Practice Essentials
Germ cell tumors (GCTs) in the central nervous system (CNS) typically affect children and young 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 3-5% of all intracranial tumors seen in patients younger than 20 years of age. CNS germinomas are over three times more common in males than in females. [4]
Pathologically, intracranial GCTs are similar to GCTs in the gonads and other extragonadal areas. [5] The 2016 World Health Organization classification of CNS GCTs divides these tumors into the following major forms [6] :
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Germinoma
-
Embryonal carcinoma
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Yolk sac tumor/endodermal sinus tumor
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Choriocarcinoma
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Teratoma – Mature and immature
-
Teratoma with malignant transformation
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Mixed germ cell tumor
CNS GCTs are broadly classified as germinomatous and nongerminomatous germ cell tumors (NGGCTs) on the basis of clinicopathological and laboratory features, including tumor markers. An alternative therapeutic classification proposed by the Japanese Pediatric Brain Tumor Study Group bases stratification on the prognostic grouping of the histologic variants, as follows [7] :
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Good prognosis: Germinoma, pure and mature teratoma
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Intermediate prognosis: Germinoma with syncytiotrophoblastic giant cellsteratoma, immature teratoma, teratoma with malignant transformation, mixed germinoma and teratoma tumors
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Poor prognosis: Yolk sac tumor, choriocarcinoma, embryonal carcinoma, and mixed tumors of yolk sac, choriocarcinoma or embryonal carcinoma
The most common locations for CNS GCTs are the pineal (45%) and suprasellar region (30%) of the brain. From 5% to 10% of patients have tumors arising in both the suprasellar and pineal locations, and the histology is most frequently a germinoma. Other areas that may be involved, though rarely, include the following [8, 1] :
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Basal ganglia
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Ventricles
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Thalamus
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Cerebral hemispheres
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Medulla
Clinical presentation is mainly related to the location and size of the tumor and the patient`s age. Pineal tumors usually cause obstructive hydrocephalus with signs of increased intracranial pressure, including the following:
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Headaches
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Vomiting
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Lethargy
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Parinaud syndrome (upward gaze palsy, loss of light perception and accommodation, nystagmus, failure of convergence)
The most common initial manifestation of suprasellar tumors is diabetes insipidus. Hypothalamic and pituitary dysfunction may result in the following:
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Delayed or precocious puberty
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Growth hormone deficiency
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Hypothyroidism
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Adrenal insufficiency
Many patients with unrecognized CNS GCTs may have had a long history of complications such as movement disorders, enuresis, anorexia, and behavioral and psychiatric complaints including obsessive-compulsive disorder, tics, and psychosis. Diagnosis in such cases has been delayed from 7 months to 3 years. [9, 10]
CNS GCTs may secrete tumor markers, the most common being alpha fetoprotein (AFP) and β–human chorionic gonadotropin (β-HCG). Measurement of serum and cerebrospinal fluid (CSF) levels of tumor markers may aid in the diagnosis and treatment plan. [11, 12]
The majority of bifocal (pineal and neurohypophyseal) GCTs in patients with typical imaging study findings, detectable hCG levels, and normal AFP levels are germinomas. However, some bifocal nongerminomatous germ cell tumors (NGGCTs) may have similar radiographic features, detectable hCG levels, and normal or modestly elevated AFP. [13, 14]
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. [12]
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. Evidence in support of this theory includes a genome-wide methylation profiling study of 61 GCTs that found pure germinomas are characterized by global low DNA methylation, a unique epigenetic feature making them distinct from all other GCT subtypes. The patterns of methylation strongly resemble that of primordial germ cells (PGC) at the migration phase, possibly indicating the cell of origin for these tumors. [15]
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. [16, 17] 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 (i[12p]). Chromosomal comparison of CNS GCTs with gonadal tumors using genomic hybridization analysis has found the two to be essentially identical. [18, 19] 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. [20]
The most common chromosomal imbalance comprises gains of 1p, 8p, and 12q and losses of 13q and 18q. [18, 19] 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. [21]
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. [22, 23] 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 messenger RNA and microRNA profiles, which may correlate with histological differentiation, and clinical outcome. In future, these may serve as novel therapeutic targets. [24]
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. [25]
In a study of 62 patients with intracranial GCTs, more than 50% had mutations of the KIT/RAS signalling or AKT1/mtor pathways. [26] Both represent potential therapeutic targets.
Histologically, germinomas often exhibit a "two pattern" of immune cells intermingled with tumor cells. This two pattern is also observed in GCTs in other locations, such as dysgerminomas of the ovaries. The immune cells consist largely of T cells and to a lesser degree B-cells and natural killer cells. The precise mechanism by which the immune system may affect tumor growth is complex. Tumor-infiltrating lymphocytes in germinomas have shown dual functions in suppressing and promoting germinoma cell growth. [27]
A study that examined the microenvironment of germinomas found that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. The degree of immune cell infiltration varied in specimens of germinoma, and the balance between tumor cells and immune cells correlated with clinical outcome: patients whose germinomas had a higher tumor content (ie, less immune cell infiltration) had a worse progression-free survival. [28]
A study from the Intracranial Germ Cell Tumor Genome Analysis Consortium that integrated clinical, histopathological, and molecular data on 190 CNS GCTs suggested that tumorigenesis in these cases may be different in males than in females. MAPK pathway mutations were found in 51.4% of males but only 14.3% of females (P=0.007), suggesting that females may develop GCT through mechanisms other than MAPK pathway. [29]
Etiology
The exact cause of CNS GCTs is unknown. GCTs appear to arise from primordial germ cells that migrate to the germinal ridges in the developing embryo. [30, 31, 20, 21] This process appears to be under the control of complex molecular events. Aberration in any of these molecular pathways may potentially give rise to GCTs.
Important factors in cell migration include the extracellular matrix, which affects cell adherence and migration. Other factors, such as chemotropic factors, may also be involved in cell migration. [32] In vitro studies have shown that tumor growth factor beta 1 may initiate the migration of primordial germ cells. [33]
Some primordial germ cells that have left the yolk sac endoderm migrate aberrantly cranially towards the diencephalic midline structures rather than laterally to genital ridges.
Maturation of the fetal hypothalamus coincides with the migration of primordial germ cells. The fetal hypothalamus may secrete chemotrophic factors that attract primordial germ cells to the diencephalon. [34]
The vacular theory may be an alternative event in which the primodial germ cells migrate into the mesenchyme of the mesentery and stimulate blood vessel formation and may reach intracranial locations via the circulation.
Once the primordial germ cells have reached their intracranial location through abnormal pathways, congenital or acquired aberrant molecular events occur in the primordial germ cell itself or in the surrounding microenvironment, leading to the formation of CNS GCTs.
The surge of the neuroendocrine functions of reproduction in the diencephalon may also be a cause or contributing factor to the development of CNS GCTs, as demonstrated by the location of these tumors and their predominance in the pubertal age group. [2]
Epidemiology
According to the CBTRUS report, the overall incidence of malignant CNS GCTs in the United States from 2010 to 2014 was 0.07 per 100,000 population. The CNS GCT incidence rate was 60% higher in Asian/Pacific Islanders than in whites and non-Hispanics, and was lowest in African Americans (0.04 per 100,000). [35]
Primary CNS GCTs are more common in Japan and other countries in Asia than in North America. In particular, CNS GCTs account for relatively high proportions of pediatric brain tumors in East Asia—7.8% in Japan, 14.0% in Taiwan, 7.9% in China, and 9.5% in Korea—whereas their frequency in North America and Europe is 4%. [36] However, a study analyzing 4 tumor registries from Japan and the United States found a similar incidence of primary CNS GCTs in the two countries. [37]
Registry data and clinical series around the world show variation and discrepancies, which raises questions regarding the quality and reliability of the information available.
An overall male predominance is noted in CNS GCTs. Data from the National Cancer Institute's 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. [8] 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]
Likewise, a review by McCarthy et al of primary CNS GCT registries in Japan and the United States found an overall male-to-female incidence-rate ratio (IRR) of 3.1:1, but with marked differences with GCTs in different sites: for malignant tumors of the pineal region, the male-to-female IRR was as high as 16.0:1, compared with 1.9:1 for tumors in a nonpineal region of the CNS. [4]
CNS GCTs are seen almost exclusively in individuals between birth and 34 years of age, with 71% of cases diagnosed before 20 years of age. The peak incidence is from 10-19 years of age with the highest incidence (0.28 per 100,000) at ages 10-14 years. The pediatric age distribution of CNS GCTs is as follows [35] :
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0-4 years: 9% of cases
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5-9 years: 18% of cases
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10-14 years: 39% of cases
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15-19 years: 34% of cases
Prognosis
Germinomas are generally associated with an excellent prognosis. Even in patients with syncytiotrophoblasts that secrete β-hCG, 5-year survival is 70-90% and 10-year survival is 70%. [1, 3, 38, 39] With mixed GCTs, 5-year survival is 60-80%. With nongerminomatous GCTs, 5-year survival is 30-50%. [40, 41]
Patients with pure germinomas have a 10-year survival rate of 90%. For nongerminomatous GCT, the 10-year overall survival rates were reported to be 30%-80%. [36]
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.
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. Pineal-region tumors have a surgical morbidity of 2-5%. Patients may suffer from transient movement abnormalities of eyes, ataxia, and cognitive dysfunction.
Late sequelae of radiation therapy to the CNS include growth effects, hearing loss, neuropsychological and cognitive impairments, and neuro-endocrine disorders. [42, 43, 44] Risks of treatment-related secondary cancers are well described. Larger irradiation volume and dose both adversely affect intellectual functions, concept, executive function, memory, decline in neurocognitive function, and performance IQs, particularly in children. [42]
Patients may have persistent neurological deficits, even after tumor control. Neurological deficits may be significant and are multifactorial in origin. Damage by the tumor itself, surgical intervention, radiation therapy, and chemotherapy all contribute to neurological impairment irrespective of age. Patients with tumors located in the basal ganglia perform poorly compared with those who have tumors in the pineal and suprasellar regions; they have lower full-scale IQs and short-term retention of verbal and visual stimuli. [45]
Several long-term studies have demonstrated poor performance in adaptive skills, particularly in psychosocial domains, behavioral dysfunction, and financial difficulties, leading to poor quality of life. [45, 46, 47, 48] Patients who had undergone surgical biopsies did worse than patients who had surgical resection. Lower Karnofsky performance status scale scores following surgery have been associated with impaired neurocognitive function that may decline over time, particularly in children. [46, 49]
More than 50% of patients may continue to suffer from endocrine abnormalities, with growth hormone deficiency and growth retardation, hypopituitarism, and hypothyroidism. They may require lifelong hormonal replacement therapy. [46, 50]
Brain injury in the form of atrophy, multifocal encephalomalacia, leukoencephalopathy, and focal necrosis has been reported in patients with intracranial GCTs. [43] The occurrence of cerebrovascular occlusion may lead to the development of strokes, with an almost 59-fold increase risk of death in long-term survivors. [47]
Patients with intracranial GCTs have a cumulative incidence of secondary cancer of 6%, with a cumulative risk of death due to malignancy of 16%. Radiation therapy and chemotherapy may both promote the development of secondary cancers, including but not limited to acute myeloid leukemia and radiation-induced brain neoplasms. [47]
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MRI of the brain - T1 weighted-image- coronal view- showing a heterogeneously enhancing, multicystic mass in the suprasellar region
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MRI of the brain - axial view- heterogeneous mass lesion measuring approximately 3.2 x 2.9 x 4.0 cm.
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MRI of the brain - T1-weighted image - post-gadolinium sagittal view- A suprasellar lesion that severely compresses the optic chiasm encases the posterior aspect of the optic nerves bilaterally and causes superior displacement of the third ventricle, with significant compression of the brain stem.
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Biopsy specimen from an intracranial germ cell tumor - Large tumor cells with large nuclei; prominent nucleoli; and abundant, clear cytoplasm (rich in glycogen) are noted among reactive inflammatory cells--lymphocytes and histiocytes. Elsewhere there are well-formed granulomas, a well-known phenomenon in germinomas, especially of the pineal region.
Tables
Tumor type |
β- HCG |
AFP |
PLAP |
c-Kit |
Germinoma - Pure |
- |
- |
+/- |
+ |
Germinoma with STGC* |
+ |
- |
+/- |
+ |
Endodermal sinus tumor |
- |
+ |
+/- |
- |
Choriocarcinoma |
+ |
- |
+/- |
- |
Embryonal Carcinoma |
- |
- |
+ |
- |
Mixed Teratoma |
+/- |
+/- |
+/- |
+/- |
Mature Teratoma |
- |
- |
- |
- |
Immature teratoma |
+/- |
+/- |
- |
+/- |
*Syncytiotrophoblastic giant cells |
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