St.

Jude Solid Tumor Board

01 February 2013

St. Jude Solid Tumor Board

01 February 2013

Germ Cell Tumor

Germ Cell Tumor

Meaghann Weaver, MD
Jamie L. Coleman, MD
Jesse J. Jenkins, III, MD

Meaghann Weaver, MD

Competencies
MedicalKnowledgebyprovidinginformationonnewresearch
findingsinthebasicandclinicallysupportedsciences

PatientCareSkillsbyprovidinganupdateondiagnosisskillsand
managementstrategies

SystemBasedPracticesbyrecognizinghowindividualpractices
relatetothelargersystemofmedicalcare

17yofemale:CasePresentation

Objectives
Reviewtheclinicalpresentationanddiagnostic
evaluationofovariangermcelltumors

Recognizethepathology,serumtumormarkers,and
geneticmutationsrelevanttogermcelltumors

Describethetreatmentoptionsandprognosisofgerm
celltumorsbasedonriskstratification

DifferentialDiagnosis:OvarianMass

HPI:Increasedabdominalgirth,concernedfornoticeable
abdominalballooning(pregnant?),earlysatiety,weightgain
despiteexercise,constipationwiththin/lighterstools,urinary
g
y/ q
y,
p
y
urgency/frequency,mensesreportedlynormal
PMH:Fullterm,BW7ib 12oz,healthychildhood,acidreflux,no
priorhospitalizationsorsurgeries
Medications:Oralcontraceptives
FamilyHistory:Nofamilyhistoryofcancer,autoimmune
disorders,orblooddisorders
BillmireD,etal.PediatrSurg.2004Mar;39(3):4249;discussion4249.Outcomeandstagingevaluationinmalignantgermcelltumorsoftheovaryinchildrenand
adolescents:anintergroupstudy.

17yofemale:LaboratoryFindings
PreOperativeHCG<1
AlphaFP305(normal0.5to8);postoperative91>36
Ca125157(normal032)
LDH581(
LDH581(normal94260)
l94 260)

8.9
7

526
28

MCV57(80100)
MCH18(2634)
MHCH32(3137)
RDW22(1115)

17yofemale:LaboratoryFindings

MCV57(80100)
(
)
MCH18(2634)
MHCH32(3137)
RDW22(1115)
8.9
7

526
28

Iron26uL/dL(24154)
Ferritin36ug/mL(8110)
Transferrin228mg/dL(159288)
Transferrin%saturation8%(758%)

HemoglobinA
HemoglobinC
HemoglobinA2
Hemoglobinother

58.5% (80 100%)

30.5% (0%)
2.6% (1.5 3.5%)
8.4%

ScoutimageCT12/16/2012

St. Jude Solid Tumor Board

01 February 2013

Radiographic Findings

Jamie L. Coleman, MD

Ascites
Smallvolume
pericardiophrenic
adenopathy

 Massiveasciteswith
centralizationofbowel
loops

Large
heterogeneous
massCa++,fat,
solidtissue,fluid
Ascites
15cmx21cm

Omental
caking/peritoneal
carcinomatosis

Pelvicdeposits/implants
Ascites

PostoperativeCT
12/26/2012
Concernforresidual
tumorinthepelvis
Residualascites

St. Jude Solid Tumor Board

01 February 2013

Pathology:
Germ Cell Tumors of Childhood

Jesse J. Jenkins, III, MD

Teratoma=Ectoderm+Mesoderm+Endoderm

ImmatureRetina

Teratoma=Ectoderm+Mesoderm+Endoderm

CystsLinedbyVariousKindsofEpithelium
Skin

Colon

ToothBud

Bone

ImmatureNeuroectodermalTissue

Omental&PeritonealNodules
GliomatosisPeritonei

Germ Cell Tumors

2 to 3 per 1,000,000 births in USA

Primordial germ cell origin
Heterogenous group of tumors
Site and age
Siteage-specific
specific differences in
biology, prognosis, and therapy
Biphasic age distribution

YolkSacCarcinoma

First peak at 2 years of age

Second peak at 15-20 years of age

Germ Cell Tumors

Biphasic age distribution
First peak at 2 years of age
Extragonadal and gonadal
Mature teratoma
Immature teratoma (20% have yolk sac carcinoma)
Yolk sac carcinoma

Second peak at 15-20 years of age

Mostly gonadal

Immature Teratoma
No i(12p) in childhood cases
Immaturity in one or more of the three
y but usuallyy neuroepithelial
p
tissue
layers
Grades (?)

0 = no immaturity
1 = no more than one low power field
2 = >1 to <4 low power fields
3 = many consecutive fields

Germ Cell Tumors

Mature teratoma (benign)

Immature teratoma (less benign)
Embryonal carcinoma (malignant)
G
Germinoma/dysgerminoma/seminoma
i
/d
i
/
i
(malignant)
( li
t)
Choriocarcinoma (malignant)
Yolk sac carcinoma (malignant)
Gonadoblastoma (mixed germ cell-sex cord stromal)
Somatic tumors within teratomas (benign or malignant)

Immature Teratoma
Virtually all grade 1 and 2 are benign in
children
Extraovarian sites extremely rare - ?
sufficient numbers to evaluate the grading
system
Elevated serum -fetoprotein
Usually means small foci of yolk sac carcinoma
that may not stain with immunoperoxidase
May mean fetal liver (or hepatoid pattern yolk
sac carcinoma) - ?? immature tissue or tumor

Yolk Sac Carcinoma

Commonest malignant GCT in prepuberal
children
Pre
Pre-existing
existing teratoma in most
Usually elevated alpha fetoprotein
Lots of confusing histologic patterns and
overlap with embryonal carcinoma

fetoprotein

St. Jude Solid Tumor Board

01 February 2013

Germ Cell Tumor

Meaghann Weaver, MD
fetoprotein

Epidemiology:Incidence

Epidemiology

Bimodal;normalembryonaldevelopmentvstumorigenesis
Femalegermcellsentermeiosisat1112weeksofgestationwhile
malegermcellsbeginmeiosiswiththeonsetofpuberty

Poynter,JNetal.TrendsinIncidenceandSurvivalofPediatricandAdolescentPatientswithGermCellTumorsintheUnitedStates,1975to2006.Cancer2010.

Poynter,JNetal.TrendsinIncidenceandSurvivalofPediatricandAdolescentPatientswithGermCellTumorsintheUnitedStates,1975to2006.Cancer2010.

Epidemiology

Epidemiology:RiskFactors
Incidenceashighas30%inpatientswithgonadaldysgenesisand
10%forundervirilizationsyndrome
Cryptorchidismand3xto9xincreasedriskofGCTs(mostly
o
)
seminomas)
Congenitalgenitourinaryanomalies(retrocavalureter,bladder
diverticulum)associatedwithincreasedrisk
Turnersyndromeandgonadoblastoma(30%),childrenwithDown
SyndromeareatapredispositiontodeveloptesticularGCT,
whereaspatientswithKlinefeltersyndromehaveanincreased
riskofmediastinal(nottesticular)GCT.

Poynter,JNetal.TrendsinIncidenceandSurvivalofPediatricandAdolescentPatientswithGermCellTumorsintheUnitedStates,1975to2006.Cancer2010.

PotternLM,BrownLM,HooverRN,etal.Testicularcancerriskamongyoungmen:roleofcryptorchidismandinguinalhernia.JournaloftheNationalCancerInstitute
1985:74(2):377381.

Embryology

ClinicalPresentation:Gonadal&Extragonadal
Inchildren,theextragonadalsitesaccountfor4055%oftumors1
comparedwithadults,whereonly510%areextragonadal2
Regionalspreadresultinginsurgicallyunresectabletumorsoccursin
approximately25%ofpatientsatpresentation

Cellsoriginateneartheallantoisoftheyolksacendoderm
andmigratealongthedorsalmesenterytothegenitalridge
MigrationmitigatedbycKITreceptorsandstemcellfactors
Arrestedmigrationversusaberrantmigrationdepositscells

Approximately20%ofchildrenwithGCTpresentwithmetastaticdisease,
mostcommonlytolung,liver,lymphnodes,andrarelytothecentral
nervoussystem,bone,orbonemarrow

1.DeBackerA,MadernGC,PietersR,etal.Influenceoftumorsiteandhistologyonlongtermsurvivalin193childrenwith extracranialgermcelltumors.EurJ
PediatrSurg2008;18:16.2.RescorlaFJ.BreitfeldPP.PediatricGermCellTumors.CurrProblCancer.1999:23:257303.

Lamb,DJ.Growthfactorsandtesticulardevelopment.JUrol1993;150(58392).StrohmeyerT,ReeseD,PressM,etal.Expressionoftheckitprotooncogoneandits
ligandstemcellfactor.JUrol1995;153:511515.

Extragonadal:Sacrococcygeal
Ininfancy,themostcommonsiteofextragonadal tumorsissacrococcygeal
region(TypesItoIV),oftendetectedinuterowithprenatalultrasonography

Extragonadal:Retroperitoneum
Represent4%ofallgermcelltumors
Onehalfoccurduringthefirstyearoflifeand73%occur
beforeage5
2:1femalepredominance
Majoritybenignwith4%malignant
Duetolocation,prevalenceofadvancedstagediseaseon
initialpresentation

Imagefrom:Horton,Z.Schlatter,M.Schultz,S.Pediatric
GermCellTumors.SurgicalOncology2007(16):206213

Imagefrom:Rescorla,F.PediatricGermCellTumors.Seminarsin
PediatricSurgery2012(21):5160.

Extragonadal:Mediastinal
Represents5%ofallgermcelltumorsand12%ofall
pediatricmediastinaltumors
Carrytheworstprognosisofallgermcelltumors
Usuallylocatedintheanteriormediastinum,but
occasionallywithinthepericardium

Imagefrom:Rescorla,F.PediatricGermCellTumors.Seminarsin
PediatricSurgery2012(21):5160.

ClinicalPresentation:Testicular
Bimodal
Infantsandtoddlers:predominantlyendodermalsinus(yolksac)histology
Adolescent:seminomas,embryonal carcinomas,andchoriocarcinomas
Maypresentashydrocele
Avoidtransscrotalbiopsy

Extragonadal:Intracranial
Rare,usuallylocalizedtopinealandsuprasellar regions.
Clinicallymanifestedwithocularsymptomsorobstructivehydrocephalus
Prognosisbestforgerminomas andmatureteratomas ;worsefor
choriocarcinomas andembryonal carcinomas

Kyritsis,AP.Managementofprimaryintracranialgermcelltumors.JNeurooncol2010Jan;96(2):143149.

ClinicalPresentation:Ovarian
Theovaryisthemostcommonsiteforgermcelltumorsafter
infancy
Painandpalpablemass(85%),lowerabdominalfullness,
obstruction andlesscommonlyanacuteabdomen(10%)from
obstruction,andlesscommonlyanacuteabdomen(10%)from
torsionortumorrupture
Tumordisseminationoccursbylocalextension,intracavitary
seeding,orhematogenousspread.Intracavitaryseedingmay
involveomentum,bowel,spleen,diaphragm,orpelvicorgans.
Rarely,boneinvolvementcanoccurbydirectextension.

Embryology Classification

ClinicalMarkers

Seminomasand
Dysgerminomas

Oncofetoproteins =AFPandBHCG

Teratomas

CellularEnzymes=lactatedehydrogenaseand
PLAP

Choriocarcinomaand
endodermalsinus
tumor(yolksac)

Cytogeneticandmolecularmakers

Rescorla,F.PediatricGermCellTumors.SeminarsinPediatric
Surgery.2012(21):5160

Alphafetoprotein

Alphafetoprotein

Elevatedserumlevelsorpositiveimmunohistochemical
stainingofgermcelltumorsforAFPindicatesthe
presenceofmalignantcomponents,specificallyyolksac
orembryonal
o
yo carcinoma
o

Reachespeakconcentrationat13weeksgestationand
graduallyfallstoreachadultnormallevelsof<10ng/dL at
age812months

SeveralinternationalpediatricGCTtrialshavesuggested
thattumormarkerelevationwasasignificantprognostic
predictor
SerumhalflifeofAFPis5to7days
BaranzelliMC,KramarA,BouffetE.Prognosticfactorsinchildrenwithlocalizedmalignantnonseminomatousgermcelltumors. JClinOncol17:1212,1999.

BSubunitofHumanChorionicGonadotropin
Elevationimpliespresenceofclonesof
synctiotrophoblasticcells,foundindysgerminomas
Increaseinluteinizinghormonethatresultsin
immunologiccrossreactivity(alphasubunit)
OtherconditionsassociatedwithelevatedBHCG:
multiplemyeloma,livermalignancies,pancreas,GItract,
breast,lung,andbladder
Occassionally,hormonalmanifestation
Serumhalflifeis24to36hours

OtherconditionsassociatedwithelevatedAFP:
hepatoblastoma,pancreaticandgastrointestinal
malignancies,lungcancers
Ratioofconcanavalin Atononbound AFPcanbeuseful
indiscerningAFPproductionfromtumorcell(ratio12
43%)versusliverproduction(<10%)
SchneiderDT,CalaminusG,GobelU.DiagnosticValueofAFPandHCGininfancyandchildhood.PediatrematolOncol18;1126,2001.

NonspecificMarkers
Serumlactatedehydrogenase (LDH),aglycolytic
enzyme,hasnotshownspecificity
Inpatientswithdysgerminomas,serumlevelsofthe
LDHisoenzyme 1,thegeneforwhichresideson12p,
correlateswiththetumorburden
Placentalalkalinephosphatase (PLAP)isafetal
isoenzyme ofalkalinephosphatase thatiselevatedin
theseraofupto30%ofpatientswithstage1
dysgerminomas andalmost100%ofcaseswithadvanced
seminomas

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CarcinoembryonicAntigen

Staging

Carbohydrateantigen(CA125)isrelatedtothetissuesofthe
coelomicepitheliumandmullerianducts
Usefulnesshamperedbylackoftumorspecificity
ExtremeelevationofserumlevelsofCA199,antigenintheLewis
l
f
l
l f
h
Abloodgroupsystem,hasbeenreportedatrecurrenceofovarian
immatureandmatureteratomawithyolksacelements;however,
theroleofCA199evenlessclearthanCA125

Ovaryandprimaryperitonealcarcinoma.In:EdgeSB,ByrdDR,ComptonCC,FritzAG,GreeneFL,TrottiA,eds.AJCCCancerStagingManual.7th ed.NewYork,NY:
SpringerVerlag;2010:493506

Staging

Staging
Differencesbetweenstagingsystems:
higherriskoftumorrecurrenceinpatientswhohave
positiveperitonealwashing
utilityoftumormarkersforpredictionofoutcome
thelackofnegativeprognosticimpactofgliomatosis
peritonei ifonlymatureglialtissueispresent

CushingB,etal.RandomizedComparisonofCombinationChemotherapyWithEtoposide,Bleomycin,andEitherHighDoseorStandardDoseCisplatin
inChildrenandAdolescentswithHighRiskMalignantGermCellTumors.JournalofClinicalOncology22(13):26912700.

Pediatric GCT: Treatment

Survival: Poor
before the use of
chemotherapy

Adult GCT: Treatment

Introduction of
cisplatin-based
therapy curative in
adults
Einhorn regimen
(cisplatin, vinblastine,
bleomycin): highcomplete remission
rate (Einhorn, Ann Int Med 87:293, 1977)

Kurman et al. Cancer 38: 2404, 1976

Increasing cisplatin
dose-intensity:
increased toxicity
without improving
outcome
(Nichols, J Clin Oncol 9:1163, 1991)

11

CisplatinDosing
RandomizedcomparisonofHDPEB(cisplatin 40mg/m2)orstandard
dosePEB(cisplatin 20mg/m2)
Excessivetoxicdeathsandsignificantototoxicityassociatedwith
thehighdoseregimen

Ovariantumors
4yearOSof67%andEFSof63%.
Cisplatinlowdose(60mg/m2)every9weeks.

IntergroupTrials

RiskStratification

Between1990and1996,twoorganizations,theChildrensCancer
GroupandthePediatricOncologyGroup,conductedintergroup
trialsforchildrenwithmalignantgermcelltumors.

RescorlaF,PediatricGermCellTumors.SeminarsinPediatricSurgery(2012)21:5160.

RescorlaF,PediatricGermCellTumors.SeminarsinPediatricSurgery(2012)21:5160.

StageI(lowrisk)
Stage1managementwithsurgeryalone
excellentsurvivalofgirlswithmicroscopicyolksac
tumorstreatedwithsurgeryalone
39casesofstageItumorstreatedwithsurgeryalone
whohada67%EFSandOSof97.4%(12of13recurrences
salvagedwithchemotherapy)
lowriskarmoftheCOGstudyclosedearlybecauseof
thegreaterthananticipatedrateofrecurrenceforstage
Iovariantumors(<70%EFS)

StageIItoIVTreatment:
PrinciplesofChemotherapy
Treatedwithbleomycin,etoposide,andcisplatin(BEP)regimens
for34weekcycles
Patientswithapoorresponsetotherapiesorwithrecurrent
diseasemaybenefitfromsecond linetherapiessuchaspaclitaxel,
diseasemaybenefitfromsecondlinetherapiessuchaspaclitaxel,
ifosfamide,cisplatin(TIP);vinblastine,ifosfamide,cisplatin(VeIP),
orgemcitabine/oxaliplatin
Radiosensitive,althoughthehighcureratesseenwith
chemotherapyalonehaveobviatedtheneedforradiationinmost
cases

RogersPC,OlsonTA,CullenJW,etal.TreatmentofchildrenandadolescentswithstageIItesticularandstageIandIIovarian malignantgermcelltumor:A
PediatricIntergroupStudyPediatricOncologyGroup9048andChildrensCancerGroup8891.JClinOncol2004;22:35639.

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Treatment:PrinciplesofSurgery
Obtainpreoperativeimagingstudiesandtumormarkers
Surgicalresectionistreatmentofchoiceinbenigntumors(teratomas);
resectionindicatedformalignantlesions,butweighavailabilityofeffective
chemotherapywhensacrificingvitalstructures
P
Primaryissuesaretoavoidspill(upstagingtumor)andadequatecompletionof
i
i
t
id ill(
t i t
) d d
t
l ti f
thestagingprocedure

RescorlaF,PediatricGermCellTumors.SeminarsinPediatricSurgery(2012)21:5160.

Treatment:PrinciplesofSurgery

Treatment:PrinciplesofSurgery
Highsurvivalratein
conservativesurgery
Nogrosstumorfindingsto
distinguishmalignantfrom
benign(cysticcomponents
commoninmalignant
pediatricovariantumors
withincidenceof57%)

BillmireD,etal.PediatrSurg.2004Mar;39(3):4249;discussion4249.Outcomeandstagingevaluationinmalignantgermcelltumorsoftheovaryinchildrenand
adolescents:anintergroupstudy.

Surgery:SecondLook

BillmireD,etal.PediatrSurg.2004Mar;39(3):4249;discussion4249.Outcomeandstagingevaluationinmalignantgermcelltumorsoftheovaryinchildrenand
adolescents:anintergroupstudy.

Surgery:SecondLook

Sixgirlshadbiopsyonlyatdiagnosisfollowedbychemotherapy.
Onehadbiopsyofavertebralmetastasiswithoutfurthersurgery.
Theremaining5girlsallhaddiagnosticlaparotomy andweretreated
withchemotherapyfollowedbysecondlooklaparotomy at3to6
months Allhaddecreaseinsizeofthemass
months.Allhaddecreaseinsizeofthemass.

21patientsincompleteremission(normalimagingandmarker
studies)and36patientsinpartialremissionhadsecond
operationpostchemo

Twoweretreatedwithsalpingooophorectomy.Twoweretreated
withTAH/BSO.

21/36patients(61%)inPRhadnoevidenceofmalignantdisease.
2/21hadelevatedAFPwithlaterhavingrecurrentdisease.Of
the14patientswithconfirmedactivediseaseatthetimeof
secondsurgery,fourhadallapparenttumorremoved.

Onespecimencontainedmatureteratoma,and3hadnoevidenceof
tumor.

BillmireD,etal.PediatrSurg.2004Mar;39(3):4249;discussion4249.Outcomeandstagingevaluationinmalignantgermcelltumorsoftheovaryinchildrenand
adolescents:anintergroupstudy.

3/21patients(14%)inCRhadresidualmalignanttumor.
3/21patients(14%)inCRhadresidualmalignanttumor

AlbinAR,etal.Resultsoftreatmentofmalignantgermcelltumorsin93children:areportfromtheChildrensCancerStudyGroup.JClinOncol.1991Oct;9(10):1782
92.

13

Surgery:SecondLook

Surgery:SecondLook
Doesapatientwithcompleteremission(normalizationoftumormarkers
andresidualmass<1cm)requirepostchemoretroperitoneallymphnode
dissection?Inretrospectivefollowupof141patientstreatedwith
chemotherapyaloneaftermedian15.5years,12patients(9%)experienced
relapse.

Leeetal.WorldJournalofSurgicalOncology2011;9:123.

YaronEhrlich,MaryJ.,etal.JournalofClinicalOncology.LongTermFollowUpofCisplatinCombinationChemotherapyinPatientsWithDisseminatedNonseminomatousGermCellTumors:Isa
__
PostchemotherapyRetroperitonealLymphNodeDissectionNeededAfterCompleteRemission?February1,2010vol.28no.4531536

Survival

FutureDirection
Molecularmechanismsofgermcell
tumorigenesis
cKIToncogeneoverexpressionresponsiveto
kinaseinhibitors?
epidermalgrowthfactorinhibitors?
enhancedgeneticunderstanding

Poynter,Jenny.TrendsinIncidenceandSurvivalofPediatricandAdolescentPatientswithGermCellTumorsintheUnitedStates,1975to2006.Cancer.
2010:48824891.

NoAudio

KeyReferences

SchlatterM,RescorlaF,GillerR,etal.ExcellentoutcomeinpatientswithStageIgermcelltumors
ofthetestes:astudyoftheChildrensCancerGroup/PediatricOncologyGroup.(2003)JPediatr
Surg38:31924.

AlbinAR,etal.Resultsoftreatmentofmalignantgermcelltumorsin93children:areportfromthe
ChildrensCancerStudyGroup.JClinOncol.1991Oct;9(10):178292.

BillmireD,VinocurC,RescorlaF,etal.Outcomeandstagingevaluationinmalignantgermcell
tumorsoftheovaryinchildrenandadolescents:anintergroupstudy.(2004)JPediatrSurg
39:424429.

Poynter,Jenny.TrendsinIncidenceandSurvivalofPediatricandAdolescentPatientswithGerm
CellTumorsintheUnitedStates,1975to2006.Cancer.2010:48824891.

RescorlaF,PediatricGermCellTumors.SeminarsinPediatricSurgery(2012)21:5160.

Gratitude
Dr.AlbertoPappo Oncology
Dr.JesseJ.Jenkins Pathology
Dr.JamieL.Coleman
Dr JamieL Coleman RadiologicalSciences

14

Question1.
Alphafetoproteinismostcommonlyelevated
inwhichoncologiccondition?
A.
B.
C.
D.

Medulloblastoma
Wilms tumor
Germcelltumorwithyolksacelements
Neuroblastoma

Question2.
Whichagenthasbeenresponsibleforthemost
recentdramaticimprovementinoutcomein
germcelltumortreatment?
A.
B.
C.
D.

Radiationtherapy
Cisplatin
Vincristine
Methotrexate

Question3.
Howcouldtheepidemiologytrendin
incidenceofgermcelltumorsbedescribed?
A.
B.
C.
D.

Bimodaldistribution
Cyclicalfluctuation
Unimodal curve
Multimodalcurvewithprolongedlatency

Question4.
CompleteresectionofStageIovariangerm
celltumorsfollowedbycloseobservationisan
acceptabletreatmentapproach:
A. True
B. False

End
Meaghann Weaver, MD
Jamie L. Coleman, MD
Jesse J. Jenkins, III, MD

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