小细胞肺癌合并高血钙及急性肾衰竭.docx
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小细胞肺癌合并高血钙及急性肾衰竭
Smallcelllungcancerwithhypercalcemiaandacuterenalfailure:
anuncommoncomplicationandliteraturereview
Yen-HungYao1,Sung-HuaChuang1,Wu-ChangYang1,NgYee-Yung1
1DivisionofNephrology,DepartmentofMedicine,TaipeiVeteransGeneralHospital
Runningtitle:
Smallcelllungcancerandhypercalcemia
Correspondenceshouldbeaddressedto:
Yee-YungNg,MD.
DivisionofNephrology,DepartmentofMedicine,TaipeiVeteransGeneralHospitalNo.201,Sec.2,Shih-PaiRoad,Taipei112,Taiwan
Tel:
886-2-2871-2121ext2993;Fax:
886-2-28204735
E-mail:
yyng@vghtpe.gov.tw
Adressforreprintrequests:
TaipeiVeteransGeneralHospitalNo.201,Sec.2,Shih-PaiRoad,Taipei112,Taiwan
小細胞肺癌合併高血鈣及急性腎衰竭
高血鈣常見於乳癌、鳞狀細胞肺癌、及多發性骨髓瘤等病患,但少見於小細胞肺癌。
各種細胞型態的肺癌,包括小細胞肺癌,均有相當高比例會分泌副甲狀腺荷爾蒙相關蛋白(Parathyroidhormone-relatedprotein,PTHrP)。
不同細胞型態的肺癌合併高血鈣的發生率各異,這可能與PTHrP的分泌型態或速度不同有關。
文獻報告小細胞肺癌引發高血鈣的機會與腫瘤大小有關。
此外,我們回顧有關小細胞肺癌合併高血鈣(>12mg/dL)的個案報告,發現病患均有骨轉移。
本文報導一位小細胞肺癌病患,腫瘤迅速擴大且合併骨轉移,於住院中發生高血鈣與急性腎衰竭,最後過世。
雖然小細胞肺癌患者甚少發生高血鈣,若腫瘤體積較大或合併骨轉移時,臨床醫師仍需追蹤血鈣濃度,以及早診斷高血鈣並預防其併發症。
關鍵字:
小細胞肺癌,高血鈣,骨轉移
Abstract
Hypercalcemiaisrelativelycommoninpatientswithmalignancies,especiallybreastcancer,squamouscelllungcancerandmultiplemyeloma,butuncommoninpatientswithsmallcelllungcancer.Actuallyalltypesoflungcancerhavehighincidenceofabnormalparathyroidhormone-relatedprotein(PTHrP)secretion,includingsmallcelllungcancer.ThedifferentincidenceofhypercalcemiabetweensquamouscellandsmallcelllungcancersmayresultfromdifferentpatternsorratesofPTHrPsecretion.Besides,patientsofsmallcelllungcancerwithserumcalciumlevelgreaterthan12mg/dLusuallyhadconcurrentbonemetastasisorlargertumorburden.Wereportapatientofsmallcelllungcancerwithlargetumorburdenandextensivebonemetastases.Thepatientsufferedfromhypercalcemiawithacuterenalfailureandwasexpiredsoonafterthediagnosiswasmade.
Insummary,althoughhypercalcemiaisuncommonamongpatientswithsmallcelllungcancer,thiscomplicationshouldbekeptinmindwheneverweencounteracuterenalfailureinthesepatients.Serumcalciumshouldbemonitoredregularlyinwhohavelargetumorburdensorbonymetastasesinordertodiscoverhypercalcemiaearlyaswellaspreventrelatedacuterenalfailureandothercomplications.
Keywords:
smallcelllungcancer,hypercalcemia,bonemetastasis
Introduction
Hypercalcemiaisarelativelycommonparaneoplasticsyndromeinpatients
withbreastcancer,squamouscelllungcancer,ormultiplemyeloma,butuncommoninpatientswithsmallcelllungcancer.Wepresentacaseofsmallcelllungcancercomplicatedwithhypercalcemiaandacuterenalfailure,andreviewtheliteraturesabouthypercalcemiainsmallcelllungcancer.
CaseReport
A35year-oldmalepatientwasfoundtohavearightlungmassbyachestplainfilminMarch2008.HewasadmittedinJuly2008duetoprogressivelowbackpainfor3months.Onadmission,hisvitalsignswerestable,andphysicalexaminationsrevealedknockingpainoverthelowerback.Bloodtestsdisclosed:
whitebloodcellcount10100/mm3,hemoglobin13.4g/dL,plateletcount251000/mm3,bloodureanitrogen(BUN)18mg/dL,creatinine(Cr)0.96mg/dL,albumin3.8g/dL,calcium10.6mg/dL,phosphate4.6mg/dL.Thechestplainfilmdemonstrateda6.3cmx6.1cmmassoverrightlowerlungfield(Figure1A),andthechestcomputedtomography(CT)showeda6.2x6.1cmmasslesionattherightlowerlobeoflungwithencasementofrightlowerlungbronchus,mediastinallymphadenopathyandbonemetastases.TheCTscanoflumbarspinerevealeddiffusebonymetastasesatvertebra,rightsacrum,andleftiliacbones,withpathologicfractureofthethirdlumbarvertebrabody(Figure2).Therefore,heunderwenttotallaminectomyofT10andL3aswellasinternalfixationoverT9-11andL2-5levelstorelievebonepainandspinalcordcompression.Thepathologicexamofspecimenfromhisvertebraandsurroundingsofttissueshowedmetastaticsmallcellcarcinoma.Oneweekafteroperation,serumBUNandCrlevelswereelevated(BUN45mg/dL,Cr2.08mg/d),andthetumormasswasenlargedto8.3cmindiameterinthechestplainfilm(Figure1B).Fivedayslater,consciousnessdrowsinesswasnoted.Theresultsofbloodtestswereasfollows:
albumin3.4g/dL,calcium21mg/dL,phosphate4.4mg/dL,alkalinephosphatase541U/L,BUN79mg/dLandCr5.28mg/dL.SerumlevelofintactPTHwas2.71pg/mL(normalrange<50pg/mL).
Afterhydrationwithintravenousisotonicsalineand3coursesofhemodialysis,thepatient’sserumcalciumleveldecreasedto11.1mg/dL,andconsciousnessrecovered.Unfortunately,thepatientdiedfrommassiveuppergastrointestinalbleedingthreeweekslater.
Discussion
Hypercalcemiaisacommonparaneoplasticsyndrome,whichoccursinabout20%ofpatientswithcancer.1Themostcommonmalignanciesthatcauseparaneoplastichypercalcemiaarebreastcancer,squamouscelllungcancer,andmultiplemyeloma.1,2Generally,therearethreemechanisms1ofhypercalcemiainpatientswithcancer.Firstly,osteolyticmetastasesreleaselocalcytokines,suchastumornecrosisfactor,interleukin-1,andosteoclastactivatingfactors.Secondly,sometumorcellssecretecalcitriol.Thefinalandmostimportantmechanismisparathyroidhormone-relatedprotein(PTHrP)3,4secretedbytumorcellsthemselves.PTHrPisundoubtedlythemostcommoncauseofhypercalcemiainpatientswithnonmetastaticsolidtumors(so-calledhumoralhypercalcemiaofmalignancy,HHM),andaccountsforabout80%ofmalignancy-associatedhypercalcemia.3Tumor-derivedPTHrPstimulatesosteoclasticresorption,withreleaseofbone-derivedgrowthfactors(ex:
TGF-β)whichacceleratetumorgrowthandsubsequentPTHrPexpression.Thisprocessesbecomeaviciouscircle.3,4
It’swell-knownthathumoralhypercalcemiaofmalignancyiscommoninpatientswithsquamouscelllungcancer,butrareinthosewithadenocarcinomaorsmallcelllungcancer,despitethefactthatincidencesofPTHrPsecretionandlyticbonemetastaseswerehighinbothcancers.5-10Infact,accordingtothestudyofL.A.Davidsonetal,9themajorityoflungcancershavePTHrPexpressedinthetumortissues(100%insquamouscellcarcinoma,95%inadenocarcinoma,84%insmallcelllungcancer,and93%incarcinoid).Whatmechanismsleadtodifferentincidencesofhypercalcemiaamongdifferenttypesoflungcancer?
ThereasonswhysomemalignanciescauseelevatedPTHrPsecretionbutnothypercalcemiainclude:
peptidelevelsnothighenoughtoraiseserumcalcium,increasedrateofpeptidebreakdown,orpeptidewithoutappropriatebiologicalactivity.Inaddition,PTHrPmayneedsynergesticeffectsofothertumor-derivedgrowthfactorsorcytokinestocausehypercalcemia,andtheremaybesomecounter-regulatorysubstancesinvolvedinthisprocess.5Furthermore,tumorspecificposttranslationalmodificationofPTHrPmaybeimportantinthesynthesisofspecificmolecularformsofPTHrPwithhypercalcemicactivity.5,11Inbrief,oneormoreabovementionedmechanismsmightleadtoheterogeneityofPTHrPeffectsamongdifferentcellstypesoflungcancer,whichhavedifferentabilitytoaltercalciummetabolism.SerumPTHrPlevelwasnotcheckedinthiscase,becausethismeasurementisusuallynotnecessaryfordiagnosisconsideringmostpatientshaveclinicallyapparentmalignancy,especiallyifotherfactorspredisposinghypercalcemiacouldbeexcluded,suchasdehydrationoruseofthiazidediuretics.
WemadeasearchinPubmedandcollectcasereportsofpatientswithconcurrentsmallcelllungcancerandhypercalcemia(greaterthan12.0mg/dL).(Table1)12-17Includingourpatient,therearetwelvepatientsreported,andallofthemhadbonemetastasis.Incontrast,BenderRA’sreport10pointedoutthatosseousinvolvementwasdetectedonlyin66%ofpatientsofsmallcelllungcancerwithnormalcalciumlevel.Theserumcalciumlevelofcase5(Table1)was10.8mg/dLinitiallywhiletherewasnobonemetastasis;thelevelroeto12.0mg/dLsixmonthslaterwhenbonemetastasesoccurred.Hence,inadditiontohumoralmechanism,multiplelyticbonemetastasesmightcontributetothehypercalcmeiaandacuterenalfailureinourpatient.Thetumorinthispatientgrewrapidlyfrom6cmto8cmindiameteramongtwoweeks,atthesametimehypercalcemiawasdeveloping.Thisiscompatiblewithpreviousreportthathypercalcemiawasusuallyassociatedwithlargertumorburdensandshortersurvival.18Althoughhypercalcemiawascorrected,ourpatientdiedwithinthreeweeks.
Inthispresentedcase,hypercalcemiawithacuterenalfailureoccurredsoonaftertheorthopaedicsurgeryforspinalcompressionandpathologicfracture.Itisnotclearifthereisanyassociationbetweenhypercalcemiaandorthopaedicsurgery.Prophylacticsurgicalcorrectionofbonemetastasesisindicatedforimpendingfractureofweight-bearingbones,2andthereisnoreportofhypercalcemiaassociatedwithsurgicalmanagementofspinalmetastasis.Hence,hypercalcemiaofthiscaseisnotlikelytoberelatedtothedecompressiveoperation.
Insummary,hypercalcemiainpatientswithsmallcelllungcancerisrelatedtomultifacetedfactorssuchasPTHrP,bonymetastasisandtumorsize.Inthiscase,serumcalciumwasnotfolloweduntilhisconsciousnesschanged.Therefore,thiscaseremindsustomonitorserumcalciumfrequentlyinpatientswithhugesmallcelllungcancerandbonymetastasisinordertodiscoverhypercalcemiaearlyandtopreventassociatedacuterenalfailureorneurologicmanifestation.
Conflictofintereststatement.Nonedeclared.
Reference
1.AndrewF.Stewart:
Hypercalcemiaassociatedwithcancer.NEnglJMed2005;352:
373-379.
2.GAClines,TAGu