ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 21, No. 1 Copyright © 1991, Institute for Clinical Science, Inc. Brain Tumors in Children: A Review* ALVARO LACAYO, M .D .,t and PETER M. FARMER, M .D4 Departments of Neurology f and Pathologyt , North Shore University Hospital and Department of Pathologyt , Cornell University Medical College Manhasset, NY 11030 ABSTRACT Brain tumors are the second most common malignancy of children. In contrast to adults, childhood brain tumors are usually of glial origin; metastases and meningiomas are rare. Some tumors, i.e., medulloblas- tomas, are found almost exclusively in children. The posterior fossa is the most frequent site of occurrence. The prognosis for childhood neoplasms tends to be more favorable than in adults, and some lesions are curable. New techniques, including immunostaining, tumor markers, and cyto- genetics, have improved diagnostic accuracy. A review of some of the most important brain tumors of children is presented along with an upgrade on recent developments in diagnoses and treatment. Introduction Intracranial tumors are the second most common group of neoplasms in children, exceeded only by the leuke- mias .9 The estimated incidence of brain tumors in patients under 15 years of age ranges from 2.5 to 3.5 per 100,000 .29,50 There is distinct familial trend in pediat- ric brain tumors. The inherited neurocu- taneous disorders are regularly asso- ciated with intracranial neoplasms. Gliomas are frequently seen with neuro- fibromatosis ;8,30 subependymal giant cell astrocytomas with tuberous sclerosis ;47 capillary hemangioblastomas with von Hippel-Lindau disease ;41 and basal-cell * Send reprint requests to: Peter M. Farmer, M.D., Neuropathologist, North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030. nevus syndrome with medulloblastoma .9 A higher incidence of brain tumors has been observed in patients with a strong family history of seizures and stroke .44 The posterior fossa is the most fre- quent location of brain tumors in chil- dren in contrast to adults who typically have supratentorial lesions. The median time interval between symptom onset and tumor diagnosis is two months .29 Astrocytomas account for about 60 per- cent of pediatric brain tumors , 12 and their biologic behavior differs from adult tumors .41 In children, five year survival rates may vary from 90 percent in cere- bellar astrocytomas 22 to less than 20 per- cent in brainstem gliomas .31 Because of their location, brain tumors in children have unique features in their clinical presentation. Symptoms of increased intracranial pressure are fre- 26 0091-7370/91/0100-0026 $01.50 © Institute for Clinical Science, Inc.
Brain Tumors in Children: A Review
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ANNALS O F CLINICAL AND LABORATORY SCIEN CE, Vol. 21, No. 1 Copyright © 1991, Institute for Clinical Science, Inc.
Brain Tumors in Children: A Review*
ALVARO LACAYO, M .D .,t and PETER M. FARMER, M .D 4
Departments o f Neurology f and Pathologyt, North Shore University Hospital and Department o f Pathologyt,
Cornell University Medical College Manhasset, NY 11030
ABSTRACT
Brain tumors are the second most common malignancy of children. In contrast to adults, childhood brain tum ors are usually of glial origin; metastases and meningiomas are rare. Some tumors, i.e., medulloblas- tomas, are found almost exclusively in children. The posterior fossa is the most frequent site of occurrence. The prognosis for childhood neoplasms tends to be more favorable than in adults, and some lesions are curable. New techniques, including immunostaining, tum or markers, and cyto genetics, have improved diagnostic accuracy. A review of some of the most im portant brain tumors of children is presented along with an upgrade on recent developm ents in diagnoses and treatm ent.
Introduction
In tracran ial tum ors are the second m ost com m on group of neoplasm s in children, exceeded only by the leuke- mias.9 The estim ated incidence of brain tumors in patients under 15 years of age ranges from 2.5 to 3.5 per 100,000.29,50 There is distinct familial trend in pediat ric brain tumors. The inherited neurocu- taneous d iso rders are regu larly asso c ia ted w ith in tra c ra n ia l neoplasm s. Gliomas are frequently seen with neuro fibromatosis;8,30 subependymal giant cell astrocytomas with tuberous sclerosis;47 capillary hemangioblastom as with von Hippel-Lindau disease;41 and basal-cell
* Send re p r in t re q u e s ts to: P e te r M. F arm er, M .D ., N europathologist, N orth Shore U niversity H ospital, 300 C om m unity D rive, M anhasset, NY 11030.
nevus syndrome with medulloblastoma.9 A higher incidence of brain tumors has been observed in patients with a strong family history of seizures and stroke .44
The posterio r fossa is the m ost fre quen t location of brain tum ors in chil dren in contrast to adults who typically have supratentorial lesions. The median tim e interval betw een symptom onset and tum or diagnosis is two m on ths .29 Astrocytomas account for about 60 per cen t of ped iatric brain tum ors ,12 and their biologic behavior differs from adult tum ors .41 In children, five year survival rates may vary from 90 percent in cere bellar astrocytomas22 to less than 20 per cent in brainstem gliomas.31
Because of their location, brain tumors in children have unique features in their c lin ica l p re s e n ta t io n . Sym ptom s of increased intracranial pressure are fre
26 0091-7370/91/0100-0026 $01.50 © Institute for Clinical Science, Inc.
BRAIN TUMORS IN CHILDREN; A REVIEW 27
quently seen with headaches and vomit ing being the most conspicuous. O ther non-specific symptoms and signs should be sought; these include changes in per sonality and school perform ance, le th argy, fluctuations in weight, and neuro endocrine problem s .16’17 Early signs of papilledema, such as cecal scotomas and dyschromatopsia, may be present. Incip ient tonsillar herniation may induce a head tilt or neck stiffness. Hemisensory, hemimotor, or hemianopic 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 po in ts to b ra in stem in v o lv e m e n t .36 Radicular symptoms such as pain, weak ness, or paresthesias that follow a der- matonal pa ttern suggest cerebrospinal fluid seeding by tum or cells and should prom pt a search for the primary tumor and the extent of its dissemination .21
Visual com plain ts in ch ild ren w ith neurofibromatosis Type I may be symp toms of an optic nerve glioma; visual acuity and visual fields should be moni to red carefu lly in these p a tie n ts .2425 Signs o f n eu ro en d o c rin e dysfunction such as fluctuations in growth and devel opm ent suggest lesions in midline struc tures such as the hypothalamus and pin eal gland .40
Seizures are m ore frequen tly asso ciated with slow growing tum ors than with more aggressive lesions. Complex partial seizures are the most common se iz u re ty p e se en w ith in tra c ra n ia l m asses. Tumors in the tem poral lobe usually cause seizures early in the course of disease.2
Pathology
It is an axiom of pediatric neurology that in the first decade of life 50 percent of all brain tumors will be in the poste rior fossa and will most frequently be of glial origin.
Astrocytomas
A strocy tom as in c h ild ren a re f re quently of low grade. They are charac terized by a feltw ork of fibrillar p ro cesses. Pilocytic (figure 1), protoplasmic, microcystic (figure 2), and gemistocytic p a tte rn s a re reco g n ized . O ccasional transformation to higher grade lesions, including glioblastomas, may occur. The recent Mayo Clinic classification is sim ple, precise, reproducible, and corre lates histologic grade with probability of su rv iva l.10 A strocytom as in ch ild ren , even anaplastic tumors, generally have a b e tte r prognosis than adult tum ors of comparable grade.
Cerebellar astrocytomas have the best prognosis of any childhood brain tum or.9 Lesions corresponding to the “Glioma A” of Gilles comprise two thirds of cere bellar astrocytomas and are character ized by m icrocysts, R osenthal fibers, leptomeningeal deposits, and foci of oli godendrog liom a .20 “ G liom a B” has a poor prognosis and shares histologic fea tures with ependymomas including peri vascular pseudorosettes, mitosis, high cell density, and necrosis. Vascular endo thelial proliferation and leptomeningeal invasion are som etim es seen in low grade cerebellar astrocytom as o f ch il dren and do not have the ominous prog nostic conno ta tion th a t th ey carry in adult tu m o rs .49 N inety p e rcen t of 25- year survivals after surgery are reported in ped iatric cerebellar astrocytom as .9 Rare malignant degeneration may be seen in association with neurofibromatosis.32,39
Ependym omas
Ependymomas in children are usually found in the posterior fossa, often within th e cavity of th e fo u rth v e n tr ic le .36 Tum or cells have a p in p o in t nuclear ch ro m a tin p a tte rn and a re typ ica lly arran g ed in a rad ia l fashion to form
28 LACAYO AND FARMER
F ig u r e 1. Juvenile pilocytie astrocytoma. C erebellum . Many eosinophilic granular bodies and Rosenthal fibers are p resent. Tumor cells are bipolar with piloid cytoplasmic processes. Nuclear atypia is not indicative o f poor prognosis. (H& E X400)
F ig u r e 2. Microcystic astrocytoma. Lateral cerebellum . Tumor nuclei are bland, and there is a delicate fibrillar background. N um erous microcysts contain a proteinaceous transudate. (H&E X 250)
BRAIN TUMORS IN CHILDREN; A REVIEW 29
r o s e t t e s o r p e r iv a s c u la r p s e u d o r o se tte s .18 Cilia and blepharoplasts may be p re s e n t in th e ap ica l cy to p lasm and w hen p resen t help to confirm the diag nosis (figure 3). E pendym om as have an u n fo r tu n a te te n d e n c y to m e ta s ta s iz e th roughout the cerebrospinal flu id pa th ways. M itoses and o ther m alignant fea tu res are seen in 50 p e rcen t of cases, usually in infants.41
M edulloblastomas
M edulloblastom as are said to originate from th e fe ta l g ra n u la r ce ll la y e r o f O b e r s t e i n e r . 47 By d e f in i t io n th e s e tum ors are exclusively cerebellar. They are found m ost often in the m idline and constitu te about 40 percen t of all poste rior fossa lesions.38 They are grossly soft, friable and often well dem arcated tum ors w ith occasional necrosis, cyst formation and calcification. L ep tom en ingea l and ce reb ro sp in a l flu id seed ing occurs fre
q u e n tly . E x t r a n e u ra l m e ta s ta s e s to lym ph nodes and bone m arrow may be seen .27 T hese tum ors are characterized by th 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 om er W right rosettes. A nodu lar o r follicular g row th p a tte rn is som etim es encoun te red in m edulloblas tom as. F req u en tly , this p a tte rn is the consequence of proliferation of desm o- p lastic e le m e n ts w ith in th e tum or, or m ay in d ica te n eu ro b la s tic o r g lial d if fe re n tia tio n w ith in th e tu m o r .26 M e d u llob lastom as once ca rried a d ism al prognosis, b u t w ith the advancem ent in rad ia tion and chem otherapy , five year survival can be as high as 70 p e rc e n t.19 P o ly a m in e s m ay b e u s e f u l tu m o r m arkers to m on ito r d u rin g th e course of tre a tm e n t.13
Prim itive N euroectoderm al Tum ors
T um ors h isto logically and clin ically s im ilar to m ed u llo b lasto m as a re occa
F ig u r e 3. Ependym om a. Fourth ventricle. Tumor cells form a characteristic rosette. B lepharoplasts are seen as densities in the apical cytoplasm. (H&E X400)
30 LACAYO AND FARMER
s io n a lly s e e n in th e c e re b ra l h e m i spheres, and have been referred to by a variety of term s including “cerebral n eu rob lastom as” . R ecently , it has becom e fashionable to refer to these poorly dif f e r e n t ia te d sm all c e ll n e o p la sm s as “ p r im itiv e n e u ro e c to d e rm a l tu m o rs ” (PNET) (figure 4).35 This unifying con cept suggests an origin of these lesions from u n d iffe ren tia ted n eu ral cells and im plies a m echanism of oncogenesis that is unproven. W hile this term (PNET) is w idely and uncritica lly used , S cheith- auer states: “A lthough it is a provocative co n cep t, it does litt le to forw ard o u r u n d erstan d in g o f neoplasia and it is a poor basis for a m orphological system of tum or classification.”42
G erm Cell Tumors
G erm cell tum ors of the brain are rare bu t distinctly ped iatric neoplasm s. They
account for about 15 p ercen t o f all brain tu m o rs in c h ild re n , b u t less th an one p ercen t of adult brain tum ors. They are located in the m idline e ith e r in the p in eal region or less often in a suprasellar site. M ore often found in males, they are typically associated w ith developm ental abnorm alities and n eu ro en d o crin e d is o rders, especially precocious puberty . H istologically , th ese lesions re sem b le the germ cell tum ors of the testis. The m ost f re q u e n t ty p e is a g e rm in o m a. M ixed patterns w ith features of chorio carcinom a, em bryonal carcinom a, endo- derm al sinus tum ors, and teratom as with m a tu re an d im m a tu re e le m e n ts a re encoun te red (figure 5).6 Tum or m arkers including alpha-fetoprotein, hum an cho rionic gonadotropin, and hum an p lacen tal lactogen may be e laborated by germ ce ll n eo p lasm s. T h e id e n tif ic a tio n of these m arkers in the blood and cereb ro spinal flu id may facilitate diagnosis and trea tm en t.37
F ig u r e 4. Prim itive neuroectoderm al tum or (PNET). C erebral hem isphere. T here is a nesting pattern of undifferentiated neuroepithelial cells. (H&E x 250)
BRAIN TUMORS IN CHILDREN; A REVIEW 31
F ig u r e 5. T eratom a. P in ea l r eg io n . T h e re is a m ix tu re o f cartilage , e p ith e lia l e le m e n ts a n d u n d iffer e n tia ted m e sen ch y m e . (H & E X 250)
Sarcomas
True, p rim ary central nervous system sarcom as a re ra re , b u t th e y m ay be found in th e first decade of life. Some arise from th e m eningeal coverings of th e brain, bu t a certain nu m b er clearly originate from the cerebral parenchym a w ithout any a ttachm ent to the arachnoid or d u ra .41 T he polym orphic cell variant is the least d ifferentiated type, has the m ost aggressive biology, and has a p ro pensity to d issem inate th ro u g h o u t th e su b arach n o id space. P rim ary rh a b d o myosarcomas of the brain m ay be found in p u re form or m ixed w ith o th er m esen chym al e lem en ts .23
Diagnosis
S ev era l re c e n t d e v e lo p m e n ts have en h an ced th e accuracy of bra in tum or diagnosis. C om puted tom ography of the brain and nuclear m agnetic resonance,
along w ith the use of contrast m aterial and p a ram ag n e tic ag en ts , have e n o r mously facilitated brain tum or diagnosis an d p ro v id e fin e an a to m ic d e ta i l .3,15 O ncogenes are genes that are inappro priately expressed and con tribu te to the developm ent of neoplasia. M ore than 40 o n c o g e n e s h av e b e e n id e n tif ie d . O f in te re s t in p ed ia tric neuro-oncology is the amplification of the N-myc oncogene in n e u ro b la s to m a . S urv ival w ith th is tu m o r c o r re la te s in v e rs e ly w ith th e degree of am plification found.34 In five p ercen t of non-inherited forms of re tino b lastom a, a co n stitu tio n a l d e le tio n of c h ro m o s o 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 genetic linkage betw een esterase D and the disease. Associations betw een C-m yc and ERB-B oncogenes have been found w ith g lio b la s to m a s .46 T h e s p re a d in g availability of polym erase chain reaction technology m ay m ake m olecular d iag nosis rou tine in hospital laboratories.
32 LACAYO A N D FARMER
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 cytometry a helpful modality in the diag nosis of bladder irrigates, effusions, spu tum , bronchial washings, and cerebro spinal flu id collections. The adverse impact of aneuploidy and S percentage m ay m ake th e s e u se fu l p ro g n o s tic param eters. Studies have docum ented higher rates of relapse in brain tumors found to be aneuploid, especially medul- loblastomas.4
Immunohistochemistry and Tumor Markers
Im m u n o h is to ch e m is try and tu m o r markers have greatly strengthened the arm em entarium of oncologists. Peroxi- dase-antiperoxidase techniques for the demonstration of neural and non-neural cell m arkers have contributed to diag nostic accuracy of histologically rare, complex or otherwise difficult tumors of the central nervous system .7 It is impor tant to emphasize, however, that none of these markers is specific, and that each should be in te rp re te d in the light of other clinical and laboratory information. Some tum or m arkers, such as polya mines, can be m onitored during trea t m ent to gauge disease progression or efficacy of therapy .13 In table I are p re sented some of the more useful markers available.
Electron Microscopy
E lectron m icroscopy often makes a valuable contribution in identifying and classifying tum ors that pose diagnostic problem s. E lectron microscopy can be especially decisive in the diagnosis of
TABLE I ab Tumor Markers
Tumor Marker
Germ cell neoplasia
Meningeal carcinoma tosis
hCG d, pregnancy specific beta 1-glycoprotein (SP-1) and AFP®
Beta glucoronidase Cytokeratins, AFP «,
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. Is routinely detected in choroid plexus carcinomas, but not in papillomas.
small cell tumors of the brain, poorly dif ferentiated gliomas, unusual meningeal tum ors,…
Brain Tumors in Children: A Review*
ALVARO LACAYO, M .D .,t and PETER M. FARMER, M .D 4
Departments o f Neurology f and Pathologyt, North Shore University Hospital and Department o f Pathologyt,
Cornell University Medical College Manhasset, NY 11030
ABSTRACT
Brain tumors are the second most common malignancy of children. In contrast to adults, childhood brain tum ors are usually of glial origin; metastases and meningiomas are rare. Some tumors, i.e., medulloblas- tomas, are found almost exclusively in children. The posterior fossa is the most frequent site of occurrence. The prognosis for childhood neoplasms tends to be more favorable than in adults, and some lesions are curable. New techniques, including immunostaining, tum or markers, and cyto genetics, have improved diagnostic accuracy. A review of some of the most im portant brain tumors of children is presented along with an upgrade on recent developm ents in diagnoses and treatm ent.
Introduction
In tracran ial tum ors are the second m ost com m on group of neoplasm s in children, exceeded only by the leuke- mias.9 The estim ated incidence of brain tumors in patients under 15 years of age ranges from 2.5 to 3.5 per 100,000.29,50 There is distinct familial trend in pediat ric brain tumors. The inherited neurocu- taneous d iso rders are regu larly asso c ia ted w ith in tra c ra n ia l neoplasm s. Gliomas are frequently seen with neuro fibromatosis;8,30 subependymal giant cell astrocytomas with tuberous sclerosis;47 capillary hemangioblastom as with von Hippel-Lindau disease;41 and basal-cell
* Send re p r in t re q u e s ts to: P e te r M. F arm er, M .D ., N europathologist, N orth Shore U niversity H ospital, 300 C om m unity D rive, M anhasset, NY 11030.
nevus syndrome with medulloblastoma.9 A higher incidence of brain tumors has been observed in patients with a strong family history of seizures and stroke .44
The posterio r fossa is the m ost fre quen t location of brain tum ors in chil dren in contrast to adults who typically have supratentorial lesions. The median tim e interval betw een symptom onset and tum or diagnosis is two m on ths .29 Astrocytomas account for about 60 per cen t of ped iatric brain tum ors ,12 and their biologic behavior differs from adult tum ors .41 In children, five year survival rates may vary from 90 percent in cere bellar astrocytomas22 to less than 20 per cent in brainstem gliomas.31
Because of their location, brain tumors in children have unique features in their c lin ica l p re s e n ta t io n . Sym ptom s of increased intracranial pressure are fre
26 0091-7370/91/0100-0026 $01.50 © Institute for Clinical Science, Inc.
BRAIN TUMORS IN CHILDREN; A REVIEW 27
quently seen with headaches and vomit ing being the most conspicuous. O ther non-specific symptoms and signs should be sought; these include changes in per sonality and school perform ance, le th argy, fluctuations in weight, and neuro endocrine problem s .16’17 Early signs of papilledema, such as cecal scotomas and dyschromatopsia, may be present. Incip ient tonsillar herniation may induce a head tilt or neck stiffness. Hemisensory, hemimotor, or hemianopic 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 po in ts to b ra in stem in v o lv e m e n t .36 Radicular symptoms such as pain, weak ness, or paresthesias that follow a der- matonal pa ttern suggest cerebrospinal fluid seeding by tum or cells and should prom pt a search for the primary tumor and the extent of its dissemination .21
Visual com plain ts in ch ild ren w ith neurofibromatosis Type I may be symp toms of an optic nerve glioma; visual acuity and visual fields should be moni to red carefu lly in these p a tie n ts .2425 Signs o f n eu ro en d o c rin e dysfunction such as fluctuations in growth and devel opm ent suggest lesions in midline struc tures such as the hypothalamus and pin eal gland .40
Seizures are m ore frequen tly asso ciated with slow growing tum ors than with more aggressive lesions. Complex partial seizures are the most common se iz u re ty p e se en w ith in tra c ra n ia l m asses. Tumors in the tem poral lobe usually cause seizures early in the course of disease.2
Pathology
It is an axiom of pediatric neurology that in the first decade of life 50 percent of all brain tumors will be in the poste rior fossa and will most frequently be of glial origin.
Astrocytomas
A strocy tom as in c h ild ren a re f re quently of low grade. They are charac terized by a feltw ork of fibrillar p ro cesses. Pilocytic (figure 1), protoplasmic, microcystic (figure 2), and gemistocytic p a tte rn s a re reco g n ized . O ccasional transformation to higher grade lesions, including glioblastomas, may occur. The recent Mayo Clinic classification is sim ple, precise, reproducible, and corre lates histologic grade with probability of su rv iva l.10 A strocytom as in ch ild ren , even anaplastic tumors, generally have a b e tte r prognosis than adult tum ors of comparable grade.
Cerebellar astrocytomas have the best prognosis of any childhood brain tum or.9 Lesions corresponding to the “Glioma A” of Gilles comprise two thirds of cere bellar astrocytomas and are character ized by m icrocysts, R osenthal fibers, leptomeningeal deposits, and foci of oli godendrog liom a .20 “ G liom a B” has a poor prognosis and shares histologic fea tures with ependymomas including peri vascular pseudorosettes, mitosis, high cell density, and necrosis. Vascular endo thelial proliferation and leptomeningeal invasion are som etim es seen in low grade cerebellar astrocytom as o f ch il dren and do not have the ominous prog nostic conno ta tion th a t th ey carry in adult tu m o rs .49 N inety p e rcen t of 25- year survivals after surgery are reported in ped iatric cerebellar astrocytom as .9 Rare malignant degeneration may be seen in association with neurofibromatosis.32,39
Ependym omas
Ependymomas in children are usually found in the posterior fossa, often within th e cavity of th e fo u rth v e n tr ic le .36 Tum or cells have a p in p o in t nuclear ch ro m a tin p a tte rn and a re typ ica lly arran g ed in a rad ia l fashion to form
28 LACAYO AND FARMER
F ig u r e 1. Juvenile pilocytie astrocytoma. C erebellum . Many eosinophilic granular bodies and Rosenthal fibers are p resent. Tumor cells are bipolar with piloid cytoplasmic processes. Nuclear atypia is not indicative o f poor prognosis. (H& E X400)
F ig u r e 2. Microcystic astrocytoma. Lateral cerebellum . Tumor nuclei are bland, and there is a delicate fibrillar background. N um erous microcysts contain a proteinaceous transudate. (H&E X 250)
BRAIN TUMORS IN CHILDREN; A REVIEW 29
r o s e t t e s o r p e r iv a s c u la r p s e u d o r o se tte s .18 Cilia and blepharoplasts may be p re s e n t in th e ap ica l cy to p lasm and w hen p resen t help to confirm the diag nosis (figure 3). E pendym om as have an u n fo r tu n a te te n d e n c y to m e ta s ta s iz e th roughout the cerebrospinal flu id pa th ways. M itoses and o ther m alignant fea tu res are seen in 50 p e rcen t of cases, usually in infants.41
M edulloblastomas
M edulloblastom as are said to originate from th e fe ta l g ra n u la r ce ll la y e r o f O b e r s t e i n e r . 47 By d e f in i t io n th e s e tum ors are exclusively cerebellar. They are found m ost often in the m idline and constitu te about 40 percen t of all poste rior fossa lesions.38 They are grossly soft, friable and often well dem arcated tum ors w ith occasional necrosis, cyst formation and calcification. L ep tom en ingea l and ce reb ro sp in a l flu id seed ing occurs fre
q u e n tly . E x t r a n e u ra l m e ta s ta s e s to lym ph nodes and bone m arrow may be seen .27 T hese tum ors are characterized by th 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 om er W right rosettes. A nodu lar o r follicular g row th p a tte rn is som etim es encoun te red in m edulloblas tom as. F req u en tly , this p a tte rn is the consequence of proliferation of desm o- p lastic e le m e n ts w ith in th e tum or, or m ay in d ica te n eu ro b la s tic o r g lial d if fe re n tia tio n w ith in th e tu m o r .26 M e d u llob lastom as once ca rried a d ism al prognosis, b u t w ith the advancem ent in rad ia tion and chem otherapy , five year survival can be as high as 70 p e rc e n t.19 P o ly a m in e s m ay b e u s e f u l tu m o r m arkers to m on ito r d u rin g th e course of tre a tm e n t.13
Prim itive N euroectoderm al Tum ors
T um ors h isto logically and clin ically s im ilar to m ed u llo b lasto m as a re occa
F ig u r e 3. Ependym om a. Fourth ventricle. Tumor cells form a characteristic rosette. B lepharoplasts are seen as densities in the apical cytoplasm. (H&E X400)
30 LACAYO AND FARMER
s io n a lly s e e n in th e c e re b ra l h e m i spheres, and have been referred to by a variety of term s including “cerebral n eu rob lastom as” . R ecently , it has becom e fashionable to refer to these poorly dif f e r e n t ia te d sm all c e ll n e o p la sm s as “ p r im itiv e n e u ro e c to d e rm a l tu m o rs ” (PNET) (figure 4).35 This unifying con cept suggests an origin of these lesions from u n d iffe ren tia ted n eu ral cells and im plies a m echanism of oncogenesis that is unproven. W hile this term (PNET) is w idely and uncritica lly used , S cheith- auer states: “A lthough it is a provocative co n cep t, it does litt le to forw ard o u r u n d erstan d in g o f neoplasia and it is a poor basis for a m orphological system of tum or classification.”42
G erm Cell Tumors
G erm cell tum ors of the brain are rare bu t distinctly ped iatric neoplasm s. They
account for about 15 p ercen t o f all brain tu m o rs in c h ild re n , b u t less th an one p ercen t of adult brain tum ors. They are located in the m idline e ith e r in the p in eal region or less often in a suprasellar site. M ore often found in males, they are typically associated w ith developm ental abnorm alities and n eu ro en d o crin e d is o rders, especially precocious puberty . H istologically , th ese lesions re sem b le the germ cell tum ors of the testis. The m ost f re q u e n t ty p e is a g e rm in o m a. M ixed patterns w ith features of chorio carcinom a, em bryonal carcinom a, endo- derm al sinus tum ors, and teratom as with m a tu re an d im m a tu re e le m e n ts a re encoun te red (figure 5).6 Tum or m arkers including alpha-fetoprotein, hum an cho rionic gonadotropin, and hum an p lacen tal lactogen may be e laborated by germ ce ll n eo p lasm s. T h e id e n tif ic a tio n of these m arkers in the blood and cereb ro spinal flu id may facilitate diagnosis and trea tm en t.37
F ig u r e 4. Prim itive neuroectoderm al tum or (PNET). C erebral hem isphere. T here is a nesting pattern of undifferentiated neuroepithelial cells. (H&E x 250)
BRAIN TUMORS IN CHILDREN; A REVIEW 31
F ig u r e 5. T eratom a. P in ea l r eg io n . T h e re is a m ix tu re o f cartilage , e p ith e lia l e le m e n ts a n d u n d iffer e n tia ted m e sen ch y m e . (H & E X 250)
Sarcomas
True, p rim ary central nervous system sarcom as a re ra re , b u t th e y m ay be found in th e first decade of life. Some arise from th e m eningeal coverings of th e brain, bu t a certain nu m b er clearly originate from the cerebral parenchym a w ithout any a ttachm ent to the arachnoid or d u ra .41 T he polym orphic cell variant is the least d ifferentiated type, has the m ost aggressive biology, and has a p ro pensity to d issem inate th ro u g h o u t th e su b arach n o id space. P rim ary rh a b d o myosarcomas of the brain m ay be found in p u re form or m ixed w ith o th er m esen chym al e lem en ts .23
Diagnosis
S ev era l re c e n t d e v e lo p m e n ts have en h an ced th e accuracy of bra in tum or diagnosis. C om puted tom ography of the brain and nuclear m agnetic resonance,
along w ith the use of contrast m aterial and p a ram ag n e tic ag en ts , have e n o r mously facilitated brain tum or diagnosis an d p ro v id e fin e an a to m ic d e ta i l .3,15 O ncogenes are genes that are inappro priately expressed and con tribu te to the developm ent of neoplasia. M ore than 40 o n c o g e n e s h av e b e e n id e n tif ie d . O f in te re s t in p ed ia tric neuro-oncology is the amplification of the N-myc oncogene in n e u ro b la s to m a . S urv ival w ith th is tu m o r c o r re la te s in v e rs e ly w ith th e degree of am plification found.34 In five p ercen t of non-inherited forms of re tino b lastom a, a co n stitu tio n a l d e le tio n of c h ro m o s o 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 genetic linkage betw een esterase D and the disease. Associations betw een C-m yc and ERB-B oncogenes have been found w ith g lio b la s to m a s .46 T h e s p re a d in g availability of polym erase chain reaction technology m ay m ake m olecular d iag nosis rou tine in hospital laboratories.
32 LACAYO A N D FARMER
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 cytometry a helpful modality in the diag nosis of bladder irrigates, effusions, spu tum , bronchial washings, and cerebro spinal flu id collections. The adverse impact of aneuploidy and S percentage m ay m ake th e s e u se fu l p ro g n o s tic param eters. Studies have docum ented higher rates of relapse in brain tumors found to be aneuploid, especially medul- loblastomas.4
Immunohistochemistry and Tumor Markers
Im m u n o h is to ch e m is try and tu m o r markers have greatly strengthened the arm em entarium of oncologists. Peroxi- dase-antiperoxidase techniques for the demonstration of neural and non-neural cell m arkers have contributed to diag nostic accuracy of histologically rare, complex or otherwise difficult tumors of the central nervous system .7 It is impor tant to emphasize, however, that none of these markers is specific, and that each should be in te rp re te d in the light of other clinical and laboratory information. Some tum or m arkers, such as polya mines, can be m onitored during trea t m ent to gauge disease progression or efficacy of therapy .13 In table I are p re sented some of the more useful markers available.
Electron Microscopy
E lectron m icroscopy often makes a valuable contribution in identifying and classifying tum ors that pose diagnostic problem s. E lectron microscopy can be especially decisive in the diagnosis of
TABLE I ab Tumor Markers
Tumor Marker
Germ cell neoplasia
Meningeal carcinoma tosis
hCG d, pregnancy specific beta 1-glycoprotein (SP-1) and AFP®
Beta glucoronidase Cytokeratins, AFP «,
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. Is routinely detected in choroid plexus carcinomas, but not in papillomas.
small cell tumors of the brain, poorly dif ferentiated gliomas, unusual meningeal tum ors,…
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