Literature Review Paper

N e u r o p a t h o l o g y o f P e d i a t r i c B r a i n T u m o r s

Anthony T. Yachnis

Pediatric central nervous system neoplasms include a spectrum of both glial and nonglial tumors that differ significantly in location and biological behavior from those of adults. Brain tumors in infants and children most often arise from central neuroepithelial tissue, whereas a significant number of adult tumors arise from central nervous system coverings (eg, meningioma), adjacent tissue (eg, pituitary adenoma), or metastases. Most adult brain tumors are supratentorial malignant gliomas, whereas the most common malignant pediatric brain tumor is the cerebellar primitive neuroectodermal tumor ( m e d u l l o b l a s t o m s ) . T h i s article reviews neuropathological charac- teristics of the more common pediatric brain tumors. Entities, such as the brainstem glioma, and less common neoplasms like t h e desmoplastic infantile ganglioglioma and the central nervous system atypical teratoid/rhabdoid tumor are reviewed because they occur almost exclusively in children. Known cytogenetic and molecular characteristics of childhood brain tumors are also reviewed. Copyright �9 1997 by W.B. Saunders Company

p EDIATRIC CENTRAL NERVOUS system (CNS) tumors include a variety of histological

types, many of which differ pathoanatomically and, in some cases, genetically from adult brain tu- mors. ~-3 Although most primary intra-axial brain tumors in adults are supratentorial, diffusely infil- trating gliomas (the most common being the highly malignant glioblastoma multiforme), pediatric brain tumors include a spectrum of both supratentorial and infratentorial tumors that, for simplicity, can be divided into glial and nonglial types. The pilocytic astrocytoma represents a distinct subtype of glioma that is most common in children and is genetically and biologically distinct from the diffuse, infiltrat- ing gliomas that affect both adults and children. Nonglial brain tumors of childhood include a group of poorly differentiated, embryonal tumors with distinct clinicopathological characteristics. The me- dulloblastoma is the prototype of embryonal CNS tumors and is among the most common malignant solid tumors of childhood. 4 Whereas CNS metasta- ses and extrinsic CNS tumors, such as meningioma and pituitary adenoma, account for about a third of adult brain tumors, in a series of 744 pediatric brain tumors, they accounted for only 4.8% of cases.1

The gross and histological characteristics o f some common intrinsic pediatric CNS tumors are reviewed. This article focuses on neuroepithelial tumors that arise from brain parenchyma because

From the Department o f Pathology, Immunology, and Labora- tory Medicine, University o f Florida Brain Institute and College o f Medicine, Gainesville, FL.

Address reprint requests to Anthony T. Yachnis, MD, Depart- ment o f Pathology and Laboratory Medicine, University o f Florida College o f Medicine, 1600 S W Archer Rd, JHMHC, Gainesville, FL 32610.

Copyright �9 1997 by W..B. Saunders Company 1071-9091/97/0404-000455.00/0

these are most common in children. Also reviewed are some less common entities with which the pediatric neurologist or neuro-oncologist should be familiar because they present almost exclusively in children and because o f their important prognostic and therapeutic significance. Tumors arising from non-neuroepithelial tissues are only briefly consid- ered. Although the etiology and pathogenesis o f most pediatric brain tumors remain incompletely understood, recent cytogenetic and molecular data are becoming available and are summarized for relevant tumors types. More complete and detailed accounts o f the neuropathology, molecular genet- ics, and histopathologic classification o f tumors discussed in this article are available in several excellent texts and reviews.l,5-8

THE ROLE OF THE NEUROPATHOLOGIST

Establishing the correct pathological diagnosis o f a pediatric brain tumor is critical in directing subsequent therapeutic efforts. A child may be needlessly exposed to radiation if an essentially benign pilocytic astrocytoma is not distinguished from a nonpilocytic, diffusely infiltrating astrocy- toma. A primitive neuroectodermal tumor that requires craniospinal irradiation must be correctly distinguished from a poorly differentiated glial neoplasm. The interpretation o f surgically resected material requires the skills of a diagnostic patholo- gist with experience in pediatric CNS neoplasia. Knowledge of the clinical history and radiographic findings are extremely helpful in the accurate evaluation o f frozen sections and touch prepara- tions during intraoperative consultation. Arriving at a final diagnosis may require the full range o f diagnostic techniques available in the m o d e m ana- tomic pathology laboratory including immunohisto- chemistry, flow cytometry, and electron micros-

282 Seminars in Pediatric Neurology, Vol 4, No 4 (December), 1997: pp 282-291

PEDIATRIC BRAIN TUMORS: PATHOLOGY 283

copy. Finally, the pathologist must evaluate the usefulness and cost-effectiveness and test new diagnostic methods. The basic principles of neuro- pathological diagnosis of pediatric brain tumors have recently been reviewed. 9,1~

TUMORS OF NEUROEPITHELIAL ORIGIN

Glial Neoplasms Glial neoplasms (gliomas) are the most common

brain tumors of children. Classically, these tumors display histological characteristics that are reminis- cent of mature CNS glia; hence the term astrocy- toma (astrocytes), oligodendroglioma (oligodendro- cytes), and ependymoma (ependymal cells). Most glia, with the exception of oligodendrocytes, show some degree of immunoreactivity for glial fibrillary acidic protein (GFAP), the major intermediate filament of glial cells. Choroid plexus tumors are also usually included in the glioma group.

The pilocytic astrocytoma is a clinicopathologi- cally distinct form of glioma that occurs most commonly in childhood and is usually histologi- cally and clinically benign.l.5,7,8 Pilocytic astrocyto- mas arise most commonly in the cerebellum where they often present as a well-circumscribed cyst with a mural nodule (Fig 1A). Solid (noncystic) variants may also be encountered. Tumors of similar type may also occur in the optic nerves and chiasm, hypothalamus, cerebral hemispheres, and brainstem. In the latter location, pilocytic astrocyto- mas tend to be dorsally exophytic rather than diffusely infiltrating (see brainstem gliomas be-

low). Symptoms are due to local effects of the tumor.

Histological characteristics of the pilocytic astro- cytoma are similar regardless of location. A typical biphasic pattern consists of areas containing tightly packed, piloid (hairlike) tumor cell processes alter- nating with areas having numerous microscopic cysts (Fig 1B). The latter often coalesce to form larger cysts. Nonspecific changes of astrocytic cell processes, such as Rosenthal fibers and eosino- philic granular bodies, are also characteristic. In an otherwise typical pilocytic astrocytoma, the pres- ence of vascular proliferation or nuclear atypia do not correlate with aggressive behavior (as they do in diffuse forms of astrocytoma). Mitoses are usually rare. Although grossly circumscribed, these tumors may locally infiltrate adjacent tissues and may extend into the adjacent subarachnoid space. Neither of these features suggests a tendency for aggressive behavior. Anaplastic (malignant) pilo- eyrie astrocytomas are rare.11

Although most pilocytic astrocytomas have nor- mal karyotypes, 3 deletions on the long arm of chromosome 17 have been reported.12 A p53 muta- tion (exon 9, codon 324) was recently identified in one of seven pilocytic astrocytomas, but this was a silent mutation and its significance is uncertain. ~3

Diffuse astrocytomas constitute a spectrum of infiltrating astroglial tumors that display increasing grades of anaplasia and include the low-grade diffuse (fibrillary) astrocytoma, anaplastic (interme- diate grade) astrocytoma, and glioblastoma multi-

Fig1. (A) Cerebellar pilocytic astrocytoma consisting of a large, well-circumscribed cyst that compresses the fourth ventricle (v). Arrow indicates a mural nodule of solid tumor. (B) Histological section from the mural nodule of a pUocytic astrocytoma. The tumor contains abundant piloid (hairlike) processes and microscopic cysts. Arrows indicate Rosenthal fibers. (H&E; original magnification x 200.)

284 ANTHONY T. YACHNIS

forme (high grade). These intra-axial tumors m a y present as supratentorial or infratentorial masses and are similar in histology and biological behavior to those affecting adults. 5,7,8 The common pathologi- cal features o f this group are: (1) extensive infiltra- tion o f CNS tissue and (2) a tendency o f lower grade lesions to progress to higher grade lesions. 7 Diffuse (fibrillary) astrocytomas tend to arise in white matter and often extensively invade adjacent gray matter structures. In contrast to the pilocytic astrocytoma, these tumors are difficult to eradicate by surgery alone because o f poor demarcation between tumor and surrounding normal tissues.

The histologically malignant astrocytomas (ana- plastic astrocytoma and glioblastoma multiforme) o f childhood are infiltrative, biologically aggres- sive neoplasms as they are in adults. However, cytogenetic characteristics of pediatric malignant astrocytomas differ from those most commonly encountered in adults. Structural abnormalities in chromosbmes 9, 13, 17, and double minutes were observed in malignant astrocytomas (anaplastic a s t r o c y t o m a and glioblastoma) o f childhood, whereas the most common chromosomal abnormali- ties in adult glioblastomas are losses o f chromo- some 10 and 19q or gains in chromosome 7. 3 Furthermore, to date, the pattern of chromosomal abnormalities found in malignant astrocytomas o f childhood are similar to those reported in a geneti- cally distinct subset o f glioblastomas that was found to arise in young adults. 14

Brainstem gliomas f o r m a distinct group o f brain tumors that are most c o m m o n in children and account for t 0 % o f pediatric CNS neoplasmsJ 5 Approximately 80% o f pediatric brain stem glio- mas are diffusely infiltrating astrocytomas and, o f these, about 50% are histologically malignant at presentation. ~6 Grossly, brainstem structures are diffusely expanded and normal structures are ef- faced by the tumor (Fig 2). Extensive infiltration o f tumor along white matter tracts is typical. At autopsy, there is usually evidence o f radiation necrosis as well as residual tumor. Louis et aP 7 reported losses o f portions of chromosome 17p, mutations o f p53, and allelic losses of chromosome 10q in brainstem gliomas; a pattern that is similar to a subset o f supratentorial glioblastomas that occurs in young adultsJ 4

Less common forms o f brainstem glioma include focal, cystic, cervicomedullary, and tectal types? 8 In contrast to the diffuse type, these tumors tend to

Fig 2. Brainstem glioma diffusely expanding the pons and effacing normal structures. Several small cysts are present on the left side of the infiltrated brainstem.

be well circumscribed, exophytic, and display histological and biological characteristics o f pilo- cytic astrocytomas.

The pleomorphic xanthoastrocytoma (PXA) is a primary, CNS neoplasm originally described b y Kepes et a119,2~ which tends to be superficially located, supratentorial, and has a predilection for the temporal lobe. The tumor characteristically affects children and young adults who often present with a history o f intractable seizures. Imaging studies usually reveal a large, well-circumscribed mass with cystic and solid components. Histologi- cal characteristics include considerable nuclear and cellular pleomorphism with frequent cytoplasmic lipidization and giant cell forms. Mitotic figures and areas o f necrosis are rare. The superficial location o f these tumors makes them accessible to surgical excision and favorable outcomes have been achieved. However, some tumors locally infiltrate adjacent brain tissue and recurrences have been reported. PXAs are immunoreactive for glial fibrillary acidic protein (GFAP), establishing their astrocytic differentiation. 19,2~ The occasional coex- istence o f ganglioglioma and PXA and recently documented immunoreactivity of PXAs for neuro- nal antigens suggests a relationship between P X A and ganglion cell neoplasia. 21,22 Novell p53 mis- sense mutations were recently found in two o f eight PXAs. 23

Oligodendrogliomas are infiltrating glial neo- plasms that are composed primarily of oligodendro- cytes. They account for only about 2% pediatric intracranial tumors. 1 They arise most c o m m o n l y in

PEDIATRIC BRAIN TUMORS: PATHOLOGY 285

the cerebral hemispheres (especially the frontal lobes) but may occur anywhere in the neuraxis. 5,7 The cortical location o f many oligodendrogliomas accounts for clinical findings o f a long history o f seizures in many patients. These frequently calci- fied tumors are composed o f a uniform population o f round cells with clear perinuclear cytoplasm. Tumors are usually permeated by a delicate mesh- work o f angulated capillaries. Allelic deletions o f chromosomes l p and 1 9q appear to occur preferen- tially in oligodendrogliomas. 24,25

Ependymomas are most c o m m o n in children where they most frequently arise in the fourth ventricle (Fig 3A). In this case, symptoms are related to fourth ventricular obstruction. These tumors may also arise in association with the lateral ventricles and, in adults, the spinal cord is a c o m m o n site of origin.~,5.7 Grossly, fourth ventricu- lar ependymomas are exophytic growths that often arise from the ventricular floor and fill this cavity. Tumor m a y extend into the basal subarachnoid space through the foramina o f Lushka or protrude into the cisterna magna. Ependymomas invade adjacent parenchymal structures but, in general, tend to be better circumscribed than infiltrating astrocytomas. They tend to be gray-tan, granular, and may contain cysts or areas o f hemorrhage. Microscopically, the tumor is composed o f a uni- f o r m population o f cells with round to oval nuclei and fibrillary processes; the latter directed toward abundant intratumoral blood vessels forming a distinct perivascular pseudorosette pattern (Fig 3B). Better differentiated examples m a y contain

tubular structures and canals. Although ependymal tumors with increased cellularity, pleomorphism, mitoses, and necrosis have been termed anaplastic or malignant, such histological features have been less predictive o f biological behavior or patient outcome than in the diffuse astrocytomas. At least part o f the reason for this could be the tendency for (even histologically benign) ependymomas to un- dergo spontaneous hemorrhage and to invade struc- tures of the fourth ventricular floor. 1

Chromosomal abnormalities identified in ependy- momas include m o n o s o m y and deletions of chromo- some 22, trisomy o f chromosome 7, loss o f sex chromosomes, and structural rearrangements of chromosome 2. 7 In addition, chromosomes 9 and 11 may harbor genes involved in the pathogenesis o f ependymoma. A deletion o f chromosome 1 has been identified in the myxopapillary ependymoma, a distinct subtype that arises in the region o f the ilium terminale. 7

Choroid plexus papillomas also present as intra- ventricular tumors. They are most common in children in whom the lateral ventricles are the most frequent location. ~,8 Patients often present with increased intracranial pressure and hydrocephalus that have been attributed to increased production o f cerebrospinal fluid by the tumor as well as ventricu- lar obstruction. Tumors arise as cauliflowerlike masses that histologically resemble normal choroid plexus. These papillary neoplasms show increased cell density and low mitotic activity. Increased mitotic activity and evidence of invasion suggest a potential for local recurrence and aggressive behav-

Fig 3. (A) Ependymoma filling the fourth ventricle. Darker regions of the tumor correspond to areas of hemorrhage. (B) Histological section of an ependymoma showing a uniform population of cells with round to slightly oval nuclei and indistinct cell borders. Perivascular clear areas ("pseudorosettes") represent tumor cell processes oriented perpendicular to intratumoral vessels. (H&E; original magnification x500.)

286 ANTHONY T. YACHNIS

ior. Choroid plexus carcinomas are most c o m m o n in young children, usually less than 3 years o f age. 26'27 These are typically poorly differentiated, anaplastic neoplasms that are frankly invasive.

Choroid plexus tumors have occurred in familial syndromes including von Hippel-Lindau, Li- Fraumeni, and Aicardi's syndromes, but consistent abnormal genetic loci have not yet been identi- fied. 28 Although abnormal p o l y o m a virus se- quences have been associated with these tumors, a definitive role in pathogenesis remains uncertain.

Ganglion Cell Tumors

Ganglion cell tumors include a spectrum o f CNS neoplasms that have in c o m m o n a population of neoplastic or hamartomatous mature neurons (called ganglion cells). The ganglioglioma is the prototype of this group. Approximately 75% of ganglioglio- mas present in the temporal lobe. Less c o m m o n locations include the brainstem, spinal cord, optic nerve and chiasm, pineal gland, and cerebellum. Mean age at diagnosis is approximately 20 years, but because many patients present with a long history o f seizures, it is safe to say that most o f these tumors arise during childhood and adoles- cence. 7 These slowly growing neoplasms are usu- ally well circumscribed, often cystic, and m a y be associated with adjacent areas o f cortical dyspla- sia. 5,8 Gangliogliomas are composed o f two histo- logic components: a neoplastic astroglial element, which tends to be well-differentiated (low grade) and a population o f ganglion cells. The latter have features o f mature neurons including the following: large vesicular nuclei; prominent nucleoli; cytoplas- mic Nissl substance; immunoreactivity for neuro- nal antigens, such as neurofilament protein and synaptophysin; and little if any proliferative activ- ity. 29 Abnormal ganglion cells o f a ganglioglioma tend to occur in clusters, have abnormally oriented cell processes, and m a y occasionally be binucle- ated (Fig 4). 3o Varying degrees of calcification, desmoplasia, lymphocytic infiltration, and "pilo- cytic" differentiation m a y also be observed. Al- though rare malignant degeneration has been de- scribed, surgical resection is the treatment o f choice and is curative in many cases. 31 No consistent genetic abnormalities have been reported as of this writing.

The desmoplastic infantile ganglioglioma (DIG)

Fig 4. Ganglioglioma with binucleate ganglion cell immuno- stained for synaptophysin, Unstained cells at upper right hand corner are of astrocytic lineage. (Original magnification • 1200,)

is a more recently described variant o f ganglio- glioma that accounts for less than 0.1% o f primary intracranial tumors. 32 Patients are usually less than 2 years o f age at presentation and m a y have a history o f rapidly increasing head circumference. These tumors are typically huge, well-circum- scribed, supratentorial masses that are superficially located and often involve the leptomeninges. They are firm owing to extensive deposition o f stromal collagen and may contain cystic areas. Both glial and neuronal elements can be identified by immu- nohistochemical staining.

The desmoplastic cerebral astrocytoma o f in- fancy is similar clinicopathologically to the D I G except that neuronal elements are not identified. 33

Another more recently described glioneuronal lesion that tends to present in childhood is the dysembryoplastic neuroepithelial tumor (DNT). 34-36 Similar to the ganglioglioma, the D N T typically arises in the temporal lobe in patients with pro- longed seizures. Patients are usually less than 15 years o f age. Grossly, DNTs are nodular, intracorti- cal masses that do not extend into the adjacent subcortical white matter. Key histological findings include a specific glioneuronal element composed of bundles o f axons attached to columns or cords o f oligodendroglia-like cells with intervening cystic areas containing mucoid interstitial fluid. Mature neurons are occasionally observed floating in the mucoid fluid. Circumscribed microscopic nodules o f low-grade astrocytoma, oligodendroglioma, and mixed-oligoastrocytroma are also common. Slow growth is confirmed by low proliferative indices displayed by most o f these tumors. 34,35 The fre- quent finding o f cortical dysplasia adjacent to

PEDIATRIC BRAIN TUMORS: PATHOLOGY 287

apparent neoplastic areas, along with the multiple cell lineages found in the DNT, suggests an abnor- mality in embryologic development. 34,35 These tu-

mors are slowly growing and generally benign.

Embryonal Tumors

Embryonal tumors of the CNS include a group of malignant growths that are much more common in children than in adults. For purposes of this article, they include the medulloblastoma and related primi- tive neuroectodermal tumors, medulloepithelioma, and CNS atypical teratoid/rhabdoid tumor.

Primitive neuroectodermal tumors (PNETs) of the CNS are malignant, poorly differentiated neo- plasms that can be shown to express glial and neuronal/neuroendocrine features by immunohisto- chemistry. Rarely, myoblastic and melanotic char- acteristics are observed. Although the cerebellar medulloblastoma (PNET/MB) is the prototype of this group, Rorke 1,37,38 has emphasized that other pediatric CNS tumors with similar histological and immunophenotypic characteristics, such as the "ep- endymoblastoma," "pineoblastoma," and "cere- bral neuroblastoma," should he included within the spectrum of CNS PNETs until more is learned about the etiology, molecular genetics, and patho- genesis of these lesions. The above tumors remain as distinct clinicopathologic entities that are de- fined by location and, to some extent, biological behavior. For example, with current therapies, the PNET/MB typically has a far better prognosis than pineoblastomas or cerebral PNETs. For a more complete discussion of the pathology of nonmedul- loblastoma PNETs, the appropriate sections in texts by Burger et al 5 or Lantos et al 7 may be consulted.

The cerebellar PNET/MB is among the most common malignant solid tumor of childhood. 4 It arises from the cerebellum, classically in the mid- line from the inferior vermis in the roof of the fourth ventricle. Growth of this usually fleshy, solid mass leads to ventricular obstruction and symp- toms of increased intracranial pressure. Tumor tends to infiltrate the cerebellar peduncles and sometimes the brainstem and leptomeninges. Spread along CSF pathways with spinal ( " d r o p " ) metasta- ses are characteristic.

Histologically, PNET/MBs are highly cellular and are composed of small to medium-sized cells with round to oval, often molded (carrot-shaped),

hyperchromatic nuclei, and poorly defined cell borders. Homer Wright rosettes (ringlike accumula- tions of tumor cell nuclei around a neuropil- containing or fibrillary core) are occasionally ob- served (Fig 5). These tumors express a variety of neuronal/neuroendocrine markers including synap- tophysin (a 38 kDa synaptic vesicle protein) and neurofilament proteins. 39,4~ Photoreceptor differen- tiation (retinal S-antigen and rhodopsin) is identi- fied in 27% to 50% of these tumors. 7 Glial fibrillary acidic protein has been reported in between 13% and 62% of PNET]Mbs. 7,41 One recent study found that patients with PNET/MBs that contained sheets or clumps of GFAP-immunoreactive neoplastic cells had a threefold increased risk of recurrence than those tumors without GFAP immunoreactiv- ity. 41

The most common molecular genetic abnormal- ity that has been identified to date in PNET/MB is loss of heterozygosity of chromosome 17p that occurs in 30% to 50% of cases and seems to predict a poor prognosis. 42,43 However, the PNET/MB- related locus on 17p appears to be distinct from p 5 3 . 44 Flow cytometric analyses have indicated a worse prognosis for D N A diploid tumors, whereas aneuploid tumors have a better prognosis. 45

The "desmoplastic" variant of PNET/MB was reported in about 12% of pediatric medulloblasto- mas and tends to affect an older age group. 7 In contrast to the "classic" form it often arises in a hemisphere. The presence of reticulin-free "pale islands" is a characteristic histopathologic f e a t u r e . 46

In contrast to the PNET/MB, the medulloepithe- lioma is a rare CNS embryonal tumor that typically presents as a large, paramidline mass of the cere-

Fig 5. Primitive neuroectodermal tumor of the cerebellum (medulloblastoma) with several Homer Wright rosettes. (H&E; original magnification • 1000.)

288 ANTHONY T. YACHNIS

brum. Such tumors may also arise in the cerebel- lum, brainstem, third ventricle, and spinal c o r d . 47 The characteristic histological features include primitive-appearing areas composed o f cords and trabeculae o f tumor cells and vesicular structures that resemble the embryonic neural tube. Over half of these tumors show some evidence o f differentia- tion along glial or neuronal lines. Medulloepithelio- mas are highly malignant. Molecular genetic data are currently lacking.

Primary CNS atypical teratoid/malignant rhab- doid tumors (ATT/RhT) are highly malignant neo- plasms of infancy and childhood. Rorke et al48,49 recently reported the most extensive clinicopatho- logic series and reviewed the prior literature. The tumor usually presents in infancy or early child- hood with a mean age at diagnosis o f 29 months. 48 Although such tumors have been reported at all levels o f the neuraxis, the posterior fossa (espe- cially the cerebellum) is the most common site o f origin. In the latter site, AT17RhTs display similar clinical and radiographic features as primitive neuroectodermal tumor-medulloblastomas (PNET- MBs). In addition, most o f CNS ATT/RhTs are histologically mixed tumors that contain a "rhab- doid" element plus variable amounts of PNET-like areas. Recognition o f the rhabdoid element by the pathologist is critical because this phenotype corre- lates with a significantly worse prognosis that the classic PNET/MB. 48,49 Extensive brain invasion and early cerebrospinal fluid dissemination are consistent findings that contribute to an overall survival of only 6 months. 48

ATT/RhTs are characterized by the presence o f a distinct cell type (the rhabdoid cell) that contains a large, vesicular (ie, lightly staining chromafin) nucleus, prominent nucleolus, and a concentration o f whorled cytoplasmic intermediate filaments (Fig 6). Although early observers noted the superfi- cial resemblance to a rhabdomyoblast, the immuno- phenotype o f rhabdoid cells is complex with epithe- lial, mesenchymal, glial, and occasionally, neural/ neuroendocrine antigens having been identified. Tumors composed o f morphologically similar cells were first described in the kidneys o f infants and young children) ~ However, only a few pediatric CNS ATT/RhTs contain a pure population o f rhab- doid cells. Approximately 70% o f cases contain areas o f both rhabdoid and PNET (ie, small blue

Fig 6. CNS atypical teratoid/rhabdoid tumor. Many tumor cells contain whorls of cytoplasmic "inclusions" that contain intermediate filaments (arrows). (H&E; original magnification x 400,)

cell) histology. The only consistent cytogenetic abnormality is loss o f chromosome 22. 51

NON-NEUROEPITHELIAL TUMORS

Tumors of Epithelial Cell Rests

Craniopharyngiomas account for approximately 5% to 6% o f all pediatric intracranial tumors with a peak incidence in the first decade. 1,52 They are believed to be derived from remnants o f Rathke's pouch (pituitary anlage), typically arise as suprasel- lar masses, and about half have an intrasellar component. 52 The "adamantinomatous" type is usually seen in children and is discussed in this article. (A second, more recently described "papil- lary" variant o f craniopharyngioma occurs almost exclusively in adults.)

Grossly, adamantinomatous craniopharyngio- mas have cysts containing viscous material and are frequently calcified. Histological study reveals a stratified squamous epithelium with peripheral ac- cumulation o f tumor cells and more internally situated loose, degenerative-appearing epithelium called "stellate reticulum" (Fig 7). Plump deposits o f so-called " w e t keratin" that may undergo dystro- phic calcification are typical (Fig 7). Craniopharyn- giomas are locally invasive and the adjacent brain tissue usually shows an exuberant reactive gliosis. The latter m a y contain large numbers o f Rosenthal fibers, which in some cases may simulate a pilo- cytic astrocytoma. 5

Epidermoid and dermoid cysts m a y occur at any age. Epidermoid cysts typically present as cerebel- lopontine angle masses and are composed o f strati-

PEDIATRIC BRAIN TUMORS: PATHOLOGY 289

Fig 7. Craniopharyngioma with intraepithelial vacuolated areas ("stellate reticulum") and islands of "wet" keratin, (H&E; original magnification x 500.)

fled s q u a m o u s e p i t h e l i u m that e l a b o r a t e s e x t e n s i v e f l a k y o r " d r y " k e r a t i n . M u c h o f the t u m o r v o l u m e r e s u l t s f r o m the s l o w a c c u m u l a t i o n o f such " d r y " k e r a t i n . I n contrast, d e r m o i d c y s t s are u s u a l l y m i d l i n e i n t r a c r a n i a l m a s s e s c o m p o s e d o f stratified s q u a m o u s e p i t h e l i u m p l u s skin a d n e x a l structures ( s u c h as h a i r f o l l i c l e s and s e b a c e o u s g l a n d s ) .

Pituitary Tumors

P i t u i t a r y a d e n o m a s a r e u n u s u a l in c h i l d r e n a c - c o u n t i n g for o n l y 1.1% o f all i n t r a c r a n i a l t u m o r s in one l a r g e p e d i a t r i c series, t T h e y a r i s e f r o m the a d e n o h y p o p h y s i s and are h i s t o l o g i c a l l y m o n o m o r - p h o u s a n d b e n i g n - a p p e a r i n g . P i t u i t a r y a d e n o m a s m a y p r o d u c e s y m p t o m s b y s e c r e t i n g a d e n o h y p o h y - seal h o r m o n e s or b y l o c a l effects o f the e x p a n d i n g mass.

Pineal Region Tumors

T u m o r s o f the p i n e a l r e g i o n a c c o u n t for 3% to 10% o f all p e d i a t r i c i n t r a c r a n i a l tumors. G e r m c e l l t u m o r s are m o s t f r e q u e n t and the m o s t c o m m o n i n t r a c r a n i a l g e r m c e l l t u m o r is the g e r m i n o m a .

G e r m i n o m a s are b i p h a s i c t u m o r s c o n s i s t i n g o f a

n e o p l a s t i c c o m p o n e n t o f large, g l y c o g e n - r i c h , g e r m c e l l s w i t h large n u c l e i and p r o m i n e n t n u c l e o l i a n d a

n o n - n e o p l a s t i c c o m p o n e n t o f s m a l l m a t u r e l y m p h o - cytes. T h e g e r m c e l l c o m p o n e n t is i m m u n o r e a c t i v e for p l a c e n t a l a l k a l i n e p h o p h a t a s e . A p p r o x i m a t e l y 5% to 50% o f g e r m i n o m a s c o n t a i n s y n c y t i o t r o p h o - b l a s t i c t u m o r g i a n t c e l l s that e l a b o r a t e b e t a - h u m a n c h o r i o n i c g o n a d o t r o p i n . T h e p r e s e n c e o f such c e l l s in an o t h e r w i s e t y p i c a l g e r m i n o m a d o e s not i n d i - c a t e the p r e s e n c e o f a c h o r i o c a r c i n o m a e l e m e n t .

O t h e r g e r m c e l l t u m o r s i n c l u d i n g the e m b r y o n a l c a r c i n o m a , e n d o d e r m a l sinus t u m o r ( y o l k sac tu- mor), c h o r i o c a r c i n o m a , a n d t e r a t o m a (mature and i m m a t u r e ) are m u c h less c o m m o n than g e r m i n o - m a s and t e n d to o c c u r as m i x e d t u m o r s rather than

one p a r t i c u l a r type. T u m o r s o f p r i m a r y p i n e a l p a r e n c h y m a are r a r e

and i n c l u d e the p i n e o c y t o m a , p i n e o b l a s t o m a , inter- m e d i a t e , and m i x e d types. D e t a i l s o f the p a t h o l o g y and p a t i e n t o u t c o m e s h a v e b e e n r e p o r t e d b y S c h i l d et al. 53

SUMMARY

It is o f p a r a m o u n t i m p o r t a n c e f o r all m e m b e r s o f the p a t i e n t c a r e t e a m to r e a l i z e that p e d i a t r i c C N S t u m o r s are often c l i n i c o p a t h o l o g i c a l l y , h i s t o l o g i - cally, and g e n e t i c a l l y d i f f e r e n t f r o m t h o s e o f adults. P e d i a t r i c b r a i n t u m o r s are m o s t l i k e l y to b e o f p r i m a r y n e u r o e p i t h e l i a l o r i g i n a n d i n c l u d e b o t h g l i a l and e m b r y o n a l types. A l t h o u g h n o n - n e u r o e p i - thelial, i n t r a c r a n i a l t u m o r s , such as m e n i n g i o m a s , p i t u i t a r y a d e n o m a s , a n d m e t a s t a t i c n e o p l a s i a s , are r e l a t i v e l y c o m m o n in adults, such t u m o r s are r a r e in children. E s t a b l i s h i n g a c o r r e c t d i a g n o s i s is c r i t i c a l in e n s u r i n g a p p r o p r i a t e p a t i e n t m a n a g e m e n t and in the a c c u r a t e e v a l u a t i o n o f n e w t h e r a p e u t i c

p r o t o c o l s .

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