The risk in each group of DSD is difficult to evaluate, because the reported prevalence per diagnostic group varies considerably and also because statistical data from literature reviews are based on gonadectomies performed during the previous decades, mainly prophylactically in early childhood; therefore, the real incidence of GCT may be higher. In addition, an accurate risk for malignant transformation in DSD patients is hard to predict because of two major problems: first, the confusing terminology and classification systems referred to the different forms of DSD, in which several synonyms and eponyms are used in literature, and definitions for the terminology are often lacking from bibliographical sources; second, there are no well-established criteria for the identification of malignant germ cells, especially in young children. This is specifically due to the phenomenon of delay of germ cell maturation, which might result in overdiagnosis of germ cell neoplasia in situ (GCNIS) [20].

Seminoma (if the gonad is considered a testis)/dysgerminoma (if the gonad is considered an ovary) and the non-seminomatous germ cell tumors are by far the most frequently occurring tumors in patients with DSD [24, 25, 27–33]. However, other gonadal (benign and malignant) neoplasms have sporadically been reported in patients with DSD, often in combination with the above-mentioned GCT. The development of invasive GCT is always preceded by the presence of an in situ neoplastic lesion. In gonads of DSD patients, the precursor of cancer may be GCNIS in testicular tissue or gonadoblastoma (GB), in those without obvious testicular differentiation or in patients with testicular dysgenesis [26, 34, 35]. Because gonadectomies in patients with DSD have often been performed prophylactically, most of the encountered changes in germ cells are benign or in situ malignant conditions. Recently, detailed histologic investigation of gonads of DSD patients led to the identification of the putative precursor of GB, which was referred to as undifferentiated gonadal tissue [25].

The prevalence of GCT is increased in patients with DSD containing Y chromosome material in their genome and especially the chromosome Y “GBY” region, which is related to the presence of the TSPY gene, the most likely candidate [36, 37]. The presence of SRY or other sex determining genes is irrelevant in this context. Specifically DSD patients with gonadal dysgenesis (DSD with maldeveloped gonads, including streak gonads and testicular dysgenesis) or undervirilization (DSD with abnormal androgen function) are at risk. Traditionally, the prevalence of GCT in patients with gonadal dysgenesis is estimated at around 30 % [25] and in patients with undervirilization syndromes at 5–10 % [22, 23]. However, reported prevalence numbers per diagnostic group may vary considerably.

A clear insight into the prevalence of GCT in patients with gonadal dysgenesis (either complete or partial) is hampered by confusing nomenclature, which is most pronounced for this patient category, as well as an overestimated incidence of GCNIS in some series, reported as high as 91 % [38] to 100 % [39] that probably corresponds to a state of arrested or delayed maturation of the germ cells. GCT in patients with gonadal dysgenesis are frequently found at a very young age, during the first year of life [25, 29, 33, 40] or may even at birth [41]. Nearly all the in situ neoplastic lesions in patients with gonadal dysgenesis are GB, leading to seminoma/dysgerminoma in 92 % of the cases. A high risk of GB exists when sex determination is disrupted at an early stage of Sertoli cell differentiation (due to abnormalities in SRY, SOX9, or WT1). It must be remembered that development of GB requires the GBY region of the Y chromosome, which is in and of itself sufficient to lead to this neoplasm. Early Sertoli cell development is also disturbed in patients with mixed gonadal dysgenesis, who also carry a high risk of developing GB as precursor lesion. The same is true for patients with 9p deletions, likely related to the loss of DMRT1 [42]. Careful histological analysis of gonadal tissue of DSD patients revealed that undifferentiated gonadal tissue is the most likely precursor stage of GB [26]. The GCNIS lesion accounts for only 8 % of precursor lesions in patients with gonadal dysgenesis and is probably only encountered in the presence of testicular tissue [25].

In the group of undervirilized patients (DSD with abnormal androgen function), the overall prevalence of GCT approximates 2.3 % [25]. In the androgen insensitivity syndrome (AIS), the reported prevalence of GCT has varied from 5–10 % [22, 23] to 22 % [43], although in more recent series of prophylactic gonadectomies, the estimated prevalence is 5.5 % [28, 34, 44–51]. Tumor prevalence in AIS markedly increases after puberty and reaches 33 % by 50 years of age [28]. Although data are limited, the risk seems to be markedly higher in the partial form (PAIS) (15 %) [34, 44, 49] than in the complete variant (CAIS) (0.8 %) [28, 34, 44, 47–49]. This difference may be explained by the fact that there is a rapid and total loss of germ cells by apoptosis in CAIS patients, starting from the age of 1 year, whereas PAIS patients maintain their germ cell population at about two-thirds of the normal number at puberty [34]. The risk of cancer in the PAIS patients is influenced by the anatomical localization of the gonad, being the highest in abdominal sites and the lowest in scrotal localization [42, 52]. In contrast to patients with gonadal dysgenesis, nearly all the reported tumors in the group of patients with undervirilization syndromes are GCNIS lesions (81 %) or seminomas (19 %), probably because these defects have occurred in late gonadal development. For other causes of undervirilization, the development of GCT is exceptional: one tumor is reported in a series of six patients with 17β-hydroxysteroid dehydrogenase deficiency (17 %) [34]; no tumors were found in a series of three patients with 5α-reductase deficiency [47] and of two patients with Leydig cell hypoplasia [34].

The risk for GCT development in patients with DSD can be grouped into four categories: high, intermediate, low, and unknown. High-risk patients include those with gonadal dysgenesis (DSD with maldeveloped gonads) [20], intra-abdominal gonads and the GBY region in their genome, including Frasier [53] and Denys–Drash syndromes and also patients with PAIS and non-scrotal gonads. The percentages found in the literature vary from 15 to 60 %. At intermediate risk are patients with the Y+ (GBY+) Turner syndrome and those with 17β-hydroxysteroid dehydrogenase deficiency, gonadal dysgenesis (harboring the Y chromosome), or PAIS, the two latter categories with scrotal gonads. The low-risk group includes patients with CAIS as well as patients with ovotesticular DSD (in which the gonads mostly consist of well-differentiated ovarian and testicular tissue) [54] and those with Turner syndrome lacking an apparent Y chromosome. The unknown category includes 5α -reductase deficiency, Leydig cell hypoplasia and specific gene mutations for which there are insufficient or no data for proper analysis [52, 55].

An interesting question is why GB forms in some patients and GCNIS in others. Hersmus et al. [42] hypothesized that this is due to the specific microenvironment, especially the absence of functional Sertoli cells, leading to female development. In other words, GCNIS can only be formed at a certain level of testicular development. Thus, GB and GCNIS are simply two variants of the same defect, being in fact a continuum, of which the phenotypic presentation is determined by the microenvironment, the level of virilization [42].

The most common GCT in the pediatric population, teratomas are often composed of multiple embryologic layers, arising from multipotent cells, containing one or more embryonic germ layers (ectoderm, mesoderm, endoderm) of tissue foreign to the anatomic site of origin [56]. In its usual definition, tissue elements of all three blastoderm layers (endoderm, mesoderm, and ectoderm) are present; however, teratomas also occur in which only one or two of the germ layers are present (referred to as monodermal or bidermal teratomas, respectively) [6]. They are divided into both mature and immature forms. Mature teratomas are benign; they are commonly cystic and may contain several well-differentiated cell types (i.e., skin, hair, teeth, thyroid, gastric mucosa, brain tissue). Immature teratomas are less differentiated and more reminiscent of embryonal tissue, frequently including neuroectoderm typically in the form of neuroepithelial rosettes and tubules and often mixed with mature tissue [3, 6, 57].

A grading system has been developed for immature teratomas, based on the amount of neuroepithelial tissue present. Mature teratomas containing only fully differentiated tissue are considered grade 0 and immature teratomas range from grade 1 (composed of <10 % immature neuroepithelium) to grade 3 (>50 % immature neuroepithelium present). In adult ovarian teratomas, the finding of grade 2 or 3 immature teratoma predicts the likelihood of metastasis and confers a worse prognosis [57]. In children, however, it is not clear that the same relationship of grade to outcome of immature teratomas applies. A Pediatric Oncology Group study concluded that surgery alone was curative in children and adolescents with stage I immature teratomas of any grade and that chemotherapy should be reserved for cases of relapse [58–60]. However, an association between grade 3 immature teratoma and microscopic foci of YST (83 %) has been demonstrated, emphasizing the need for thorough histologic evaluation of tumors [59].

These GCT result from abnormal premeiotic differentiation [3]. Seminoma or dysgerminoma has a reduced ability for further differentiation and is rare before puberty but occurs at gonadal sites in adolescence [1]. Testicular seminoma and ovarian dysgerminomas are analogous malignant tumors that occur more commonly in young adults. When they occur in younger children, it is typically in association with gonadal dysgenesis [3].

Choriocarcinomas and YST result from abnormal postmeiotic extraembryonic differentiation [3].

YST is the most frequent malignant histological type in pediatric GCT and is common at the sacrococcygeal, retroperitoneal, mediastinal, and prepubertal testicular locations [1, 4, 6]. In neonatal GCT, YST most commonly occurs within a teratoma; about 5 % of neonatal teratomas have a yolk sac component [4]. In older infants and young children, YST more commonly occurs as a pure YST, not as a component of a teratoma [6]. AFP elevation is seen in the presence of YST and serves as a marker of persistent or recurrent disease, especially in infants between 6 months and 2 years of age, when the normally elevated newborn levels ranging from 41,000 to 160,000 ng/ml decrease. AFP levels are reported up to 87 ng/ml within 95.5 interval assuming a logarithmic normal distribution, decreasing to a mean of 8 ng/ml at 2 years of age before finally reaching the normal adult serum level of 0–6 ng/ml (vide infra) [61].

Choriocarcinoma is rare in childhood. It is even rarer in the infant and is usually thought to originate from a focus of choriocarcinoma that has arisen in the placenta as a variant of gestational trophoblastic disease [1, 6]. Choriocarcinoma is composed of cytotrophoblast, syncytiotrophoblast, and extravillous trophoblast, often mixed in random fashion surrounding areas of hemorrhage and necrosis. Vascular invasion is a common feature of choriocarcinomas [6]. The disease is rapidly fatal if left untreated [62]. Given that placental choriocarcinoma can also metastasize to the mother (up to 60 % of cases), if an infantile choriocarcinoma is diagnosed, the mother should also be screened for the disease [6].

Embryonal carcinoma possesses the ability to differentiate into embryonic and extraembryonic tumors [1, 7]. It most frequently presents in postpubertal GCT [9].

GB are benign tumors that contain both germ cells and stromal cells. As mentioned above, neonates can also present with GB in patients with dysgenetic gonads.