Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from AbbVie as a guest speaker, from NewLink Genetics and Reneuron for consulting work, and from Monetris as an advisory board member.)
This article includes discussion of intracranial nongerminomatous germ cell tumors, central nervous system differentiated germ cell tumor, and central nervous system nongerminomatous germ cell tumor. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Historical note and terminology
Primary intracranial germ cell tumors are relatively uncommon malignancies in Western countries, historically comprising only about 1% of the histopathological diagnoses of central nervous system tumors in adults (Bloom 1983; Hoffman et al 1991) and 3% in children (Fuller et al 1994). In the 2017 statistical report from the Central Brain Tumor Registry of the United States (CBTRUS) of the population-based incidence of primary brain and other CNS tumors, germ cell tumors accounted for only 0.9% of all histological types of malignant brain tumors. However, among children and adolescents 0 to 19 years of age, germ cell tumors constituted 3.8% of all brain tumors (Ostrum et al 2017). Primary intracranial germ cell tumors were previously thought to be considerably more frequent in Japan, constituting up to 20% of intracranial tumors in males between the ages of 10 and 25 years in older studies (Takeuchi et al 1978), although more recent work suggests a similar incidence in Japan as in the U.S. (Nakamura et al 2011). However, among children less than 15 years old, the incidence of primary intracranial germ cell tumors remains higher in Japan than in Western countries and constitutes nearly 12% of all primary brain tumor in this age group (Makino et al 2013). These tumors most commonly arise in midline central nervous system locations, predominantly in the pineal or suprasellar regions.
Tumors of germ cell derivation are usually histologically classified by cell of origin into 2 main groups: (1) undifferentiated germ cell tumors or germinoma (called seminoma or dysgerminoma in the testis or ovary, respectively) and (2) differentiated or nongerminomatous germ cell tumors, including teratoma (mature and immature), teratoma with malignant transformation, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mixed germ cell tumor (Louis et al 2016). Although teratomas are made up of a mixture of tissues derived from all 3 germinal cell layers, mature teratomas are composed of fully differentiated ectodermal, mesodermal and endodermal elements. Immature teratomas have embryonal or fetal primitive elements with malignant potential. Pure mature teratomas are benign and can be cured surgically. However, these tumors often have a mixture of mature and immature elements, making their behavior difficult to predict.
The nongerminomatous germ cell tumor has been classified as a separate clinical entity because of its different response to therapy, particularly in the central nervous system and other extragonadal locations. Germinoma (although histologically the least differentiated variant) is readily cured by radiotherapy, whereas the malignant variants of the nongerminomatous germ cell tumor are relatively radio-resistant and, without other additional therapy, have had a much poorer prognosis. Some Japanese investigators have distinguished between some subtypes of intracranial nongerminomatous germ cell tumor and, in particular, have separated malignant teratomas from the rest of the nongerminomatous germ cell tumor because they appear to have a somewhat better prognosis (Matsutani et al 1997; Aoyama et al 1998). This was not observed among the teratomas in an earlier literature review (Jennings et al 1985).
Each of the histological germ cell tumor variants is derived from cells of a normal stage of embryonic development. Germinoma is the malignant correlate of the primordial germ cell itself; teratoma has origin in all 3 differentiated embryonic cell layers (endoderm, mesoderm, and ectoderm); embryonal carcinoma arises from the pluripotential stem cell of the embryo; endodermal sinus tumor and choriocarcinoma are extraembryonic derivatives of the yolk sac and trophoblast (Takei and Pearl 1981).
Germ cell tumors most commonly arise in gonadal tissue (testis or ovary), and the central nervous system is only 1 of several extragonadal sites of origin that also include the retroperitoneum, the sacrococcygeal region, the mediastinum, and rarely the nasopharynx, neck, thorax, abdomen, bladder, or prostate (Gonzalez-Crussi 1982). Irrespective of their site of origin, germ cell tumor, germinoma, and nongerminomatous germ cell tumor appear to be virtually indistinguishable with respect to their histopathology by light and electron microscopy and by histochemistry (Koide et al 1980; Bjornsson et al 1985).
The histology of germ cell tumors as initially described in the ovaries and testes was thought to resemble the primordial precursors of mature germ cells. In 1944, Russel noted a similarity between the most common testicular germ cell tumor (called seminoma) and some pineal tumors; these he named atypical teratomas (Russel 1944). Recognition of histologic similarity between some suprasellar and infundibular tumors, the pineal region atypical teratoma tumors, and certain mediastinal tumors led to classification of all of these as germ cell tumors (Friedman 1951; Russel 1954).
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