小细胞肺癌合并高血钙及急性肾衰竭.docx

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