Glioblastoma multiforme in children
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1 GEOI~CE J. DOHRMANN, M.D., ProD., JACQUELINE R. FARWELL, M.D., AND JOHN T. FLANNERY, B.S. Sections of Neurosurgery and Neuropathology. and Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut Of 488 children with central nervous system neoplasms, 43 (8.8%) had glioblastomas, 22 of which were in the cerebral hemispheres, 16 in the brain stem, two in the cerebellum, and three in the spinal cord. The male to female ratio was 3:2. Glioblastoma multiforme of the cerebral hemispheres occurred at a mean age of 12.7 years, and the frontal lobe was the most commonly involved. Main presenting symptoms included headache (85%), nausea or vomiting (65%), and seizures (35%). Papilledema (45%) was the most common physical finding. The longest survivals were achieved by a combination of operation and radiation (22 months). Brain stem glioblastomas occurred at a mean age of 6.7 years, with the pons as the most frequent site. Nausea or vomiting (50%) and headache (36%) were the main presenting symptoms; the major physical findings were ataxia (43%), cranial nerve palsies (28%), and paresis (28%). The length of survival was greatest with radiation alone (10.5 months). The period of survival of children with glioblastoma multiforme was significantly increased with steroid therapy. Glioblastoma multiforme behaves similarly in children and adults. Intracranial glioblastomas have a more rapidly fatal course than that of other similarly situated gliomas in childhood. KEy WoRos 9 glioblastoma multiforme 9 childhood glioblastoma 9 brain tumor 9 spinal cord tumor TABLE 1 LIOBLASTOMA multiforme occurs less,~ often in children than in adults., 8 38 Incidence ofglioblastoma multiforme in In large series of patients with children reported in nine large series glioblastomas, less than 3% occurred in Author, Total Children children (Table 1). Glioblastomas accounted Year Cases No. 7o for approximately 7% of all intracranial neoplasms of childhood (Table 2). Because Busch & Christensen, the number of glioblastoma patients younger Davis, et al., than 20 years of age is so small, the natural LCken, history and survival of children with Marsh, glioblastoma multiforme have not been well Earle, et al., documented. Frankel & German, The purpose of the present study is to Bouchard & Pierce, review and analyze cases of glioblastoma 1960 multiforme that have occurred in children in Taveras, et al., Connecticut during a 39-year period (1935 to Jelsma & Bucy, ). total J. Neurosurg. / Volume 44 / April, 1976
2 Materials and Methods The files of the Connecticut Tumor Registry, 7 which contain reports of all diagnosed cancer patients in Connecticut hospitals and their lifelong follow-up, were searched for cases of histologically confirmed glioblastoma multiforme occurring in persons younger than 20 years of age over a 39-year period (1935 to 1973). Each case was analyzed in relation to age, sex, location of neoplasm, date of onset of symptoms, date of diagnosis, presenting symptoms, main physical findings, treatments, and period of survival after diagnosis. In instances where the diagnosis of glioblastoma multiforme was not made by a neuropathologist, the slides, when available, were reviewed by one of the authors. TABLE 2 b~cidence of glioblastoma multifi)t~te in 18 large series oj' #ltracranial neoplasms i~t children* Author, Age Total Glioblastomas Year (yrs) Neoplasms No. '~ Cushing, 1927 < t 4.8t Z(ilch, 1937 < Bailey, et al., < French, 1948 < Keith, et al., < Walker & < Hopple, 1949 L~bken, 1952 < Miller, et al., <15 (189{) { Bodian & < 12 (129w --w --w Lawson, 1953 Odom, et al., < Katsura, et al., < Troupp, 1960 < Backus & < l0 3.4 Millichap, 1962 Low, etal., <17 (12l**) (14"*) (I 1.6"*) 1965 MacKay & < Sellers, 1968 Matson, 1969 < Koos & Miller, <t Farwell & < Dohrmann, 1975 total * Series containing more than 100 primary intracranial neoplasms in children excluding "tumors" such as abscess, tuberculoma, aneurysm, arteriovenous malformation, parasite inclusion. t Listed as "spongioblastoma group;" term "glioblastoma multiforme" not yet used. { Supratentorial neoplasms only. No incidence of glioblastoma multiforme given. w Unable to determine from classification system how many glioblastomas in series. ** Supratentorial neoplasms only. Results Of a total of 488 central nervous system neoplasms in children, 43 glioblastomas (8.8%) were noted. Forty occurred intracranially (8.6% of childhood intracranial tumors), and three glioblastomas were intraspinal. The male to female ratio was 3:2. Thirty-four children were treated with operation and/or radiation and nine children were not treated. All affected children have died (Table 3). TABLE 3 Clinical summary in 40 children with glioblastoma multiforme Intracranial Cere- Intra- Total bral Brain Cere- spinal Hemi- Stem bellum spheres no. of cases sex" male female mean age (yrs) survival: onset to diagnosis (mean, wks) diagnosis to death (mean, mos) at 1 yr 30% 45~ 6~ 50~ 0% at 2 yrs 8~ 9% 6~ 0~ 0~ treatment: operation radiation both none survival (mos): operation radiation both none J. Neurosurg. / Volume 44 / April
3 G. J. Dohrmann, J. R. Farwell and J. T. Flannery FIG. 1. Graph showing the occurrence by age of intracranial glioblastoma multiforme in children. Two peaks are noted: one in the first decade and one in the second decade of life. TABLE 4 Symptoms of childhood glioblastoma All Cerebral Intracranial Hemispheres Brain Stem Symptoms ( % of 40 ( ~ of 22 ( ~ of Cases) Cases) 16 Cases) headache nausea/vomiting paresis diplopia seizures ataxia lethargy dysarthria meningismus FI~. 2. Graph showing age at diagnosis by location of glioblastoma multiforme in children. Those located in the brain stem occur earlier (mean age, 6.7 years) than those in the cerebral hemispheres (mean age, 12.7 years). FIG. 3. Graph showing survival time from diagnosis in children with intracranial glioblastoma multiforme. Only one-third of the children were alive 1 year after diagnosis. Intracranial Glioblastomas A diagnosis of intracranial glioblastoma was made in 40 children ranging in age from 3 weeks to 19 years, with a mean age of 10 years (Figs. 1 and 2). A slight male predominance was observed. No preferential side of occurrence was noted. Headache and nausea or vomiting each occurred in over half of the patients, while diplopia and paresis each were present in one fifth of the patients (Table 4). The mean duration of symptoms before diagnosis was 10 weeks (Table "3). Physical findings included papilledema in one third of the patients, and cranial nerve palsies and paresis, each in approximately one fourth (Table 5). The mean survival period from diagnosis was 10.8 months. Of the 12 children diagnosed prior to 1962, when dexamethasone came into use for treating patients with central nervous system neoplasms, 17a~ only one lived a year and the mean survival period was 4.6 months. Since 1962, 11 of 28 children survived 1 year and the mean survival was 13.6 months (Table 3 and Fig. 3). Cerebral Hemispheres. Glioblastomas of the cerebral hemispheres occurred in 22 children, at a mean age of 12.7 years. The male to female ratio was 1:1 (Table 3). Most of the neoplasms were located in the frontal or parietal lobes with no predilection as to side (Fig. 4). Presenting symptoms are shown in Table 4, and physical findings in Table 5. The mean time from onset of symptoms to diagnosis was 12.7 weeks. Ten of the 22 children were alive after 1 year, one lived 10 years. The mean survival time from diagnosis was 14.5 months (Fig. 5), and was longest for patients treated with a combination of operation and radiation (Table 3). Brain Stem. The mean age of presentation in the 16 children with glioblastoma of the brain stem was 6.7 years, and the mean time from onset of symptoms to diagnosis was 7.3 weeks. There was a slight male predominance (Table 3). Most of the neoplasms were 444 J. Neurosurg. / Volume 44 / April, 1976
4 TABLE 5 Physical findings in childhood glioblastoma Findings All Cerebral [ntracranial Hemispheres Brain Stem (/o ~ of 40 ( To of 22 ( ~ of Cases) Cases) 16 Cases) papilledema paresis cranial nerve 23 2t) 28 palsies lethargy ataxia 1 s 0 43 nystagmus located in the pons (Fig. 4). Presenting symptoms are given in Table 4, and physical findings in Table 5. Only one child (6%) was alive at 1 year (Fig. 5). The mean survival from diagnosis was 6 months, with the longest average survival (10.5 months) in those children who were treated with radiation alone (Table 3). Cerebellum. Cerebellar glioblastoma occurred in two boys with a mean age of 5 years. Both children complained of ataxia, nausea or vomiting, diplopia, and paresis. The major physical finding was ataxia. The time from onset of symptoms to diagnosis was 3 weeks. One child was treated by operation and radiation and the other child was not treated. The mean survival was 9.5 months from diagnosis (Table 3). lntraspinal Glioblastomas Three primary glioblastomas of the spinal cord were noted, one in the cervical and two in the thoracic regions. All were in boys with a mean age of 12 years. Paresis and paresthesiae were the presenting symptoms and also the main physical findings. The time from onset of symptoms to diagnosis was 17.3 weeks; 3.3 months elapsed from diagnosis to death. One child was treated by operation and the other two by operation and radiation (Table 3). Discussion Glioblastoma multiforme, the most malignant of the neuroepithelial neoplasms, is characterized by cellular pleomorphism, numerous mitotic figures, and often mul- Fro. 4. Diagrams showing the location of intracranial glioblastoma muitiforme in children. The frontal lobe and the pons are most commonly involved. FIG. 5. Graph showing that glioblastoma multiforme of the brain stem is more rapidly fatal (mean survival, 6.0 mos) than that of the cerebral hemispheres (mean survival, 14.5 mos). FIG. 6. Graph showing incidence of glioblastoma multiforme in children in Connecticut. A peak occurrence was noted in the mid-1960's. tinucleated giant cells. Proliferation of the vascular endothelium is seen as well as areas of necrosis with circumjacent pseudopalisading of the neoplastic cells. In large series of glioblastomas, only 2.6% (0.6% to 7.9%) of the cases have been reported in children (Table 1). Glioblastoma multiforme constitutes 6.5% (1.9% to 10.7%) J. Neurosurg. / Volume 44 / April,
5 of childhood intracranial neoplasms (Table 2). In the present series, glioblastomas accounted for 8.8% of central nervous system neoplasms and 8.6% of intracranial neoplasms in children. Approximately one case of childhood glioblastoma is reported each year in Connecticut. During the mid-1960's a peak of childhood glioblastomas was noted (Fig. 6). The affected children were from different geographical areas in the state and were diagnosed and treated at various Connecticut hospitals. It is doubtful that this peak represents an increased recognition of this neoplasm because the incidence has not remained that high since; therefore, the reason for the peak in incidence is unclear. As in glioblastomas of adults, ~,ss the overall male to female ratio in children was 3:2. In adults, glioblastomas are noted most frequently in the frontal lobe, with the temporal lobe second in frequency. "'8~ Childhood glioblastomas of the cerebral hemispheres were also located most often in the frontal lobe; with the second most frequent site being the parietal lobe (Fig. 4). Koos and Mille~ 3 deny any lobe predominance in childhood glioblastoma, and Escalona-Zapata 13 describes six cases, all located in the temporal or temporoparietal regions. Dohrmann and Dunsmore ~ reviewed glioblastoma multiforme of the cerebellum and noted that it is rare in adults or children; however, two cases occurred in this series. Primary glioblastoma of the spinal cord in childhood has been reviewed by Arumugasamy and Tarkington, ~ who reported only 10 cases, most of which involved the cervical spinal cord. Three such spinal cord glioblastomas were noted in the present study. Glioblastoma multiforme in children appears to have two characteristic courses, each of which is related to location of the tumor. Glioblastomas of the brain stem, a more primitive part of the central nervous system, occurred at a younger age (6.7 years) and had a shorter mean survival (6 months) relative to those of the cerebral hemispheres (Figs. 2 and 5). Glioblastoma multiforme of the cerebral hemisphere, a more highly developed part of the central nervous system, was characterized by onset in older children (12.7 years) and by a longer mean survival (14.5 months) (Figs. 2 and 5). Interestingly, Matson 29 noted a peak incidence of cerebral G. J. Dohrmann, J. R. Farwell and J. T. Flannery hemisphere gliomas at the age of 2 years while that for gliomas of the brain stem was at 7 years. Separation of glioblastoma multiforme from this group of gliomas was not done, however. Headache was the most common complaint and papilledema was the most common physical finding in children with hemisphere glioblastomas. Seizures were noted in one third of the children. These symptoms and findings are in agreement with those of hemisphere gliomas in general." Children with glioblastoma multiforme of the brain stem often presented with nausea or vomiting, ataxia, cranial nerve palsies, and paresis, which is consistent with the reports of Matson" and Panitch and Berg s~ in series of brain-stem gliomas in childhood. In adults, glioblastoma multiforme usually occurs in the cerebral hemispheres? 7 Jelsma and Bucy l''2~ found that the longest survivals occurred in adults treated by both operation and radiation. In one study, TM they obtained the following survivals: 80% at 6 months, 40% at 1 year and 18% at 2 years. Likewise, in the present series of cerebral hemisphere glioblastomas in children, the longest survivals were obtained by a combination of operation and radiation: 83% at 6 months, 67% at 1 year and 17% at 2 years. In this regard the glioblastomas of childhood are quite similar to their adult counterparts (Table 6). Relative to cerebral hemisphere astrocytomas in childhood, the glioblastomas of the cerebral hemispheres have quite a different prognosis. Gol as reported a mean survival of 5.2 years in children operated on for hemisphere astrocytomas (Grades I and II), while the longest average survival (opera- TABLE 6 Adult versus childhood survival with optimal treatment in glioblastoma patients* %of %of Survival Adults Children 6mos mos mos * Operation and radiation of glioblastoma multiforme of the cerebral hemispheres. The adult series was reported by Jelsma and Bucy, TM and is compared with the present series of children. 446 J. Neurosurg. / Volume 44 / April, 1976
6 tion and radiation) for glioblastoma of the hemisphere was less than 2 years in the present series. The longest survival in glioblastoma of the brain stem was in the group of children treated by radiation alone (10.5 months). This was considerably less than the survival of 47.2 months noted in childhood gliomas of various types treated by radiation alone? ~ The more rapid course of the glioblastomas of the brain stem is also apparent in survivals of untreated children: 2.0 months in this series as compared to 15.5 months in the brain-stem glioma series of Panitch and Berg? 2 Survivals of children with glioblastoma multiforme of either the cerebral hemispheres or the brain stem were significantly increased after the advent of dexamethasone therapy. In summary, glioblastoma multiforme behaves similarly in children and adults. The course of intracranial glioblastomas in children is more rapidly fatal than that of other similarly situated gliomas in childhood. References 1. Arumugasamy N, Tarkington JA: Primary glioblastoma multiforme of the spinal cord in infancy and childhood. Med J Malaysia 27: , December, Backus RE, Millichap JG: The seizure as a manifestation of intracranial tumor in childhood. Pediatrics 29: , Bailey P, Buchanan DN, Bucy PC: Intracranial Tumors of Infancy and Childhood. Chicago: University of Chicago Press, Bodian M, Lawson D: The intracranial neoplastic diseases of childhood. A description of their natural history based on a clinicopathological study of 129 cases. Br J Surg 40: , Bouchard J, Pierce CB: Radiation therapy in management of neoplasms of central nervous system, with a special note in regard to children: twenty years' experience, Am J Roentgenol Radium Ther Nucl Med 84: , Busch E, Christensen E: The three types of glioblastoma. J Neurosurg 4: , Connelly RR, Campbell PC, Eisenberg H: Central registry of cancer cases in Connecticut. US Public Health Serv Public Health Rep 83: , Cuneo HM, Rand CW: Brain Tumors of Childhood. Springfield, Illinois: Charles C Thomas, 1952, pp Cushing H: The intracranial tumors of preadolescence. Am J Dis Child 33: , Davis L, Martin J, Goldstein SL, Ashkenazy M: A study of 211 patients with verified glioblastoma multiforme. J Neurosurg 6:33-44, Dohrmann G J, Dunsmore RH: Glioblastoma multiforme of the cerebellum. Surg Neuroi 3: , Earle KM, Rentschler EH, Snodgrass SR: Primary intracranial neoplasms. Prognosis and classifications of 513 verified cases. J Neuropathol Exp Neurol 16: , Escalona-Zapata J: Das undifferenzierte Glioblastom des Kindesalters. Zbl Neurochir 28: , Farwell JR, Dohrmann G J: Central nervous system tumors in children. Presented at the First International Congress of Child Neurology, Toronto, Canada, October 7, Frankel SA, German W J: Glioblastoma multiforme. Review of 219 cases with regard to natural history, pathology, diagnostic methods, and treatment. J Neurosurg 15: , French LA: Brain tumors in children. Minu Med 31: , Galicich JH, French LA: Use of dexamethasone in the treatment of cerebral edema resulting from brain tumors and brain surgery. Am Pratt 12: , Gol A: Cerebral astrocytomas in childhood. A clinical study. J Neurosurg 19: , Jelsma R, Bucy PC: Glioblastoma multiforme: its treatment and some factors effecting survival. Arch Neurol 20: , Jelsma R, Bucy PC: The treatment of glioblastoma multiforme of the brain. J Neurosurg 27: , Katsura S, Suzuki J, Wada T: A statistical study of brain tumors in the neurosurgical clinics in Japan. J Neurosurg 16: , Keith HM, Craig W McK, Kernohan JW: Brain tumors in children. Pediatrics 3: , Koos WT, Miller MH: Intracranial Tumors of Infants and Children. St. Louis: CV Mosby, L~ken AC: Histological grouping of brain tumors in a 10 years material. Acta Pathol Microbiol Scand [Suppl] 93: , Low NL, Correll JW, Hammill JF: Tumors of the cerebral hemispheres in children. Arch Neurol 13: , MacKay EN, Sellers AH: Malignant neoplasms of the central nervous system, Ontario Cancer Foundation Clinics, Can Med Assoc J 99: , Manuelidis EE, Solitare GB: Glioblastoma multiforme, in Minckler J (ed): Pathology of the Nervous System, vol 2, New York: McGraw-Hill, 1971, pp J. Neurosurg. / Volume 44 / April,
7 G. J. Dohrmann, J. R. Farwell and J. T. Flannery 28. Marsh JS: Necropsy incidence of glioblastoma multiforme with reference to its age and sex occurrence in series of 423 intracranial gliomas verified at autopsy. Bull Los Angeles Neurol Soc 21:27-29, Matson DD: Neurosurgery of Infancy and Childhood. Springfield, Illinois: Charles C Thomas, Miller RH, Craig W McK, Kernohan JW: Supratentorial tumors among children. Arch Neurol Psychiatry 68: , Odom GL, Davis CH, Woodhall B: Brain tumors in children: clinical analysis of 164 cases. Pediatrics 18: , Panitch HS, Berg BO: Brain stem tumors of childhood and adolescence. Am J Dis Child 119: , Rubinstein L J: Tumors of the central nervous sytem, in: Atlas of Tumor Pathology, Second Series, Fascicle 6. Washington, DC: Armed Forces Institute of Pathology, 1972, pp Russell DS, Rubinstein L J: Pathology of Tumours of the Nervous System, ed 3. London: Edward Arnold, 1971, pp Taveras JM, Thompson HG Jr, Pool JL: Should we treat glioblastoma multiforme? A study of survival in 425 cases. Am J Roentgenol Radium Ther Nuci Med 87: , Troupp H: Pathology, diagnosis, and treatment of supratentorial tumours in infancy and childhood. Ann Pediatr Fenn 6:21-33, Walker AE, Hopple TL: Brain tumors in children. 1. General considerations, d Pediatr 35: , Z~lch K J: Brain Tumors: Their Biology and Pathology, ed 2. Rothballer AB, Olszewski J, translators. New York: Springer-Verlag, Z~ilch K J: Zur Histopathologie der Grosshirngliome in den ersten beiden Lebensjahrzehnten. Z Neurol Psychiatr 158: , 1937 This paper was presented in part at the annual meeting of the American Association of Neurological Surgeons, Miami, Florida, on April 8, This work was supported in part by Grant NS from the National Institute of Neurological and Communicative Disorders and Stroke. Address reprint requests to: George J. Dohrmann, M.D., Ph.D., Sections of Neurosurgery and Neuropathology, Yale University School of Medicine, New Haven, Connecticut J. Neurosurg. / Volume 44 / April, 1976
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