 240 cases of other primary malignant tumors of ovary and peritoneum. The mean and medium age of these patients was 30 years and 28 years, respectively. The presenting symptoms included abdominal pain, distention and a pelvic mass. Hypercalcemia was found in 3 patients. The maximum diameter of tumors ranged from 13.5 to 22.0 cm. Extraovarian spread was demonstrated in all of the patients on presentation. Histologically, the tumors were composed of closely packed small round cells with scanty cytoplasm, hyperchromatic nuclei and irregular chromatin clumps. The tumor cells grew in sheets, nests, cords or trabecular pattern. Follicle-like spaces were observed in 4 cases. Three of the tumors contained large cells with abundant eosinophilic cytoplasm. Spindle cell morphology was found in 1 case. There were 2 cases with myxoid or hyaline stroma. Four out of five of SCCOHT cases showed loss of SMARCA4 protein while only 6.3% (15/240) of the other primary malignant tumors of ovary and peritoneum , including undifferentiated carcinoma (1/5), high-grade serous carcinoma (4.6%, 5/109), endometrioid carcinoma (7.7%, 2/26), clear cell carcinoma (1/9), mucinous carcinoma (1/5), mixed carcinoma (4.9%, 3/61), carcinosarcoma (1/9) and high-grade serous carcinoma of peritoneum (1/9), were negative. SCCOHT is a rare malignant tumor and often misdiagnosed as other types of ovarian small cell tumor. Loss expression of SMARCA4 protein is characteristic and facilitates the diagnosis and differential diagnosis of SCCOHT.

Abstract A1-27: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) beyond SMARCA4 mutations: A comprehensive genomic analysis

Abstract Background: Small cell ovarian carcinoma of the hypercalcemic type (SCCOHT) is an extremely rare and aggressive tumor that affects mainly young women (median age = 24 years). Prognosis is poor as most patients die within 2 years of diagnosis. Until recently, the literature describing the genomic profile of SCCOHT was scarce. In the last few months, four groups have now confirmed that SMARCA4 mutations are a frequent event in SCCOHT. Methods: We performed an integrated genomic analysis using WES, RNA-seq and CGH approaches to identify other recurrent genomic alteration and potential therapeutic targets. Candidate SNVs identified by WES were validated by Sanger and RNA-Seq. 8 frozen tumors were available, including 6 with matching normal control DNA. In addition 33 tumor samples were available as FFPE. Results: Despite their high grade and aggressive clinical course, SCCOHT tumors display genomic stability, low mutation load (0.53mut.Mb) and few SCNAs. However when present, genomic alterations were recurrent. Integrated WES and CGH analysis revealed a frequent and unusual 19p CN LOH (in 5 of 6 tumors). Although overall mutation rate was low, the mutations that did occur were novel and recurrent in 50%-80% of SCCOHT. In addition to SMARCA4 mutation (M+), we validated 10 novel recurrent M+ (including ABCA7, ANKRD24, CACTIN, EMR1, FBN3, FUT5, GRIN3B, KANK3, KRI1 and PLK5) in 50%-80% of tumors at high allelic frequencies (mean=0.87). Similarly, when present, amplifications were recurrent, common to a third of tumors: such as the mitochondrial redox enzymes (SHMT2, NDUFA4L2) or the transmembrane transporter LRP1 were amplified (Log2>2.3). No common fusion transcripts were identified. Since SCCOHT often display initial chemosensitivity, but rapid progressions, we investigated the differential genomic profiles of treatment naive versus chemotherapy treated tumors to uncover candidate resistance genes. The only alteration significantly enriched in post treatment tumors were M+ in the putative efflux pump, ABCA7. These M+ could not be identified even at low allele fractions in treatment naive tumors, but were identified in all 3 treated tumors with a mean allelic frequency of 0.83. In terms of therapeutic implications, modulating mitochondrial metabolism or targeting the membrane transporter LRP1 or the ABCA7 efflux pump could provide therapeutic venues in the future. However the most promising approaches for now may be targeting cell cycle checkpoint regulators or chromatin remodelling. M+ in the tumor suppressor PLK5 were confirmed in 79% of a cohort of 33 SCCOHT and many were predicted as damaging. Inactivation of PLK5 is associated with a loss of G2/M checkpoint regulation and cell harbouring PLK5 mutations were sensitive to PLK1 inhibitors. More interestingly, SMARCA4-M+ SCCOHT demonstrated complete loss of SMARCA4 expression as well as loss of the only other SWI/SNF catalytic subunit SMARCA2 suggesting that double SMARCA4/SMARCA2 negative SCCOHTs are characterized by a catalytically inactive SWI/SNF complex. This hypothesis was supported by changes in RNA expression levels in the main transcriptional targets for SWI/SNF (RHOA, RB and the E2F family). Importantly, the double SMARCA2/4 negative BIN-67 SCCOHT cell line displaying both a SMARCA4 M+ and loss of SMARCA2 expression was exquisitely sensitive to HDAC and MT inhibitors, while cell lines with either a SMARCB1-M+ or SMARCA4-M+ with retained SMARCA2 expression were not. These data make double SMARCA2/4 negative by IHC a potential predictive biomarker for histone modifying inhibitors in SCCOHT or potentially in other double SMARCA2/4 negative malignancies. Conclusions: We present the 1st integrated genomic analysis of SCCOHT. SCCOHT demonstrate a remarkably homogeneous genomic profile and potentially actionable alterations. In particular, dual null SMARCA2/SMARCA4 SCCOHTs could be selected for clinical trials with EZH2, HDAC or MT inhibitors. Citation Format: Aurélie Auguste, Marc Deloger, Joanna Cyrta, Audrey Le Formal, Catherine Richon, Nathalie Droin, Beatrice Brunn, Olivier Caron, Mojgan Devouassoux, Catherine Lhomme, Patricia Pautier, Catherine Genestie, Alexandra Leary. Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) beyond SMARCA4 mutations: A comprehensive genomic analysis. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-27.