Rare large cell neuroendocrine tumor of the endometrium: A case report and review of the literature

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ContentslistsavailableatSciVerseScienceDirect

International

Journal

of

Surgery

Case

Reports

j o u r n al ho me p a g e : w w w . e l s e v i e r . c o m / l o c a t e / i j s c r

Rare

large

cell

neuroendocrine

tumor

of

the

endometrium:

A

case

report

and

review

of

the

literature

My-Linh

T.

Nguyen

a,∗

,

Liying

Han

b

,

Anjoinette

M.

Minors

a

,

Stuart

Bentley-Hibbert

c

,

Tana

S.

Pradhan

a,d

,

Tara

L.

Pua

a,d

,

Sean

S.

Tedjarati

a,d

aDepartmentofObstetricsandGyencology,NewYorkMedicalCollege,UnitedStates bDepartmentofPathology,NewYorkMedicalCollege,UnitedStates

cDepartmentofRadiology,NewYorkMedicalCollege,UnitedStates dDivisionofGynecologicOncology,NewYorkMedicalCollege,UnitedStates

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received11April2013 Accepted15April2013 Available online 3 May 2013 Keywords: Largecell Neuroendocrinetumor Endometrialcancer Synaptophysin Chromogranin CD56

a

b

s

t

r

a

c

t

INTRODUCTION:Largecellneuroendocrinecarcinoma(LCNEC)oftheendometriumisararemalignancy

withanaggressivecourse.Althoughdataislimitedtocasereports,theprognosisappearstobepoor,

similartoothertypeIIuterinecancers.Atotalof12casesofLCNECoftheuterushavebeenpublishedto

date.

PRESENTATIONOFCASE:A71year-oldwomanpresentedwithpostmenopausalvaginalbleeding.

Endome-trialbiopsywasnon-diagnosticforLCNEC.Sheunderwentsurgicaldebulkingandstagingofa22cm

endometrialtumorwithomentalmetastasisandpositivelymphnodes.HerfinalFIGOstagewasIVB.

DISCUSSION:WesummarizeallpriorcasereportsofLCNECoftheendometriumanddiscussthe

defini-tion,presentation,imagingandsurgicalmanagement.Thepathologywithimmunohistochemicalreview,

adjuvanttherapyandprognosisofLCNECoftheendometriumarealsoreviewed.

CONCLUSION:Pathologicfindingsandimmunohistochemistryareessentialinmakingadiagnosisof

LCNECoftheendometrium.Primarydebulkingandsurgicalstagingistypicallyperformed, butifa

diagnosisofLCNECcanbemadepreoperativelywithimmunohistochemistry,surgeonsshouldconsider

neoadjuvantchemotherapyduetoitshighgradehistologyandaggressivecourse.Otherwiseadjuvant

chemotherapyisusuallygiven.Evenwithearlystagedisease,theprognosisseemspoor.Duetotherarity

ofthisaggressivemalignancy,moredataisneededtoestablishincidence.

©2013 Surgical Associates Ltd. Published by Elsevier Ltd.

1. Introduction

Large cell neuroendocrine carcinoma (LCNEC) of the endometrium is a rare malignancy with an aggressive course. Althoughdata islimited tocase reports, theprognosisappears to be poor,similar to other type II uterine cancers. A total of 12 casesofLCNEC of theuterus,notincludingours, havebeen publishedintheEnglishliterature(Table1).1–7 Herewediscuss

theclinicalcourseofa71year-oldwomanwithwidelymetastatic disease.

2. Casepresentation

A71year-oldCaucasianfemale,withaBMIof44,presented withher firstepisode of postmenopausal vaginal bleeding. She

∗ Correspondingauthorat:DepartmentofObstetrics&Gynecology,NewYork MedicalCollege,MungerPavilion,Room617,Valhalla,NY10595,UnitedStates. Tel.:+14082021927;fax:+19145944775.

E-mailaddresses:Miminguyen17@gmail.com,dr.miminguyen@gmail.com

(M.-L.T.Nguyen).

underwentanendometrialbiopsywhichrevealedextensive necro-sisandapoptosis.Tumorcellswerediffuselypositiveforvimentin, desmin,andKi67,whilenegativeforAE1/AE3,CD10andSMA.The differentialdiagnosisfrombiopsyincludedundifferentiated sar-coma,poorlydifferentiatedadenocarcinomaandmalignantmixed mulleriantumor.

MRIrevealedauterusmeasuring19.5cm×13.1cm×12.3cm withcompletelossofusualmyometrialarchitecturewithincreased T2signalattheinfiltrativelesion(Fig.1A–D).Themassappearedto involvetheentiremyometriumandappearedtoextendalongthe rightfallopiantubesurroundinga7.4cmmyomalyinginthebroad ligament.Theendometrialechowasthickenedto3.5cm contain-ingheterogeneousdebris.Nodefiniteextensiontoparametriawas seenonMRI.A3.1cm×2.5cmleftexternaliliaclymphnodewas enlargedalongwitha1.9cm×2.4cmparaaorticnode,whichboth appearedconcerningformetastasis.

Twoweekslater,thepatientunderwentanexploratory laparo-tomy,radicalhysterectomy,debulkingofaretroperitonealtumor, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph nodedissection,bilateralureterolysis,omenectomy,andresection oftheposteriorbladderwallwithrepair.Intraoperatively,alarge primary tumorapproximately 25cm in sizeextruded from the

2210-2612 © 2013 Surgical Associates Ltd. Published by Elsevier Ltd.

http://dx.doi.org/10.1016/j.ijscr.2013.04.027

Open access under CC BY-NC-ND license.

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Case Year Author Age Surgery Stage Histology Treatment Immunoprofile positivity

Outcome (months)

1 2004 Erhan 52 TAH,BSO ICa PureLCNEC RT,Cis,Eto NSESNP DOD3

2 2007 Mulvany 50 TAH,BSO,

OMY,LN

IIIC PureLCNEC RT,Cis,Eto NSESNP AWD12

3 2007 Mulvany 80 TAH,BSO,LN ICa LCNEC+endometrioid NFT NSECGA DOD5

4 2007 Mulvany 77 TAH,BSO IIBa LCNEC+endometrioid RT NSESNPCGACD56 DOD23

5 2007 Mulvany 79 TAH,BSO,

omentalbx, peritoneum

IIIA LCNEC+endometrioid RT NSECGACD56 AWD2

6 2007 Mulvany 88 TAH,BSO,LN IIIC LCNEC+SCNEC

+endometrioid

RT NSECGACD56 AWD1

7 2008 Albores-Saavedra 42 RH ICa PureLCNEC Cis,Eto SNPCGACD56 AWD9

8 2010 Terada 40 TAH,BSO,

PLND,OMY

IB LCNEC+sarcomatoid None SNPCD56 AWD16

9 2011 Deodhar 70 TAH,BSO,OMY 1B PureLCNEC Cis,Eto SNPCGACD56 AWD6

10 2011 Shahibi 59 TAH,BSO,OMY,

PPALND,APPY

IIIC2 PureLCNEC Carbo,Taxol,

RT. Doxil. Cis,Eto,Oct

NSESNPCGACD56 DOD12

11 2012 Makihara 73 None IVB PureLCNEC NFT NSESNPCGA DOD1

12 2012 Makihara 73 TAH,BSO,

OMY,PPALND

IIIC1 PureLCNEC Cis,Iri SNPCGACD56 AWD13

13 2013 Presentcase 71 RH,BSO,OMY,

PPALND

IVB PureLCNEC PlannedCis,

Eto,Oct

SNPCGACD56 DOD1

TAH=Total abdominal hysterectomy, BSO=Bilateral salpingoophorectomy, OMY=Omentectomy, RH=Radical hysterectomy, PLND=Pelvic lymph node dissec-tion,PPALND=Pelvic and paraaortic lymph node dissection, APPY=Appendectomy, RT=Radiotherapy, NFT=No further treatment, Cis=Cisplatin,Eto=Etoposide, Carbo=Carboplatin,Oct=Octreotide,Doxil=Pegelateddoxorubicin,Iri=Irinotecan,NSE=Neural-specificenolase,SNP=Synaptophysin,CGA=ChromograninA,DOD=Dead ofdisease,AWD=Alivewithdisease

a1998FIGOstaging.

Fig.1. Sagittal(A)andcoronal(B)T2weightedimageswithoutfatsaturation throughthepelvisdemonstratesabnormaldiffuselyinfiltrativehigh T2signal throughoutthemyometriumwithlossofthenormalarchitecture.Roundedmass lesionswithdecreasedT2signalwithinthemyometriumrepresentleiomyomas. Heterogeneoussignalwithintheendometrialcanalislikelydebris.Axialdiffusion weightedimages(C)andaxialT2-weightedimageswithfatsaturation(D) redemon-strateddiffuselyinfiltrativeprocesswithincreasedsignalonerestricteddiffusion imagessuggestiveofahypercellularstaterestrictingthemotionofwatermolecules. Theprocesscanbeseentoextendalongthebroadligamentontheleftsurrounding abroadligamentleiomyoma.

uterusandinvolvedthesmallbowelmesenterywithbulkylymph nodesmeasuringupto4cmNogrossresidualdiseasewasnotedat theendoftheprocedure.

Ongrosspathologicexam,theuterusweighed2120gand mea-sured22cminwidestdiameter.Theendometrialcavitywasfilled

withnecrotic-hemorrhagicmaterialandshowedafriable,polypoid massattachedtotheanteriorfundus(Fig.2A).Thetumorinvolved thefullthicknessofthemyometriumaswellasthecervix, bilat-eralovariesandtubes.Theuppervaginaandbilateralparametria werealsoinfiltratedbytumorandlymphovascularspaceinvasion waspresent.Oneof18pelviclymphnodesandoneof13 paraaor-ticlymphnodeswerepositiveformetastasis.Theomentumwas diffuselyinfiltratedbytumor.HerfinalFIGOstagewasIVBdueto omentalinvolvement.

Microscopically,thetumorwaspoorlydifferentiated(Fig.2B and C). Immunohistochemical stains confirmed the diagnosis of a large cell neuroendocrine carcinoma of the endometrium (Table2).Synaptophysin,chromograninA(CGA),andCD56were diffuselyandstronglypositiveneuroendocrinemarkers.P53and

Table2

IHCprofileofpresentcase.

Antibody Markerfor Results

CK7 Cytokeratin7 Negative

AE1/3 CytokeratinAE-1/AE-3cocktail Negative

EMA Epithelialmembraneantigen Negative

CK8/18 CAM5.2Ck,LMW Negative

VIMENTIN Vimentin Focalpositive

CD10 CD10 Negative

SYN Synaptophysin Diffusestronglypositive

CHRO Chromogranin Diffusepositive

CD56 CD56 Diffusestronglypositive

P53 Oncoprotein 70%;3+

P16 Dysplasticepithelialcell 90%;3+

ER Estrogenreceptor Negative

PR Progesteronereceptor 70%;2+

S100 S100 Negative

HMB45 Humanmelanoma Focalpositive

MYOGENIN Myogenin Negative

DESMIN Desmin Negative

CD45 CD45 Negative

CD3 Tcell Negative

CD20 Bcell Negative

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Fig.2.(A)Uterusandcervixshowsmarkedthickened,yellow-tan,fleshywallsandasubserosal,calcifiednoduleontheupperside.Theendometrialcavityisfilledwith necroticandhemorrhagicdebris.(B)Sheetsofthetumorcells.H&E100×.(C)Tumorcellsarearrangedinsheetswithoutadefinedborder.Individualcellsarelargewith highnuclear/cytoplasmicratios,prominentnucleoli,andamphophilliccytoplasm.Numerousmitoticfiguresandapoptoticbodiesareseen,aswellasmultiple,interspersed areasofnecrosis.H&E400×.

Fig.3.Positiveimmunohistochemicalstains(Synaptophysin,Chromogranin,CD56, P53,P16andPR).

P16revealed70–90%stainingwith3+intensity,estrogen recep-tor(ER) wasnegative, progesterone receptor (PR)was positive (Fig.3).

Postoperatively, the patient’s course was complicated by a superficialwoundinfectionandseparation.Shewastreatedwith antibiotics,discharged home,and wasplannedtoreceive com-binationchemotherapywithetoposide,cisplatinand octreotide. On the 32nd post-operative day,she expired due to recurrent malignantascitesandacuterenalfailuresecondarytoher malig-nancy.

3. Discussion 3.1. Definition

LCNECisanextremelyraremalignancyoftheuterus,mostoften foundinthecervixand/orovariesandmorecommonlyofthesmall cellneuroendocrinetype.TheWHOdefinessmall-cellcarcinomaas anundifferentiatedcarcinomawithcellularandnuclearfeatures whichincludesmall-sizedcells,scantcytoplasm,hyperchromatic, finelygranularandmoldednucleiand inconspicuousnuclei.4 In

contrast,largecellcarcinomaisdefinedasundifferentiatedlarge cellsthatlackcytologicandarchitecturalfeaturesofsmallcell car-cinomaandglandularorsquamousdifferentiation.4Moresimply,

LCNECaredefinedasmalignanttumorscomposedoflargecells thatshowneuroendocrinedifferentiation.6Allreportedlargecell

carcinomasoftheuterushavecontainedneuroendocrinefeatures.

3.2. Presentation

ThemedianageatdiagnosisforallcasesofendometrialLCNEC is71years(range40–88years).Inthecurrentcase,the71-year old patientpresentedwithpostmenopausal vaginal bleedingas wascommonamongallpriorreports.Onendometrialsampling, the biopsywasnot suggestive of a neuroendocrinecarcinoma; theusualdifferentialdiagnosisforsuchaspecimenincludestype 2 tumors such as undifferentiated carcinoma or mesenchymal tumors such as sarcoma or mixed mullerian tumor based on immunohistochemicalstaining.

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Preoperatively,imagingwasobtainedtoevaluateformetastatic disease.PreoperativeMRI,performedwithoutintravenous gadolin-iumsecondarytothepatient’srenalfunction,demonstrateddiffuse abnormalinfiltrativemyometrialsignalthroughouttheuteruswith lossofthenormaluterinearchitecture.Thisdiffuselyinfiltrative process extended along the broad ligament to theleft adnexa anddemonstrated restricteddiffusionsuggestive ofa hypercel-lularprocess.Conglomeraterightexternaliliaclymphadenopathy andparaaorticlymphadenopathyalsowithrestricteddiffusionwas present.Thesefindingsweresuggestiveofauterinesarcoma.

InanotherreportbyMakiharaetal.,theMRIfindingsofLCNEC seemtomimicMRIfindingsfoundinotherpoorlydifferentiated endometrialadenocarcinomasanduterinesarcomas.7A

gyneco-logicexam,endometrialsamplingandMRIshouldbeincludedin theinitialworkupofasuspecteduterineLCNEC.

3.4. Surgicalmanagement

The most common initial management of LCNEC is cytore-ductive surgery, based on prior published reports. Typically, a hysterectomyandbilateralsalpingo-ophorectomyareperformed atminimum.Inonereportedcasewhereabiopsyconfirmedwidely metastaticdisease,thepatientdidnotundergosurgeryanddied.7

A post-mortem autopsy then confirmed LCNEC of the uterus.7

Althoughseveralcasereportshavenotedanearlystageatthetime ofsurgery,manyofthesepatientswentontohavedistant metasta-sisand/orrapidrecurrence.IncaseswhereonlyTAHandBSOwere performedwithoutlymphnodedissection,stageIIIdiseasemay havebeenmissed.Though thereisnosurgicalstandardfor this rarehistology,mostpatientswillundergohysterectomypresumed highgradesarcomaorcarcinomathatisinfactLCNEC.IfaLCNEC canfeasiblybediagnosedonapreoperativeendometrialbiopsyor curettagespecimen,providersmaywanttoconsiderneoadjuvant therapyversusprimarysurgeryasis doneinadvanced casesof ovariancancer.Althoughcompletesurgicalstagingwith omentec-tomyandpelvicandparaaorticlymphadenectomyisrequiredfor accuratestagingofuterinecancer,treatingphysiciansmaywant toassesthepatient’sresponsetochemotherapyfirst,sincesurgery hasnotbeenproventobeentirelybeneficialinmostcases. 3.5. Pathology

BecauseLCNECcansometimesbemixedwithother histolog-icaltypes,theycanbeeasilydismissedaspoorlydifferentiated endometrioidcarcinomasandarelikelyunderreported. Histogeni-cally,LCNECoftheuterusmostlikelyarisesfromneuroendocrine cellsoftheendometrium.1Grossly,thetypicalfindingisapolypoid

massconfinedtotheendometriuminstage1disease.1–5The

patho-logicfeaturestypicallyincludehighgradescantstroma,ulceration, extensivetumornecrosis,anda trabecular,organoid,palisading orrosette-likegrowthpattern.1–3,5 Inthemajorityofcases,the

followingcellularfeaturesofabundantcytoplasmwithagranular eosinophilicorbasophilicappearance,largenuclei,smallbut fre-quentnucleoliandmitoticrates>10per10HPFwereobserved.1–7

3.6. Immunoprofile

The most useful tool for diagnosing uterine LCNEC is the immunohistochemicalprofile.Neuroendocrinedifferentiationin LCNECof theuteruscan beconfirmedbystaining for synapto-physin,chromograninandCD56.Asummaryofpreviousreports suggests that two of the three tumor markers may confirm a diagnosis of LCNEC. Cervical LCNEC may express neuroen-docrinemarkerswithapproximately25to38%ofcasesexpressing

liercasereportssuggestthatneuron-specificenolase(NSE)maybe asensitivemarkerbutmaynotbeasusefulfordiagnosis.1,2,7

3.7. Adjuvanttherapy

In previous reports on uterine LCNEC, adjuvant chemotherapy1–3,5–7and/orradiation1,2,6waseitherperformedor

planned.ThereislimiteddatatoguidetreatmentforLCNECofthe uterusorcervix.NoprospectivetrialsexistforuterineLCNECor evenforSCNECofthecervix.Currentlythereisnoconsensusasto theoptimalmanagementofthesetumors.LikeLCNECofthecervix, LCNECoftheendometriumrequiresa multi-modalityapproach. Most physicians will favor surgery, followed by chemother-apy,radiationorboth. Thepatientin thisreportwasoptimally debulkedtonogrossresidualdisease,butshestillrecurredwithin onemonthofsurgeryandsuccumbedtoherdisease.Octreotide, asyntheticsomatostatinanalog,wasplannedforthepatientin thepresentcase.Twoothercasereportshavereporteditsusefor neuroendocrinetumors,onecasedemonstratingapartialresponse andtheotherwithprogressionofdisease.6,13Giventhisaggressive

course and poor prognosis, perhaps surgeonswho are able to preoperativelydiagnoseLCNECoftheendometriumshould con-siderneoadjuvantchemotherapyand/ortherapywithoctreotide prior to surgery. Platinum and Etoposide based chemotherapy is generally used as adjuvant therapy, and this data is largely extrapolatedfromSCNECofthelungsincedataforcervicaland uterineneuroendocrinetumorsislimited.14

3.8. Prognosis

Evenforearlystages,LCNECoftheendometriumappearstohave anaggressivecoursewithastrongpropensityfordistantmetastasis andrapidrecurrence.NoprognosticdataisavailableforLCNECof theuterusorcervix.Thebestavailablesurvivaldataisfromsmall cellneuroendocrinecarcinoma(SCNEC)ofthecervix.Onesmall, retrospectivestudyshowedthattheestimated3-yearprogression freesurvival(PFS)andoverallsurvival(OS)ratesforcervicalSCNEC were22%and30%,respectively8.Themediantimetoprogression

was9.1monthsand theextentofdiseasewastheonly signifi-cantprognosticfactor.8Inthesamestudy,patientswhoreceived

platinum-basedchemotherapyhadbotha3-yearrecurrence-free survival(RFS)anda3-yearoverallsurvival(OS)of83%.8Inpatients

whodidnotreceivechemotherapy,theRFSandOSwere0%and 20%,respectively.8Inourreviewofallreportedcasesofuterine

LCNEC,sixoutof13patientsdiedoftheirdisease.Ofthesesix, onlytworeceivedchemotherapyand fourweredeadofdisease byfivemonths,twoofwhomwereearlystage(IC)atdiagnosis (Table1).Ofthesevenpatientswhoarereportedtobealivewith LCNEC,fourreceivedplatinum-basedchemotherapy,tworeceived radiotherapyonly,andonereceivednofurthertreatment(Table1). Ofall13reportedcases,eightpatientspresentedwithadvanced FIGOstageIIIorIVdisease.Baseduponthesereportedcases,there maybesomebenefittochemotherapyinLCNEC.Again,providers mayconsideradministeringneoadjuvantchemotherapywhen a preoperativediagnosisofuterineLCNECispossible,giventhepoor prognosisofthediseaseevenaftersurgicaldebulking.

3.9. Classification

Endometrial LCNEC is a rare entity which is often likely under-reported and misdiagnosed. When LCNEC of the uterus is diagnosed, whether treatment should proceed as suggested in earlier reports is questionable.Although the dataon LCNEC

(5)

is limited, endometrial LCNEC appears to behave very aggres-sively,akintotypeIIuterinecancers.In brief,typeIIcancersof theendometriumtypicallypresentinolder-aged,postmenopausal women, are unrelated tounopposed estrogen, have P53 muta-tions,havepoorly-differentiatedandnon-endometrioidhistology, present with stage 3 or 4 disease, and have an unfavorable prognosis.15,16 Allof theabovewere trueof thepatient inthe

presentcase. Most,ifnotall,ofthesesameelementswerealso foundin the12othercasesofendometrialLCNEC listedin this review(Table1).

4. Conclusion

The presentation of endometrial LCNEC can mimic uterine sarcomawithpostmenopausalorabnormaluterinebleeding. Pre-operativeimagingwithMRIcanbeusefulinassessingtheextent ofdisease. Cytoreductivedebulking and surgicalstagingis typ-ically performed for diagnostic and staging accuracy. Common pathologicalfindingsandatypicalimmunohistochemistryprofile (synptophysin,chromograninandCD56)areparamountin mak-ingadiagnosisofuterineLCNEC.Intheory,adiagnosisofLCNEC maybemadepreoperativelywithimmunohistochemistry.Ifthis is the case, surgeons may considerneoadjuvant chemotherapy withetoposideandaplatinumagentfollowedbysurgical cytore-duction.Adjuvant therapy should consistof a similar regimen, although prognosiseven withearlystagedisease and adjuvant therapyappearstobepoor.LCNECoftheendometriumbehaves similarlytoothertypeIIuterinecancersandshouldbeclassified assuch.Duetotherarityofthisaggressivemalignancy,moredata isneededtoestablishincidence.Cliniciansareurgedtoreportany newcasesandmayneedtorelyoncasereportsandreviewsto guidetreatment.

Conflictofintereststatement

Theauthorshavenoconflictsofinteresttodeclare. Funding

None. Ethicalapproval

Writteninformedconsentwasobtainedfromthepatientfor publicationofthiscasereportandaccompanyingimages.Acopy ofthewrittenconsentisavailableforreviewbytheEditor-in-Chief ofthisjournalonrequest.

Authorcontributions

My-LinhNguyenistheprimaryauthorofmanuscript,data col-lection,draftingoffullarticle,finalapproval.LiyingHaninvolved indraftingofthefollowingmanuscriptsections:casepresentation, pathology,immunoprofile,concessionofimagesandfinalapproval. AnjoinetteMinorsinvolvedindatacollection,draftingofthe fol-lowingmanuscriptsections:Introduction,Definition,editingoffull

article.StuartBentley-Hibbertinvolvedindraftingofthe follow-ingmanuscriptsections:Casepresentation,Imaging;concession ofimagesandfinalapproval.Tana Pradhaninvolved indrafting ofthefollowingmanuscriptsections:Casepresentation,Surgical management,Adjuvanttreatment;classificationandfinalreview. Tarah Puaand TanaPradhan involvedindraftingofthe follow-ingmanuscriptsections:Casepresentation,Surgicalmanagement, Adjuvanttreatment;classificationandfinalreview.SeanTedjarati isprimarysurgeonforpresentcaseandinvolvedindraftingofthe followingmanuscriptsections:Casepresentation,Surgical man-agement,Adjuvanttreatment;classificationandfinalapproval. References

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