Central Nervous System Germinoma

Updated: May 04, 2015
  • Author: Amani A Al Kofide, MD; Chief Editor: Jules E Harris, MD, FACP, FRCPC  more...
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Overview

Background

Germ cell tumors (GCTs) in the central nervous system (CNS) affect children and adults, predominantly occurring in the first and second decade of life [1] ; the peak incidence is from 10-19 years of age. [2, 3] GCTs account for approximately 5% of all intracranial tumors seen in patients younger than 20 years of age.

Pathologically, intracranial GCTs are similar to GSTs in the gonads and other extragonadal areas. [4] CNS GCTs are broadly divided into germinomas and nongerminomatous germ cell tumors (NGGCTs). The current World Health Organization classification of CNS GCTs, which is based primarily on histological elements, divides these tumors into the following major forms: [5, 6]

  • Germinoma – Pure and with syncytiotrophoblasts
  • NGGCTs
  • Teratoma – Mature and malignant
  • Embryonal carcinoma
  • Yolk sac tumor/endodermal sinus tumor
  • Choriocarcinoma

Tumors consisting of more than one of the above histological types are termed mixed GCTs. [1] Pure germinomas account for 65% of all CNS GCTs, germinomas with mature and/or immature teratoma account for 15%, while mixed germinomas and NGGCTs represent approximately 20% of CNS GCTs. Pure germinomas carry a better prognosis than NGGCTs.

CNS GCTs are believed to arise from nests of embryonic cells arrested during their migration in fetal development in the midline structures. Consequently, CNS GCTs are found in midline sites, specifically in the pineal gland and suprasellar regions.

An overall male predominance is noted in CNS GCTs. [2]

Clinical presentation is mainly related to the location and size of the tumor and the patient`s age. Endocrine abnormalities, headache, vomiting, and visual changes are among the most common symptoms. Many patients with unrecognized CNS GCTs may have had a long history of symptoms such as movement disorders, enuresis, anorexia, and psychiatric complaints. Diagnosis in such cases has been delayed from 7 months to 3 years. [7]

CNS GCT may secret tumor markers, the most common are alpha-fetoprotein (AFP) and β-human chorionic gonadotropin (b-HCG). Measurement of serum and cerebral spinal fluid (CSF) levels of tumor markers may aid in the diagnosis and treatment plan. [8, 9]

Total surgical resection of CNS GCTs has been hampered by the deep-seated location of these tumors. Therefore, craniospinal irradiation has been the standard adjuvant therapy. Advances in diagnostic imaging, surgical and anesthetic techniques, and radiation therapy and the addition of chemotherapy have improved the outcome in patients with these tumors. [9]

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Pathophysiology

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.

Studies of malignant testicular tumors have shown that the most common chromosomal abnormality is an isochromosome of the short arm of chromosome 12 (12p). Chromosomal comparison of CNS GCTs with gonadal tumors using genomic hybridization analysis has found the two to be essentially identical. [14, 15] In adult-onset extragonadal germinomas, the most common abnormality is duplication of the short arm of chromosome 12.

In children, cytogenetic abnormalities include loss of 1p and 6q, alterations in sex chromosomes, and abnormalities in 12p. A study in children revealed that a subset of patients with pineal tumors demonstrated a gain of chromosomal material at 12p. [16]

The most common chromosomal imbalance comprises gains of 1p, 8p, and 12q and losses of 13q and 18q. [14, 15] Increased copies of the X chromosome are seen in CNS GCTs; 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 Down syndrome and those with neurofibromatosis, type 1. [17]

Frequent alterations of the p14 gene have been detected, especially in intracranial pure germinomas, suggesting that this gene plays an important role in the development of these tumors. Mutations of the c-kit gene have been found in 23–25% of intracranial germinomas. [18, 19] These mutations are believed to promote the development of intracranial GCTs. 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.

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Epidemiology

Frequency

United States

  • According to data from the Surveillance, Epidemiology and End Results (SEER) program, CNS GCTs were seen almost exclusively in individuals between birth and 34 years of age, with a peak incidence of 0.2 per 100,000 person-years at ages 15 to 19. [1, 3, 5]
  • Median age at diagnosis is 10-12 years
  • Intracranial GCTs account for only 0.4-3.4% of all CNS tumors.
  • Based on data from the Central Brain Tumor Registry of the United States, less than 93 GCTs are expected to be diagnosed annually in US males under age 19, and less than 38 diagnosed in females. [1, 16]
  • Pineal lesions occur more commonly than suprasellar lesions, at a ratio of 2:1. Tumors of the pineal area comprise 50-60% of CNS GCTs; those of the suprasellar region, 30-40%. CNS GCTs may also occur in the basal ganglia, thalamus, and cerebral hemispheres.

International

Primary CNS GCTs are more common in Japan and other countries in Asia compared with North America. [23] They account for approximately 2-3% of all intracranial tumors and 8-15% of pediatric brain tumors in the Far East. [3, 24, 25] However a recent study analyzing 4 tumor registries from Japan and the United States revealed that the incidence of primary of CNS GCT is similar. [26]

Mortality/Morbidity

5-year survival

Patients with pure germinomas have a 5-year survival rate of 70-90%. Those with predominantly germinoma or teratoma mixed with other NGGCTs have a 5-year survival of approximately 70%. [27] Patients with pure malignant NGGCT (embryonal carcinoma, yolk sac tumor, or choriocarcinoma) have a 5-year survival of 30-50%. [28]

Tumor-related morbidity

Diabetes insipidus, hypopituitarism, and visual field deficits are the most common presentation of CNS GCTs and may persist despite therapy. Parinaud syndrome is common in patients with pineal tumors and often persists even after therapy.

Treatment-related morbidity

  • Surgery of deep-seated structures within the brain may be associated with significant morbidity. However, modern neurosurgical navigation techniques have minimized this risk. Tissue sampling by stereotactic biopsy is a safe and rapid method of determining tumor histology
  • Late sequelae of radiation therapy to the CNS include growth effects, hearing loss, neuropsychological and cognitive impairments, and neuro-endocrine disorders. [29, 30, 31]
  • Risks of treatment-related secondary cancers are well described.

Race

Registry data and clinical series around the world show variation and discrepancies, which raises questions regarding the quality and reliability of the information available. However, the highest incidence of CNS GCTs has been reported in many Asian countries, including Japan, Taiwan, and Singapore. [28, 25]

Sex

An overall male predominance is noted in CNS GCTs. Data from the NCI Surveillance, Epidemiology and End-Results (SEER) Program on CNS GCTs in the United States [3, 1] showed that the incidence of CNS germ cell tumors in males, all ages combined, was 3.7 times that seen in females. [32]

Location of CNS GCTs also varies by sex. In males, 70% of tumors occur in the pineal area; In females, 75% of CNS GCTs occur in the suprasellar areas. [1]

Age

CNS GCTs may occur at any age; however, they are considered primarily a disease of adolescents and young adults. [5, 27, 1] The peak incidence is from 10-19 years of age. Age distribution of CNS GCTs is as follows:

  • 0 – 14 years: 34% of cases
  • 15 – 29 years: 57% of cases
  • 30 – 44 years: 9% of cases.
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