Received: 28 March 2003Published online: 22 May 2003© Springer-Verlag 2003

P. NakajiDepartment of Neurosurgery,University of California, San Diego,San Diego, Calif., USA

P. Symons · V. TobiasDepartment of Anatomical Pathology,SEALS Sydney Children’s Hospital,Randwick, NSW 2031 Australia

R. CohnDepartment of Haematology and Oncology,Sydney Children’s Hospital,Randwick, NSW 2031 Australia

R. SmeeDepartment of Radiation Oncology,Prince of Wales Hospital,Randwick, NSW 2031 Australia

Abstract Introduction: The man-agement of a patient with an epen-dymoma is controversial. Althoughthe necessity for a multi-disciplined approach is accepted, the exact rolesfor all disciplines are poorly defined.Review: This review article exam-ines the current status of histopatho-logical and cytogenetic diagnosis,surgical, chemotherapeutic and radiotherapeutic treatment and futuredirections.

Keywords Ependymoma · Paediatric · Brain tumour

Childs Nerv Syst (2003) 19:270–285DOI 10.1007/s00381-003-0753-x R E V I E W PA P E R

Charles TeoPeter NakajiPatricia SymonsVivienne TobiasRichard CohnRobert Smee

Ependymoma

Introduction

Ependymomas are the third most common brain tumoursin children and account for approximately 10% of allposterior fossa tumours in the paediatric population. Sofar the cure for this disease has eluded us and despite itshistological benignancy, the majority of patients will diefrom their disease. Further research into this tumour isvitally important for all scientists concerned with thetreatment of these patients; for surgeons, because theprognosis appears to be directly related to the degree ofresection; for pathologists, because the histological fea-tures are so inconsistently predictive of outcome; for on-cologists, because the role of chemotherapy is currentlyundefined; and for radiotherapists because more precisedelivery may hold the key to a cure. This review articlewill attempt to provide the most contemporary assess-ment of the current roles of all those involved in themanagement of patients with these tumours, underscorethe recent developments, and provide insight into futuredirections in their management.

Pathology

Ependymomas are tumours composed of neoplasticependymal cells that arise from ependymal or subepend-ymal cell layers surrounding the ventricles and centralcanal of the spinal cord [45, 92]. Embryologic “rests” ofependymal cells may account for cases arising in brainparenchyma and the myxopapillary ependymoma nearthe filum terminale-conus-cauda equina region [36].

The most recent classification scheme for ependymo-mas is the 2000 World Health Organisation (WHO) clas-sification [45], which classifies these tumours as fol-lows:

– Ependymomas (cellular, papillary, clear cell and tan-ycytic)

– Anaplastic (malignant)– Myxopapillary– Subependymomas

Ependymal tumours may arise anywhere along the ven-tricular system and in the spinal canal. In children they

C. TeoDepartment of Neurosurgery,Sydney Children’s Hospital,Randwick, NSW 2031, Australia

C. Teo (✉)Centre for Minimally Invasive Neurosurgery,Prince of Wales Private Hospital,Suite 3, Level 7, Barker Street, Randwick,NSW 2031, Australiae-mail: charlie@neuroendoscopy.infoTel.: +61-29-6504940Fax: +61-29-6504902

are most common in the posterior fossa, and are less often supratentorial. Intracranial cases constitute 90% ofchildhood ependymomas, whereas in adults, 60% arespinal/filum lesions and 40% are intracranial [36].

Posterior fossa tumours usually arise in the floor orroof of the fourth ventricle. They grow into the ventricu-lar lumen as exophytic lesions [45]. They may extend (orarise) inferiorly through the foramen of Magendie intothe cervical spinal canal, or laterally into the sub-arachnoid space within the cerebellopontine angle viathe foramina of Luschka [92]. They may protrude intothe cisterna magna and extend along the surface of thebrain stem and through the foramen magnum [45]. Theyare usually well demarcated, but they occasionally infil-trate the floor of the fourth ventricle and brain stem [92].

Spinal cord lesions of the cervical or cervicothoracicregion are of the usual pathological types, whereas thoseof the filum terminale-conus-cauda equina region areusually myxopapillary [45].

Supratentorial cases usually arise in the midline orwithin the lateral ventricle, filling the ventricle and fre-quently involving periventricular regions [36, 92].

Unusual sites have included intraparenchymal supra-tentorial lesions (especially in children) remote from the ventricles [45] and rare extraneural cases have beenreported in the ovaries, soft tissues, mediastinum andsacrococcygeum [13, 31, 41, 42, 57, 88].

Spread of ependymomas may occur via the CSF [59,92] and there are case reports of lung or occasionallyother extraneural metastases [45, 110].

Ependymomas

Ependymomas are usually well-demarcated, solid, softgrey-red tumours [45]. They occasionally invade the ad-jacent brain parenchyma. They may be partly cystic,with foci of necrosis and haemorrhage, and are calcifiedin up to 50% of cases [92]. In the spinal cord, the lesionsare circumscribed intramedullary masses usually involv-ing several spinal cord segments [45].

Microscopically, ependymomas are moderately cellu-lar gliomas corresponding to WHO grade 2 neoplasms[45]. They are expansile and well demarcated with asharp tumour-parenchyma interface [79]. Isolated tu-mour cells may be seen in adjacent brain tissue [45].Their constituent cells are usually uniform, cuboidal toelongated cells with oval or round nuclei. On light mi-croscopy one may see nuclear atypia with scatteredlarge, pleomorphic cells [45]. Mitoses are rare or absentand foci of coagulative, non-palisading necrosis are fre-quently seen [45, 79]. Key features of ependymomas areperivascular pseudorosettes, in which tumour cells arearranged radially around vessels, with cytoplasmic pro-cesses condensed about the stromal blood vessels in fi-brillary cuffs (Fig. 1) [45]. These are seen in the majority

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of conventional cases [45], and are the feature that mostoften allows histopathologic recognition. However, they are not unique to ependymomas [45]. Ependymalrosettes and canals, however, whilst pathognomonic ofependymal differentiation and diagnostic for ependymo-mas, are seen in only a minority of cases (Fig. 2) [45].The latter consist of columnar cells around a central lumen (i.e. epithelial features).

In some cases, features of (presumed) regression maybe seen including [45]:

1. Myxoid degeneration2. Intratumoral haemorrhage3. Calcification4. Hyalinisation of vessels (which may precede calcifi-

cation [45])5. Occasional foci of cartilage and bone (Fig. 3) [53]

Fig. 1 Ependymomas are moderately cellular and composed ofuniform cells with round to ovoid nuclei. Perivascular pseudoro-settes are seen when tumour cells are arranged radially aroundstromal blood vessels, with their cytoplasmic processes condensedinto fibrillary cuffs (H&E, original magnification ×120)

Fig. 2 A well-formed ependymal canal consisting of columnarcells around a central lumen (H&E, original magnification ×300)

other entities must be excluded. Immunoperoxidasestaining is not useful for distinguishing other gliomaswith pseudorosettes from ependymomas [79]. Ependy-momas stain as glial neoplasms being positive in mostcases for vimentin and glial fibrillary acidic protein(GFAP) in the cytoplasmic processes [79, 103]. The peri-vascular pseudorosettes are prominent on GFAP staining(useful in distinguishing pseudorosettes of medulloblas-toma/PNET), but the ependymal rosettes/canals are vari-ably positive with some negative cells admixed with pos-itive cells. Papillary formations are also variably posi-tive. S100 is usually positive [44, 103], and epithelialmembrane antigen (EMA) is positive in many tumourswith restricted but strong labelling of the luminal surfaceof ependymal rosettes/canals [103]. Occasionally EMAstains with dot-like positivity [79], and there may be fo-cal cytokeratin positivity (including CK7, CK20, CAM5.2) [51, 103]. AE 1/3 keratin may stain up to 98% ofcases [103]. Importantly, ependymomas are negative forsynaptophysin and other neuronal markers [45] (in con-trast to medulloblastomas and PNETs).

Whilst not routinely used in many laboratories, elec-tron microscopy demonstrates characteristic features ofependymal cells and may be useful in establishing a di-agnosis in difficult cases [45, 79]. Characteristic findingsin ependymal cells include complex intercellular junc-tions at the lateral surfaces of the cells (zipper-like com-plexes) reflecting the cohesive growth pattern of ependy-momas, “micro-rosettes” or intercellular lumina intowhich microvilli and cilia project, microvillous arraysand cilia projecting from cell surfaces [85]. Intermediatefilaments (which have been shown to be GFAP-positiveon colloidal gold studies [45]) may be seen in the cyto-plasmic processes. Ependymal cells lack basement mem-brane at the internal cell surfaces. They lack neurosecre-tory granules and other features of neuronal differentia-tion such as parallel arrays of microtubules [79].

Significantly, junctional complexes together with mi-crovilli may be demonstrated even in poorly differentiat-ed lesions, which may be difficult to recognise on lightmicroscopy [45]. These features are not seen in astro-cytomas, oligodendrogliomas, neurocytomas and medul-loblastomas and PNETs [79].

The combination, then, of immunoperoxidase andelectron microscopic studies may be essential in estab-lishing the correct diagnosis in difficult cases [45].

The cellular subtype

The cellular subtype (Fig. 5) [45] shows increased(dense) cellularity but without increased mitotic activity.Mitoses are rare or absent. Pseudorosettes may be incon-spicuous or very narrow, and true rosettes may be absent.This subtype is regarded as WHO grade 2. The cytologi-cal features of the constituent cells are similar to those of

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Occasionally, ependymomas show unusual histopatho-logic features, such as lipomatous differentiation [83],melanin pigment [80], signet ring cells (i.e. intracyto-plasmic lumen formation [101, 114], eosinophilic inclu-sions [43], giant cell change [71, 112] and mucin secre-tion [11].

Smear preparations of fresh tissue (Fig. 4) demon-strate a population of small cells with round to oval orelongated nuclei in which nucleoli and a small amount ofcytoplasm may be seen. Some cellular cohesion may beappreciated, and the cells may appear closely associatedwith blood vessels and show apparent multilayering oftumour cells in a papilliform pattern [1].

Immunoperoxidase staining may be useful in helpingto establish a diagnosis, particularly in subtypes where

Fig. 3 Foci of cartilage and bone may be seen (H&E, originalmagnification ×78)

Fig. 4 Smear preparations demonstrate a population of small cellswith round to oval or elongated nuclei and a small amount of cyto-plasm. Some cellular cohesion may be seen, and there is apparentmultilayering of tumour cells in a papilliform pattern (Diff Quick,original magnification ×198)

plexus papilloma, papillary meningioma and metastaticpapillary carcinoma. Choroid plexus papillomas are epi-thelial and consistently display diffuse strong cytokeratinpositivity [3, 51] as well as staining for laminin, corre-sponding to subepithelial basement membranes [30], andoften pre-albumin (transthyretin) [3]. There can be smallfoci, however, of apparent ependymal differentiation thatare GFAP-positive [79]. Papillary meningiomas areGFAP-negative, usually dural-based lesions that oftenhave some more obviously recognisable meningothelialareas. Metastatic papillary carcinomas are also consis-tently diffusely- and strongly cytokeratin-positive re-flecting their epithelial nature [3, 51, 103]. No clinicalsignificance is attached to the papillary ependymomasubtype but its recognition is important for correct diag-nosis.

The clear cell subtype

The clear cell subtype consists of a predominant popula-tion of clear cells having an “oligodendroglial-like” [45]appearance with clear perinuclear haloes. Occasionalclear cells can often be seen in conventional ependymo-mas. The clear cell subtype is usually supratentorial andextraventricular [45, 56], often abutting or bulging intothe ventricles, and not generally confined to the ventricu-lar compartment (unlike neurocytomas) [45, 79]. Oftenoccurring in young patients [45], it is a sharply demar-cated lobulated lesion with pushing borders [79]. Usefulfeatures in suggesting the diagnosis are perivascularpseudorosettes or ependymal rosettes occurring in a dis-crete lesion [79]. If the rosettes are difficult to identify,immunoperoxidase (GFAP positivity) or electron micro-scopic studies may be necessary to establish the diagno-sis [79].

Clear cell ependymomas often show regional or dif-fuse contract enhancement, in contrast to non-enhancingoligodendrogliomas. Lesions that must be differentiatedon light microscopy from clear cell ependymomas in-clude oligodendrogliomas, central neurocytomas, meta-static clear cell carcinomas and haemangioblastomas[56, 79]. Oligodendrogliomas are usually extraventricu-lar lesions occurring superficially with characteristic dif-fuse cortical infiltration. They lack the pushing bordersof ependymomas. The electron microscopic features ofependymomas are not seen in oligodendrogliomas orneurocytomas [79]. As yet, no biological differenceshave been identified between clear cell and conventionalependymomas [56].

The tanycytic subtype

The tanycytic subtype was excluded from the 1993WHO-II classification but has been included in the re-

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conventional ependymomas. Whilst recognised as a his-tological subtype, cellular ependymomas are not thoughtto behave differently to conventional cases.

The papillary subtype

The papillary subtype is rare (Fig. 6) [45, 79]. It is com-posed of well-formed papillae with columnar lining cellsresting on fibrillary glial “stroma” (unlike the cells ofchoroid plexus papillomas which rest on vascularisedconnective tissue cores) [45]. The tumour cell processesabutting capillaries are vimentin and GFAP-positive onimmunoperoxidase staining, and there may be focalEMA positivity along the tumour cell apices. Focal cyto-keratin positivity is seen only occasionally [51, 79]. Themain differential diagnoses to consider include choroid

Fig. 5 The cellular subtype shows increased cellularity but mito-ses are rare or absent. The cytological features are similar to con-ventional ependymomas (H&E, original magnification ×120)

Fig. 6 The papillary subtype is composed of well-formed papillaewith columnar lining cells resting on fibrillary glial “stroma”(H&E, original magnification ×198)

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vised WHO 2000 classification [45]. In these lesions,particularly those of the spinal cord, fascicles of spin-dled, bipolar cells may be seen. These cells resemble“tanycytes” (elongated paraventricular glial cells withcytoplasmic processes that extend to ependymal surfac-es; from the Greek tanyos meaning “to stretch”) [28].The fascicles vary in width and cell density. Ependymalrosettes are typically absent and pseudorosettes may bepoorly delineated. One must distinguish these lesionsfrom astrocytomas. Electron microscopy may be usefulin the diagnosis of difficult cases.

Subependymomas

Subependymomas (Fig. 7) [79] are rarely found in chil-dren and are more common in adults. They are usuallyfound incidentally at autopsy but may become largeenough to present with obstructive symptoms in life.They are indolent, well-demarcated lesions occurring inthe fourth or lateral ventricles and are classed by theWHO as grade 1. Rarely, they are eccentric intramedul-lary masses of the cervical or cervico-thoracic cord.They have hybrid ependymal/astrocytic features but areclassified with ependymal lesions because they may con-tain ependymal rosettes, have electron microscopic fea-tures of ependymomas and some have distinct ependy-moma areas.

Microscopically, subependymomas show clusters ofsmall, uniform, bland nuclei set in a fibrillary back-ground. The background fibrillary cytoplasm is S100-and GFAP-positive. There may be extensive calcifica-tion, haemosiderin (they often haemorrhage) and mayshow microcystic change. There may be nuclear degen-erative atypia, occasional mitoses and zones of coagula-tive necrosis (of no known clinical significance). Even

gemistocytic-like cells may be seen. Some lesions havedistinct areas resembling subependymomas and conven-tional ependymomas. Such “combined” tumours (classi-fied as mixed ependymoma/subependymoma), may beconsidered WHO grade 2, with the ependymoma compo-nent determining behaviour [45].

Subependymomas are composed of firm tissue thatmay be difficult to smear [1]. They are usually adequate-ly treated by resection [45].

Myxopapillary ependymomas

These lesions are also uncommon in children [92]. Theyare low-grade (WHO grade 1) neoplasms that arise mostoften in the region of the filum terminale [36, 92, 93] butmay arise in the cervico-thoracic spinal cord or rarely intracranially. They have also been reported in sacro-coccygeal soft tissues [38, 47].

Whilst these tumours are low grade, they may recurpost-resection in 10–19% of cases [93]. The soft tissueexamples have been reported to have a significant risk ofdistant metastases [36].

Myxopapillary ependymomas are lobulated, highlyvascular and often haemorrhagic gelatinous tumours.They are well demarcated and may have a fibrous pseu-docapsule. They may erode bone, invade adjacent mus-cles and fibroadipose tissue.

Microscopically they have a papillary pattern with cuboidal cells around cores of mucinous perivascularstroma (Fig. 8) [79, 92]. There may be microcysts andspindle cell elements forming perivascular pseudoro-settes. Often, fibrino-haemorrhagic exudates, haemosid-erin, vascular sclerosis, thrombosis and dense collageni-sation are seen. There may be foci of haemorrhagic in-farction, occasional mitoses and scattered large, pleo-

Fig. 7 A subependymoma showing clusters of small, bland nucleiset in a fibrillary background (H&E, original magnification ×120)

Fig. 8 Myxopapillary ependymomas have a papillary pattern withcuboidal cells around cores of mucinous perivascular stroma(H&E, original magnification ×120)

morphic cells. None of these features is regarded as be-ing of clinical significance. Giant cell variants have beendescribed [93, 112]. Whilst usually easily recognised,they may occasionally be confused with chordomas (es-pecially if they are very myxoid), schwannomas (if veryspindled), paragangliomas (rarely this may be pseudo-papillary) and metastatic mucinous adenocarcinomas.

Smear preparations of fresh tissue demonstrate a papillary pattern with abundant metachromatic mucoidstroma [1].

On immunoperoxidase studies, myxopapillary epen-dymomas are GFAP- and vimentin-positive, usuallyS100 positive and are usually negative for EMA, cyto-keratin, CEA and chromogranin. Ultrastructural studiesshow features of ependymomas as well as microtubularaggregates in rough endoplasmic reticulin (rER).

Anaplastic ependymomas

Anaplastic ependymomas are malignant gliomas ofependymal origin, recognised as a distinct entity in viewof their rapid growth and unfavourable outcome [45].The WHO classes them as grade 3. Their reported inci-dence varies widely in differing series, largely becauseof difficulty in their recognition, but they probably con-stitute approximately 30% of ependymal tumours [92,110]. Although they may occur at any “ependymoma”site, they are usually intracranial (especially posteriorfossa) [88] and are noted particularly in the paediatricpopulation. Whilst usually well demarcated, they may befrankly invasive [45], and CSF spread is seen at diagno-sis in 3–17% of cases [92].

The definition and histological recognition of ana-plastic ependymomas remains somewhat controversial,because the criteria traditionally used to recognise ana-plasia in gliomas do not seem to apply to ependymalneoplasms [23, 88, 89]. Numerous studies have tried tocorrelate histopathologic features with clinical outcome,and have yielded conflicting, inconsistent results [18, 21,23, 40, 45, 77, 79, 81, 88, 89, 90]. In addition, the histo-pathologic features studied have often been subjectiveand poorly reproducible [89]. Anaplastic ependymomas,as defined in the 1993 WHO-II classification, are nowregarded as vague and poorly reproducible [23, 89, 90].The criteria used were: nuclear atypia, high cellularity,marked mitotic activity and often prominent vascularproliferation [46].

It has subsequently become clear that the criteria forglioma grading need re-evaluation for ependymal tumoursif histology is to be prognostically relevant. The most con-sistent and clinically relevant feature of “anaplasia” re-ported in the literature is brisk mitotic activity [23, 79,89]. Various studies have used differing definitions of“brisk”, however, it would seem that greater than 5–10mitoses per 10 high power fields (HPF) in general consti-

tutes a high level of mitotic activity [23]. In a study bySchiffer et al. of 298 cases of ependymomas (108 in chil-dren), survival related only to high cell density (greaterthan 800 cells × HPF (×400)) and brisk mitotic activity(greater than 20 mitoses/10 HPF) and not the other tradi-tional criteria used to recognise malignant gliomas [89](i.e. necrosis, pleomorphism, microvascular proliferation).The anaplastic lesions had barely recognisable pseudoro-settes [79, 90, 103]. Schiffer’s group have stressed the im-portance of dense cellularity. However, this is somewhatsubjective (being dependent on technical variables such assection thickness, fixative used, etc.) and was not found tobe statistically significant on multivariate analysis in a re-cent study [23]. Pseudopalisading necrosis may be seenand is considered a feature of anaplasia, while coagulativenecrosis without palisading, which is commonly seen inconventional ependymomas, is not.

Figarella-Branger’s group found that a high mitoticindex (MI) was associated with necrosis (not further de-scribed) and endothelial proliferation, and that necrosisitself was associated with endothelial proliferation [23].Necrosis or endothelial proliferation was related to pro-gression-free survival on univariate analysis but not onmultivariate analysis [23].

Lesions with absent differentiating structures (i.e. ro-settes) are also regarded as anaplastic, as seen on multi-variate analysis as a strong prognostic indicator (poorprognostic factor) in overall survival and progression-free survival statistics [23]. Perivascular pseudorosettesmay be seen and are a useful clue to the ependymal na-ture of the lesion. The pseudorosettes may be narrow orpoorly delineated. Typically, ependymal rosettes/canalsare absent or rare [45].

GFAP staining may be reduced in comparison withconventional ependymomas, but the immunophenotypicprofile of anaplastic ependymomas is otherwise similar.Ultrastructural studies are sometimes necessary for diag-nosis of poorly differentiated lesions [45].

By definition, lesions composed of “embryonal” typecomponents (medulloblastomas and PNETs) with epen-dymal differentiation are excluded from the category ofanaplastic ependymoma [45].

Recurrent intracranial ependymomas

The prognostic importance of histology in recurrent tumours has been rarely reported in the literature. Onestudy of 36 cases of recurrent paediatric tumours con-cluded that aggressive therapy could salvage only thosethat showed low-grade histology [32]. These authors alsonoted that in comparison with histology at initial diagno-sis recurrent tumours were a higher grade in 6 out of 12cases and a lower grade in 3 out of 12 cases. In 12 out of33 lesions, the histology of the recurrent tumour differedfrom that of the initial lesion.

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40] has histology achieved statistical significance onmultivariate analysis in correlating with outcome. Part ofthe problem in identifying adverse prognostic factors instudies of ependymal lesions (particularly intracranial le-sions) is the small number of cases, which means thatstudies have not necessarily been able to subdivide casesinto categories, such as by age or site of tumour for com-parison, and the difficulty in comparing studies that haveused various diagnostic criteria and treatment modalities[79, 88, 92]. No large prospective studies have evaluatedtreatment regimes [92], and the results of retrospectivestudies have been conflicting in terms of outcome andthe identification of prognostic factors [92]. Even multi-variate analysis has failed to resolve the controversy asto which factors are of prognostic significance [36, 88].

The difficulty of histologic grading and recognition ofanaplasia in ependymal lesions has hindered the contri-bution of histopathology to diagnosis and prognosis.However, the recent studies re-evaluating the criteria tra-ditionally used for identifying glial anaplasia have dem-onstrated that significant prognostic features for ependy-mal lesions may be identified by tumour morphology,and have opened the way for further studies. From thecurrent literature, it would seem that more than 5–10 mi-toses per 10 HPF, absence of differentiating structures,pseudopalisading necrosis and (most likely) high celldensity are the most important features required to iden-tify a lesion as “anaplastic”.

Cytogenetics and molecular biology

Recent years have seen a rapid expansion of our knowl-edge of the cytogenetics and molecular biology of epen-dymomas, in parallel with overall increases in knowl-edge in molecular neurobiology and oncology. New mo-lecular techniques such as serial analysis of gene expres-sion (SAGE), total gene expression analysis (TOGA),and the use of DNA microarrays (cDNA microarray,Affymetrix GeneChip) are likely to significantly im-prove our understanding of the genetic basis of all tu-mours. Nonetheless, significant gaps remain in ourknowledge of the genetic alterations producing ependy-momas. As with many brain tumours, the pattern of ge-netic change in ependymomas is inconstant. No specificgenetic alteration has been identified that is shared byall, or even most, ependymomas. Many tumours show nocytogenetic abnormalities [75]. Furthermore, when alter-ations are seen, they do not consistently help to distin-guish between lower- and higher-grade tumours [36, 72].We will now review what is known about the traditionalcytogenetics and molecular biology of ependymomas.

With respect to traditional cytogenetics, the most fre-quent alteration observed is loss of heterozygosity in chro-mosome 22q; this change is seen in about 30% of ependy-momas [33, 54]. Other abnormalities of chromosome 22

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Proliferative indices

In addition to traditional histopathologic features, prolif-erative indices have been studied in order to try to im-prove or supplement the morphological prediction ofprognosis. However, the studies have been less informa-tive than expected, with problems demonstrating cell cy-cle related antigens, small sample sizes, sampling errorsand calculating proliferative state from proliferativemarker labelling indices [88]. There is overlap betweenranges of labelling indices for conventional and anaplas-tic ependymomas by PCNA and Ki-67 (MIB-1), makingevaluation in individual cases difficult. In general, ana-plastic lesions have higher proliferative indices than con-ventional ependymomas [79]. The prognostic signifi-cance of Ki-67 staining has not yet been firmly estab-lished [45]. In one study [73] a %MIB-1 labelling index(% positive tumour cell nuclei) greater than or equal to4% emerged as a factor for differentiating conventionalfrom anaplastic ependymomas (Fig. 9). However, MIB-1indices were not reliably predictive of tumour behaviour[73]. A recent study [23] is reportedly the first to identifyKi-67 immunoperoxidase staining of archival material aspredictive for shorter progression-free survival on multi-variate analysis. DNA measures, flow cytometry andother proliferative marker studies have not yet reliablypredicted prognosis, and have not yet been adequatelycompared with survival outcomes [88].

Prognosis

In summary, histopathology has been the most inconsis-tent of the assessed risk factors in the English literaturefor prognostic prediction, and in only two studies [23,

Fig. 9 Ki-67 immunoperoxidase staining of formalin-fixed, paraf-fin-embedded tissue demonstrates a high proliferative index in ananaplastic ependymoma (immunoperoxidase staining, originalmagnification ×198)

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such as deletions and translocations have also been ob-served [54, 74, 78, 87, 108]. Adult ependymomas and themyxopapillary subtype are most likely to have chromo-some 22 changes. The 22q region is of special interest be-cause it contains the neurofibromatosis type 2 (NF-2) tu-mour suppressor gene, and an increased incidence ofependymomas is seen in NF-2. A number of other tu-mours seen in NF-2, such as vestibular schwannomas andmeningiomas, show chromosomal defects that include thischromosomal region [25, 65, 91, 108]. Although onestudy found NF-2 mutations in 71% of ependymomas [7],others have found such changes only rarely. Rubio et al.found that only 1 out of 8 tumours had NF-2 mutations[82]. With these findings we may conclude that malfunc-tion of the NF-2 gene may predispose to the formation ofcertain tumour types, including ependymoma, in NF-2 pa-tients. However, since many ependymomas lack this de-fect, it is clearly not essential to their formation. This viewis further supported by the fact that investigators haveidentified familial ependymomas that do not have thechromosome 22 defect, like most sporadic ependymomas.It is likely that some other tumour suppressor gene onchromosome 22q, still undiscovered, is more commonlyinvolved in ependymoma formation [105].

Monosomy 17 is the next most common chromosom-al abnormality. This change has been seen in up to 50%of paediatric ependymomas [105]. The p53 tumour sup-pressor gene resides on 17p. Individual case reports haveidentified some instances of p53 mutation in ependymo-ma patients, including a family who also had a mutationin chromosome 22 [63]. The p53 gene has been implicat-ed in many human tumours, and is the gene mutationthat produces the Li-Fraumeni tumour syndrome; how-ever, Li-Fraumeni patients do not characteristically de-velop ependymomas. Because wild-type p53, like othertumour suppressors, acts in a dominant fashion, bothcopies must fail before tumour suppression is lost. Whileloss of one copy of the gene sometimes occurs in epen-dymomas, mutations in the remaining p53 gene in epen-dymomas are very uncommon [24, 64, 97, 100, 105,109]. We must therefore conclude that although chromo-some 17 changes are often seen in ependymomas, p53does not play an essential role in its pathogenesis.

Loss of a region on 6q has been found in a number ofcases [48, 62, 75, 78]. However, no known tumour sup-pressor gene has yet been implicated at this locus. Otherfrequent chromosomal alterations include losses of chro-mosomes 1p, 6, 9q, 11, 13q, 22q, and gains of 1q, 2, 5, 9,12, 15, and 18, 20q, and X [39]. A recent study using allelic markers also found instances of deletions of chro-mosomes 13q, 16p, 16q, 19q, 20p and 20q [99]. Ward etal. used comparative genomic hybridisation to examine40 paediatric ependymomas [106]. Forty-five percenthad no regions of imbalance, while 25% showed loss ofchromosome 22, and 20% showed gain of 1q. Otherchanges were seen less frequently.

Molecular biological analyses of specific genes haveyielded many new findings. A number of genes knownto function as oncogenes or tumour suppressors havebeen studied. Among the interesting findings are amplifi-cation and rearrangement in the epidermal growth factorreceptor gene (c-erb B) [16]; enhanced gene expressionin the oncogene v-fos [29], and rarely in the Ha-ras andc-mos alleles [15]. These alterations, like many of thecytogenetic changes seen in other studies, are sporadic.A recurring breakpoint at 11q13 has been identified [84].Rearrangements in the MEN1 gene at 11q13 have beenimplicated in ependymoma progression to higher grades[49]. Examinations focused on p15, p16, CDK4, and cy-clin D1 have found no alteration in ependymomas [86].It is likely that traditional cytogenetic techniques are toogross to find the defects that are common to all ependy-momas, and gene-by-gene searches are too slow. Ge-nomic techniques, as discussed above, may bridge thegap.

The last topic of interest in this area is the intriguingfinding of SV40-like DNA sequences in ependymomasand other brain tumours [6, 113]. This discovery raisesthe question of a possible viral role in tumour pathogene-sis. Most studies have found only a small percentage oftumours contain the SV40 large tumour antigen (Tag)[107]. Nonetheless, this remains an exciting direction ofinquiry. However, if a link is found, it is likely that SV40is only one of the possible activators of a common finalpathway whose nature still eludes us.

The role of surgery

Surgical management of secondary hydrocephalus

Secondary hydrocephalus from a fourth ventricular epen-dymoma is common. Most patients are not acutely com-promised and can be scheduled for semi-elective and de-finitive surgery on the next routine operating list. Resec-tion of the tumour is the preferred means of re-establish-ing normal cerebrospinal fluid (CSF) pathways. How-ever, some patients present acutely unwell with signs andsymptoms of intracranial hypertension requiring urgenttreatment. Invariably, there is no time for preoperativestaging of their tumours and the surgeon must operatebased on a CT or MRI scan of the head only. In these circumstances, endoscopic third ventriculostomy is thetreatment of choice. External ventricular drainage orventriculo-peritoneal shunting are reasonable alterna-tives but carry the added risk of infection, overdrainageand subdural haematoma formation, peritoneal tumourseeding and upward, transtentorial herniation. The majorcontra-indication to ETV is absence of the interpeduncu-lar cistern with either anterior displacement of the brain-stem from a large fourth ventricle tumour or cisternalseeding with ependymoma (Fig. 10).

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Surgical management of the tumour

Surgery is the mainstay of the treatment of ependymo-mas. Surgery provides tissue for a pathological diagno-sis, reduces local mass effect, and can open obstructedCSF pathways. Radical surgery can sometimes achievecomplete resection of an ependymoma, which raises theprospect of a cure for this tumour. In the pre-microsurgi-cal era, some series documented high morbidity andmortality rates for surgery on ependymomas, particularlyinfratentorial disease [76]. The complication rate hasdropped considerably in modern series. Morbidity, pri-marily related to brainstem and cranial nerve involve-ment, ranges from 10 to 30% [60]. Current mortalityrates are generally less than 13% [67, 96].

Of all the therapies available for ependymomas, sur-gery provides the greatest benefit. Furthermore, evidenceover the last decade demonstrates that the greater the surgical removal, the longer the disease-free survival,particularly if a complete removal can be achieved (Table 1) [5, 12, 36, 37, 68, 94, 96, 102, 104]. This is true

regardless of other therapy given. The observation thatrecurrences after surgery are predominantly local [12, 37,50, 60, 102] suggests that recurrent tumours arise fromthe residua of the original tumours (Fig. 11). This sup-ports further the aggressive removal of the primary tu-mour. The majority of studies strongly support the bene-fits of complete resection [2, 55], but some do not.

The question of surgery as sole therapy is being revis-ited. Recently, some authors have suggested that no otheradjuvant treatment may be necessary if a total resectioncan be achieved [4, 5, 68]. A desire to avoid the devas-tating effects of radiation in younger patients has moti-vated this theory. Prior to widespread microsurgery andmagnetic resonance imaging, surgical therapy alone hada 5-year survival rate of 16–32% [14, 58, 66, 76]. Thefact that most patients died is perhaps not as remarkableas the observation that so many lived. In Olivecrona’sseries (1967), 8 out of 25 patients who received surgeryonly survived disease-free for at least 10 years [66]. It isdifficult to assess by modern standards the degree of resection achieved in these series. Surgeons’ estimates oftotal versus subtotal resection are often inaccurate. He-aley et al. found only a 68% agreement between the clin-ical and radiographic assessment [37]. Hence, it is possi-ble that with confirmed gross total resection better re-sults can be achieved.

Table 1 Overall survival as afunction of completeness of resection

Series Number Complete resection Subtotal resection p(reference) of patients (% surviving at 5 years) (% surviving at 5 years)

[96]a 45 60 21 <0.01[60] 35 87 30 <0.01[37] 19 75 0 0.03[72] 40 80 22 <0.0001[69] 92 70 33 <0.01[17] 48 61 30 n/a[104] 18 83 0 0.001[35] 73 74b 35b <0.0009

a Includes near-complete resec-tionsb Survival at 4 years

Fig. 10 This MRI shows the brainstem is pushed forward againstthe clivus thereby obliterating the interpeduncular cistern and pre-cluding an ETV

Fig. 11 This 5-year-old girl presented with recurrent disease afterher initial tumour was subtotally resected. The recurrence is typi-cally in the cerebello-pontine angle

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Awaad et al. reported their results of following pa-tients after radical removal of ependymomas in whomthe radiologic absence of disease could be obtained [5].Out of 38 children with intracranial ependymomas, 7elected to forgo radiation. A complete resection was con-firmed radiographically in 5 out of the 7 children; thesepatients were all alive with no evidence of disease at24–70 months. In the other 2 patients, blood clots pre-vented the disease status from being discovered and theyboth had local recurrence on MRI within 1 year.

Palma et al. had 6 patients with non-malignant epen-dymomas who did not receive radiation after total tu-mour removal. Of these, 4 were alive without recurrenceat 178–242 months [68]. Despite these results, the pres-ent inability to predict which patients will go on to pro-

Fig. 12 This MRI shows a very large posterior fossa ependymomafilling the fourth ventricle and extending into the left cerebello-pontine angle through the foramen of Luschka

Fig. 13 Supratentorial ependymoma. The location makes these tu-mours more readily resectable. This patient did not have adjuvanttherapy and has enjoyed 4 years of recurrence-free survival

Fig. 14 Intraoperative photograph of a fourth ventricular ependy-moma. Although the nodule looks quite discreet, there is tumourinvolving the floor of the fourth ventricle in the background

gress means most patients will receive local radiationwhether they have a radical tumour resection or not.

Surgery may have other benefits with respect to dis-ease progression. Complete removal of intracranial tu-mours decreased the rate of spinal seeding of tumours inone study from 9.5% to 3.3% versus patients who had in-complete tumour removal [102].

The exact surgical approach is dependent on the loca-tion of the tumour. In young children, ependymomas aremost commonly located in the posterior fossa. They fre-quently originate in the fourth ventricle and extendthrough the foramina of Luschka or Magendie into theextra-axial spaces (Fig. 12). Midline and hemispheric cer-ebellar tumours can be resected via a midline suboccipitalcraniectomy. Cerebellopontine angle tumours, whichmake up about 25% of the total in the posterior fossa,may be approached by a suboccipital retrosigmoid ap-proach. Endoscopic assisted techniques are particularlyhelpful in achieving a complete resection of tumours inthis location. Supratentorial tumours are approached via astandard craniotomy with the exact nature of the flap de-termined by the location of the tumour. Multiple authorshave noted that complete removal can be more oftenachieved in supratentorial than infratentorial cases [5, 19,20, 68, 72, 105]. Lateral ventricular ependymomas andthose in non-eloquent regions have the highest likelihoodof total resection (Fig. 13). Tumours invading the brain-stem and those in the posterior fossa intimately associatedwith the cranial nerves are less likely to be completely re-sected (Fig. 14) [70, 98]. Pierre-Kahn et al. found that thecomplication rates between patients receiving total andsubtotal resection were no different [70]. Rather than sug-gesting that total resection is as safe as subtotal resection,this finding implies that good judgment will determinethe extent of resection that can safely be achieved.

In summary, the literature supports aggressive at-tempts to remove ependymomas, and suggests that sur-gery might be considered as a sole means of therapy incases where this can be achieved. Although achieving acomplete resection remains far from the rule, improvingthe degree of surgical removal is the most promisingmeans of improving outcome.

The role of radiotherapy

The radiotherapy management of ependymomas has un-dergone considerable change over the last 10 years. Thiscomes from a background of acknowledgment that theaddition of post-operative radiotherapy improves the lo-cal control and survival prospects. The beginning of the1990s saw the requirement for craniospinal radiotherapyfor all posterior fossa-located ependymomas and mostsupratentorial tumours, and high-grade tumours requir-ing more extensive volume and coverage irrespective ofsite. In addition, even low-grade completely resected supratentorial tumours were required to have postopera-tive radiotherapy even if only in the involved field. Thisnecessity for craniospinal irradiation (CSI) was generat-ed on the theoretical basis of shedding tumour cells intothe CSF as occurs with medulloblastomas, and retrospec-tive analysis of single centre experience reporting “high”distant failure rates where the CNS axis was not treated.However, this was in earlier series when CNS imagingwas usually not available, and thus documentation of theextent of disease at presentation was poor. Bloom report-ed twice on his experience, the earlier study noting highdistant CNS failure rates, the later study with further fol-low-up noting neuraxis dissemination in only 2 out of 33children with posterior fossa control [8, 9]. Importantly,there was no difference in the distant failure rate for chil-dren receiving CSI versus posterior fossa only, for classi-cal ependymoma (5%) versus anaplastic lesions (8.7%).Subsequent reviews confirmed the situation with no dif-ference in distant failure rates where the radiotherapyhas been posterior fossa only compared with CSI. This isin a circumstance where posterior fossa control isachieved, and local failure carries with it an ultimatehigh neuraxis dissemination rate. The time sequence isusually that local failure occurs first.

There is less debate about the dose to be given. Onthe basis of earlier reports of high failure rates with lower doses, standard doses now being delivered are45–50 Gy in 1.5–1.8 Gy fractions, with boost doses of anextra 10 Gy for macroscopic disease.

Neurological deficit including cognitive impairmenthas been the justifiable argument against standard radio-therapy particularly in a circumstance where whole braintreatment is being given as in CSI. This approach auto-matically excludes radiotherapy for children less than3 years of age at presentation, a feature that may contrib-

ute to the high failure rate in this group of patients. Itwas thus anticipated that by confining the treatment tothe posterior fossa that this morbidity would be dramati-cally decreased. The standard approach, therefore, hasbeen for a parallel opposed technique, which, whilst de-livering uniform doses to the posterior fossa, delivers thesame doses to the internal and external ear apparatus,structures not known to ever be afflicted by this tumoureven where extensive neuraxis dissemination occurs.

With new imaging techniques (MRI and PET scan-ning) that better document the extent of disease andspread patterns at presentation, and failure patterns uponrecurrence, it is now possible to take advantage of thenewer radiotherapy techniques, which provide the oppor-tunity to deliver high doses with much lower likelihoodof morbidity. For small, discrete lesions this can be viastereotactic radiosurgery, delivering a therapeutic dose asa single fraction. However, this approach cannot be usedwhere the target volume consists of the entire fourth ven-tricle particularly where there may have been disease ex-tension down into C1–2 preoperatively. The exclusionfeatures for stereotactic radiosurgery are the volume tobe treated, and the fact that the treatment is given as asingle fraction with a risk of normal tissue damage.

The advantage of the stereotactic approach is that itprovides precise delivery of treatment, a feature now attainable on a fractionated basis with relocatable head-rings even where general anaesthetics are necessary fordaily treatment. More conformal beam shaping is nowavailable with Multileaf Collimators (MLC) incorporat-ed into the Linear Accelerator with the X-ray beam sur-face area defined by the 1-cm leaf collimator. The newerand more advanced approach, which allows better beamshaping, is the Mini MLC (MMLC) with 4-mm leafwidth leaves for more precise conformality. Both thesecollimator devices can be used in Intensity ModulatedRadiotherapy (IMRT) whereby within each directedbeam the intensity of the dose delivered can be variedacross that beam, thus sparing more normal tissue. The4-mm leaf width collimation with the MMLC providesbetter beam shaping even with this approach, an advan-tage where critical structures such as the brain stem arenearby. This treatment approach can be delivered stereo-tactically.

Thus, given that benefit has been consistently report-ed in the use of postoperative radiotherapy and failurepatterns are now well recorded, involved field radiother-apy with approaches such as stereotactic IMRT allowsafer delivery of treatment enabling better managementof the standard case, as well as the high risk-patients (re-sidual macroscopic disease with dose escalation possi-ble, and presentation at an age of less than 3 years). Itmust be acknowledged, however, that there is no long-term follow-up on patients treated using this method sothat efficacy has not yet been determined; time awaitsthis.

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The role of chemotherapy

Given the poor prognosis of ependymomas in childhood,there has been a trend towards considering the systematicuse of chemotherapy in their management, but the ratio-nale for the use of adjuvant chemotherapy remains poorwith little evidence suggesting improved survival beyondthat achieved with radiation therapy [10, 26, 40, 69, 72].Most of the studies have not focused on ependymomas asa single histological subtype. There have been smallnumbers of patients and no standardisation in the earlierstudies of postoperative neuroimaging or for variablessuch as the use of mannitol, which may affect the bloodbrain barrier.

Response rates in single agent phase ll studies of re-current ependymomas have been disappointing. Theoverall response rate with cisplatin, the most active agentidentified from the single agent studies is 33%, with18% complete responses [10]. Bouffet et al. analysed theoverall response rates to single agents reported in the literature and found it to be 11%, with less than 5% complete responses [10].

The Children’s Cancer Group (CCG), between 1975and 1981, conducted the only randomised trial compar-ing radiation alone versus radiation and chemotherapy inchildren with ependymomas, aged between 2 and16 years [22]. Adjuvant chemotherapy with lomustine,vincristine and prednisone did not improve outcome inchildren with posterior fossa ependymomas (CCG 942).Overall survival at 10 years is 39%, with no differencebetween the two regimens. No benefits of chemotherapywere shown in another CCG study (CCG 921), a pro-spective randomised study of radiation therapy followedby either lomustine, vincristine and prednisone or “8drugs administered in one day” [77]. Survival statisticson either regimen were no different from historical controls treated with similar doses of radiation and nochemotherapy.

Much of the information available on combinationchemotherapy in the treatment of ependymomas comesfrom studies on children less than 3 years of age at diag-nosis, in whom chemotherapy was used prior to radio-therapy in an attempt to avoid the adverse neurocogni-tive, neuroendocrine and growth outcomes on the imma-ture nervous system. The Paediatric Oncology Group(POG) began a study in 1986 (POG 8633) in which afour-drug regimen was given for 1 or 2 years accordingto the age of the child at the time of diagnosis, followedby radiation therapy [17]. Twelve out of 25 (48%)evaluable infants with residual tumours after initial sur-gery had an objective response to a combination of vincristine, cyclophosphamide, cisplatin and etoposide.The study suggested that chemotherapy can allow for adelay in radiation therapy by 1 year without compromis-ing survival. Younger infants who received 2 years ofchemotherapy before radiotherapy did worse, suggest-

ing the possibility that survival in this study was primar-ily due to irradiation. The successor study (POG 9233)showed a significant advantage in event-free survivalfor patients with ependymomas treated with dose-inten-sive chemotherapy, although there was no difference in overall survival (Asco 2000) [95]. The Australian and New Zealand CCSG reported an 86% response rate in eight children to four cycles of vincristine, etopo-side and cyclophosphamide, but most patients pro-gressed at a median of 7 months [111]. Using cisplatin,vincristine, etoposide and cyclophosphamide as induc-tion chemotherapy, Mason et al. found a 17% responserate in ten children under the age of 6 years with re-sidual ependymomas [52]. An analysis by Bouffet andForeman of combination chemotherapy documented inthe literature shows a response rate of 26%, with only12% complete response [10]. Intensification with high-dose multiagent chemotherapy followed by stem-celltransplantation has shown little benefit in the limitedstudies in recurrent and newly diagnosed ependymomas[34, 52].

A role for chemotherapy was suggested by a recentprospective pilot study by Needle et al., who used radia-tion followed by carboplatin and vincristine alternatingwith ifosfamide and etoposide in patients older than36 months of age with newly diagnosed ependymomas[61]. The 5-year actuarial PFS estimate of 74% for pa-tients with incompletely resected tumours is higher thanall previous reports. A proportion of patients in thisstudy received hyperfractionated radiation therapy,which confounds the analysis.

A multicentre prospective trial of the French Societyof Paediatric Oncology concluded that a significant pro-portion of children under the age of 5 years with ependy-momas can be cured without radiotherapy with pro-longed adjuvant chemotherapy [35]. Twenty-three per-cent of the children in whom surgery was deemed com-plete on early imaging studies were alive without receiv-ing radiotherapy 4 years after the diagnosis. Deferringradiotherapy to the time of relapse or progression did notcompromise OS of the whole patient population. Thechildren with posterior fossa ependymomas most likelyto benefit from this approach are those with radiological-ly documented complete resection. The chemotherapywas incapable of eradicating residual disease. The strate-gy applied in this trial allowed irradiation to be deferredfor a mean of 15 months.

The COG is currently considering a multi-institution-al study designed to examine the possibility that a shortcourse of neoadjuvant chemotherapy will safely increasethe rate of complete resection at the time of second sur-gery. Foreman et al. reported the use of chemotherapybetween the initial and second surgery in 4 patients withependymomas, enabling complete resection in 3 of the 4 patients, with all 3 progression-free 23–34 months after second-look surgery [27].

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Currently, chemotherapy for older children is recom-mended only as part of a clinical trial until proof is avail-able that chemotherapy can improve survival.

Conclusion

There is no doubt that the optimal treatment for ependy-momas is through a multi-disciplinary approach. Al-though some of the roles are currently poorly defined,each discipline offers hope of improvement in diagnosisand treatment in the future. Currently, there are someclear recommendations and some questionable dogma.No-one disputes the need for thorough preoperative in-vestigations to stage the disease. If the clinical situationallows, spine and head MRI are mandatory. If the childpresents with intracranial hypertension secondary to hy-drocephalus, then endoscopic third ventriculostomy willallow time for more thorough preoperative staging. Un-questionably, every attempt should be made at the initialprocedure to resect the tumour as completely as possible.If the surgeon believes he has achieved a complete resec-tion and postoperative imaging demonstrates otherwise, itremains to be seen whether second-look surgery will im-

prove the prognosis. Clearly, this review article provesthere are many uncertainties when discussing adjuvanttreatment, but in so-called high-risk patients, adjuvanttherapy should be considered. Patients should be consid-ered high risk if they have one or more of the following:age of less than 3 years at presentation, preoperative metastases, anaplastic histological features or residualdisease. Conversely, the patient who presents at an olderage, with no evidence of metastases and who has a com-plete resection, both clinically and radiologically, of a tumour that has no anaplastic features may require no ad-juvant therapy. This and many other questions remain un-answered. Will cytogenetic analysis be a more reliableprognosticator? Will intensity-modulated radiotherapy al-low low-risk treatment in all age groups? Will upfrontchemotherapy improve the prognosis by improving thedegree of resection? And finally, will genetic modifica-tion obviate the need for all other treatment modalities?To answer these questions it is incumbent on all physi-cians caring for these patients to continue searching forbetter diagnostic tools, better surgical techniques and bet-ter treatment modalities. Tumours need to be frozen forfuture analysis, patients need to be entered into multicen-tre trials and the honest reporting of results is imperative.

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