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An epithelioid trophoblastic tumor is a rare form of gestational trophoblastic neoplasia that mostly affects the uterus and endocervix in female patients of the reproductive age group. The tumor is believed to arise from chorion leave-type intermediate trophoblast. The epithelioid trophoblastic tumor in men is extremely rare and mostly described in association with mixed germ cell tumors of the testis. It is more commonly identified at the metastatic sites than in the testis. The epithelioid trophoblastic tumor should be differentiated from placental site trophoblastic tumor and squamous cell carcinoma. The distinctive morphology and characteristic immunohistochemical staining pattern help differentiate epithelioid trophoblastic tumors from other neoplasms. Only 7 male patients with epithelioid trophoblastic tumors have been described to date. Of these 7 patients, 4 were in metastatic sites, 2 in the testis, and 1 in the lung without the involvement of the testis or retroperitoneum. The proportion of epithelioid trophoblastic tumors was only 5% in the 2 patients with testis involvement. Here, we report the third patient with a primary testicular epithelioid trophoblastic tumor in a young man. Further, this is the first report to document epithelioid trophoblastic tumor as dominant histology in a testicular germ cell tumor.

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BACKGROUND: Disturbances in gonadal development lead to increased risk of gonadal malignancy in some but not all patients with differences in sex development (DSD). However, the natural history of these tumors is poorly described, and the literature remains sparse. OBJECTIVE: The objective of this study was to describe the incidence of germ cell neoplasia in situ (GCNIS) and germ cell tumor (GCT) in a contemporary cohort of patients with DSD undergoing surgery and to provide long-term oncologic outcomes for these patients. STUDY DESIGN: Patients with DSD who have undergone gonadectomy or gonadal biopsy were identified at four institutions. Clinical characteristics, pathology, and treatment details were obtained retrospectively. Patients were stratified into risk categories based on DSD diagnosis. Oncologic treatment and outcomes were recorded. Descriptive statistics are reported using parametric methods. RESULTS: 83 patients were identified. Distribution of diagnoses is summarized in the summary table. 14 (16.9%) patients underwent gonadal biopsy, and 71 (85.5%) patients underwent gonadectomy (50/71 gonadectomies were bilateral). 8/83 (9.6%) patients had GCNIS or GCT (7 GCNIS, 1 GCT). Median age at surgery was 2.95 years (y) (interquartile range [IQR] 0.6-12.2) and 14y (IQR 0.85-16.9) in patients without and with GCNIS/GCT, respectively. All 8 patients with GCNIS/GCT had high or intermediate risk DSD diagnoses (4 mixed gonadal dysgenesis, 3 Turner with Y, 1 partial gonadal dysgenesis). Of the patients with high-risk diagnoses, 8/54 (15%) had GCNIS/GCT. No patient received adjuvant therapy, no patient had a recurrence, and all patients were living with mean follow up 6.4y. DISCUSSION: The risk of gonadal malignancy is heterogeneous in the DSD population and can vary based on DSD diagnosis as well as maturation, testicularization, and location of the gonads. The most recent consensus recommendations on gonadal management emphasize risk stratification and consideration of gonadal surveillance based on gender of rearing, but supporting literature remains sparse. In this contemporary cohort of DSD patients who underwent gonadal surgery, most patients did not have evidence of adverse pathology, all patients with malignant or premalignant pathology had a high/intermediate risk DSD diagnosis, and all patients with GCNIS/GCT were treated with surgery alone without recurrence. CONCLUSIONS: The distribution of patients with premalignant and malignant gonadal pathology and DSD in this cohort aligns with prior literature, and oncologic outcomes were excellent. These data add valuable information to the current literature and highlight the necessity to develop appropriate screening regimens for retained gonads.

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Objectives: This retrospective study sought to investigate the risk and proportion of gonadal neoplasms in phenotypic female pediatric patients with DSD and the presence of the Y chromosome and different genetic backgrounds in a single Chinese center. Materials and Methods: From January 2012 to December 2020, pediatric and adolescent patients with DSD and the presence of the Y chromosome who had unambiguous female genitalia and underwent bilateral gonadectomy or gonadal biopsy were included in this study. Patients' demographics, karyotype, laboratory test results, gross pathology, and histology of gonadal tissue were all collected. The patients were divided into three groups based on their different genetic backgrounds, and the percentage of gonadal tumors was calculated to assess the risk of gonadal tumor and malignancy by etiology. Results: A total of 22 patients with DSD and an unambiguous female phenotype with a Y chromosome were recruited. The mean age was 10.91 ± 4.99 years (9 months to 19 years). Gonadal neoplasia was confirmed in six (27.3%) cases by pathological examination of surgical gonadal tissue samples. Among 44 gonadal samples from these 22 patients, the following were identified: five gonadoblastomas, three dysgerminomas, and two Leydig cell tumors. The youngest patient with a tumor was a 2-year-old girl with 46,XY complete gonadal dysgenesis (46,XY CGD or Swyer syndrome) and bilateral gonadoblastoma. Patients with 46,XY complete gonadal dysgenesis (4/6; 66.7%) had the highest tumor occurrence rate. Among 10 patients with Turner syndrome with the presence of the Y chromosome, only one patient was diagnosed with a gonadal tumor. Leydig cell tumor was diagnosed in only one of six patients with 46,XY androgen synthesis/action disorders. Conclusion: Pediatric patients with 46,XY complete gonadal dysgenesis had a significantly increased risk of developing gonadal tumors and underwent prophylactic gonadectomy as soon as the diagnosis was confirmed, whereas those with Turner syndrome with Y chromosome and 46,XY androgen synthesis/action disorders had a relatively low risk. In view of the limited number of patients, a large multicenter study with close follow-ups is needed to support these conclusions.

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BACKGROUND: Mixed gonadal dysgenesis (MGD) is a subtype of the disorders of sex development (DSD) associated with sex chromosome abnormalities characterized by abnormal external genitalia, short stature, and primary amenorrhea. This disease is generally diagnosed from the neonatal stage to early childhood, and by puberty at the latest. Cases that are phenotypically female or those with ambiguous genitalia experience a high risk of gonadal tumor formation. As tumor risk is known to increase with age, prophylactic bilateral gonadectomy is recommended following early diagnosis. CASE PRESENTATION: Here we report a case of an adult Japanese woman diagnosed with MGD during treatment for a giant pelvic tumor. The patient initially visited a gynecology clinic during puberty for primary amenorrhea, at which time an abnormality was found with the external genitalia. However, a diagnosis of MGD was not made at this time, resulting in the development of a malignant gonadal germ cell tumor in adulthood. CONCLUSIONS: For early diagnosis of MGD and the prevention of gonadal tumor formation, it is essential that gynecologists fully understand MGD and other DSD.

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OBJECTIVE: To identify the genetic cause of a pedigree with four patients with 46,XY pure gonadal dysgenesis (PGD). DESIGN: Genetic mutation study. SETTING: Academic medical center. PATIENT(S): Four first cousins, from three households of a Chinese pedigree, affected by 46,XY PGD. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The patients were studied from clinical and genetic perspectives. Whole-genome sequencing was conducted in family members. RESULT(S): Four first cousins in the third generation were affected by 46,XY PGD. A specific familial characteristic was the prevalence of as high as 100% of gonadal tumors in patients. Whole-genome sequencing identified a new ferritin heavy chain-like 17 (FTHL17) mutation, c.GA442_443TT (p.E148L), which has the potential to interfere with protein function and cause 46,XY PGD. Moreover, the location (Xp21.2) of the FTHL17 gene proves that the family is X-linked recessive. In vitro functional study revealed that the perturbation of FTHL17 caused the decrease of protein expression and cell proliferation. CONCLUSION(S): We describe the first 46,XY PGD pedigree that may be attributed to mutations of the FTHL17 gene. We speculated that the FTHL17 gene is involved in the testis-determining pathway and tumorigenesis.

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The presence of a Y chromosome in patients with Turner syndrome (TS) is a risk factor for the development of gonadal tumor and/or virilization. With conventional cytogenetic analysis, some cells containing a Y chromosome can be missed. The aim of this study was to determine the presence and incidence of Y chromosome-derived material in TS patients using PCR and the markers SRY, DYZ1, DYZ3, DYS132, ZFY, and TSPY. Fifty-five TS patients (aged 5.5-26.75 years) were analyzed. A total of 17/55 (30.9%) were Y-positive, but only 7/17 had a Y chromosome in their karyotype and underwent gonadectomy. In 2 of these patients (28.6%), histopathologic examination revealed gonadoblastoma and dysgerminoma, respectively. In 8 patients in the studied group (8/55; 14.5%), the TSPY gene was detected, and the SRY gene (or a fragment) was identified in 9(3)/55 patients. No coding region mutations were observed in these SRY-positive patients. In conclusion, we have shown a high prevalence of Y chromosomal material in TS. Y markers were also observed in patients who had no Y chromosome in their karyotype, and PCR is very precise in detecting the presence of genetic material from the Y chromosome. Further follow-up of these Y-positive TS patients is mandatory.

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Anti-Mullerian hormone (AMH), secreted by immature testicular Sertoli-cells, triggers the regression of male fetal Mullerian ducts. During puberty, AMH is downregulated by intratesticular testosterone. In females, AMH is secreted from granulosa cells of immature ovarian follicles from late prenatal life until menopause; serum concentration is 5-20 times lower in females than in males through lifetime. In boys, AMH determination is useful in the clinical setting as a marker of Sertoli cell function. Serum AMH is low in infants with hypogonadotrophic hypogonadism (and increases with FSH treatment), in patients with primary hypogonadism from early postnatal life and in Klinefelter syndrome from midpuberty. In boys with nonpalpable gonads, AMH determination is useful to distinguish between cryptorchidism and anorchism, as well as differentiating the dysgenetic causes of disorders of sexual development from those due to defective androgen synthesis or action. AMH can be used as a marker of sertoli/granulosa cell tumors and primary ovarian insufficiency in girls with delayed puberty, Turner Syndrome and after treatment with gonadotoxic agents.

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Androgen insensitivity syndrome (AIS) results from androgen receptor dysfunction and is a common cause of disorder of sex development. The AIS phenotype largely depends on the degree of residual androgen receptor (AR) activity. This review describes the molecular action of androgens and the range of androgen receptor gene mutations, essential knowledge to understand the pathogenesis of the complete and partial forms of this syndrome. A multidisciplinary approach is recommended for clinical management from infancy through to adulthood. Hormone replacement therapy is needed following gonadectomy. Patients who choose to retain the gonads are at risk of developing germ cell tumors for which sensitive circulating tumor markers may soon become available. Whilst the contribution of AR dysfunction to complete AIS is well understood, the involvement of the AR and associated proteins as contributors to partial AIS is an area of active research. Disorders of sex development such as AIS which are related to AR dysfunction offer a breadth of manifestations for the clinician to manage and opportunities for further research on the mechanism of androgen action.

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Transforming growth factor-ß (TGF-ß) superfamily signaling pathway and its ligands are essential regulators of cellular processes such as proliferation, differentiation, migration, and survival. Alteration of this pathway results in uncontrolled proliferation and cancer progression. This review focuses on a specific member of the TGF-ß superfamily: activin-ßC. After its initial discovery, activin-ßC has been considered non-biologically relevant. Therefore, for years several experimental designs have ignored the potential contribution of this molecule to the final biological outcome. Here we focus on recent advances in the activin field, with a particular emphasis on activin-ßC, its antagonistic mechanism, and the physiological relevance of activin-ßC actions in reproductive and cancer biology. Covering a novel and previously unexplored function of activin-ßC on cancer associated weight loss and muscle metabolism, this review suggests an imminent need to re-evaluate the function of activin-ßC in biological systems and advances the understanding of how activin-ßC antagonizes the activin signaling pathway. Thus, challenging activin biologists to consider the impact of activin-ßC when interpreting their work.

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Swyer syndrome is caused by abnormal sex differentiation during the embryonic period, resulting in incomplete intrauterine masculinization and undifferentiated gonads. The current case report describes a patient with Swyer syndrome associated with stage 3 gonadal dysgerminoma who has survived for 23 years. At age 18, this patient sought assistance for primary amenorrhea from the Gynecological Services Department of the University of Brasília Hospital. A physical examination revealed that the patient was at Tanner stage 4 with respect to axillary hair, breasts, and pubic hair; she presented with a eutrophic vagina and a small cervix. She was treated with a combination of estrogens and progestogens to induce cycling. Approximately 4 years later, a complex tumor was found and resected; a histopathological analysis revealed that this tumor was a right adnexal dysgerminoma with peritoneal affection. The patient was also subjected to chemotherapy. Her follow-up has continued to the present time, with no signs of tumor recurrence. In conclusion, this report describes an extremely rare case in which Swyer syndrome was associated with ovarian dysgerminoma; relative to similar patients, the described patient has survived for an unusually prolonged time.

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We present a patient with complete androgen insensitivity syndrome (CAIS) diagnosed with a serous papillary cystadenofibroma. A 41-year-old married female with a mass in the left inguinal region and a history of primary amenorrhea. A bulging mass of 13.7 cm × 8 cm × 12.4 cm in the left inguinal region extending from the hip joint to the level of labia majus, and a 3.2 cm × 2.8 cm mass in her right inguinal region were found by ultrasonography and magnetic resonance imaging. We performed bilateral gonadectomy. The pathology showed testicular tissue in the right inguinal mass and a serous papillary cystadenofibroma in the left one. CAIS is an infrequent clinical entity, occurrence of serous papillary cystadenofibroma is even rarer in this syndrome serous cystadenofibroma should come to mind in patients with a huge inguinal mass. Gonadectomy should be performed right after puberty to prevent the risk of malignancy development in the testes.

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BACKGROUND: Neoplasm-related precocious puberty (PP) is a rare presenting feature of childhood cancer. Moreover, evaluation of suspected PP in a child is complex, and cancer is often not considered. We characterized the clinicopathologic features of patients presenting with PP at a large pediatric cancer center, reviewed the relevant literature, and developed an algorithm for the diagnostic work-up of these patients. METHODS: We examined the records of all patients with a neoplasm and concomitant PP treated at St. Jude Children's Research Hospital from January 1975 through October 2011, reviewed the available literature, and analyzed the demographic, clinical, endocrine, and neoplasm-related features. RESULTS: Twenty-four of 13,615 children and adolescents (0.18%) were diagnosed with PP within 60 days of presentation. Primary diagnoses included brain tumor (12), adrenocortical carcinoma (5), hepatoblastoma (4), and others (3). PP was observed 0-48 months before diagnosis of neoplasm; 17 patients had peripheral PP and 7 had central PP. CONCLUSIONS: Neoplasm-related PP is rare and takes the form of a paraneoplastic syndrome caused by tumor production of hormones or by alteration of physiologic gonadotropin production. PP can precede diagnosis of malignancy by months or years, and neoplastic causes should be considered early to avoid delayed cancer diagnosis. Treatment of the primary malignancy resolved or diminished PP in surviving patients with an intact hypothalamic-pituitary-gonadal axis.

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Gonadal tumors occur in a small percentage of patients who are diagnosed as having gonadal dysgenesis. Most of the tumors were gonadoblastomas and dysgerminomas. We present here with brief review of literature one case of mixed germ cell tumor of phenotycally typical female without sexual ambiguity who presented with primary amenorrhea, short stature and minimal abnormal somatic features, whose chromosome analysis showed 45,X/ 46,X, +mar karyotype.

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