Pediatric Germ Cell tumors are rare tumors which include the following:
A teretoma is composed of different tissue types representative of ectoderm, endoderm, and mesoderm. A mature teratoma is compsed exclusively of fully differentiated tissues. Mitosis is rare or absent. An immature teratoma resoembles incompletely differentiated tissues resembling that of an adolescent.
CNS GCT are rares accountint for 3-5% of all CNS tumors in kids. They are more common in Asia, accounting for 15% - 18%. The peak age incidence is 10-12 years with boys more frequently affected than girls. CNS germ cell tumors are thought to arise from primordial germ cells in vicinity of the third ventricle. The pineal gland region is the most common site of origin followed by the suprasellar region.
GCT present with symptoms and signs depending on tumor type and location. Tumors in the pineal region cause obstruction to CSF flow at the Sylvian aquaduct causing hydrocephalus. Patients have a relatively short history of increased ICP. Other signs include precocious puberty, diabetes insipitus, and growth failure. Tumors fo the pineal regoin can result in Parinaud's syndrome from dorsal midbrain compression. Tuors of the suprasellar region are more likely to create neurendocrine deficits. Most GCT appear as a solid mass on MR. Choriocarcinomas more frequently hemorrhage.
Workup after a complete history and physical exam with close attention to neurologic, endocrine and s/s of increased ICP, includes MR of the brain. Serum βHCG, αfp and LDH are important both systemically and in CSF. Modest elevation of βHCG (< 100 IU/ml) is seen in some pure germinomas that may contain syncytiotrophoblastic cells. Elevated αfp is diagnostic of a yolk sac tumor.
Imaging includes MRI of the brain and a biopsy follows. Previously a biopsy was not mandated, however, there are a variety of disease that present similarly. Biopsy should be performed to rule out Langerhan's Histiocytosis, astrocytoma and ependymoma. All patients should undergo biopsy unless tumor markers are elevated in serum or CSF, which confirms the presence of a NGGCT. Pineal reagion tumors associated with hydrocephalus, the usual surgical approach is an endoscopic third ventriculostomy, which permits an incision for biopsy purposes.
The goal of surgery is twofold: therapeutic and to provide a definitive tissue specimen for histological diagnosis. Biopsy is considered mandatory in tumors without elevated markers (βHCG, αfp). Aggressive up front surgery is not advocated either in North America or Europe. Delayed surgery after chemotherapy for persistent disease is preferred. Japan argues for a more aggressive surgical approach. There is no known benefit for a gross total resection of a pure germinoma, but some suggest there is for a NGGCT, but this also is controversial. For teratomas (mature teratomas) surgery is reasonable as they often do not respond to chemotherapy and may even progress.
For pure germinomas, radiation is the primary curative modality. Long term disease control rates from 80% to more than 90 - 95% are seen with radiation alone. There is ongoing debate regarding the appropriate volumes:
Dose is also debated, although generally 40 Gy - 50 Gy is recommended to GTV for primary tumor control. The selection for radiation is a function of tumor site, tumor extent, child's age, child's functional status, at presentation. The selection of RT alone or some combination of chemotherapy with reduced dose/limited volume radiation remains in debate.
While radiation therapy treatment volumes for Germinomas are subject to debate, the dose itself appears to be well established. There is less controversy with respect to RT dose: Results are excellent with as low as 21 Gy to the CSI, even in patients with clear leptomeningeal spread. The primary disease site is generally 40 Gy - 45 Gy but some suggest it can be reduced to as low as 30 Gy or 24 Gy when used in combination with chemotherapy if a complete response is obtained. Dose per fraction is 1.5 Gy.
Combine chemotherapy and radiation is the standard of care, with some uncertainty regarding appropriate radiation volume (local v. whole ventricle v. whole brain v. CSI). The use of SRS boost to local disease visible on imaging, which is persistent after chemotherapy and radiation is reasonable, but unproven, and surgery should be performed when safe.
Chemotherapy for intracranial GCT is used. The tumors are radiosensitive and excellent objective response rates are seen. These have been shown for CDDP, carboplatin, cyclophosphamide, CDDP + VP16, ifosfamide, carbo/vp16, and CDDP/VP16/bleomycin. Objective response rates reach 100% for pure germinomas. Carboplatin ± VP16 has largely replaced CDDP due to lower toxicity.
For NGGCT, radiation alone is inadequate. Long term OS is 20% - 40%. Adding platinum based chemotherapy to radiation has markedly improved outcome, with short term survival in excess of 70%. Chemotherapy has become a standrd component of therapy for NCGGT prior to radiation. The French SFOP trial used alternating carbo/etoposide and ifosphamide/etoposide with good results and good tolerance. If thre is not a complete response to surgery/radiation/chemotherapy, stem cell transplant is considered.
In the past, standard treatment was radiation therapy alone. Results of treatment using CSI → boost to primary site are excellent with long term DFS=100% in some series. For unifocal disease, without leptomeningeal spread, radiotherapy alone to limited volumes (ie whole brain) or whole ventricle results in a high probability of local disease control and a low risk of failure at 0-5%. Radiation therapy in the young population carries significant morbidity. For that reason chemotherapy has been considered as an option to radiation. Studies have demonstrated that chemotherapy alone is not reasonable with only 40% to 50% remaining disease free.
Platinum based Chemotherapy given with reduced dose and reduced volume radiation therapy has been demonstrated to be an attractive treatment option with DFS in the range of 90%-96%. There is still debate on the optimal volume to be treated. Local failure appears to be lower after treating the whole ventricular region. For this reason, whole ventricle radiation is generally accepted as the appropriate treatment volume.
For patients with metastatic disease, the North American approach is chemotherapy → CSI → boost to all sites of involvement. All patients with metastatic disease require CSI. The general doses are 24 Gy - 30 Gy without chemotherapy and 21 Gy - 24 Gy with chemotherapy. Local doses to gross disease and visible metastatic foci are 30 Gy when combined with chemotherapy or 45 Gy without chemotherapy.
For NGGCTs the consensus is that higher radiation doses are required even in the setting of chemotherapy. The volume irradiated remains controversial. Studies using chemotherapy followed by CSI plus boost have yielded long- term survival rates of 67% - 74%. The most recent study used alternating carbo/vp16 and ifosphamide/vp16 with CSI to 36 Gy → 54 Gy to the tumor bed. Lack of response to chemotherapy is a poor prognostic indicator.