Germinoma pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Gross pathology
On gross examination, the external surface is smooth and bosselated (knobby), and the interior is soft, fleshy and either cream-coloured, gray, pink or tan.
Microscopic pathology
Microscopic examination typically reveals uniform cells that resemble primordial germ cells. Typically, the stroma contains lymphocytes and about 20% of patients have sarcoid-like granulomas. The tumor is uniform in appearance, consisting of large, round cells with vesicular nuclei and clear or finely granular cytoplasm that is eosinophilic. Pure germinomas are composed of large polygonal undifferentiated cells with abundant cytoplasm arranged in nests separated by bands of connective tissue. The histologic appearance of Nongerminomatous germ cell tumors (NGGCTs) varies depending upon the specific cell types present.
Pathogenesis
Central nervous cell germ cell tumors (GCTs) are believed to arise from nests of embryonic cells arrested during their migration in fetal development in the midline structures. As a result, CNS GCTs are found in midline sites, especially in the suprasellar and pineal gland regions. The cell of origin of CNS GCTs remains controversial. The germ cell theory postulates that these tumors arise from primordial germ cells that have migrated aberrantly during embryonic development and subsequently undergone malignant transformation.[10, 11, 12]
In contrast, the embryonic cell theory suggests that GCTs arise from a mismigrational pluripotent embryonic cell. It has also been postulated that pure germinomas arise from germ cells whereas mixed NGGCTs are a result of misfolding and misplacement of embryonic cells into the lateral mesoderm, causing these cells to become entrapped in different areas of the brain.[10, 13] Current evidence suggests that GCTs arise from germinal elements at various stages of development.
Intracranial GCTs express germ cell–specific proteins comprising MAGE-A4, NY-ESO-1, and TSPY, which are associated with embryonic stem cell pluripotency. This indicates that GCTs may originate from primordial germ cells.
Genetics
In adult-onset extragonadal germinomas, the most common abnormality is duplication of the short arm of chromosome 12. Cytogenetic abnormalities in children include loss of 1p and 6q, alterations in sex chromosomes, and abnormalities in 12p. In a study involving children, a subset of patients with pineal tumors demonstrated a gain of chromosomal material at 12p. In majority of cases, the most common chromosomal imbalance comprises gains of 1p, 8p, and 12q and losses of 13q and 18q. The most frequent genotype abnormality is XXY, similar to that in Klinefelter syndrome. Individuals with Klinefelter syndrome are prone to develop intracranial GCTs, as are those with neurofibromatosis, type 1 and Down syndrome. Gene p14 plays an important role in the development of intracranial germ cell tumors as frequent alterations of the p14 gene have been detected, especially in intracranial pure germinomas. In approximately 23-25% of intracranial germinomas, mutations of the c-kit gene have been found. C-myc and N-myc amplifications were seen in a minority of tumors. Genomic analysis of GCTs has revealed distinct mRNA and miRNA profiles, which may be correlated with histological differentiation, clinical outcome, and, in future, serve as novel therapeutic targets.[20]
Profiling of intracranial GCTs using DNA copy number alterations and loss of heterozygosity has revealed frequent aberrations of CCND2 (12P13), and RB1 indicating possible cyclin/CDK-RB-E2F pathway involvement in its pathogenesis. Gains in the transcriptional regulator PRDM14 have also been implicated in the genesis of GCTs.[21]
In a recent study of 62 patients with intracranial GCT more than 50% had mutations of the KIT/RAS signalling or AKT1/mtor pathways.[22] Both represent potential therapeutic targets.