Central Nervous System Germinoma 

Updated: Mar 25, 2021
Author: Amani A AlKofide, MD; Chief Editor: Herbert H Engelhard, III, MD, PhD, FACS, FAANS 

Overview

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] :

  • Germinoma
  • Embryonal carcinoma
  • Yolk sac tumor/endodermal sinus tumor
  • Choriocarcinoma
  • Teratoma – Mature and immature
  • Teratoma with malignant transformation
  • 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] :

  • Good prognosis: Germinoma, pure and mature teratoma
  • Intermediate prognosis: Germinoma with syncytiotrophoblastic giant cellsteratoma, immature teratoma, teratoma with malignant transformation, mixed germinoma and teratoma tumors
  • 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] :

  • Basal ganglia
  • Ventricles
  • Thalamus
  • Cerebral hemispheres
  • 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:

  • Headaches
  • Vomiting
  • Lethargy
  • 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:

  • Delayed or precocious puberty
  • Growth hormone deficiency
  • Hypothyroidism
  • 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] :

  • 0-4 years: 9% of cases
  • 5-9 years: 18% of cases
  • 10-14 years: 39% of cases
  • 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]

 

Presentation

History

The clinical presentation in central nervous system (CNS) germ cell tumors (GCTs) varies, depending on the age of patient, the site of the tumor, and the duration of the disease.[9, 31, 51, 52] Typical presentations by age are as follows:

  • Prenatal/neonate – Congenital teratomas produce polyhydramnios and hydrocephalus; ultrasound will show a heterogeneous echogenic mass with cystic and solid components.

  • Young infants – The teratoma and choriocarcinoma subtypes of nongerminoma GCT are most common in this age group[53] ; these patients may present with irritability, listlessness, failure to thrive, macrocephaly, and bulging fontanelle

  • Beyond infancy – Presentation depends on tumor location

Pineal region tumors

Parinaud syndrome is one of the most common presentation in CNS GCTs, seen in 34-50% of cases. It is due to compression of the tectum. The syndrome includes the following ophthalmic manifestations:

  • Paralysis of upward gaze
  • Loss of light perception and accommodation
  • Nystagmus
  • Failure of convergence

Features of increased intracranial pressure may supervene. These include headache, nausea and vomiting, and papilledema. Somnolence, ataxia, seizures, and behavioral abnormalities may develop.

Precocious puberty may develop in a pre-pubertal child.

Diabetes insipidus and anterior hypopituitarism are rare occurrences and may indicate involvement of the floor of the fourth ventricle and suprasellar area.[16]

Suprasellar region tumors

Patients with suprasellar GCTs usually present with endocrine deficits. These include the following:

  • Anterior hypopituitarism and Diabetes insipidus (DI)

  • Thyroid and/or cortisol deficiency

  • Growth failure from growth hormone deficiency

  • Delayed puberty from gonadotropin deficiency

  • Regression of sexual development or sexual dysfunction

  • Posterior pituitary dysfunction (vasopressin deficiency)

  • Precocious puberty may develop in a pre-pubertal child (due to tumor-induced hypothalamic injury or secretion of human chorionic gonadotropin by the tumor).

Visual disturbances may include diplopia, blurred vision, and diminished vision. Enuresis and psychiatric abnormalities may develop.[9, 30, 54, 10] In general, patients with symptoms of increased intracranial pressure and visual changes tend to present earlier in the disease course than patients with endocrine dysfunction.

Rare presentations

Rare presentations of CNS GCTs include the following:

  • Multiple lesions - GCTs in the pineal, sellar region, corpus callosum, and ventricles was reported in an 18-year-old man who presented with psychosis[55]

  • Wide skull base extension - This was reported in a 15-year-old girl with radiologic evidence of central skull base and suprasellar tumor extending into the cavernous sinus, intraorbital region, ethmoid sinus, sphenoid sinus, and pituitary fossa[56]

  • Optic pathway - Intracranial germ cell tumors may occur primarily in the optic nerve and/or optic chiasma with progressive, painless visual loss[57, 58, 59, 60] ; therefore, biopsy for definitive diagnosis may be required in patients with imaging studies suggestive of optic gliomas who have visual loss with hypothalamic-pituitary-adrenal dysfunction[61]

  • Midbrain outflow tremor (Holmes tremor) - Holmes tremor is a hyperkinetic movement disorder that presents as mild to severe tremors, dystonia, and cerebellar deficits; it has been reported in patients with germinoma[62, 63]

Physical Examination

The clinical evaluation should include the following:

  • General physical examination
  • Check of growth parameters
  • Careful neurological evaluation, with assessment for neurocutaneous stigmata
  • Assessment of primary and secondary sexual characteristics
  • Ophthalmologic exam
 

DDx

Diagnostic Considerations

Delay in diagnosis is a significant concern in central nervous system (CNS) germ cell tumors (GCTs). Sethi et al reported that diagnosis was delayed for 6 months or longer in 38 of 70 children with CNS GCTs.[51] Endocrine symptoms are very common in young patients with CNS GCTs and can appear long before neuroimaging verification is possible.[64] Delay in diagnosis has major implications on the prognosis and the risk of dissemination of disease.

Other problems to consider in the differential diagnosis include the following:

  • Glial tumors - Astrocytomas, gangliomas
  • Granular cell tumor
  • Hamartomas
  • Meningiomas
  • Xanthogranuloma

Differential Diagnoses

 

Workup

Approach Considerations

The diagnostic workup for central nervous system (CNS) germ cell tumors (GCTs) should include the following[65, 66, 67] :

  • Magnetic resonance imaging (MRI) studies of the brain and spine
  • Measurement of the tumor markers β–human chorionic gonadotropin (β-hCG) and alpha fetoprotein (AFP) in both serum and cerebrospinal fluid (CSF)
  • Tissue confirmation by biopsy

MRI of the brain and spine are essential for diagnosis, assessing extent of intracranial disease and detecting metastatic disease. Postoperative MRI of the brain is essential to assess residual tumor.

CSF cytology is used to detect malignant cells.[68]  Measurement of serum and CSF levels of tumor markers may aid in the diagnosis and treatment plan.[11, 12, 65, 66] Evaluation of the disease outside the CNS is usually unnecessary.

Due to the heterogeneity of germinomas and the fact that only a small biopsy specimen may be obtained, central pathology review is essential to achieve accurate diagnosis, which is necessary for appropriate treatment planning.[29]

Laboratory Studies

Studies to detect the hormonal dysfunction that may occur in patients with central nervous system (CNS) germinomas are as follows:

  • Diabetes insipidus – Serum sodium, serum osmolality, and urine osmolality
  • Hypopituitarism – Thyroid function tests, growth hormone levels, cortisol levels
  • Gonadal dysfunction – Testosterone level in males; prolactin level in females

Tumor markers may be measured in serum and cerebrospinal fluid (CSF).[65, 66] Tumor marker levels are usually higher in CSF than in serum.[65] Detection of elevated tumor markers may be sufficient for diagnosis in patients in whom endoscopic biopsy is not considered possible.

Alpha fetoprotein (AFP) levels may be elevated in pure endodermal sinus tumor (yolk sac), embryonal carcinoma, and malignant teratoma. However, AFP levels may be normally elevated both in serum and CSF of neonates and infants. Accurate interpretation of the AFP level must take into account the normal variation seen in this age group. In normal infants, the median AFP levels in CSF are as follows:

  • Age ≤31 days - 61 kIU/L
  • Age 32-110 days - Age 8-12 months - Adult levels

Other relevant tumor marker findings are as follows:

  • Levels of beta human chorionic gonadotropin (β-hCG) above 50-100 IU/L indicate the presence of choriocarcinoma; lower levels may indicate pure germinoma that contain syncytotrophoblastic giant cells.[21, 69, 53, 6]

  • Carcinoembryonic antigen (CEA) levels may be increased in nongerminomatous germ cell tumors (NGGCTs) or their components.

In addition to tumor marker measurement, CSF cytology may be performed to detect malignant cells.[68]

Imaging Studies

Computed tomography of the brain

Germinomas show a homogeneous pattern and are hyperdense compared with brain tissue; with pineal gland tumors, calcification of the gland may be seen. NGGCTs are irregular in shape, with edema, and are less dense than germinomas. Mature teratomas have mixed densities, with large cysts and areas of calcification with distinct tumor margins

Magnetic resonance imaging

MRI of the brain and spine with and without gadolinium is the gold standard imaging study. Leptomeningeal metastasis is present at diagnosis in 10-15% of patients.[30]  (See images below.)

MRI of the brain - T1 weighted-image- coronal view MRI of the brain - T1 weighted-image- coronal view- showing a heterogeneously enhancing, multicystic mass in the suprasellar region
MRI of the brain - axial view- heterogeneous mass MRI of the brain - axial view- heterogeneous mass lesion measuring approximately 3.2 x 2.9 x 4.0 cm.
MRI of the brain - T1-weighted image - post-gadoli 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.

Germinomas are homogeneous and show isointensity or slightly low signal intensity on T1-weighted images, and isointensity or high intensity on T2-weighted images. NGGCTs are more heterogeneous and may have hemorrhage. Malignant teratomas are heterogeneous, with small cysts and irregular tumor margins, and may demonstrate peri-tumor edema.

Imaging studies show diverse features of intracranial GCTs in different locations and histological subgroups; however, some distinct neuroimaging patterns have been reported in the literature.[70] Early-stage basal ganglia germinomas demonstrate ill-defined T2-weighted hyperintensity without contrast enhancement and are isointense to hypointense or hyperintense in some cases on T1-weighted images. With more advanced disease these tumors appear large and heterogeneous with cystic components and enhancement.[71, 72] Suprasellar-region germinomas have ill-defined margins with irregular shape.

Pineal germinomas show hyperattenuation on unenhanced CT, restriction on diffusion-weighted imaging, and isointense signal relative to gray matter on T2-weighted images. This is primarily due to the high cellularity in germinomas compared with other pineal lesions and serves to differentiate those tumor types.[73] Other distinguishing features may include high mean apparent diffusion coefficient (ADC) value in germinomas compared with other pineal tumors.[74] The finding of thick peritumoral edema with T2 high signal intensity thicker than 5 mm and bithalamic extension may differentiate between germinomas and NGGCTs in the pineal area.[75]

On perfusion-weighted imaging MRI, lower relative blood suggests the diagnosis of germinoma rather than NGGCT. In their study of 20 patients with CNS GCTs, Takano et al found that the relative tumor blood flow ranged from 0.90 to 1.71 (mean 1.21, median 1.09) in patients with germinoma, while it ranged from 1.14 to 5.75 (mean 3.91, median 3.31) in those with NGGCT.[76]

MRI is excellent in delineating tumor anatomy and may suggest specific tumor type; however, the findings may be similar for germinomas, NGGCTs, and pineal parenchymal tumors. Therefore, imaging studies alone may not suffice for precise diagnosis.

Positron emission tomography

Several studies have investigated the utility of positron emission tomography (PET) scans. In a retrospective review of 10 patients, Okochi et al reported that 18F-fluorodeoxyglucose PET(FDG-PET) was able to detect the presence of germinomas while 11C-methionine PET (MET-PET) can help define tumor contour to plan for biopsy or surgery.[77] Limited information is available on the value of 18F-fluroethylcholine PET/MRI for the diagnosis of intracranial GCTs and followup by assessing for residual tumor.[78]

Histologic Findings

The World Health Classification (WHO) system of CNS GCTs is based on histology, serum and CSF tumor markers, and protein markers on tumor cells.[21, 6] See Table 1, below.

Table 1: Immunohistochemical findings of CNS GCTs [6, 21, 44] (Open Table in a new window)

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

 

Histological features of CNS GCTs are as follows:

  • Germinomas consist of undifferentiated, uniform large cells with abundant glycogen-rich cytoplasm arranged in nests separated by bands of connective tissue along trophoblastic lines. Scattered β-hCG–secreting syncytiotrophoblasts may be present.
  • Biopsy specimen from an intracranial germ cell tum 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.
  • Embryonal carcinoma is composed of large cells with a high mitotic index that proliferate in cohesive nests and sheets demonstrating zones of coagulative necrosis.

  • Choriocarcinoma is characterized by extraembryonic differentiation along trophoblastic lines with β-hCG–secreting syncytiotrophoblasts.

  • Endodermal sinus tumors are composed of primitive-appearing epithelial cells linked to extraembryonic mesoblast.

  • Mixed germ cell tumors have more than one histological component.

Teratoma

Histologic findings are as follows:

  • Mature teratomas comprise fully differentiated tissue elements of ectoderm, mesoderm, and endoderm.
  • Immature teratomas contain incompletely differentiated tissue elements.
  • Teratomas with malignant transformation usually contain rhabdomyosarcoma or undifferentiated sarcoma.

Biopsy

Currently, the recommendation for all patients with pineal and suprasellar tumors is to undergo surgical biopsy for histological confirmation, which is accomplished by means of endoscopic/stereotactic biopsy or open biopsy. Advances in endoscopic techniques have led to less morbidity and mortality with this procedure. Suprasellar tumors are generally more accessible to surgical biopsy than are pineal tumors.

Adequate specimen size is important because in nongerminomatous GCT, a specimen that is too small may miss a tumor component and thus may not be representative of the actual tumor type.

Only patients with elevated serum or CSF levels of AFP or β-hCG >50-100 IU/ml do not warrant surgery for the sole purpose of tissue diagnosis.[79, 69, 53] Diagnosis without tissue verification should be considered in such patients because high postoperative mortality has been reported after resection of secreting tumors.

 

Treatment

Medical Care

Radiation therapy

In the past, patients with imaging findings typical of central nervous system (CNS) germinoma were treated empirically with radiation therapy.[2] This approach has largely been abandoned, since current stereotactic biopsy techniques permit histological diagnosis with minimal risk of morbidity. Identification of the histological elements of CNS germ cell tumors (GCTs) is important in determining the most appropriate therapeutic strategy, because the different histological types vary in their sensitivity to radiation.[12, 80, 81]

Germinomas are highly responsive to radiation therapy[82, 83, 84] ; a complete response rate with a 5-year survival of more than 90% is seen with radiation therapy alone.[2, 85] Nongerminomatous GCTs (NGGCTs) are less radiosensitive than pure germinomas, with an overall 5-year survival of 30-50%.

Full-dose craniospinal radiation (CSI) was traditionally employed for patients with pure germinomas. Side effects of CSI may be significant. Studies comparing CSI with reduced-volume radiation, whether whole-brain or whole-ventricular, have shown no significant difference in the pattern of relapse in germinomas.[12, 7, 86, 87, 88] Therefore, CSI is no longer used for localized germinomas.[86, 89]

Currently, effective therapy uses whole-ventricular irradiation and chemotherapy to reduce the radiation therapy dose.[90] Because radiation exposure of the temporal ventricular horns and hippocampi may lead to long-term poor cognitive function, Yan et al reviewed the outcome in pediatric cases in which the temporal ventricular horns were excluded from ventricular clinical target volumes. Exclusion resulted in significant dose sparing to the hippocampi and temporal lobes, while clinical outcomes remained excellent, with no deaths and no temporal ventricular horn failures. However, long-term neuropsychological studies are required to confirm the benefit.[91]

Trials to determine the best regimen for radiation therapy are ongoing.[85, 92] Currently, patients with localized or multifocal disease may receive 24 Gy to the whole-ventricular system and a 21-Gy boost to all measurable disease.

Radiation therapy to include the whole ventricles appears to be essential in controlling disease. Higher rates of recurrence have been documented in patients who received radiation therapy to the localized tumor alone.[83, 93]

Most experts advocate a boost to the primary tumor bed in order to prevent local recurrence; 45 Gy appears to be a satisfactory upper dose limit.[69, 94, 95, 96] Patients with disseminated disease may receive 24 Gy to the craniospinal axis.[83, 92, 97]

Studies of radiation therapy alone versus neoadjuvant chemotherapy followed by response-based radiotherapy have shown that chemotherapy followed by reduced-dose radiation therapy appears to be effective in patients with pure CNS germinomas, with no deterioration in neurocognitive function and no compromise in outcome.[11, 79, 83, 86, 88, 98, 99, 100]

A report from a prospective, multinational nonrandomized trial in children and adults with intracranial germinoma (the SIOP CNS GCT 96 study) further supports the results of previous trials. This study used chemotherapy followed by reduced-dose CSI of 24 Gy CSI and a 16-Gy tumor boost for patients with both localized and metastatic disease, with a 5-year progression-free survival of 98%.[101]

The use of intensive chemotherapy alone without radiation therapy has proven less effective, resulting in inferior outcome compared with chemotherapeutic regimens and radiation therapy together.[102] Therefore, radiation therapy remains an important and integral part of therapy for patients with CNS GCTs.

Chemotherapy

In patients with germinomas, chemotherapy has been added to the treatment regimen to permit the use of a lower radiation dose, thereby reducing the long-term morbidity associated with radiation therapy while maintaining the excellent survival rates.[30, 11, 12, 81, 69, 85] Germinomas are chemosensitive, especially to platinum-based agents.[103] The current recommendation is to proceed with neoadjuvant therapy prior to lower-dose and lower-volume radiation therapy.

Patients with NGGCTs have an inferior outcome compared with patients with germinomas. Combined therapy with neoadjuvant and adujant chemotherapy with radiation therapy is intended to improve outcome.[12, 79, 31, 85, 104] The increase in survival seen with combination therapy has made chemotherapy an integral part of treatment for NGGCTs.[7, 87, 94, 105]

The role of full-dose CSI is controversial in patients with localized NGGCTs. Results from the forthcoming Children’s Oncology Group (COG) trial for children with localized NGGCT (ACNS1123) may clarify this issue. In this trial by the COG, children with localized NGGCT who attain complete response to chemotherapy alone or chemotherapy and second-look surgery will receive radiation to the whole ventricle plus a tumor boost (3-dimensional conformal radiation therapy) rather than CSI.

As with gonadal germ cell tumors, the agents that to date have shown the best activity against CNS GCTs are cisplatin, etoposide, vinblastine, bleomycin, and carboplatin.[69] Ifosfamide and cyclophosphamide are also used.[81]

Patients with relapsed or progressive disease, especially those with NGGCTs, have a poor prognosis. High-dose chemotherapy followed by autologous stem cell transplantation may be effective in this group of patients.[106]

Surgical Care

Currently the recommended practice is to acquire a tissue biopsy sample, with the exception of patients who have a characteristic elevation in tumor markers and in whom surgical intervention may lead to significant sequelae.[30, 82, 31, 69, 94]

Surgical treatment of CNS GCTs varies according to the tumor type. Germinomas carry a relatively excellent prognosis and management has therefore focused on reducing morbidity. Partial and gross total resection of germinomas has no proven benefit and may lead to neurological or endocrinological deterioration. Therefore, most neurosurgeons limit surgical intervention to biopsy and instead treat these patients with radiation and chemotherapy.[11, 12, 86]

Patients with choriocarcinoma have an increased tendency to hemorrhage; current recommendation is for early and radical surgery.

Patients with NGGCTs have poor long-term survival, and surgery for these patients is aimed at improving outcome. Reduction of tumor burden by partial resection is often an option when removal of all tumor tissue is impossible. Adjuvant radiation therapy and chemotherapy are often incorporated in the treatment plan.[79, 107, 104]

Conflicting results may occur, in particular with small surgical samples that may not be representative, such as histological diagnosis of pure germinoma and raised alpha fetoprotein levels, in which case the patient should be treated more aggressively than those with pure germinoma with normal CSF/serum marker levels. Patients with a tissue diagnosis of NGGCT should be treated as such regardless of CSF/serum tumor marker levels.

Patients presenting with obstructive hydrocephalus may require a ventriculoperitoneal shunt.

In patients who have had an incomplete response to initial chemotherapy, second-look surgery may be performed to remove the residual tissue and permit its histological verification. The remaining tissue may contain malignant elements; however, it may consist of fibrosis, necrosis, or a mature teratoma—the so-called growing teratoma syndrome.[69, 94] The growing teratoma syndrome is characterized by enlarging tumor mass during or after chemotherapy in the presence of normal or declining tumor markers. Surgical resection of the tumor is considered curative.[80, 108]

Consultations

Neurology and neuropsychology

Patients should undergo preoperative, postoperative, and followup neurological assessment, utilizing tools such as the following:

  • Karnofsky Performance Scale (KPS)
  • Modifed Rankin Scale (m-RS)
  • Neurological Performance Scale (MRC)
  • Cognitive Performance Scale (CPS)
  • Barthel Activities of Daily Living (ADL) Index

The performance assessment should be consistent throughout the patients course.

Neuropsychological assessment should be provided—especially for adolescents, to ensure proper schooling and adjustment.

Endocrinology

Patients with CNS GCTs may have a range of endocrine dysfunctions, including diabetes insipidus, hypothyroidism, precocious or delayed puberty, sexual dysfunction, growth failure, adrenal crises, and panhypopituitarism. Proper monitoring of hormone levels and electrolytes is essential. Lifelong hormonal replacement may be required for most of these patients.

Ophthalmology

Disturbance in vision is a common presenting feature. Evaluation by an ophthalmologist will identify the visual deficit.

Audiometry

Audiogram studies should be performed, especially in patients expected to receive radiation therapy and ototoxic agents—specifically, cisplatin.

 

Medication

Medication Summary

Chemotherapeutic agents (eg, cisplatin, bleomycin, etoposide, cyclophosphamide) are used to treat germinomas. They are discussed below along with desmopressin acetate, which is used for the treatment of diabetes insipidus.

Chemotherapeutic agents

Class Summary

These agents are chemical substances or drugs that treat neoplastic diseases by interfering with DNA synthesis.

Cisplatin (Platinol)

Inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of double helix.

Bleomycin (Blenoxane)

Glycopeptide antibiotic that inhibits DNA synthesis. For palliation in management of several neoplasms.

Etoposide, VP-16 (Toposar, VePesid)

Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 phase of cell cycle.

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Vasopressin analogs

Class Summary

These agents treat diabetes insipidus, a neuroendocrine abnormality associated with CNS germinomas.

Desmopressin acetate (DDAVP, Stimate)

Increases cellular permeability of collecting ducts, resulting in reabsorption of water by kidneys.