Embryogenesis and Metastatic Testicular Germ Cell Tumors of Adolescents

This issue of Klinische Padiatrie contains two highly interesting contributions to the field of clinical management of human germ cell tumors of adolescents and young adults [1] [4]. Although both cases in fact relate to metastatic disease, they also show the benefit and relevance of early diagnosis of this particular type of cancer. Testicular germ cell tumors of adolescents and young adults are the seminomas and nonseminomas, also referred to type II TGCTs [17] [20]. Histologically, the nonseminomas are divided into the stem cell component, known as embryonal carcinoma, the yolk sac tumor and choriocarcinoma [extra-embryonal elements], and teratoma [somatic differentiation]. In other words, these tumors show similarities to early embryogenesis, and are in fact really totipotent. They have unique epidemiological characteristics [11] [13]. In fact, they are one of the few solid cancers in adolescents and young adults [2], and represent the most frequent solid tumor in the age group of 15–45 years in the Caucasian population. The cells of origin is the malignant counterpart of an embryonic germ cell, either a primordial germ cell or gonocyte, known as carcinoma in situ(CIS) [18], intratubular germ cell neoplasia unclassified [20], or testicular intratubular neoplasia (TIN) [7]. Specific risk factors for this type of cancer are identified, amongst others cryptorchidism, sub- and infertility, familial predisposition and certain variants of disorders of sex development [6], all related to a delayed maturation of primordial germ cells/gonocytes into pre-spermatogonia. This has been suggested to be part of the so-called testicular dysgenesis syndrome [19]. Invasive TGCTs are characterized on the chromosomal level by gain of the short arm of chromosome 12, mainly due to isochromosome 12p formation [17], which interestingly can also be identified in human embryonic stem cells, grown in vitro [8]. TGCTs are exceptional because of the fact that they can be effectively treated, using a combinatory strategy of surgery, irradiation and/or chemotherapy in most cases [12]. In fact, overall, they are highly sensitive to DNA damaging agents, which can be related to their embryonic origin. However, this specific sensitivity is lost in the mature teratomas, which indeed have no embryonic characteristics anymore, and are in that context similar to normal adult tissue [14] [15], and therefore need surgical intervention for sure. In spite of this sensitivity, it has become obvious that late effects of chemotherapy exposure at young age occur [10]. This has initiated further studies on limiting exposure thereby reducing these side effects. Another clinical obstacle is development of refractory disease, which is often the cause of death of patients with this disease, because of highly limited treatment options [3] [9] [16].

Both case reports in this issue are related to young patients [1] [4]. The patient with the metastatic choriocarcinoma demonstrates a number of very important issues, needed to be appreciated by the clinical society [1]. It clearly shows that full physical examination, including the testes, is of highly importance in adolescent and young males, especially from Caucasian origin. This allows a relatively simple tool to detect TGCTs, already in an early stage of it development. Moreover, it shows that awareness of the epidemiological characteristics of TGCTs, and the impact of self-examination is not sufficiently appreciated by the society in total, as well as by the medical community. Most likely, this had resulted in earlier diagnosis of the disease. Based on the histology of the primary testicular tumor, i.e., mature teratoma, the malignant behavior of this tumor is not obvious. In this context, it would be worth to investigate the presence of the precursor CIS [see above]. These cells are identifiable using a number of highly informative diagnostic markers known to be present in embryonic germ cell, including OCT3/4 [5]. However, in this case, the malignant behavior is no question, because of the presence of metastases. From a biological point of view it would be of interest to carefully examine the primary cancer for choriocarcinoma components. The statement of the authors that in case of a skin metastasis in a young patient, a choriocarcinoma must be considered, must be interpreted in a broader context. Specifically in patients in the age group of the highest risk for TGCTs, the presence of skin metastasis must trigger clinicians to include physical examination of the testes. Moreover, the case nicely demonstrates the power of serum levels, in this specific case elevated b-HCG in the diagnosis of TGCTs.

The other case report is an elegantly performed experimental treatment strategy for an unresectable metastatic TGCT [4]. Interestingly, this patient was also diagnosed having a TGCT based on extensive clinical examination, detecting multiple metastasis. Again, serum level investigations were instrumental in the diagnostic procedure. The primary TGCT had a mixed nonseminomatous composition. The patient was initially treated with standard strategy, and in spite of normalizing serum levels, multiple extragonadal growing tumor sites were identified, which resulted in a more intensified treatment. In spite of this, a growing teratoma was identified, being a completely somatically differentiated lesion, which can not be cured by either irradiation or chemotherapy, because the tumor cells lost their sensitivity to DNA damage [see above]. Moreover, growing teratoma can also not be identified based on elevated serum levels of tumor markers (AFP and b-HCG). This TGCT origin was supported by genomic analysis, showing gain of 12p-sequences. In this case even surgical intervention was not found to be applicable because of the extension of the lesion, resulting in no treatment options. Therefore, an alternative approach was undertaken, using antiangiogenetic drugs. In fact, a combined approach was applied, including vinblastine, thalidomide, interferon alpha and bevacizumab. The treatment was tolerated very well, without significant side effects, demonstrated by the fact that the patient continued his education during the treatment. At various time points, the metastatic lesions were surgically removed, of which the histology was in accordance to earlier observations. As the authors correctly state, it is too early to conclude about possible broader application of this treatment strategy. However the observations are more than interesting. Therefore, indeed, an international database and collaboration is required to allow firm conclusions. In this set up collection of tissue of the primary tumors and metastases (if available) would be of great interest, both retrospectively as well as prospectively. This will allow biological side studies, which will shed light on the pathobiological mechanisms involved in the development of this intriguing type of cancer.

The manuscripts also demonstrate the discrepancy in nomenclature used, which hampers exchange of information, both between clinicians and scientists. Therefore, it will be of interest to develop a single internationally accepted classification system for TGCTs, reflecting the different entities with their clinical impact.

Conflict of interest: The author has no conflict of interest to disclose.

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