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CHAPTER32NeoplasmsoftheMediastinumRobertB.
CameronPatrickJ.
LoehrerSr.
CharlesR.
Thomas,Jr.
Tumorsinvolvingthemediastinummaybeprimaryorsecondaryinnature.
Primaryneoplasmscanoriginatefromanymediastinalorganortissuebutmostcommonlyarisefromthymic,neurogenic,lymphatic,germinal,andmesenchymaltissues.
Allprimarymediastinalneoplasms,exceptthoseofthymicorigin,alsooccurelsewhereinthebodyandarediscussedinotherchapters.
Secondary(metastatic)mediastinaltumorsaremorecommonthanprimaryneoplasmsandmostfrequentlyrepresentlymphaticinvolvementfromprimarytumorsofthelungorinfradiaphragmaticorgans,suchaspancreatic,gastroesophageal,andtesticularcancer.
Thischapterprovidesanoverviewofprimarymediastinalneoplasms.
Specifictumorsarecoveredindetail,includingthymic,primarymediastinalgermcell,mesenchymal,cardiac,andneurogenictumors.
Esophagealcancerandlymphomasarecoveredelsewhere,inChapter33.
2(CanceroftheEsophagus)andChapter45(Lymphomas),respectively.
AnatomyThemediastinumoccupiesthecentralportionofthethoraciccavity.
Itisboundedbythepleuralcavitieslaterally,bythethoracicinletsuperiorly,bythediaphragminferiorly,bythesternumanteriorly,andbythechestwallposteriorly.
Themediastinumcanbedividedintothreeclinicallyrelevantcompartments:anterior,middle,andposterior(Fig.
32-1A).
1Theanteriormediastinumliesposteriortothesternumandanteriortothepericardiumandgreatvessels,extendingfromthethoracicinlettothediaphragm.
Themiddlemediastinumisdefinedasthespaceoccupiedbytheheart,pericardium,proximalgreatvessels,andcentralairways.
Theposteriormediastinumisboundedbytheheartandgreatvesselsanteriorly,thethoracicinletsuperiorly,thediaphragminferiorly,andthechestwallofthebackposteriorly,anditincludestheparavertebralgutters.
Table32-1liststhemajoranatomicstructureswithineachofthecompartments.
Athoroughunderstandingofeacharea'scontentshelpsdefinethediagnosticpossibilities.
Otherdivisionshavebeenproposed,dividingthemediastinumintothreeorfourcompartments(Fig.
32-1B,C).
Heitzmanevenproposedsevenanatomicregions.
1Althoughtheexactschemethatshouldbeusedisstilldebated,theseotherschemeshavelimitedclinicalutility.
IncidenceandPathologyMediastinalneoplasmsareuncommontumorsthatcanoccuratanyagebutaremostcommoninthethirdthroughthefifthdecadesoflife.
2–4Table32-2reviewstheclassificationofmediastinalneoplasms.
Theincidenceofprimarymediastinaltumorswasdocumentedinareviewof1900patients(Table32-3).
2Additionally,439patients(18%ofallmediastinalmasses)werefoundtohavecysticlesions.
ThedistributionofprimarymediastinalneoplasmsisshowninTable32-4.
Thymicneoplasmspredominateintheanteriormediastinum,followedinfrequencybylymphomas,germcelltumors,andcarcinoma.
Bronchial,enteric,andpericardialcystsarethemostcommonmassesinthemiddlemediastinum,followedbylymphomas,mesenchymaltumors,andcarcinoma.
5Intheposteriormediastinum,neurogenictumorsandesophagealcancersaremostcommon,followedbyentericcysts,mesenchymaltumors,andendocrineneoplasms.
2–4Theincidenceofmediastinaltumorsineachanatomiccompartmentalsovarieswithage.
Inadults,54%ofmediastinalneoplasmsoccurintheanterior,20%inthemiddle,and26%intheposteriormediastinum.
2Inpediatricpopulations,43%,18%,and40%ofneoplasmsoccurintheanterior,middle,andposteriormediastinum,respectively.
4,6Ahigherincidenceofthymictumorsandlymphomasinadultsandneurogenictumorsinchildrenaccountforthesedifferences.
Azarow4comparedmediastinalmassesin195adultand62pediatricpatients(Table32-5).
Cystswerenotincludedbutaccountedfor16%to18%ofadultand24%ofpediatricmediastinalmasses.
4Therefore,ageaswellaslocationestablishestheprobablediagnosis.
2–4,6–9DiagnosticConsiderationsAmeticuloushistoryandphysicalexamination,alongwithavarietyofimaging,serologic,andinvasivetests(Table32-6),oftencanconfirmthesuspecteddiagnosis.
Withimprovedimaging,biopsy,andpathologictechniques,themajorityofpatientsnolongerrequireopensurgicalbiopsybeforeplanningdefinitivetherapy.
SymptomsandSignsApproximately40%ofmediastinalmassesareasymptomaticanddiscoveredincidentallyonaroutinechestradiograph.
2,3Theremaining60%ofcaseshavesymptomsrelatedtocompressionordirectinvasionofsurroundingmediastinalstructuresortoparaneoplasticsyndromes.
Asymptomaticpatientsaremorelikelytohavebenignlesions,whereassymptomaticpatientsmoreoftenharbormalignancies.
2–4,7,8Davisfoundthat85%ofpatientswithamalignancyweresymptomatic,butonly46%ofpatientswithbenignneoplasmshadidentifiablecomplaints.
SymptomsandsignsofmediastinalneoplasmsareshowninTable32-7.
Themostcommonlydescribedsymptomsarechestpain,cough,anddyspnea.
2,3,8Superiorvenacavasyndrome,Horner'ssyndrome,hoarseness,andneurologicdeficitsmorecommonlyoccurwithmalignancies.
10SystemicsyndromesassociatedwithmediastinalneoplasmsareshowninTables32-8and32-9.
RadiographicImagingStudiesRadiographicimagingstudiesinitiallylocalizemediastinalneoplasms.
Theposteroanteriorandlateralchestradiographsdefinethelocation,size,density,andcalcificationofamass,limitingthediagnosticpossibilities.
11Aftertheseresults,anintravenouscontrast-enhancedcomputedtomography(CT)scancanfurtherassessthenature(cysticvs.
solid)ofthelesionanddetectfatandcalcium.
12–17Therelationshiptosurroundingstructuresandbloodvesselsalsocanbedetermined,andinsomeinstancestheinvasivenessoftumorscanbepredicted.
18.
Magneticresonanceimaging(MRI)isusedlessfrequentlythanCT.
198–210Itsadvantagesincludemultiplanarimagingandabsenceofionizingradiation.
12MRIscansaresuperiortoCTindefiningvascularinvolvementandindistinguishingrecurrenttumorfromradiationfibrosis.
20,22However,patientclaustrophobia,time,andexpenselimittheuseofMRIscanning.
Otherimagingmodalitiesthatmaybeusefulincludetransthoracicsonography,andtransesophagealechocardiography,andtransesophagealultrasouns.
213,22-25AlthoughtTheuseutilityofpositronemissiontomographyiswellestablishedfortheassessmentofmediastinallymphnodesinlungcancerandlymphoma,theutilityofPETintheevaluationofprimarymediastinalneoplasmsmasseshasnotfullybeenfullydefinedisyettobedetermined.
,butitThereissomeevidencethatPETmayhelpclarifythenatureofsuchmassesandthepresenceofneoplasminresidualmediastinaltissueaftertherapy.
2326SerologyandChemistrySomemediastinalneoplasmsreleasesubstancesintotheserumthatcanbemeasuredbyspecificradioimmunoassays.
Thesesubstancesmaybeusedtoconfirmadiagnosis,evaluateresponsetotherapy,andmonitorfortumorrecurrence.
-Fetoprotein(AFP),humanchorionicgonadotropin-(-HCG),andlactatedehydrogenaseareelaboratedbysomegermcelltumorsandshouldbeobtainedinmalepatientswithanteriormediastinalmasses.
1Also,adrenocorticotropichormone,thyroidhormone,andparathormonemayhelpdifferentiatecertainmediastinaltumors(seeTable32-9).
InvasiveDiagnosticTestsThedeterminationofthehistologicdiagnosisofmediastinalmassesoftenisessentialforimplementationofappropriatetreatment.
Previously,mostpatientsunderwentsurgicalprocedurestoestablishthediagnosisofmediastinalneoplasms;however,improvementsinlessinvasivediagnosticandimmunohistochemicaltechniquesandinelectronmicroscopyhavegreatlyimprovedtheabilitytodifferentiatethecelltypesinmediastinalneoplasms.
247–314CT-guidedpercutaneousneedlebiopsy,usingeitherfine-needleaspirationtechniquesandcytologicassessmentorlarger-coreneedlebiopsyandhistologicevaluation,nowarestandardintheinitialevaluationofmostmediastinalmasses.
3235Althoughfine-needlespecimensareusuallyadequatetodistinguishcarcinomatouslesions,corebiopsiesarerecommendedtodistinguishmostothermediastinalneoplasms,especiallylymphomaandthymoma.
2629–2831Mostseriesreportdiagnosticyieldsforpercutaneousneedlebiopsyof72%to100%,and,mostrecently,thatfigureisinexcessof90%.
2528–2730,2932Complicationsincludesimplepneumothorax(25%),pneumothoraxrequiringchesttubeplacement(5%),andhemoptysis(7%to15%).
2932Insomecircumstances,fineneedleaspirationofposteriorandmiddlemediastinaltumorscanbeperformedendoscopicallyusingtransesophagealultrasonography.
25Surgicalproceduresarestilloccasionallyrequiredinthediagnosisofmediastinaltumors.
2427,303Mediastinoscopyisarelativelysimpleprocedure,accomplishedundergeneralanesthesia.
Itprovidesaccesstothemiddleandalimitedportionoftheupperposteriormediastinumandhasadiagnosticaccuracyofmorethan90%.
336,347Anteriorparasternalmediastinotomy(Chamberlainprocedure)yieldsadiagnosisin95%ofanteriormediastinalmasses.
336,347and,ifnecessary,canbeaccomplishedunderlocalanesthesia.
38Thoracoscopyrequiresgeneralanesthesiabutisminimallyinvasiveandprovidesadiagnosticaccuracyofnearly100%inmostareasofthemediastinum.
347Thoracoscopyshouldbereserved,however,forbiopsiesthatcannotbeobtainedwithmediastinoscopyorparasternalmediastinotomy.
Thoracotomyisalmostnevernecessaryfordiagnosisandshouldbereservedforrarecircumstances.
ThymicNeoplasmsThethymusisanincompletelyunderstoodlymphaticorganfunctioninginT-lymphocytematuration.
Itiscomposedofanepithelialstromaandlymphocytes.
Althoughlymphomas,carcinoidtumors,andgermcelltumorsallmayarisewithinthethymus,onlythymomas,thymiccarcinomas,andthymolipomasarisefromtruethymicelements.
Epithelialthymicneoplasmshavebeenclassifiedintothreeproposedcategories:(1)thymomas,well-differentiatedneoplasms;(2)atypicalthymomas,moderatelydifferentiatedneoplasms;and(3)thymiccarcinomas,poorlydifferentiatedneoplasms.
Thisclassificationisbasedonfeaturesofglandulardifferentiation;however,furthervalidationofthissystemisneeded.
359–3741ThymicAnatomyandPhysiologyThethymusdevelopsfromapairedepithelialanlageintheventralportionofthethirdpharyngealpouch.
Itiscloselyassociatedwiththedevelopingparathyroidglands.
3842Thestromaofthethymusconsistsofepithelialcells,whicharelikelyderivedfrombothectodermalandendodermalcomponents.
3943Duringweeks7and8ofdevelopment,thethymuselongatesanddescendscaudallyandventromediallyintotheanteriormediastinum.
Byweek12,aseparatecortexandmedullabecomeevident,andmesenchymalseptaedevelopperivascularspacesthatcontainbloodvessels.
Lymphoidcellsarrivefromtheliverandbonemarrowduringweek9andareseparatedfromtheperivascularspacebyaflatlayerofepithelialcellsthatcreatetheblood–thymusbarrier.
Maturationanddifferentiationoccursinthisantigen-freeenvironment.
Bythefourthfetalmonth,lymphocytescirculatetoperipherallymphoidtissue.
3943Sixsubtypesofepithelialcellshavebeenidentifiedinmaturethymus.
3439Fourexistprimarilyinthecorticalregionandtwointhemedullaryregion.
Type6cellsformHassall'scorpusclesthatarecharacteristicofthymus.
Thesecellshaveanectodermaloriginandaredisplacedintothethymicmedulla,wheretheyhypertrophyandformtonofilaments,finallyappearingasconcentriccellswithoutnuclei.
342,438,39Atmaturity,thethymusglandisanirregular,lobulatedorgan.
Itattainsitsgreatestrelativeweightatbirth,butitsabsoluteweightincreasesto30to40gbypuberty.
Duringadulthood,itslowlyinvolutesandisreplacedbyadiposetissue.
3439Ectopicthymictissuehasbeenfoundtobewidelydistributedthroughoutthemediastinumandneck,particularlytheaortopulmonarywindowandretrocarinalarea,andoftenisindistinguishablefrommediastinalfat.
404,415Thisectopictissueisthelikelyexplanationforthymomasoutsidetheanteriormediastinumandpossiblyforfailureofthymectomyinsomecasestoimprovemyastheniagravis.
404–426ThymomaThymicneoplasms,mostlythymomas,constitute30%ofanteriormediastinalmassesinadults.
2–4,8,437,448Thymomasarelesscommoninchildren,accountingforonly15%ofanteriormediastinalmasses.
8Thymomasexhibitnogenderpredilectionandoccurmostofteninthefifthandsixthdecadesoflife.
459Nearlyone-halfofthesetumorsareasymptomaticandarediscoveredonlyonroutineradiographs.
Insymptomaticpatients,40%havemyastheniagravis359(diplopia,ptosis,dysphagia,fatigue,etc.
),whereasotherscomplainofchestpainandsymptomsofhemorrhageorcompressionofmediastinalstructures.
459PathologyandClassificationNinetypercentofthymomasoccurintheanteriormediastinum,andtheremainderarelocatedintheneckorotherareasofthemediastinum.
Grossly,theyarelobulated,firm,tan-pinktograytumorsthatmaycontaincysticspaces,calcification,orhemorrhage.
Theymaybeencapsulated,adherenttosurroundingstructures,orfranklyinvasive.
5046Microscopically,thymomasarisefromthymicepithelialcells,althoughlymphocytesmaypredominatehistologically.
4517Truethymomascontaincytologicallyblandcellsandshouldbedistinguishedfromthymiccarcinomas,whichhavemalignantcytologiccharacteristics.
Confusionexistsbecauseofprevious"benign"or"malignant"designations.
Currently,thetermsnoninvasiveandinvasiveareused.
Noninvasivethymomashaveanintactcapsule,aremovable,andareeasilyresected,althoughtheycanbeadherenttoadjacentorgans.
Incontrast,invasivethymomasinvolvesurroundingstructuresandcanbedifficulttoremovewithoutenblocresectionofadjacentstructures.
Despitethisdifficulty,theircytologicappearanceremainsbenign.
4650Metastaticdiseasedoesoccurandismostcommonlyseenaspleuralimplantsandpulmonarynodules.
Metastasestoextrathoracicsitesarerare.
4506Originallyin1976RosaiandLevineproposedthatthymomasbedividedintothreetypesdependingonthepredominantarchitectureofthetumor:lymphocytic,epithelial,ormixed(lymphoepithelial);however,therehasbeenlittledirectcorrelationbetweenthisclassificationsystemandprognosis.
52In1985,MarinoandMuller-Hermelink4853proposedahistologicclassificationsystemdeterminedbythethymicsiteoforigin—thatis,tumorsarisingfromepithelialcellsofthecortexaretermedcorticalthymomas,thosearisingfromthemedullaryareasarecalledmedullarythymomas,andthosewithfeaturesofbotharetermedmixedthymomas.
Spindle-shapedcellspredominateinthemedullaryareaandlikelycorrespondtospindlecellthymomasofthetraditionalclassificationsystem.
Likewise,thecortexcontainspredominantlyroundtoovalepithelialcells;thus,corticalthymomasprobablycorrespondtothetraditionalepithelialthymoma.
4954TheMuller-Hermelinkclassificationwaslaterrevisedandfurtherdividedintomedullary,mixed,predominantlycortical,andcorticalthymomas.
Well-differentiatedandhigh-gradethymiccarcinomawerealsodescribed.
505Medullaryandmixedthymomaswereconsideredbenignwithnoriskofrecurrence,evenwithcapsularinvasion.
Predominantlycorticalandcorticalthymomasexhibitedintermediateinvasivenessandalowbutdefiniteriskoflaterelapse,regardlessoftheirinvasiveness.
Well-differentiatedthymiccarcinomaswerealwaysinvasive,withahighriskofrelapseanddeath.
516Somesupportthisrevision,claimingthatitbettercorrelatespathologywithprognosis.
516–538Othersbelievethatithasnodistinctclinicopathologicadvantageoverthetraditionalsystem.
4549,505,549–561Thisissuehasbeenre-examined,562,637,58andtheWorldHealthOrganizationCommitteeontheClassificationofThymicTumorsadoptedanewclassificationsystemforthymicneoplasmsbasedoncytologicsimilaritiesbetweencertainnormalthymicepithelialcellsandneoplasticcells,whichisofprognosticsignificance(Table32-10).
5964In1981,Masaokaetal.
605developedastagingsystembasedonthepreviousworkofBerghetal.
616ThefourstagesareshowninTable32-11.
TheMasaokastageIIclassificationassessesbothmicroscopicinvasion(occultin28%)andgrosstumoradherenceasdeterminedbysurgicalfindings.
49,54,59,672Stagingwasfoundtocorrelatewithprognosis,with5-yearsurvivalrates96%forstageI,86%forstageII,69%forstageIII,and50%forstageIV.
605TheGrouped'EtudesdesTumeursThymiques(GETT)stagingsystemissurgery-basedanddemonstrates90%concordancewiththeMasaokasystem(Table32-12).
638,649Interestingly,theexpressionofgenesc-JUNandAL050002recentlywerefoundusingmicroarraytechnologyandreal-timeRT-PCRtocorrelatewithMasaokastageandprognosis;inaddition,AL050002expressionwasfoundalsotocorrelatewiththeWHOtumorclassificationsystem.
70AssociatedSystemicSyndromesAwidevarietyofsystemicdisordersareassociatedwith71%ofthymomas.
6571Thesymptomsoftheseassociateddisordersoftenleadtotheoriginaldiscoveryofthemediastinaltumor.
Autoimmunediseases(systemiclupuserythematosus,polymyositis,myocarditis,Sjgren'ssyndrome,ulcerativecolitis,Hashimoto'sthyroiditis,rheumatoidarthritis,sarcoidosis,andscleroderma)andendocrinedisorders(hyperthyroidism,hyperparathyroidism,Addison'sdisease,andpanhypopituitarism)aremostcommon.
6726Blooddisorders,suchasredcellaplasia,hypogammaglobulinemia,T-celldeficiencysyndrome,erythrocytosis,pancytopenia,megakaryocytopenia,T-celllymphocytosis,andperniciousanemia,alsohavebeennoted.
6672Otherthanmyasthenia,neuromuscularsyndromesincludemyotonicdystrophy,myositis,andEaton-Lambertsyndrome.
6672Miscellaneousdiseasesincludehypertrophicosteoarthropathy,nephroticsyndrome,minimalchangenephropathy,pemphigus,andchronicmucocutaneouscandidiasis.
6672Nearly15%ofpatientswiththymomadevelopasecondmalignancy,suchasKaposi'ssarcoma,chemodectoma,multiplemyeloma,acuteleukemia,andvariouscarcinomas(e.
g.
,lung,colon).
6672myastheniagravisMyastheniagravisisthemostcommonautoimmunedisorder,occurringin30%to50%ofpatientswiththymomas.
Youngerwomenandoldermenusuallyareaffected,withafemaletomaleratioof2:1.
Myastheniaisadisorderofneuromusculartransmission.
Symptomsbegininsidiouslyandresultfromtheproductionofantibodiestothepostsynapticnicotinicacetylcholinereceptoratthemyoneuraljunction.
Ocularsymptomsarethemostfrequentinitialcomplaint,eventuallyprogressingtogeneralizedweaknessin80%.
Theroleofthethymusinmyastheniaremainsunclear,butautosensitizationofTlymphocytestoacetylcholinereceptorproteinsoranunknownactionofthymichormonesremainpossibilities.
527,673Pathologicchangesinthethymusarenotedinapproximately70%ofpatientswithmyastheniagravis.
Lymphoidhyperplasia,characterizedbytheproliferationofgerminalcentersinthemedullaryandcorticalareas,ismostcommonlyseen.
Thymomasareidentifiedinonlyabout15%ofpatientswithmyasthenia.
Thetreatmentofmyastheniagravisinvolvestheuseofanticholinesterase-mimeticagents[i.
e.
,pyridostigminebromide(Mestinon)].
Inseverecases,plasmapheresismayberequiredtoremovehighantibodytiters.
Thymectomyhasbecomeanincreasinglyacceptedprocedureinthetreatmentofmyasthenia,althoughtheindications,timing,andsurgicalapproachremaincontroversial.
426Someimprovementinmyasthenicsymptomsalmostalwaysoccursafterthymectomy,butcompleteremissionratesvaryfrom7%to63%.
426Patientswithmyastheniagravisandthymomasdonotrespondaswelltothymectomyasthosewithoutthymomas.
Overallsurvivalformyastheniapatientsalsoislowerforpatientswiththymomas,butnodifferenceswerenotedbasedontheextentofinvasionpresent.
6748redcellaplasiaPureredcellaplasiaisconsideredanautoimmunedisorderandisfoundinapproximately5%ofpatientswiththymomas.
Ofpatientswithredcellaplasia,30%to50%haveassociatedthymomas.
6759Ninety-sixpercentofthepatientsaffectedareolderthan40yearsofage.
Examinationofthebonemarrowrevealsanabsenceoferythroidprecursorsand,in30%,anassociateddecreaseinplateletandleukocytenumbers.
Thymectomyhasproducedremissionin38%ofpatients.
Octreotideandprednisonewereeffectiveinonepatientwithrecurrentdisease.
706Thepathologicbasisoftheseresponsesispoorlyunderstood.
6975hypogammaglobulinemiaHypogammaglobulinemiaisseenin5%to10%ofpatientswiththymoma,and10%ofpatientswithhypogammaglobulinemiahavebeenshowntohavethymoma.
Defectsinbothcellularandhumoralimmunityhavebeendescribed,andmanypatientsalsohaveredcellhypoplasia.
Thymectomyhasnotprovenbeneficialinthisdisorder.
TreatmentThymomasareslow-growingneoplasmsthatshouldbeconsideredpotentiallymalignant.
Surgery,radiation,andchemotherapyallmayplayaroleintheirmanagement.
surgeryCompletesurgicalresectionisthemainstayoftherapyforthymomasandisthemostimportantpredictoroflong-termsurvival.
71–77-83Althoughmediansternotomywithaverticalorsubmammaryincisionismostcommonlyused,bilateralanterolateralthoracotomieswithtransversesternotomy,or"clam-shellprocedure,"ispreferredwithadvancedorlaterallydisplacedtumors.
459,717,728,7682Video-assistedthoracoscopyalsohasbeenreported,butlong-termresultsremainunproven.
784Becauseofconcernabouttumorseeding,biopsyproceduresarenotroutinelyperformed.
728Duringsurgery,acarefulassessmentofareasofpossibleinvasionandadherenceshouldbemadebythesurgeon,whoisthebestjudgeoftumorinvasiveness.
672Extendedtotalthymectomy,includingalltissueanteriortothepericardiumfromthediaphragmtotheneckandlaterallyfromphrenicnervetophrenicnerve,isrecommendedinallcases.
Completesurgicalresectionisassociatedwithan82%overall7-yearsurvivalrate,whereassurvivalwithincompleteresectionis71%andwithbiopsyisonly26%.
717Survivalaftercompletetumorresectionhasbeensimilarinpatientswithnoninvasiveandinvasivethymomasinseveralstudies.
605,728,7480,7581,8579PatientswithmyastheniagravisandthymomawerestudiedbyCrucittietal.
,846whoreporteda78%10-yearsurvivalrateanda3%recurrenceratewith4.
8%(1.
7%since1980)operativemortalityafterextendedthymectomy.
Aggressiveresection,includinglung,phrenicnerve,pericardium,pleuralimplants,andpulmonarymetastases,isoccasionallyhelpful.
605,717,7984TheroleofdebulkingorsubtotalresectioninstageIIIandIVdiseaseremainscontroversial.
Severalstudieshavedocumented5-yearsurvivalratesfrom60%to75%aftersubtotalresectionand24%to40%afterbiopsyalone.
605,717,7682,8377,8579Morerecentstudies,however,suggestnosurvivaladvantagetodebulkingfollowedbyradiationwhencomparedtoradiationalone.
807,818Noneofthesestudiestakeintoaccountthepotentialadditiveroleofsystemictherapyuponsurvival.
Theuseofsurgeryinrecurrentdiseaseremainstobedefined.
Maggietal.
717reporteda71%5-yearsurvivalratein12surgerypatientsanda41%survivalratein11patientstreatedwithradiationandchemotherapyalone.
Prolongedtumor-freesurvivalalsowasreportedbyKirschner829in23patients.
Urgesietal.
,8390however,noteda74%5-yearsurvivalratein11patientsundergoingsurgeryandradiation,comparedwith65%intenpatientstreatedwithradiationalone(notstatisticallydifferent).
8390radiationtherapyThymomasareradiosensitivetumorsand,consequently,radiationhasbeenusedtotreatalltumorstagesaswellasrecurrentdisease.
437,459,717,728,7480,7682,7837,7859,818,8915InstageIthymomas,adjuvantradiotherapyhasbeenadministeredbuthasnotimprovedontheexcellentresultswithsurgeryalone(morethan80%10-yearsurvivalrate).
717,782,7804,7837,7859InstageIIandIIIinvasivedisease,adjuvantradiationcandecreaserecurrenceratesaftercompletesurgicalresectionfrom28%to5%.
437,7826,8926,8937Inaddition,Pollacketal.
7826reportedanincreasein5-yeardisease-freesurvivalforstageIItoIVafrom18%to62%withtheadditionofadjuvantradiation.
Othershavedocumentedsimilarresults.
728,7985StageIIpatientswithcorticaltumors8948–960andmicroscopicinvasionofpleuraorpericardiumaremostlikelytobenefitfrompostoperativeradiation.
971,928Morerecently,investigatorshavequestionedtheroleofadditionalradiationfollowingcompleteresection(negativesurgicalmargins)ofStageIIandIIIdisease.
Inareviewof1320patientswiththymomaandthymiccarcinoma,postoperativeradiotherapydidnotimprovetherecurrenceratesortheoverallsurvival{KondoK,MondenY:TherapyforThymicEpithelialTumors:AClinicalStudyof1,320PatientsfromJapan.
AnnThoracSurg2003;76:878-85}.
Preoperativeradiotherapyforextensivetumorshasbeenreportedinlimitedstudiesthatsuggestadecreasedtumorburdenandpotentialfortumorseedingatthetimeofsurgery.
717,7837,8692Radiationtherapyhasprovenbeneficialinthetreatmentofextensivedisease.
7826,7837,807,818,8915,8926,939Radiotherapyafterincompletesurgicalresectionproduceslocalcontrolratesof35%to74%and5-yearsurvivalratesrangingfrom50%to70%forstageIIIand20%to50%forstageIVatumors.
728,7837,807,8903,8915,8926Inaddition,Cierniketal.
807andothers818,8390havereportedsimilarsurvivalrates(87%5-yearand70%7-year)inpatientstreatedwithradiationalonecomparedwithpartialsurgicalresectionandadjuvantradiationinsmallnumbersofstageIIIandIVpatientsandpatientswithintrathoracicrecurrences.
Largevariationsintheamountoftumortreatedandradiationdeliveredaswellasdataonsystemictherapy,however,makeinterpretationoftheseresultsdifficult.
649,7826,7837,8870,8915,91004Radiationtherapyisdeliveredindosesrangingfrom30to60Gyin1.
8or2.
0cGyfractionsover3to6weeks.
437,717,739,7826,7783,7859,8591,8926,94100–91026Noimprovementinlocalcontrolhasbeenshownwithdosesexceeding60Gy8093;however,completelyresectedandmicroscopicresidualdiseasecanbewellcontrolledwithonly40to45Gy.
7783,8093,8591Treatmentportalshaveincludedsingleanteriorfield,unequallyweighted(2:1or3:2)opposedanterior-posteriorfields,wedge-pair,andmultifieldarrangements.
4347,91037Thegrosstumorvolumeisdefinedbyvisibletumororsurgicalclipsseenonatreatment-planningCTscan.
Areasofpossiblemicroscopicdiseaseandasmallbordertoaccountfordailyvariabilityandrespiratorymotionareaddedtodefinetheclinicalandplanningtargetvolumes.
Gatingtechniquestominimizerespiratoryvariationandintensity-modulatedradiationtherapyarenewtechniquesthatcanminimizethedoseheterogeneity,increasetotaldoseandfractionsize,andminimizetoxicity.
91048–1006Prophylacticsupraclavicularandhemithoraxfieldshavebeenusedbutarenotwarrantedbecauseofincreasedrisksofpulmonaryfibrosis,pericarditis,andmyelitis.
4347,7783,8093,818,101107,102108chemotherapyChemotherapyhasbeenusedwithincreasingfrequencyinthetreatmentofinvasivethymomas.
Bothsingle-agentandcombinationtherapyhavedemonstratedactivityintheadjuvantandneoadjuvantsettings.
Doxorubicin,cisplatin,ifosfamide,corticosteroids,andcyclophosphamideallhavebeenusedassingle-agenttherapy.
103109,104110Themostactiveagentsarecisplatin,ifosfamide,andcorticosteroids;however,onlycisplatin,andifosfamideandoctreotidehaveundergonephaseIItesting.
4347,104110,110511Cisplatin,atdosesof100mg/m2,hasproducedcompleteresponseslastingupto30months,butlowerdoses(50mg/m2)haveassociatedresponseratesofonly11%.
103109,104110Ifosfamide(withmesna)atasingledoseof7.
5g/m2orasacontinuousinfusionof1.
5g/m2/dfor5daysevery3weekshasresultedin50%completeand57%overallresponserates.
Durationofcompleteremissionrangedfrom6to66months.
105111Varyingregimensofcorticosteroidshaveshowneffectivenessinthetreatmentofallhistologicsubtypesofthymoma(withandwithoutmyasthenia),witha77%overallresponserateinlimitednumbersofpatients.
103109,106112Corticosteroidsalsohavebeeneffectiveforpatientsunsuccessfulwithchemotherapy109103;however,theactualimpactmayonlybeonthelymphocyticandnotthemalignantepithelialcomponentofthetumor.
Palmierietalreportedacompleteresponsewithoctreotideandprednisoneinapatientwithpureredcellaplasiaandchemotherapyresistantthymoma.
{Palmierig,LastoriaS,ColaoAetal:Successfultreatmentofapatientwithathymomaandpurered-cellaplasiawithoctreotideandPrednisone.
NEJM1997;336:263-4.
}AsubsequentECOGtrialevaluatedoctreotidealonefor2cyclesandifnoresponseaddedprednisoneinpatientswithoctreotidepostitiveradioisotopescans.
Twocompleteand10partialresponseswerenotedin38evaluablepatients.
Only4(10.
5%)ofthepatientsrespondedtotheoctreotidealone.
{LoehrerPJ,WangW,JohnsonDH,EttingerDS:OctreotideAloneorWithPrednisoneinPatientswithAdvancedThymomaandThymicCarcinoma:AnEasternCooperativeOncologyGroupPhaseIITrialJClinOncol(Acceptedforpublication)}Combinationchemotherapyregimenshaveshownhigherresponseratesandhavebeenusedinbothadjuvantandneoadjuvantsettingsinthetreatmentofadvancedinvasive,metastatic,andrecurrentthymoma.
Cisplatin-containingregimensappeartobethemostactive.
Fornasieroetal.
107113reporteda43%completeand91.
8%overallresponseratewithamediansurvivalof15monthsin37previouslyuntreatedpatientswithstageIIIorIVinvasivethymomatreatedwithmonthly(median,5months)cisplatin,50mg/m2onday1;doxorubicin,40mg/m2onday1;vincristine,0.
6mg/m2onday3;andcyclophosphamide,700mg/m2onday4.
Loehreretal.
108114documented10%completeand50%overallresponserateswithamediansurvivalof37.
7monthsin29patientswithmetastaticorlocallyprogressiverecurrentthymomatreatedwithcisplatin,50mg/m2;doxorubicin,50mg/m2;andcyclophosphamide,500mg/m2,givenevery3weeksforamaximumof8cyclesafterradiotherapy.
Parketal.
109115retrospectivelydescribed35%completeand64%overallresponserateswithamediansurvivalof67monthsinrespondingand17monthsinnonrespondingpatientsin17patientswithinvasivestageIIandIVthymomainitiallytreatedafterrelapsewithcyclophosphamide,doxorubicin,andcisplatin,withorwithoutprednisone.
TheEuropeanOrganizationforResearchandTreatmentofCancernoted31%completeand56%overallresponserateswithamediansurvivalof4.
3yearsinasmallstudyof16patientswithadvancedthymomatreatedwithcisplatinandetoposide.
110116Theadditionofifosfamidetocisplatinandetoposidehadalowerthananticipatedresponserate(approximatelyninepartialresponsesin28(32%)evaluablepatients)32%andamediansurvivaltimeof2.
5years)inpatientswiththymomaandthymiccarcinoma.
111117{LoehrerPJ,JiroutekM,GreenM,AisnerJ,ThomasCR,LivingstonR,JohnsonDH:CombinedEtoposide,Ifosfamide,andCisplatinintheTreatmentofPatientswithAdvancedThymomaandThymicCarcinoma:AnIntergroupTrial.
Cancer91:2010-2015,2001.
}combinednodalityapproachesTheuseofneoadjuvantchemotherapyaspartofamultimodalityapproachtostageIIIandIVthymomawasreviewedbyTomiakandEvans.
103109Sixcombinedreportsdocument31%completeand89%overallresponseratesin61totalpatientstreatedwithavarietyofneoadjuvantchemotherapyregimens(80%cisplatin-based).
Twenty-twopatients(36%)underwentsurgery,with11(18%)achievingacompleteresection(alltreatedwithcisplatin).
Nineteenpatientsweretreatedwithradiotherapy,butonlyfivepatientshaddisease-freesurvivalsexceeding5years.
103109Reaetal.
112118reported43%completeand100%overallresponserateswithmedianand3-yearsurvivalratesof66monthsand70%,respectively,in16stageIIIandIVapatientstreatedinitiallywithcisplatin,doxorubicin,vincristine,andcyclophosphamide,followedbysurgery.
Atsurgery,69%werecompletelyresectedandtheother31%receivedpostoperativeradiation.
Macchiarinietal.
113119reportedsimilarfindings.
Twenty-fivepercentcompleteand92%overallresponserateswitharemarkable83%7-yeardisease-freesurvivalratewerereportedin12patientsattheM.
D.
AndersonCancerCenterwhoreceivedcisplatin,doxorubicin,cyclophosphamide,andprednisoneinductionchemotherapyfollowedbysurgicalresection(80%complete)andadjuvantradiotherapyforlocallyadvanced(unresectable)thymoma.
114120Thedegreeofchemotherapy-inducedtumornecrosiscorrelatedwithKi-67expression.
Amultiinstitutionalprospectivetrialdemonstrateda22%completeand70%overallresponseratewithamediansurvivalof93monthsandaKaplan-Meier5-yearfailure-freesurvivalrateof54.
3%in23patientswithstageIII(22/23)unresectablethymoma(GETTstageIIIA/IIIB)stageIV(1/23)thymoma,andthymiccarcinoma(2/23)treatedwith2to4cyclesofcisplatin,doxorubicin,andcyclophosphamidechemotherapyandsequentialradiationtherapy(54Gy).
115121,116122Justmorethan25%hadmyastheniagravis.
Althoughtheseresultscomparefavorablytothoseobtainedwithneoadjuvanttherapyfollowedbysurgicalresectionandradiation,furtherconfirmationisneeded.
ResultsofTreatmentFive-and10-yearsurvivalratesforstageI,III,andIVtumorsarereportedtobe89%to95%and78%to90%,6715,7804,11712370%to80%and21%to80%,6571,7480,117123and50%to60%and30%to40%,6065,6571,7480,117123respectively.
Disease-freesurvivalratesof74%,71%,50%,and29%alsohavebeenreportedforstageI,II,III,andIVdisease,respectively.
7177AlthoughMaggietal.
7177reporteda10%overallrecurrenceratein241patients,lessthan5%ofnoninvasivethymomasand20%ofinvasivethymomaswerenotedtorecur.
6571Althoughmyastheniagraviswasonceconsideredanadverseprognosticfactor,thisisnolongerthecasebecauseofimprovementsinperioperativecare.
Currently,myastheniaactuallymayleadtoimprovedsurvivalowingtoearlierdetectionofthymomas.
6571,84,118124,119125ThymicCarcinomaThymiccarcinomaisarareaggressivethymicneoplasmthathasapoorprognosis.
Likethymoma,itisanepithelialtumor,butcytologicallyitexhibitsmalignantfeatures.
Extensivelocalinvasionanddistantmetastasesarecommon.
Approximately150caseshavebeenreported.
120126–125131SusterandRosai120Rosai126reportedthelargestsingleseries,whichincluded60patientsranginginagefrom10to76yearsandwithaslightmalepredominance.
Nearly70%ofpatientshadsymptomsofcough,chestpain,orsuperiorvenacavasyndrome.
Myastheniaandotherthymoma-associatedsyndromesarerare.
120126ThehistologicclassificationofthymiccarcinomawasproposedbyLevineandRosai126Rosai132andrevisedbySusterandRosai.
120126Thetumorsareclassifiedbroadlyasloworhighgrade.
Low-gradetumorsincludesquamouscellcarcinoma,mucoepidermoidcarcinoma,andbasaloidcarcinoma.
High-gradeneoplasmsincludelymphoepithelioma-likecarcinomaandsmallcell,undifferentiated,sarcomatoid,andclearcellcarcinomas.
120126,122128,123129,127134Theclassificationofthymiccarcinomahasprognosticsignificance,withlow-gradetumorsfollowingafavorableclinicalcourse(mediansurvivalratesof25.
4monthstomorethan6.
6years)becauseofalowincidenceoflocalrecurrenceandmetastasis,andhigh-grademalignanciesexhibitinganaggressiveclinicalcourse(mediansurvivalofonly11.
3to15.
0months).
120126–122128AlthoughtheMasaokathymomastagingsystem120system126,122128,124130andaproposedtumor-node-metastasisclassificationsystem125system131havebeenusedinstagingthymiccarcinoma,theirutilityisunproven.
Thehistologicgraderemainsthebestprognosticindicator.
Theoptimaltreatmentofthymiccarcinomaremainsundefined,butcurrentlyamultimodalityapproach,includingsurgicalresection,postoperativeradiation,andchemotherapy,isrecommended.
Initialsurgicalresectionfollowedbyradiationhasbeenusedinmoststudies.
4517,111117,120126,122128–125131Completeresectionshouldbeattempted,butusuallyisnotpossible.
122128,133Oneanalysisnoteda9.
5-monthmediansurvivalafterresectionandpostoperativeelectronbeamradiationtherapy,111117withatrendtowardimprovedsurvivalinotherstudies.
122128,123129,126Chemotherapywithcisplatin-basedregimenssimilartothoseusedwiththymomashaveproducedvariableresponsesinsmallnumbersofpatients.
120126,122128–124130Combinationsofcisplatin,doxorubicin,cyclophosphamide,andvincristinealsohavegeneratedpartialresponses,ashasthecombinationof5-fluorouracilandleukovorin.
124130{KoizumiT,TakabayashiY,YamagishiS:Chemotherapyforadvancedthymiccarcinoma:clinicalresponsetocisplatin,doxorubicin,vincristine,andcyclophosphamide(ADOCChemotherapy).
AmJClinOncol25:266-68,2002;LucchiM,MussiA,AmbrogiMetal:ThymicCarcinoma:areportof13cases.
EJSO27:636-40;2001;KitamiA,SuzukiT,KamioYandSuzukiS:Chemotherapyofthymiccarcinoma:Analysisofsevecasesandreviewoftheliterature.
JpnJClinOncol31:601-04,2001}.
Useofneoadjuvantchemotherapyhasbeenreportedinasmallnumberofpatientsbutconsideredappropriateinselectedpatientswithunresectablediseasewiththeintentiontodownsizethetumorforpossiblecompleteresection.
124130Theprognosisofthymiccarcinomaispoorbecauseofearlymetastaticinvolvementofpleura;lung;mediastinal,cervical,andaxillarylymphnodes;bone;andliver.
120126Theoverallsurvivalrateat5yearsisapproximately35%.
120126,122128Improvedsurvivalhasbeencorrelatedwithencapsulatedtumors,lobulargrowthpattern,lowmitoticactivity,earlystagetumors,andlowhistologicgrade,andcompletesurgicalresection.
120126,133ThymicCarcinoidThymiccarcinoidtumorsarerare,withfewerthan125200reportedcases.
128135–131138{TehBT,ZedeniusJ,KytoiaSetal:ThymicCarcinoidsinMultipleEndocrineNeoplasiaType1.
AnnSurgery228:99-105,1998}Theyoccurpredominantlyinmales129males136andoriginatefromnormalthymicKulchitsky'scells,whicharepartoftheamineprecursoruptakeanddecarboxylation(APUD)group.
Mosthavetheabilitytomanufacturepeptides,amines,kinins,andprostaglandins.
Theyareaggressivetumorsthatinvadelocallyandcommonlymetastasizetoregionallymphnodes.
Metastasesoccurin70%ofpatientswithin8yearsofinitialdiagnosis.
131138Thegrossappearanceofthymiccarcinoidsissimilartothatofthymomas,buttheyarerarelyareencapsulated.
Microscopically,thetumorsexhibitaribbon-likegrowthpatternwithrosetteformationinafibrovascularstroma.
Thecellsaresmall,round,orovalwitheosinophiliccytoplasmanduniformlyroundnuclei.
129136Immunohistochemicalstudiesrevealargyrophiliccellsthatstainwithcytokeratinandneuronal-specificenolase.
Electronmicroscopyrevealsthepresenceofsecretorygranules.
130137Thymiccarcinoids,likeotherforegutcarcinoids,areassociatedwithCushing'ssyndrome,multipleendocrineneoplasiaand,rarely,thecarcinoidsyndrome.
129136–132139Thediagnosisofthymiccarcinoidoftenrequiresopensurgicalbiopsy.
Completesurgicalresectionisrecommended,althoughrecurrenceiscommon.
129136–131138Theeffectivenessofadjuvanttherapyisunproven,butmostreportsadvocateadjuvantradiotherapyforincompletelyresectedtumors.
129136–131138Chemotherapyrarelyhasbeenusedincasesofmetastaticorrecurrentdisease.
129136–131138Althougha5-yearsurvivalrateof60%hasbeenreportedwithcompletesurgicalresection,130137localrecurrencesarecommonanddistantmetastasesoccurinapproximately30%ofpatients.
129136Thelong-termprognosisisgenerallypoor.
ThymolipomaThymolipomasarerarebenignneoplasmscomposedofmatureadiposeandthymictissue,andtheyaccountfor1%to5%ofthymicneoplasms.
133140Thesetumorsarealsoknownaslipothymomas,mediastinallipomaswiththymicremnants,andthymolipomatoushamartomas.
133140,134141Inareviewof27patients,Rosado-de-Christensonetal.
134141notedanequalgenderdistributionandameanageof27years.
Approximately50%ofpatientspresentedwithsymptomsofvaguechestpain,dyspnea,andtachypnea.
Othershavereported,inadultsonly,anassociationwithmyastheniagravis,redcellaplasia,hypogammaglobulinemia,lichenplanus,andGraves'disease.
133140,135142Thymolipomasaresoft,lobulated,encapsulatedtumorsthatoriginateintheanteriormediastinum.
Theyoftenattainalargesizebeforebecomingsymptomatic.
Theyfrequentlyconformtotheshapeofthecardiacandmediastinalstructuresandarefoundintheanteriorinferiormediastinum"drapedalongthediaphragm"andconnectedtothethymusbyasmallpedicle.
134141Microscopically,thetumorsarecomposedofthymictissue,oftenwithcalcifiedHassall'scorpuscles,andmorethan50%adiposetissue.
134141Histologically,thymolipomasdonotappearmalignant,andmalignanttransformationdoesnotoccur.
134141Treatmentinvolvescompleteresection.
Long-termfollow-upisnotavailable,butrecurrenceshavenotbeenreported.
GermCellTumorsThevastmajorityofgermcelltumorsarisewithingonadaltissue,butthemediastinumisthemostcommonsiteforthedevelopmentofextragonadalgermcelltumors.
Theyaremostcommonlyseenintheanteriormediastinumandaccountfor10%to15%ofallprimarymediastinaltumors.
2Thesetumorshavegeneratedconsiderableinterestbecauseoftheiruncertainhistogenesis.
EtiologyExtragonadalgermcelltumorsarefoundalongthebody'smidlinefromthecranium(pinealgland)tothepresacralarea.
Thislinecorrespondstotheembryologicurogenitalridge.
Itispresumedthatthesetumorsarisefrommalignanttransformationofgermcellsthathaveabnormallymigratedduringembryonicdevelopment.
136143,137144Mediastinalgermcellneoplasmsaccountforonly2%to5%ofallgerminaltumors,buttheyconstitute50%to70%ofallextragonadaltumors.
137144,138145ClassificationMediastinalgermcelltumorsarebroadlyclassifiedasbenignormalignant.
Benigntumorsincludematureteratomasandmatureteratomaswithanimmaturecomponentoflessthan50%.
Malignantgermcelltumorsaredividedintoseminomas(dysgerminomas)andnonseminomatoustumors.
Nonseminomatoustumorsincludeembryonalcarcinomas,choriocarcinomas,yolksactumors,andimmatureteratomas.
139146Seminomasmayexistinapureform,butanyelevationofAFPindicatesthepresenceofanelementofanonseminomatoustumor.
Inaddition,mediastinalgermcelltumorshaveapropensitytodevelopacomponentofnon–germcellmalignancy(e.
g.
,rhabdomyosarcoma,adenocarcinoma,permeativeneuroectodermaltumor),whichcanbecomethepredominanthistology.
IncidenceandClinicalPresentationInadults,benigngermcelltumorshavenogenderpredilection,but90%ofmalignantgermcelltumorsoccurinmen.
136143Inthepediatricpopulation,bothbenignandmalignantextragonadalgermcelltumorsoccurwithequalgenderdistribution.
Mediastinalgermcelltumorsaremostcommonlydiagnosedinthethirddecadeoflife,butpatientsasoldas60yearsofagehavebeenreported.
Theincidenceoftheseneoplasmsisequalinallraces.
Manypatientswithbenigntumors,including50%ofteratomas,areasymptomatic;however,90%to100%ofpatientswithmalignanttumorshavesymptomsofchestpain,dyspnea,cough,fever,orotherfindingsrelatedtocompressionorinvasionofsurroundingmediastinalstructures.
140147,141148DiagnosisMediastinalgermcelltumorsaremostoftendetectedonthebasisofstandardchestradiographs.
Morethan95%ofthechestfilmsareabnormal,withalmostallmassesnotedintheanteriormediastinum.
Threepercentto8%oftumorsarisewithintheposteriormediastinum.
136143ChestCTscansdemonstratetheextentofdisease,relationshiptosurroundingstructures,andpresenceofcysticareasandcalcificationwithinthetumor.
16Abdominalimagingshouldbeperformedtoassessforpossiblelivermetastases.
Althoughcarefulexaminationofthetestes,includingatesticularultrasound,shouldalwaysbeperformed,anisolatedtumormassintheanteriormediastinumwithoutretroperitonealinvolvementisnotconsistentwithatesticularprimarytumor.
Itisnotnecessarytoperformblindorchiectomyortesticularbiopsyinpatientswithnormalphysicalexaminationsandunremarkableultrasoundfindings.
137144Recently,mediastinalsonographyimagingpatternshavebeensuggestedasameanstoimprovethediagnosticaccuracyofmediastinalteratomas.
149Determinationofserumtumormarkersisimportantinthediagnosisandfollow-upofmediastinalgermcelltumors.
Immunoassaysfor-HCGandAFPshouldbeobtainedinallpatientspossessingmediastinalmassessuspiciousforgermcelltumors.
Elevationsof-HCGandAFPconfirmamalignantcomponenttothetumor.
AFPor-HCG,orboth,areelevatedin80%to85%ofnonseminomatousgermcelltumors,withAFPbeingdetectedin60%to80%ofthesetumorsand-HCGin30%to50%.
140147Patientswithbenignteratomashavenormalmarkers,andpatientswithpureseminomamayhavelowlevelsof-HCG,butAFPisnotdetected.
TeratomasBenignteratomasarethemostcommonmediastinalgermcelltumor,accountingfor70%ofthemediastinalgermcelltumorsinchildrenand60%ofthoseinadults.
136143Theycanbeseeninanyagegroupbutmostcommonlyoccurinadultsfrom20to40yearsofage.
Thereisnogenderpredilection.
Teratomasmaybesolidorcysticinappearanceandareoftenreferredtoasdermoidcystsifunilocular.
Teratomascontainelementsfromallthreegermcelllayers,withapredominanceoftheectodermalcomponentinmosttumors,includingskin,hair,sweatglands,sebaceousglands,andteeth.
Mesodermisrepresentedbyfat,smoothmuscle,bone,andcartilage.
Respiratoryandintestinalepitheliumareoftenseenastheendodermalcomponent.
Themajorityofmediastinalteratomasarecomposedofmatureectodermal,mesodermal,andendodermalelementsandexhibitabenigncourse.
Immatureteratomasphenotypicallymayappearasamalignancyderivedfromtheseectodermal,mesodermal,andendodermalelements.
Theselattertumorsbehaveaggressivelyandgenerallyarenotresponsivetosystemictherapy.
Treatmentof"benign"mediastinalteratomaincludescompletesurgicalresection,whichresultsinexcellentlong-termcurerates.
Radiotherapyandchemotherapyplaynoroleinthemanagementofthistumor.
Thetumormaybeadherenttosurroundingstructures,necessitatingresectionofpericardium,pleura,orlung.
Completeresectionofteratomasshouldbethegoaloftreatment.
Resectionofmatureteratomashasbeenshowntoresultinprolongedsurvivalwithlittlechanceofrecurrence.
139146,142150Immatureteratomasarepotentiallymalignanttumors;theirprognosisisinfluencedbytheanatomicsiteofthetumor,patientage,andthefractionofthetumorthatisimmature.
139146Inpatientsyoungerthan15years,immatureteratomasbehavesimilarlytotheirmaturecounterparts.
Inolderpatients,theymaybehaveashighlymalignanttumors.
Currently,atrialofcisplatin-basedcombinationchemotherapy(upto4cyclesofcisplatin,etoposide,andbleomycinBleomycin(BEP)oretoposidevinblastine,ifosfamide,andcisplatin(VIP),ifresponding)isfrequentlyadministeredbeforeattemptedsurgicalresection.
139146{HintonS,CatalanoP,EinhornLH,NicholsCR,CrawfordED,VogelzangN,TrumpD,LoehrerPJ:Cisplatin,EtoposideandEitherBleomycinorIfosfamideintheTreatmentofDisseminatedGermCellTumors.
FinalAnalysisofanIntergroupTrial.
Cancer97(8):1869-1875,2003.
}SeminomaPrimarypuremediastinalseminomaaccountsforapproximately35%ofmalignantmediastinalgermcelltumors;itisprincipallyseeninmenaged20to40years.
143151Seminomasgrowslowlyandmetastasizelaterthantheirnonseminomatouscounterparts,andtheymayhavereachedalargesizebythetimeofdiagnosis.
Symptomsareusuallyrelatedtocompressionoreveninvasionofsurroundingmediastinalstructures.
Twentypercentto30%ofmediastinalseminomasareasymptomaticwhendiscovered,143151butmetastasesarepresentin60%to70%ofpatients.
Pulmonaryandotherintrathoracicmetastasesaremostcommonlyseen.
Extrathoracicmetastasesusuallyinvolvebone.
143151Thetreatmentofmediastinalseminomahasevolvedsincetheearly1970s.
Definitiveconclusionsregardingtreatmentaredifficult,becauseseveralpotentiallycurativetreatmentmodalitiesexist.
Seminomasareextremelyradiosensitivetumors,andformanyyears,high-dosemediastinalradiationhasbeenusedasinitialtherapy,resultinginlong-termsurvivalratesof60%to80%.
144152AreviewofrecommendationsforradiationtherapytreatmentinextragonadalseminomawasreportedbyHainsworthandGreco.
143151Thirty-fiveto40Gyarethemostcommonlyusedradiationdoses.
Dosesaslowas20Gyhavebeenreportedtobecurative,butmostreportsnoteasignificantlocalrecurrenceratewithdosesoflessthan45Gy.
143151Radiationportalsshouldincludeashapedmediastinalfieldandbothsupraclavicularareas.
143151Mediastinalseminomaoftenpresentsasbulky,extensive,andlocallyinvasivedisease,requiringlargeradiotherapyportals.
Theseportalsresultinexcessiveirradiationofsurroundingnormallung,heart,andothermediastinalstructures.
Additionally,for20%to40%ofpatientsinwhomlocalcontrolisachieved,treatmentcanbeexpectedtofailatdistantsites.
136143,143151Chemotherapywaspreviouslyusedonlyinadvancedgonadalseminoma,butencouragingresultsandtheabove-mentionedproblemswithradiotherapyhaveledtobroadenedindications;chemotherapyisnowbeingusedasinitialtherapyinmanypatientswithbulkytumors.
Puremediastinalseminomafallsintotheintermediate-riskcategoryofthenewInternationalStagingSystemforGermCellTumors.
Evenpatientswithvisceralmetastasesfallintothisintermediatecategoryand,assuch,haveaprognosiswithcisplatin-basedcombinationchemotherapyexceeding75%for5-yearsurvival.
Standardsystemictherapyconsistsofcisplatin-basedcombinationchemotherapy.
Lemarieandcoworkers140coworkers147reportedthat12of13patientstreatedexperiencedcompleteremission,withtworecurrencesaftertreatment.
Cisplatin-basedcombinationtherapyachievedacompleteresponseinthreeoffivepatientstreatedbyGiaccioneBokemeyerreportedaninternationalanalysisof51patientswithmediastinalseminoma.
145153Inthisstudy,patientsweretreatedwithchemotherapy(38=74.
5%),chemotherapyandradiation(10=19.
6%),orradiationalone(3=5.
9%).
Chemotherapywasprimarilycisplatin-based(45=94%)butincludedcarboplatin(3=6%)whichhadaninferiorobjectiveresponserate(80%versus93%).
Theprogression-freesurvivalandoverallsurvivalwere77%and88%,respectivelybutpatientswithextrathoracicmetastases(6=11.
8%)hadaworseprognosis.
Acollectivereviewof52patientswasundertakenbyHainsworthandGreco.
143151Fourteenpatientshadreceivedpriorradiationtherapy,butallunderwentchemotherapywithcisplatinandvariouscombinationsofcyclophosphamide,vinblastine,bleomycin,oretoposide.
Completeresponsestotreatmentwerenotedin85%ofpatients,and83%werelong-termdisease-freesurvivors.
143151Althoughchemotherapyappearstobeasuperiormodalityinthesesmallseries,radiotherapyislesstoxic,chemotherapyappearstobesuperior,andandthehighsalvageratewithchemotherapyafterradiotherapyfailuremakesselectiondifficult.
Ttherefore,therecommendedtreatmentiscisplatin-basedcombinationchemotherapycurrentlyisrecommendedeitherwithorwithoutbutsupradiaphragmaticradiationisconsideredforpatientswithsmallvolumeandlocalizeddiseaseor4cyclesofcisplatin-basedcombinationchemotherapy.
Themanagementofpatientswithresidualradiographicabnormalitiesafterchemotherapyiscontroversial.
Studieshaveshownthattheresidualmassisadensescirrhousreactionin85%to90%ofpatients,andthepresenceofviableseminomaisrare.
Othershaveshowna25%incidenceofresidualviableseminomainthesepatientstreatedwithchemotherapyfollowedbyresectionofresidualmasseslargerthan3cm.
146154Closeobservationwithoutsurgeryisrecommendedforresidualmassesafterchemotherapyunlessthemassenlarges.
147154,148155EvaluationwithPETscanshavehadmixedresults,butifperformedshouldbedone4-6weeksafterchemotherapyadministration.
snotprovenhelpfulandeEEmpiricradiationtherapyisnotrecommended.
143151,156{Bob:ThereisanabstractfromascothisyearthatIwillfindasareferenceforyou}Despitearecentreportof76.
9%long-termsurvivalutilizingprimarysurgicalresectionfollowedbyadjuvanttherapy,157Mmostauthorsbelievethatsurgerydoesnotplayaroleinthedefinitivetreatmentofseminoma.
144152Inaddition,surgicaldebulkingoflargetumorshasnotbeenshowntobeofbenefitinimprovinglocalcontrolorsurvival.
143151Allpatientswithmediastinalseminomashouldbetreatedwithcurativeintent.
Isolatedmediastinalseminomawithminimaldiseaseandwithoutevidenceofmetastaticdiseaseismostoftenmanagedwithradiotherapyalone,withanexcellentprognosisandlong-termsurvival.
Locallyadvancedandbulkydiseasemayshouldbetreatedinitiallywithcisplatin-basedcombinationchemotherapy,usually4cyclesofcisplatinandetoposide,withradiotherapy,andfollowedbysalvagechemotherapy(vinblastine,ifosfamide,andcisplatin)intheeventofrecurrence.
149158Patientswithdistantmetastasesshouldundergocisplatin-basedcombinationchemotherapyasinitialtreatment.
NonseminomatousGermCellTumorsNonseminomatousgermcelltumorsincludechoriocarcinoma,embryonalcarcinoma,teratoma,andendodermalsinus(yolksac)tumors.
Theymayoccurinpureform,butinapproximatelyone-thirdofcases,multiplecelltypesarepresent.
Othermalignantcomponents,includingadenocarcinomas,squamouscellcarcinomas,andsarcomas,maybepresentorevenrepresentthepredominanttissuetype,asusuallyoccursinimmatureteratomas.
Nearly85%ofnonseminomatousgermcelltumorsoccurinmen,withameanageof29years.
136143Karyotypicanalyseshavebeenperformedonanumberofthesepatients,andthe47,XXYpatternofKlinefelter'ssyndromehasbeenfoundinupto20%ofpatients.
136143Mediastinalnonseminomatousgermcelltumorsaremostcommonlyfoundintheanteriormediastinumandappeargrosslyaslobulatedmasseswithathincapsule.
Theyarefrequentlyinvasiveatthetimeofdiagnosis,withalmost90%ofpatientsexhibitingsymptoms.
TheyappearonCTscansaslargeinhomogeneousmassescontainingareasofhemorrhageandnecrosis.
Elevatedlevelsof-HCGareseenin30%to50%ofpatients,andAFPisdetectedin60%to80%.
ThesePrimarymediastinalnonseminomatousgermcelltumorscarryapoorerprognosisthaneitherpureextragonadalseminomaortheirgonadalnonseminomatouscounterparts,andallpatientswithprimarymediastinalnonseminomatousgermcelltumorsfallintothepoorriskcategoryofthenewInternationalGermCellConsensusClassification.
150159Eighty-fivepercentto95%ofpatientshaveobviousdistantmetastasesatthetimeofdiagnosis.
Commonmetastaticsitesincludelung,pleura,lymphnodes,liver,and,lesscommonly,bone.
143151Anumberofnon–germcellmalignantprocesseshavebeenfoundinassociationwithnonseminomatousgermcelltumors.
Oneofthemostinterestingisthatfoundinassociationwithacutemegakaryocyticleukemia.
Otherhematologicmalignancies,suchasacutemyeloidleukemia,acutenonlymphocyticleukemia,erythroleukemia,myelodysplasticsyndrome,malignanthistiocytosis,andthrombocytosis,haveallbeenreported.
Thesemalignanciesmayantedatethediscoveryofthegermcelltumororoccursynchronously.
Solidtumors,suchasembryonalrhabdomyosarcoma,smallcellundifferentiatedcarcinoma,neuroblastoma,andadenocarcinomahavebeendescribedandoccurmorefrequentlyinprimarymediastinaltumorscomparedtogonadalgermcellneoplasms.
137144Thediagnosisofnonseminomatousgermcelltumorscanoftenbemadewithouttissuebiopsy.
144152Inmanycenters,thepresenceofananteriormediastinalmassinayoungmalewithelevatedserumtumormarkers(AFPand-HCG)isadequatetoinitiatetreatment.
Ifatissuediagnosisisdeemednecessary,fine-needleguidedaspirationwithcytologicstainingfortumormarkersmaybeusedforconfirmation.
Ananteriormediastinotomyprovidesthebestexposureforopenbiopsyifnecessary.
144152Treatmentofnonseminomatousgermcelltumorsincorporatescisplatin-basedchemotherapy,whichhasmarkedlyimprovedtheprognosisinthesepatients.
Inthepast,long-termsurvivalaftertreatmentofnonseminomatousgermcelltumorswasveryrare;today,however,overallcompleteremissionratesof40%to50%areobtainedinmostseries.
139146,140147,143151,145153Treatmentisinitiatedwithcisplatin-containingcombinationchemotherapy,whichoftenincludesetoposideandbleomycin.
Treatmentshouldbeadministeredevery3weeksfor4courses;patientsshouldthenberestagedwithserumtumormarkersandCTscansofthechestandabdomen.
143151Inacollectivereviewof158patientsundergoingavarietyofcombinationchemotherapeuticregimensfortheinitialtreatmentofnonseminomatousgermcelltumors,completeresponseswerenotedin54%ofpatients,and42%werelong-termdisease-freesurvivors.
143151Inaninternationalreviewof287patients,responseswerenotedin178(64%)andtheprogression-freeandoverallsurvivalwere44%and45%,respectively.
153Patientswithnegativetumormarkersandnoradiographicevidenceofresidualdiseaseafterinitialchemotherapyrequirenofurthertreatment.
Persistentelevationofserumtumormarkers,particularlyiftheybegintoriseagain,usuallyrequiressalvagechemotherapy.
143151Patientswithnormalserumtumormarkersbutradiographicevidenceofresidualmassesafterinductionchemotherapyshouldundergosurgicalresection4to6weeksaftercompletionofchemotherapy.
143151,144152Completeresectionshouldbeattempted,becausedebulkingproceduresprovidenobenefit.
Patientsfoundtohaveresidualviablegermcelltumorundergo2additionalcyclesofchemotherapy.
Patientswithimmatureteratomaornon–germcellmalignanciescansimplybeobservedaftercompleteresection.
Nichols136Nichols143reportscompleteremissionsin18of31patientsusingthisregimen,andotherseriesreportcompleteremissionratesof50%to70%,withlong-termsurvivalratesapproximating50%.
136143Equivalentresultsareobtainedinallhistologicsubtypes.
Thetreatmentofrecurrentdiseaseisdifficult,becausepatientswithrelapsingmediastinalnonseminomatousgermcelltumorsdoextraordinarilypoorlywithsalvagetherapy,suchasvinblastine,ifosfamide,andcisplatin151cisplatin160;optimaltherapyhasnotbeendetermined.
Standardsalvagechemotherapyhasnotprovenbeneficialwithonly9of79patients(8%)becomingdisease-freeinonestudy,153andfewpatientseverachieveingdurableremissions.
High-dosechemotherapywithstemcellrescueiseffectiveinonlyafewselectedpatients.
152161,153162Occasionally,surgicalresectionofresidualdiseasedespitepersistentlyelevatedtumormarkerscanbebeneficial.
163MostpatientsarecandidatesforexperimentalphaseItrials.
MesenchymalTumorsMediastinalmesenchymaltumors,orsofttissuetumors,originatefromtheconnectivetissueelementsofthemediastinum.
Smoothandstriatedmuscle,lymphatictissue,fat,andvasculartissueallgiverisetoavarietyofneoplasms,whichmaybebenignormalignant.
Mostofthesetumorsalsooccurinotherpartsofthebodyandarediscussedindetailelsewhereinthechapteronsofttissuesarcomas.
Mesenchymaltumorsaccountforapproximately6%ofprimarymediastinalneoplasms.
2Theyarelesscommoninthemediastinumthaninotherlocations.
Approximately55%aremalignant,andthereisnogenderpredilection.
10,154164Ingeneral,treatmentofmalignantmesenchymaltumorsinvolvescombinationtherapy,includingsurgicalresection,radiationtherapy,andchemotherapy.
Benigntumorsshouldbecompletelyexcisedcompletely,afterwhichlittlechanceofrecurrenceremains.
Lipomasarethemostcommonmesenchymaltumorofthemediastinum,representing2%ofallmediastinalneoplasms.
8Benignlipomasaremostoftenlocatedintheanteriormediastinum.
Theymaygrowtolargesizewithoutsymptoms.
Treatmentiscompleteresection,andalthoughlocalrecurrenceispossible,itisunusual.
Malignantliposarcomaismorecommonlyfoundintheposteriormediastinum.
Fibromasareencapsulatedasymptomatictumorsthatmaygrowtoaverylargesize.
Fibrosarcomasoftenaresymptomaticmalignanciesassociatedwithhypoglycemia.
Fibromasarecuredwithcompletesurgicalexcision,butfibrosarcomasareusuallyunresectableandrespondpoorlytoradiationandchemotherapy.
10Leiomyomas,leiomyosarcomas,rhabdomyomas,rhabdomyosarcomas,synovialcellsarcomas,mesotheliomas,andxanthogranulomasalsooccasionallyoccurinthemediastinum.
8,154164Vasculartumorsofthemediastinumincludehemangiomas,hemangioendotheliomas,andbenignandmalignanthemangiopericytomas.
8,154164Tenpercentto30%ofallvasculartumorsaremalignant.
10Mediastinalhemangiomasrepresent0.
5%ofallmediastinalneoplasmsbutarethemostcommonvasculartumor.
155165Theymaybecavernousorcapillaryandareoftenassociatedwithhemangiomasinotherareasofthebody.
155165,156166Sixtypercentoccurintheanteriormediastinum,and25%occurposteriorly.
10DiagnosisisbestaccomplishedbyCTscanorMRI,inwhichphlebolithsmaybeseenin30%ofthesetumors.
Angiographyisimportantinidentifyingandembolizingmajorfeedingvesselsbeforesurgery.
156166Totalexcisionisconsideredthetreatmentofchoice;however,large,incompletelyresectedhemangiomasusuallydonotrecur.
155165Lymphangiomas,alsoknownascystichygromas,oftenextendintotheanteriormediastinumfromthecervicalarea.
Seventeenpercentarelocatedexclusivelyinthemediastinum.
Theytendtoenlargeaspatientsgrow,particularlyduringpuberty.
Treatmentinvolvessurgicalresection,butthisisoftendifficultbecauseofadherencetosurroundingstructures.
Responsetoradiationisvariable.
10Otherlymphaticsofttissuetumorsincludelymphangiosarcomaandlymphangiopericytoma.
NeurogenicTumorsThoracicneurogenictumorsoccurmostcommonlyintheposteriormediastinumbutoccasionallyarefoundintheanteriormediastinumandelsewhere.
Theycomposebetween19%and39%ofallmediastinaltumors157tumors167,158168and75%ofposteriormediastinaltumors.
159169Theyoriginatefromperipheralnerves(nervesofthebrachialplexusandintercostalnerves),autonomicsympatheticgangliaand,rarely,fromthevagusnerve.
160170Neurogenictumorsintheanteriormediastinumoriginateinchemoreceptorparagangliomas.
Whereasneurogenictumorsininfantsandchildrenarefrequentlymalignantandoftenpresentwithmetastaticdisease,161171inadultsthemajorityofthesetumorsarebenign.
Theyoccurwithoutgenderpredilectionatanyagebutaremorelikelyinyoungadults.
Oftenasymptomatic,theyaresolitary(exceptinneurofibromatosis)andfoundonaroutinechestx-ray.
Benigntumorscanattainaconsiderablesize.
Theyfrequentlyariseintheparavertebralsulcusfromtheposteriorrootsofthespinalnervesatthezoneoftransitionbetweenthecentralandperipheralmyelin.
162172Theyalsomayariseontheposteriorportionofthespinalnerverootinthespinalcanalandgrowthroughtheintervertebralforamenintotheparavertebralarea,givingrisetotheappearanceofadumbbell-orhourglass-shapedtumor.
Thesetumorsmustberecognizedtoplananappropriateoperationinconjunctionwithaneurosurgeon.
Dependingontheirsizeandlocation,lesionsmaycausespinalcordcompression,pain,paresthesias,Horner'ssyndrome,andmuscleatrophy.
Superiorvenacavasyndrome,dyspnea,cough,andbonyerosions,whichwronglysuggestamalignantprocess,alsohavebeendescribed.
Neurilemoma(Schwannoma)Neurilemoma(schwannoma)isthemostcommontumorintheparavertebralsulcus.
Arisingfromtheintercostalnervesheath,thetumorisencapsulated,whiteoryellowishpinkincolor,withcalcificationsandcysticdegeneration.
Histologically,itiscomposedofuniformslenderbiphasicfusiformcellswithelongated,twistednucleithathaveatendencytoaligninaregimentedorpalisadedappearance.
163173Thetumormaycontainlargebloodvesselsandmaybeasourceofconsiderablebloodlossduringsurgicalremoval.
Schwannomamaybefurtherdifferentiatedintomelanotic,adenomatous,orpsammomatoustumors(Fig.
32-2).
163173NeurofibromaNeurofibromasaremostoftenbenignandasymptomatic.
However,theycanhaveanintraduralaswellasanextraduralcomponentandmaycausesymptomsofcordcompression.
Theyarenotencapsulatedandmayhaveaplexiformappearance.
164174Microscopically,neurofibromashaveaheterogeneouscellpopulation,butSchwanncelldifferentiationisnotalwayspresent.
157167Neurogenictumorscanbedifferentiatedfromleiomyomas,meningiomas,andfibroushistiocytomasbytheimmunohistochemicalidentificationofS-100protein.
Solitaryneurofibromasarecuredbysurgicalexcision.
NeurofibromascanoccurasmultiplelesionsinvonRecklinghausen'sdisease.
165175Neurofibromatosisisinheritedasanautosomaldominanttraitaffectingbothgendersequally;however,approximatelyone-halfofthecasesaresporadic.
166176,167177Theclinicalfeaturesvaryandincludehyperpigmentedcaféaulaitskinspots,skinandsubcutaneousmultipleneurofibromas(hamartomas),scoliosis,bowingoflongbones,disordersofsexualdevelopment,andmultipleneurogenictumorsandmalignancies,suchasmalignantschwannomas.
168178,169179Mediastinalneurofibromasmaybemultipleandappearaslongplexiformmasses.
Histologically,theyconsistoflargenervefibersmixedwithconnectivetissuestromacontainingSchwanncellsandfibroblasts.
Surgicalinterventionisjustifiedforlesionslocatedinthespinalcanalthatcausespinalcordornerverootcompression.
Theprognosisgenerallyispoor.
170180MalignantSchwannomaMalignantschwannomasarethemalignantcounterpartsofneurilemmomasandneurofibromas.
Ultrastructuralstudies,however,cannotalwaysdocumentSchwanncellsinthesetumorsderivedfromnervesheaths,andthereforethetermsmalignantnervesheathtumor,neurogenicsarcoma,andneurofibrosarcomaaresometimesused.
170180Malignantnervesheathtumorscommonlyarelarge.
Theyarepainfulandmaycausesuperiorvenacavaobstruction;Horner'ssyndrome;dyspnea;dysphagia;hoarseness;andinvasionofthelung,bones,andaorta,dependingontheirlocationandsize.
Thediagnosticcriteriaformalignantnervesheathtumorsarecontroversial.
166176Originfromamajornerve,presenceofSchwanncellsandS-100protein,thediagnosisofneurofibromatosis,andnuclearpalisadingareimportantfeatures.
Histologicfindingsincludehypercellularity,pleomorphicdensenuclei,multipleandabnormalmitoses,andinvasionofthesurroundingstructures.
160170Themalignantnervesheathtumorsareusuallylarge(oftenlargerthan5cmindiameter),partiallyencapsulated,soft,andgray,withhemorrhageandnecrosis.
Histologically,theyarecomposedofspindlecellswithcomma-shaped,irregularnuclei.
Neuralandperineuralinvasion,maturecartilage,bone,striatedmuscle,squamousdifferentiation,andmucin-secretingglandsalsomaybeseen.
171181,172182Clinically,thesetumorsareaggressive,locallyinvasive,andhighlymetastatic.
Theyoftenrecurafterresection,leadingtoa75%5-yearsurvivalrate.
Patientswithneurofibromatosisandamalignantnervesheathtumorhavea15%to30%5-yearsurvivalrate.
CombinationchemotherapyisrecommendedinstageIIIandIVdisease(Fig.
32-3).
TumorsofSympatheticGangliaMediastinalganglioneuromasarefoundintheposteriormediastinumalongthesympatheticchaininchildrenolderthan4yearsandinadultsinthethirdandfourthdecadesoflife.
Occasionally,aneuroblastomamaymatureintoabenignganglioneuroma.
173183–175185Thetumorusuallyisasymptomatic,butsometimespresentswithHorner'ssyndromeand,rarely,withdiarrheacausedbyproductionofvasoactiveintestinalpolypeptide.
Ganglioneuromashaveasmoothcontourandcontainareasofstippledcalcification.
Theymayresembleotherbenignneurogenictumors,causingriberosions.
176186Microscopically,spindlecellproliferationisseenthatappearsidenticaltothatinaneurofibroma,exceptthatganglioneuromasexhibitthepresenceoflargeganglioncells.
160170Ganglioneuromasarebenigntumors,althoughregionallymphnodesmaycontainislandsoftumorcellsattributedtomaturedneuroblasts.
166176Theyrequirecompleteexcision.
NeuroblastomasAlthoughneuroblastomascanbefoundinanylocationinwhichembryonicneuroblastsmigratedfromtheneuralcrest,theyusuallyoriginateintheadrenalglandsandalongnerveplexuses.
Inthechest,theyoccuralongthesympathetictrunkintheparavertebralsulcus.
Thistumoristhemostcommonmalignancyofearlychildhood,occurringmostcommonlyinthefirst2yearsoflife.
Patientswithmediastinalneuroblastomasusuallyaresymptomaticandfrequentlyhavemetastaticdisease.
177187,178188Symptomsarerelatedtolocalcompression(Horner'ssyndromeandheterochromiaoftheiris)ortosystemicreleaseofvasoactivepeptides,suchascatecholamines,vanillylmandelicacid,homovanillicacid,and3-methoxy-4-hydroxyphenylglycol.
Encephalopathy,myasthenia,andCushing'ssyndromemaybepresent.
179189Radiographically,amassisseenintheposteriormediastinumwithstippledcalcifications,skeletalerosion,andoccasionalextensionintothespinalcanal.
Pathologyrevealslobulatedgrayorredtumorswithhemorrhagicareas.
Microscopically,smallcellswithscantcytoplasmandpolygonalnucleiexhibitvariousdegreesofdifferentiation.
Intracytoplasmicneurofilamentsandneurosecretorygranulesandextracellularmaterialseenonelectronmicroscopydistinguishneuroblastomafromotherchildhoodtumors,suchaslymphoma,Ewing'ssarcoma,andrhabdomyosarcoma.
160170Neuroblastomasarehighlyaggressivetumors.
Survivaldependsontheageofthepatient,thestageofdisease,thelocationofthetumor,andhistologicdifferentiation.
Theprognosisisbetterinpatientsyoungerthan1yearofageandinpatientswithlimited,well-differentiatedtumors.
Neuroblastomasmayregressspontaneouslyorundergomaturationintoganglioneuromas.
Ganglioneuroblastomashaveabetterprognosisthanneuroblastomas.
180190ThestagingsystemforneuroblastomashowninTable32-13wasdevelopedtohelpguidetherapy.
TreatmentforstageIandIIdiseaseissimplesurgicalresection,althoughadjuvantpostoperativeradiotherapyisrecommendedforstageIItumors.
ForstageIIIandIV,acombinationofchemotherapyandradiationisadvised.
GranularCellTumorGranularcelltumors(granularcellmyoblastomas)areconsideredbenign.
TheyarefoundintheposteriormediastinumandarederivedfromSchwanncells.
Theyaresoft,gray,andpoorlycircumscribedtumorsconsistingofuniformpolygonalcellseitherinnestsorstrandswitheosinophilicgranularcytoplasmandastromaoffibrousconnectivetissue.
181191Resectionisalwayscurative.
DiagnosisAlthoughposteriormediastinalneoplasmsarepredominatelyneurogenic,othertumorsalsomustbeconsideredinthedifferentialdiagnosis.
Goiters,esophagealleiomyomas,solitaryfibroustumors,andbronchial/esophagealduplicationcystsallhavebeenreported.
Onceidentified,thenatureoftheselesions,theirrelationshiptootherstructures,andthepresenceofdistantmetastasescanbedeterminedbyCTscans.
MRIscanscandefinevascularinvolvementandprovidemultiplanarviewsthatarevaluableinassessingtumorextensionintoparavertebralforamina.
Aniodine131nuclearscanmaybehelpfulifagoiterissuspected.
Histologicdiagnosisisnotnecessarybeforesurgery.
However,ifsurgicalresectionisnotcontemplated,adefinitivediagnosisisrequiredforfurthertreatmentplanning.
ThisdiagnosisgenerallyrequiresagenerousbiopsyobtainedbyanopensurgicalprocedureoraCT-guidedcore-needlebiopsy.
ManagementIfnocontraindicationispresent,resectionofallneurogenictumorsisadvised.
Neurogenictumorsgrowandcancauselife-threateningsymptoms,dependingontheirsizeandlocation.
Therefore,observationofneurogenictumorsmaybejustifiedonlywithastable,asymptomatic,benigntumorinanotherwisepoorsurgicalcandidate.
Thestandardapproachusesaposterolateralthoracotomyincision,removingthetumorwithnormaltissuemargins.
Morerecently,thorascopicresectionofsmall-tomoderate-sizetumorshasbeenreported.
192Indumbbelltumors,theintraspinalcomponentshouldberemovedfirst.
Themortalityrateforsurgicalresectionislessthan1%.
ComplicationsincludeHorner'ssyndromeandchylothorax.
Surgeryontumorswithspinalcanalinvolvementmaybecomplicatedbydirectspinalcordtrauma,ischemiafromspinalarteryinjuryand,rarely,anepiduralhematomawithspinalcordcompression.
PrimaryCardiacMalignanciesThevastmajorityoftumorsinvolvingtheheartandpericardiumaremetastatic.
182193,183194Inaddition,mostprimarycardiactumorsarebenignmyxomas,75%to80%ofwhicharisefromtheleftatrium.
Otherbenignprimarycardiacneoplasmsincluderhabdomyoma,fibroma,lipoma,hemangioma,teratoma,andfibroelastoma.
Primarymalignantcardiactumorsmakeupone-fourthofallprimarycardiacneoplasmsandmostcommonlyoriginatefromtheatria.
184195,185196Mostaresomevariantofsarcomas,186197includingangiosarcoma,187198rhabdomyosarcoma,leiomyosarcoma,188199fibrosarcoma,189200lymphoma,malignantfibroushistiocytoma,190201andmesotheliomaofthepericardium.
191202Pheochromocytomasalsooccurasprimarycardiacneoplasms.
Ahighindexofsuspicionisimperativeinestablishingadiagnosis,becausethepresentingsymptomsoftenmimicothernonneoplasticcardiacpathology.
Wholebodygalliumscans,192203echocardiography,CT,andMRIallmayservetolocalizeaprimarycardiacneoplasm.
WiththeadventofEKGgating,MRIhastakentheforefrontinimagingofcardiaclesions.
204Upto80%ofprimarycardiacmalignanciespresentwithsystemicmetastases193metastases205andhaveclinicalevidenceofrightheartfailure,andmanydeveloptamponade.
Surgicalresectionisrequiredforcure;however,negativemarginsusuallyarenotpossible.
194206Chemotherapyandexternal-beamradiationcanbeadministeredaftersurgery,althoughareportof15casestreatedattheInstitutGustave-Roussydoesnotsupporttheroutineuseofadjuvantchemotherapyforprimarycardiacsarcomas.
190201Therehasbeenareportofapatientreceivingneoadjuvant(induction)chemotherapy,whichresultedinaresponseandsubsequentsurgicalresection.
195207Newsurgicaltechniques,includingorthotopicandautotransplantation,maybebeneficialincarefullyselectedpatients.
196208,197209Withtheadventof"gating"technologyandsophisticatedtreatmentplanning,moreaccuratetargetingwithelectronbeamradiationtherapymaybepossible,similartostereotacticradiosurgeryofthebrain.
Attimes,apericardialwindowmayberequiredtopalliatesymptomsofpericardialtamponade.
Currently,long-termsurvivalisrare.
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FIGURE32-1.
Mediastinalcompartments.
FIGURE32-2.
Schwannomaintheparavertebralareaintheapexoftheleftchest.
FIGURE32-3.
A:Malignantneurofibroma,initiallyconsideredtobenonresectable,ina34-year-oldman.
B:Thetumorwasresectedafteracombinationofchemotherapyandradiationtherapy.
TABLE32-1.
AnatomicStructureswithintheMediastinumANTERIORMEDIASTINUMThymusglandInternalmammaryarteryandveinLymphnodesParathyroid(rarely,ifectopic)Thyroid(rarely,ifectopic)MIDDLEMEDIASTINUMHeartandpericardiumAscendingandtransverseaorticarchSuperiorandinferiorvenacavaeInnominatearteryandveinMainandrightpulmonaryarteryPulmonaryveinsTracheaandmainstembronchiPhrenicnervesLymphnodesPOSTERIORMEDIASTINUMEsophagusDescendingaortaSympatheticchainsVagusnervesAzygousandhemiazygousveinsThoracicductLymphnodesTABLE32-2.
ClassificationofMediastinalTumorsNEUROGENICArisingfromperipheralnervesNeurofibromaNeurilemoma(schwannoma)NeurosarcomaArisingfromsympatheticganglionGanglioneuroblastomaGanglioneuromaNeuroblastomaArisingfromparaganglionictissuePheochromocytomaChemodectoma(paraganglioma)GERMCELLSeminomaNonseminomatousPureembryonalcellMixedembryonalcell__Withseminomatouselements__Withtrophoblasticelements__Withteratoidelements__WithendodermalsinuselementsTeratoma,benignHERNIASHiatalMorgagniCYSTSPericardialBronchogenicEntericThymicThoracicductMeningocelesTHYMICThymomaCarcinoidThymolipomaThymiccarcinomaAscendingaorticTransversearchDescendingaorticGreatvesselsMESENCHYMALTUMORSFibroma,fibrosarcomaLipoma,liposarcomaMyxomaMesotheliomaLeiomyoma,leiomyosarcomaRhabdomyosarcomaXanthogranulomaMesenchymomaHemangiomaHemangioendotheliomaHemangiopericytomaLymphangiomaLymphangiopericytomaLymphangiomyomaLYMPHADENOPATHYInflammatoryGranulomatousSarcoidLYMPHOMAHodgkin'sdiseaseHistiocyticlymphomaUndifferentiatedENDOCRINEThyroidParathyroidANEURYSMSAscendingaorticTransversearchDescendingaorticGreatvesselsMESENCHYMALTUMORSFibroma,fibrosarcomaLipoma,liposarcomaMyxomaMesotheliomaLeiomyoma,leiomyosarcomaRhabdomyosarcomaXanthogranulomaMesenchymomaHemangiomaHemangioendotheliomaHemangiopericytomaLymphangiomaLymphangiopericytomaLymphangiomyomaLYMPHADENOPATHYInflammatoryGranulomatousSarcoidLYMPHOMAHodgkin'sdiseaseHistiocyticlymphomaUndifferentiatedENDOCRINEThyroidParathyroidTABLE32-3.
RelativeFrequencyofPrimaryMediastinalTumorsTumorIncidence(%)Neurogenic25.
3Thymoma23.
3Lymphoma15.
3Germcellneoplasm12.
2Endocrinetumor7.
8Mesenchymaltumor7.
3Primarycarcinoma5.
7Other2.
9(Adaptedfromref.
2,withpermission.
)TABLE32-4.
DistributionofPrimaryMediastinalMassesbyAnatomicLocationANTEROSUPERIORMEDIASTINUMThymicneoplasmsLymphomasGermcelltumorsCarcinomaCystsMesenchymaltumorsEndocrinetumorsMorgagniherniasMIDDLEMEDIASTINUMCystsLymphomasMesenchymaltumorsCarcinomaHiatalherniaSarcoidosisPOSTERIORMEDIASTINUMNeurogenictumorsCystsMesenchymaltumorsEndocrinetumorsEsophagealmassesHiatalherniaAorticaneurysmsTABLE32-5.
RelativeFrequencyofPrimaryMediastinalTumorsinAdultsandChildrenTumorIncidence(%)AdultsChildrenThymic3128Neurogenic1547Lymphoma269Germcell159Vascular16Miscellaneous132(Adaptedfromref.
4,withpermission.
)TABLE32-6.
DiagnosticEvaluationofMediastinalMassesHISTORYANDPHYSICALEXAMINATIONRADIOGRAPHY_Standardchestradiography_Computedtomographicscanning_Bariumswallow_Radioisotopescanning_Angiography_Myelography_Ultrasonography_MagneticresonanceimagingENDOSCOPYSEROLOGYNEEDLEBIOPSYPROCEDURES_Computedtomographyguided_UltrasoundguidedSURGICALPROCEDURES_Mediastinoscopy_Mediastinotomy_ThoracotomyTABLE32-7.
SymptomsandSignsofMediastinalMassesSYMPTOMChestpainDyspneaCoughFatigueDysphagiaNightsweatsHemoptysisHoarsenessSIGNWeightlossFeverAdenopathyWheezing,stridorSuperiorvenacavasyndromeVocalcordparalysisNeurofibromatosisNeurologicabnormalitiesPericardialtamponadeArrhythmiasTABLE32-8.
SystemicSyndromesAssociatedwithMediastinalNeoplasmsTumorSyndromeThymomaAcutepericarditis,Addison'sdisease,agranulocytosis,alopeciaareata,Cushing'ssyndrome,hemolyticanemia,hypogammaglobulinemia,limbicencephalopathy,myastheniagravis,myocarditis,nephroticsyndrome,panhypopituitarism,perniciousanemia,polymyositis,pureredcellaplasia,rheumatoidarthritis,sarcoidosis,scleroderma,sensorimotorradiculopathy,Stiff-personsyndrome,thyroiditis,ulcerativecolitisHodgkin'sdiseaseAlcohol-inducedpain,Pel-EbsteinfeverNeurofibromavonRecklinghausen'sdisease,osteoarthritisThymiccarcinoidMultipleendocrineneoplasiaNeuroblastomaOpsomyoclonus,erythrocyteabnormalitiesNeurilemomaPepticulcerTABLE32-9SystemicManifestationsofHormoneProductionbyMediastinalNeoplasmsSymptomsHormoneTumorHypertensionCatecholaminesPheochromocytoma,chemodectoma,neuroblastoma,ganglioneuromaHypercalcemiaParathyroidhormoneParathyroidadenomaThyrotoxicosisThyroxineThyroidCushing'sACTHCarcinoidtumorsyndromeGynecomastiaHCGGermcelltumorHypoglycemiaInsulinMesenchymaltumorsDiarrheaVIPGanglioneuroma,neuroblastoma,neurofibromaACTH,adrenocorticotropichormone;HCG,humanchorionicgonadotropin;VIP,vasoactiveintestinalpolypeptide.
TABLE32-10.
WorldHealthOrganizationStagingSystemforThymicEpithelialTumorsTumorTypeCellsClinicopathologicClassificationHistologicTerminologyASpindleorovalBenignthymomaMedullaryBEpithelioidordendriticCategoryImalignantthymomaCortical;organoid__B1Lymphocyte-rich;predominatelycortical__B2Cortical__B3Well-differentiatedthymiccarcinomaABBenignthymomaMixedCCategoryIImalignantthymomaNonorganotypic;thymiccarcinoma,epidermoidkeratinizingandnonkeratinizingcarcinoma,lymphoepithelioma-likecarcinoma,sarcomatoidcarcinoma,clearcellcarcinoma,basaloidcarcinoma,mucoepidermoidcarcinoma,undifferentiatedcarcinomaTABLE32-11.
ThymomaStagingSystemofMasaokaStageDescriptionIMacroscopicallycompletelyencapsulatedandmicroscopicallynocapsularinvasionIIMacroscopicinvasionintosurroundingfattytissueormediastinalpleuraMicroscopicinvasionintocapsuleIIIMacroscopicinvasionintoneighboringorgans(pericardium,greatvessels,lung)IVaPleuralorpericardialdisseminationIVbLymphogenousorhematogenousmetastasis(Fromref.
60,withpermission.
)TABLE32-12.
ThymomaStagingSystemofGrouped'EtudesdesTumeursThymiquesStageDescriptionI__IaEncapsulatedtumor,totallyresected__IbMacroscopicallyencapsulatedtumor,totallyresected,butthesurgeonsuspectsmediastinaladhesionsandpotentialcapsularinvasionIIInvasivetumor,totallyresectedIII__IIIaInvasivetumor,subtotallyresected__IIIbInvasivetumor,biopsyIV__IVaSupraclavicularmetastasisordistantpleuralimplant__IVbDistantmetastases(Fromref.
63,withpermission.
)TABLE32-13.
StagingSystemforNeuroblastomaStageDescriptionITumorislimitedtositeoforigin.
IITumorextendsbeyondsiteoforigin,orwhenlimitedtositeoforigin,hasmetastaticregionallymphnodespresentonsameside.
IIITumorextendstocontralateralside.
IVMetastasesarepresentbeyondregionallymphnodes.