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 in GCTs found similar copy number alterations whether the GCT was systemic or CNS based.
The World Health Organization has classified CNS GCTs into the following major groups:
- Embryonal carcinoma.
- Mixed germ cell tumor.
- Teratoma with malignant transformation.
- Yolk sac tumor.
Nongerminomatous germ cell tumors (NGGCTs), also called secreting tumors, include embryonal carcinoma, yolk sac tumors, choriocarcinoma, and mixed GCTs. In addition to the microscopic appearance of the various CNS GCTs, tumor markers (proteins, such as alpha-fetoprotein [AFP] and beta subunit human chorionic gonadotropin [beta-HCG], secreted by the tumor cells) found in the serum and cerebrospinal fluid (CSF) aid in diagnosis (see Tables 1 and 2). The diagnosis and classification of CNS GCTs can be based on histology alone, tumor markers alone, or a combination of both.[1,6,8,9] Favorable-risk germinomas can secrete low levels of beta-HCG. NGGCTs frequently contain germinomatous plus other malignant GCT components, such as embryonal carcinoma, yolk sac or endodermal sinus tumor, and choriocarcinoma. 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.
|AFP = alpha-fetoprotein; HCG = human chorionic gonadotropin; PLAP = placental alkaline phosphatase.|
|Mixed germ cell tumor||±||±||±||±|
|Yolk sac tumor||-||+||±||-|
|AFP = alpha-fetoprotein; HCG = human chorionic gonadotropin; + = positive; - = negative; ± = equivocal; +++ = strongly positive; (±) equivocal, not diagnostic; (+) = positive, not diagnostic.|
|Yolk sac tumor||-||+++|
Elevations of tumor markers along with the imaging findings are used as surrogate diagnostic markers of CNS GCT and may obviate the need for histologic diagnosis. The tumor markers AFP and beta-HCG are the most useful, although other markers such as placental alkaline phosphatase and c-kit are being investigated. Distinguishing between different GCT types by CSF protein marker levels alone is somewhat arbitrary, and standards vary. For example, several European and Asian groups designate tumors with serum and/or CSF AFP levels of 50 ng/mL or higher and/or beta-HCG levels of 100 mIU/mL or higher as secreting GCTs, whereas others in the United States and Europe consider tumors as secreting if serum and/or CSF AFP levels are 10 ng/dL or higher and/or serum and/or CSF beta-HCG levels are 50 mIU/mL or higher. Pure germinomas and teratomas usually present with negative markers, but very low levels of beta-HCG can be detected in germinomas. The use of tumor markers and histology in GCT clinical trials is evolving. For example, in the COG-ACNS1123 [NCT01602666] trial, patients are eligible for assignment to the germinoma regimen without biopsy confirmation if they have (1) either pineal region tumors or suprasellar primary tumors, normal AFP levels, and beta-HCG levels between 5 and 50 mIU/mL in serum and/or CSF or (2) bifocal presentation (pineal and suprasellar), diabetes insipidus, normal AFP levels, and beta-HCG levels lower than 100 mIU/mL in CSF.
Alternative classification schemes for CNS GCTs have been proposed by others, including the Japanese Pediatric Brain Tumor Study Group, who based 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.
|Prognostic Group||Tumor Type|
|Intermediate||Germinoma with syncytiotrophoblastic giant cells|
|Mixed tumors mainly composed of germinoma or teratoma|
|Teratoma with malignant transformation|
|Mixed tumors composed of choriocarcinoma, yolk sac tumor, or embryonal carcinoma|
|Yolk sac tumor|
- 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]
- 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]
- Hoffman HJ, Otsubo H, Hendrick EB, et al.: Intracranial germ-cell tumors in children. J Neurosurg 74 (4): 545-51, 1991. [PUBMED Abstract]
- 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]
- 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.
- 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]
- 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]
- 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.
- Allen J, Chacko J, Donahue B, et al.: Diagnostic sensitivity of serum and lumbar CSF bHCG in newly diagnosed CNS germinoma. Pediatr Blood Cancer 59 (7): 1180-2, 2012. [PUBMED Abstract]
- 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.