Germ Cell Tumors in the Intersex Gonad: Old Paths, New Directions, Moving Frontiers

Abstract

The risk for the development of germ cell tumors is an important factor to deal with in the management of patients with disorders of sex development (DSD). However, this risk is often hard to predict. Recently, major progress has been made in identifying gene-products related to germ cell tumor development (testis-specific protein-Y encoded and octamer binding transcription factor 3/4) and in recognizing early changes of germ cells (maturation delay, preneoplastic lesions, and in situ neoplasia). The newly recognized "undifferentiated gonadal tissue" has been identified as a gonadal differentiation pattern bearing a high risk for the development of gonadoblastoma. It is expected that the combination of these findings will allow for estimation of the risk for tumor development in the individual patient (high risk/intermediate risk/low risk). This article reviews the recent literature regarding the prevalence of germ cell tumors in patients with DSD. Some major limitations regarding this topic, including a confusing terminology referring to the different forms of intersex disorders and unclear criteria for the diagnosis of malignant germ cells at an early age (maturation delay vs. early steps in malignant transformation) are discussed. Thereafter, an overview of the recent advances that have been made in our knowledge of germ cell tumor development and the correct diagnosis of early neoplastic lesions in this patient population is provided. A new classification system for patients with DSD is proposed as a tool to refine our insight in the prevalence of germ cell tumors in specific diagnostic groups.

Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology

“…This lack-of-androgen theory would correlate with a significantly higher risk for tumor development in patients with partial androgen insensitivity syndrome (15% versus 0.8% in complete androgen insensitivity syndrome according to Cools et al). 4 Because we did not observe any significant differences in the persistence of POU5F1-positive germ cells and KITLG expression in relation to the expected level of AR activity among patients with complete androgen insensitivity syndrome, the residual activity of AR in complete androgen insensitivity is likely not powerful enough to achieve a similar effect on survival of abnormal germ cells and their progression into neoplasia as in partial androgen insensitivity. The result may be partly influenced by the relatively small sample size.…”

“…5 The risk was estimated to be 0.8% in another meta-analysis, but this estimation was mainly based on a group of patients in which gonadectomy was carried out during childhood. 4 In fact, the risk is very difficult to predict because the approaches to manage patients with complete androgen insensitivity have continually changed over time. Whereas older reports included many adult patients and mainly reported the presence of invasive germ cell tumors, 6,28,29 more recent studies on pediatric patients refer to pre-invasive lesions, ie, intratubular germ cell neoplasia, of the testis.…”

“…Increased risk of germ cell cancer development has been noted in complete androgen insensitivity syndrome. 4,5,6 The occurrence of germ cell cancer has been reported to be up to 22% in adult patients. 5 Germ cell cancer is very rare in childhood and adolescence; 7 however, non-invasive precursor lesions characterized as intratubular germ cell neoplasia, also termed as carcinoma in situ of the testis, have been repeatedly described in this age group.…”

“…2,[8][9][10][11] The prevalence of intratubular germ cell neoplasia appears to be remarkably higher (15%) in pediatric patients with partial androgen insensitivity than in patients with complete androgen insensitivity. 4 Hannema et al described that residual activity of AR has a positive effect on the development of Wolffian structures and the enlargement of seminiferous tubules during puberty in patients with complete androgen insensitivity syndrome. 2,12 Whether residual AR activity also has an impact on the survival of normal and/or atypical germ cells has not yet been reported.…”

XY Female with Complete Androgen Insensitivity Syndrome with Bilateral Inguinal Hernia

“…Some studies have shown carcinomatous changes in the testes of the children of CAIS in the age group of 13-14 years and it is believed that testicular biopsy is warranted as soon as the syndrome is diagnosed. Recent studies reveal a tumor incidence (dysgerminoma, gonadoblastoma) of 0.8 % in CAIS and 5.5 % in AIS overall, and the risk increases markedly after puberty and reaches 33 % at the age of 50 [1,2]. Thus, gonadectomy is advised after puberty.…”