pediatric atypical teratoid

8/9/2019 Pediatric Atypical Teratoid

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CHAPTER

PEDIATRIC ATYPICAL TERATOID/

RHABDOID TUMORS (AN OVERVIEW)

Krishan Kumar Bansal and Deepak Goel


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Table of contents

1. ABSTRACT2. INTRODUCTION3. EPIDEMIOLOGY4. CLINICAL PRESENTATION OF CNS AT/RT5. IMAGING OF AT/RT6. GROSS AND MICROSCOPIC PATHOLOGY OF AT/RT7. CYTOMORPHOLOGICAL FEATURES8. MOLECULARPATHOLOGY OF AT/RT9. TREATMENT OF AT/RT: SURGERY10.TREATMENT OF AT/RT: CHEMOTHERAPY11.TREATMENT OF AT/RT: RADIOTHERAPY12.OUTCOME13.REFERENCES


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ABSTRACT

Paediatric Atypical teratoid/rhabdoid tumors (AT/RT) of the centralnervoussystem (CNS)

areamongthemostmalignantneoplasmsandmostoftendiagnosedinchildrensmallerthan3

yearsofageandincidenceis1-2% ofallbraintumorsinchildren. 63% ofthe AT/RT ofthe

CNS is seen in infra-tentorial compartment, there are no precise imaging features that

differentiate AT/RT from the other posterior fossa tumor. The rhabdoid cells are

characteristiconcytopathology. Ithasbeenestablishednow that CNS, AT/RT often shows

deletionofthelongarmofchromosome 22q11.2. Theinitialtreatmentformostchildrenwith

AT/RT issurgicalwithandwithoutcerebrospinalfluiddiversionaryprocedure. Childrenwith

lessthan3yearsofageofferedchemotherapybutinolderchildrenradiotherapy isgiven in

addition.


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INTRODUCTION

Paediatric Atypical teratoid/rhabdoid tumors (AT/RT) ofcentralnervoussystem (CNS) are

rare and very aggressive malignant lesion of early childhood. Because of both the

infrequency and rapid course of disease, consensus has notbeen made for the standard

treatmentsofar (Rorkeetal.,1996; Strother, 2005; Hildenet al.,1998; Biegelet al.,1990;

Gandhiet al., 2004).

Beckwith and Palmer In 1978 first described a histological variant of Wilms tumor that

occurred primarily in infants and was correlated with extremely poor prognosis. It was

subsequentlycalledmalignantrhabdoid tumor-meant for thereason that the tumor looked

likearhabdomyosarcoma,butthecellsdidnotdemonstrateusualmorphologicalorimmuno-

histo-chemicalfeaturesofmuscle (Haaset al.,1981). A CNS tumorcomposedofrhabdoid

cells was first reported in 1985by Briner et al.,but the unique clinical andpathological

featureswerenotwelldefineduntil1995-1996 (Rorkeet al., 1996).

Since approximately 70% of these tumors contain fields indistinguishable from

Medulloblastomaorprimitiveneuroectodermaltumor,pathologistsbyandlargegaveoneor

the other diagnosis. The histological diagnosis is not easy, as there maybe considerable

microscopic overlapwith these embryonal tumors (Biegelet al., 2000, 2002). However,

study of these tumorswith high indexof suspicion even in routine HandEstainsdisclosed

fields of rhabdoid cells with or without areas of primitive neuroepithelial cells and in a

quarter to a third of samples, mesenchymal and/or epithelial elements were seen as well.

Thus,eventhoughsuchacombinationofdivergenttissuetypessuggestedthatthesetumors

wereteratomas,althoughtheylackedthestandardfeaturesessentialforsuchadiagnosis.

Thediagnostictermthatseemedmostsuitablewas AT/RT andsoitwascoined (Rorkeet al.,

1995, 1996; Bhattacharajee et al., 1997). The histogenesis of this curious and highly


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malignant tumor of the early childhood has remained unidentified (Packer et al., 2002;

Burgeret al., 1998; andFisheret al., 1996). Regardingeffectivetherapyofthesetumorstill

date no standardprotocolhasbeen setup and overall survival even after multidisciplinary

effortslikesurgery,radiationandchemotherapyhasnotimprovedsignificantly (Rorkeet al.,

1996; Tekautzet al., 2005; andHildenet al., 2004).

EPIDEMIOLOGY

AT/RT of the CNS most frequently occurs in infants or neonates, themajority ofpatients

diagnosedbeingyoungerthan3yearsofage (Rorkeet al., 1996;and Gyure, 2005) although

itisnotoftenseeninolderchildrensaswell,70% v/s30% (Rorkeet al., 1996; andTekautz

et al., 2005). Themeanageatdiagnosisranges from17 to 29months (Rorkeet al., 1996;

Burgeret al., 1998; Gandhiet al., 2004; andGyure, 2005). Thesetumorsaresomewhatmore

frequent inboys [3-4: 1-2, male: female ratio] in younger than 3 years age groupbut in

childrensolderthan3yeartheratioisnotconsistent (Tekautzet al., 2005; andHildenet al.,

2004). Their incidence is 1-2% of allbrain tumors in children, while some investigators

report that 6.7% ofCNS tumors in infants0 to 2 yearswere AT/RT (Robertset al., 2000;

Wonget al., 2005; RickertandPaulus, 2001).

Mostcommon location is infratentorial [60-70%] in thecerebellumorCPangleandrest in

supratentorial,spinalormultifocal. ATRT ofCNS hasrecentlyshownsomeagespecificsite

preference,posterior fossa is themost common site in younger than3but in older than 3

preferred location for the development of this tumor is supratentorial (Rorkeet al., 1996;

Rorke et al., 1995; Bhattacharjee et al., 1997; Tekautz et al., 2005; and Gyure, 2005).

AT/RT hasbeen reported in an in-utero infant,apregnant female and also in apatientof


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neurofibromatosis-1; inbothofthelatertumorwassupratentorial (Ericksonet al., 2005; and

Kababriet al., 2006).

Prognosis inpatientsyounger than3years isverygrim ifcomparedwitholder then3-year

children.Moreover, youngerpatients are more likely topresentwithmetastatic disease at

diagnosisandtendtodevelopprogressionwithhigherfrequencyandearlierinthecourseof

treatmentthanolderchildrens (Rorkeet al., 1995; andTekautzet al., 2005). Theresultsof

Hildenetalsuggestedthatolderchildrendiagnosedwith AT/RT havebettersurvival (Hilden

et al., 2004).

CLINICAL PRESENTATION OF CNS AT/RT

Sincerhabdoidtumorswereoriginallyfoundinthekidney,suchtumorshavebeendescribed

inmanydifferentorgansandsoft tissues,aswellas in the CNS. 63% of the AT/RT of the

CNS isseenininfra-tentorialcompartment,restarisesinsupratentorial [27%]or8% maybe

multifocal (Rorkeet al., 1996; Bhattacharjeeet al., 1997; Burgeret al., 1998; Wonget al.,

2005). Whilethecerebellumandcerebralhemispheresarethemostcommonlocations,these

tumorshaveapredilectionforthecerebellopontineangle (Rorkeet al., 1996). Theymayalso

ariseinthespinalcord,pinealglandandsupra-sellarregion (Burgeret al., 1998; Wonget al.,

2005).Posteriorfossaisafavouritelocationinchildrenyoungerthan3years,asopposedto

olderchildren; the few examples inadultsarealmostexclusively in thecerebrum (Rorkeet

al., 1996; Wonget al., 2005). A smallgroupofchildrenhavebothrenaland CNS rhabdoid

tumors which most likely represent metachronous tumors, possibly due to a germ-line

mutationinthehSNF5gene.

Infantswhosecranialsutureshavenotyetfusedtendtopresentwithnon-specificsymptoms

such as macro-cephalic, lethargy, vomiting and/or failure to thrive (Gyure, 2005). Older


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childrenpresentwithhead tilts [IVnervepalsy],diplopia [VInervepalsy],facialweakness

[VIInervepalsy],headacheand/orhemiplegia. Themajorityofchildrenwithposteriorfossa

AT/RT have hydrocephalus at presentation due to obstruction of the cerebrospinal fluid

(CSF) flowat the fourthventricle. The setof clinicalsigns and symptoms inchildrenwith

AT/RT is similar to those childrenwithPNET/medulloblastoma [PNET/MB] or any other

tumorinposteriorfossa.

One-thirdofchildrenwith AT/RT presentwith Leptomeningealspreadoftumoratdiagnosis,

aratesimilartothatseeninchildrenwithPNET/MB (Gyure, 2005). Therewasnonoticeable

differenceinageofthepatientformetastaticdiseaseandthosewhodonot,butrecentstudies

showing that dissemination of the disease is early and with higher frequency in patients

youngerthan3-year (Tekautzet al., 2005).Examinationofthe CSF atthetimeofdiagnosis

revealed malignant cells in one third of thepatients and CSF maybepositive evenwhen

cranio-spinalimagingisnegative (Burgeret al., 1998).

IMAGING OF AT/RT

The imagingprocedureof choice in childrenwith AT/RT isa cranio-spinalMRIwith and

without gadolinium [Fig. 1 and 2]. The tumor shows low signal intensity on T1weighted

imagesandisointenseordecreasedsignalon T2 weightedimages (Rorkeet al., 1996). Cysts

andhaemorrhagesarecommonlyseen. Thesetumorscanbeofheterogeneous intensitywith

heterogeneous enhancement with peripheral cystic components (Cheng et al., 2005).

Obstructivehydrocephalusandperi-ventricularlucencymaybeseen,especiallywithtumors

located intheposteriorfossathatblockthefourthventricleor itsoutletforamina. Themain

tumormassenhances inhomogeneouslyafteradministrationofgadolinium. Leptomeningeal

spreadappearsasdiffuseenhancementof themeningesand/orenhancingclumpsalong the

spinal cord and cauda equinaas dropmetastasis. All of these features are similar to those


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seeninPNET/MB and,infact,therearenopreciseimagingfeaturesthatdifferentiate AT/RT

from the PNET/MB. Some children may undergo CT scanning aspart of their diagnostic

workup. AswithPNET/MB, the AT/RT appearsasahyperdense lesiononanunenhanced

CT scan,presumablyduetothehighcellularityofthetumor(Rorkeet al., 1996).

GROSS AND MICROSCOPIC PATHOLOGY OF AT/RT

Macroscopic features of these tumors differ in noway from thoseofPNET/MB. They are

soft, pinkish-red, necrotic and/or hemorrhagic. Those with a prominent mesenchymal

component may be firm and contain tan-white foci. Tumorsprimarily in the cerebello-

pontine anglemay incorporate cranial nerve roots in the vicinity. Leptomeningeal deposits

displaynospecificdistinguishingfeaturesandarebasicallysimilartoPNET/MB. Onsection,

thesetumorstendtoinfiltrateandhavepoorly-demarcatedmargins.

MicroscopiccharacteristicsofAT/RT arevariable,although it isself-evidentthattheymust

contain rhabdoid cells [Fig.3]. Some tumors consist of only this cell type, whereas more

commonly there is a mixture of rhabdoid fields and areas indistinguishable from classical

PNET/MB (Rorkeet al., 1996; Bhattacharjeeet al., 1997; andOkaand Scheithauer,1999).

Although thisportion may rarely contain Flexner-Wintersteiner or Homer Wright rosettes,

neither desmoplastic nor the nodularneuroblastic histological types have been observed.

Basically,thePNET/MB portionssimplyconsistofsmallprimitiveappearingneuroepithelial

cells (Parwaniet al., 2005).

The typical rhabdoid cell is of medium to large size and consists of an eccentric nucleus

adjacent towhich is eosinophilic cytoplasm equal to or larger than the size of the nucleus

(Gyure, 2005). This tends tobe round or slightlybulbous and may have a faintpink rim

accentuatingadenserpinkcore.Manynucleicontainaprominentnucleolus.Mitoticfigures

are frequent. The rhabdoid cells may range from small to large size, pale cells may


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sometimes-containing two nuclei, in a jumbled architectural arrangement (Burger et al.,

1998). ThesmallcellcomponentresembledMedulloblastomaandrarelyhadcordsofcellsin

amucinousbackground,imitatingchordoma. Thecytoplasmofthe largercells isprominent

with a somewhat rhabdoid appearance, although rhabdoid features were not-always

prominent (Rorkeet al., 1995).

Rhabdoid andPNET fields tend to remain separate, asdo the epithelial andmesenchymal

components, although there are no sharply delineated margins. A recognizable epithelial

component, which may be adenomatous or squamous, occurs in about a quarter of the

tumors,although amuchhighernumberof tumorcells express epithelialantigens. A small

groupofthesetumorsmaymimic Choroidplexuscarcinoma; hencethispossibilityshouldbe

kept in mind. In addition, about one-third of tumors contain neoplastic mesenchymal

elements,which, in the extreme,mimic sarcomas (Rorke et al., 1996). These tumorsoften

exhibit largeareasofnecrosis,mitosesandhaemorrhage,but intrinsicvasculaturegenerally

manifestsnodistinctivefeatures (Bhattacharjeeet al., 1997).

CertaintyinmakingaspecifichistologicaldiagnosisofAT/RT maybeimprovedbystudying

the tumorwithapanelofmonoclonalantibodies.Mosthelpfulare the following: epithelial

membrane antigen (EMA), vimentin (V), smooth muscle actin (SMA), keratin (K), glial

fibrillaryacidicprotein (GFAP) andneurofilamentprotein (NFP) (Bhattacharjeeet al., 1997;

Burger et al., 1998; and Gyure, 2005). Desmin is rarely expressedby the neuroepithelial

cells,butnotbyrhabdoidcells.Markersforgermcellsareconsistentlynegative (Rorkeet al.,

1996).

Thepatternofexpressionoftheseantigensiscomplex; henceattentionmustbepaidtowhich

specific cellular component is expressing the antigen. The rhabdoid cells typically express

vimentinandEMA,but SMA lessfrequently (Gyure, 2005). TheymayalsoexpressK, GFAP

and/orNFP. Theneuroepithelialcellsexpressonly GFAPand/orNFP,whereastheepithelial


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component expresses K plus or minus EMA; the mesenchymal cells typically express

vimentinand SMA (Rorkeet al., 1996).

Ultra structural findings vary, depending upon sampling. The classical, but not

pathognomonic finding in the rhabdoid cell consists of large bundles of intermediate

filamentsinthecytoplasm.

CYTOMORPHOLOGICAL FEATURESForcytologicalstudyofthesetumorsmaterialscanbeobtainedfromsmearscraping,squash

preparationorfineneedleaspiration (Parwaniet al., 2005). Cyto-morphologicalstudyofthe

tumorshowshyper-cellularity,primarily large tissue fragmentswith tumorcellsadjacent to

growing capillaries illustrating a papillary-like appearance and characteristic rhabdoid

cells i.e., intermediate-sized cells with granular or fibrillary, brilliantly eosinophilic

cytoplasmwithorwithoutgloboid inclusions ; large,eccentrically located,singlenucleoli,

small,round,primitive neuronal-appearingcellswithahighnuclear tocytoplasmicratio,

speckled chromatin and atypical, occasionally multinucleated giant cells. In addition, few

apoptoticbodies,mitoses,considerablenecrosisandprominentdystrophiccalcificationmay

befound (Parwaniet al., 2005).

MOLECULAR PATHOLOGY OF AT/RT

It has been established now that CNS, AT/RT often show deletion of the long arm of

chromosome 22q11.2, furthermolecularstudieshave led to the identificationofarhabdoid

suppressorgene [INI1/hSNF5]atsaid location (Hilden et al., 2004; Versteegeet al., 1998;

and Biegel,1997). Somatic mutations in this genepredispose children to develop AT/RT.

Earlier,thiswasoftentheonlykaryotypicchangeseeninthistumoranditwasthoughtthata

tumorsuppressorgenewascontainedtothatregion. Furthermore, itwassuggestedthat loss


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of one copy of chromosome 22q coulddistinguish an AT/RT from aPNET/MB,which is

frequentlyassociatedwith lossof17p/isochromosome17q. Later,Versteegeet al. identified

deletionsand truncatingmutationsof thehSNF5geneonchromosome 22q11 inaseriesof

celllinesderivedfromrenalrhabdoidtumors (Versteegeet al., 1998).

ThehSNF5protein ishighly conservedand isnotgreatly changedbetween flies,miceand

humans. The hSNF5 protein is the smallest member of a family of proteins that form a

complex,which regulates the DNA through changes in the nucleosome. By winding and

unwinding DNA, thiscomplexchanges theconfigurationofgenomic DNA, thusallowing

ordenying transcription factorsaccess to the DNA and changinggene expressionpatterns.

Biegelet al. subsequentlyidentifiedsomaticmutationsofhSNF5inaseriesofCNS AT/RT

(Biegelet al., 1999).

Some childrenwith AT/RT arebornwithheterozygousgerm-linemutations of the hSNF5

gene,suggestingthatthesechildrenwerepredisposedtodevelop AT/RT.Inmostcases,these

germlinemutationsaredenovo (anewmutation,notinheritedfromtheparents),butinsome

instances,theymaybeinheritedfromphenotypicallynormalparents (Biegelet al., 1999; and

Tayloret al., 2000).Individualsandfamilieswithgerm-linemutationsofhSNF5arealsoat

increased risk to develop carcinoma of the choroid plexus. However, it remains to be

determinedwhetherthesearetruechoroidplexustumorsorAT/RT whichmaysometimesbe

misdiagnosedasachoroidplexuscarcinoma.

HeterozygousmSNF5 knockoutmicedeveloptumorsresembling AT/RT,supportingthe

roleofhSNF5asa tumorsuppressorgene. Althoughmost AT/RTsshowevidenceofsome

geneticderangementatthehSNF5locus,mutationalanalysisofthehSNF5geneinaseriesof

PNET/MBsdiscoveredmutations inonly4/52 tumors (Biegelet al., 2000). Of those4, 2/4

was re-classified, as AT/RT on re-examination of thepathology,but therewas insufficient

clinicalmaterialtoestablishanaccuratediagnosisintheothertwocases. Thissuggeststhat


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tumorsdiagnosedasPNET/MB withhSNF5aremost likely AT/RT. Suchconfusion isnot

surprising, given the largenumber of AT/RTs,which contain fields indistinguishable from

PNET/MB. Whilemutation/deletionofhSNF5 isnot currently sufficient foradiagnosisof

AT/RT, it appears to be related to the clinical outcome and hence, searching for it is

becomingpart of the diagnostic work-up. Over-expression of osteopontin gene hasbeen

reported as apotential diagnostic marker for atypical teratoid/rhabdoid tumor(Kao et al.,

2005). In one study, Alpha-internexin expression is seen in the atypical teratoid/rhabdoid

tumors,indicatethattheseprimitivetumorsusuallyexhibitneuronaldifferentiation (Kayaet

al., 2003).

TREATMENT OF AT/RT: SURGERY

The initial treatment for most children with AT/RT is surgical. Children presenting in

extremis with severe hydrocephalus require a cerebrospinal fluid (CSF) diversionary

procedure, either a ventriculostomy, a ventriculo-peritoneal shunt or, more recently, an

endoscopic third ventriculostomy (Sainte-Rose et al., 2001).Most children undergo a

craniotomy, with maximal safe resection of tumor. The interface of the AT/RT and

cerebellummaybeabruptor infiltrativeand illdefined (Burger et al., 1998). Totalornear

total,resectionof the tumor isfeasible inabout50% ofpatients. Whilesurgery isexcellent

for reducing themass effect, childrenwho receive surgery alonewith no adjuvant therapy

typicallydiewithinonemonthaftersurgery (Rorkeet al., 1996).

There is no high quality, prospective data on the value of surgical resection in the

managementofAT/RT,butinpatientswithPNET/MB,progression-freesurvivalinchildren

withoutdisseminateddiseaseatdiagnosisis 20% betteriftheamountofresidualtumorpost-

operatively is less than1.5 cm3 compared to childrenwhere the amount of residual tumor

wasgreater than1.5cm3

(Albrightet al., 1996). Gross totalresection is feasible in 64% of


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patientswithyounger than3yearwhile itspossible in78% childrenmore than3-yearsof

age. 81% ofpatients younger than 3-year at diagnosis develop recurrent disease within 3

monthsaftersurgeryandrecurrenceismainlylocalinmorethan70% ofpatients (Tekautzet

al., 2005).

TREATMENT OF AT/RT: CHEMOTHERAPY

Mostchildrenwith AT/RT receivechemotherapyatsomepointduring theirclinicalcourse,

especiallythoselessthan 2 yearsofage,inviewtodelayradiationtherapy. Severaldifferent

chemotherapeutic regimens have been tried, including baby Paediatric Oncology Group

(POG) protocols, eight drugs in one day, single agent cyclophosphamide and single agent

ifosphamide (Rorkeet al., 1996).Mostoftheseregimenswerechosenbasedontheirefficacy

in treatingPNET/MB. However,patientswith AT/RT respondpoorly tochemotherapyand

only 6/33childrenwhoreceivedchemotherapyaloneaftersurgeryorchemotherapypriorto

radiation had a response as definedby greater than 50% reduction in tumor mass. In

addition,mostresponseswereshort-lived,thelongestbeing10months (Rorkeet al., 1996).

Some AT/RTshavebeendocumentedtoprogressduringthecourseofchemotherapy (Burger

et al., 1998).

In contrast to the older children, recurrent or progressive AT/RT in children 3 years or

youngerappearsrefractorytochemotherapy (Tekautzet al., 2005). Twochildrentreatedwith

high-dose chemotherapy, followed by autologous bone marrow transplant had a good

response,with one child surviving 19months and another alive and well at 46 months of

follow-up (Hildenet al., 1998). Thereisonereportwherechemotherapypreviouslydescribed

foruseinpatientswithparameningealrhabdomyosarcoma,wasadministeredtothreepatients

with AT/RT. Therapy included surgery, radiotherapy, chemotherapy and triple intra-thecal

chemotherapy. All threepatients were reported tobe alive and well, with no evidence of


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diseaseat5years, 2 yearsand9months,respectively (Olsonet al., 1995). Thisexcitingresult

awaitsconfirmation in larger,prospective trials.Inoneretrospectivestudy,mediansurvival

withchemotherapy inyounger than3-year is0.3yrandwith Radiation inolder than3was

0.4yrandmediansurvivalis0.6 yrsinthosewhoreceivedbothchemotherapyandradiation

(Tekautz et al., 2005). Hilden et al. reported event free survival of 16 months in children

olderthan3 incomparisontoonly7.7months inyoungerthan3year,theirpatientstreated

withsurgeryandchemotherapyonly.

TREATMENT OF AT/RT: RADIOTHERAPY

Most children diagnosedwith AT/RT are usually less than 2 years of age, so,because of

toxicityofradiationtoyoungbrains,radiotherapyisinitiallynotoffered. Currently,thegoal

istocontinuewithchemotherapyuntilthechildisatleast 2 or3yearsofage,atwhichtime,

radiation effects are less severe. As children with AT/RT commonly present with

Leptomeningealspreadorelsedevelop itatthetimeofrelapse, it isdesirable toadminister

cranio-spinalradiotherapy,inadditiontotreatmentoftheprimarytumor. Someauthorshave

advocatedaboostofradiationtotheprimarytumorbyconventionalmeansorbystereotactic

radiosurgeryatthetimecranio-spinaltherapyareadministered. However,radiotherapydoes

not seem to alter theprogression of disease in childrenwith AT/RT; indeed, an objective

responsetoradiotherapywasobtainedinonly 2/10patients (Burgeret al., 1998).

Recentlygammaknifehasalsobeenused; butthereareonlytworeportsoftheuseofgamma

knifeperformed inpatientswith AT/RT thatresulted in local controlof thepost-operative

lesion (Bambakidiset al., 2002; and Hirthet al., 2003). In recent studies radiotherapy has

shownpromisingresultswithprolongedsurvivalofolderchildrenandadultswith ATRT and

it appears most effective if administered early in the course of treatment, though the

unacceptablesequelaeofcranialradiation ininfantsandyoungspreclude itsuse (Packeret


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al., 2002).Inspiteoftheseinconsistentstatistics,childrenwhoarebetween 2 and3yearsof

ageandolderwillreceiveradiotherapyatsomepointinthecourseoftheirdisease.

In conclusion the prognosis for children with AT/RT is bleak. The median time to

progressionis4.5monthsandthemedianreportedsurvivalsrangefrom 6-11months (Burger

et al., 1998 andTekautzet al., 2005). Currently,thelongestreportedsurvivingpatientwasa

3-year-oldgirlwhosurvived5.5yearsafterpresentingwithathalamictumorthatwastreated

with craniospinal irradiation. At relapse, the disease may be local (31%), in the

leptomeninges (11%) or both (58%). Rorke et al., 1996 had found at post-mortem

examination, that 10/11 children with AT/RT had widespread Leptomeningeal metastatic

disease. Obviously, current treatments for this tumor in the formof surgery, chemotherapy

and/orradiationarenotsufficient. Identificationandcharacterizationof therhabdoid tumor

predispositiongeneonchromosome 22q mayallowdevelopmentofmorefocused,effective

therapeuticagentswhichmayincreasesurvivaltime.


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