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

Abstract

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.

Distribution of Y-chromosome-bearing cells in gonadoblastoma and dysgenetic testis in 45,X/46,XY infants

“…6 The tumor development in these patients had been associated with the presence of normal or abnormal Y-chromosomes, molecular evidence for Y-derived sequences and intrabdominal location of the abnormal gonads. 3,4,7,8,18 The age at diagnosis is variable ranging from birth to the fourth decade; around 94% of cases Distribution of Y-chromosome-bearing cells R Peña-Alonso et al reported in the literature was diagnosed during the second or third decades of life. 22 Data in the literature revealed 10 cases where the tumor developed during childhood, five of them had a 45,X/ 46,XY mixed gonadal dysgenesis and the diagnosis was performed only in one case at 9 months old while the rest were diagnosed around 10 years of age.…”

“…6 Tumor development in these patients is associated with the presence of either normal or abnormal Y-chromosomes or molecular evidence for Y-derived sequences and intrabdominal location of the abnormal gonad. 3,7,8 Histologically, the tumor is composed of well-circumscribed round to oval nests with a mixture of germ cells and sex-cord-type cells resembling immature Sertoli or granulosa cells that often show central calcification. 9 Gonadoblastoma per se does not show invasive behavior but 30% of the specimens demonstrate evidence of overgrowth by the germinal component.…”

New insights into type II germ cell tumor pathogenesis based on studies of patients with various forms of disorders of sex development (DSD)

“…It has been indicated that GB and CIS are fundamentally different (Jørgensen et al, 1997;Slowikowska-Hilczer et al, 2003). We will summarize a number of arguments to support the model that this is not the case, and that GB and CIS are in fact a continuum, of which the phenotypic presentation is determined by the micro-environment, i.e., the level of virilization.…”

Origins and molecular biology of testicular germ cell tumors

“…This particular distribution is thought to be due to the migration route of the primordial germ cells to the genital ridge. [1][2][3] Testicular germ cell tumors (TGCT) comprise approximately 98% of all testicular neoplasms and are the most common malignancy in males between the ages of 15 and 35 years. 4 It is possible to define three epidemiologically, clinically and histologically diverse groups of testicular germ cell tumors (Table 1).…”