Malignant Sex Cord-stromal Tumors Research Articles

Impact of surgery and chemotherapy in ovarian sex cord-stromal tumors from the multicentric Salomé study including 469 patients. A TMRG and GINECO group study

ObjectiveIdentifying prognostic factors and evaluating the impact of adjuvant chemotherapy in patients with sex cord stromal tumors (SCST) is crucial. In this study, we aimed to address these challenges. MethodsWe conducted a retrospective analysis of data from 13 centers of the French Rare malignant gynecological tumors (TMRG) network. We enrolled 469 adult patients with malignant SCST who received upfront surgery since 2011 to July 2015. Results75% were diagnosed with adult Granulosa cell tumors, and 23% had another subtype. With a median follow-up of 6.4 years, 154 patients (33%) developed a first recurrence, 82 (17%) two recurrences, and 49 (10%) three recurrences. Adjuvant chemotherapy was administered in 14.7% of patients at initial diagnosis. In relapse, perioperative chemotherapy was administered in 58.5%, 28.2%, and 23.8% of patients, respectively, in the first, second, and third relapse.In the first-line therapy, age under 70 years, FIGO stage, and complete surgery were associated with longer progression-free survival (PFS). Chemotherapy had no impact on PFS in early-stage disease (FIGO I-II). The PFS was similar using BEP or other chemotherapy regimens (HR 0.88 [0.43; 1.81]) in the first-line therapy. In case of recurrence, PFS was statistically prolonged by complete surgery, but perioperative chemotherapy use did not impact PFS. ConclusionChemotherapy use did not impact survival in the first-line or relapse setting in SCST. Only surgery and its quality demonstrated benefit for PFS in ovarian SCST in any lines of treatment.

A Deep Learning–Based System Trained for Gastrointestinal Stromal Tumor Screening Can Identify Multiple Types of Soft Tissue Tumors

The accuracy and timeliness of the pathologic diagnosis of soft tissue tumors (STTs) critically affect treatment decision and patient prognosis. Thus, it is crucial to make a preliminary judgement on whether the tumor is benign or malignant with hematoxylin-and-eosin-stained images. Here, we present a deep learning-based system, STT-BOX, with only hematoxylin-and-eosin images for malignant STT identification from benign STTs with histopathologic similarity. STT-BOX assumed gastrointestinal stromal tumor as a baseline for malignant STT evaluation, and distinguished gastrointestinal stromal tumor from leiomyoma and schwannoma with 100% area under the curve in patients from three hospitals, which achieved higher accuracy than the interpretation of experienced pathologists. Particularly, this system performed well on six common types of malignant STTs from The Cancer Genome Atlas data set, accurately highlighting the malignant mass lesion. Moreover, without any fine-tuning, STT-BOX was capable of distinguishing ovarian malignant sex-cord stromal tumors. Our study includes mesenchymal tumors that originated from the digestive system, bone and soft tissues, and reproductive system, where the high accuracy of migration verification may reveal the morphologic similarity of the nine types of malignant tumors. Further evaluation in a pan-STT setting would be potential and prospective, obviating the overuse of immunohistochemistry and molecular tests, and providing a practical basis for clinical treatment selection in a timely manner.

Treatment and survival of patients with malignant ovarian sex cord-stromal cell tumours: An analysis of the Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) study group CORSETT database.

Malignant sex cord-stromal cell tumours (SCST) account for only 7% of ovarian malignancies. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) study group has established a clinicopathological database to provide an overview of the current treatment strategies and survival of SCST patients and to identify research needs. Twenty centres provided mixed retro- and prospective data of patients with tumour specimens and second-opinion pathology review treated between 2000 and 2014. Descriptive analyses of treatment strategies, Kaplan-Meier curves and cox regression analyses were conducted. Two hundred and sixty-two SCST patients were included. One hundred and ninety-one Granulosa-cell tumour (GCT) and 17 Sertoli-Leydig cell tumour (SLCT) patients were stage I disease (>80%). Forty four GCT (18.7%) and two (8.3%) SLCT patients received adjuvant systemic treatment. After a median observation time of 78.2 months, 46% of all SCST patients experienced disease recurrence, treated predominantly with secondary debulking surgery (> 90%). Advanced FIGO stage, lymph node involvement and intra-operative capsule rupture were associated with disease recurrence on univariate analysis (all p < 0.05). Median OS time was not reached. In this analysis of SCST patients, adjuvant chemotherapy was unable to prevent disease recurrence. Despite high recurrence rates, overall survival rates were excellent.

Analysis of the Safety and Pregnancy Outcomes of Fertility-sparing Surgery in Ovarian Malignant Sex Cord-stromal Tumours: A Multicentre Retrospective Study

AimsTo assess the difference in survival between fertility-sparing surgery (FSS) and radical surgery and explore pregnancy outcomes after FSS in stage I malignant sex cord-stromal tumours (MSCSTs). Materials and methodsWe carried out a multicentre retrospective cohort study on patients who were diagnosed with MSCSTs and the tumour was confined to one ovary. The patients were divided into FSS and radical surgery groups. Inverse probability of treatment weighting (IPTW) was used to balance variables between the two groups. Kaplan–Meier analysis was used to compare the difference in disease-free survival (DFS). Univariate and multivariate Cox regression analysis was used to find risk factors of DFS. Univariate logistic regression analysis was used to assess risk factors of pregnancy. ResultsIn total, 107 patients were included, of whom 54 (50.5%) women underwent FSS and 53 (49.5%) received radical surgery. After IPTW, a pseudo-population of 208 was determined and all of the covariates were well balanced. After a median follow-up time of 50 months (range 7–156 months), 10 patients experienced recurrence and two died. There was no significant difference in DFS between the two groups, both in unweighted (P = 0.969) or weighted cohorts (P = 0.792). In the weighted cohort, stage IC (P = 0.014), tumour diameter >8 cm (P = 0.003), incomplete staging surgery (P = 0.003) and no adjuvant chemotherapy (P < 0.001) were the four high-risk factors associated with a shorter DFS. Among 14 patients who had pregnancy desire, 11 (78.6%) women conceived successfully; the live birth rate was 76.9%. In univariate analysis, only adjuvant chemotherapy (P = 0.009) was associated with infertility. ConclusionsOn the premise of complete staging surgery, FSS is safe and feasible in early stage MSCSTs with satisfactory reproductive outcomes.

Malignant testicular unclassified sex cord stromal tumor: a case report

BackgroundMost testicular tumors are germ cell tumors; sex cord stromal tumors are infrequent, accounting for only 3–5% of testicular tumors. Unclassified sex cord stromal tumors are extremely rare. Generally, 10% of sex cord stromal tumors are malignant. We report a case of malignant unclassified sex cord stromal tumor with retroperitoneal lymph node metastasis at first visit and a corresponding literature review.Case presentationA 72-year-old Japanese man visited our department primarily for indolent right scrotum enlargement in September 2020. Blood biochemistry examination, urinalysis, and tumor markers (alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase) showed no abnormal findings. Contrast-enhanced computed tomography showed enlarged para-aortic lymph node (18 × 16 and 10 × 102 mm); a 50 × 452 mm mass with uneven contents was found in the right testicle. The patient underwent inguinal orchiectomy in September 2020. As per immunohistochemistry, the tumor cells were diffusely positive for SF-1 and Ki-67, partially positive for inhibin, and negative for CAM5.2, CK7, CK20, C-KIT, CD30, LCA, GATA-3, TTF-1, and PAX8. Calretinin was expressed in approximately 5% of tumor cells; thus, sex cord/gonadal stroma components were considered to be involved. The final pathological diagnosis was unclassified malignant sex cord stromal tumor. The patient was diagnosed with pT1, N1, M0, S0, and tumor–node–metastasis stage IIA disease. The patient received postoperative chemotherapy with four courses of etoposide and cisplatin therapy from November 2020. Post-chemotherapeutic computed tomography showed new metastatic lesions including lung, liver, pancreas, and para-aortic lymphadenopathy, which increased in size. Disease progression was observed. Cancer genome research was performed using the OncoGuide National Cancer Center oncopanel system; however, no gene mutation for which the drug could be expected to be effective was found. The patient opted for best supportive care at a nearby hospital and died from cancer progression in January 2022.ConclusionWe encountered a case of malignant testicular unclassified sex cord stromal tumor pathologically diagnosed as testicular tumor with retroperitoneal lymph node metastasis in a patient who underwent inguinal orchiectomy. Future data collection is necessary to establish multimodality therapy for malignant testicular unclassified sex cord stromal tumor.

Survival and pregnancy outcomes of fertility-sparing surgery for ovarian malignant sex cord-stromal tumors: A multicenter retrospective study (176)

<b>Objectives:</b> To assess the survival and pregnancy outcomes of fertility-sparing surgery (FSS) in stage I ovarian malignant sex cord-stromal tumors (MSCSTs). <b>Methods:</b> Inverse Probability of Treatment Weighting (IPTW) was performed between the FSS and radical surgery (RS) groups. The Chi-square test and Kaplan-Meier method were used to compare the categorical variables and disease-free survival (DFS). The binary logistic regression analysis and Cox proportional hazards regression analysis were used to identify risk factors related to pregnancy and DFS. <b>Results:</b> A total of 107 patients were included, of whom 54 (50.5%) women underwent FSS, and 53 (49.5%) women underwent RS. After IPTW, 208 patients were obtained, and all of the covariates were well balanced. After a median follow-up time of 50 months (range: 7-156 months), there was no significant difference of DFS between the two groups in both unweighted cohort (p=0.969) or weighted cohort (p=0.792). In the weighted cohort, stage IC (p=0.014), tumor diameter >8 cm (p=0.003), without staging surgery (p=0.003), and no adjuvant chemotherapy (P <0.001) were the four high-risk factors associated with a shorter DFS. Among 14 patients who had pregnancy desire, 11 (78.6%) women conceived successfully, and the live birth rate was 76.9%. In univariate analysis, only adjuvant chemotherapy (p=0.009) was associated with pregnancy. <b>Conclusions:</b> FSS is safe in stage IA and IC MSCSTs with a satisfactory reproductive outcome on the premise of complete staging surgery.

Three Different Ways to Miss a Granulosa Cell Tumor – A Lesson to be Learne

Granulosa cell tumours (GCTs) account for approximately 70% of malignant sex-cord stromal tumors but are still uncommon and comprise only 2–5% of all ovarian neoplasms. They are classified as adult and juvenile GCTs. These are often low grade malignancies and are usually diagnosed in early stages, but with an potential for late recurrence. Case 1: A 51-year woman with c/o PMB with biopsy showing endometrial polyp. She underwent a total abdominal hysterectomy and a bilateral salpingo-oophorectomy (TAH BSO) with omental biopsy after intraoperative pathology confirmation of a Adult granulosa cell tumor (AGCT) of the ovary. She had a good post-operative recovery and was advised for regular and long term follow up. Case 2: A 63-year woman c/o PMB with an adult granulosa cell tumor that initially presented as endometrial hyperplasia on biopsy. She underwent a TAH BSO and omental biopsy after intraop frozen section confirmed of AGCT of the ovary. She had an uneventful post-operative recovery. Case 3: A 68-year womanwith an AGCT that was initially treated as endometrial carcinoma. She underwent a Comprehensive Surgical Staging due to initial misdiagnosis of endometrial carcinoma. Her final biopsy report showed it to be a granulosa cell tumor of the ovary and adenocarcinoma of the endometrium. She had a good post-operative recovery and is being followed up till now. The multifaceted presentations with its erratic biological behaviour coupled with late recurrences are diagnostic pitfalls necessitating a high degree of suspicion for accurate clinical diagnosis.

The 2020 Japan Society of Gynecologic Oncology guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

The fifth edition of the Japan Society of Gynecologic Oncology guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer was published in 2020. The guidelines contain 6 chapters—namely, (1) overview of the guidelines; (2) epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (3) recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (4) borderline epithelial tumors of the ovary; (5) malignant germ cell tumors of the ovary; and (6) malignant sex cord-stromal tumors. Furthermore, the guidelines comprise 5 algorithms—namely, (1) initial treatment for ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (2) treatment for recurrent ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (3) initial treatment for borderline epithelial ovarian tumor; (4) treatment for malignant germ cell tumor; and (5) treatment for sex cord-stromal tumor. Major changes in the new edition include the following: (1) revision of the title to “guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer”; (2) involvement of patients and general (male/female) participants in addition to physicians, pharmacists, and nurses; (3) clinical questions (CQs) in the PICO format; (4) change in the expression of grades of recommendation and level of evidence in accordance with the GRADE system; (5) introduction of the idea of a body of evidence; (6) categorization of references according to research design; (7) performance of systematic reviews and meta-analysis for three CQs; and (8) voting for each CQ/recommendation and description of the consensus.

Ovarian fibrosarcoma: A single-institution experience and a review of the literature

Ovarian fibrosarcoma is an extremely rare and malignant sex cord-stromal tumor. Due to its low incidence and poor prognosis, until now, very few cases have been reported, and most of the reported cases have been sporadic. Therefore, the treatments and prognostic factors of ovarian fibrosarcoma are still debatable. Here, we report 5 cases of ovarian fibrosarcoma that presented at Peking Union Medical College Hospital over the past 20 years. The 5 patients were 41, 51, 54, 76, and 76 years of age when initial symptoms of pelvic mass or pain appeared. On ultrasound, this disease usually manifests as unilateral pelvic masses, within which uneven echo enhancement and some blood flow signals are observed. No significant increase was observed in the levels of preoperative tumor markers, such as serum CA125 and sex hormones. The final diagnosis depends on postoperative histopathological results since these tumors are easily misdiagnosed when intraoperative frozen sections are used for examination. Pathologic examinations showed that the tumor cells were spindle-shaped with moderate to severe atypia and high mitotic counts. The immunohistochemistry profile is not specific, but the positive rate of Ki-67 was consistent with the degree of malignancy and the prognosis of patients with this tumor. In addition, the tumor may also be positive for Vimentin, α-inhibin, SMA, estrogen receptor and progesterone receptor. Significant differences were observed in the surgical methods used, and no unified chemotherapy regimen has been established. The overall survival was > 15, >7, > 6, <1, and < 1 year for each patient. After reviewing the literature, evidence-based large-scale case studies were lacking. For treatments, complete cytoreductive surgery plus regimens typically used against malignant sex cord-stromal tumors, as described in the NCCN guidelines, are recommended. Due to its low incidence, both multicenter clinical studies and molecular studies are required to provide gynecologists with a better understanding and guidance for future management of patients with ovarian fibrosarcoma.

Preoperative Differentiation of Benign and Malignant Non-epithelial Ovarian Tumors: Clinical Features and Tumor Markers.

To evaluate the role of clinical features and preoperative measurement of cancer antigen 125 (CA125), human epididymis protein (HE4), and carcinoembryonic antigen (CEA) serum levels in women with benign and malignant non-epithelial ovarian tumors. One hundred and nineteen consecutive women with germ cell, sex cord-stromal, and ovarian leiomyomas were included in this study. The preoperative levels of biomarkers were measured, and then surgery and histopathological analysis were performed. Information about the treatment and disease recurrence were obtained from the medical files of patients. Our sample included 71 women with germ cell tumors (64 benign and 7 malignant), 46 with sex cord-stromal tumors (32 benign and 14 malignant), and 2 with ovarian leiomyomas. Among benign germ cell tumors, 63 were mature teratomas, and, among malignant, four were immature teratomas. The most common tumors in the sex cord-stromal group were fibromas (benign) and granulosa cell tumor (malignant). The biomarker serum levels were not different among benign and malignant non-epithelial ovarian tumors. Fertility-sparing surgeries were performed in 5 (71.4%) women with malignant germ cell tumor. Eleven (78.6%) patients with malignant sex cord-stromal tumors were treated with fertility-sparing surgeries. Five women (71.4%) with germ cell tumors and only 1 (7.1%) with sex cord-stromal tumor were treated with chemotherapy. One woman with germ cell tumor recurred and died of the disease and one woman with sex cord-stromal tumor recurred. Non-epithelial ovarian tumors were benign in the majority of cases, and the malignant cases were diagnosed at initial stages with good prognosis. The measurements of CA125, HE4, and CEA serum levels were not useful in the preoperative diagnosis of these tumors.

A clinicopathological study of granulosa cell tumors of the ovary: Can morphology predict prognosis?

Granulosa cell tumors (GCT) are low-grade malignant sex cord-stromal tumors (SCST) with late metastasis/recurrences and long disease-free periods. We performed a clinicopathological evaluation of GCT to ascertain features having prognostic impact. All cases of GCT of ovary from January 2006 to December 2018 were assessed for architectural patterns, nuclear grooves, and Call-Exner bodies. Each feature was graded on frequency of occurrence: not present (0)-very frequent (3). Anisonucleosis, necrosis, and inflammation were noted. Cases were grouped on mitotic count; <10 mitosis/10 High power field (HPF) or >=11 mitoses/10 HPF and Ki-67 index; <10% Ki-67 and >=11% Ki-67. GCT formed 60.1% of SCST. Sixty cases' ages were in the range of 15-78 years (median 45). Clinical details were available in 37. Commonest presentation was abnormal uterine bleeding. Serum CA125 was raised in 16.1% and Inhibin in 58.8%. Seventy percent were in stage I. Disease recurrence was associated with higher stage (P = 0.007). The most frequent pattern was diffuse sheets (47%). Call-Exner bodies were absent in 22.2%. Grooves with score 1, 2, and 3 were seen in 35.8%, 23.5%, and 13.6%, respectively. Anisonucleosis was present in 26.7%, necrosis in 11.1%, and lympho-plasmacytic infiltrate in 43%. Out of total, 93.3% had <10 mitosis/10 HPF and 43.2% had recurrence, most with high Ki-67 (P = 0.064). Our study outlines histomorphological spectrum of GCT and emphasizes its frequent occurrence in lower stages with late recurrences. The presence of grooves may indicate granulosa-cell origin. Call-Exner bodies are not a necessity. Histomorphological features are not prognostically important. However, prognostic value of Ki-67 cannot be excluded. Limitation of the study was a small number of cases with follow-up.

An Overview of Ovarian Tumours at B.P. Koirala Memorial Cancer Hospital, Nepal

Introduction: Ovarian cancer is the seventh most commonly diagnosed cancer among women in the world. This study was conducted with the aim to find out different histological types of ovarian tumours reported at B.P. Koirala Memorial Cancer Hospital (BPKMCH), Chitwan, Nepal.&#x0D; Methods: This was a retrospective study carried out at the Department of Pathology of BPKMCH from January 1, 2018 to December 31, 2018. This study included the patients who were operated at BPKMCH or referred cases from elsewhere, but the specimen was processed and reported at BPKMCH. All the data were retrieved and analyzed from the records of Pathology Department.&#x0D; Results: Altogether 87 cases of ovarian tumours were reported during the study period. Out of which, 31 cases were benign ovarian tumours whereas 56 cases were malignant ovarian tumours. Both benign and malignant ovarian tumours were most common in age group 41 to 50 years of age. Among benign ovarian tumours, 12 cases were serous cystadenoma, 7 cases mucinous cystadenoma, 6 cases mature cystic teratoma, 2 cases serous cyst adenofibroma, 2 cases benign Brenner tumour and 2 endometroid cystadenoma. Among malignant ovarian tumours, 33 cases were serous cystadenocarcinoma, 11 cases mucinous cystadenocarcinoma, 2 cases immature teratoma, 3 cases were malignant sex cord stromal tumours (granulosa cell tumour), 2 cases dysgerminoma, 1 case yolk sac tumour, 1 case endometroid carcinoma and 3 cases were metastatic adenocarcinoma.&#x0D; Conclusion: Surface epithelial tumours were most common ovarian tumours in this study. Serous cystadenomas were most common benign ovarian tumours whereas serous cystadenocarcinomas were the most common malignant ovarian tumours.

Characterization of an Unusually Aggressive Ovarian Malignant Sex Cord Stromal Tumor in an Adolescent Female With Peutz-Jeghers Syndrome

Abstract Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder with mutations in SKT11 (19p13.3), mucocutaneous hyperpigmentation, gastrointestinal hamartomatous polyposis, and increased cancer predisposition. A PJS-associated distinctive ovarian tumor is sex cord tumor with annular tubules (SCTAT), which is multifocal, microscopic, bilateral, and almost always clinically benign. Non-SCTAT ovarian tumors with malignant behavior are exceptionally rare. We describe a malignant, multiply recurrent, widely metastatic sex cord stromal tumor in PJS. Case Report: A 17-year-old female presented with new complaints of unintentional weight loss, alopecia, and abdominal fullness. She had a PJS diagnosis at age 7 with mucocutaneous pigmentation, gastrointestinal polyposis, and STK11 mutation. CT showed a 23-cm abdominopelvic mass with diffuse peritoneal metastases and malignant pleural effusion. CA-125 was elevated. CEA, CA 19-9, β-hCG, AFP, and LDH were normal. Laparoscopic biopsy pathology revealed a tumor composed of sheets and loose aggregates of mitotic spindled and round heterogenous eosinophilic and basophilic cells within fibromyxoid stroma. Rare tubules with eosinophilic cytoplasm and focal foamy cells were also seen. IHC was significant for inhibin, calretinin, CD56 and WT1 positivity, and cytokeratin and EMA negativity, consistent with poorly differentiated sex cord stromal tumor. Interestingly, EM showed neurosecretory dense core granules and neurite-like processes. After neoadjuvant therapy, the resected left adnexal mass was 25.5 cm, purple-gray/tan-red, heterogeneous, diffusely cystic, diffusely edematous, rubbery to spongy. In the left ovary were also found unassociated microscopic SCTAT foci. During adjuvant chemotherapy, the patient became pregnant. During the pregnancy, the patient developed liver and pelvic peritoneal recurrence and continued altered chemotherapy. She delivered a healthy late-preterm infant but also concurrently had diffuse peritoneal recurrence. She underwent two more cycles of adjuvant chemotherapy. Approximately 2 years after finishing adjuvant chemotherapy, she again developed peritoneal recurrences, which were resected, and partial chemotherapy response was seen on pathology. She is currently undergoing additional chemotherapy cycles 4 years since the initial diagnosis.

The value of MRI for differentiating benign from malignant sex cord-stromal tumors of the ovary: emphasis on diffusion-weighted MR imaging

BackgroundTo investigate MRI for differentiating benign from malignant sex cord-stromal tumors of the ovary (SCSTs) emphasizing on the value of diffusion-weighted (DW) magnetic resonance (MR) imaging.MethodsThis retrospective study included 29 benign SCSTs in 28 patients and 13 malignant SCSTs in 13 patients. DW imaging as well as conventional MR imaging was performed. Signal intensity on DW imaging was assessed and apparent diffusion coefficient (ADC) value was measured. In addition, T2 signal intensity and contrast enhancement pattern were also assessed and compared between benign and malignant SCSTs.ResultsBoth of the T2 hypointensity and mild enhancement were specific to benign SCSTs. The majority of malignant SCSTs showed high signal intensity on DW imaging, whereas most benign SCSTs showed low or moderate signal intensity (p = 0.000). Fibromas were the tumors with the lowest observed ADC value (0.470 × 10− 3 mm2/s). Sclerosing stromal tumors were the tumors with the highest observed ADC value (2.291 × 10− 3 mm2/s). ADC value of solid component was significantly lower in malignant SCSTs (0.825 ± 0.129 × 10− 3 mm2/s) than in benign SCSTs (1.343 ± 0.528 × 10− 3 mm2/s) when fibromas were excluded (p = 0.024). T2, DCE and DW imaging has a limited value on the differential diagnosis of the benign and malignant SCSTs with an accuracy of 69.0%,71.4% and 78.1% respectively. Combination of T2, DCE and DW imaging permitted the distinction with an accuracy of 88.0%.ConclusionsIt is more helpful for distinction of the benign and malignant SCSTs by combining of T2, DCE and DW imaging than using each of the three sequences independently.

Abstract PR13: TERT is frequently mutated in adult-type granulosa cell tumors of the ovary compared to other malignant sex cord-stromal tumors

Abstract The telomerase reverse transcriptase (TERT) gene is highly expressed in stem cells and silenced upon differentiation. Cancer cells can attain immortality by activating TERT to maintain telomere length and telomerase activity, a crucial step of tumorigenesis. Two somatic mutations in the TERT promoter (C228T; C250T) have been identified in multiple cancers, such as melanoma and glioblastoma, as gain-of-function mutations that promote transcriptional activation of TERT. A recent study investigating TERT promoter mutations in ovarian carcinomas found mutations in 15% of clear cell carcinomas. However, it is unknown whether these mutations are prevalent in adult-type granulosa cell tumors (AGCTs) of the ovary, Sertoli-Leydig cell tumors (SLCTs), and other malignant sex cord-stromal tumors. We performed whole-genome sequencing on ten AGCT cases with matched normal and identified the TERT C228T promoter mutation in 50% of cases. We found that AGCT cases with mutated TERT promoter have increased expression of TERT mRNA compared to those with wild-type TERT promoter. All five TERT promoter mutated cases had high levels of TERT mRNA expression, whereas three of the five wild-type TERT cases had no measurable TERT mRNA expression. There was a tendency towards longer telomere lengths in AGCT cases with the TERT promoter mutation relative to those without, although it was not statistically significant. These results suggest that telomerase may be activated by a different method in the cases with no TERT promoter mutations but have TERT mRNA expression. The remaining cases with neither TERT promoter mutations nor TERT mRNA expression likely maintain their telomeres using a telomerase-independent method, such as the alternative lengthening of telomeres pathway. TERT C228T allelic discrimination analysis of 331 AGCTs, 5 SLCTs, and 18 other malignant sex cord-stromal tumors detected the mutation in 56/247 (23%) of primary AGCTs, 22/84 (26%) of recurrent AGCTs, 1/5 (20%) of SLCTs and (0/18) 0% of other malignant sex cord-stromal tumors. The single SLCT case with the TERT promoter mutation was poorly differentiated and harbored the pathognomonic FOXL2 mutation of AGCT, suggesting this SLCT case may actually be an AGCT. In 204 AGCT cases with available survival data, there was a trend towards worse disease-specific survival in patients with the TERT promoter mutation compared to those without; however, statistical significance was not reached (p = 0.128, log-ranked test). In 5 AGCT cases with primary and recurrent tissues, we found that the TERT promoter mutation was absent in the primary tumors but present in the recurrent tumors, suggesting that TERT C228T mutation may play an active role in progression of AGCTs. Overall, we found that TERT C228T promoter mutation was most common in AGCTs among the different malignant sex cord-stromal tumors. Our data confirm the activation of telomerase in AGCTs via TERT C228T promoter mutation, although alternative telomerase activation methods in AGCTs may exist. Our results suggest that TERT activation may play a role in AGCT recurrence. As such, telomere biology may be important for the progression of AGCTs. This abstract is also being presented as Poster B54. Citation Format: Jessica A. Pilsworth, Dawn R. Cochrane, Zhouchunyang Xia, Geraldine Aubert, Anniina E. M. Färkkilä, Hugo M. Horlings, Satoshi Yanagida, Winnie Yang, Jamie L. P. Lim, Yikan Wang, Ali Bashashati, Jacqueline Keul, Adele Wong, Esther Oliva, Sohrab P. Shah, Stefan Kommoss, Friedrich Kommoss, Peter M. Lansdorp, Duncan M. Baird, David G. Huntsman. TERT is frequently mutated in adult-type granulosa cell tumors of the ovary compared to other malignant sex cord-stromal tumors. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr PR13.

Contribution of lymph node staging method and prognostic factors in malignant ovarian sex cord-stromal tumors: A world wide database analysis

ObjectiveTo investigate the clinicopathologic prognostic factors in patients with malignant sex cord-stromal tumors (SCSTs) with lymph node dissection, and at the same time, to evaluate the influence of the log odds of positive lymph nodes (LODDS) on their survival. MethodsPatients diagnosed with malignant SCSTs who underwent lymph node dissection were extracted from the 1988–2013 Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were estimated by Kaplan-Meier curves. The Cox proportional hazards regression model was used to identify independent predictors of survival. Results576 patients with malignant SCSTs and with lymphadenectomy were identified, including 468 (81.3%) patients with granulosa cell tumors (GCTs) and 80 (13.9%) patients with Sertoli-Leydig cell tumors (SLCTs). 399 (69.3%) patients and 118 (20.5%) patients were in the LODDS < −1 group and −1 ≤ LODDS < −0.5 group, respectively. The 10-year OS rate was 80.9% and CSS was 87.2% in the LODDS < −0.5 group, whereas the survival rates for other groups were 68.5% and 73.3%. On multivariate analysis, age 50 years or less (p < 0.001), tumor size of 10 cm or less (p < 0.001), early-stage disease (p < 0.001), and GCT histology (p ≤ 0.001) were the significant prognostic factors for improved survival. LODDS < −0.5 was associated with a favorable prognosis (OS: p = 0.051; CSS:P = 0.055). ConclusionsYounger age, smaller tumor size, early stage, and GCT histologic type are independent prognostic factors for improved survival in patients with malignant SCST with lymphadenectomy. Stratified LODDS could be regarded as an effective value to assess the lymph node status, and to predict the survival status of patients.

Prognostic significance of lymphadenectomyin malignant ovarian sex cord stromal tumor: A retrospective cohort study and meta-analysis

ObjectivesTo evaluate the prognostic significance of lymphadenectomy in malignant ovarian sex cord stromal tumor (SCST). MethodsThe medical records of patients with malignant ovarian SCST who underwent primary surgery from April 2005 to December 2016 were retrospectively reviewed in the Department of Obstetrics and Gynecology of Qilu Hospital. A meta-analysis was performed by searching the PubMed and Embase database up to July 20, 2017. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by STATA statistical software version 19.0. ResultsSeventy-two patients with malignant SCST were identified in our institution. The mean age of the patients was 44.3years (range, 8–80years). Among the 72 patients, 69.4% had granulosa cell tumors (GCTs, n=50); 47.2% (n=34) underwent lymphadenectomy, and 52.8% (n=38) did not undergo the surgery. None of the lymph nodes had pathologically confirmed metastasis. No significant differences in overall survival of the patients with SCST or GCT were noted based on patient age, tumor size, surgery extent, or administration of cytotoxic chemotherapy, except tumor stage (P=0.010 in SCTs and 0.029 in GCTs, respectively). Lymphadenectomy showed no statistically significant difference in overall survival of patients with SCST or GCT (P=0.734 and 0.079, respectively).In our meta-analysis, a total of 179 studies were identified through a search strategy, and 13 studies were included eventually; 3223 cases were identified, including those from our institution. The random-effects model was used because of moderate heterogeneity (I2=43.8%, P=0.040). The estimated pooled OR was 0.87 (95% CI, 0.57–1.31), indicating that lymphadenectomy has no statistical significance in improving overall survival in SCSTs (Z=0.68, P=0.496). ConclusionsTumor stage is the most important prognostic factor affecting SCST overall survival. There is no significant effect of lymphadenectomy in improving the overall survival of SCSTs. Lymphadenectomy is not recommended in initial staging surgery of SCST due to the extremely low lymph node metastasis rate.

Safety of Fertility-Sparing Surgery for Premenopausal Women With Sex Cord-Stromal Tumors Confined to the Ovary.

The aim of this retrospective population-based study was to investigate the oncologic safety of fertility-sparing surgery (FSS) for premenopausal women with malignant sex cord-stromal tumors (SCSTs) confined to the ovary. A cohort of women aged 18 to 49 years and diagnosed with a stage I malignant SCST between 1984 and 2013 was drawn from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Based on site-specific surgery codes, women who had FSS, defined as unilateral oophorectomy/tumor resection without hysterectomy, and definite surgery were identified. Cancer-specific survival and overall survival were evaluated after generation of Kaplan-Meier curves, whereas comparisons between the 2 groups were made with the log-rank test. A total of 255 women who met the inclusion criteria were identified; 161 (63.1%) underwent FSS whereas 94 (36.9%) had definitive surgery (bilateral salpingo-oophorectomy and hysterectomy). Median follow-up was 104 months. Cancer-specific survival (P = 0.015) but not overall survival (P = 0.76) was superior for women who had definite surgery. In this retrospective population-based cohort of premenopausal women with SCSTs confined to the ovary, FSS was associated only with a worse long-term cancer-specific survival compared with definitive surgery. Women undergoing FSS for early stage SCSTs should be extensively counseled and closely monitored.

A retrospective study of reproductive outcomes after fertility-sparing surgery and postoperative adjuvant chemotherapy in malignant ovarian germ cell tumors and sex cord-stromal tumors

BackgroundTo retrospectively investigate reproductive outcomes after fertility-sparing surgery and postoperative adjuvant chemotherapy in malignant ovarian germ cell tumors (MOGCT) and sex cord-stromal tumors (SCST).MethodsData from 32 MOGCT (6 dysgerminomas, 6 yolk sac tumors, 17 immature teratomas, and 3 mixed germ cell tumors) and 9 SCST (4 granulosa cell tumors and 5 sertoli-leydig cell tumors) aged from 18 to 35, treated in the Obstetrics and Gynecology Hospital of Fudan University from October 2003 to October 2013 were collected and analyzed.ResultsAverage follow up was (86.3 ± 34.4) months. Average diagnosed age was (25.3 ± 3.5) years. Average chemotherapy course was (4.4 ± 1.3) times. Patients are all living. Thirty one patients (75.6%) reported normal menstrual cycles. Twelve patients (29.3%) wished to conceive, 10 (83.3%) naturally conceived and 8 (66.7%) had lived birth.ConclusionsReproductive outcomes after fertility-sparing surgery and postoperative adjuvant chemotherapy in MOGCT and SCST are favorable, meanwhile education and consultation is needed.

Luteinizing hormone elevation in ovarian granulosa cell tumor: a case report and review of the literature

BackgroundOvarian granulosa cell tumors (GCTs) are the most common type of potentially malignant ovarian sex cord-stromal tumor. GCTs often produce estrogen and/or progesterone; consequently, symptoms related to hyperestrogenism are common at diagnosis. Nonspecific symptoms or signs associated with this neoplasm include amenorrhea and changes in various sex hormone levels, which can be hard to diagnose or explain. The aims of this report were to describe a case of GCT with rare presentations and to review the pertinent literature.Case presentationA 33-year-old woman presented with secondary amenorrhea and elevated LH with normal FSH and low estradiol levels. Laparoscopy revealed an ovarian GCT, and the patient underwent left adnexectomy and platinum-based chemotherapy. Removal of the ovarian GCT resulted in the normalization of LH levels and a return to spontaneous menses.ConclusionsThe mechanisms responsible for elevations in serum LH due to GCTs require further investigation. However, addressing the patient’s clinical problems remains the most important treatment consideration.