Testicular Pathology in 46,XY Dysgenetic Male Pseudohermaphroditism: An Approach to Pathogenesis of Testis Cancer

SłOWIKOWSKA‐HILCZER, JOLANTA; SZARRAS‐CZAPNIK, MARIA; KULA, KRZYSZTOF

doi:10.1002/j.1939-4640.2001.tb02581.x

Cited by 35 publications

References 41 publications

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Testicular germ cell tumors exhibit evidence of hormone dependence

Douglas

Richardson

Nicol

2005

Intl Journal of Cancer

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The aim of this investigation was to test the hypothesis that testicular germ cell tumors (TGCTs) are hormone-dependent cancers. Human TGCT cells were implanted in the left testis of male severe combined immunodeficient mice receiving either no treatment or hormone manipulation treatment [blockade of gonadotropinreleasing hormone secretion and/or signaling using leuprolide or leuprolide plus exogenous testosterone]. Real-time RT-PCR analysis was used to determine the expression profiles of hormone pathway-associated genes. Tumor burden was significantly smaller in mice receiving both leuprolide and testosterone. Real-time RT-PCR analysis of follicle-stimulating hormone (FSH) receptor, luteinizing hormone (LH) receptor and P450 aromatase revealed changes in expression in normal testis tissue related to presence of xenograft tumors and manipulation of hormone levels but a complete absence of expression of these genes in tumor cells themselves. This was confirmed in human specimens of TGCT. Reduced TGCT growth in vivo was associated with significant downregulation of LH receptor and P450 aromatase expression in normal testes. In conclusion, manipulation of hormone levels influenced the growth of TGCT in vivo, while the presence of xenografted tumors influenced the expression of hormone-related genes in otherwise untreated animals. Human TGCTs, both in the animal model and in clinical specimens, appear not to express receptors for FSH or LH. Similarly, expression of the P450 aromatase gene is absent in TGCTs. Impaired estrogen synthesis and/ or signaling may be at least partly responsible for inhibition of TGCT growth in the animal model. ' 2005 Wiley-Liss, Inc.Key words: testicular cancer; gonadotropin-releasing hormone; orthotopic xenograft model Testicular germ cell tumor (TGCT) is the most commonly occurring cancer affecting young men between 15 and 35 years of age.1-3 Worldwide, the incidence rates of TGCT continue to rise for reasons that are not understood.1 These tumors appear to arise from abnormal germ cells in the testis, which bear a resemblance to gonocytes, the germ cells in the fetal stage of development. 4,5 In normal development, gonocytes transform into spermatogonia in neonates and remain dormant until the onset of puberty, at which time spermatogenesis commences and these cells mature into viable sperm. The aberrant gonocytes, referred to as carcinoma in situ (CIS) cells, do not become spermatogonia but remain dormant until the onset of puberty, at which time they appear to transform into malignant cells. 5TGCTs represent 98% of all testicular neoplasms and are recognized to have 3 distinct histopathologic subtypes: seminomas (occurring in approximately 60% of cases), nonseminomas (representing approximately 39% of cases) and spermocytic seminomas (found in less than 1% of patients). The latter are seen in elderly men while seminomas and nonseminomas appear following the onset of puberty and are most commonly diagnosed in patients aged in their 30s. Seminomas are homogeneous in appearance and be...

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Testicular germ cell tumors exhibit evidence of hormone dependence

Douglas

Richardson

Nicol

2005

Intl Journal of Cancer

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Lack of RBM Expression as a Marker for Carcinoma In Situ of Prepubertal Dysgenetic Testis

Schreiber,

Lifschitz‐Mercer,

Paz

et al. 2003

Journal of Andrology

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Individuals with various intersex states who carry Y‐chromosome material bear a high risk of developing testicular neoplasia. In order to gain more insight into the pathogenesis of this neoplasia, the current study evaluates the differentiation of the seminiferous epithelium in 46,XY dysgenetic male pseudohermaphroditism. Immunohistochemical evaluation was performed using the germ cell‐specific RNA‐binding motif (RBM) protein (encoded by the Y‐chromosome) to identify normal germ cells, whereas placental alkaline phosphatase (PLAP) was used to detect neoplastic germ cells. Differentiation of somatic Sertoli cells was assessed using cytokeratin‐18 (CK‐18) and anti‐Müllerian hormone (AMH) as markers for immature Sertoli cells. Specimens were taken from surgically removed dysgenetic gonads of five children (46XY karyotype). Intratubular germ cell neoplasia (carcinoma in situ [CIS] of the testis) was detected in all of them. Normal germ cells revealed immunoreactivity for RBM, whereas the PLAP‐positive neoplastic germ cells were negative for RBM expression. Sertoli cells revealed an immature phenotype indicated by AMH expression in their cytoplasm. The design of the current study is unique in its assessment of the state of germ cell differentiation in dysgenetic gonads by the use of the RBM protein, which was expressed only in normal germ cells but not in those of CIS. Testicular dysgenesis interrupted the normal differentiation of the germ line and had no effect on the immature phenotype of the prepubertal Sertoli cells. This points toward the germinal component of CIS as the precursor for the promotion of testis cancer.

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Neoplastic Potential of Germ Cells in Relation to Disturbances of Gonadal Organogenesis and Changes in Karyotype

Słowikowska-Hilczer

Romer²,

Kula

2003

Journal of Andrology

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The study consisted of 46 intersexual patients who underwent gonadectomy at the age of 3 months to 19 years because of gonadal dysgenesis (GD; 40 cases) or true hermaphroditism (bisexual gonads; 6 cases). In patients with GD, the incidence of the 46,XY karyotype was 67.5%, whereas the remaining patients exhibited numerical and structural aberrations of sex chromosomes (NSASs), and all patients with bisexual gonads revealed NSAS. Seminoma was diagnosed in 1 patient with the 46,XY karyotype and pure GD (streak gonads). Intratubular carcinoma in situ (CIS) appeared as an exclusive lesion in 61.5% of 13 patients with mixed GD, in 54% of 11 patients with partial GD (bilateral testes), in 16.7% of 6 patients with bisexual gonads, and in none of 13 patients with pure GD. CIS also appeared in tubules in the vicinity of sex cord-derived tumors (gonadoblastoma nests and unclassified mixed germ cell-sex cord-stromal tumor; MGCSCST) and within the tumors. In 3 patients, gonadoblastoma replaced the whole bilateral gonads and is referred to as gonadoblastoma-only GD. The incidence of neoplastic lesions (mostly bilateral) was 90.9% in patients with partial GD, 76.9% (mostly unilateral) in patients with mixed GD, 23.1% (unilateral) in patients with pure GD, and 16.7% (unilateral) in patients with bisexual gonads. Disregarding types of disturbances of gonadal organogenesis, the incidence of lesions was 71.4% in 28 patients with the 46,XY karyotype and 35.3% in 17 patients with NSAS. We conclude, first, that NSAS is not a prerequisite for the appearance of GD and GD is more frequently associated with the 46,XY karyotype. Second, the spectrum of germ cell neoplastic lesions in GD is wider than reported. Besides germ cell carcinoma, CIS, and gonadoblastoma nests, the spectrum also includes a tumor of gonadoblastoma-only in cases of GD and MGCSCST. Third, the incidence of neoplastic lesions is related more to the severity of the disturbances of gonadal organogenesis than it is to aberrations in sex chromosomes. Fourth, less disturbed testicular organogenesis predisposes these patients more toward germ cell neoplastic lesions, which suggests that the testicular environment of a dysgenetic gonad plays an important role in germ cell neoplasia initiation, maintenance, or both.

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Testicular Pathology in 46,XY Dysgenetic Male Pseudohermaphroditism: An Approach to Pathogenesis of Testis Cancer

Cited by 35 publications

References 41 publications

Testicular germ cell tumors exhibit evidence of hormone dependence

Testicular germ cell tumors exhibit evidence of hormone dependence

Lack of RBM Expression as a Marker for Carcinoma In Situ of Prepubertal Dysgenetic Testis

Neoplastic Potential of Germ Cells in Relation to Disturbances of Gonadal Organogenesis and Changes in Karyotype

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