✓ The natural history of primary intracranial germ-cell tumors (GCT's) is defined from 389 previously published cases, of which 65% were germinomas, 18% teratomas, 5% embryonal carcinomas, 7% endodermal sinus tumors, and 5% choriocarcinomas. Intracranial GCT's display specificity in site of origin. Ninety-five percent arise along the midline from the suprasellar cistern (37%) to the pineal gland (48%), and an additional 6% involve both sites. The majority of germinomas (57%) arise in the suprasellar cistern, while most nongerminomatous GCT's (68%) preferentially involve the pineal gland (p < 0.0001). The age distribution of afflicted patients is unimodal, centering with an abrupt surge in frequency in the early pubertal years; 68% of patients are diagnosed between 10 and 21 years of age. Nongerminomatous GCT's demonstrate an earlier age of onset than do germinomas (p < 0.0001). Prolonged symptomatic intervals prior to diagnosis are common in germinomas (p = 0.0007), in suprasellar GCT's (p = 0.001), and a...

Intracranial germ-cell tumors: natural history and pathogenesis.

SummaryThe authors report two cases of a rare tumor in adults which were inserted on the fornix and caused a frontal syndrome. By light microscopy, the tumors, highly calcified, were composed of small clear cells forming dense areas in a patchy fibrillary stroma. Electron microscopy revealed a striking neuronal differentiation with numerous synapses. These tumors, for which the term neurocytomas was proposed, were compared with the other CNS neuronal tumors described in the literature.

Central neurocytoma. An electron-microscopic study of two cases.

The authors believe that the preferred treatment for pineal region tumors in children requires definitive surgery with a histological diagnosis and that a conservative approach consisting of shunting and radiation therapy no longer seems to be appropriate. The results are reported of a retrospective review of the presentation, treatment, and outcome of 36 children under the age of 18 years treated between 1974 and 1986. Eleven children had germinomas (two-cell type), seven had astrocytomas, and the remaining 18 had 15 histologically different tumor types. Surgery was performed on 30 patients; there were no deaths, but a 10% rate of persistent morbidity was found. The median follow-up period was 4 years. Nine (82%) of 11 patients with germinomas are alive without evidence of recurrence; one child died from recurrent tumor in the pineal region and another is presently being treated for recurrent tumor of the spinal cord. Six (86%) of the seven patients with astrocytoma are well after biopsy and radiation therapy. Of the remaining 18 children, five (28%) died from tumor progression. The cerebrospinal fluid (CSF) tumor markers alpha-fetoprotein and beta-human chorionic gonadotropin were helpful in determining the presence of malignant germ-cell tumors, particularly those with a poor prognosis. Magnetic resonance imaging was useful for diagnosis and for planning the operative approach. Magnetic resonance images showed the presence of pineal region tumors in four children with hydrocephalus who had no evidence of tumor on computerized tomography scans. Because the great variety of tumor types found in the pineal region must be treated in different ways and because improved microsurgical and stereotaxic surgical techniques have made mortality and morbidity rates acceptably low, a biopsy diagnosis should be obtained in all patients. Preoperative assessment of CSF tumor markers and cytology is useful for the identification of patients who have a poor prognosis.

Pineal region tumors in children.

High-resolution 1H NMR spectroscopy has been used to measure the concentrations of metabolites (alanine, N-acetylaspartate, γ-aminobutyric acid, glutamate, glutamine, aspartate, taurine, glycine, succinate, creatine, cholines, inositol, and glucose) in perchloric acid extracts of human epileptic cortex and brain tumors. All tissue was obtained by surgical biopsy, excised before thermal coagulation, and immediately frozen in liquid nitrogen. Lower levels of N-acetylaspartate and γ-aminobutyric acid and a shift in the glutamate/glutamine ratio toward glutamine in the tumors reflect neuronal loss. Abnormal glucose metabolism (aerobic glycolysis) in the tumors gives decreased levels of succinate, glutamate, aspartate, glutamine, and creatine and generally increased concentrations of glycine and alanine. Differences in metabolite concentrations that may be of use in differential tumor diagnosis include lower creatine and inositol in meningiomas than in astrocytomas. Lower taurine differentiates benign from malignant astrocytomas. Malignant astrocytomas and metastatic tumors are more regionally heterogeneous than meningiomas or benign astrocytomas. Mannitol, administered perioperatively to all patients from whom tissue was obtained, was observed only in the spectra of extracts of tissue from tumors which enhanced on computerized tomographic imaging. © 1992 Academic Press, Inc.

High-resolution 1H NMR spectroscopy studies of extracts of human cerebral neoplasms.

Computerized tomographic (CT) scanning is revealing more clearly the response and resistance of certain intracranial tumors to radiotherapy and to chemotherapy. Pure germinomas in the pineal and suprasellar regions are very radiosensitive and highly curable and, following whole central nervous system (CNS) irradiation, a 5-year survival rate in excess of 80 % may be reached. Chemical markers may reveal the presence, persistence or recurrence of more resistant teratoid tissue in germ cell tumors. Medulloblastomas are also very radiosensitive, but the presence of local residual resistant tumor has restricted cure rates to approximately 40% following post-operative megavoltage irradiation. Adjuvant chemotherapy may increase the survival rate of children with these tumors to 60% or 70%: children surviving a period of time equivalent to their age at diagnosis plus 9 months are likely to be cured. Ependymomas are moderately radiosensitive tumors and following high dose and, in certain circumstances, whole CNS irradiation, the 5-year survival rate is approximately 50 % : at present, adjuvant chemotherapy for patients with high grade ependymomas appears to increase length of survival but not cure rate. Low grade astrocytomas of the cerebral hemispheres, widely regarded as radioresistant, do respond to irradiation and also to chemotherapy. Optic gliomas should not be regarded as self-limiting malformations: they destroy vision, and lesions in the chiasma may prove fatal. They are not entirely radio-resistant and good responses may follow radiotherapy. High grade astrocytomas (glioblastoma) remain resistant and virtually incurable. While there is a chance with post-operative irradiation of extending survival for up to 5 years in grade III patients, there is no such hope for patients with grade IV lesions. Attempts to overcome the remarkable resistance to treatment of these tumors are described. Changes in dose/time/volume factors in radiotherapy, and the use of hyperbaric oxygen, chemical radio-sensitizers, adjuvant chemotherapy, immunotherapy and particle beam therapy have all, so far, failed to significantly improve overall prognosis. However, it has been shown that the tumor can be destroyed by neutron beam irradiation, but at the expense of normal brain damage and with no improvement in survival. Inoperable deep gliomas arising in adjacent areas of the brain can vary widely in their response to irradiation. For example, in children the 5-year survival rate for intrinsic hypothalamic tumors is 83%, compared with only 20% for thalamic tumors. Inoperable tumors of the brain-stem present a special challenge to the radiotherapist since they are generally limited in size, show a good initial response to irradiation, but recur and kill within 1–2 years. A trial of radiosensitizers such as misonidazole would seem indicated in such cases. Craniopharyngiomas and meningiomas are benign lesions and are expected to be radioresistant. They do, in fact, respond to irradiation. Following conservative surgery the operative mortality and morbidity for craniopharyngioma is greatly reduced and with radiotherapy the post-operative recurrence rate is substantially decreased: a 5-year survival rate of 90 % may be reached. The response of meningiomas to radiotherapy is often difficult to assess, but worthwhile regression may be seen in patients with large inoperable or recurrent tumors. Apart from tumor response to treatment, consideration must also be given to reaction of normal tissue to irradiation, to chemotherapy and to a combination of these modalities: these may produce late effects leading to disturbance of neurological and endocrine function and of intellectual and emotional status. Factors in the host, particularly age and certain pre-existing endocrine disturbances, may influence tissue reactions. Some intracranial gliomas appear to respond better to treatment in children than in adults, and survival rates for patients under 16 have become substantial. Of a total of 415 patients under the age of 16 completing radiotherapy for all types of intracranial tumor at the Royal Marsden Hospital, 53 % survived 5 years, 45 % 10 years, and of 41 % 20 years. It is particularly in very young patients that serious late effects are more likely to occur. Continued clinical efforts will undoubtedly increase survival rates further in those tumor groups which already show a substantial response to current treatments. It will, however, probably require considerable further progress in radio- and chemico-biological research, as well as some bold clinical experiments, before we can effectively overcome the resistance of glioblastoma without exceeding therapeutic tolerance of the normal brain. Cell culture and xenograft laboratory models for pre-clinical studies are being used to assess glioma responsiveness to new cytotoxic and radiosensitizing agents and to combination treatments.

Intracranial tumors: response and resistance to therapeutic endeavors, 1970-1980

Eight patients with primary malignant pineal tumors have been seen at this institution over the past 6 years; six of them underwent definitive surgical exploration. Complete gross microsurgical excision of well encapsulated tumors was possible in four of these patients. In two cases of pineal germinomas, a biopsy and a subtotal resection were carried out because of the known radiosensitivity of this tumor. These six surgical patients all received postoperative craniospinal radiation and continue to do well up to 6 years postoperatively. Two nonoperative patients were initially treated at other institutions by ventriculoperitoneal shunt and radiation and were the only ones to develop metastatic disease. One patient had metastasis of her pineoblastoma to her unirradiated spinal canal and the other patient had metastasis of his germinoma to the peritoneum. The former patient was quadriplegic on admission, although her pineal tumor was no longer visible on computerized tomography (CT), and she died of pneumonia. The latter patient's tumor secreted the beta chain of human chorionic gonadotropin (HCG). This patient's massive metastatic tumor burden completely regressed as determined by body CT scan and HCG levels after four courses of chemotherapy with bleomycin, vinblastine, and cis-platinum. In 20 patients with lesions of the pineal region, craniotomy was associated with only one death (a patient with metastatic adenocarcinoma). Thus, microsurgery for pineal tumors provides either a reasonably safe potential for complete tumor extirpation and possible cure, or a tissue diagnosis which is necessary for appropriate therapeutic planning for radiotherapy and/or chemotherapy. The traditional therapeutic approach of empiric radiotherapy without a tissue diagnosis for pineal lesions may no longer be warranted.

Eugene P Frenkel

Papers

Malignant pineal region tumors: A clinico-pathological study