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TheMDAndersonManualofMedicalOncology,2e>

Chapter36.GermCellTumors
HeatherD.BrooksLanceC.PagliaroZitaDubauskasLimLouisL.PistersNizarM.Tannir

Introduction
Germcelltumors(GCTs),themajorityarisingfromthetesticle,areahighlycurablegroupofcancers
primarilyseeninyoungmen.Thisgroupofpatientsshouldpresentaspecialconsiderationforoncologists,as
appropriatemanagementinthefrontlinesettingcanleadtomanyyearsofliferecovered,makingGCTthe
paradigmofthecurablesolidtumors.ThischapterwillprimarilydiscussGCTsarisinginthetesticle,dividing
thiscategoryintoseminomaversusnonseminomagermcelltumors(NSGCTs).Then,therareentityof
extragonadalGCTs,whichcanariseinthemediastinum,retroperitoneum,orpinealbody,willbedescribed.

OverviewofGermCellTumors
Epidemiology
GCTsarethemostcommoncancerinyoungmen.Roughly8400newcaseswerebeingdiagnosedinthe
UnitedStatesin2009,representingonlyafractionofnewgenitourinarycancerswhichareestimatedtobe
over280,000(1).Highlightingthehighcurabilityofthiscancer,GCTsonlyclaimedapproximately380lives
in2009(1)andcarrya5yearoverallsurvival(OS)rateofgreaterthan90%(2,3).GCTshaveabimodalage
distribution,withmostmendiagnosedbetweenages15and25.Thereisasecondpeakofdiagnosisaround
age60,whichlargelyrepresentsseminomahistologyandalowermortalityrisk.Lifetimeriskforthe
developmentofGCTsisapproximately0.5%or1in200(4).
Worldwide,GCTsaresixtimesmorecommonindevelopedcountries,withthelargestincidencereportedin
DenmarkandSwitzerlandandthelowestinJapan,Finland,andIsrael(4).IntheUnitedStates,theoverall
incidenceofGCTsappearstobegraduallyincreasing.TheincidencehasspecificallyincreasedamongAfrican
Americans,withthegreatestincreaseinseminomahistology.Thisdoesnotappeartoberelatedtoscreeningor
earlierdiagnosis.Caucasianmen,althoughstillrepresentingthegroupmostlikelytobediagnosed,aremore
likelytobeidentifiedatanearlierstagethaninthepast(5,6).

RiskFactors
CryptorchidismisoneofthemajoridentifiableriskfactorsforthedevelopmentofGCTs,although
representingonlyabout10%ofcases.Whenpresent,cryptorchidismimpartsarelativeriskbetween2.5and
17.1(7,8).Thisincreasedriskincludesthecontralateraltesticle,evenifdescendednormallyorviaorchiopexy.
ItisuncleariforchiopexyreducesthelifetimeriskofGCTs,althoughdatashowingincreasedincidenceeven
inthecontralateraltesticlesupportsthetheorythattheetiologyofGCTslieinabnormalgonadaldevelopment
ratherthananatomicmalposition(9,10).MenwithapriorhistoryofGCTsalsohaveanincreasedriskofGCTs
inthecontralateraltesticle,suggestingageneticpredisposition,althoughmenwithafamilyhistoryofGCTs
accountforonly1.5%ofpatientswithnewdiagnosis(11).ApersonalhistoryofGCTcarriesanincreased
lifetimeriskofsecondarycancers,irrespectiveofhistologictype(12).
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TumorBiology
ThemostcommongeneticabnormalityinGCTsisanisochromosomeoftheshortarmofchromosome12,
whichhasbeenidentifiedinapproximately80%ofGCT(13).Thisabnormalitycanbefoundinallhistologic
subtypes,includingintratubulargermcellneoplasia(ITGCN)(14,15).Otherchromosomalanomalieshave
alsobeenidentified.Overexpressionofckitisseeninseminoma(16).Ofnote,p53israrelyalteredinGCTs,a
factthatmayberelatedtothequalitativelydifferentresultsseenwithchemotherapyandradiationwhen
appliedtoGCTscomparedtoothersolidtumors(17).Recently,Korkolaetal.(18)identifiedagene
expressionsignaturewhichmayimprovepredictionofprognosisinGCTs.
Carcinomainsitu(CIS),orITGCN,hasbeenidentifiedastheprecursorlesioninmostGCTs.Itis
histologicallydescribedasatypicalgermcellsintheseminiferoustubules.Suchchangesarefoundadjacentto
mostinvasiveGCTs,withthenotableexceptionofspermatocyticseminoma.TheITGCNcellsexpress
numerousprotooncogenicproteinsthatplayaroleintumorigenesis,includingthereceptortyrosinekinase
CD117orckit,aproteinnormallyinvolvedingermcellmigrationandearlydifferentiation(19,20).

TumorHistology
ThemainhistologiesencounteredinGCTsareseminoma,embryonalcarcinoma,endodermalsinustumor
(EST,alsoknownasyolksactumor),choriocarcinoma,andteratoma.Thelattercanbefurtherclassifiedas
mature,immature,orteratomawithmalignanttransformation.Itisverycommontoseemorethanone
histologicsubtypewithinatumor.Importantly,theclinicalcoursecanbelargelyinferredfromthehistology.
GCTswhichshowexclusivelytheseminomahistologyconstitutepureseminomas,whilethosecontainingany
otherhistologicpatternareclassifiedasNSGCT,evenifthedominanthistologicpatternisseminoma.Thus,
thetermseminomaisusedintwoverydifferentsenses:asahistologicpatternandasamainsubdivisionof
GCT.Thebiologyandclinicalexpressionaredominatedbythenonseminomacomponent,andthusthe
presenceofanyhistologiccomponentotherthanseminomaplacesthetumorinthecategoryofNSGCT.

ClinicalPresentation
MostpatientswithGCTspresentwithpainlesstesticularswellingoranodule.Insomecases,testicular
swellingcanbeaccompaniedbypainsecondarytobleedingorinfarctionwithinthetumor.Inthepresenceof
painorahistoryofinjury,anappropriatedifferentialdiagnosiswouldincludetesticulartorsion,epididymitis,
orchitis,hydrocele,spermatocele,andhematoma.Itisextremelyimportantthatregardlessofpainorother
associatedsymptoms,allscrotalmassesshouldbeapproachedasiftheyweremalignant.Inpatientswho
presentwithgynecomastia,especiallybilateral,GCTsshouldbeconsidered(21).Othersymptomscaninclude
fever,weightloss,backpain,andhemoptysis(mostoftenseeninpatientspresentingwithhighvolume
disease).

Diagnosis
Theimportanceofearlydiagnosiscannotbestressedenoughbecausetheextentofdiseaseatpresentation
predictsoverallprognosis.IncreasedawarenessoftheoccurrenceofGCTsinyoungmenisimportantforboth
generalpractitionersandthegeneralpublic.Radiographicevaluationofasuspectedprimaryshouldinclude
highresolution,transscrotalultrasonographywithcolorDopplerofbothtesticles,andanysuspiciouslesion
shouldbedefinitivelyevaluatedwithradicalorchiectomy.
Transscrotalbiopsyiscontraindicatedinthediagnosticworkupofasuspectedtesticularneoplasm,asthis
procedurecandisruptregionallymphatics,potentiallyalteringtheotherwisepredictablenodalspread.Since
thediagnosisofGCTsisrarelyinquestion,thepreferreddiagnosticandtherapeuticprocedureforatesticular
massisradicalinguinalorchiectomy.Ifatissuediagnosisisfelttobenecessarypriortoorchiectomy,anopen
biopsyshouldbeperformedviaaninguinalincisiontoallowforproperexaminationandtissuesamplingwith
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minimalriskofinguinalorscrotalcontamination.

TumorMarkers
Serummarkers,specificallyhumanchorionicgonadotropin(hCG),alphafetoprotein(AFP),andlactate
dehydrogenase(LDH),haveuniquediagnosticandprognosticsignificanceinGCTs.Thesemarkersenablethe
cliniciantoinferclinicalbehavior,monitortherapy,decidewhentoapplysurgicalconsolidation,anddetect
residualorrecurrentdisease.
Elevatedinpregnancy,hCGisnotnormallydetectableinmalesexceptinthesettingofGCTs.Withahalflife
of18to36hours,hCGcanalsobemarkedlyelevatedingestationaltrophoblasticdisease,andrarely
detectableinepithelialcancers(22).Itiscomposedoftwosubunits,and,whichexistinmultipleisoforms.
Thesubunitishighlyhomologoustothesubunitofthyroidstimulatinghormone(TSH),follicle
stimulatinghormone(FSH),andluteinizinghormone(LH)whichleadsto"crosstalk"betweenthese
hormonesandhCG.Forthisreason,hCGassaysmeasurethesubunit.This"crosstalk"canbeclinically
significantinhighvolumediseaseaccompaniedbyhighlevelsofhCG,wherehCGbindstotheTSHreceptor.
Prophylacticuseofblockersisoftenneededforsymptommanagementandreliefofclinicalhyperthyroidism
(23).ExtremeelevationofhCGinmalesshouldbeconsideredpathognomonicforGCTs,and,inselectedcases
ofthreateningdisease,justifiesinitiationoftherapyevenbeforetissueconfirmation.
AFPisnormallyproducedbythefetalyolksacandalsoexistsinmultipleisoforms.ItiselevatedinGCTcells
derivedfromtheembryologicalyolksac,includingendodermalsinustumorandembryonalcarcinoma.Ithas
alsobeenfoundtobeelevatedinotherneoplasmssuchashepatocellularcarcinoma,pancreatic,gastric,and
lungcancer,andhasahalflifeofapproximately5days(24).Ingeneral,anypresenceofAFPinthesettingof
GCTsimpliesthatthehistologyisnotthatofapureseminoma(25).
LDHisexpressednormallybymultipletissuesincludingmuscle,liver,brain,andkidneyandiselevatedin
manydiseases,malignantandotherwise.Itisalsofoundinmultipleisoforms,andalthoughelevationofLDH
isanonspecificmarkerforGCTs,LDH1ismostspecificforGCTs.Todate,thereisnoestablishedroutine
useforthefractionationofLDHandprecisemeasurementofLDH1,althoughtotalLDHcanbeusedto
estimatetheprognosisasitrelatestothevolumeofdisease,ortodetectrecurrentdisease(26).

AnatomicProgression
GCTsfollowadistinctpatternofspreadandmetastasis.Thelymphaticdrainagefromthetesticlereflects
embryologicorigin,andthustherighttesticledrainstotheinteraortocavallymphnodesandthelefttesticle
drainstotheleftparaaorticlymphnodes.Theseinitialnodesofspreadaretermedthe"landingzone."
Epididymallymphaticsdrainviatheexternaliliacchainandscrotallymphaticsviathepelvicchaintherefore,
locallyadvanceddisease(involvingtheepididymisandscrotum)canpresentwithinvolvementofthesenodal
basins.Distantmetastasisinvolvesthelungsprincipally,followedbytheliver,brain,andbones.

Staging
Table361showsthemostrecentAmericanJointCommissiononCancer(AJCC)TNMstagingoftesticular
cancer(27).Thissystemisbasedontheanatomiccharacteristicsofthetumor,thepresenceofelevatedtumor
markers,andthepresenceofdistantdisease.Thesewelldefinedriskfactorsareusedtoplacepatientsinrisk
stratificationgroups.Ingeneral,stageIdiseaseisconfinedtothetestes,stageIIdiseaseisconfinedtothe
retroperitoneumwithmarkersinthegoodprognosisrange,andstageIIIdiseaseincludesnodesthatextend
beyondtheretroperitoneum,extranodalmetastases,andelevationoftumormarkerstotheintermediateor
poorprognosisrange.
Table361.GermCellTumor:TheNewAJCCTNMStagingofTesticularCancer
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PRIMARYTUMOR(T)
Theextentofprimarytumorisusuallyclassifiedafterradicalorchiectomy,andforthisreasonapathologic
stageisassigned.
pTXPrimarytumorcannotbeassessed
pT0Noevidenceofprimarytumor(eg,histologicscarintestis)
pTisIntratubulargermcellneoplasia(carcinomainsitu)
pT1Tumorlimitedtothetestisandepididymiswithoutvascular/lymphaticinvasiontumormayinvadeinto
thetunicaalbugineabutnotthetunicavaginalis
pT2Tumorlimitedtothetestisandepididymiswithvascular/lymphaticinvasion,ortumorextendingthrough
thetunicaalbugineawithinvolvementofthetunicavaginalis
pT3Tumorinvadesthespermaticcordwithorwithoutvascular/lymphaticinvasion
pT4Tumorinvadesthescrotumwithorwithoutvascular/lymphaticinvasion
REGIONALLYMPHNODES(N)CLINICAL
NXRegionallymphnodescannotbeassessed
N0Noregionallymphnodemetastasis
N1Metastasiswithalymphnodemass2cmingreatestdimensionormultiplelymphnodes,none>2cmin
greatestdimension
N2Metastasiswithalymphnodemass>2cmbutnot>5cmingreatestdimensionormultiplelymphnodes,
anyonemass>2cmbutnot>5cmingreatestdimension
N3Metastasiswithalymphnodemass>5cmingreatestdimension
PATHOLOGIC(PN)
pNXRegionallymphnodescannotbeassessed
pN0Noregionallymphnodemetastasis
pN1Metastasiswithalymphnodemass2cmingreatestdimensionand5nodespositive,none>2cmin
greatestdimension
pN2Metastasiswithalymphnodemass>2cmbutnot>5cmingreatestdimensionor>5nodespositive,
none>5cmorevidenceofextranodalextensionoftumor
pN3Metastasiswithalymphnodemass>5cmingreatestdimension
DISTANTMETASTASIS(M)
M0Nodistantmetastasis
M1Distantmetastasis
M1aNonregionalnodalorpulmonarymetastasis
M1bDistantmetastasisotherthantononregionallymphnodesandlungs
SERUMTUMORMARKERS(S)
SXMarkerstudiesnotavailableornotperformed
S0Markerstudylevelswithinnormallimits
S1LDH<1.5NAND
hCG(mIU/mL)<5000AND
AFP(ng/mL)<1000
S2LDH>1.510NOR
hCG(mIU/mL)500050,000OR
AFP(ng/mL)100010,000
S3LDH>10NOR
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hCG(mIU/mL)>50,000OR
AFP(ng/mL>10,000
NindicatestheupperlimitofnormalfortheLDHassay.
StageGrouping
Stage0
pTis
StageI
pT14
StageIA
pT1
StageIB
pT2
pT3
pT4
StageIS
AnypT/Tx
StageII
AnypT/Tx
StageIIA
AnypT/Tx
AnypT/Tx
StageIIB
AnypT/Tx
AnypT/Tx
StageIIC
AnypT/Tx
AnypT/Tx
StageIII
AnypT/Tx
StageIIIA
AnypT/Tx
AnypT/Tx
StageIIIB
AnypT/Tx
AnypT/Tx
StageIIIC
AnypT/Tx
AnypT/Tx
AnypT/Tx

N0
N0
N0
N0
N0
N0
N0
N13
N1
N1
N2
N2
N3
N3
AnyN
AnyN
AnyN
N13
AnyN
N13
AnyN
AnyN

M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1
M1a
M1a
M0
M1a
M0
M1a
M1b

S0
SX
S0
S0
S0
S0
S13
SX
S0
S1
S0
S1
S0
S1
SX
S0
S1
S2
S2
S3
S3
AnyS

Reproduced,withpermission,fromEdgeSB,ByrdDR,ComptonCC,eds.AJCCCancerStagingManual,7th
edition.NewYork,Springer,2010,pp.47577.

ConsiderationofFertilityPreservation
OfparticularimportanceinGCTsisthepreservationoffertility.BoththediagnosisandtreatmentofGCTscan
affectfertilitynegatively,potentiallydecreasingaman'sabilitytoconceiveindefinitely.Itisrecommended
that,ifclinicallyfeasible,thepatientbecounseledaboutandofferedtheopportunitytopursuespermbanking
beforestartingchemotherapy.Itisnotrecommendedtodelaychemotherapyinsymptomaticpoorriskpatients,
aspoorphysicalconditionoftenmakesspermdonationdifficultorevenimpossible(28).

TesticularSeminoma
Histology
Undermicroscopicvisualization,classicseminomahasa"friedegg"appearancedefinedasamonotonous
proliferationoflarge,roundedcellsarrangedinsheetsorcordswithlargecentralizednucleiandnucleoli.
Thesetumorscanbedifficulttodistinguishfromlymphomaifthereisabackgroundoflymphocytic
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infiltration.Furtherconfirmation(ie,negativityforlymphocytemarkerssuchascommonleukocyteantigen)is
oftenrequired.Althoughnotspecific,seminomasstainpositiveforplacentalalkalinephosphatase(PLAP)and
areroutinelynegativeforAFPandhCG.Figure361showsthehistologicalappearanceofclassicseminoma.
Figure361.

Histologicalappearanceofclassicseminoma.
Onpathologicexaminationofthetestis,seminomatendstobeasemisolidtumorthatreadilyoozesontothe
grossexaminationtable.Thismakesthepresenceofmalignantcellsonthesurfaceofthespermaticcordandat
themarginsofresectionaubiquitousfinding.Thus,theclinicianmustbecarefulnottobeundulyinfluenced
byreportsof"marginpositivity"and"involvementofthespermaticcord"inthepathologyreport(29).Figure
362showsthetypicalgrossappearanceofseminoma.
Figure362.

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Grossappearanceofseminoma.
Eveninthepresenceofsignificantmetastaticdisease,itisnotuncommontofindonlyascarinthetesticle.
Thisphenomenonisknownas"burnedout"seminomaandisnotaprominentfeatureofNSGCTs,except
choriocarcinoma.Thebiologicalbasisforthisspontaneousregressionoftheprimaryisnotknown.Seminomas
aretypicallyassociatedwithasignificantinflammatoryinfiltration,andtheycharacteristicallyleaveadense
desmoplasticresidualmassaftertreatmentoftenmakingthemdifficulttoresect.

ClinicalFeatures
PureseminomaisthemostcommonGCTofthetesticle,accountingforapproximately50%ofGCTs.By
definition,seminomashavenoevidenceofanonseminomacomponentanddonotproduceAFP,butmayhave
modestelevationofhCG.Spermatocyticseminomas,ararevariantcomprisingonly10%ofseminomas,are
notassociatedwithITGCN.Thesetumorstypicallyoccurinmenover50yearsold,instageIdisease,and
havealowmetastaticrate.Thissubtypeportendsanexcellentprognosiswithresectionalone(radiotherapy)
(30).Seminomastendtospreadvialymphaticsinitially,withlatehematogenousspread,andaremorelikelyto
spreadlocally,asevidencedbypositivemarginsandinvolvementofthespermaticcordonhistology.Themost
commonhematogenousspreadistothelungs,andmetastaticseminomasrarelymetastasizetothebrain.
Remarkably,verybulkytumorsrapidlyrespond,withdramaticlossoftumorbulk,buttumorlysissyndromeis
neverencountered.

Prognosis
TheInternationalGermCellCancerCollaborativeGroup(IGCCCG)establishedastandardriskclassification
forbothseminomasandNSGCTs.Patientswithseminomaaredividedintoeithergoodorintermediaterisk
categories,withnodefinablepoorriskcategory.Theonecharacteristicthatpredictedpatientprognosiswas
thepresenceorabsenceofnonpulmonaryvisceralmetastases.Interestingly,prechemotherapytumormarkers
didnotinfluenceprognosis(unlikeinNSGCTstobediscussedlater).Theprognosticcategoriesfromthis
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researchareoutlinedinTable362.Ninetypercentofpatientswithseminomafellintothegoodprognosis
categoryandhad5yearOSof86%.Patientswithseminomaintheintermediateprognosiscategoryhada5
yearOSof72%(2).
Table362.IGCCCGClassificationPrognosticRiskStratification(2)
Seminoma
Nonseminoma
GOODRISK
Anyprimarysite
Testis/retroperitonealprimary
and
and
Nononpulmonaryvisceral Nononpulmonaryvisceral
metastases
metastases
and
and
NormalAFP,anyhCG,
AFP<1000ng/mL
anyLDH
hCG<5000mIU/mL
LDH<1.5ULN
82%5yearPFS86% 86%5yearPFS90%
5yearOS
5yearOS
INTERMEDIATERISK
Anyprimarysite
Testis/retroperitonealprimary
and
and
Nonpulmonaryvisceral
Nononpulmonaryvisceral
metastases
metastases
and
and
NormalAFP,anyhCG,
AFP100010,000ng/mL
anyLDH
hCG500050,000mIU/mL
LDH1.510ULN
67%5yearPFS72% 75%5yearPFS80%
5yearOS
5yearOS
POORRISK

Mediastinalprimary
or

Nonpulmonaryvisceral
metastases
or

AFP>10,000ng/mL
hCG>50,000mIU/mL
LDH>10ULN

41%5yearPFS48%
5yearOS

ManagementofClinicalStageISeminoma
ClinicalstageIseminomapatients,representing70%ofpatientsatdiagnosis,generallyhavediseaseconfined
tothetesticlewithnoevidenceofnodalordistantmetastasis.Mostpatientswillbecuredbyradical
orchiectomyalone,butbetween12and32%willrecurwithoutfurthertreatment.Definingthepatientswho
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areathighriskforrecurrentdiseasecouldavoidunnecessaryinterventionandexposuretotreatmentrisks.
ActiveSurveillance
Withthemajorityofpatientscuredpostsurgery,activesurveillanceremainsareasonableoptionforthe
motivatedandreliablepatient.Thebenefitsofsurveillanceincludeavoidanceofunnecessarytreatmentand
riskinpatientswhocanhavediseasecontrolregainedatthefirstsignofrecurrence.Wardeetal.reporteddata
on638patientsmanagedwithsurveillancewithamedianfollowupof7years.Patientswithaprimarytumor
lessthan4cmandwithoutinvasionofretetestishad5yearriskofrelapseof12%.Patientswithbothrisk
factorshadriskofrecurrenceof32%,whileoneofthetworiskfactorsportendsa16%riskofrelapse(31).
Becauseofexcellentoutcomesofpatientslatertreatedforrecurrentdisease,activesurveillanceisstill
consideredareasonableoptioninpatientswithbothriskfactors.
Radiotherapy
Deliveryof20GytotheparaaorticsaloneisastandardmanagementstrategyforclinicalstageIseminoma.
Theradiationfieldtotheparaaorticsisdefinedasa10cmwidefieldbetweenT12andL5.Thiscurrent
standardisbasedondatafromtwotrials.Thefirst,byJonesetal.,randomlyassignedpatientstoeither20Gy
in10fractionsover2weeksor30Gyin15fractionsover3weeks.Patientsreceivingthe30Gydosereported
moresymptomsat4weeks(nodifferenceat12weeks),withnoevidencefordecreasedrelapserateatmedian
followupof61months(32).Fossaetal.reportedtheirexperiencewith478patientswithstageIdisease
randomlyassignedtoreceiveradiationtoboththeparaaorticandipsilateraliliacfieldsversustheparaaortic
fieldalone.Thosetreatedwithreducedfieldshad3yearsurvivalof99.3%versus100%withtheextended
field.Thisminimallossoftreatmentefficacywasaccompaniedbyareductioninbothgastrointestinalside
effectsandinfertilityrisk.Adeterminationoftheriskofsecondarymalignancieswasnotyetassessable,butit
ispresumedtobereducedinthefaceofthedecreasedsizeofradiationportals(33).
Chemotherapy
Recently,datahavebeenreportedfromarandomizedcomparisonofsingleagentcarboplatindosebasedon
AUC7versusradiotherapyfortheadjuvanttreatmentofclinicalstageIseminoma(34).Medianfollowup
was4years,andtherelapsefreesurvivalwassimilarinbothgroups,96.7%and97.7%,respectively,showing
noninferiorityoftheonecycle,singleagentcarboplatinstrategy.Thistreatmentapproachisavaluableoption
forpatientswhocannottolerateorhavecontraindicationstoradiationtherapy.Therearenodatacurrently
comparingthelongtermsafetyofthisstrategyorsufficientevidencetocommentonanyriskofsecondary
malignancy.Figure363outlinesourapproachtotherapyforstageIseminoma.
Figure363.

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Managementoftesticularcancer(seminoma).

ManagementofNonbulky,GoodRiskSeminoma(StagesIIA/IIB)
PatientswithstageIIseminomaareoftendividedintononbulkyversusbulkydiseasefortreatmentdiscussion.
Ingeneral,nonbulkydiseaseisdefinedasnodeslessthan5cmintheCTorMRI.Theprimarymodeof
therapyforpatientsinthiscategoryisradiotherapyunlessthepatienthascontraindicationorisunableto
tolerateradiationtreatment.
Radiotherapy
ItisnolongerrecommendedthatstagesIIAandIIBseminomapatientsreceivehighdoseradiation(3035
Gy),mediastinalradiation,orleftsupraclavicularradiation.Thecurrentrecommendationisforradiotherapyto
adoseof20Gytotheparaaorticandipsilateraliliacnodalfieldswitha6Gyboosttotheparaaorticlymph
nodes(35).Occasionally,radiographicevidenceforresidualdiseaseispresentpostradiotherapy,butifthe
abnormalityislessthan3cm,observationisrecommended.
AlternativestoRadiotherapy
Thereisasubsetofpatientswhowillnotbeabletoreceiveradiationtherapyforvariousreasons.These
reasonsmayincludepatientrefusal,inflammatoryboweldisease,horseshoeorpelvickidney,andhistoryof
abdominalsurgery.Inthissetting,systemicchemotherapycouldbeoffered.InaseriespublishedbyXiaoetal.
(36),goodprognosisseminomapatientswereincludedintheanalysisandweretreatedwithfourcyclesof
etoposideandcisplatin(EP).AlthoughthisdoesnotrepresentthestandardofcareforstagesIIAandIIB
seminoma,itisareasonablealternativeforpatientswhoabsolutelycannotreceiveradiationtherapy.

ManagementofAdvanced,GoodRiskSeminoma(StagesIIC/III)
ThistreatmentgroupincludesstageIIpatientswithbulkylymphadenopathy(>5cm)andstageIIIpatients
withgoodriskdisease.Inthisgroupofpatients,theriskofrecurrenceremainshighdespitelocaltherapyand
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thereforetheprimarytreatmentrecommendationissystemicchemotherapy.Itisalsointhiscategoryof
patientsthattheroleofpositronemissiontomography(PET)scanmaybeintroducedinitslimitedrolefor
GCTs.
Chemotherapy
Therecommendedsystemicchemotherapyregimenforpatientswithgoodriskadvancedseminoma(stages
IICorIIIA)isthreecyclesofbleomycin,etoposide,andcisplatin(BEP).Theevidenceforuseofthreecycles
ofBEPversusfourcycleswaspresentedbydeWitetal.(37,38).Theseinvestigatorsshowedthatthreecycles
ofBEPisequivalenttofourcycles,with2yearprogressionfreesurvival(PFS)of90.4%and89.4%,
respectively(39).Alternatively,patientswhoareunableorrefusetoreceivebleomycinorareolderthan50
yearscanbesuccessfullytreatedwithfourcyclesofEP.
ResidualDiseaseafterChemotherapyandtheRoleofPET
Aftercompletionofchemotherapy,restagingCTscansareperformed.Ifapatientisfoundtohavenoresidual
diseaseorresidualdiseasemeasuringlessthan3cminsizewithnormaltumormarkers,activesurveillance
shouldbepursued.Postchemotherapy,residualdiseasemeasuringgreaterthan3cmcanbefurtherevaluated
byPETimaging.EvidencefortheroleofPETimaginginthesettingofresidualdiseasegreaterthan3cmwas
presentedbyDeSantisetal.(40).Inthisevaluationof33patientswithfollowuptimeof23months,the
positivepredictivevalueofFDGPETwas100%,withaspecificityandsensitivityof100%and89%,
respectively,fortheidentificationofresidualdiseaseinlesionsmorethan3cm.Althoughencouraging,the
roleofPETimaginginthissettingisbeingreexamined,becauseseveralfalsepositivecasesfromour
institutionhavebeenrecentlyidentified.
PETNegativeDiseasePostchemotherapy
IfthereisnoevidenceofaviduptakeonPET,thepatiententerstheactivesurveillancestrategy.Ifthepatientis
unabletohavePETimaging,surgicalbiopsyorconsolidativeradiationtherapycanbeconsideredforthose
patientswithresidualdiseasemeasuringgreaterthan3cm.
PETPositiveDiseasePostchemotherapy
AtMDAnderson,apositivePETscanrequiresaconfirmatorybiopsy.Ifresidualdiseaseisconfirmed,several
optionscanbeconsidered.First,salvageradiationtherapytotheresidualmasscanbeoffered,butthisdoesnot
providelongtermcontrol.Second,thepatientcanbeofferedsalvagechemotherapy.Finally,thepatientmay
undergohighdosechemotherapywithautologousstemcelltransplantation.SeeFigure363forthealgorithm
ofourmanagementstrategy.

ManagementofAdvanced,IntermediateRiskSeminoma
Patientswithadvanced,intermediateriskseminomahavenonpulmonaryvisceralmetastasis.Themost
commonsitesofdiseasearetheliverandbone.Theserarepatientsareofferedsystemicchemotherapyupon
presentation(seeFigure363).ThechemotherapyregimenscommonlyusedarefourcyclesofBEP,four
cyclesofetoposide,ifosfamide,cisplatin(VIP),orfourcyclesofpaclitaxel,ifosfamide,cisplatin(TIP)(41).

SalvageTherapyforRefractory/RecurrentSeminoma
Theprimarytreatmentofrecurrentseminomaissalvagechemotherapy.Forpatientswithlungmetastasis
(goodriskcategory),thestandardofcareisadministrationofeitherthreecyclesofBEPorfourcyclesofEP.
Inpatientswithboneorlivermetastasis(intermediateriskcategory),salvagechemotherapyispursuedwith
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eitherfourcyclesofBEP,TIP,orVIP.Bleomycinshouldbeavoidedinmenolderthan50years.
Clinicalsignsofrefractorydiseaseshouldbeapproachedwithanaggressivechangeofstrategy,includingthe
optionofhighdosechemotherapyandstemcelltransplantation.UsuallyreservedforBEPfailuresand
recurrentdisease,theroleofstemcelltransplantationinrefractory/recurrentadvancedseminomawas
addressedbyEinhornetal.(42).Nineteenpercentofaseriesof184patientswerepatientswithmetastatic
testicularseminoma.Atamedianfollowupof48months,26of35seminomapatientstreatedwerein
completeremission.Patientsinthiscategoryshouldbeconsideredforreferraltotransplantcentersifpossible.

Case361:SeminomaPresentingwithRenalInsufficiency
A37yearoldmanhadaleftinguinalorchiectomyforclassicseminoma.Laboratorydataatpresentationto
MDACCrevealedserumcreatinineof1.8mg/dL,calcium12.7mg/dL,Hgb10.5g/dL,hCG113mIU/mL,Alk
phos194IU/L,andLDH1773IU/L(ULN618).ACTscanofabdomenandpelvisrevealedalarge
retroperitonealmasswithmarkedlefthydronephrosis(Fig364A).Thepatientreceivedinitiallyonecycleof
cyclophosphamideandcarboplatinum.Repeatlaboratorydatarevealedserumcreatinineof1.1mg/dL,calcium
8.2mg/dL,LDH483IU/L,andundetectablehCG.HesubsequentlyreceivedthreefullcyclesofEPwith
excellentresponse.RepeatimagingshowninFig364Brevealedmarkedimprovementinthesizeofthemass
(from147cm).PostchemotherapyPETimagingshowedtheresidualmasstobemetabolicallyinactive.
Figure364A.

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Baselineimagingfromcase361showingalargeleftretroperitonealmasswithlefthydronephosis.
Figure364B.

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Repeatimagingfrompatientincase361showingmarkedimprovementinmassafter3cyclesof
chemotherapy.
Comment:Apatientwithadvancedseminomapresentingwithhydronephrosisandrenalinsufficiencymay
receiveinductionchemotherapywithcyclophosphamideandcarboplatinumratherthanplacingnephrostomy
tubestoallowadministrationofBEPorEPinthefirstcycle.Thepatientcansubsequentlyreceivestandard
therapyafternormalizationofrenalfunction.

NonseminomatousGermCellTumors
Histology
EmbryonalCarcinoma
EmbryonalcarcinomaisthesecondmostcommonpurepresentationofGCT.Itisrarelyseenattheextremes
ofage,mostcommonlypresentinginthe20to30yearagegroupandpresentswithmetastasisinonethirdof
cases.Microscopically,embryonalcarcinomacellsarethemostundifferentiatedoftheGCTtypesandare
characterizedbymicroscopicallyvariedcellswithindistinctbordersandscantcytoplasm,givingthe
appearanceofoverlappingnuclei.Tumorcellscanbeseeninsheetsorarrangedaspapillaryortubular
structureswithahighmitoticrate.Thereisapropensityforvascularinvasion.Phenotypiccharacterizationcan
revealpositivityforcytokeratin,CD30,PLAP,AFP,andhCG.ModestelevationsofbothAFPandhCGare
typical,butimportantly,pureembryonalcancerscanbemarkernegativeintheserum.Figure365showsthe
typicalhistologicappearanceofembryonalcarcinoma.
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Figure365.

Histologicalappearanceofembryonalcarcinoma.
EndodermalSinusTumors(orYolkSacTumors)
PureyolksactumorsareextremelyrareintheadultpatientbutaccountforthemajorityofchildhoodGCTs.In
adults,endodermalsinustumor(EST)oryolksacelementsarecommonlyseenasacomponentofmixed
NSGCTs.Microscopically,ESTcanmanifestasmacrocystic,papillary,solid,oraglandular/alveolarpattern
withperivasculararrangementsofepithelialcellsknownasglomeruloidorSchillerDuvalbodies.HighAFP
levelsgenerallyreflectanESTcomponent,andserumlevelsofAFPareimportantprognosticallyinthe
classificationofgood,intermediate,andpoorriskmetastaticNSGCTs.Figure366showsthetypical
histologicalappearanceofanESTcarcinoma.
Figure366.

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HistologicalappearanceofESTcarcinoma.
Choriocarcinoma
Alsorareinthepureformintheadultpopulation,choriocarcinomafrequentlypresentsasacomponentof
NSGCTs.Choriocarcinomascomprisebothsyncytiotrophoblastsandcytotrophoblasts,typicallyarrangedin
sheetsornests.ChoriocarcinomasgenerallymakecopiousamountsofhCG,andthelevelofthismarkerisalso
anindicationofprognosisinmetastaticNSGCTs.HalfofchoriocarcinomasarePLAPpositive.
Choriocarcinomaelementstendtodominatetheclinicalcourseandfrequentlymetastasizetothebrain.Figure
367showsthetypicalhistologicalappearanceofchoriocarcinoma.
Figure367.

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Histologicalappearanceofchoriocarcinoma.
Teratoma
Teratomaspossesssomaticcellsfromatleasttwogermcelllayers(ectoderm,endoderm,andmesoderm).
Variabledegreesofdifferentiationallowforthesubclassificationofmatureandimmatureforms.Mature
teratomaconsistsofterminallydifferentiatedtissuesandcanformcysticstructures.Althoughhistologically
bland,thislowgrademalignancycangrowtoathreateningdimensionandbecomeunresectable.Onlyabout2
to3%ofallGCTsshowmatureteratomaastheonlyhistologiccomponent,butteratomaiscommonlypresent
asanelementofamixedGCT.Immatureteratomaislessdifferentiatedanddisplaysacorrespondinglymore
aggressivebiology.OneoftheunfortunatemanifestationsisthedevelopmentofnonGCTwithintheteratoma.
Knownasteratomawithmalignanttransformation,thisentitytypicallydisplaysthebiologyofwhatever
histologydevelopsandcanrangefromleukemiastosarcomastocarcinomas.Ingeneral,suchatransformation
beliesapoorprognosis(43).Figures368and369representthetypicalhistologicalandgrossappearanceof
teratoma,respectively.
Figure368.

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Histologicalappearanceofteratoma.
Figure369.

Grossappearanceofteratoma.

ClinicalFeatures
Asdescribedpreviously,approximatelyhalfoftesticularGCTsshowhistologicelementsotherthanseminoma
orproduceserumelevationofAFPindicatingnonseminoma.Thesecancersarecollectivelyknownasmixed
GCTsorNSGCTs,andtheyformagroupofhistologicallyandclinicallydiversecancers(44).NSGCTsare
morelikelytospreadhematogenouslywithincreasedriskofdistantmetastasiswhencomparedtoseminomas.
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BecauseoftheuniqueandheterogeneousnatureofNSGCTs,thereareseveralclinicalpresentationswhich
warrantfurtherdiscussion,becauseoftheirsignificancetopatientcareandprognosis.
GrowingTeratomaSyndrome
Residualteratomaisalowgrade,slowgrowingmalignancythatcanbefatalbyinexorablegrowth.Thiscan
take10oreven20yearstobecomethreateningandthuscanbemissedwithoutdedicatedlifelongfollowupof
patientswithNSGCTs.Oneofthemostremarkableandclinicallyimportantfeaturesofteratomasisthatthey
areoften"pushing,"andrarelyinvasive.Thusatsurgery,evenverylargemassesaresometimesremovedfar
moreeasilythanwouldbeexpectedonthebasisofthepreoperativeimaging.Itisimportanttoconsultacenter
wheresufficientsurgicalexperienceisavailablebeforeconcludingthataresidualteratomais"unresectable"
(45).
ChoriocarcinomaSyndrome
Asthenameimplies,thisisseeninthesettingofhighvolumeNSGCTthatshowspredominantly
choriocarcinomahistologyandisassociatedwithveryhigh(typicallyabout1,000,000U/L)levelsofhCG.
Thissyndromeischaracterizedbyprominentconstitutionalsymptomsthatrepresenttheeffectsofbothabulky
cancer,andsecondaryhyperthyroidismcausedbycrossreactionofhCGwithTSHreceptors.Typically,
patientsarerapidlylosingweight,tachycardic,anxious,diaphoretic,andhavetender,swollenbreastsfrom
secondaryhyperprolactinemia.Inaddition,mostpatientshavehighvolumelungmetastaseswithimpending
respiratorycompromisefromtheburdenofpulmonarymetastasis.Thisisamedicalemergency,andtreatment
shouldnotbedelayedforhistologicconfirmation,sincethisisapathognomonicconstellationinayoungman.
Metastaticchoriocarcinomahasapropensityforbrainmetastasis,althoughtheyarenotalwaysapparenton
baselineimaging.

Prognosis
Asdescribedabovewithseminoma,theIGCCCGdevelopedaprognosticstagingsystemforNSGCTswith
nonpulmonaryvisceralmetastasisfoundasamajorfactorinprognosis.Unlikeseminoma,prechemotherapy
tumormarkerswereidentifiedassignificantintheprognosisofthesepatients.Theprognosticcategoriesare
outlinedinTable362.Ingeneral,patientswithmediastinalprimary,nonpulmonaryvisceralmetastasisand
"poormarkers"asdefinedinthefigureareconsideredtohavepoorprognosisandhavea5yearOSof48%.
Patientswithtestisorretroperitonealprimary,nononpulmonaryvisceralmetastasisareplacedinthegood
prognosiscategorybasedontumormarkerlevelsasdescribedinthefigure.Goodprognosispatientshavea5
yearOSof92%.Allothersareplacedintheintermediateriskgroupandhavea5yearOSof80%(2).Van
Dijketal.(3)updatedthe5yearOSdataforNSGCTsinapooledmetaanalysis.Theauthorsreported5year
OSof94%forgoodprognosis,83%forintermediateprognosis,and71%forpoorprognosis.Thisillustrates
theimprovingsurvivalratesinthehighriskgroup.

ManagementofClinicalStageINSGCT
Ingeneral,clinicalstageINSGCTincludespatientswithnormalmarkerspostorchiectomyandnoevidenceof
diseaseoutsidetheresectedtestis,epididymis,orcord.Aswithseminoma,radicalinguinalorchiectomyisthe
initialtherapyforearlystageNSGCT.Appropriatesurgerywillcureapproximately70%ofclinicalstageI
patients.Thetwoidentifiedriskfactorsinthesepatientsincludepercentageofembryonalhistologyand
lymphovascularinvasion(LVI),withLVIthemostpredictive(46).Patientsareconsideredlowriskfor
recurrencepostorchiectomy,ifthereislessthan50%embryonalcomponentinthetumorandnoevidenceof
LVI.Theroleofpercentageofembryonalcomponentisdebatable.Infact,Europeanguidelinesutilizeonly
absenceofLVIfordeterminationof"lowrisk"forrecommendationofobservation(47).
Observation
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Observationisareasonablestrategyforthereliable,lowriskpatient,whichinpracticecanbethosewith
absenceofLVI.TheactivesurveillancescheduleasoutlinedbytheNationalComprehensiveCancerNetwork
(NCCN)ClinicalPracticeGuidelinesinOncologyrecommendsthatpatientsshouldhaveaphysical
examination,chestradiography,andtumormarkermeasurementseverymonthduringthefirstyear,every2
monthsduringthesecondyear,andeverythirdmonthduringthethirdyear.AbdominalandpelvicCTis
recommendedapproximatelyevery3monthsduringthefirstyearandevery4monthsforyears2and3(48).
RetroperitonealLymphNodeDissection
Retroperitoneallymphnodedissection(RPLND)isasurgicalremovalofthe"landingzone"lymphnodes.An
accuratestagingstrategy,itsroleinprimarypreventionofrecurrenceinstageINSGCTpatientsis
controversial.MorbidityofRPLNDincludessympatheticnervedamagethatmayleadtofailureofejaculation
andinfertilityhowever,useofamodifiedsurgicaltemplateisanervesparingapproachthatcanpreservethe
sympatheticnervesandmayfacilitateantegradeejaculationin90%ormorepatients.Stephensonetal.(49)
reportedthatRPLNDinclinicalstageIpatientsyieldeda4yearprogressionfreeprobabilityof96%andisan
optionfortherapyinthispatientpopulation.Higherfailurerateshavebeenreportedforpatientswithhighrisk
clinicalstageINSGCT.PatientswhodonotundergoprophylacticRPLNDmustundergoperiodicCT
scanningoftheabdomentoruleoutgrowingteratomaintheretroperitoneum.
Chemotherapy
Inthepast,adjuvantchemotherapyforstageINSGCTpatientswithhighriskofrecurrenceconsistedoftwo
cyclesofBEP.Recently,tworandomizedtrialsevaluatedtheimpactofonecycleofBEP.Albersetal.(50)
comparedRPLNDtoonecycleofBEPin382patientswithamedianfollowupof4.7years.The2year
recurrencefreesurvivalwas99.46%inthechemotherapygroupand91.87%intheRPLNDgroup,suggesting
anadvantageofonecycleofBEPchemotherapy,althoughthisfindingdidnotreachstatisticalsignificance.
Tandstadetal.(51),intheSWENOTECAstudy,confirmedthesefindingsin745patientswhowere
prospectivelyrandomizedbasedonthepresenceofLVI.TheseinvestigatorsreportedthatonecycleofBEP
reducedtheriskofrecurrenceby90%inpatientswithorwithoutLVI.Ouralgorithmformanagementofnon
seminomatesticularcancerisshowninFigure3610.
Figure3610.

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Managementoftesticularcancer(nonseminoma).

ManagementofGoodRiskClinicalStagesIIAandIIBNSGCT
Patientswithtumormarkernegative,stagesIIAorIIBNSGCTspresentauniqueclinicalsituation.Atour
institution,thesepatientsaredividedintogroupsbyCTevidenceofdiseasegreaterthanorlessthan3cm.If
patientshavenegativetumormarkerswitharetroperitonealmasslessthan3cmafterorchiectomy,surgical
biopsyispursued.Ifnegative,thenobservationisareasonablealternativeforthereliablepatient.Patientswith
largerthan3cmdisease,positivetumormarkers,orpositivebiopsyaretreatedwithprimarychemotherapy
withBEPforthreecycles.Asdiscussed,severalgroupshavereportedlongtermfollowupdataconfirmingthe
equivalenceofthreecycleswhencomparedtofourcyclesofBEP(37,38).Aspreviouslyrecommended,four
cyclesofEPisalsoareasonablealternativeinpatientswhorefuseorhaveacontraindicationtoreceive
bleomycin(39).Ifresidualtumorisdetectedonfollowupstaging,surgicalresectionisrecommended.

ManagementofGoodRiskStagesIICandIIINSGCT
Patientswithbulkyretroperitonealdiseaseofgreaterthan5cmorpulmonarymetastasis,withrelativelylow
serummarkersconstitutethosewithadvanceddisease,butstillwithfavorableprognosis.Thesepatientsmay
beeitherstageIICorIIIAaccordingtotheAJCCcriteriaandareconsideredtogetherinthisdiscussion.The
primarymodeoftreatmentinthispatientpopulationissystemicchemotherapy.Thismaybeadministered
beforeorafterradicalorchiectomyaslongassurgicalresectionoftheprimaryisperformedaftercompletion
oftherapy.Onceagain,threecyclesofBEPchemotherapyisconsideredstandardofcareandfourcyclesofEP
consideredareasonablealternativeforpatientswithacontraindicationtoreceivebleomycin.Resectionof
residualdiseasepresentonrestagingshouldbeperformed(3739).
Pathologyoftheresectedtumoraftersalvagechemotherapyisdifferentthanafterprimarychemotherapy.
Followingprimarychemotherapy,viableGCT,fibrosis,orteratomaarefoundinapproximately20%,40%,
and40%ofpathologicalspecimens,respectively,comparedto50%,10%,and40%followingsalvage
chemotherapy,respectively.Patientswithgreaterthan10%viableGCTintheresidualpathologyspecimen
afterprimarychemotherapyshouldreceiveadditionaltwocyclesofplatinumbasedchemotherapy(Figure36
10).
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ManagementofIntermediateandPoorRiskAdvancedStagesIIIBandIIICNSGCT
PatientswithadvancedNSGCTswhopresentwithintermediateorpoorriskfeaturesaremanagedwith
systemicchemotherapyconsistingoffourcyclesofBEP.Thismaybegivenpriortoradicalorchiectomy.For
advanced,intermediateorpoorriskpatientswithacontraindicationtoreceivebleomycin,VIP,orTIPis
recommended(52).Thesepatientsshouldalsobeconsideredforparticipationinclinicaltrials.

ManagementofRecurrentandRefractoryNSGCT
Severalchemotherapyregimenswithclinicalactivityinthesalvagesettinghavebeenreported,andthese
includeVIP,TIP,VeIP(vinblastine,ifosfamide,cisplatin),IPO(irinotecan,paclitaxel,oxaliplatin),or
gemcitabine/oxaliplatin.Ingeneral,manypatientsrespondandsomeareevencuredwithsalvage
chemotherapyandsurgicalconsolidation,especiallythosewithasmallormoderatevolumeofdisease.There
hasbeensomesuggestionthatrotationofchemotherapyregimensmayoffersomebenefit.Wearecurrently
evaluatingourownexperiencewiththistreatmentstrategy.
Thestrategymostsupportedbyrecentdataistheroleofhighdoseinductionchemotherapywithstemcell
transplantation.Einhornetal.(42)retrospectivelyreviewed184patients(149patientswithadvancedNSGCT)
withamedianfollowupof48months.Ninetyofthe149patientswithNSGCTtreatedwithhighdose
chemotherapyandsubsequentautologousstemcelltransplantationwerediseasefreeatfollowup.Theauthors
suggestthatuseofthisaggressivetreatmentassecondlinetherapyisdistinctlyadvantageouswhencompared
topatientswhoreceivethistreatmentinthethirdlinesetting.Basedonthisstudyanddespitetheabsenceofa
randomizedtrial,patientswithrecurrentorrefractoryadvancedstageNSGCTmaybeconsideredforthis
aggressive,yeteffective,treatmentstrategy.

SpecialConsiderations
PitfallsinTumorMarkerElevation
MildelevationofhCG(usually<20)mayoccursecondarytohypogonadismormarijuanause,andtherefore,
shouldnotalwaysbeattributedtoresidualorrecurrenttumor.ModestelevationofAFPmaybepresentwith
residualteratomaandwillnormalizefollowingsurgicalresection,butmayalsobeconstitutionallyelevatedor
indicatepresenceofliverdisease.Additionally,elevatedtumormarkersmayindicateunidentifiedCNSdisease
orresidualprimarytesticulartumor.
RoleofDesperationSurgery
TherearepatientswithNSGCTswhohaverisingtumormarkers,despiteoptimalsystemictherapy.Inthese
instances,surgerytoresectallvisibledisease,atermwecoin"desperationsurgery"couldbeconsidered.Itis
estimatedthatupto20%ofpatientswhofitthesecriteriamaybecuredwithsurgicalresection.Patientswith
isolatedretroperitoneallymphnodedisease,AFPonlyelevation,andwhoundergoacompleteresectionof
residualdiseasehavethemostfavorableoutcome.Referraltoacenterwithhighsurgicalexpertiseinthis
settingisrecommended,aspotentiallylargeenblocresectionsmayberequiredtoachievethedesiredoutcome
ofcompleteresection.
TreatmentofLateRelapse
Laterelapseisdefinedasdiseaserecurrenceafter24monthsfromprimaryBEPchemotherapy.Teratomaand
yolksacarethemostcommonhistologiesinthissetting,withpureteratomaconferringabetterprognosis.
Surgeryisthepreferredinitialtreatmentinthesecases,ifthetumorisfelttobecompletelyresectable.
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LateComplicationsofTherapy
Althoughrare,therearespecificcomplicationsassociatedwithtreatmentofGCTs,whichareespecially
importantinthispatientpopulation,ascurabilitymayleadtoanormallifeexpectancy.Secondaryleukemias
occurinfewerthan0.5%patientsandareassociatedwithuseofetoposide.Bleomycintoxicitycanappear
earlyandismostassociatedwithdosegreaterthan200IU.Patientsmayalsohaveincreasedriskofvascular
sideeffects,includingRaynaudsyndromeandhypertension.Upto25%ofpatientsmaydevelopthemetabolic
syndrome.Additionalcomplicationsincluderenalinsufficiency,chronicperipheralneuropathy,chronic
electrolyteabnormalities,andneuropsychiatricabnormalities.

Case362:Bep/TipFailure
A24yearoldmanpresentedwithlowerbackpain,anorexia,nightsweats,andweightloss.Imagingstudies
revealedextensiveretroperitoneallymphadenopathy,arighttesticularmass,andbilaterallungnodules.Tumor
markerswerehCG33,261,AFP4.1,andLDH1847.Afineneedleaspirationoftheretroperitonealmass
revealedembryonalcarcinoma.BEPchemotherapywasinitiated.ThekineticsofdeclineofserumhCGlevels
areshownbelowforthefirstthreeoutoffourplannedcycles:
s/pcycle1:1507
s/pcycle2:279
s/pcycle3:323
SalvagechemotherapyiscommencedafterthethirdcycleofBEP.ThepatientreceivedfourcyclesofTIP,
withdecreaseinadenopathyanddeclineofserumhCGtoundetectable.Thepatientwasthenreferredfor
RPLNDandrightradicalorchiectomy.Pathologyrevealednoviabletumor.Twomonthspostoperatively,
serumhCGroseto161.Hereceivedonecycleofirinotecan,paclitaxel,andoxaliplatinwithtumormarker
normalization.Hethenunderwenttandemperipheralbloodstemcelltransplantation(SCT)withhighdose
ICE.Heremainsdiseasefree3.5yearslater.
Comments:ForsymptomaticpatientswithintermediateorpoorriskGCTs,chemotherapycanbeinitiated
beforeorchiectomy.RisingtumormarkersduringBEPchemotherapysignalBEPfailureanddictatechangeof
therapy.ThebestresultsareachievedwithhighdosechemotherapyandSCT.

Case363:TheChallengeofManagingIntercurrentIllness
A35yearoldheavysmokerandmarijuanausermanunderwentaleftorchiectomyfora3.5cmmixed
NSGCTandpresented2monthslatertoMDACCwithleftgroinpainandleftthighnumbness.Tumormarkers
wereAFP6575,hCG1059,andLDH2441.CTscansrevealedbilaterallungnodules,alarge(14.7cm)
retroperitonealmass,lefthydronephrosis,andmultipleotherenlargedabdominalandpelviclymphnodes.
DuringthefirstBEPchemotherapycycle,hesufferedaninferiormyocardialinfarction(MI)secondarytoan
occludingatheroscleroticplaqueintherightcoronaryartery.Aftercoronarystentingandoptimalmedical
therapy,thepatientwasabletocompletefourcyclesofBEPonscheduleandatfulldose,withoutdelayor
significantcomplications,exceptformoderateperipheralneuropathy.Histumormarkersdeclinedasfollows:
FavoriteTable|Print
s/pcycle1 AFP=3853hCG=34.7
s/pcycle2 AFP=542hCG=5.2
s/pcycle3 AFP=88.1hCG=4.6
s/pcycle4 AFP=42hCG=4.7
Thepatientreceivedintramusculartestosteroneinjectionforlowserumtestosteronelevel,and3weekslater
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serumhCGwas<1.0.SixmonthsafterhisMI,thepatienthadresectionofthelargeleftretroperitonealmass,
theleftkidneyandleftadrenalgland,RPLND,andsegmentalresectionoftheleftpsoasmuscle.Pathologyof
thespecimenrevealed98%necrosisandonlytwomicroscopicfociofresidualviableESTintransitionto
adenocarcinoma.Thepatienthasbeenrecurrencefreefor3years.
Comments:Thiscaseillustratesthreepoints.Thefirstistheimportanceofpursuingchemotherapywhile
managinganintercurrentillness.Thesecondpointistorememberthattherearecausesofelevatedtumor
markersotherthantumor.ThethirdpointisthatwedonottreatfociofMTT.

Case364:DesperationSurgery
A46yearoldmanpresentedwithbackpainandwasfoundtohavean11cmretroperitonealmass,biopsyof
whichrevealedhighgradeGCT(Figure3611A).Heunderwentaleftradicalorchiectomyfora2.8cmmixed
GCT(99%seminoma,1%teratoma).Postoperatively,serumAFPwasgreaterthan10,000.Hereceivedsix
cyclesofEP,followedbyonecycleofVeIPbutneverachievedtumormarkernormalization(Figure3611B).
AtpresentationtoMDACC,hisserumAFPwas604.Thepatientreceivedmultipleadditionalcyclesof
rotatingsalvagechemotherapy,includingactinomycinD,cyclophosphamide,andetoposide(ACE)TIP,
cisplatinum,vincristine,methotrexate,andbleomycin(POMB)doxorubicin,paclitaxel,andgemcitabine
(ATG)andcisplatinum,cyclophosphamide,anddoxorubicin(CisCa)(Figure3611C).Thepatientdeveloped
renalinsufficiency,recalcitrantanemia,andgrade3peripheralneuropathy,andhadtransientnormalizationof
serumtumormarkerswhileawaitingsurgicalresection.Atthetimeofsurgery,serumAFPwas46.9.The
patientunderwentRPLNDwithexcisionofretroperitonealmasses,leftradicalnephrectomy,andexcisionof
retrocrurallymphnodemasses.PathologydemonstratedmetastaticmixedGCT,includingareasofEST,
matureteratoma,andfocalareassuspiciousforembryonalcarcinomaandchoriocarcinoma.Heremains
diseasefreepast5yearsfromthetimeofhissalvagesurgery.
Figure3611A.

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Baselineimagingofpatientdescribedincase364withlargeretroperitonealmass.
Figure3611B.

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Repeatimagingofpatientincase364aftersixcyclesofEP.
Figure3611C.

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Imagingofpatientfromcase364showingresidualdiseasedespitemultiplelinesofsalvagechemotherapy
priortodesperationsurgery.
Comments:FourcyclesofBEPandnotEPisthestandardforpatientswithintermediateandpoorrisk
NSGCT.Inrarecases,wherethetumormarkersdonotnormalize,evenafterexhaustingallchemotherapeutic
options,patientsmaybesalvagedsurgically.PatientswhohaveprimarilyAFPelevationandESTorteratoma
benefitthemostfromsuchanapproach.

Case365:GSTwithOccultPrimary
A29yearoldmanpresentedwithweightlossandleftsupraclavicularlymphadenopathy(seeFigure3612A),
buthadanegativetesticularexaminationandultrasound.Imagingstudiesconfirmeda5cmleft
supraclavicularlymphnodeandshowedasmallleftpleuraleffusion.Abiopsyofthesupraclavicularlymph
nodedemonstratedpoorlydifferentiatedadenocarcinoma.Embryonalcarcinomacouldnotbeexcluded.
ImmunostainsforPLAPandKi1werepositivebutwerenegativeforAFPandinconclusiveforhCG.
Laboratoryevaluationrevealedazoospermiabutnormalserumchemistriesandtumormarkers.Thepatient
wastreatedwiththreecyclesofBEPandachievedacompleteremissionandisnowdiseasefreefor5years
withoutsurgicalconsolidation(Figure3612B).
Figure3612A.

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BaselineimagingofpatientdescribedinCase365showingbulkyleftsupraclavicularadenopathy..
Figure3612B.

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Imagingafterthreecyclesofchemotherapy.
Comments:Thecaseofunknownprimarycarcinomainayoungman,eveniftumormarkersarenegative,
shouldraisethediagnosisofGCTandshouldbetreatedassuch.Surgicalconsolidationisnotalways
necessary,whenaclinicalcompleteresponseisachievedwithchemotherapy.

ExtragonadalGermCellTumors
Patientswithseminomasarisinginthemediastinumhavesimilarprognosistopatientswithtesticular
seminomasandaretreatedwithfourcyclesofEPatourinstitution,iftheydonothavenonpulmonaryvisceral
metastasis.NonseminomatousextragonadalGCTsrepresentadistinctsubsetofGCTsandcarryapoorer
prognosisthanprimarytesticularNSGCTs.Themostcommonoriginisthemediastinum,buttheycanalso
ariseintheretroperitoneumorpinealregion.Rarecasesinvolvethevagina,prostate,liver,andorbit.
MediastinalEGCTsappearaslargeanteriormassesonradiographs.Thissubsetischaracterizedby
prominenceofESTandteratomahistology,comparedtoprimarytesticularGCTs(53).Initialdiagnosismay
beaidedbyelevationsofAFPorhCG.Klinefeltersyndromeisassociatedwithincreasedriskofprimary
nonseminomatousmediastinalGCTs(54).Additionalassociationsincludeacutemegakaryoblasticleukemia,
acutemyeloidleukemia,myelodysplasticsyndrome,andmalignanthistiocytosis.Someofthesecases
representmalignanttransformationofimmatureteratomaelements.
NonseminomatousGCTsareclassifiedashighriskGCTs(2),anddatasuggestthatlongtermsurvivalisas
lowas20%(5557).Theaggressivenatureofthisentityiscoupledbythesurgicaldifficultyofresectionof
residualdiseaseaftertherapy.EarlydiagnosisandaggressiveresectionofmediastinalNSGCTsmayimprove
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theoutcome.Atourinstitution,thetreatmentstrategyforthisrareentityincludespresurgicalchemotherapyto
optimumresponseandthenconsolidationsurgery.

Conclusion
GCTsrepresenttheparadigmofcurablesolidtumors.Optimalmanagementofthesepatientsrequiresa
multidisciplinaryapproach,integratingchemotherapyandsurgery,toachievethehighestcurerates.Patients
whoposeauniquediagnosticortherapeuticchallengeshouldbeconsideredforearlyreferraltoalargetertiary
carecenter.

References
1.AmericanCancerSociety.CancerFactsandFigures2009.Atlanta:AmericanCancerSociety2009.
2.InternationalGermCellCancerCollaborativeGroup.Internationalgermcellconsensusclassification:A
prognosticfactorbasedstagingsystemformetastaticgermcellcancers.JClinOnc199715:594603.
3.VanDijkMR,SteyerbergEW,HabbemaDF.Survivalofnonseminomatousgermcellcancerpatients
accordingtotheIGCCCGclassification:Anupdatebasedonmetaanalysis.EurJCancer200642:820826.
4.BrayF,FerlayJ,DevesaSS,etal.Interpretingtheinternationaltrendsintesticularseminomaand
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undefined
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Silverchair
Histologicalappearanceofclassicseminoma.
Grossappearanceofseminoma.
Managementoftesticularcancer(seminoma).
Baselineimagingfromcase361showingalargeleftretroperitonealmasswithlefthydronephosis.
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Repeatimagingfrompatientincase361showingmarkedimprovementinmassafter3cyclesof
chemotherapy.
Histologicalappearanceofembryonalcarcinoma.
HistologicalappearanceofESTcarcinoma.
Histologicalappearanceofchoriocarcinoma.
Histologicalappearanceofteratoma.
Grossappearanceofteratoma.
Managementoftesticularcancer(nonseminoma).
Baselineimagingofpatientdescribedincase364withlargeretroperitonealmass.
Repeatimagingofpatientincase364aftersixcyclesofEP.
Imagingofpatientfromcase364showingresidualdiseasedespitemultiplelinesofsalvagechemotherapy
priortodesperationsurgery.
BaselineimagingofpatientdescribedinCase365showingbulkyleftsupraclavicularadenopathy..
Imagingafterthreecyclesofchemotherapy.

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