Klinefelter syndrome and germ cell tumors: review of the literature

Articles that were included were published from 1972 until march 2020. From 1971 until 1986 only several reports were written (total of 38 patients). Most patients found in case reports (total 72 patients; 51%) were published between 1987 and 2006. Since 2006 30 patients with KS and GCS were published in several case series.

Mean age was 17.3 years (StDev + − 10.2). Thirty percent (42 cases) of the reported cases were in the age-group of 15–19 years old. Of 141 patients, 54 patients were below the age of 14 (prepubertal), as 87 patients were postpubertal with the oldest age of 64 years. The incidence of germ cell tumors by age group are represented in Fig. 1.

The most frequent location of the germ cell tumors appeared to be the mediastinum (n = 90), followed by the central nervous system (n = 23), testis (n = 15) and abdomen (n = 13) (Table 1). Especially in age 5–19 years the mediastinal germ cell tumors comprise the largest fraction (Fig. 2). Children under the age of 5 show more intra-abdominal localizations (n = 6). The central nervous system seems to be more involved at postpubertal age (15–29 years old).

Tumors of germ cell origin occur with increased frequency in disorders of sexual differentiation, including cryptorchidism, XY dysgonadal dysgenesis, testicular feminization syndrome and KS. The overall incidence of cancer in men with KS is similar to that of the general population, but some malignancies show a significantly higher prevalence in these patients. The reported incidence of eGCT in KS patients is 1.5/1.000, a fifty-fold increase over the general population [16]. Although it has been estimated that 1–2% of KS patients develop a neoplasm, previous data demonstrated that young males with KS have a relative risk of around 66.7 for developing extra-gonadal germ cell tumors [17, 18]. Several reports describe the association between KS and GCT, although the cause of this association is unknown. Some postulate that the hypergonadotropism due to the gonadal insufficiency promote germ cell proliferation, while others hypothesize the assignment of a GCT susceptibility gene to the X chromosome [19]. In KS is the mediastinum the most prevalent site compared to the gonads in those with KS. Until now the altered hormones, such as elevated estrogen-to-testosterone ratio and elevated gonadotropin level have been the focus for explaining the observed increase in male breast cancer and extragonadal germ cell tumors among Klinefelter syndrome patients [7, 20]. The abnormal hormonal influence could also increase the malignant potential [10].

GCTs originate from primitive germ cells, which migrate during the embryogenesis from their origin in the endoderm in the yolk sac along the urogenital ridge to the gonads. Abnormal migration causes the germ cells to be distributed, to the gonads and to extragonadal localizations. In the normal course of development these cells die off, but if they are persistent or misplaced, they may give rise to germ cell tumors. This may be the result of an abnormality in the primordial germ cell itself or in its micro-environment [21]. Furthermore, there is a hypothesis that the germ cells transformed in the testis have a reserve migration pathway [22]. This hypothesis is supported by the fact that testicular GCTs and ECTGs share the common cell of origin [23, 24]. Germ cell tumors are classified as extragonadal if there is no evidence of a primary tumor in the testis [25]. By unknown factors, dislocated germ cells undergo malignant transformation and to give rise to GCTs in extragonadal localizations. Germ cell tumors arise in both gonadal and extragonadal sites. In adults, 90% of primary germ cell tumors involve the testis or ovary, but it is known that in the pre-pubertal years there is a preference for extragonadal sites [26]. It is known that most primary eGCTs are found in midline structures (pineal region (6%), mediastinum (7%), retroperitoneum (4%), sacrococcygeal region (42%) or in the ovary (24%), testis (9%), and other sites (8%) [27]. The anterior mediastinum is the third most common location for germ cell tumors in children. The mediastinum gives a generous space for expansion before the mass will cause symptoms, mediastinal germ cell tumors may achieve enormous size prior to detection. The patient’s age at diagnosis appears to be a critical prognostic factor. EUROCARE data (European Cancer Registry based study on survival and care of cancer patient’s project) stated that GCTs have an incidence of 31/1.000.000 people. Most GCTs arise in the gonads, with the highest incidence between age 25–40 years (testis) and 14–34 years (ovarian). eGCTs occur most frequently in the age-groups 0–4 years and 15–34 years. It is assumed that the most common extragonal localizations in children are the central nervous system, followed by mediastinum/thorax and abdomen/pelvis. In our study more eGCTs were found in the mediastinum than in the central nervous system. The most common localization of a GCT in KS, is the mediastinum (n = 83) except for children under the age of 5 year in which the abdominal location is more frequent (n = 8). This is comparable with other known data. The GCTs are mostly located in the anterior mediastinum [28, 29].

In adults without KS, GCTs are mostly gonadal, whereas in children without KS, GCTs are mostly extragonadal (CNS responsible for the primarily location). Beresford et al. proposed that chest Rx should be performed as routine in young patients with KS [30]. The risk to develop a mediastinal GCT for children with KS is difficult to assess due to the rarity of mediastinal GCT and the underdiagnosed KS.

Extragonadal germ cell tumors (eGCTs) represent 5–10% of all GCTs and most arise in the midline [31]. The most common midline sites are mediastinal, retroperitoneal, pineal gland and sacrococcygeal [32]. They can be divided into two histologic groups, germinoma and non-germinoma. For a tumor to be considered in one group, it must entirely consist of that single histology and cannot contain other GCT elements. The germinoma group is divided in germinoma (most often brain), dysgerminoma (ovary) and seminoma (testis), while the non-germinoma group is divided in teratoma (mature and immature), yolk sac tumor (endodermal sinus tumor), choriocarcinoma, embryonal carcinoma, gonadoblastoma and mixed GCTs. Seminomas may exist in a pure form, but any elevation of AFP indicates the presence of an element of a non-seminomatous tumor [33]. In addition, mediastinal germ cell tumors have a propensity to develop another malignancy (e.g., rhabdomyosarcoma, adenocarcinoma, permeative neuroectodermal tumor), which can become the predominant histology. Determination of serum tumor markers, β-HCG and AFP, is important in the diagnosis and follow-up of germ cell tumors. AFP and or beta-hCG is elevated in 85% of cases of extragonadal non-seminomatous GCTs [34] [35]. Elevations of β-HCG and AFP confirm a malignant component to the tumor. Yolk sac tumors produce AFP, while germinomas and choriocarcinomas, produce β-HCG. Benign teratomas may produce small elevation of the tumor markers.