Symposium on Pediatric Oncology
Diagnosis and Treatment of Brain Tumors Michael D. Walker, M.D. *
Malignancy within the central nervous system is the second most frequent cause of death due to cancer in children and is only surpassed by leukemia. Despite this incidence, there has been little coordinated effort placed on the treatment of this almost inevitably fatal disease. There are differences in the biology and histology of brain tumors of children as compared to adults, which may relate to differences in the developing and maturing central nervous system. The infant is unable to verbally communicate and children seem more capable of adjusting to adversity; hence, subtle changes frequently go unnoticed at an early stage. The complexity of presentation of signs and symptoms is frequently confused with the association of development and maturational processes and social and environmental pressures. Because of the difficulty and morbidity of neurodiagnostic procedures, physicians are frequently reluctant to have children undergo unpleasant examinations and tests. The reliability of these procedures is further compromised as most examinations require the patient to remain physically stable so as to avoid movement artifacts. Therefore, totality of the diagnosis and treatment of tumors of the central nervous system in children is less clearly defined than it is in adults. The spectrum of tumors presenting in children is different from that found in the adult population. Many do not bear a specific relationship to adult brain tumors and have their own unique biology, cellular kinetics, effects on adjacent structures, and management procedures. Numerous reports appear in the literature concerning the treatment of brain tumor, but are difficult to compare as the data reported does not stratify and define the tumors in such a way as to permit intercomparison. Rather, the report reflects the specific approaches of a given discipline or individual. If there were gross changes or a "quantum jump" in survival of these patients, it would quickly become apparent to all. However, this does not appear to be the case and probably will not become a reality in the near future. *Head, Section of Neurological Surgery, and Director, Baltimore Cancer Research Center of the National Cancer Institute, Baltimore, Maryland
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Considerable emphasis is placed upon the classification of "benign" or malignant tumors of the brain based upon the histopathologic appearance, and frequently the locational characteristics which make the removal of a "benign" tumor virtually impossible are not taken into account. The difficulties of examination, operation, and subsequent treatment are brought more sharply into focus in the pediatric age group. Of particular interest is the relative failure of the primary brain tumor to metastasize from the central nervous system, despite the fact that onequarter of the cardiac output is delivered to the brain and a large proportion of the cerebrospinal fluid exists by bulk flow directly into the venous sinuses. The therapeutic armamentarium traditionally has included surgery, or radiotherapy, or both. The application of these treatment modalities has varied not only from center to center, but within centers, and, at times, is an individualistic approach which does not easily permit comparative analysis and assessment. Radiotherapy has been the primary mode of adjuvant treatment and, in many cases, the only mode of therapy when surgery was felt to be too hazardous. Radiotherapy is limited by the total cumulative dose which may be delivered before its effect on normal tissues becomes excessive. The effective dose for most tumors of the central nervous system is at the upper limit and hence the therapeutic index is small. Total doses of 4,500 to 6,000 rads given in daily increments of approximately 200 rads for 5 days per week appeared to be the accepted and tolerated limit, although each center has variations. 3 • 21 To place it in prospective, dosage does not usually vary by more than 20 per cent in any given institution. The dose-limiting critical tissue of radiotherapy of the central nervous system appears to be the cerebral vasculature which develops a late (1 to 3 years) small vessel adventitial fibrosis, arteriosclerotic changes, and acclusive disease.t 7, 25 Such effects may be even more pronounced in the developing central nervous system or may be more apparent as patients live long enough for these complications to develop.27 When neuraxial radiotherapy is employed, the additional effects on blood-forming elements, bone growth, and soft tissues must be taken into account. Despite the limits, toxicity, and hazards of radiotherapy, it still remains one ofthe effective treatments for tumors of the central nervous system and, in what are frequently lethal diseases, its efficacy far outweighs its disadvantages. Chemotherapy, as a rule, is used even more infrequently in brain tumors of childhood. It is hampered by the lack of extremely effective agents and a general reluctance to treat children vigorously. In most instances, it is applied only at the time of recurrence or as a desperation attempt to stem relentlessly progressing disease. 32 The value of corticosteroids in the treatment of intracranial tumor is established. By rapidly reducing cerebral edema associated with brain tumor, time is provided to obtain sophisticated neurodiagnostic studies, to carefully plan the therapeutic approach, and to operate under optimal conditions. No other drug has made as much of an impact on brain tumor therapy, yet its effect on brain tumor, per se, is not known, and its antineoplastic activity remains
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to be defined. Immunotherapy, although in its infancy, may some day playa definitive role in the oblation of residual tumor. 35 Coordinated studies taking into account selective criteria and concomitant or sequentially applied therapeutic modalities are just becoming a reality through the efforts of the Children's Cancer Study Group and the Radiation Therapy Oncology Group. Further carefully controlled studies need to be carried out in order to establish the best treatment criteria for children's brain tumor.
INCIDENCE, EPIDEMIOLOGY, AND NOMENCLATURE It is estimated that approximately 18 per cent of cancers in children under the age of 15 are tumors of the central nervous system. This is in comparison with 31 per cent who have leukemia and the 6 to 8 per cent who have Wilms' tumor, neuroblastoma, or lympho-proliferative disorders, respectively. As a group, brain tumors are reported slightly more frequently in males than females, and the peak age appears to be five to nine years, in contrast to the peak incidence at 50 to 60 years of age in brain tumors in adults. 20 In children, two-thirds of the intracranial tumors are beneath the tentorium, whereas in the adult population, only 1 of 10 tumors are infratentorial. Precise data as to histologic type and locational distribution are not always reported in children alone. Ependymomas, for example, may be found in both the supratentorial and infratentorial spaces, but frequently are reported as ependymoma only without an indication of location. Table 1 indicates an estimated occurrence rate derived from the literature. 3. 10, 20. 22, 23, 33 In some series, as many as 20 per cent of infratentorial tumors are unverified,20 whereas others report only verified (Le., operated upon) tumors. S
Table 1. Estimated Occurrence of Primary Intracranial
Tumors in Children TUMOR
I
I
Infratentorial Cerebellar astrocytoma Medulloblastoma Brainstem glioma Ependymoma Other TOTAL
Supratentorial Astrocytoma Ependymoma Malignant glioma Craniopharyngioma Other TOTAL
PERCENTAGE
20 18 10 8 10
66
8
6 6 5 8
33
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The etiology of brain tumor in children is not known. A few medulloblastomas and gliomas appear to be congenital by virtue of having become apparent within a few weeks of birth. 3! Some of the more dedifferentiated tumors seen particularly in infancy may well originate from primitive neuronal cell precursors. Unclear, however, is the relationship between histopathologically identical tumors seen in infants and adults (e.g., medulloblastoma). Although a wide variety of brain tumors may be created in experimental animals by chemical carcinogens, ionizing radiation, and oncogenic viruses, there is no evidence to date that these bear a significant cause and effect relationship in the human. The nomenclature utilized in the literature is variable in the precise terminology used. Often a tumor has mixed cellularity and is classified under the most prevalent cell type. In addition, there are subsets or variants which do not precisely fit a given designation. Finally, the clinical-histologic correlation is not always apparent. For purposes of simplicity, we use the common nomenclature, including variations. A great need exists to develop a universally agreed upon system of nomenclature which will allow classification and stratification and permit direct intercomparison between various studies. The reader is referred to the excellent classical monograph by Rubinstein for precise descriptions of these various tumors.3!
GENERAL SIGNS AND SYMPTOMS Children are generally more difficult to diagnose in that they may be noncommunicative as are infants, or present soft signs and symptoms which can be confused with the processes of growth and maturation, or brief self-limiting intercurrent disease. Virtually every symptom with which a child presents can be related to some specific event in the life of an active child. Thus, vomiting is frequently associated with "the flu." The alert clinician listening to the symptom complexes which present frequently is led to an earlier and prompter diagnosis. The clinical findings are basically dependent upon whether the tumor is diffuse, infiltrating, and directly interrupts neuronal function, oris predominantly more extraparenchymal leading to displacement of normal tissues. In virtually all cases, there are elements of both present. Symptoms, therefore, may be either generalized, as found in lesions causing obstruction to the flow of cerebrospinal fluid with resultant hydrocephalus, or they may be specific and localizing to the involved area of the brain. 34 ,37 Any localized tumor may increase in size to the point where its mass effect becomes predominant and impedes the flow of cerebrospinal fluid. The more contiguous with specific nuclei or identifiable areas within the brain a tumor may be, the more frequent the appearance of early symptoms and signs with specific localizing characteristics. Because the child's cranial vault can expand by spreading of the sutures, children appear to tolerate a comparatively "large" tumor burden. 37
Symptoms Headache is frequently seen in children with intracranial masses and increased intracranial pressure. 23 It often starts insidiously without a
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clear-cut onset, is intermittent being found more frequently on arising, and may become progressive. Headache in children should be considered as an important symptom because children infrequently complain of headaches that are not associated with organic disease. Vomiting is more frequently reported as the first symptom which precipitates action, as it is a specific dramatic event which calls attention to itself. Vomiting often occurs after the head has been in a dependent position (Le., following a night's sleep) and is not particularly associated with nausea. The patient may eat a normal meal shortly thereafter. Vomiting is seen in a variety of childhood diseases in which its character is to become progressive, to occur over a relatively short time frame, and to occur in association with the development of other diagnostic signs and symptoms as the disease process runs its natural course. Children with increased intracranial pressure will frequently show fatigability requiring longer naps, and may have a decrease in normal activity. There may be a discernible decrease in normally anticipated mental growth and, at times, it may appear as though the child's disposition has changed, or he has become more irritable. Although, at first, there may not be loss of weight, there may be a change in the normal weight gain pattern. The persistence of these general symptoms of increased intracranial pressure after a suspected infectious process ought to have passed should alert the clinician to the possibility of hydrocephalus. Seizure activity is seen in one-third of supratentorial lesions, but rarely in infratentorial tumors, and must be differentiated from convulsions secondary to other diseases.
Signs On occasion, the patient or parents will note strabismus or diplopia, usually secondary to lateral rectus palsy (sixth cranial nerve), indicating an immediate need for further diagnostic evaluation. Fundoscopic examination revealing papilledema provides a clear indication of increased intracranial pressure. Although it may be difficult in older infants, fundoscopic examination should be pursued as the finding of papilledema demands further evaluation. In infants, bulging of the fontanelle, rapidly increasing head circumference, and prominent venous patterns in the scalp all signal the need for further investigation. Patients with posterior fossa tumors may demonstrate disturbances which may be seen with any intracranial neoplasm; however, ataxia is more frequent with posterior fossa midline tumors. Paresis is not common with cerebellar tumors, but is found in one-half of patients with supratentorial and brain stem neoplasms. Although more difficult to elicit due to uncooperation, reflexes are often abnormal. Nystagmus, specific cranial nerve losses, and sensory disturbances all indicate more specific localized disease. The report of any of the above generalized signs and symptoms requires a very careful evaluation for specific signs which may lead to localization of the tumor, a preliminary diagnosis, and definition of the sequence of diagnostic procedures to follow.
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DIAGNOSTIC APPROACHES The neurologic examination in children with intracranial malignancies remains the single most important evaluation. The demonstration of positive findings will frequently indicate whether the lesion is infratentorialor supratentorial and the area of involvement. Negative findings on neurologic examination are equally as important to elicit in that the development of a sign which was not previously present indicates progressive disease. It is not infrequent that the suspicion of brain tumor is confirmed on the second examination, when original findings were thought to be due to intercurrent systemic disease. Diagnostic procedures may be classified as invasive or noninvasive. In either case, they are rendered more difficult to perform due to the inability of children to hold still during either frightening or painful procedures. It is, of course, more appropriate to proceed with the less traumatic procedures first. Computerized axial tomography (CAT, CT, EMI scan, etc.) has become a major reality in the armamentarium of the neurodiagnostician. 1Q ,15 In the course of a few moments, a computerized axial tomography scan can be performed which will evaluate the intracranial contents at various levels of both the supratentorial and infratentorial spaces, and calculate their specific densities. The effects of increased intracranial pressure and mass lesions can frequently be seen. If a mass is not defined and abnormal findings are present (such as enlarged ventricles), the addition of intravenous contrast medium will often delineate the tumor. Although equipment used for computerized axial tomography and the procedure itself are expensive, the wealth of information which it can supply, and the fact that it can be performed on an outpatient basis without invasion of the arterial system or cerebral spinal fluid space, places it very high on the list of useful procedures. The exact limits of computerized axial tomography, its level of accuracy, and its specific use in children remain to be defined; however, it should be seriously considered as the first and possibly the most useful diagnostic procedure.1 5 Plain skull films, in the past, have been considered to be the first diagnostic step. In children, these films can indicate the presence of chronic increased intracranial pressure by demonstrating the opening up of the cranial sutures or characteristic changes in the sella turcica. These may be due either to direct involvement of tumor or pressure from the dilated third ventricle above. In addition, slower growing tumors, such as ependymomas, may show calcification. The finding of the generalized effects of increased intracranial pressure on skull films indicates an absolute necessity for further diagnostic evaluation. Radionucleotide brain scanning (primarily technetium 99 ) is of particular value in identifying lesions located above the tentorium. Because of overlying structures, radionucleotide scanning is less satisfactory in infratentoriallesions, but frequently is capable of assisting in localization of a mass lesion. Radionucleotide scanning requires 15 to 30 minutes to perform and it is difficult for children to hold still for this period of time. N ewer techniques with radionucleotide scanning as well as computerized
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axial tomography are reducing the length of time to a matter of a few minutes, and therefore the chances for a successful scan will become greater. Electroencephalogram, considered an atraumatic and noninvasive diagnostic procedure, is frequently used in convulsive disorders. A normal electroencephalogram, however, should not be considered as indicating the absence of a tumor, particularly when other signs and symptoms indicate further work-up is warranted. Cerebral angiography has become a more sophisticated and precise procedure with the development of selective catheterization studies. In small children, however, these procedures are still difficult to perform and require anesthesia. It is frequently easier to obtain simultaneous multivessel studies. Angiography is still considered the mainstay of neurodiagnostic procedures, as it not only shows the displacement of normal vascular architecture, but the presence of abnormal tumor vessels, aneurysms, or vascular anomalies. Angiography of posterior fossa lesions is, again, not as precise as that for supratentorial lesions. However, with the addition of biplainar serial studies and the utilization of magnification and subtraction techniques, angiography allows for extremely sophisticated identification of microvasculature. Pneumoencephalogram, the first procedure to be utilized to identify intracranial displacement, has been gradually replaced by more sophisticated techniques. Nevertheless, the pneumoencephalogram is still extremely useful in defining intraventricular or paraventricular tumors, such as those which arise from the sella or encroach on the third or fourth ventricle. Pneumoencephalography is clearly an invasive procedure which should be reserved for those difficult diagnostic cases where previous studies have indicated definite but ill-defined abnormalities. If, on computerized axial tomography scan or angiography there is evidence of increased intracranial pressure, great caution should be taken in pursuing pneumoencephalography, and consideration should be given to ventriculography. This is particularly true when there is a high index of suspicion of a posterior fossa mass which will require surgical intervention. Lumbar puncture is considered to be at the bottom of the list of neurodiagnostic procedures and, as a rule, should not be carried out for the diagnosis of brain tumor. Only when there is serious consideration of bacterial meningitis or meningeal carcinomatosis, and there is no evidence on other studies of space-occupying tumor, should lumbar puncture be undertaken.
POSTERIOR FOSSA TUMORS The infratentorial brain volume is approximately one-tenth that of the supratentorial space. In addition, all the cranial nerve nuclei as well as cerebellar function are contained within it. Hence, considerably smaller lesions than those found supratentorially produce severe deficits when located in the posterior fossa.
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Cerebellar Astrocytomas Cerebellar astrocytoma is reported as 11 to 30 per cent of the brain tumors of children and has an estimated occurrence of 20 per cent. Seen slightly more frequently than medulloblastoma, it nevertheless is considered one of the most surgically successfully treatable tumors of children and is extremely rare in adults. 23 Patients with cerebellar astrocytoma often have a longer duration of symptoms prior to operation in comparison with other posterior fossa masses. Located within the cerebellar hemisphere, the localizing signs and symptoms will be ipsilateral incoordination, ataxia with a tendency to drift toward the side of the lesion, nystagmus with the slow component on ipsilateral gaze, and hyporeflexia on the side of the lesion. The diagnosis is made by the symptom complex seen and the demonstration of a cerebellar mass lesion on contrast study. Computerized axial tomography scans are clearly capable of showing the cystic component, thus increasing the preoperative diagnostic accuracy. Histologically, these tumors appear well differentiated as low grade astrocytomas with varying density of fibrillated cells and cystic areas. Approximately one-half contain a definitive mural nodule. 31 Astrocytomas ofthe cerebellum in children, as a group, are considered to be surgically treatable lesions. 2 • 12 Removal of the cyst and its mural nodule is curative in a large percentage of patients, or, at least, leads to long-term survival. 6 If subtotal excision is accomplished, the remaining tumor is slow-growing and does not appear to become more dedifferentiated with time. 31 When a cystic component is not present, or invasion of the peduncle, vermis, or brain stem is apparent, subtotal resection should be carried out. Because of the slow-growing nature of cerebellar astrocytomas and the possibility of surgical oblation, radiotherapy is not routinely carried out. However, in incompletely removed lesions or those invading vital structures, the addition of radiotherapy has provided a 64 per cent 10 year disease-free interva1. 33 Equally, long-term survivors, however, have been reported who did not have the benefit of radiotherapy. Therefore the role of radiotherapy in cerebellar astrocytoma is not clear.1 2 Because of the long-term survivals noted above, chemotherapy has not been utilized. Chemotherapy for recurrence of cerebellar astrocytoma or for those which appear to have a more malignant characteristic certainly should be considered, particularly at the first sign of recurrence.
Medulloblastoma Fifteen to twenty-five per cent of brain tumors in children are reported to be medulloblastomas with an estimated occurrence of 18 per cent. They occur virtually exclusively subtentorial, and are seen in males at least twice as frequently as in females. 4 • 37 They are found more frequently in infants than in older children, but extend through the adult years. Eighty per cent of these tumors occur in children under 15 years of age. Med ulloblastomas arise predominantly from the vermis of the cerebellum and grow mostly in the midline of young patients, whereas they appear to extend laterally more frequently in older patients. Medulloblastoma is
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thought to arise from germinative cells of the external granular layer of the cerebellum any time during its lateral migration. Tumors appear to arise from the vermis, fill and invade the fourth ventricle, and may extend laterally into the cerebellar hemispheres. It is a highly cellular tumor frequently in sheets of small cells with hyperchromatic nuclei and little cytoplasm. Mitotic figures may frequently be seen and "pseudorosettes" are seen in about one-third of cases. Medulloblastomas are infiltrating gliomas, invading the subarachnoid space and not infrequently the cerebrospinal fluid pathways leading to dissemination and metastases. The symptoms of medulloblastoma frequently include gait disturbances with truncal ataxia. A patient may be unable to sit without support; however, involvement of cranial nerves or nystagmus is rare, unless specific invasion has taken place. The nonspecific signs and symptoms of increased intracranial pressure may be present. Occasionally, patients present with dissemination in the cerebrospinal fluid and localized compressive lesions of nerve roots, the spinal cord, or the cerebral hemispheres. The diagnosis of medulloblastoma is suspected by the signs and symptoms presented, is enhanced by scans and air studies, but is confirmed only upon biopsy. It cannot be differentiated from other posterior fossa tumors prior to biopsy. The treatment of choice is judicious surgical reduction of the tumor burden wherever possible without invading the floor or the walls of the fourth ventricle. The historic operative mortality is approximately 20 per cent, whereas current surgical therapy has markedly reduced this. 4 , 5, 14 Metastasis within cerebrospinal fluid pathways is seen in one-third of cases. Radiotherapy is the treatment of choice following establishment of the diagnosis. 33 Treatment should include the entire neuraxis with 4500 to 5500 rads delivered to the posterior fossa and upper cervical cord, 3500 rads to the supratentorial contents, and 4000 rads to the spinal cord. Approximately 35 per cent of patients are disease-free at 5 years, and 25 per cent at 10 years. More aggressive therapy appears to be successful in significantly increasing survival rates. Chemotherapy has not been pursued in a coordinated fashion, and has been reserved for progressive and recurrent cases. 32 Medulloblastoma is felt to be a highly radiosensitive tumor and therefore may also be responsive to chemotherapeutic agents. Twenty-five per cent of recurrent medulloblastomas treated with the nitrosoureas (BCNU or CCNU) were considered to be responders, whereas 60 to 70 per cent of very small groups of patients treated with procarbazine, intrathecal methotrexate, or vincristine were considered to be responders. 32 Recurrent medulloblastoma with dropped metastasis in close continuity with cerebrospinal fluid pathways should be an ideal tumor for use ofintrathecal therapy.ltis also the custom to treat myelographically demonstrated metastasis with a limited area booster dose of radiotherapy. The response is frequently dramatic. Medulloblastoma has been reported to metastasize outside of the central nervous system more frequently than other gliogenous tumors. 31 With the increased use of preresection or postresection shunts to control the accumulation of cerebrospinal fluid, there appears to be an increased incidence of systemic and/or intraperitoneal seeding. 16 ,34 With the im-
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proved quality of life being demonstrated by judicious surgery and aggressive radiotherapy, care should be taken not to lose this advantage by unnecessary systemic seeding. Controlled studies in the treatment of medulloblastoma are extremely difficult to carry out due to: (1) a comparatively low incidence of medulloblastoma (4 per cent) in the general population; (2) the long and highly variable period of time to recurrence; (3) the different sites of recurrence; and (4) the difficulty of obtaining uniform agreement in grading, therapy, and follow-up among investigators. Considering the long-term survival of children with medulloblastoma and the considerable care placed on their treatment, rehabilitation, follow-up, and treatment after recurrence by physicians, specialists, and parents, a treatment protocol acceptable to many should be carried out. A carefully designed study by the Children's Cancer Study Group and the Radiation Therapy Oncology Group is evaluating radiotherapy versus radiotherapy and vincristine followed by eight cycles of prednisone, vincristine, and CCNU. Upon recurrence, the patient will receive procarbazine or vincristine, CCNU, and procarbazine dependent upon prior treatment. Data from this important study will take several years to accrue.
Brainstem Glioma Included in this group are gliomas of the pons and medulla. These lesions are frequently the smallest cancers seen, as they are intrinsic to the brains tern and in close continuity with ascending and descending pathways as well as cranial nerve nuclei. They are reported in 8 to 20 per cent of patients, with an expected occurrence of 10 per cent without unusual male, female, or age ratios. Because of their anatomic location, insidious onset of cranial nerve dysfunction, long track involvement, and ataxia with infrequent evidence of increased cranial pressure are seen.2S Gait disturbance is the most common symptom followed by seventh nerve involvement, in turn followed by involvement of the sixth, ninth, and tenth cranial nerves, and a sensory portion of the fifth nerve. Long track signs, such as extensor plantar responses and reflex abnormalities, are frequently seen. 19 Localized cranial nerve findings, in the absence of the generalized signs and symptoms of increased intracranial pressure, strongly indicate brainstem glioma. Such findings, however, may be confused by rather marked laterality, and extension toward the cerebellum or fourth ventricle. The diagnosis of brains tern glioma is made by demonstrating the size, shape, and configuration of the brains tern by air encephalography or positive contrast studies demonstrating characteristic enlargement of the pons with posterior bowing of the aqueduct and displacement ofthe fourth ventricle. The diagnosis is primarily neuroradiologic and, hence, the computerized axial tomography scan should be ofconsiderable value. Not infrequently, the symptom complex and neurodiagnostic studies will be suggestive of a mass lesion not solely confined to the brainstem, therefore surgical exploration is indicated. Histologically, gliomas of the brainstem show a wide variety of pathology from frank glioblastoma multiforme to low grade astrocytoma. 13 There appears to be correlation between the
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rapidity of development of symptoms and duration of survival with the degree of anaplasia. Surgical exploration of brain stem glioma should be restricted to those cases in which the neuroradiologic diagnosis is not clear-cut, or where there may be evidence of a cyst which could be evacuated. Differentiation in cases with atypical neurodiagnostic findings cannot be made from medulloblastoma, ependymoma, or cerebellar astrocytomas with brainstem extension. In those cases in doubt, exploration with visualization and selective biopsy, if possible, should be undertaken. Radiotherapy of brainstem tumors is the treatment of choice and, on occasion, can be extremely gratifying as progressive cranial nerve signs and symptoms remit. Standardized doses of 5000 to 5500 rads over 5 to 6 weeks with 180 rads per fraction have been successfully utilized. Patients with low grade astrocytoma so treated have a median survival of three to five years, whereas those with more malignant-appearing brainstem tumor will have a median survival of only a few months. l3 • 33 Symmetrically located brainstem gliomas rarely produce obstruction to the flow of cerebrospinal fluid, thus increased intracranial pressure requiring shunting is not frequently seen. As with many other posterior fossa tumors, chemotherapy of brainstem glioma is usually not carried out until recurrence following radiotherapy is evident. 32 Considering the histologic similarity between brainstem gliomas and those found within the cerebral hemispheres, it would be reasonable to anticipate that those agents efficacious in treatment of supratentorial masses should also be effective in brainstem gliomas. Thirty per cent of 23 patients treated with the nitrosoureas (BCNU and CCNU) responded primarily by stabilization of progressive disease or, in some cases, improvement. A single case has been reported to respond to procarbazine. 32 • 36 Because the brainstem is intimately bathed in cerebrospinal fluid, it is ideally located for intrathecal therapy. The penetration of but a few millimeters should be able to provide cytotoxic concentrations of drug to active tumor. Intrathecal methotrexate has been utilized with five of six patients responding. Detailed studies utilizing this potentially promising mode of therapy have not been carried out. High dose systemic methotrexate, followed by leucovorin rescue, resulted in a remarkable shrinkage of tumor which was sustained for over six months. 30 Since the blood-brain barrier is disrupted in the area of active tumor growth, it can be postulated that high concentrations of methotrexate would be found within the immediate tumor area. As with other childhood brain tumors, determination of the efficacy of specific modalities in the treatment of brainstem glioma awaits more carefully designed studies.
Ependymoma (Infratentorial) Ependymoma of the posterior fossa of children occurs in about 8 per cent ofpatients. l • 23 It not infrequently arises in the region of the obex and, consequently, causes the generalized signs and symptoms of increased intracranial pressure noted above. Ependymoma may be difficult to differentiate grossly from medulloblastomas or other tumors existing within the fourth ventricle. Ependymomas tend to enlarge slowly as cir-
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cumscribed lesions which may grow through the cisterna magna and encroach upon the cervical cord. They are modestly cellular with polygonal or effusive formed cells, irregular nuclei, and a tendency to form ependymal rosettes. Mitotic figures are rare, calcification occasional, and necrosis uncommon. The diagnosis is most frequently made on histopathology. The treatment of infra tentorial ependymomas is careful surgical resection, leaving the fourth ventricle intact, followed by radiotherapy. Shunting to control hydrocephalus prior to surgical resection is fraught with the problems noted in medulloblastoma above.1 6 • 34 Ependymomas are considered to be highly radiosensitive and therefore incomplete resection should be followed by radiotherapy.1 Despite being within the cerebrospinal fluid pathways, they do not frequently metastasize unless they show poor differentiation and a high grade of malignancy. Radiotherapy to the posterior fossa for those of low grade appears to provide adequate control with approximately 80 per cent five year surviva1. 33 Ependymomas with more malignant characteristics or with evidence of spinal seeding, should have neuraxial irradiation. 29 More aggressive therapy is probably indicated in this disease. l l Too few patients with ependymoma have been treated with chemotherapy in order to draw any conclusions as to its efficacy. A few instances have been gleaned from the literature where patients have responded to the nitrosoureas or epipodophyllotoxin. 32
SUPRA TENTORIAL TUMORS Astrocytomas and Malignant Glioma Astrocytomas are estimated to occur in approximately 8 per cent of children, whereas more malignant tumors are seen in only 5 per cent. These lesions may be located any place within the cerebral hemisphere, and may often produce signs and symptoms of increased intracranial pressure or have their appearance heralded by focal or nonspecific convulsions. Specific symptoms are referable to the hemisphere and location of predominant involvement. The diagnosis has been made in the past by ventriculography and arteriography, and more recently by use of the computerized axial tomography scan. Astrocytomas may be cystic containing large quantities offluid. Due to the expansive nature of children's skulls, these lesions may reach a large size before becoming apparent. Histologically, the full range of malignancy may be seen, although it is more common to have low grade astrocytomas with cystic components in children. Treatment is surgical to provide a diagnosis and reduce the tumor burden. Because of the relative infrequency of these tumors in children, the value of radiotherapy has not been defined and chemotherapy has been little explored. 9 However, it is apparent that modest palliation may be obtained by use of 5000 to 6000 rads. 33 Deep astrocytomas in and around the third ventricle and involving the thalamus, hypothalamus, and midbrain are not amenable to surgical therapy at all, and upon establishing a reasonable probability of diag-
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nosis, radiotherapy should be undertaken. The use of chemotherapy for hemispheric tumors in children has been undertaken only occasionally, and should be pursued more vigorously.
Ependymoma (Supratentorial) Ependymomas of the cerebral hemisphere presumably arise from the ependyma of the ventricles and are seen in 5 to 6 per cent of patients with brain tumors. They may appear to be encapsulated and have a cystic component. They may be distant from or encroach upon the ventricle. By pneumoencephalography or angiography, they may not be distinguished from astrocytoma. However, occasionally they show calcification which may be found on plain skull films or more eloquently, on computerized axial tomography scan. Judicious resection of ependymomas of cerebral hemispheres should be undertaken where it will not interfere with vital structures. IS Ependymomas are considered to be radiosensitive tumors, therefore vigorous radiotherapy should be considered. 29 Patients with ependymomas ofthe cerebral hemispheres appear to have a better survival rate than those with ependymomas below the tentorium; ependymomas of the cerebral hemispheres are not noted to seed the cerebrospinal fluid pathways. 33 The quality of life following re section and irradiation of supratentorial ependymomas which do not involve vital structures is considered to be excellent.
Craniopharyngiomas Craniopharyngiomas are not frequently seen in children and account for an estimated 4 per cent of the brain tumors in children. The most common signs and symptoms are increased intracranial pressure and visual loss. Diabetes insipidus is rarely seen.24 Supracellar calcification is frequently seen, as are abnormalities of the sella turcica. Diagnosis may be confirmed by air study, angiography, or more recently by computerized axial tomography scans. From the histopathologic point of view, craniopharyngiomas are considered to be benign; yet, because of their location and difficulties of surgical exposure, as well as their close continuity with vital structures, craniopharyngioma should be considered an extremely difficult disease to manage surgically.3 The use of meticulous technique, steroid replacement, and the control of diabetes insipidus, should it occur, have led to better results. 24 More careful preparation of the patient, conservative retraction of the brain, and the magnification provided by the operating microscope have allowed surgeons to more carefully approach these tumors, resect major portions, or, at least, provide drainage and decompression. Total excision is frequently difficult without serious consequences. The combination of aspiration or excision, followed by radiation, has led to excellent results in the treatment of patients with craniopharyngiomas of all ages; however, the specific results of children have not been reported. 3 Reoperation upon these patients is often considered necessary for further decompression, but is fraught with increased postoperative morbidity.24
1
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Other Tumors (Mixed Location) A variety of other infratentorial tumors, such as choroid plexus papillomas, dermoids, and a large percentage of unverified posterior fossa tumors reported in the literature, should be approached through the usual diagnostic armamentarium with the hope of uncovering either a surgically resectable lesion, or one which will be considered as having radiosensitive elements. Failure to examine closely the diagnostic studies on these patients and judiciously explore those in whom there is reasonable hope of success will not allow enlightened future therapy to be provided. Gliomas of the anterior visual pathway are a rare entity in which the optic nerve, optic chiasm, or both may be involved and are found in association with neurofibromatosis. Symptoms depend upon the area of involvement with visual loss found in all cases, ptosis being seen only in optic nerve gliomas, and hypothalamic dysfunction being found with optic chiasm gliomas. Gliomas of the optic nerve are more confined, are frequently surgically accessible, and have a favorable prognosis. Gliomas involving the chiasm or both the optic nerve and chiasm frequently invade the hypothalamus and structures around the third ventricle and have a much poorer prognosis,15 There is no consistent opinion concerning the value of radiotherapy. Oligodendroglioma, very rarely seen in children, is a variant of malignant gliomas, which usually grow slowly, develop calcification, may be subtotally surgically resected, and may be treated with radiotherapy.2o.26 Upon recurrence, reoperation should be considered in favorably located tumors. Pineal germinomas, also rarely seen in children, present a unique problem by virtue of their location and varying cellular components. 31 They are seen in older children, predominantly males, more frequently in the Japanese, and present as mass lesions causing increased intracranial pressure. 26 They may obstruct the flow of cerebrospinal fluid, produce anterior hypothalamic involvement, or upper brain stem dysfunction with paralysis of conjugate upward gaze (Parinaud's syndrome), pupillary reaction to accommodation but not light, and loss of convergence. Surgically difficult to approach, tumors in the pineal region are often treated by cerebrospinal fluid shunting and radiotherapy to which they are often extremely sensitive. There is also a wide variety of tumors of the central nervous system which are of mal development in origin. 31 By their very nature, these are more frequently seen in children, and are midline and supratentorial. The most commonly reported are teratomas, dermoids, and epidermoid cysts. In addition to these tumors, a comparatively large percentage of tumors of the central nervous system in childhood are not histopathologically diagnosed. 20 Therefore therapeutic approach by classification is extremely difficult. CONCLUSION The availability of hard correlatable data in the treatment of pediatric brain tumors is discouraging. The reasons for the paucity of information relates to the comparatively few tumors treated per year by each hospital
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and center, changes in equipment and approach, and lack of uniform criteria for diagnosis, staging, and response. There are not many choices for the future. We can continue to treat patients as we have in the past and continue to achieve that degree of success. On the other hand, we can outline a logical and sequential program designed to provide basic data on brain tumors in children in such a way as to be able to characterize their biologic behavior, determine predictive criteria, correlate histopathologic and biochemical parameters, and develop a powerful flexible data base. While accumulating this information, the currently acceptable modes of treatment (surgery and radiotherapy) can be more clearly defined and categorized in order to give quantitative rather than qualitative results. Chemotherapeutic study designs, so successful in the treatment of leukemia, neuroblastoma, and other tumors of childhood, must be modified and applied to the treatment of intracranial malignancy. In order to accrue sufficient patient material, many clinicians will have to establish common principles. This does not require that the physician abandon his rights to treat the patients as he deems best, but is a more honest statement of the fact that we do not know the best ways of treating intracranial malignancy in children. Such approaches in the past have been said to lead to the least common denominator of acceptable therapy. This will only occur if the participants permit it to happen. The time frame in which such studies can be carried out and over which improvement can be anticipated is indeed long, but is, nevertheless, considerably shorter than continuing with individual therapeutic approaches. The treatments proposed should become at least as aggressive as the disease. We should not shirk from developing the necessary diagnostic information, applying vigorous therapy, and utilizing costly follow-up approaches, so long as the expected cost-benefit ratio is in the patient's favor and to the tumor's detriment. Whether we will continue our experience of the last four decades, or will take the necessary steps to move forward in improving the quality and quantity of survival, remains to be seen.
REFERENCES J. Neurosurg., 33 :428-438, 1970. Bernell, W. R., Kepes, J. J., and Seitz, E. P.: Late malignant recurrence of childhood cerebellar astrocytoma. Report of two cases. J. Neurosurg., 37:470, 1972. Bloom, H. J. G.: Combined modality therapy for intracranial tumors. Cancer, 35: 111-120, 1975. Bloom, H. J. G.: Concepts in the natural history and treatment of medulloblastoma in children-Increasing survival rates and possible risks with current radiotherapy techniques. C. R. C. Crit. Rev. Radiol. Sci., 2:89-143, 1971. Bloom, H. J. G., Wallace, E. N. K., and Henk, J. M.: The treatment and prognosis of medulloblastoma in children: A study of 82 verified cases. Am. J. Roentgenol., 105 :43-62, 1969. Bucy, P. C., and Thieman, P. W.: Astrocytomas ofthe cerebellum-A study of a series of patients operated upon over 28 years ago. Arch. Neurol., 18:14-19, 1968. Butler, A. B., and Netsky, M. G.: Classification and biology of brain tumors. J. Neurol. Surg., 3:1297-1339; 1973. Chatty, E. M., and Earle, K. M.: Medulloblastoma-A report of201 cases with emphasis on the relationship of histologic variants to survival. Cancer, 28:977, 1971.
1. Barone, B. M., and Elvidge, A. R.: Ependymomas-A clinical survey.
2. 3. 4. 5. 6. 7. 8.
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9. Concannon, J. P., Kramer, S., and Berry, R.: The extent ofintracranial gliomata at autopsy and its relationship to techniques used in radiation therapy of brain tumors. Am. J. Roentgenol., 84:99, 1960. 10. Cornell, S. J., Christie, J. H., Chiu, C. L., et al.: Computerized axial tomography of the cerebral ventricles and subarachnoid spaces. Neurology, 124:186-194, 1975. 11. Fokes, E. C., and Earle, K. M.: Ependymomas: Clinical and pathological aspects. J. Neurosurg., 30:585, 1969. 12. Geissinger, J. D., and Bucy, P. C.: Astrocytomas of the cerebellum in children. Arch. Neurol., 24:125-135,1971. 13. Golden, G. S., Ghatak, N. R., et al.: Malignant glioma of the brain stem. J. Neurol. Neurosurg. Psychiatry, 35:732-738, 1972. 14. Hope-Stone, H. F.: Results of treatment of medulloblastoma. J. Neurosurg., 32:83-88, 1970. 15. Houser, O. W., Smith, J. B., Gomez, M. R., et al.: Evaluation of intracranial disorders in children by computerized trans axial tomography: A preliminary report. Neurology, 25:607-613, 1975. 16. Kessler, L. A., Dugan, P., and Concannon, J. P.: Systemic metastases of medulloblastomas promoted by shunting. Surg. Neurol., 3:147-152,1975. 17. Kramer, S.: The hazards of therapeutic irradiation of the central nervous system. Clin. Neurosurg., 15:301-318, 1968. 18. Kricheff, I. I., Becker, M., Schneck, S. A., et al.: Intracranial ependymomas. J. Neurosurg., 21 :167-175, 1964. 19. Lassman, L. P., and Arjona, V. E.: Pontine gliomas of childhood. Lancet, 1 :913-915, 1967. 20. Mackay, E. N., and Sellers, A. H.: A statistical review of malignant neoplasms of central nervous system. Ontario Cancer Foundation Clinic, 1950-1964. 14th Annual Clinical Conference, 1967, pp. 1-20. 21. Marsa, G. W., Probert, J. C., Rubenstein, L. J., et al.: Radiation therapy in the treatment of childhood astrocytic gliomas. Cancer, 32:646-655, 1973. 22. Matson, D. D.: Intracranial tumors of the first two years oflife. J. Surg. Obstet. Gynecol., 72 :117-122, 1964. 23. Matson, D. D.: Neurosurgery of Infancy and Childhood. Springfield, Charles C Thomas, 1969. 24. Matson, D. D., and Crigler, J. F., Jr.: Management of craniopharyngioma in childhood. J. Neurosurg., 30:377, 1969. 25. Nakagaki, H., Brunhart, G., Kemper, T. L., et al.: Monkey brain damage from radiation in the therapeutic range. Neurology, 44 :3-11, 1976. 26. Onoyama, Y., Abe, M., Takahashi, M., et al.: Radiation therapy of brain tumors in children. Radiology, 115 :687-693, 1975. 27. Painter, M. J., Chutorian, A. M., and Sadek, S. K.: Cerebrovasculopathyfollowingirradiation in childhood. Neurology, 25:189-194, 1975. 28. Panitch, H. S., and Berg, B. 0.: Brain stem tumors of childhood and adolescence. Am. J. Dis. Child., 119 :465, 1970. 29. Philips, T. L., Sheline, G. E., and Boldrey, E.: Therapeutic considerations in tumors affecting the central nervous system: Ependymomas. Radiology, 83:98-105, 1964. 30. Rosen, G., Ghavimi, F., Vanucci, R., et al.: Pontine glioma-High-dose methotrexate and leucovorin rescue. J.A.M.A., 230:1149-1152, 1974. 31. Rubinstein, L. J.: Tumors of the central nervous system. Armed Forces Institute of Pathology, 1972, pp. 19-50. 32. Shapiro, W. R.: Chemotherapy of primary malignant brain tumors in children. Cancer, 35 :975, 1975. 33. Sheline, G. E.: Radiation therapy of tumors of the central nervous system in childhood. Cancer, 35:957-964, 1975. 34. Stein, B. M., Tenner, M. S., and Fraser, A. R.: Hydrocephalus following removal of cerebellar astrocytomas in children. J. Neurosurg., 36:763, 1972. 35. Takakura, K., Yoshimasa, M., and Kubo, 0.: Adjuvant immunotherapy for malignant brain tumors in infants and children. Child's Brain, 1 :141-147, 1975. 36. Vasantha Kumar, A. R., Renaudin, J., Wilson, C. B., et al.: Procarbazine hydrochloride in the treatment of brain tumors-Phase 2 study. J. Neurosurg., 40:365-371, 1974. 37. Wilson, C. B.: Medulloblastoma-Current views regarding the tumor and its treatment. Oncology, 24:273-299, 1970. Baltimore Cancer Research Center 22 South Greene Street Baltimore, Maryland 20014
Diagnosis and Treatment of Brain Tumors Michael D. Walker, M.D. *
Malignancy within the central nervous system is the second most frequent cause of death due to cancer in children and is only surpassed by leukemia. Despite this incidence, there has been little coordinated effort placed on the treatment of this almost inevitably fatal disease. There are differences in the biology and histology of brain tumors of children as compared to adults, which may relate to differences in the developing and maturing central nervous system. The infant is unable to verbally communicate and children seem more capable of adjusting to adversity; hence, subtle changes frequently go unnoticed at an early stage. The complexity of presentation of signs and symptoms is frequently confused with the association of development and maturational processes and social and environmental pressures. Because of the difficulty and morbidity of neurodiagnostic procedures, physicians are frequently reluctant to have children undergo unpleasant examinations and tests. The reliability of these procedures is further compromised as most examinations require the patient to remain physically stable so as to avoid movement artifacts. Therefore, totality of the diagnosis and treatment of tumors of the central nervous system in children is less clearly defined than it is in adults. The spectrum of tumors presenting in children is different from that found in the adult population. Many do not bear a specific relationship to adult brain tumors and have their own unique biology, cellular kinetics, effects on adjacent structures, and management procedures. Numerous reports appear in the literature concerning the treatment of brain tumor, but are difficult to compare as the data reported does not stratify and define the tumors in such a way as to permit intercomparison. Rather, the report reflects the specific approaches of a given discipline or individual. If there were gross changes or a "quantum jump" in survival of these patients, it would quickly become apparent to all. However, this does not appear to be the case and probably will not become a reality in the near future. *Head, Section of Neurological Surgery, and Director, Baltimore Cancer Research Center of the National Cancer Institute, Baltimore, Maryland
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Considerable emphasis is placed upon the classification of "benign" or malignant tumors of the brain based upon the histopathologic appearance, and frequently the locational characteristics which make the removal of a "benign" tumor virtually impossible are not taken into account. The difficulties of examination, operation, and subsequent treatment are brought more sharply into focus in the pediatric age group. Of particular interest is the relative failure of the primary brain tumor to metastasize from the central nervous system, despite the fact that onequarter of the cardiac output is delivered to the brain and a large proportion of the cerebrospinal fluid exists by bulk flow directly into the venous sinuses. The therapeutic armamentarium traditionally has included surgery, or radiotherapy, or both. The application of these treatment modalities has varied not only from center to center, but within centers, and, at times, is an individualistic approach which does not easily permit comparative analysis and assessment. Radiotherapy has been the primary mode of adjuvant treatment and, in many cases, the only mode of therapy when surgery was felt to be too hazardous. Radiotherapy is limited by the total cumulative dose which may be delivered before its effect on normal tissues becomes excessive. The effective dose for most tumors of the central nervous system is at the upper limit and hence the therapeutic index is small. Total doses of 4,500 to 6,000 rads given in daily increments of approximately 200 rads for 5 days per week appeared to be the accepted and tolerated limit, although each center has variations. 3 • 21 To place it in prospective, dosage does not usually vary by more than 20 per cent in any given institution. The dose-limiting critical tissue of radiotherapy of the central nervous system appears to be the cerebral vasculature which develops a late (1 to 3 years) small vessel adventitial fibrosis, arteriosclerotic changes, and acclusive disease.t 7, 25 Such effects may be even more pronounced in the developing central nervous system or may be more apparent as patients live long enough for these complications to develop.27 When neuraxial radiotherapy is employed, the additional effects on blood-forming elements, bone growth, and soft tissues must be taken into account. Despite the limits, toxicity, and hazards of radiotherapy, it still remains one ofthe effective treatments for tumors of the central nervous system and, in what are frequently lethal diseases, its efficacy far outweighs its disadvantages. Chemotherapy, as a rule, is used even more infrequently in brain tumors of childhood. It is hampered by the lack of extremely effective agents and a general reluctance to treat children vigorously. In most instances, it is applied only at the time of recurrence or as a desperation attempt to stem relentlessly progressing disease. 32 The value of corticosteroids in the treatment of intracranial tumor is established. By rapidly reducing cerebral edema associated with brain tumor, time is provided to obtain sophisticated neurodiagnostic studies, to carefully plan the therapeutic approach, and to operate under optimal conditions. No other drug has made as much of an impact on brain tumor therapy, yet its effect on brain tumor, per se, is not known, and its antineoplastic activity remains
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to be defined. Immunotherapy, although in its infancy, may some day playa definitive role in the oblation of residual tumor. 35 Coordinated studies taking into account selective criteria and concomitant or sequentially applied therapeutic modalities are just becoming a reality through the efforts of the Children's Cancer Study Group and the Radiation Therapy Oncology Group. Further carefully controlled studies need to be carried out in order to establish the best treatment criteria for children's brain tumor.
INCIDENCE, EPIDEMIOLOGY, AND NOMENCLATURE It is estimated that approximately 18 per cent of cancers in children under the age of 15 are tumors of the central nervous system. This is in comparison with 31 per cent who have leukemia and the 6 to 8 per cent who have Wilms' tumor, neuroblastoma, or lympho-proliferative disorders, respectively. As a group, brain tumors are reported slightly more frequently in males than females, and the peak age appears to be five to nine years, in contrast to the peak incidence at 50 to 60 years of age in brain tumors in adults. 20 In children, two-thirds of the intracranial tumors are beneath the tentorium, whereas in the adult population, only 1 of 10 tumors are infratentorial. Precise data as to histologic type and locational distribution are not always reported in children alone. Ependymomas, for example, may be found in both the supratentorial and infratentorial spaces, but frequently are reported as ependymoma only without an indication of location. Table 1 indicates an estimated occurrence rate derived from the literature. 3. 10, 20. 22, 23, 33 In some series, as many as 20 per cent of infratentorial tumors are unverified,20 whereas others report only verified (Le., operated upon) tumors. S
Table 1. Estimated Occurrence of Primary Intracranial
Tumors in Children TUMOR
I
I
Infratentorial Cerebellar astrocytoma Medulloblastoma Brainstem glioma Ependymoma Other TOTAL
Supratentorial Astrocytoma Ependymoma Malignant glioma Craniopharyngioma Other TOTAL
PERCENTAGE
20 18 10 8 10
66
8
6 6 5 8
33
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The etiology of brain tumor in children is not known. A few medulloblastomas and gliomas appear to be congenital by virtue of having become apparent within a few weeks of birth. 3! Some of the more dedifferentiated tumors seen particularly in infancy may well originate from primitive neuronal cell precursors. Unclear, however, is the relationship between histopathologically identical tumors seen in infants and adults (e.g., medulloblastoma). Although a wide variety of brain tumors may be created in experimental animals by chemical carcinogens, ionizing radiation, and oncogenic viruses, there is no evidence to date that these bear a significant cause and effect relationship in the human. The nomenclature utilized in the literature is variable in the precise terminology used. Often a tumor has mixed cellularity and is classified under the most prevalent cell type. In addition, there are subsets or variants which do not precisely fit a given designation. Finally, the clinical-histologic correlation is not always apparent. For purposes of simplicity, we use the common nomenclature, including variations. A great need exists to develop a universally agreed upon system of nomenclature which will allow classification and stratification and permit direct intercomparison between various studies. The reader is referred to the excellent classical monograph by Rubinstein for precise descriptions of these various tumors.3!
GENERAL SIGNS AND SYMPTOMS Children are generally more difficult to diagnose in that they may be noncommunicative as are infants, or present soft signs and symptoms which can be confused with the processes of growth and maturation, or brief self-limiting intercurrent disease. Virtually every symptom with which a child presents can be related to some specific event in the life of an active child. Thus, vomiting is frequently associated with "the flu." The alert clinician listening to the symptom complexes which present frequently is led to an earlier and prompter diagnosis. The clinical findings are basically dependent upon whether the tumor is diffuse, infiltrating, and directly interrupts neuronal function, oris predominantly more extraparenchymal leading to displacement of normal tissues. In virtually all cases, there are elements of both present. Symptoms, therefore, may be either generalized, as found in lesions causing obstruction to the flow of cerebrospinal fluid with resultant hydrocephalus, or they may be specific and localizing to the involved area of the brain. 34 ,37 Any localized tumor may increase in size to the point where its mass effect becomes predominant and impedes the flow of cerebrospinal fluid. The more contiguous with specific nuclei or identifiable areas within the brain a tumor may be, the more frequent the appearance of early symptoms and signs with specific localizing characteristics. Because the child's cranial vault can expand by spreading of the sutures, children appear to tolerate a comparatively "large" tumor burden. 37
Symptoms Headache is frequently seen in children with intracranial masses and increased intracranial pressure. 23 It often starts insidiously without a
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clear-cut onset, is intermittent being found more frequently on arising, and may become progressive. Headache in children should be considered as an important symptom because children infrequently complain of headaches that are not associated with organic disease. Vomiting is more frequently reported as the first symptom which precipitates action, as it is a specific dramatic event which calls attention to itself. Vomiting often occurs after the head has been in a dependent position (Le., following a night's sleep) and is not particularly associated with nausea. The patient may eat a normal meal shortly thereafter. Vomiting is seen in a variety of childhood diseases in which its character is to become progressive, to occur over a relatively short time frame, and to occur in association with the development of other diagnostic signs and symptoms as the disease process runs its natural course. Children with increased intracranial pressure will frequently show fatigability requiring longer naps, and may have a decrease in normal activity. There may be a discernible decrease in normally anticipated mental growth and, at times, it may appear as though the child's disposition has changed, or he has become more irritable. Although, at first, there may not be loss of weight, there may be a change in the normal weight gain pattern. The persistence of these general symptoms of increased intracranial pressure after a suspected infectious process ought to have passed should alert the clinician to the possibility of hydrocephalus. Seizure activity is seen in one-third of supratentorial lesions, but rarely in infratentorial tumors, and must be differentiated from convulsions secondary to other diseases.
Signs On occasion, the patient or parents will note strabismus or diplopia, usually secondary to lateral rectus palsy (sixth cranial nerve), indicating an immediate need for further diagnostic evaluation. Fundoscopic examination revealing papilledema provides a clear indication of increased intracranial pressure. Although it may be difficult in older infants, fundoscopic examination should be pursued as the finding of papilledema demands further evaluation. In infants, bulging of the fontanelle, rapidly increasing head circumference, and prominent venous patterns in the scalp all signal the need for further investigation. Patients with posterior fossa tumors may demonstrate disturbances which may be seen with any intracranial neoplasm; however, ataxia is more frequent with posterior fossa midline tumors. Paresis is not common with cerebellar tumors, but is found in one-half of patients with supratentorial and brain stem neoplasms. Although more difficult to elicit due to uncooperation, reflexes are often abnormal. Nystagmus, specific cranial nerve losses, and sensory disturbances all indicate more specific localized disease. The report of any of the above generalized signs and symptoms requires a very careful evaluation for specific signs which may lead to localization of the tumor, a preliminary diagnosis, and definition of the sequence of diagnostic procedures to follow.
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DIAGNOSTIC APPROACHES The neurologic examination in children with intracranial malignancies remains the single most important evaluation. The demonstration of positive findings will frequently indicate whether the lesion is infratentorialor supratentorial and the area of involvement. Negative findings on neurologic examination are equally as important to elicit in that the development of a sign which was not previously present indicates progressive disease. It is not infrequent that the suspicion of brain tumor is confirmed on the second examination, when original findings were thought to be due to intercurrent systemic disease. Diagnostic procedures may be classified as invasive or noninvasive. In either case, they are rendered more difficult to perform due to the inability of children to hold still during either frightening or painful procedures. It is, of course, more appropriate to proceed with the less traumatic procedures first. Computerized axial tomography (CAT, CT, EMI scan, etc.) has become a major reality in the armamentarium of the neurodiagnostician. 1Q ,15 In the course of a few moments, a computerized axial tomography scan can be performed which will evaluate the intracranial contents at various levels of both the supratentorial and infratentorial spaces, and calculate their specific densities. The effects of increased intracranial pressure and mass lesions can frequently be seen. If a mass is not defined and abnormal findings are present (such as enlarged ventricles), the addition of intravenous contrast medium will often delineate the tumor. Although equipment used for computerized axial tomography and the procedure itself are expensive, the wealth of information which it can supply, and the fact that it can be performed on an outpatient basis without invasion of the arterial system or cerebral spinal fluid space, places it very high on the list of useful procedures. The exact limits of computerized axial tomography, its level of accuracy, and its specific use in children remain to be defined; however, it should be seriously considered as the first and possibly the most useful diagnostic procedure.1 5 Plain skull films, in the past, have been considered to be the first diagnostic step. In children, these films can indicate the presence of chronic increased intracranial pressure by demonstrating the opening up of the cranial sutures or characteristic changes in the sella turcica. These may be due either to direct involvement of tumor or pressure from the dilated third ventricle above. In addition, slower growing tumors, such as ependymomas, may show calcification. The finding of the generalized effects of increased intracranial pressure on skull films indicates an absolute necessity for further diagnostic evaluation. Radionucleotide brain scanning (primarily technetium 99 ) is of particular value in identifying lesions located above the tentorium. Because of overlying structures, radionucleotide scanning is less satisfactory in infratentoriallesions, but frequently is capable of assisting in localization of a mass lesion. Radionucleotide scanning requires 15 to 30 minutes to perform and it is difficult for children to hold still for this period of time. N ewer techniques with radionucleotide scanning as well as computerized
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axial tomography are reducing the length of time to a matter of a few minutes, and therefore the chances for a successful scan will become greater. Electroencephalogram, considered an atraumatic and noninvasive diagnostic procedure, is frequently used in convulsive disorders. A normal electroencephalogram, however, should not be considered as indicating the absence of a tumor, particularly when other signs and symptoms indicate further work-up is warranted. Cerebral angiography has become a more sophisticated and precise procedure with the development of selective catheterization studies. In small children, however, these procedures are still difficult to perform and require anesthesia. It is frequently easier to obtain simultaneous multivessel studies. Angiography is still considered the mainstay of neurodiagnostic procedures, as it not only shows the displacement of normal vascular architecture, but the presence of abnormal tumor vessels, aneurysms, or vascular anomalies. Angiography of posterior fossa lesions is, again, not as precise as that for supratentorial lesions. However, with the addition of biplainar serial studies and the utilization of magnification and subtraction techniques, angiography allows for extremely sophisticated identification of microvasculature. Pneumoencephalogram, the first procedure to be utilized to identify intracranial displacement, has been gradually replaced by more sophisticated techniques. Nevertheless, the pneumoencephalogram is still extremely useful in defining intraventricular or paraventricular tumors, such as those which arise from the sella or encroach on the third or fourth ventricle. Pneumoencephalography is clearly an invasive procedure which should be reserved for those difficult diagnostic cases where previous studies have indicated definite but ill-defined abnormalities. If, on computerized axial tomography scan or angiography there is evidence of increased intracranial pressure, great caution should be taken in pursuing pneumoencephalography, and consideration should be given to ventriculography. This is particularly true when there is a high index of suspicion of a posterior fossa mass which will require surgical intervention. Lumbar puncture is considered to be at the bottom of the list of neurodiagnostic procedures and, as a rule, should not be carried out for the diagnosis of brain tumor. Only when there is serious consideration of bacterial meningitis or meningeal carcinomatosis, and there is no evidence on other studies of space-occupying tumor, should lumbar puncture be undertaken.
POSTERIOR FOSSA TUMORS The infratentorial brain volume is approximately one-tenth that of the supratentorial space. In addition, all the cranial nerve nuclei as well as cerebellar function are contained within it. Hence, considerably smaller lesions than those found supratentorially produce severe deficits when located in the posterior fossa.
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Cerebellar Astrocytomas Cerebellar astrocytoma is reported as 11 to 30 per cent of the brain tumors of children and has an estimated occurrence of 20 per cent. Seen slightly more frequently than medulloblastoma, it nevertheless is considered one of the most surgically successfully treatable tumors of children and is extremely rare in adults. 23 Patients with cerebellar astrocytoma often have a longer duration of symptoms prior to operation in comparison with other posterior fossa masses. Located within the cerebellar hemisphere, the localizing signs and symptoms will be ipsilateral incoordination, ataxia with a tendency to drift toward the side of the lesion, nystagmus with the slow component on ipsilateral gaze, and hyporeflexia on the side of the lesion. The diagnosis is made by the symptom complex seen and the demonstration of a cerebellar mass lesion on contrast study. Computerized axial tomography scans are clearly capable of showing the cystic component, thus increasing the preoperative diagnostic accuracy. Histologically, these tumors appear well differentiated as low grade astrocytomas with varying density of fibrillated cells and cystic areas. Approximately one-half contain a definitive mural nodule. 31 Astrocytomas ofthe cerebellum in children, as a group, are considered to be surgically treatable lesions. 2 • 12 Removal of the cyst and its mural nodule is curative in a large percentage of patients, or, at least, leads to long-term survival. 6 If subtotal excision is accomplished, the remaining tumor is slow-growing and does not appear to become more dedifferentiated with time. 31 When a cystic component is not present, or invasion of the peduncle, vermis, or brain stem is apparent, subtotal resection should be carried out. Because of the slow-growing nature of cerebellar astrocytomas and the possibility of surgical oblation, radiotherapy is not routinely carried out. However, in incompletely removed lesions or those invading vital structures, the addition of radiotherapy has provided a 64 per cent 10 year disease-free interva1. 33 Equally, long-term survivors, however, have been reported who did not have the benefit of radiotherapy. Therefore the role of radiotherapy in cerebellar astrocytoma is not clear.1 2 Because of the long-term survivals noted above, chemotherapy has not been utilized. Chemotherapy for recurrence of cerebellar astrocytoma or for those which appear to have a more malignant characteristic certainly should be considered, particularly at the first sign of recurrence.
Medulloblastoma Fifteen to twenty-five per cent of brain tumors in children are reported to be medulloblastomas with an estimated occurrence of 18 per cent. They occur virtually exclusively subtentorial, and are seen in males at least twice as frequently as in females. 4 • 37 They are found more frequently in infants than in older children, but extend through the adult years. Eighty per cent of these tumors occur in children under 15 years of age. Med ulloblastomas arise predominantly from the vermis of the cerebellum and grow mostly in the midline of young patients, whereas they appear to extend laterally more frequently in older patients. Medulloblastoma is
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thought to arise from germinative cells of the external granular layer of the cerebellum any time during its lateral migration. Tumors appear to arise from the vermis, fill and invade the fourth ventricle, and may extend laterally into the cerebellar hemispheres. It is a highly cellular tumor frequently in sheets of small cells with hyperchromatic nuclei and little cytoplasm. Mitotic figures may frequently be seen and "pseudorosettes" are seen in about one-third of cases. Medulloblastomas are infiltrating gliomas, invading the subarachnoid space and not infrequently the cerebrospinal fluid pathways leading to dissemination and metastases. The symptoms of medulloblastoma frequently include gait disturbances with truncal ataxia. A patient may be unable to sit without support; however, involvement of cranial nerves or nystagmus is rare, unless specific invasion has taken place. The nonspecific signs and symptoms of increased intracranial pressure may be present. Occasionally, patients present with dissemination in the cerebrospinal fluid and localized compressive lesions of nerve roots, the spinal cord, or the cerebral hemispheres. The diagnosis of medulloblastoma is suspected by the signs and symptoms presented, is enhanced by scans and air studies, but is confirmed only upon biopsy. It cannot be differentiated from other posterior fossa tumors prior to biopsy. The treatment of choice is judicious surgical reduction of the tumor burden wherever possible without invading the floor or the walls of the fourth ventricle. The historic operative mortality is approximately 20 per cent, whereas current surgical therapy has markedly reduced this. 4 , 5, 14 Metastasis within cerebrospinal fluid pathways is seen in one-third of cases. Radiotherapy is the treatment of choice following establishment of the diagnosis. 33 Treatment should include the entire neuraxis with 4500 to 5500 rads delivered to the posterior fossa and upper cervical cord, 3500 rads to the supratentorial contents, and 4000 rads to the spinal cord. Approximately 35 per cent of patients are disease-free at 5 years, and 25 per cent at 10 years. More aggressive therapy appears to be successful in significantly increasing survival rates. Chemotherapy has not been pursued in a coordinated fashion, and has been reserved for progressive and recurrent cases. 32 Medulloblastoma is felt to be a highly radiosensitive tumor and therefore may also be responsive to chemotherapeutic agents. Twenty-five per cent of recurrent medulloblastomas treated with the nitrosoureas (BCNU or CCNU) were considered to be responders, whereas 60 to 70 per cent of very small groups of patients treated with procarbazine, intrathecal methotrexate, or vincristine were considered to be responders. 32 Recurrent medulloblastoma with dropped metastasis in close continuity with cerebrospinal fluid pathways should be an ideal tumor for use ofintrathecal therapy.ltis also the custom to treat myelographically demonstrated metastasis with a limited area booster dose of radiotherapy. The response is frequently dramatic. Medulloblastoma has been reported to metastasize outside of the central nervous system more frequently than other gliogenous tumors. 31 With the increased use of preresection or postresection shunts to control the accumulation of cerebrospinal fluid, there appears to be an increased incidence of systemic and/or intraperitoneal seeding. 16 ,34 With the im-
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proved quality of life being demonstrated by judicious surgery and aggressive radiotherapy, care should be taken not to lose this advantage by unnecessary systemic seeding. Controlled studies in the treatment of medulloblastoma are extremely difficult to carry out due to: (1) a comparatively low incidence of medulloblastoma (4 per cent) in the general population; (2) the long and highly variable period of time to recurrence; (3) the different sites of recurrence; and (4) the difficulty of obtaining uniform agreement in grading, therapy, and follow-up among investigators. Considering the long-term survival of children with medulloblastoma and the considerable care placed on their treatment, rehabilitation, follow-up, and treatment after recurrence by physicians, specialists, and parents, a treatment protocol acceptable to many should be carried out. A carefully designed study by the Children's Cancer Study Group and the Radiation Therapy Oncology Group is evaluating radiotherapy versus radiotherapy and vincristine followed by eight cycles of prednisone, vincristine, and CCNU. Upon recurrence, the patient will receive procarbazine or vincristine, CCNU, and procarbazine dependent upon prior treatment. Data from this important study will take several years to accrue.
Brainstem Glioma Included in this group are gliomas of the pons and medulla. These lesions are frequently the smallest cancers seen, as they are intrinsic to the brains tern and in close continuity with ascending and descending pathways as well as cranial nerve nuclei. They are reported in 8 to 20 per cent of patients, with an expected occurrence of 10 per cent without unusual male, female, or age ratios. Because of their anatomic location, insidious onset of cranial nerve dysfunction, long track involvement, and ataxia with infrequent evidence of increased cranial pressure are seen.2S Gait disturbance is the most common symptom followed by seventh nerve involvement, in turn followed by involvement of the sixth, ninth, and tenth cranial nerves, and a sensory portion of the fifth nerve. Long track signs, such as extensor plantar responses and reflex abnormalities, are frequently seen. 19 Localized cranial nerve findings, in the absence of the generalized signs and symptoms of increased intracranial pressure, strongly indicate brainstem glioma. Such findings, however, may be confused by rather marked laterality, and extension toward the cerebellum or fourth ventricle. The diagnosis of brains tern glioma is made by demonstrating the size, shape, and configuration of the brains tern by air encephalography or positive contrast studies demonstrating characteristic enlargement of the pons with posterior bowing of the aqueduct and displacement ofthe fourth ventricle. The diagnosis is primarily neuroradiologic and, hence, the computerized axial tomography scan should be ofconsiderable value. Not infrequently, the symptom complex and neurodiagnostic studies will be suggestive of a mass lesion not solely confined to the brainstem, therefore surgical exploration is indicated. Histologically, gliomas of the brainstem show a wide variety of pathology from frank glioblastoma multiforme to low grade astrocytoma. 13 There appears to be correlation between the
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rapidity of development of symptoms and duration of survival with the degree of anaplasia. Surgical exploration of brain stem glioma should be restricted to those cases in which the neuroradiologic diagnosis is not clear-cut, or where there may be evidence of a cyst which could be evacuated. Differentiation in cases with atypical neurodiagnostic findings cannot be made from medulloblastoma, ependymoma, or cerebellar astrocytomas with brainstem extension. In those cases in doubt, exploration with visualization and selective biopsy, if possible, should be undertaken. Radiotherapy of brainstem tumors is the treatment of choice and, on occasion, can be extremely gratifying as progressive cranial nerve signs and symptoms remit. Standardized doses of 5000 to 5500 rads over 5 to 6 weeks with 180 rads per fraction have been successfully utilized. Patients with low grade astrocytoma so treated have a median survival of three to five years, whereas those with more malignant-appearing brainstem tumor will have a median survival of only a few months. l3 • 33 Symmetrically located brainstem gliomas rarely produce obstruction to the flow of cerebrospinal fluid, thus increased intracranial pressure requiring shunting is not frequently seen. As with many other posterior fossa tumors, chemotherapy of brainstem glioma is usually not carried out until recurrence following radiotherapy is evident. 32 Considering the histologic similarity between brainstem gliomas and those found within the cerebral hemispheres, it would be reasonable to anticipate that those agents efficacious in treatment of supratentorial masses should also be effective in brainstem gliomas. Thirty per cent of 23 patients treated with the nitrosoureas (BCNU and CCNU) responded primarily by stabilization of progressive disease or, in some cases, improvement. A single case has been reported to respond to procarbazine. 32 • 36 Because the brainstem is intimately bathed in cerebrospinal fluid, it is ideally located for intrathecal therapy. The penetration of but a few millimeters should be able to provide cytotoxic concentrations of drug to active tumor. Intrathecal methotrexate has been utilized with five of six patients responding. Detailed studies utilizing this potentially promising mode of therapy have not been carried out. High dose systemic methotrexate, followed by leucovorin rescue, resulted in a remarkable shrinkage of tumor which was sustained for over six months. 30 Since the blood-brain barrier is disrupted in the area of active tumor growth, it can be postulated that high concentrations of methotrexate would be found within the immediate tumor area. As with other childhood brain tumors, determination of the efficacy of specific modalities in the treatment of brainstem glioma awaits more carefully designed studies.
Ependymoma (Infratentorial) Ependymoma of the posterior fossa of children occurs in about 8 per cent ofpatients. l • 23 It not infrequently arises in the region of the obex and, consequently, causes the generalized signs and symptoms of increased intracranial pressure noted above. Ependymoma may be difficult to differentiate grossly from medulloblastomas or other tumors existing within the fourth ventricle. Ependymomas tend to enlarge slowly as cir-
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cumscribed lesions which may grow through the cisterna magna and encroach upon the cervical cord. They are modestly cellular with polygonal or effusive formed cells, irregular nuclei, and a tendency to form ependymal rosettes. Mitotic figures are rare, calcification occasional, and necrosis uncommon. The diagnosis is most frequently made on histopathology. The treatment of infra tentorial ependymomas is careful surgical resection, leaving the fourth ventricle intact, followed by radiotherapy. Shunting to control hydrocephalus prior to surgical resection is fraught with the problems noted in medulloblastoma above.1 6 • 34 Ependymomas are considered to be highly radiosensitive and therefore incomplete resection should be followed by radiotherapy.1 Despite being within the cerebrospinal fluid pathways, they do not frequently metastasize unless they show poor differentiation and a high grade of malignancy. Radiotherapy to the posterior fossa for those of low grade appears to provide adequate control with approximately 80 per cent five year surviva1. 33 Ependymomas with more malignant characteristics or with evidence of spinal seeding, should have neuraxial irradiation. 29 More aggressive therapy is probably indicated in this disease. l l Too few patients with ependymoma have been treated with chemotherapy in order to draw any conclusions as to its efficacy. A few instances have been gleaned from the literature where patients have responded to the nitrosoureas or epipodophyllotoxin. 32
SUPRA TENTORIAL TUMORS Astrocytomas and Malignant Glioma Astrocytomas are estimated to occur in approximately 8 per cent of children, whereas more malignant tumors are seen in only 5 per cent. These lesions may be located any place within the cerebral hemisphere, and may often produce signs and symptoms of increased intracranial pressure or have their appearance heralded by focal or nonspecific convulsions. Specific symptoms are referable to the hemisphere and location of predominant involvement. The diagnosis has been made in the past by ventriculography and arteriography, and more recently by use of the computerized axial tomography scan. Astrocytomas may be cystic containing large quantities offluid. Due to the expansive nature of children's skulls, these lesions may reach a large size before becoming apparent. Histologically, the full range of malignancy may be seen, although it is more common to have low grade astrocytomas with cystic components in children. Treatment is surgical to provide a diagnosis and reduce the tumor burden. Because of the relative infrequency of these tumors in children, the value of radiotherapy has not been defined and chemotherapy has been little explored. 9 However, it is apparent that modest palliation may be obtained by use of 5000 to 6000 rads. 33 Deep astrocytomas in and around the third ventricle and involving the thalamus, hypothalamus, and midbrain are not amenable to surgical therapy at all, and upon establishing a reasonable probability of diag-
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nosis, radiotherapy should be undertaken. The use of chemotherapy for hemispheric tumors in children has been undertaken only occasionally, and should be pursued more vigorously.
Ependymoma (Supratentorial) Ependymomas of the cerebral hemisphere presumably arise from the ependyma of the ventricles and are seen in 5 to 6 per cent of patients with brain tumors. They may appear to be encapsulated and have a cystic component. They may be distant from or encroach upon the ventricle. By pneumoencephalography or angiography, they may not be distinguished from astrocytoma. However, occasionally they show calcification which may be found on plain skull films or more eloquently, on computerized axial tomography scan. Judicious resection of ependymomas of cerebral hemispheres should be undertaken where it will not interfere with vital structures. IS Ependymomas are considered to be radiosensitive tumors, therefore vigorous radiotherapy should be considered. 29 Patients with ependymomas ofthe cerebral hemispheres appear to have a better survival rate than those with ependymomas below the tentorium; ependymomas of the cerebral hemispheres are not noted to seed the cerebrospinal fluid pathways. 33 The quality of life following re section and irradiation of supratentorial ependymomas which do not involve vital structures is considered to be excellent.
Craniopharyngiomas Craniopharyngiomas are not frequently seen in children and account for an estimated 4 per cent of the brain tumors in children. The most common signs and symptoms are increased intracranial pressure and visual loss. Diabetes insipidus is rarely seen.24 Supracellar calcification is frequently seen, as are abnormalities of the sella turcica. Diagnosis may be confirmed by air study, angiography, or more recently by computerized axial tomography scans. From the histopathologic point of view, craniopharyngiomas are considered to be benign; yet, because of their location and difficulties of surgical exposure, as well as their close continuity with vital structures, craniopharyngioma should be considered an extremely difficult disease to manage surgically.3 The use of meticulous technique, steroid replacement, and the control of diabetes insipidus, should it occur, have led to better results. 24 More careful preparation of the patient, conservative retraction of the brain, and the magnification provided by the operating microscope have allowed surgeons to more carefully approach these tumors, resect major portions, or, at least, provide drainage and decompression. Total excision is frequently difficult without serious consequences. The combination of aspiration or excision, followed by radiation, has led to excellent results in the treatment of patients with craniopharyngiomas of all ages; however, the specific results of children have not been reported. 3 Reoperation upon these patients is often considered necessary for further decompression, but is fraught with increased postoperative morbidity.24
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Other Tumors (Mixed Location) A variety of other infratentorial tumors, such as choroid plexus papillomas, dermoids, and a large percentage of unverified posterior fossa tumors reported in the literature, should be approached through the usual diagnostic armamentarium with the hope of uncovering either a surgically resectable lesion, or one which will be considered as having radiosensitive elements. Failure to examine closely the diagnostic studies on these patients and judiciously explore those in whom there is reasonable hope of success will not allow enlightened future therapy to be provided. Gliomas of the anterior visual pathway are a rare entity in which the optic nerve, optic chiasm, or both may be involved and are found in association with neurofibromatosis. Symptoms depend upon the area of involvement with visual loss found in all cases, ptosis being seen only in optic nerve gliomas, and hypothalamic dysfunction being found with optic chiasm gliomas. Gliomas of the optic nerve are more confined, are frequently surgically accessible, and have a favorable prognosis. Gliomas involving the chiasm or both the optic nerve and chiasm frequently invade the hypothalamus and structures around the third ventricle and have a much poorer prognosis,15 There is no consistent opinion concerning the value of radiotherapy. Oligodendroglioma, very rarely seen in children, is a variant of malignant gliomas, which usually grow slowly, develop calcification, may be subtotally surgically resected, and may be treated with radiotherapy.2o.26 Upon recurrence, reoperation should be considered in favorably located tumors. Pineal germinomas, also rarely seen in children, present a unique problem by virtue of their location and varying cellular components. 31 They are seen in older children, predominantly males, more frequently in the Japanese, and present as mass lesions causing increased intracranial pressure. 26 They may obstruct the flow of cerebrospinal fluid, produce anterior hypothalamic involvement, or upper brain stem dysfunction with paralysis of conjugate upward gaze (Parinaud's syndrome), pupillary reaction to accommodation but not light, and loss of convergence. Surgically difficult to approach, tumors in the pineal region are often treated by cerebrospinal fluid shunting and radiotherapy to which they are often extremely sensitive. There is also a wide variety of tumors of the central nervous system which are of mal development in origin. 31 By their very nature, these are more frequently seen in children, and are midline and supratentorial. The most commonly reported are teratomas, dermoids, and epidermoid cysts. In addition to these tumors, a comparatively large percentage of tumors of the central nervous system in childhood are not histopathologically diagnosed. 20 Therefore therapeutic approach by classification is extremely difficult. CONCLUSION The availability of hard correlatable data in the treatment of pediatric brain tumors is discouraging. The reasons for the paucity of information relates to the comparatively few tumors treated per year by each hospital
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and center, changes in equipment and approach, and lack of uniform criteria for diagnosis, staging, and response. There are not many choices for the future. We can continue to treat patients as we have in the past and continue to achieve that degree of success. On the other hand, we can outline a logical and sequential program designed to provide basic data on brain tumors in children in such a way as to be able to characterize their biologic behavior, determine predictive criteria, correlate histopathologic and biochemical parameters, and develop a powerful flexible data base. While accumulating this information, the currently acceptable modes of treatment (surgery and radiotherapy) can be more clearly defined and categorized in order to give quantitative rather than qualitative results. Chemotherapeutic study designs, so successful in the treatment of leukemia, neuroblastoma, and other tumors of childhood, must be modified and applied to the treatment of intracranial malignancy. In order to accrue sufficient patient material, many clinicians will have to establish common principles. This does not require that the physician abandon his rights to treat the patients as he deems best, but is a more honest statement of the fact that we do not know the best ways of treating intracranial malignancy in children. Such approaches in the past have been said to lead to the least common denominator of acceptable therapy. This will only occur if the participants permit it to happen. The time frame in which such studies can be carried out and over which improvement can be anticipated is indeed long, but is, nevertheless, considerably shorter than continuing with individual therapeutic approaches. The treatments proposed should become at least as aggressive as the disease. We should not shirk from developing the necessary diagnostic information, applying vigorous therapy, and utilizing costly follow-up approaches, so long as the expected cost-benefit ratio is in the patient's favor and to the tumor's detriment. Whether we will continue our experience of the last four decades, or will take the necessary steps to move forward in improving the quality and quantity of survival, remains to be seen.
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