The variability and complexity of central nervous system germ cell tumors have led to controversy in both diagnosis and management. If a germ cell tumor is suspected, the measurement of cerebrospinal fluid and serum alpha-fetoprotein and beta–human chorionic gonadotropin is essential. A histologic specimen is not necessary if the patient has elevated levels; however, if the tumor markers are negative, a biopsy is needed to confirm the diagnosis of a germinoma. Germinomas are extremely radiosensitive, enabling 5-year survival rates that exceed 90%. Treatment has traditionally included focal and craniospinal axis irradiation; however, multiple ongoing studies are being conducted to examine the efficacy of reduction or elimination of radiation therapy with the addition of chemotherapy. Nongerminomatous germ cell tumors, on the other hand, are relatively radioresistant with a poorer outcome. The combination of chemotherapy and irradiation is associated with overall survival rates of up to 60%. This article provides a review of the controversies in diagnosis and treatment of central nervous system germ cell tumors.
Germ cell tumors (GCT) of the central nervous system (CNS) are thought to be derived from totipotent primordial germ cells, capable of both embryonic and extraembryonic differentiation. Based on the histologic components and the variable degree of differentiation, CNS GCTs are classified as germinomatous and nongerminomatous germ cell tumors (NGGCT). Germinomas comprise two-thirds of the CNS GCTs, and NGGCTs account for the remaining third.
The NGGCTs may be composed of elements of choriocarcinoma, endodermal sinus (or yolk sac) tumor, embryonal carcinoma or teratoma (mature or immature). Often, the NGGCTs are a mixture of the above elements. This variability and complexity of CNS GCTs leads to controversy in both diagnosis and management.
In addition, the rarity of CNS GCTs, comprising 1% to 2% of all primary CNS neoplasms, adds to the difficulty in determining optimal treatment. Very few prospective studies are available, and retrospective studies are limited based on the low number of patients involved, the variability in tumor size and location, histology, surgical approach, chemotherapy, and/or irradiation. In the past 2 decades, international cooperative trials have been conducted and advances have been made in treatment and prognosis.
CNS GCTs are typically midline tumors, most commonly seen in the pineal and/or suprasellar regions. Peak age at diagnosis is 10 to 12 years; however, CNS GCTs may be seen throughout childhood, adolescence, and young adulthood. The clinical presentation is dependent on the location of the tumor, whether suprasellar, pineal, or both. Common presentations include symptoms from increased intracranial pressure, visual tract involvement, and/or endocrine abnormalities.
If a CNS GCT is suspected, extent of disease evaluation should include: (1) high-resolution magnetic resonance imaging of the head and spine, with and without gadolinium; (2) evaluation of the cerebrospinal fluid (CSF) for cytology by lumbar puncture or sampling of ventricular fluid at time of shunt placement; (3) CSF and serum measurement of alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (BHCG); (4) baseline endocrine and neuropsychologic evaluations; and (5) a formal visual examination.
Radiologically, CNS GCTs cannot be distinguished from other CNS tumors. In the past, if patients had a pineal and/or suprasellar tumor, and suspected GCT, they were given a diagnostic trial of radiotherapy. If an early complete clinical response was seen, the patient was diagnosed with a germinoma. However, other pineal region tumors, as well as mixed NGGCT, may respond initially in the same manner and require very different treatment in order to prevent relapse. Therefore, this practice is no longer used.
The issue then arises regarding the necessity of a biopsy. A histologic specimen is unnecessary if the patient has a positive AFP or BHCG in the CSF and/or serum. Germinomas are generally negative for tumor markers, although they may secrete low levels of BHCG in the CSF (less than 100 mIU/mL). In NGGCTs, endodermal sinus tumors are associated with increased levels of AFP, while choriocarcinomas are associated with raised levels of BHCG. The secretion of these tumor markers in the CSF is pathognomonic for NGGCT, and no further histologic specimen is indicated. When low levels of BHCG are detected in the CSF, it is likely a germinoma with syncytiotrophoblastic cells, and the need for a histologic specimen is debatable. In the French Society of Pediatric Oncology (SFOP) experience, four out of nine patients with secreting germinomas were treated without a histologic diagnosis, and the outcome was the same as for germinomas with a histologic diagnosis.
All other patients with suspected GCT and negative tumor markers require a histologic specimen for diagnosis and treatment. Germinomas are exquisitely sensitive to radiotherapy with excellent cure rates, whereas NGGCTs have a poorer prognosis and require more intensive chemotherapy and irradiation. Given the differing natural histories and responses to treatment of germinomas and NGGCTs, histopathology to determine an optimal treatment strategy in tumor marker-negative patients is important.
It is possible, however, to make an erroneous diagnosis from a small biopsy specimen due to sampling error of a mixed GCT. Specifically, a diagnosis of a germinoma may be made from a small biopsy of a mixed GCT containing germinomatous elements (usually immature or mature teratoma). A gross total resection may provide greater tissue for histologic diagnosis, but given the location of these tumors and the resultant risk of postsurgical morbidity, a partial or total resection for tissue diagnosis is currently not recommended. Due to this risk of histologic sampling error, if any residual radiographic abnormality is present after two to four cycles of chemotherapy, the patient should undergo a "second-look" surgery.
Role of Surgery
Again, given the location of GCTs and the high postsurgical morbidity, the risks and benefits of surgery must be considered in light of the excellent response to irradiation and chemotherapy in germinoma patients. Based on the retrospective study of Sawamura et al, no further benefit was found in performing a resection of any kind--partial or complete--beyond treatment with irradiation and chemotherapy.
Unlike germinomas, the role of radical resection in NGGCTs is unclear, with no definitive studies having been conducted. It is possible that radical resection may increase survival rates in NGGCT. Current studies have supported the use of delayed resective surgery, or "second-look" surgery, if residual radiographic abnormalities are seen after chemotherapy and tumor markers have normalized. In this case, the residual lesion is likely to be teratoma or necrosis/fibrosis devoid of tumor. If it is a mature teratoma, surgery may be curative. These patients are then spared any further radiation therapy by performing the "secondlook" surgery.
If immature teratoma is present, then local-field irradiation is initiated without further chemotherapy.[ 3,5,6] In patients whose tumor markers have not normalized, the pathology from "second-look" surgery was also often consistent with either fibrosis or teratoma. However, the risk of subsequent recurrence or progression of disease was significant. Therefore, "second-look" surgery was not supported in cases with any elevation of tumor markers, as the surgery did not improve outcome or allow for a change in therapy.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Shibamoto Y, Takahashi M, Sasai K: Prognosis of intracranial germinoma with syncytiotrophoblastic giant cells treated with radiation therapy. Int J Radiat Oncol Biol Phys 37:505-510, 1997.
2. Matsutani M, Takakura K, Sano K: Primary intracranial germ cell tumors: Pathology and treatment. Prog Exp Tumor Res 30:307-312, 1987.
3. Weiner HL, Finlay JL: Surgery in the management of primary intracranial germ cell tumors. Childs Nerv Syst 15:770-773, 1999.
4. Sawamura Y, de Tribolet N, Ishii N, et al: Management of primary intracranial germinomas: Diagnostic surgery or radical resection? J Neurosurg 87:262-266, 1997.
5. Sawamura Y, Kato T, Ikeda J, et al: Teratomas of the central nervous system: Treatment considerations based on 34 cases. J Neurosurg 89:728-737, 1998.
6. Branzelli MC, Patte C, Bouffet E, et al: Non-metastatic intracranial germinomas. The experience of the French Society of Pediatric Oncology. Cancer 80:1792-1797, 1997.
7. Brada M, Rajan B: Spinal seeding in cranial germinomas. Br J Cancer 61:339-340, 1990.
8. Bamberg M, Kortmann R-D, Calaminus G, et al: Radiation therapy for intracranial germinoma: Results of the German Cooperative Prospective trials MAKEI 83/86/89. J Clin Oncol 17:2585-2592, 1999.
9. Ayoyama H, Shirato H, Kakuto Y, et al: Pathologically-proven intracranial germinoma treated with radiation therapy. Radiother Oncol 47:201-205, 1998.
10. Shibamoto Y, Takahashi M, Abe M, et al: Reduction of radiation dose for intracranial germinoma: A prospective study. Br J Cancer 70:984-989, 1994.
11. Buckner JC, Peethambram PP, Smithson WA, et al: Phase II trial of primary chemotherapy followed by reduced dose radiation for CNS germ cell tumor. J Clin Oncol 17:933-940, 1999.
12. Allen JC, Darosso RC, Donahue B, et al: A phase II trial of preirradiation carboplatin in newly diagnosed germinoma of the central nervous system. Cancer 74:940-944, 1994.
13. Matsutani M, Sano K, Takakura K, et al: Primary intracranial germ cell tumors: A clinical analysis of 153 histologically verified cases. J Neurosurg 86:446-455, 1997.
14. Fouladi M, Grant R, Baruchel S, et al: Comparison of survival outcomes in patients with intracranial germinomas treated with radiation alone versus reduced-dose radiation and chemotherapy. Childs Nerv Syst 14:596-601, 1998.
15. Sawamura Y, Shirato H, Ikeda J, et al: Induction chemotherapy followed by reduced volume radiation therapy for newly diagnosed CNS germinoma. J Neurosurg 88:66-72, 1998.
16. Sawamura Y, Ikeda J, Shirato H, et al: Germ cell tumors of the central nervous system: Treatment considerations based on 111 cases and their long term clinical outcomes. Eur J Cancer 34:104-110, 1998.
17. Bouffet E, Baranzelli MC, Patte C, et al: Combined treatment modality for intracranial germinomas: Results of a multicentre SFOP experience. Br J Cancer 79:1199-1204, 1999.
18. Rappaport R, Brauner R: Growth and endocrine disorders secondary to cranial radiation. Pediatr Res 25:561-567, 1989.
19. Matsutani M, Japanese Pediatric Brian Tumor Study Group: Combined chemotherapy and radiation therapy for CNS germ cell tumors— the Japanese experience. J Neurooncol 54:311-316, 2001.
20. Aoyama H, Shirato H, Ikeda J, et al: Induction chemotherapy followed by low dose involved field radiotherapy for intracranial germ cell tumors. J Clin Oncol 20:857-865, 2002.
21. Shibamoto Y, Sasai K, Kokubo M, et al: Salvage radiation therapy for intracranial germinoma recurring after primary chemotherapy. J Neurooncol 44:181-185, 1999.
22. Balmaceda C, Heller G, Rosenblum M, et al: Chemotherapy without radiation—a novel approach for newly diagnosed CNS germ cell tumors: Results of an international cooperative trial. J Clin Oncol 14:2908-2915, 1996.
23. Borg M: Germ cell tumors of the central nervous system in children: Controversies in radiotherapy. Med Pediatr Oncol 40:367-374, 2003.
24. Robertson PL, DaRosso RC, Allen JC: Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy. J Neurooncol 32:71-80, 1997.
25. Kellie SJ, Boyce H, Dunkel IJ, et al: Primary chemotherapy for intracranial nongerminomatous germ cell tumors: Results of the Second International CNS Germ Cell Study Group protocol. J Clin Oncol 22:846-853, 2004.
26. Garre ML, El-Hossainy MO, Fondelli P, et al: Is chemotherapy effective therapy for intracranial immature teratoma? A case report. Cancer 77:977-982, 1996.
27. Gobel U, Schneider DT, Calaminus G, et al: Germ cell tumors in childhood and adolescence. Ann Oncol 11:263-271, 2000.
28. Merchant TE, Davis BJ, Sheldon JM, et al: Radiation therapy for relapsed CNS germinoma after primary chemotherapy. J Clin Oncol 16:204-209, 1998.
29. Modak S, Gardner S, Dunkel I, 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 22;1934-1943, 2004.
30. Mahoney DH Jr, Strother D, Camitta B, et al: High dose melphalan and cyclophosphamide with autologous bone marrow rescue for recurrent/progressive malignant brain tumors in children: A pilot Pediatric Oncology Group study. J Clin Oncol 14:382-388, 1996.
31. Constine LS, Woolf PD, Cann D, et al: Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 328:87-94, 1993.
32. Sands SA, Kellie SJ, Davidow AL, et al: Long term quality of life and neuropsychologic functioning for patients with CNS germ cell tumors: From the First International CNS Germ Cell Tumor Study. Neur Oncol 3:174-183, 2001.
33. Sutton LN, Radcliffe J, Goldwein JW, et al: Quality of life of adult survivors of germinomas treated with craniospinal irradiation. Neurosurgery 46:1292-1298, 1999.
34. Merchant TE, Sherwood SH, Mulhern RK, et al: CNS germinoma: Disease control and long term functional outcome for 12 children treated with craniospinal irradiation. Int J Radiat Oncol Biol Phys 46:1171-1176, 2000.
35. Merchant TE, Williams T, Smith JL, et al: Preirradiation endocrinopathies in pediatric brain tumor patients determined by dynamic tests of endocrine function. Int J Radiat Oncol Biol Phys 54:45-50, 2002.