Consensus recommendations from the EXPeRT/PARTNER groups for the diagnosis and therapy of sex cord stromal tumors in children and adolescents.

As part of the European Union-funded project designated Paediatric Rare Tumours Network - European Registry (PARTNER), the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) is continuously developing consensus recommendations in order to harmonize standard care for very rare solid tumors of children and adolescents. This paper presents the internationally recognized recommendations for the diagnosis and treatment of sex cord stromal tumors (SCST). The clinical approach to sex cord stromal tumors of the testis (TSCST) and ovary (OSCST) depends on histological differentiation and tumor stage. Virtually all TSCSTs present as localized nonmetastatic tumors, with excellent prognosis after complete resection. In contrast, the prognosis of OSCSTs may be adversely affected by tumor spillage during surgery or presence of metastases. In these cases, cisplatin-based chemotherapy is recommended. Of note, some SCSTs may develop in the context of tumor predisposition syndromes, for example, DICER-1, so that specific follow-up is indicated. SCSTs should be diagnosed and treated according to standardized recommendations that include reference pathology, genetic testing for tumor predisposition syndromes in selected cases, and stratified adjuvant chemotherapy in patients with unfavorable risk profile. To ensure high quality of diagnosis and therapy, patients should be enrolled into prospective registries.

Ovarian sex cord-stromal tumors: an update on clinical features, molecular changes, and management.

Sex cord stromal-tumors are rare tumors of the ovary that include numerous tumor subtypes of variable histological features and biological behavior. Surgery is the main therapeutic modality for the management of these tumors, while chemotherapy and hormonal therapy may be used in some patients with progressive and recurrent tumors. Several studies investigated molecular changes in the different tumor types. Understanding molecular changes underlying the development and progression of sex cord-stromal tumors provides valuable information for diagnostic and prognostic biomarkers and potential therapeutic targets for these tumors. In this review, we provide an update on the clinical presentation, molecular changes, and management of sex cord-stromal tumors.

Management of Germ Cell Tumours of the Testes in Adult Patients: German Clinical Practice Guideline, PART II - Recommendations for the Treatment of Advanced, Recurrent, and Refractory Disease and Extragonadal and Sex Cord/Stromal Tumours and for the Management of Follow-Up, Toxicity, Quality of Life, Palliative Care, and Supportive Therapy.

OBJECTIVES: We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects. MATERIALS AND METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements. RESULTS: Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy. CONCLUSION: Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.

Development and Validation of a Prognostic Prediction Model for Postoperative Ovarian Sex Cord-Stromal Tumor Patients.

BACKGROUND We developed a nomogram for prognostic prediction of overall survival (OS) in postoperative ovarian sex cord-stromal tumor (SCST) patients and discuss the effect of chemotherapy at various FIGO stages. MATERIAL AND METHODS SCST patients after surgery from 2004 to 2015 were enrolled from the Surveillance, Epidemiology and End-Results (SEER) database, matched into pairs by propensity score matching (PSM), and divided into a training set and a validation set. Univariate and multivariate Cox analyses were conducted to identify significant variables for the development of the nomogram. The nomogram model was validated by concordance index (C-index), receiver operating characteristics (ROCs) curve, calibration plot, and decision curve analysis (DCA). Survival curves showed the integrative ability of prognostic prediction and the efficacy of chemotherapy. RESULTS A total of 913 SCST patients were initially enrolled, and after PSM, 506 patients were included. Age, marital status, CA125 levels, tumor size, FIGO stage, grade, and chemotherapy were indicators for building the OS nomogram. The C-index was 0.850 in the training set and 0.786 in the validation set. Calibration plots were satisfactory and the nomogram had relatively better clinical utility than FIGO stage. The survival analysis showed that the low-risk group had generally longer survival than the high-risk group based on the prognostic score, and chemotherapy had an overall reverse effect on OS. CONCLUSIONS The nomogram model displays the potential to provide individualized prognosis probability of SCSTs and to aid in clinical decision-making. The unfavorable results of chemotherapy in all stages shows the need for further exploration.

Patterns of palliative care referral in ovarian cancer: A single institution 5 year retrospective analysis.

BACKGROUND: The American Society of Clinical Oncology recommends that patients with advanced cancer receive dedicated palliative care services early in their disease course. This investigation serves to understand how palliative care services are utilized for ovarian cancer patients in a tertiary referral center. METHODS: We conducted a retrospective review of women treated for ovarian cancer at our institution from 2010 through 2015. Clinical variables included presence and timing of palliative care referral. Data were correlated utilizing univariable and multivariable parametric and non-parametric testing, and survivals were analyzed using the Kaplan-Meier method and cox-proportional hazard models. RESULTS: We identified 391 women treated for ovarian cancer, of whom 68% were diagnosed with stage III or IV disease. Palliative care referral was utilized in 28% in the outpatient (42%) and inpatient (58%) settings. Earlier use of referral was observed in those who never underwent surgical cytoreduction or had interval cytoreductive surgery (p < 0.001). Palliative care referral was independently associated with advanced stage (OR 1.7, p = 0.02), recurrence (OR 2.0, p = 0.002) and hospice referral (OR 6.0, p < 0.001). In 38% of women referral occurred within 30 days of death, and 17% within one week of death. Outpatient initial consultation was associated with an unadjusted 1 year overall survival benefit (p < 0.01) compared to inpatient consultation. CONCLUSIONS: The outcomes in this study suggest a late use of palliative care that is reactionary to patient needs and not a routine component of ovarian cancer care as national guidelines recommend.

Sex-Cord Stromal Tumors in Children and Teenagers: Results of the TGM-95 Study.

BACKGROUND: We present the results of the TGM-95 study for gonadal sex-cord stromal tumors (SCT). METHODS: Between 1995 and 2005, children (<18 years) with gonadal SCT were prospectively registered. Primary gonadal resection was recommended whenever feasible. Patients with disseminated disease or an incomplete resection received neoadjuvant or adjuvant VIP chemotherapy (etoposide, ifosfamide, cisplatinum). RESULTS: Thirty-eight children with ovarian SCT were registered. Median age was 10.7y. Endocrine symptoms were present in 21 cases. The histological diagnoses were as follows: juvenile (23) and adult (3) granulosa cell tumors, Sertoli-Leydig cell tumors (11), and mixed germ cell SCT (1). An initial oophorectomy ± salpingectomy led to complete resection in 23 patients who did not receive adjuvant treatment; two of them relapsed: one achieved second complete remission whereas the other one died of disease. Fifteen patients had tumor rupture and/or malignant ascites: 11 received chemotherapy and did not relapse, four did not receive chemotherapy and relapsed with a fatal outcome in two cases. With a median follow-up of 5.9y, the 5-y EFS and OS rates were respectively 85% and 94%. Eleven patients had localized testicular tumors (median age 0.83y): juvenile granulosa cell tumors (4), Sertoli or Leydig cell tumors (5) and not otherwise specified SCT (2). Treatment was surgery alone with an inguinal orchiectomy. None have relapsed (median follow-up: 5.4y). CONCLUSIONS: Childhood SCT carry favorable prognosis. In ovarian SCT, surgery should be complete and non-mutilating. Adjuvant chemotherapy efficiently prevents recurrences in cases of tumor rupture. In childhood testicular SCT, the prognosis is excellent with an inguinal orchiectomy, prompting the debate on testis-sparing surgery.

Gynecologic Cancer InterGroup (GCIG) consensus review for ovarian sex cord stromal tumors.

Sex cord stromal tumors (SCST) are rare cancers of the ovarian area in adults. They constitute a heterogeneous group of tumors that develop from the sex cords and the ovarian stroma. These tumors are detected typically at an early stage, and they may recur as late as 30 years after the initial treatment. Because 70% of the patients present with stage I tumors, surgery represents the most important therapeutic arm. There are no data to support any kind of postoperative adjuvant treatment for patients with stage IA or IB SCSTs, given the indolent nature of these neoplasms and the overall good prognosis. The long natural history of the disease may lead to repeated surgical procedure should a relapse occurs. Platinum-based chemotherapy is currently used for patients with advanced stage SCSTs or recurrent disease, with an overall response rate of 63% to 80%. The indolent nature of SCSTs with the tendency for late recurrence requires long-term follow-up.

Prognostic factors of germ cell and sex cord-stromal ovarian tumors in pediatric age: 5 years experience.

BACKGROUND: Ovarian tumors in the pediatric age group are not infrequent. Germ-cell tumors are the commonest ovarian neoplasm in the first two decades of life. Sex cord-stromal tumors are the most common ovarian tumors to cause precocious puberty in girls. PATIENTS AND METHODS: This retrospective study included all managed cases of malignant germ-cell and sex cord-stromal tumors in the pediatric age (less than 18 years). The medical records of the admitted cases from first of January, 2008 to 31 December, 2012 were reviewed and the following information was collected: patient age, clinical presentation, surgical stage, tumor histology, therapy, clinical course, and outcome. Serum alpha-fetoprotien on admission was studied. RESULTS: The study included 42 pediatric cases of germ-cell and granulosa cell tumors of the ovary. Mean age of the cases was 11.26 years (range: 7-15 years). Abdominal pain was the commonest presentation. Twenty-two cases (52.4%) were diagnosed as stage I disease. Twenty-eight cases (66.7%) were exposed to fertility sparing surgery. Age of the patient and site of tumor were significantly correlated to the survival (p value: 0.04 & 0.09 respectively). The correlations of stage of the disease, use of pre-operative chemotherapy, and type of surgical interference were highly significant (P value: 0.007, 0.001, and 0.001 respectively). Tumor size and histologic types were not significantly correlated to survival (P value: 0.19 & 0.67 respectively). CONCLUSION: The cumulative survival rate was 76.2%. The correlations of stage of the disease, use of pre-operative chemotherapy, and type of surgical interference were highly significant. Tumor size and histologic types were not significantly correlated to survival. Initial level of alpha-fetoprotein was not significantly correlated to survival or recurrence.

Management of ovarian and testicular sex cord-stromal tumors in children and adolescents.

Pediatric ovarian and testicular sex cord-stromal tumors are distinct from germ cell neoplasms and may present with palpable mass or signs of hormone production. Both may be associated with specific genetic syndromes. Staging for ovarian sex cord-stromal tumors is based on the International Federation of Gynecology and Obstetrics classification for ovarian carcinoma. Treatment for those with high risk disease includes multiagent chemotherapy. Testicular stromal tumors often, though not always, follow a benign course. Additional research will help to define optimal treatment strategies for children with these rare tumors.

Treatment of ovarian cancer in young women.

Ovarian cancer accounts for approximately 22,000 cases annually in the United States. Although the vast majority of ovarian cancers occur in postmenopausal women and are of advanced stage, a significant subset occurs in young women. Among those subtypes having a predisposition for young women are malignant ovarian germ cell tumors, sex cord-stromal ovarian tumors, and tumors of low malignant potential. However, invasive epithelial ovarian cancers may also occur in young women, particularly the subtypes of low-grade serous carcinoma and mucinous carcinoma. This article details the diagnosis and optimal treatment of ovarian cancers subtypes in young women.

Non-Epithelial Ovarian Cancers: How Much Do We Really Know?

Non-epithelial ovarian cancers (NEOC) are a group of uncommon malignancies that mainly includes germ cell tumours (GCT), sex cord-stromal tumours (SCST), and some extremely rare tumours, such as small cell carcinomas and sarcomas. Each of these classifications encompasses multiple histologic subtypes. The aetiology and molecular origins of each sub-group of NEOC require further investigation, and our understanding on the genetic changes should be optimised. In this article, we provide an update on the clinical presentation, pathology, genetics, treatment and survival of the main histological subtypes of the GCT and the SCST, as well as of ovarian small cell carcinomas. We also discuss miRNA expression profiles of NEOC and report the currently active clinical trials that include NEOC.

Patterns of spread and recurrence of sex cord-stromal tumors of the ovary.

OBJECTIVE: Sex cord-stromal tumors are an uncommon type of ovarian neoplasm and limited data are available in the literature to guide clinical management. Recent published series suggested a lack of lymph node involvement and recommended abandonment of the lymph node dissection as part of the primary surgical staging of these tumors. To confirm these findings, we evaluated pathologic findings in women undergoing surgical management of sex cord-stromal tumors in the Seattle metropolitan area. METHODS: A retrospective multi-institutional review of all patients treated with sex cord-stromal tumors at University of Washington Medical Center and Swedish Medical Center in Seattle was conducted. Information was collected on the pathology, evaluation, and treatment of these patients. RESULTS: A total of 87 patients were available for analysis, the majority of whom had adult granulosa cell tumors (82%) and Sertoli-Leydig cell tumors (13%). Of these patients, 68% had complete or partial surgical staging procedures, and 47 patients had some nodal tissue examined as part of the initial or restaging procedure. All nodes examined were negative. Tumor size was significantly associated with risk of recurrent disease, with a 20% increase in the hazard of recurrence for each increase of tumor size of 1cm (HR, 1.20; 95% CI, 1.11-1.07). CONCLUSIONS: This study confirms the finding that lymph node metastasis are rare in sex-cord stromal tumors. These findings support the hypothesis that routine lymphadenectomy provides limited additional information in the management of these patients and can be omitted from the primary surgical staging procedure or secondary restaging procedures.

Gynandroblastoma with the symptoms of infertility and secondary amenorrhea: a case report.

The case of a female patient who failed to get pregnant due to delayed menstruation is reported. Gynecological examination showed that the patient had a male pubic distribution, hypertrophic clitoris, unobstructed vagina and hypertrophic cervices with smooth and medium texture. B ultrasonic examination detected a 42 x 30 mm in size medium echo mass. This mass had irregular shape, smooth surface, relatively clear boundary and hard texture. Examination with paraffin-embedded section indicated that the tumor was composed of supporting cells and to a lesser amount of interstitial components. Some regions had particle-like cell differentiation. These results suggested that the tumor was gynandroblastoma. We found that the increased level of serum testosterone in the patient was the reason for amenorrhea and infertility. The diagnosis and treatment for patients with gynandroblastoma is also discussed.

Testicular and paratesticular tumours in the prepubertal population.

Prepubertal testicular and paratesticular tumours are a rare group of tumours, distinct from postpubertal paediatric and adult tumours of this region. Tumours within this group are testicular germ-cell tumours (such as benign teratoma, epidermoid cyst and malignant yolk-sac tumours) and stromal tumours (such as juvenile granulosa-cell, Leydig-cell, and Sertoli-cell tumours). Paratesticular tumours can be benign (lipoma, leiomyoma, haemangioma) or malignant (rhabdomyosarcoma, melanotic neuroectodermal tumour of infancy). Because of their rarity, centralised pathology and treatment, and national collaborative clinical trials have been important in establishing the optimum management of malignant tumours in this group. We provide an up-to-date and comprehensive review of the clinical presentation, imaging, pathology, and clinical management of prepubertal paratesticular and testicular tumours.

Promising Immunotherapy in Metastatic Testicular Sex Cord Stromal Tumours After First-Line Chemotherapy.

Background: Testicular sex cord stromal tumours (TSCSTs) are rare, with few studies focusing on the metastatic TSCST prognosis. The value of treatments, including radical orchiectomy (RO) and retroperitoneal lymph node dissection (RPLND), in preventing metastasis is controversial. Additionally, metastatic TSCSTs are resistant to chemotherapy. We aimed to assess the effectiveness and safety of immunotherapy in metastatic TSCSTs after first-line chemotherapy. Methods: We retrospectively screened patients with testicular tumours undergoing testis surgery between January 2005 and January 2019. Patients with TSCSTs who had undergone testis-sparing surgery (TSS) or RO were identified. The malignant type was defined as metastasis confirmed by pathology. Treatment responses, progression-free survival (PFS), overall survival (OS) and safety were analysed. Results: Among the 494 testicular tumour patients who received TSS or RO, 11 (2.2%) patients with histologically proven TSCSTs were identified. At the last follow-up, 7 patients survived without tumours, and 4 patients developed metastasis and received first-line cisplatin-based chemotherapy, with 1 of them achieving an objective response. Their PFS times were 1.5, 2.2, 9.0, and 17.0 months, respectively. Two patients received immune checkpoint inhibitors (ICIs) after developing chemotherapy resistance and achieved a partial response up to the last follow-up; one of them experienced Grade 1 adverse events, and the other experienced Grade 2 adverse events during immunotherapy. The median OS time of the 4 patients with metastatic TSCSTs was 32 months. Conclusions: TSCSTs are rare, and most are benign with a good prognosis. ICIs represent a promising option for improving clinical outcomes in metastatic TSCSTs.

Management of rare ovarian cancers: the experience of the French website "Observatory for rare malignant tumours of the ovaries" by the GINECO group: interim analysis of the first 100 patients.

BACKGROUND: Non-epithelial ovarian cancers are rare; their natural history is poorly understood and prognostic factors remain unclear. A French website (www.ovaire-rare.org) was developed to collect clinical cases and tumour samples in order to better define prognostic factors and develop specific trials. We report the results of the first 100 patients with germ cell (GCT) and sex cord-stromal (SCT) tumours. METHODS: All adult patients with histological evidence of GCT or SCT at diagnosis or first relapse were eligible. RESULTS: From 03/2002 to 06/2009, 180 patients were included; the first 100 were evaluated. Patient characteristics were: histology: SCT 61%, GCT 30%, others 5%; median age: 43 years; median tumour size: 12 cm; FIGO stages I-II: 83%, III-IV: 17%. Central pathology review (67 patients) differed from initial diagnosis in 37%. Fifty-six percent of the patients had initial conservative surgery and 10% lymph node dissection; 56 patients received chemotherapy. Eleven of the 78 first-line patients relapsed and 5 died; the 5-year OS rate was 94% and the median PFS 64 months. CONCLUSIONS: This online observatory allows assessing medical practice for GCT and SCT in France. Histological discrepancies between diagnosis and second opinion confirm the need for systematic review before treatment. Extension to other rare gynaecologic malignancies is on-going.

Fertility-preserving surgical procedures for patients with gynecologic malignancies.

Gynecologic malignancies often affect young women who are at the peak of their reproductive potential. The treatment for gynecologic malignancies often consists of removal of the ovaries or uterus, affecting the future fertility of these patients. Advances in surgical management have allowed patients to undergo more conservative treatment with preservation of their fertility. This review summarizes fertility-sparing surgical procedures for patients with gynecologic malignancies evaluating the role of radical trachelectomy and ovarian transposition in cervical cancer, hormonal therapy and hysteroscopic resection in endometrial cancer, and conservative surgery in ovarian cancer.