ANNALS O F CLIN ICA L AND LABORATORY SC IEN C E, Vol. 21, No. 1 Copyright © 1991, Institute for Clinical Science, Inc.

Brain Tumors in Children: A Review* ALVARO LACAYO, M .D .,t and PE T E R M. FARM ER, M .D 4 Departments o f Neurology f and Pathologyt, North Shore University Hospital and Department o f Pathologyt, Cornell University Medical College Manhasset, N Y 11030

ABSTRACT Brain tum ors are the second m ost comm on malignancy of children. In contrast to adults, childhood brain tum ors are usually of glial origin; m etastases and meningiomas are rare. Some tumors, i.e., medulloblastomas, are found almost exclusively in children. The posterior fossa is the most frequent site of occurrence. T he prognosis for childhood neoplasms tends to be m ore favorable than in adults, and some lesions are curable. New techniques, including im m unostaining, tum or m arkers, and cyto­ genetics, have im proved diagnostic accuracy. A review of some of the most im portant brain tumors of children is p resented along with an upgrade on recent developm ents in diagnoses and treatm ent.

Introduction In tra cra n ia l tum ors are th e second m ost com m on group of neoplasm s in children, exceeded only by the leukem ias .9 The estim ated incidence of brain tum ors in patients u n d er 15 years of age ranges from 2.5 to 3.5 per 100,000 .29,50 T here is distinct familial tren d in pediat­ ric brain tum ors. The inherited neurocuta n e o u s d iso rd e rs are reg u la rly asso­ c ia te d w ith in tra c ra n ia l n e o p la sm s. Gliomas are frequently seen with neuro­ fibrom atosis ;8,30 subependym al giant cell astrocytom as w ith tuberous sclerosis ;47 capillary hem angioblastom as w ith von H ippel-Lindau disease ;41 and basal-cell * S e n d r e p r in t r e q u e s ts to: P e te r M . F a rm e r, M .D ., N e u ro p ath o lo g ist, N o rth S hore U niversity H ospital, 300 C o m m u n ity D rive, M anhasset, NY 11030.

nevus syndrom e with m edulloblastom a .9 A higher incidence of brain tum ors has been observed in patients with a strong family history of seizures and stroke .44 T he p o ste rio r fossa is th e m ost fre ­ q u e n t location of brain tum ors in chil­ dren in contrast to adults who typically have supratentorial lesions. The m edian tim e interval betw een sym ptom onset and tu m o r diagnosis is two m o n th s .29 Astrocytomas account for about 60 p e r­ c e n t of p e d ia tric brain tu m o rs ,12 and th eir biologic behavior differs from adult tum ors .41 In children, five year survival rates may vary from 90 percent in cere­ bellar astrocytom as 22 to less than 20 p er­ cent in brainstem gliomas .31 Because of their location, brain tum ors in children have unique features in their c lin ic a l p r e s e n ta tio n . S y m p to m s o f increased intracranial pressure are fre­

26 0091-7370/91/0100-0026 $01.50 © Institute for Clinical Science, Inc.

BRAIN TUMORS IN C H IL D R E N ; A REVIEW

quently seen with headaches and vom it­ ing being the m ost conspicuous. O ther non-specific symptom s and signs should be sought; these include changes in p er­ sonality and school perform ance, le th ­ argy, fluctuations in weight, and neuro­ endocrine p ro b lem s .16’17 Early signs of papilledem a, such as cecal scotomas and dyschrom atopsia, may be present. Incip­ ient tonsillar hern iatio n may induce a head tilt or neck stiffness. Hemisensory, hem im otor, or hem ianopic defects sug­ gest a localization in the cerebral hem i­ sphere, while the triad of long tract signs and ataxia in association w ith lethargy p o in ts to b ra in ste m in v o lv e m e n t .36 Radicular symptom s such as pain, weak­ ness, or paresthesias that follow a derm atonal p a tte rn suggest cerebrospinal fluid seeding by tum or cells and should prom pt a search for the prim ary tum or and the extent of its dissem ination .21 V isual c o m p la in ts in c h ild re n w ith neurofibrom atosis Type I may be symp­ tom s of an optic n e rv e gliom a; visual acuity and visual fields should be m oni­ to re d carefu lly in th e s e p a tie n ts .2425 Signs o f n e u ro e n d o c rin e dy sfu n ctio n such as fluctuations in growth and devel­ opm ent suggest lesions in m idline struc­ tures such as the hypothalam us and pin­ eal gland .40 S eizures are m ore fre q u e n tly asso­ ciated w ith slow growing tum ors than with m ore aggressive lesions. Complex partial seizures are the m ost comm on s e iz u r e ty p e s e e n w ith in tr a c r a n ia l m asses. Tum ors in th e tem p o ral lobe usually cause seizures early in the course of disease .2

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Astrocytom as A stro c y to m a s in c h ild re n a re f r e ­ quently of low grade. They are charac­ te riz e d by a feltw ork of fibrillar p ro ­ cesses. Pilocytic (figure 1), protoplasmic, microcystic (figure 2), and gemistocytic p a tte r n s a re re c o g n iz e d . O c c a sio n a l transform ation to higher grade lesions, including glioblastomas, may occur. The recen t Mayo Clinic classification is sim­ ple, precise, reproducible, and c o rre ­ lates histologic grade w ith probability of su rv iv a l .10 A strocytom as in c h ild re n , even anaplastic tum ors, generally have a b e tte r prognosis th an ad u lt tu m o rs of com parable grade. C erebellar astrocytomas have the best prognosis of any childhood brain tum or .9 Lesions corresponding to th e “G liom a A” of Gilles com prise two thirds of cere­ bellar astrocytom as and are ch aracter­ ized by m icrocysts, R osenthal fibers, leptom eningeal deposits, and foci of oli­ g o d e n d ro g lio m a .20 “ G liom a B” has a poor prognosis and shares histologic fea­ tures w ith ependym om as including p eri­ vascular pseudorosettes, m itosis, high cell density, and necrosis. Vascular endo­ thelial proliferation and leptom eningeal in v asio n a re so m e tim e s se e n in low grade c e re b e lla r astrocytom as o f ch il­ dren and do not have the om inous prog­ n o stic c o n n o ta tio n th a t th e y c a rry in a d u lt tu m o rs .49 N in ety p e rc e n t of 25year survivals after surgery are reported in p e d ia tric c e re b e lla r astro cy to m as .9 Rare malignant degeneration may be seen in association with neurofibromatosis .32,39

Ependym om as Pathology It is an axiom of pediatric neurology that in the first decade of life 50 percent of all brain tum ors will be in the poste­ rior fossa and will m ost frequently be of glial origin.

Ependym om as in children are usually found in the posterior fossa, often w ithin th e cav ity of th e fo u rth v e n tr ic le .36 Tum or cells h av e a p in p o in t n u c le a r c h ro m a tin p a tte r n a n d a re ty p ic a lly a rra n g e d in a rad ia l fashion to form

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LACAYO A N D FARMER

F ig u r e 1. Juvenile pilocytie astrocytom a. C erebellum . M any eosinophilic granular bodies and R osenthal fibers are p resen t. Tum or cells are bipolar w ith piloid cytoplasm ic processes. N uclear atypia is not indicative o f poor prognosis. (H & E X400)

F i g u r e 2. M icrocystic astrocytom a. L ateral cerebellum . Tum or nuclei are bland, and th e re is a delicate fibrillar background. N um erous m icrocysts contain a proteinaceous transudate. (H & E X 250)

BRAIN TUMORS IN C H ILD R E N ; A REVIEW

r o s e t t e s o r p e r iv a s c u l a r p s e u d o r o ­ s e tte s .18 C ilia and b lepharoplasts m ay b e p r e s e n t in th e ap ic a l c y to p la s m a n d w h en p re s e n t h e lp to confirm th e diag­ nosis (figure 3). E p endym om as have an u n f o r tu n a te te n d e n c y to m e ta s ta s iz e th ro u g h o u t th e cereb ro sp in al flu id p a th ­ ways. M itoses an d o th er m alignant fea­ tu re s are see n in 50 p e rc e n t o f cases, usually in infan ts.41

M edulloblastom as M edulloblastom as are said to originate fro m th e fe ta l g r a n u la r c e ll la y e r o f O b e r s t e i n e r . 47 By d e f i n i t i o n t h e s e tu m o rs are exclusively cerebellar. T hey are found m ost often in th e m idline and c o n stitu te ab o u t 40 p e rc e n t of all p o ste ­ rio r fossa lesions.38 T hey are grossly soft, friable and often w ell d em arcated tum ors w ith occasional necrosis, cyst form ation a n d calcification. L e p to m e n in g e a l an d c e re b ro sp in a l flu id se e d in g occurs fre ­

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q u e n tly . E x t r a n e u r a l m e t a s t a s e s to lym ph n odes and b o n e m arrow m ay b e se e n .27 T h ese tum ors are ch aracterized b y t h e i r d e n s e c e llu la r ity , f r e q u e n t m itoses, and H o m er W rig h t ro settes. A n o d u la r o r follicular g ro w th p a tte rn is som etim es e n c o u n te re d in m edulloblas­ tom as. F re q u e n tly , this p a tte r n is th e co n seq u en ce o f proliferation of desm op la stic e le m e n ts w ith in th e tu m o r, or m ay in d ic a te n e u ro b la s tic o r g lial d if­ f e r e n tia tio n w ith in th e tu m o r .26 M e ­ d u llo b la sto m a s o n ce c a rrie d a d ism al prognosis, b u t w ith th e ad v an cem en t in ra d ia tio n a n d ch e m o th e rap y , five y ea r survival can b e as high as 70 p e r c e n t.19 P o ly a m in e s m a y b e u s e f u l t u m o r m ark e rs to m o n ito r d u rin g th e co u rse of tre a tm e n t.13

Prim itive N euroectoderm al Tum ors T um ors h isto lo g ica lly a n d clin ically sim ilar to m e d u llo b la sto m a s a re o cca­

F i g u r e 3. E pendym om a. F ourth ventricle. Tum or cells form a characteristic rosette. B lepharoplasts are seen as densities in the apical cytoplasm . (H & E X400)

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LACAYO A N D FARMER

s io n a lly s e e n in th e c e r e b r a l h e m i ­ sp h eres, an d have b e e n re fe rre d to by a variety of term s including “ce reb ral n e u ­ ro b lasto m as” . R ecently, it has b ec o m e fashionable to re fer to th ese poorly dif­ f e r e n t i a t e d sm a ll c e ll n e o p la s m s as “ p r im itiv e n e u r o e c to d e r m a l tu m o r s ” (P N E T ) (figure 4).35 T his unifying c o n ­ cep t suggests an origin o f th ese lesions from u n d iffe re n tia te d n e u ra l cells an d im plies a m echanism of oncogenesis th at is u n p ro v en . W hile this te rm (PN ET) is w id ely a n d u n critica lly u sed , S ch eith au e r states: “A lthough it is a provocative c o n c e p t, it d o es little to fo rw ard o u r u n d e rs ta n d in g o f n eo p lasia an d it is a poor basis for a m orphological system of tu m o r classification.”42

G erm Cell Tum ors G erm cell tu m ors of th e brain are rare b u t d istin ctly p ed iatric neoplasm s. T hey

account for about 15 p e rc e n t o f all brain tu m o rs in c h ild re n , b u t less th a n o n e p e rc e n t of ad u lt brain tum ors. T hey are located in th e m idline e ith e r in th e p in ­ eal region o r less often in a suprasellar site. M ore often found in m ales, th e y are typically associated w ith d ev elo p m en tal a b n o rm a lities a n d n e u ro e n d o c rin e d is­ o rd e rs, esp ecially p re co cio u s p u b erty . H istologically, th e s e lesio n s re s e m b le th e germ cell tum ors o f th e testis. T he m o st f r e q u e n t ty p e is a g e rm in o m a . M ixed p a tte rn s w ith featu res of chorio­ carcinom a, em bryonal carcinom a, endoderm al sinus tum ors, an d teratom as w ith m a tu r e a n d im m a tu r e e l e m e n ts a re en c o u n te re d (figure 5).6 Tum or m arkers including alpha-fetoprotein, h u m a n cho­ rionic gonadotropin, an d h u m an p lace n ­ tal lactogen m ay b e e lab o rated by germ c e ll n e o p la s m s . T h e id e n tific a tio n of th ese m arkers in th e blood an d c e re b ro ­ spinal flu id m ay facilitate diagnosis and tre a tm e n t.37

F ig u r e 4. Prim itive neuroectoderm al tu m o r (PNET). C erebral hem isphere. T h ere is a nestin g p a tte rn of undifferentiated neuroepithelial cells. (H & E x 250)

BRAIN TUMORS IN C H ILD R E N ; A REVIEW

31

F ig u r e 5. T eratom a. P in e a l r e g io n . T h e r e is a m ix tu r e o f c a rtila g e , e p ith e lia l e le m e n t s a n d u n d iff e r e n ­ tia te d m e s e n c h y m e . (H & E X 2 5 0 )

Sarcomas True, p rim ary ce n tral nervous system sa rc o m a s a re r a r e , b u t th e y m ay b e fo u n d in th e first d e c a d e of life. Som e arise from th e m en in g ea l coverings of th e brain, b u t a certain n u m b e r clearly originate from th e ce reb ral p aren ch y m a w ith o u t any a tta c h m e n t to th e arachnoid o r d u ra .41 T h e po ly m orphic cell variant is th e least d ifferen tiated type, has th e m ost aggressive biology, an d has a p ro ­ p e n sity to d isse m in a te th ro u g h o u t th e s u b a ra c h n o id sp ace. P rim a ry rh a b d o ­ m yosarcom as o f th e brain m ay b e found in p u re form o r m ixed w ith o th e r m esen ­ chym al e le m e n ts .23

Diagnosis S e v e ra l enhanced diagnosis. brain and

r e c e n t d e v e lo p m e n ts h a v e th e accuracy of b ra in tu m o r C o m p u te d tom ography of the n u clear m agnetic resonance,

along w ith th e use o f contrast m aterial a n d p a ra m a g n e tic a g e n ts , h a v e e n o r ­ m ously facilitated b rain tu m o r diagnosis a n d p ro v id e fin e a n a to m ic d e t a i l .3,15 O ncogenes are genes th at are in ap p ro ­ priately exp ressed an d c o n trib u te to th e d e v e lo p m e n t of neoplasia. M ore than 40 o n c o g e n e s h a v e b e e n i d e n tif ie d . O f in te re s t in p e d ia tric n eu ro -o n co lo g y is th e am plification o f th e N -m yc oncogene in n e u r o b la s to m a . S u rv iv a l w ith th is tu m o r c o r r e l a t e s in v e r s e ly w ith th e d e g re e of am plification fo u n d .34 In five p e rc e n t o f n o n -in h e rite d forms of re tin o ­ b la sto m a , a c o n s titu tio n a l d e le tio n of c h ro m o so m a l b a n d 1 3 q l4 h as b e e n observed. In familial cases, th e re is close g en etic linkage b e tw e e n esterase D and th e disease. Associations b etw e en C -m yc and ERB-B oncogenes have b e e n found w ith g lio b la s to m a s .46 T h e s p r e a d in g availability o f polym erase chain reaction tech n o lo g y m ay m ake m o lecu lar d iag ­ nosis ro u tin e in hospital laboratories.

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Flow Cytometry Flow cytom etry is a powerful tool in the transition from descriptive to quanti­ tative cytology. The presence of abnor­ mal desoxyribonucleic acid (DNA) stem lines in solid tum ors makes DNA flow cytom etry a helpful modality in the diag­ nosis of bladder irrigates, effusions, spu­ tum , bronchial washings, and cereb ro ­ spinal flu id collectio n s. T he a d v erse im pact of aneuploidy and S percentage m ay m a k e th e s e u s e fu l p r o g n o s tic param eters. Studies have docum ented higher rates of relapse in brain tumors found to be aneuploid, especially m edulloblastom as .4 Immunohistochemistry and Tumor Markers Im m u n o h is to c h e m is try a n d tu m o r m arkers have greatly strengthened the arm em entarium of oncologists. Peroxidase-antiperoxidase techniques for the dem onstration of neural and non-neural cell m arkers have co n trib u ted to diag­ nostic accuracy o f histologically rare, complex or otherw ise difficult tum ors of the central nervous system .7 It is im por­ tant to em phasize, however, that none of these m arkers is specific, and that each should be in te rp re te d in th e light of other clinical and laboratory information. Som e tu m o r m ark e rs, such as po ly a­ m ines, can be m onitored during tre a t­ m en t to gauge disease progression or efficacy of therapy .13 In table I are p re ­ sented some of the m ore useful m arkers available.

TABLE I ab Tumor Markers Tumor Choroid plexus carcinoma Pliocytic astrocytoma Neuroblastoma Medulloblastoma Germ cell neoplasia Meningeal carcinoma­ tosis To differentiate metas­ tasis

Marker Carcinoembryonlc antigen (CEA) * GFAP c & glutamine synthetase Neurofilament (NF) Polyamines, neuron specific enolase (NSE) hCG d, pregnancy specific beta 1-glycoprotein (SP-1) and AFP® Beta glucoronidase Cytokeratins, AFP «, CEA

a Cancer 56:1773-1777,1985. b Clin. Lab. Med. 70:151-178.1990. c Glial fibrillary acidic protein, intermediate filament, specific for the astrocytic series, either normal, reactive, or neoplastis. This protein was originally Isolated from old multiple sclerosis plaques. Cancer 5 7:233-237,1983. d Human chorionic gonadotropin. • Alpha-fetoproteln. * CEA, a marker of secretory carcinomas. Isroutinely detected in choroid plexus carcinomas, but not in papillomas. small cell tum ors of the brain, poorly dif­ ferentiated gliomas, unusual m eningeal tum ors, and anaplastic m etastatic n eo ­ plasm s .47 It may also help to distinguish m etabolic diseases or viral and o th e r infections th a t m ay b e confused w ith tum ors.

Treatment and Complications Electron Microscopy E le ctro n m icroscopy often m akes a valuable contribution in identifying and classifying tum ors th at pose diagnostic problem s. E lectro n m icroscopy can be especially decisive in th e diagnosis of

S urgical re s e c tio n , w h en feasib le, rad iatio n therapy, and ch em o th erap y rem ain th e m ainstays of tre a tm e n t for brain tum ors. Thirty percent of posterior fossa tum ors require cerebrospinal fluid diversion via shunts. Total craniospinal radiation are required for tum ors such as

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BRAIN TUM ORS IN C H ILD R E N ; A REVIEW

TABLE II °-b Treatment Sequelae Modality

Time of Appearance

Side Effect

ITc. Methotrexate Vincristine RTd (WBRT) «

Meningltic reaction Symmetrical polyneuropathy Somnolence

72 hours 2 weeks 1-2 months

RT d RT d RT d RTd RT d RT d RT à and chemo­ therapy

Brain necrosis. Myelopathy Secondary cancer Endocrine, decrease GH 9 Intellectual impairment Premature arteriosclerosis Atrophy

6 months to 3 years 12 months After 7 years — —

a j. Pediat. 93903-909, 1978. c Intrathecal e Whole brain radiation therapy

Remarks Nuchal rigitidy, nausea, headache, benign, self-limited Paresthesias, dropped ankle jerks Seen in 40% of children after prophy­ lactic RTd for ALL1 Lasts several weeks, relieved by steroids Behaves clinically as tumor recurrence Dorsal cord most vulnerable, para­ paresis & sphincter dysfunction Occurs in 1% of cases Highest Incidence if age is less than 13 or dose more than 3.000 rads Worse if age is less than 3 at time of treatment

b Cancer 5/:233-237,1983 d Radiation therapy t Acute lymphoblastic leukemia 0 Growth hormone

m edulloblastom as and anaplastic ep en ­ dym om as th a t se ed th e cereb ro sp in al flu id .19 Young children are m ore suscep­ tible to radiation toxicity. The com bina­ tion of m ethotrexate and radiation puts the brain at risk for the developm ent of su b acu te n ecro tizin g Ieukoencephalopathy 1 (table II). A cknow ledgm ents A pp reciatio n is e x p re sse d b y th e a u th o rs to Jane Ryan for p reparation o f th e m anuscript.

References 1. A l l e n , J. C .: T h e effects o f cancer therapy on

th e n erv o u s system . J. P ed iatr. 9 3 :9 0 3 -9 0 9 , 1978.

2. B a c k u s , R. E. and M il l i c h a p , J. G.: T he sei­ zure as a m anifestation of intracranial tu m o r in childhood. P ediatrics 2 9:978-984, 1962. 3. B a r k o v i c h , A. J. a n d E d w a r d s , M . S . B .: B rain tum ors in childhood. In: Barkovich, A. J. : P e d ia tr ic N e u r o im a g in g . N e w York, R a v en Press. 1990, pp. 149-203. 4. B a r l o g i e , B ., R a b e r , M . N ., a n d S c h u m a n n , J ., e t a l.: F l o w c y t o m e t r y in c l in ic a l c a n c e r r e s e a r c h . C a n c e r R e se a r c h 43:3982-3997, 1983. 5. B e c k e r , L . E . a n d H a l l id a y , W. C .: C e n tra l nervous system tum ors o f childhood. Perspect. Pediatr. Pathol. J0 :8 6 -1 3 4 , 1987. 6 . B j o r n s s o n , J., S c h e i t h a u e r , B . W ., O k a z a k i , H . , a n d L e e c h , W .: In tra c ra n ia l g e rm c ell tum ors: Pathological and im m unohistochem ical a s p e c ts o f 70 c a s e s. J. N e u ro p a th o l. E xp. N eurol. 4 4 :3 2 -4 6 , 1985. 7. B o n n i n , J. M . and R u b i n s t e i n , L . J.: Im m unoh i s t o c h e m is tr y o f c e n t r a l n e r v o u s s y s te m tum ors. R eview article. J. N eurosurg. 60:11211133, 1984.

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8. B r a f f m a n , B . H ., B i l a n i u k , L. T., a n d Z im ­ m e r m a n , R. A.-. T h e c e n tra l n e rv o u s sy ste m m a n ife s ta tio n s o f th e p h a k o m a to se s on M R. Radiol. Clin. N orth Am. 26:773—800, 1988. 9. C o h e n , M. E. and D u f f n e r , P. K.: Tumors of th e b rain a n d spinal c ord in clu d in g leukem ic involvem ent. In: Swaim an, K. F.: Pediatric N eu ­ rology, vol. II. St. Louis, T he C .V . Mosby C om ­ pany, 1989, pp. 6 6 1 -7 1 4 . 10. D a u m a s - D u p o r t , C ., S c h e i t h a u e r , B., O ’F a l LON, J . , a n d K e l l y , P . : G radings o f astro cy ­ tom as. C ancer 62:2152—2165, 1988. 11. D u f f n e r , D . K ., C o h e n , M. E ., and T h o m a s , P.: L ate effects o f tre a tm e n t on th e intelligence of children w ith p o sterior fossa tum ors. C ancer 51:2 3 3 -2 3 7 , 1983. 1 2 . D u f f n e r , P. K . , C o h e n , M . E . , M y e r s , M . H ., a n d HEISE, H . W .: S u r v iv a l o f c h ild r e n w it h b r a in t u m o r s . N e u r o lo g y 3 6 : 5 9 7 - 6 0 1 , 19 8 6 . 13. E d w a r d s , M. S. B ., D a v i s , R. L ., an d L a u ­ r e n t , J. P .: T um or m ark ers a n d cytologic fea­

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24. 25.

tu res of cerebrospinal fluid. C ancer 56:17731777, 1985. E d w a r d s , M. S., L e v i n , V. A., and W i l s o n , C. B .: C h e m o th e rap y of p ediatric posterior fossa tum ors. C hilds B rain 7:252, 1980. E l s t e r , A. D . and R ie s e r , G. D .: Gd-DTPAen h an c ed cranial M R im aging in children: Initial clinical experience and recom m endations for its use. Am. J. N euroradiol. 10:1027-1030, 1989. F a r w e l l , J. R., D o h r m a n n , G. J., and F l a n ­ n e r y , }. T .: C en tral nervous system tum ors in children. C an cer 40:3123-3132, 1977. F a r w e l l , J. R., D o h r m a n n , G. J., and F l a n ­ n e r y , J. T . : In tra c ra n ia l neoplasm s in infants. Arch. N eurol. 35:5 3 3 -5 3 7 , 1978. F o k e s , E . C. a n d P e a r l e , K . M .: E p e n d y ­ m om as: C lin ic al a n d p a th o lo g ic a l a sp e cts. J. N eurosurg. 3 0 :5 8 5 —5 9 0 , 1 9 6 9 . G a r t o n , G . R ., S c h ö m b e r g , P. J . , a n d SCHEITHAUER, B . W ., e t a l: M e d u llo b la sto m a — Prognostic factors and outco m e o f tre a tm e n t: R eview o f th e M ayo C linic ex p erien c e . Mayo Clin. Proc. 65:1077-1086, 1990. G il l e s , F. H ., W i n s t o n , K ., and F u l c h i e r o , A., e t al.: H istologic features and observational variation in c e re b e lla r gliom as in c h ild ren . J. Natl. C ancer Inst. 58:1 7 5 -1 8 1 , 1977. G l a s s , J. P., M e l a m e d , M ., a n d C h e r n i k , N. L. e t al: M alignant cells in c ere b ro sp in al flu id (CSF): T h e m ea n in g o f a positive C S F cytology. N eurology 29:1369-1375, 1979. G r i f f i n , T. W ., B e i n f a c t , D . , a n d B l a s k o , J. C .: Cystic c ere b ellar astrocytom as in child­ hood. C ancer 44:2 7 6 -2 8 0 , 1979. H i n t o n , D . R. and H a l l id a y , W. C.: Prim ary rhabdom yosarcom a o f th e cerebellum - a light, electron m icroscopic and im m unohistochem ical study. J. N e u ro p ath o l. E xp. N eurol. 43:439, 1984. H o l t , J. F.: N eurofibrom atosis in children. Am. J. Radiol. i3 0 :6 1 5 -6 1 7 , 1978. Jo n e s , R. K. and H o y t , W. F.: C hildhood chias­

26.

27.

28.

29.

30.

31.

32.

33.

34. 35.

36.

37.

38.

39.

40.

41.

42.

m al gliom as. Prog. Exp. T um or Res. 30:108— 112, 1987. K a t s e t o s , C. C ., L iu , H. M ., and Z a c k s , S. I.: Im m unohistochem ical and ultrastru ctu ral o b ser­ vations on H o m e r W right (neuroblastic) rosettes a n d th e “p a le isla n d s” o f h u m a n c e re b e lla r m e d u llo b la sto m a s . H u m a n P a th o l. 2 9 :1 2 1 9 1227, 1988. K l e i n m a n , G . M ., H o c h b e r g , F. H ., an d R ic h a r d s o n , E. P.: System ic m etastasis from m e d u llo b la s to m a . R e p o r t o f tw o c a s e s a n d review of th e literatu re. C ancer 48:2296-2305, 1981. L a M o n t e , S. M .: Im m unohistochem ical diag­ nosis of nervous system neoplasm s. Clin. Lab. M ed. ¿0:151—178, 1990. L a n n e r in g , B., M arky , I., and N o r d b o r g , C.: Brain tum ors in childhood and adolescence in W e st S w eden, 1 9 7 0 -1 9 8 4 : E pidem iology and survival. C ancer 66:604-609, 1990. L e w i s , R. A ., G e r s o n , L . P., a n d A x e l s o n , K. A ., et al: Von Recklinghausen neurofibrom a­ tosis. Incidence of optic gliom ata. O phthalm ol­ ogy 91:9 2 9 - 932, 1984. L it t m a n , P., J a r r e t t , P., and B il a n iu k , L. T., e t al: P e d ia tric b ra in ste m gliom as. C a n c e r 45:2 7 8 7 -2 7 9 2 , 1980. L o t t , I. T. and R ic h a r d s o n , E. P.: N europathological findings and th e biology of neurofibro­ matosis. A dvances N eurol. 2 9 :2 3 -3 2 , 1981. L o w , N. L ., C o r n e l l , J. W ., a n d H a m m il l , J. F . : T um ors o f th e c e re b ra l h e m isp h e re s in c hildren. Arch. N eurol. 13:547, 1965. M a l c o l m , S.: O ncogenes in malignancy. Arch. Dis. C hild 63:1099-1103, 1988. M c L e n d o n , R. E . a n d B u r g e r , P. C .: T h e prim itive n eu roectoderm al tum or: A cautionary view. J P ediatric N eurosci. 3:1—8, 1987. M e n k e s , J. H . and T il l , K .: Tumors of th e n e r­ vous system . In: M enkes, J. H .: T extbook o f C h ild N eurology, 4th ed. Philadelphia, L ea and Febiger, 1990, pp. 5 2 6-582. N ie h a n s , G. A., M a n iv e l , J. C ., and C o p e ­ l a n d , G . T., e t al: Im m u n o h isto c h em istry of germ cell and trophoblastic tum ors. Cancer. In press. Pa c k e r , R. J. and F inlay , F. L.: M edulloblas­ tom a: P resentation, diagnosis and m anagem ent. O ncology 2 :3 5 -4 9 , 1988. R ic c a r d , V. M .: N eurofibrom atosis in neurocutan e o u s d iso rd e rs. N eurol. C lin. N o rth Am. 5 :3 3 7 -3 4 9 , 1987. R ic h m o n d , I. L. and W il s o n , C. B.: Parasellar tu m o rs in c h ild re n — I. C linical p re se n ta tio n , p reo p erativ e assessm ent a n d differential diag­ nosis. C hilds B rain 7 :7 3 -7 8 , 1980. R u s s e l l , D . S. and R u b in s t e in , L. J.: Pathology o f Tum ors o f the N ervous System , 5th ed. B altim ore, W illiam s and W ilkins, 1989. S c h e it h a u e r , B. W .: D esm oplastic M e d u llo ­ b lasto m a . C a lifo rn ia T um or T issu e R egistry. E ig h ty -e ig h th S em i-annual Slide S em inar on Tumors o f th e C en tral N ervous System . June 3, 1990, pp. 3 7 -4 9 .

BRAIN TUM ORS IN C H ILD R E N ; A REVIEW

43. S c h e i t h a u e r , B . W. and B r u n e r , J. M. C entral nervous system tum ors. C lin. Lab. M ed. 7:157— 179, 1987. 44. S c h o n b e r g , B. S ., G l is t a g , G ., a n d R e a g a n , T. J.: T h e fa m ilia l o c c u r r e n c e o f g lio m a . S u rg. N e u r o l. 3 :1 3 9 -1 4 1 , 1975.

45. S e g a l l , H . D ., C h i -S h i n g , Z e e ., a n d N a i d i c h , T. P ., e t al: C o m p u te d to m o g r a p h y in n e o p la s m s o f th e p o s te r io r fo ssa in c h ild r e n . R a d io l. C lin . N o r th A m . 20:2 3 7 -2 5 3 , 1982.

46. S t e w a r t , C. C .: Flow c y to m e tric analysis of oncogene expression in hum an neoplasm s. Arch. Path. Lab. M ed. 113:6 3 4 -6 4 0 , 1989.

35

47. S t r o n i k , A. R ., H o f f m a n , H . J., a n d H e n ­ d r i c k , E. B., e t al: Diagnosis and m anagem ent o f pediatric b rain stem gliomas. J. N eurosurg. 65:7 4 5 -7 5 0 , 1986. 48. T r o m b l e y , I. K. and M ir r a , S. S.: U ltrastruc­ tu re of tu b ero u s sclerosis: C ortical tu b ers and su bependym al tum or. Ann. N eurol. 9.174—179, 1981. 49. W in s t o n , K., G i l l e s , F. H ., and L e v it o n , A., e t al: C e re b e lla r gliom as in c h ild ren . J. N atl. C an cer Inst. 5 8:833-838, 1977. 50. Y o u n g , J. L . and M il l e r , R. W. : Incidence of m alignant tum ors in U.S. children. J. Pediatr. 86:2 5 4 -2 5 9 , 1975.