Gonadal Tumors Research Articles

Intravenous leiomyomatosis treated with aromatase inhibitor therapy

[1]. The gonads of these patients develop into ovaries in utero, but then degenerate into streaks owing to the lack of a second X chromosome [1]. Cesarean is the usual mode of delivery in these patients [3], but in the present case the patient had a spontaneous vaginal delivery. Gonadal neoplasm can occur in up to 30% of cases and gonadoblastoma accounts for the majority of tumors [2]. Gonadoblastoma may synthesize estrogens or testosterone and is associated with dysgerminoma in 50% of cases [4]. In one case report 5 different histological subtypes of germ cell malignancies were described [4]. Early diagnosis is important and immediate gonadectomy is strongly recommended, as these tumors may even develop in infancy. A multidisciplinary approach with psychological support is important for the management of patients with pure gonadal dysgenesis. Normal uterine function including vaginal delivery is possible in these patients. References

Adult Type Granulosa Cell Tumor of the Testis

Dong Jun Kim, Dong Woo Song, Sang Yeop Yi, Woon Yong Yun, Tae Yung Jeong From the Departments of Urology and Pathology, College of Medicine, Kwandong University, Goyang, Korea Testicular granulosa cell tumor (GCT) is a rare neoplasm. We report here on an incidentally discovered testicular granulosa cell tumor in a 36-year-old man. The serum tumor markers were within the normal limits. The ultrasonographic findings revealed a mass with a heterogenous hypoechoic echotexture, including multiple variable sized cystic components. The histology on the orchiectomy specimen demonstrated a gonadal stromal tumor with granulosa cell features. Testicular granulosa cell tumor of the adult type is a very rare tumor, and there have been several isolated case reports and small serial studies described in the literature. (Korean J Urol 2008;49:95-97) 󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏

Detection of Y‐chromosome in gonadal tumours using fluorescence in situ hybridization: diagnostic value in intersex conditions including older patients with clinically unsuspected androgen insensitivity syndrome

To evaluate fluorescence in situ hybridization (FISH) for SRY, the testis-determining gene on the Y-chromosome, in gonadal specimens from patients with intersex disorders including two older individuals presenting with Sertoli cell adenomas and clinically unsuspected androgen insensitivity syndrome (AIS). FISH, using probes for SRY and the X-centromere, was performed on two Sertoli cell adenomas presenting as ovarian masses in phenotypic females aged 62 and 73 years with previously undiagnosed AIS. Gonadal biopsies and tumours from eight additional patients with known intersex disorders and XY phenotype were also studied. Signal for SRY was demonstrated in at least one specimen from all patients, and from 16/18 (89%) specimens overall. The specificity of FISH was determined by analysis of 10 sporadic ovarian tumours including six dysgerminomas and four Sertoli-Leydig cell tumours: all cases expressed a female XX chromosomal signal. The demonstration of SRY using FISH is useful in the assessment of gonadal specimens from patients with intersex disorders, particularly in older individuals where the diagnosis may be unsuspected clinically. However, it may be necessary to examine multiple specimens in some cases to confirm the presence of Y-chromosomal material.

Subcutaneous Neoplasms of the Ventral Abdomen with Features of Adrenocortical Tumors in Two Ferrets

A ventral abdominal subcutaneous mass was removed from each of 2 young adult spayed female ferrets. In both cases, the neoplasms were composed of islands of polygonal cells separated by interlacing streams of spindloid cells reminiscent of ferret adrenocortical tumors with smooth muscle proliferation. Immunohistochemically, the polygonal cells demonstrated strong cytoplasmic reactivity for inhibin and weak cytoplasmic reactivity for pancytokeratin and S-100 protein. Spindloid cells demonstrated strong cytoplasmic reactivity for alpha smooth muscle actin, muscle-specific actin, desmin, and glial fibrillary acidic [corrected] protein. Ultrastructurally, the polygonal cells contained numerous intracytoplasmic clear vacuoles, mitochondria, scant rough endoplasmic reticulum, and few intermediate filaments. In one tumor, vesicular tubular mitochondria were found in polygonal cells. The spindloid cells contained numerous aggregates of parallel intermediate filaments. The histologic, immunohistochemical, and ultrastructural findings are suggestive of adrenocortical tumors with smooth muscle proliferation, but cannot be differentiated from an ovarian gonadal stromal tumor. Neither ferret had a clinically detected primary adrenal gland tumor or clinical signs of adrenal-associated endocrinopathy.

Characterization of Toxic Effects of Sediment-Associated Organic Pollutants Using the λ Transgenic Medaka

A novel sediment-contact assay using embryos of the transgenic medaka was developed to fully characterize the toxic effects induced by exposure to a mixture of organic pollutants in sediments. Embryos of the lambda transgenic medaka were exposed for 10 days to a clean reference sediment spiked with either the solvent alone, benzo[a]pyrene (B[a]P), or three concentrations (0.3x, 1x, and 2x) of an organic extract (OE) of sediments from the Seine estuary. The 1 x OE-spiked sediment contained concentrations of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls similar to those in field-collected sediment. Exposure to this sediment, but not to the B[a]P-spiked sediment, significantly increased embryo-larval mortality and prevalence of spinal deformities. Mutant frequency at the cII mutation target gene in the liver of 10-week-old medaka was significantly increased following exposure to either B[a]P or the three doses of OE. The predominant OE-induced liver mutations were G:C to T:A transversions, consistent with PAHs being the major contributors to the mutation induction. Liver and gonadal tumors were observed in 35-week-old medaka exposed to either B[a]P (1/25) or to the 1 x OE (1/24). The benefits of medaka as a fish model for toxicological assessment and the benefits of the cII mutation assay for mutation detection combine to provide comprehensive assessment of a wide range of genotoxic and nongenotoxic effects of aquatic pollutants.

Tumors of dysgenetic gonads in Swyer syndrome

Background/Purpose The female with Swyer syndrome requires close follow-up because of the high risk of neoplastic transformation in the dysgenetic gonads. The aim of this work was to present our experience with tumors in patients with Swyer syndrome. Methods We studied 8 females with Swyer syndrome. At the time of diagnosis, they were 13 to 18 years old. We performed an ultrasound examination of dysgenetic gonads, hormonal (follicle-stimulating hormone, luteinizing hormone, estradiol, and testosterone) and genetic ( SRY, karyotype) tests, and histologic analysis of gonads (bilateral gonadectomy was performed in all patients). Results Gonadal tumors were found in 6 patients (3 cases of gonadoblastoma, 1 dysgerminoma, and 2 gonadoblastoma with dysgerminoma). Hormonal activity of gonadoblastoma was noted in 3 patients, with 1 tumor producing androgens. Conclusion Our data suggest that patents with gonadal dysgenesis and 46,XY karyotype should be referred for bilateral gonadectomy because of the high risk of neoplastic transformation. Estrogen-producing gonadoblastoma may mask gonadal dysgenesis and delay the diagnosis of this pathology.

Pediatric germ cell tumors

Pediatric germ cell tumors are a diverse group of neoplasms with variable clinical behaviors, depending upon the age and site of presentation. Most result from sporadic mutations, although environmental exposures and other genetic aberrations may play a role. Platinum-based chemotherapy has dramatically improved the event-free and overall survival outcomes of pediatric patients with malignant germ cell tumors over the past two decades. Prognosis is dependent on tumor stage and location. Patients with gonadal germ cell tumors have at least a 95% 5-year survival for early stage disease and at least a 85% 5-year survival for advanced stages. In general, extragonadal germ cell tumors carry a poorer prognosis with mediastinal location having the worst outcomes (70% 4-year survival). Current trials are focused on maintaining similar excellent outcomes while reducing morbidity by reducing the dose and duration of chemotherapy. Cytogenetic research studies have found chromosomal aberrations specific to some of these tumors that may serve as prognosticators and even direct therapy.

65 Differential Type I Interferon Induction by Respiratory Viruses In Vivo

Malignant gonadal (GGCT) and extragonal germ cell tumors [GCT (EGCT)] are thought to originate from primordial germ cells. In contrast to well reported population-based data of GGCTs in males, analyses of GGCTs in females and EGCTs in both sexes remain limited.In a pooling project of nine population-based cancer registries in Germany for the years 1998–2008, 16,883 malignant GCTs and their topographical sites were identified using ICD-O morphology and topography for persons aged 15 years and older. We estimated age-specific and age-standardized incidence rates.Among males, the incidence of testicular GCTs increased over time. In contrast, there was no increase in the incidence of EGCTs. Among females, rates of ovarian GCTs were stable, while rates of EGCTs declined over time. The most frequent extragonadal sites were mediastinum among males and placenta among females.Our results underline different incidence trends and distinct age-specific incidence patterns of malignant GGCTs and EGCTs, as reported recently by several population-based registries. The differences suggest that GGCT and EGCT may have different etiologies.

Recent Advances in the Pathology and Classification of Gonadal Neoplasms Composed of Germ Cells and Sex Cord Derivatives

In recent years, our understanding of neoplasms composed of germ cells and sex cord derivatives has increased. In this review, advances in the classification and pathology of ovarian germ cell-sex cord-stromal tumors are discussed. Only 2 neoplasms, each with a distinctive pathogenesis and clinicopathologic features, are included in this category. Gonadoblastoma is a tumor that usually occurs in the dysgenetic gonads of intersex patients that have a Y chromosome, whereas mixed germ cell-sex cord-stromal tumor arises in normal gonads in patients without sex chromosomal abnormalities. Ovarian mixed germ cell-sex cord-stromal tumors differ from their testicular counterparts in their histological appearance, immunohistochemical staining reactions, and biological behavior probably because the latter show a greater degree of maturity of their germ cell component. The introduction of cisplatin-based chemotherapy and the application of tumor markers have dramatically improved the clinical outlook for those patients who develop secondary malignant germ cell neoplasms.

Prevention of cachexia-like syndrome development and reduction of tumor progression in inhibin-deficient mice following administration of a chimeric activin receptor type II-murine Fc protein

Inhibin is a secreted tumor suppressor, and inhibin alpha null mice develop gonadal sex cord-stromal tumors with 100% penetrance at an early age. Inhibin-deficient mice die of a severe wasting syndrome due to increased activin signaling through activin receptor type II. The current study was designed to assess the in vivo effects of an activin antagonist, a chimeric activin receptor type II fused to the Fc region of a murine IgG2a (ActRII-mFc), administered transiently to the inhibin-deficient mice. Results showed that the severe weight loss was prevented in the ActRII-mFc-treated mice, FSH levels were reduced, and an extended life span was observed for these mice compared with phosphate-buffered saline-treated controls. Although ActRII-mFc treatment did not seem to prevent the formation of gonadal tumors, tumors were smaller in the majority of experimentally treated mice and were characterized by the presence of variable numbers and sizes of cysts in contrast to the solid hemorrhagic tumors that typically developed in the controls. Moreover, the ActRII-mFc-treated mice were less anemic, and their livers and stomachs were histologically normal. In summary, this study demonstrated that in vivo administration of the activin antagonist, ActRII-mFc, not only prevents the cachexia-like symptoms in the inhibin-deficient mouse model, but also reduces tumor progression. These results support an essential role of activins in the cachexia-like syndrome development and implicate activins as growth-promoting factors in gonadal tumor progression. The current findings have potential implications in the design of new drugs or strategies for the treatment of ovarian and testicular tumors and other conditions where ligands signal through ActRII.

SMAD3 Regulates Gonadal Tumorigenesis

Inhibin is a secreted tumor suppressor and an activin antagonist. Inhibin alpha null mice develop gonadal sex cord-stromal tumors with 100% penetrance and die of a cachexia-like syndrome due to increased activin signaling. Because Sma and Mad-related protein (SMAD)2 and SMAD3 transduce activin signals in vitro, we attempted to define the role of SMAD3 in gonadal tumorigenesis and the wasting syndrome by generating inhibin alpha and Smad3 double mutant mice. Inhibin alpha and Smad3 double homozygous males were protected from early tumorigenesis and the usual weight loss and death. Approximately 90% of these males survived to 26 wk in contrast to 95% of inhibin-deficient males, which develop bilateral testicular tumors and die of the wasting syndrome by 12 wk. Testicular tumors were either absent or unilaterally slow growing and less hemorrhagic in the majority of double-knockout males. In contrast, development of the ovarian tumors and wasting syndrome was delayed, but still occurred, in the majority of the double-knockout females by 26 wk. In double mutant females, tumor development was accompanied by typical activin-induced pathological changes. In summary, we identify an important function of SMAD3 in gonadal tumorigenesis in both sexes. However, this effect is significantly more pronounced in the male, indicating that SMAD3 is the primary transducer of male gonadal tumorigenesis, whereas SMAD3 potentially overlaps with SMAD2 function in the ovary. Moreover, the activin-induced cachexia syndrome is potentially mediated through both SMAD2 and SMAD3 or only through SMAD2 in the liver and stomach. These studies identify sexually dimorphic functions of SMAD3 in gonadal tumorigenesis.

Prepubertal testicular tumors: Frequently overlooked

Objective Prepubertal testicular tumors are fundamentally distinct from their adult counterparts. We reviewed our 10-year, two-institution experience with respect to diagnosis and treatment. Material and methods A retrospective review was performed of all testicular tumors diagnosed between 1996 and 2006 in males younger than 14 years. We analyzed clinical characteristics, diagnostic procedures, treatment methods, histopathologic findings and outcome. Results Of 15 primary testicular tumors, eight (53%) were germ-cell tumors (three teratomas, two yolk sac tumors, one seminoma, one embryonic carcinoma and one choriocarcinoma), four (27%) tumor-like lesions (epidermoid cysts), two (13%) gonadal stromal tumors (a Leydig and a Sertoli cell tumor), and one (7%) gonadoblastoma with gonadal dysgenesis. All boys were presented with a painless scrotal mass and four (27%) of them with elevated tumor markers. Ten cases (66%) were misdiagnosed by urologists preoperatively and presented for treatment of congenital or acquired scrotal disorders. Twelve children (80%) were treated with radical orchiectomy and three (20%) with a testis-sparing procedure. At a mean 4-year follow-up no patient has presented with recurrent tumor in the residual or contralateral testicle. Postoperative physical examination and scrotal ultrasound were obtained in 14 patients at a median follow-up of 48.2 months, and there was no evidence of tumor progression. One boy with a choriocarcinoma (stage IV) died due to distant metastases. Conclusions Benign teratoma and epidermoid cysts were the most common prepubertal testicular tumors. Any suspicion of a testicular tumor warrants an inguinal approach to prevent scrotal violation of the tumor. Our limited experience with testis-sparing procedures supports the current trends that organ-confined surgery should be performed for benign lesions such as teratoma, Leydig cell tumor and epidermoid cysts based on frozen biopsy findings.

Cancer incidence patterns by region and socioeconomic deprivation in teenagers and young adults in England

Data on 35 291 individuals with cancer, aged 13–24 years, in England from 1979 to 2001 were analysed by region and socio-economic deprivation of census ward of residence, as measured by the Townsend deprivation index. The incidence of leukaemia, lymphoma, central nervous system tumours, soft tissue sarcomas, gonadal germ cell tumours, melanoma and carcinomas varied by region (P<0.01, all groups) but bone tumour incidence did not. Lymphomas, central nervous system tumours and gonadal germ cell tumours all had higher incidence in less deprived census wards (P<0.01), while chronic myeloid leukaemia and carcinoma of the cervix had higher incidence in more deprived wards (P<0.01). In the least deprived wards, melanoma incidence was nearly twice that in the most deprived, but this trend varied between regions (P<0.001). These cancer incidence patterns differ from those seen in both children and older adults and have implications for aetiology and prevention.

Immunhistochemische Keimstrangmarker

Sex cord markers comprise proteins and hormones that are produced in sex cord-derivatives in normal ovaries and testes as well as in gonadal sex cord-stromal tumors. Sex cord markers (e.g. inhibin-alpha) are used clinically as serum tumor markers. Immunohistochemical staining of sex cord markers may be helpful in the differential diagnosis of ovarian sex cord-stromal tumors versus surface epithelial-stromal tumors, germ cell tumors, other ovarian tumors, and ovarian metastases. Inhibin-alpha has been shown to be the most specific marker of sex cord differentiation. In comparison, calretinin is a somewhat more sensitive albeit less specific marker. Currently, an immunohistochemical panel including inhibin-alpha and calretinin is considered most helpful in the differential diagnosis of ovarian sex cord-stromal tumors. CD99, Müllerian inhibiting substance (MIS), melan A and CD10, being sex cord markers of limited sensitivity and specificity, should only be used as part of an antibody panel in specific diagnostic settings. EMA, CK7 and chromogranin are considered additional markers that may be useful in the differential diagnosis of ovarian sex cord-stromal tumors.

The Long-Term Followup of 33 Cases of True Hermaphroditism: A 40-Year Experience With Conservative Gonadal Surgery

Little is known about long-term outcomes of conservative gonadal surgery in true hermaphroditism. We present our experience with evaluation and treatment of a large series of children with this rare form of ambiguous genitalia, focusing on gonadal structure and function before and after conservative gonadal surgery. We retrospectively reviewed 33 consecutive patients with histologically confirmed true hermaphroditism treated at the Hopital des Enfants-Malades between 1965 and 2005. The most common karyotype of true hermaphrodites was 46,XX, constituting 82% of our series. The frequency of finding the SRY gene in 46,XX cases was 35%. Ovotestis was the most frequent finding (65%) and testis the rarest (9%). Ovarian tissue was more often found on the left side, and testicular tissue on the right side (p <0.05). Proper gonadal tissue was preserved in 28 cases. No gonadal tumors were detected during followup. Ovarian tissue remained normal, while testicular tissue gradually developed signs of dysgenesis in all biopsied cases, confirmed by endocrinological studies. However, testosterone production remained satisfactory in the majority of cases during followup. Diagnosis of true hermaphroditism is well defined and the condition can be recognized even prenatally. Conservative gonadal surgery is the procedure of choice after a diagnosis of true hermaphroditism. Continued followup is necessary because of the multiple psychological, gynecological and urological problems encountered postpubertally by these patients.

Distribution of sex chromosomes in dysgenetic gonads of mixed type

In a four-week-old child with female external and internal genitalia but with clitoris hypertrophy chromosome analysis from blood lymphocytes revealed a 46,XY karyotype. No deletion of Y chromosomal sequences was detected by PCR analysis of genomic DNA isolated from peripheral blood leucocytes. Because of the increased risk for gonadal tumours, gonadectomy was performed. Conventional cytogenetic analysis of the left dysgenetic gonad revealed a gonosomal mosaicism with a 45,X cell line in 27 of 50 metaphases. The dysgenetic left gonad demonstrated a significantly higher proportion (P = 0.005) of cells carrying a Y chromosome (46.3%) than the streak gonad from the right side (33.9%). Histomorphological examination of the left gonad revealed immature testicular tissue and rete-like structures as well as irregular ovarian type areas with cystic follicular structures. Interphase FISH analysis of the different tissues of this dysgenetic gonad demonstrated variable proportions of cells with an X and a Y chromosome. Whereas Sertoli cells and rete-like structures revealed a significantly higher proportion of XY cells in relation to the whole section of the dysgenetic gonad (P < 0.0001), almost all granulose-like cells carried no Y chromosome. The proportion of XY/X cells in theca-like cells and Leydig cells was similar to that of the whole dysgenetic gonad. In contrast to these findings, spermatogonia exclusively contained an XY constellation.

Comparative Analysis of Germ Cell Transcription Factors in CNS Germinoma Reveals Diagnostic Utility of NANOG

The homeodomain transcription factor, NANOG, along with OCT3/4 (POU5F1) and SOX2, is part of the core set of transcription factors that maintain embryonic stem cell self-renewal and pluripotency. Expression of NANOG has been detected in fetal germ cells and in gonadal germ cell tumors. To assess the diagnostic utility of NANOG in central nervous system (CNS) germ cell tumors, we analyzed its expression by immunohistochemistry in a series of 12 CNS germinomas and compared its expression with other stem cell markers. Strong nuclear expression of NANOG was demonstrated in >90% of the tumor cells in all cases. In contrast, expression of OCT3/4 and placental alkaline phosphatase was inconsistent and SOX2 was expressed in only rare cells. NANOG was not detected in tumor types frequently considered in the differential diagnosis of CNS germinoma: pineoblastoma, primitive neuroectodermal tumors, medulloblastoma, lymphoma, pituitary adenoma, atypical teratoid/rhabdoid tumor, Langerhans cell histiocytosis, and gliomas. These findings demonstrate that NANOG is a sensitive and specific marker of CNS germinoma. Compared with other currently used markers, NANOG may have superior diagnostic characteristics and can facilitate identification of germinomas in minute surgical biopsies commonly obtained from these tumors. These findings also suggest a potential biologic role for NANOG in maintenance of CNS germinoma.

Germline mutation in the STK11 gene in a girl with an ovarian Sertoli cell tumour

An ovarian Sertoli cell tumour was detected in a 4-year-old girl with gonadotrophin-independent precocious puberty. Such gonadal tumours can be associated with Peutz-Jeghers syndrome, caused by mutations in the STK11 gene. We have therefore sequenced the STK11 gene. Mutation analysis revealed a nonsense mutation in exon 1 (c.130A>T;p.Lys44X) of the SKT11 gene, which resulted in a truncated, inactive protein. The mutation was heterozygous in patient's lymphocytes and almost homozygous in the tumour, indicating loss of heterozygosity. This is the first report of a STK11 germline mutation in a girl with an ovarian Sertoli cell tumour. It remains to be shown whether this particular mutation predisposes the patient to the development of ovarian tumours.

Genomic-based nursing care for women with Turner Syndrome: genomic-based nursing care

Biologic and technologic advances generated from The Human Genome Project are having a dramatic impact on the expanding role of nurses in current health care practice. New genetic research needs to be transformed rapidly into clinical protocols with recommendations for delivering care to targeted populations. Nurses can contribute significantly, as part of an interdisciplinary approach, to translate genome-based knowledge into benefits for health care and society. In this context, we describe a clinical-genetic investigation protocol, as well nursing diagnosis, interventions and outcomes for clients with Turner Syndrome (TS) at risk for develop gonadal tumors, due the presence of a normal or abnormal Y chromosome.

Testing for sex chromosome mosaicism in Turner syndrome

Ullrich–Turner syndrome (UTS) is frequently associated with chromosomal mosaicism. Conventional cytogenetic studies identify sex chromosome mosaicism in approximately 55% of patients. Roughly 2% of UTS patients who are mosaic exhibit a cell population with 46,XY or a structural rearrangement of the Y chromosome. Such patients are at an increased risk of gonadoblastoma and occasionally more clinically significant gonadal tumors. For UTS patients with a monosomy X karyotype result, we developed and validated a FISH assay to identify low level mosaicism for an XY or XX cell population, or an X or Y structural rearrangement. We have tested 44 patients with monosomy X for sex chromosomal mosaicism using FISH. A second cell line was identified in 10 patients (23%), 6 with X/XX, 1 X/i(X), and 3 X/dic(X). None of the patients studied thus far with FISH have exhibited a Y-chromosome cell population. FISH as an adjunct to karyotype analysis is useful to identify sex chromosome mosaicism in UTS patients, and has increased the rate of identification of mosaicism from 55% to 67%.