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Childhood Central Nervous System Germ Cell Tumors Treatment (PDQ®)

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Cellular Classification of Childhood CNS Germ Cell Tumors

Childhood central nervous system (CNS) germ cell tumors (GCTs) are a heterogeneous group of lesions that commonly arise from the pineal and/or suprasellar regions of the brain. In Western countries, GCTs represent less than 4% of primary brain tumors in children, while in series from Japan and Asia, CNS GCTs account for approximately 11% of pediatric CNS tumors.[1-3]

The pathogenesis of intracranial GCTs is unknown. The “germ cell theory” proposes that CNS GCTs arise from primordial germ cells that have aberrantly migrated and undergone malignant transformation. An alternative hypothesis, “the embryonic cell theory,” proposes that GCTs arise from a pluripotent embryonic cell that escapes normal developmental signals and progresses to CNS GCTs.[4,5] Recent investigations comparing the genomic alterations found in GCTs are very similar, whether they are tumors of CNS, gonadal, or extragonadal origin. These findings lend support that all GCTs have common pathogenetic mechanisms.[6]

The World Health Organization has classified CNS GCTs into the following major groups:[7]

  • Choriocarcinoma.
  • Embryonal carcinoma.
  • Germinoma.
  • Mixed germ cell tumors.
  • Teratoma.
    • Immature.
    • Mature.
    • Teratoma with malignant transformation.
  • Yolk sac tumors.

Nongerminomatous germ cell tumors (NGGCTs), commonly referred to as secreting tumors, include embryonal carcinoma, yolk sac tumors, choriocarcinoma, and mixed GCTs. Alternative classification schemes have been proposed by others, including the Japanese Pediatric Brain Tumor Study Group for CNS GCTs, who base their stratification on the therapeutic grouping of the differing histologic variants as shown in Table 3.

The classification of a childhood brain tumor is based on both the histopathologic characteristics of the tumor and its location in the brain.[6] In addition to the microscopic appearance of the various CNS GCTs, tumor markers (proteins secreted by the tumor cells) found in the serum and cerebrospinal fluid (CSF) aid in diagnosis (see Tables 1 and 2).[1,8,9]

Table 1. Immunohistochemical Markers
Tumor Type Beta-HCG AFP PLAP c-kit 
AFP = alpha-fetoprotein; HCG = human chorionic gonadotropin; PLAP = placental alkaline phosphatase.
Choriocarcinoma+-±-
Embryonal carcinoma--+-
Germinoma (syncytiotrophoblastic)+-±+
Immature teratoma±±-±
Mature teratoma----
Mixed germ cell tumor±±±±
Pure germinoma--±+
Yolk sac tumor-+±-

Table 2. Serum and Cerebrospinal Fluid Markers
Tumor Type  Beta-HCG  AFP 
AFP = alpha-fetoprotein; HCG = human chorionic gonadotropin; + = positive; - = negative; ± = equivocal; +++ = strongly positive; (±) equivocal, not diagnostic; (+) = positive, not diagnostic.
Choriocarcinoma+++-
Embryonal carcinoma--
Germinoma(±)-
Teratoma-(+)
Yolk sac tumor-+++

For some CNS GCTs, elevations of tumor markers along with the imaging findings are diagnostic of a CNS GCT and may obviate the need for initial biopsy or resection of the tumor mass. The tumor markers alpha-fetoprotein (AFP) and beta subunit human chorionic gonadotropin (beta-HCG) are the most commonly followed, although other markers such as placental alkaline phosphatase and c-kit are being investigated. The laboratory tests used to detect tumor markers have become more reliable during the last decade, but the interpretation of specific results varies within study groups. Some European and Asian groups consider tumors with serum and/or CSF AFP ≥50 ng/ml and/or beta-HCG ≥100 IU/L to be secreting GCTs, whereas others in the United States and Europe consider tumors as secreting if serum and/or CSF AFP ≥10 ng/dl and/or serum and/or CSF beta-HCG ≥50 IU/L. Pure germinomas and teratomas usually present with negative markers, but very low levels of beta-HCG can be detected in germinomas (with syncytiotrophoblastic cells) and elevations of AFP can be seen in teratomas.[9] Both AFP and beta-HCG have predictable half-lives, making these markers useful in diagnosing some CNS GCTs, and in monitoring response and early detection of recurrence.

Alternative classification schemes for CNS GCTs have been proposed by others, including the Japanese Pediatric Brain Tumor Study Group, who base their stratification on the prognostic grouping of the differing histologic variants as shown in Table 3. Pure germinomas and mature teratomas fall into the good prognostic group; choriocarcinoma, yolk sac tumor, embryonal carcinoma, or mixtures of these three histologic subtypes fall into the poor prognostic group.[8]

Table 3. Japanese Pediatric Brain Tumor Study Group Classification
Prognostic Group  Tumor Type 
GoodGerminoma, pure
Mature teratoma
IntermediateGerminoma with syncytiotrophoblastic giant cells
Immature teratoma
Mixed tumors mainly composed of germinoma or teratoma
Teratoma with malignant transformation
PoorChoriocarcinoma
Embryonal carcinoma
Mixed tumors composed of choriocarcinoma, yolk sac tumor, or embryonal carcinoma
Yolk sac tumor

References
  1. Matsutani M, Sano K, Takakura K, et al.: Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg 86 (3): 446-55, 1997.  [PUBMED Abstract]

  2. Matsutani M; Japanese Pediatric Brain Tumor Study Group: Combined chemotherapy and radiation therapy for CNS germ cell tumors--the Japanese experience. J Neurooncol 54 (3): 311-6, 2001.  [PUBMED Abstract]

  3. Hoffman HJ, Otsubo H, Hendrick EB, et al.: Intracranial germ-cell tumors in children. J Neurosurg 74 (4): 545-51, 1991.  [PUBMED Abstract]

  4. Sano K, Matsutani M, Seto T: So-called intracranial germ cell tumours: personal experiences and a theory of their pathogenesis. Neurol Res 11 (2): 118-26, 1989.  [PUBMED Abstract]

  5. Teilum G: Embryology of ovary, testis, and genital ducts. In: Teilum G: Special Tumors of Ovary and Testis and Related Extragonadal Lesions: Comparative Pathology and Histological Identification. Philadelphia, Pa: J. B. Lippincott, 1976, pp 15-30. 

  6. Schneider DT, Zahn S, Sievers S, et al.: Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization. Mod Pathol 19 (6): 864-73, 2006.  [PUBMED Abstract]

  7. Miyanohara O, Takeshima H, Kaji M, et al.: Diagnostic significance of soluble c-kit in the cerebrospinal fluid of patients with germ cell tumors. J Neurosurg 97 (1): 177-83, 2002.  [PUBMED Abstract]

  8. Rosenblum MK, Matsutani M, Van Meir EG: CNS germ cell tumours. In: Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000, pp 208-14. 

  9. Olson T, Schneider D, Perlman E: Germ cell tumors. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2011, pp 1045-67.