eMedicine Specialties > Oncology > Carcinomas of the Central and Peripheral Nervous System
Germinoma, Central Nervous System
Updated: Sep 2, 2009
Introduction
Background
Germ cell tumors (GCTs) in the central nervous system (CNS) can occur at any age, but the majority of CNS GCTs occur in the first and second decade of life1 ; 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 forms5,6 :
- Germinoma
- Teratoma
- Yolk sac tumor/endodermal sinus tumor
- Embryonal carcinoma
- Choriocarcinoma
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.
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
Total surgical resection of CNS GCTs has been hampered by the deep-seated location of these tumors. Therefore, craniospinal irradiation was historically 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.8
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. 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 while 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. Current evidence suggests that GCTs arise from germinal elements at various stages of development.
Limited data exist in regard to the cytogenetics of CNS GCTs. 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.9,10 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.11 The most common chromosomal imbalance comprises gains of 1p, 8p, and 12q and losses of 13q and 18q.9,10 Increased copies of the X chromosome are seen in CNS GCTs; the most frequent genotype abnormality isXXY, 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 1.12
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.13,14 These mutations are believed to promote the development of intracranial GCTs. C-myc and N-myc amplifications were seen in a minority of tumors.
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
- 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 ,{Ref15} .
- 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 Asia than in North America. They account for approximately 2-3% of all intracranial tumors and 8-15% of pediatric brain tumors in the Far East.3,15,16
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%.17 Patients with pure malignant NGGCT (embryonal carcinoma, yolk sac tumor, or choriocarcinoma) have a 5-year survival of 30-50%.18
- 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.19,20,21
- 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.18,16
Sex
There is an overall male predominance in CNS GCTs. Data from the NCI Surveillance, Epidemiology and End-Results (SEER) Program on CNS GCTs in the United States3,1 showed that the incidence of CNS germ cell tumors in males, all ages combined, was 3.7 times that seen in females. Among adolescents and young adults, the incidence in males was more than 12 times that seen in females.
Location of CNS GCTs also varies by sex. In males, 70% of tumors occur in the pineal area; for GCTs in this region, the male:female ratio is 18:1. In females, 75% of CNS GCTs occur in the suprasellar areas.
Age
CNS GCTs may occur at any age; however, they are considered primarily a disease of adolescents and young adults.5 17,1 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.
Clinical
History
Clinical presentation varies, depending on age of patient and site of tumor.7 22
- 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 germ cell tumor are most common in this age group53 . 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 the most common presentation, accounting for 34% of cases. It is due to compression on the tectum. The syndrome comprises paralysis of upward gaze, loss of light perception and accommodation, nystagmus, and 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 may occur.
Suprasellar region tumors
Patients with suprasellar GCTs usually present with endocrine deficits. These include the following:
- Anterior hypopituitarism and Diabetes insipidus
- Thyroid and/or cortisol deficiency
- Growth failure from growth hormone deficiency
- Delayed puberty from gonadotrophin 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 gonadotrophin by the tumor).
Visual disturbances may include diplopia, blurred vision, and diminished vision. Enuresis and psychiatric abnormalities may develop.7,5,23 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.
Physical
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
- Ophthalmological exam.
Causes
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.5,22,11,12 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. In vitro studies have shown that tumor growth factor beta 1 may initiate the migration of primordial germ cells.
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.
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.
More on Germinoma, Central Nervous System |
 Overview: Germinoma, Central Nervous System |
| Differential Diagnoses & Workup: Germinoma, Central Nervous System |
| Treatment & Medication: Germinoma, Central Nervous System |
| Follow-up: Germinoma, Central Nervous System |
| Multimedia: Germinoma, Central Nervous System |
| References |
| Next Page » |
References
Villano JL, Propp JM, Porter KR, Stewart AK, Valyi-Nagy T, Li X. Malignant pineal germ-cell tumors: an analysis of cases from three tumor registries. Neuro Oncol. Apr 2008;10(2):121-30. [Medline].
Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg. Aug 1985;63(2):155-67. [Medline].
Keene D, Johnston D, Strother D, Fryer C, Carret AS, Crooks B. Epidemiological survey of central nervous system germ cell tumors in Canadian children. J Neurooncol. May 2007;82(3):289-95. [Medline].
Bentley AJ, Parkinson MC, Harding BN, Bains RM, Lantos PL. A comparative morphological and immunohistochemical study of testicular seminomas and intracranial germinomas. Histopathology. Nov 1990;17(5):443-9. [Medline].
Echevarría ME, Fangusaro J, Goldman S. Pediatric central nervous system germ cell tumors: a review. Oncologist. Jun 2008;13(6):690-9. [Medline].
Rosenblum MK. CNS germ cell tumors: WHO Classification of Tumors of Central Nervous System ed 4. 4.
Crawford JR, Santi MR, Vezina G, Myseros JS, Keating RF, LaFond DA. CNS germ cell tumor (CNSGCT) of childhood: presentation and delayed diagnosis. Neurology. May 15 2007;68(20):1668-73. [Medline].
Finlay J, da Silva NS, Lavey R, Bouffet E, Kellie SJ, Shaw E, et al. The management of patients with primary central nervous system (CNS) germinoma: current controversies requiring resolution. Pediatr Blood Cancer. Aug 2008;51(2):313-6. [Medline].
Rickert CH, Simon R, Bergmann M, Dockhorn-Dworniczak B, Paulus W. Comparative genomic hybridization in pineal germ cell tumors. J Neuropathol Exp Neurol. Sep 2000;59(9):815-21. [Medline].
Schneider DT, Zahn S, Sievers S. Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization. Mod Pathol. Jun 2006;19(6):864-73.
Palmer RD, Foster NA, Vowler SL, Roberts I, Thornton CM, Hale JP. Malignant germ cell tumours of childhood: new associations of genomic imbalance. Br J Cancer. Feb 26 2007;96(4):667-76. [Medline].
Sato K, Takeuchi H, Kubota T. Pathology of intracranial germ cell tumors. Prog Neurol Surg. 2009;23:59-75. [Medline].
Kamakura Y, Hasegawa M, Minamoto T, Yamashita J, Fujisawa H. C-kit gene mutation: common and widely distributed in intracranial germinomas. J Neurosurg. Mar 2006;104(3 Suppl):173-80. [Medline].
Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K. c-kit gene mutations in intracranial germinomas. Cancer Sci. Sep 2004;95(9):716-20. [Medline].
Frank Saran. Pineal Tumors: Germinomas and Non-germinomatous Germ Cell Tumor. In: Clinical Endocrine Oncology Second Edition. 2008 pp 310-317.
Matsutani M,. Combined chemotherapy and radiation therapy for CNS germ cell tumors--the Japanese experience. J Neurooncol. Sep 2001;54(3):311-6. [Medline].
Kaur H, Singh D, Peereboom DM. Primary central nervous system germ cell tumors. Curr Treat Options Oncol. Dec 2003;4(6):491-8. [Medline].
Matsutani M. Pineal germ cell tumors. Prog Neurol Surg. 2009;23:76-85. [Medline].
Sugiyama K, Yamasaki F, Kurisu K, Kenjo M. Quality of life of extremely long-time germinoma survivors mainly treated with radiotherapy. Prog Neurol Surg. 2009;23:130-9. [Medline].
Sutton LN, Radcliffe J, Goldwein JW, Phillips P, Janss AJ, Packer RJ, et al. Quality of life of adult survivors of germinomas treated with craniospinal irradiation. Neurosurgery. Dec 1999;45(6):1292-7; discussion 1297-8. [Medline].
Yoshida J, Sugita K, Kobayashi T, Takakura K, Shitara N, Matsutani M, et al. Prognosis of intracranial germ cell tumours: effectiveness of chemotherapy with cisplatin and etoposide (CDDP and VP-16). Acta Neurochir (Wien). 1993;120(3-4):111-7. [Medline].
Jubran RF, Finlay J. Central nervous system germ cell tumors: controversies in diagnosis and treatment. Oncology (Williston Park). May 2005;19(6):705-11; discussion 711-2, 715-7, 721. [Medline].
Sonoda Y, Kumabe T, Sugiyama S, Kanamori M, Yamashita Y, Saito R. Germ cell tumors in the basal ganglia: problems of early diagnosis and treatment. J Neurosurg Pediatr. Aug 2008;2(2):118-24. [Medline].
Kim A, Ji L, Balmaceda C, Diez B, Kellie SJ, Dunkel IJ. The prognostic value of tumor markers in newly diagnosed patients with primary central nervous system germ cell tumors. Pediatr Blood Cancer. Dec 2008;51(6):768-73. [Medline].
Calaminus G, Bamberg M, Harms D, Jürgens H, Kortmann RD, Sörensen N, et al. AFP/beta-HCG secreting CNS germ cell tumors: long-term outcome with respect to initial symptoms and primary tumor resection. Results of the cooperative trial MAKEI 89. Neuropediatrics. Apr 2005;36(2):71-7. [Medline].
Shibamoto Y, Oda Y, Yamashita J, et al. The role of cerebrospinal fluid cytology in radiotherapy planning for intracranial germinoma. Int J Radiat Oncol Biol Phys. Jul 30 1994;29(5):1089-94. [Medline].
Shinoda J, Sakai N, Yano H, Hattori T, Ohkuma A, Sakaguchi H. Prognostic factors and therapeutic problems of primary intracranial choriocarcinoma/germ-cell tumors with high levels of HCG. J Neurooncol. Jan 2004;66(1-2):225-40. [Medline].
Friedman JA, Lynch JJ, Buckner JC, Scheithauer BW, Raffel C. Management of malignant pineal germ cell tumors with residual mature teratoma. Neurosurgery. Mar 2001;48(3):518-22; discussion 522-3. [Medline].
Kellie SJ, Boyce H, Dunkel IJ, Diez B, Rosenblum M, Brualdi L, et al. Intensive cisplatin and cyclophosphamide-based chemotherapy without radiotherapy for intracranial germinomas: failure of a primary chemotherapy approach. Pediatr Blood Cancer. Aug 2004;43(2):126-33. [Medline].
Haas-Kogan DA, Missett BT, Wara WM, Donaldson SS, Lamborn KR, Prados MD, et al. Radiation therapy for intracranial germ cell tumors. Int J Radiat Oncol Biol Phys. Jun 1 2003;56(2):511-8. [Medline].
Matsatani M. Clinical Management of Primary Central Nervous System Germ Cell Tumors. Semin Oncol. 2004;31:676-683.
Blakeley JO, Grossman SA. Management of pineal region tumors. Curr Treat Options Oncol. Nov 2006;7(6):505-16. [Medline].
Cho J, Choi JU, Kim DS, Suh CO. Low-dose craniospinal irradiation as a definitive treatment for intracranial germinoma. Radiother Oncol. Apr 2009;91(1):75-9. [Medline].
Matsutani M, Sano K, Takakura K, Fujimaki T, Nakamura O. Combined treatment with chemotherapy and radiation therapy for intracranial germ cell tumors. Childs Nerv Syst. Jan-Feb 1998;14(1-2):59-62. [Medline].
Roberge D, Kun LE, Freeman CR. Intracranial germinoma: on whole-ventricular irradiation. Pediatr Blood Cancer. Apr 2005;44(4):358-62. [Medline].
Shikama N, Ogawa K, Tanaka S. Lack of benefit of spinal irradiation in the primary treatment of intracranial germinoma: a multiinstitutional, retrospective review of 180 patients. Cancer. Jul 1 2005;104(1):126-34.
Aoyama H. Radiation therapy for intracranial germ cell tumors. Prog Neurol Surg. 2009;23:96-105. [Medline].
Sawamura Y. Strategy of combined treatment of germ cell tumors. Prog Neurol Surg. 2009;23:86-95. [Medline].
Shibamoto Y. Management of central nervous system germinoma: proposal for a modern strategy. Prog Neurol Surg. 2009;23:119-29. [Medline].
Shim KW, Kim TG, Suh CO, Cho JH, Yoo CJ, Choi JU, et al. Treatment failure in intracranial primary germinomas. Childs Nerv Syst. Oct 2007;23(10):1155-61. [Medline].
Yasuda K, Taguchi H, Sawamura Y, Ikeda J, Aoyama H, Fujieda K, et al. Low-dose craniospinal irradiation and ifosfamide, cisplatin and etoposide for non-metastatic embryonal tumors in the central nervous system. Jpn J Clin Oncol. Jul 2008;38(7):486-92. [Medline].
Schoenfeld GO, Amdur RJ, Schmalfuss IM, Morris CG, Keole SR, Mendenhall WM, et al. Low-dose prophylactic craniospinal radiotherapy for intracranial germinoma. Int J Radiat Oncol Biol Phys. Jun 1 2006;65(2):481-5. [Medline].
Kretschmar C, Kleinberg L, Greenberg M, Burger P, Holmes E, Wharam M. Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: a report from the Children's Oncology Group. Pediatr Blood Cancer. Mar 2007;48(3):285-91. [Medline].
Kellie SJ, Boyce H, Dunkel IJ, Diez B, Rosenblum M, Brualdi L, et al. Primary chemotherapy for intracranial nongerminomatous germ cell tumors: results of the second international CNS germ cell study group protocol. J Clin Oncol. Mar 1 2004;22(5):846-53. [Medline].
Ogawa K, Toita T, Nakamura K, Uno T, Onishi H, Itami J. Treatment and prognosis of patients with intracranial nongerminomatous malignant germ cell tumors: a multiinstitutional retrospective analysis of 41 patients. Cancer. Jul 15 2003;98(2):369-76. [Medline].
Modak S, Gardner S, Dunkel IJ, Balmaceda C, Rosenblum MK, Miller DC, et al. Thiotepa-based high-dose chemotherapy with autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell tumors. J Clin Oncol. May 15 2004;22(10):1934-43. [Medline].
Janmohamed S, Grossman AB, Metcalfe K, Lowe DG, Wood DF, Chew SL, et al. Suprasellar germ cell tumours: specific problems and the evolution of optimal management with a combined chemoradiotherapy regimen. Clin Endocrinol (Oxf). Oct 2002;57(4):487-500. [Medline].
Peltier J, Vinchon M, Baroncini M, Kerdraon O, Dhellemmes P. Bifocal mixed germ-cell tumor with growing teratoma syndrome and metachronous mature metastases: case report. J Neurooncol. Oct 2008;90(1):111-5. [Medline].
Skeel RT. Handbook of Cancer Chemotherapy. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999:. 85, 91, 93, 105.
Nakamura H, Takeshima H, Makino K, Kuratsu J. Evaluation of residual tissues after adjuvant therapy in germ cell tumors. Pediatr Neurosurg. 2007;43(2):82-91. [Medline].
Ogino H, Shibamoto Y, Takanaka T, Suzuki K, Ishihara S, Yamada T. CNS germinoma with elevated serum human chorionic gonadotropin level: clinical characteristics and treatment outcome. Int J Radiat Oncol Biol Phys. Jul 1 2005;62(3):803-8. [Medline].
Robertson Patricia. intracranial nongerminoma germ cell tumors. Available at www.medlink.com.
Further Reading
Keywords
Intracranial germ cell tumors, germinoma, nongerminomatous germ cell tumor, germ cell tumor, teratoma, pineal lesions, suprasellar lesions, gonadotrophines, tumor markers, alpha-fetoprotein (AFP), beta-human chorionic gonadotrophins (β-hCG) , primordial germ cells, Klinefelter syndrome, syncytiotrophoblasts
