The risk of neoplasm associated with dysgenetic testes in prepubertal and pubertal/adult patients

Abstract

Introduction. In patients with Y-chromosome in the karyotype, partial gonadal dysgenesis and disorders of male reproductive sex organs development are usually resected in childhood because of the high risk of germ cell tumours (GCT). In patients with Y-chromosome, complete gonadal dysgenesis and female genitalia gonadectomy is performed markedly later. However, due to the relatively low number of adult patients with preserved dysgenetic gonads, the true risk of neoplasm is unknown. The aim of the study was to evaluate the prevalence of neoplasia in dysgenetic gonads of children and adults with Y-chromosome in a retrospective study. Material and methods. A review of medical documentation of 94 patients with disorders of sex development (DSD), Y-chromosome and gonadal dysgenesis (GD), aged 1.2-32 years (47 prepubertal, 1.2-10 years; 47 pubertal/adult, 13-32 years), was conducted. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were determined. Bilateral gonadectomy was performed in 73.4% of patients, and unilateral gonadectomy with biopsy of the contralateral gonad in 26.4%. All gonadal tissues were subjected to immunohistochemical evaluation with antibodies against PLAP and OCT3/4 (markers of malignant germ cells, but also foetal multipotent germ cells), while gonads of prepubertal patients were examined by c-KIT, as well. Results. Streak gonads were identified on both sides (complete GD) in 30.8%, a streak gonad on one side and an underdeveloped testis on the other (asymmetric GD) in 38.3%, and underdeveloped testicular structure on both sides (partial GD) in 30.8% of cases. Germ cell neoplasia was found in 53.2% of patients (51.1% in children, 55.3% in pubertal/adults). Invasive GCT were identified in 11.7% of cases, of which 90.9% were in pubertal/adult patients. Other neoplastic lesions included gonadoblastoma (16% prevalence) and testicular carcinoma in situ www.fhc.viamedica.pl (25.5%). In younger patients FSH serum levels were increased in 81% of cases (mean 2.82 ± 2.18 IU/L), while LH in 58% (mean 1.82 ± 1.69 IU/L). Hypergonadotropic hypogonadism was diagnosed in most of the pubertal/ /adult patients (mean FSH 54.2 ± 23.3 IU/L, mean LH 21.7 ± 12.1 IU/L, mean testosterone 5.5 ± 4.5 nmol/L). Conclusions. Dysgenetic gonads in patients with Y chromosome have a high risk of germ cell neoplasia (ca. 50%). If they are preserved until puberty/early adulthood, they may develop overt, invasive GCT. The gonads also have poor hormonal activity (hypergonadotropic hypogonadism) in most of the pubertal/adult patients. Each of these cases must be considered individually and a decision to remove the gonad or not should be based on the comprehensive analysis of the phenotype by a multidisciplinary team of specialists in consultation with the patient and the parents. If dysgenetic gonads are not resected in childhood, these patients need careful ongoing follow-up examination, including biopsy and histopathological evaluation.

Fertility outcome and information on fertility issues in individuals with different forms of disorders of sex development: findings from the dsd-LIFE study

“…In the past, gonadectomy was often performed in individuals with DSD already in early childhood, because of the potential risk of malignancy in the dysplastic gonad. Especially, the high risk of germ cell tumors occurring after puberty in the dysgenetic gonads of patients with Y chromosome and their poor hormonal and gametogenic function were the reasons for the recommendation of gonadectomy before puberty (47)(48)(49). However, prophylactic gonadectomy may deprive some patients with DSD their chance for fertility (50).…”

Pathogenesis of germ cell neoplasia in testicular dysgenesis and disorders of sex development

“…Germ cell loss is particularly pronounced in pure Turner syndrome (45,X) and other forms of premature ovarian failure, so these patients have a very low risk of GCN. However, an important notion is that even streak gonads can harbour surviving germ cells, especially in 46,XY complete gonadal dysgenesis [107,122]. Five studies listed in Table 1 reported a very high risk of GCN, ranging from 32 to 75%, in 46,XY DSD individuals with complete gonadal dysgenesis, including two studies of patients with Swyer syndrome (usually caused by SRY mutations), who often have bilateral streak gonads [124,127,139].…”

“…Several studies report a very high proportion of GCN in these patients, usually in a range of 15 -30%, but occasionally higher, likely due to the selection bias. The risk may be particularly high, if testicular dysgenesis is bilateral [99,122]. The presence of the Y A c c e p t e d M a n u s c r i p t chromosome or Y chromosome-derivative genomic material, even in a small proportion of cells, markedly increases the GCN risk in individuals with 46,XX or 45,X, who otherwise rarely develop tumours.…”

“…Two large studies [99,122] reported the presence of GCNIS/TGCT in around 52% of DSD patients with bilateral dysgenetic testes, while the frequency of malignant changes was lower (up to 25%) in combined/asymmetric gonadal dysgenesis. This inverse relationship between the degree of testicular dysgenesis and risk of malignancy was first proposed by Slowikowska-Hilczer [143], and subsequently observed in several studies of children with DSD [99,100,122,129], as well as in adult men with infertility and histological signs of TDS [10].…”

“…Overt tumours are rare in early childhood but their prevalence increases rapidly during and after puberty. In one large Polish study listed in Table 1, the prevalence was 10 times higher in A c c e p t e d M a n u s c r i p t 11 adolescent or young adult patients than in prepubertal boys [122]. Stimulation of the gonad by gonadotrophins may play a role in the malignant transformation of GCN in situ [147].…”