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  • Updated 10.17.2023
  • Released 10.15.1996
  • Expires For CME 10.17.2026

Intracranial nongerminomatous germ cell tumors


Historical note and terminology

Primary intracranial or central nervous system (CNS) 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 (23; 74) and 3% in children (62). In the 2021 CBTRUS 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, among children and adolescents 0 to 19 years of age, germ cell tumors constituted 3.3% of all brain tumors (136). 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 (169), although subsequent work suggested suggests a similar incidence in Japan as in the United States (127). However, the incidence of CNS germ cell tumors among children less than 15 years old is substantially higher in Japan and other Asian countries, constituting 10% to 15% of all pediatric primary brain tumors (87; 166).

These tumors most commonly arise in midline central nervous system locations, predominantly in the pineal or suprasellar regions.

CNS germ cell tumors (as well as gonadal and other extra-gonadal germ cell tumors) are classified by cell of origin into (1) germinoma or undifferentiated germ cell tumors (called seminoma or dysgerminoma in the testis or ovary, respectively) and (2) nongerminomatous or differentiated germ cell tumor. The WHO Classification of Central Nervous System (CNS WHO) 5th edition updated many definitions of CNS tumors, with a major theme of the incorporation of molecular diagnostic techniques and recognition of new molecularly-defined tumor types. However, the classification of CNS germ cell tumors remains largely the same, with a minimal role for molecular diagnostics (106).

The nongerminomatous germ cell tumors include embryonal carcinoma, yolk sac tumor, choriocarcinoma, mixed germ cell tumor, teratoma (mature and immature), and teratoma with somatic-type malignancy—the latter now recommended in the CNS WHO 2021 Classification over the previous terminology, “teratoma with malignant transformation” (106).

Although teratomas are made up of a mixture of tissues derived from all three 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 is 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 (114; 10). This was not observed among the teratomas in an earlier literature review (84).

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 three 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 (168).

Germ cell tumors most commonly arise in gonadal tissue (testis or ovary), and the central nervous system is only one 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 (66). 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 (97; 20).

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 (147). 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 (57; 148).

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