Trousseau's Syndrome Due to Asymptomatic Pancreatic Adenocarcinoma

www.elsevier.pt/ge

CLINICAL

CASE

Trousseau’s

syndrome

due

to

asymptomatic

pancreatic

adenocarcinoma

António

Murinello

_,

_Pedro

_Guedes

_,

_Gizela

_Rocha

_,

_Ana

_Serrano

_,

António

Figueiredo

,

Helena

Damásio

,

João

Freire

,

Fernando

Cunha

,

Liliana

Alves

b_{Servic¸odeOncologiaMédica,InstitutoPortuguêsdeOncologiadeLisboadeFranciscoGentil,Lisboa,Portugal}

c_{LaboratóriodeCitologiaAspirativadoServic¸odeAnatomiaPatológica,InstitutoPortuguêsdeOncologiadeLisboadeFrancisco} Gentil,Lisboa,Portugal

Received7August2012;accepted11September2012 Availableonline11January2013

KEYWORDS Trousseau’s syndrome; Migratory thrombophlebitis; Heparin; Occultmalignancy; Pancreatic adenocarcinoma

Abstract TheauthorsreportacaseofTrousseau’ssyndromepresentinginapreviously asymp-tomatic 58-year-old man diagnosed with pancreatic adenocarcinoma and liver metastases duringaworkuppromptedby migratoryvenousthrombosisandpulmonaryembolism.Itwas followedbyanischaemicstrokethatoccurredwhilethepatientwasjustonedayoff antico-agulanttherapywithlow-molecular-weightheparintoallowforliverandpancreaticbiopsies. Trousseau’ssyndromeisdefinedbyrecurrentormigratoryvenousthrombosis,arterialembolism causedbynon-bacterialthromboticendocarditis,orboth,inpatientswithunderlying malig-nancy.Treatmentreliesonthelifelongadministrationofheparin,anditsinterruption---however brief---maypromotenewthromboticevents.

©2012SociedadePortuguesadeGastrenterologiaPublishedbyElsevierEspaña,S.L.Allrights reserved. PALAVRASCHAVE Síndromede Trousseau; Tromboflebite migratória; Heparina; Neoplasiamaligna oculta; Adenocarcinoma pancreático

SíndromedeTrousseauporadenocarcinomadopâncreasassintomático

Resumo Os autores relatam um caso de Síndrome de Trousseau, manifestado por trom-bose venosa migratória e embolia pulmonar, num doente de 58 anos assintomático até à data de internamento. O estudo desencadeado revela adenocarcinoma do pâncreas com metástases hepáticas,easituac¸ão torna-seaindamais graveapósaocorrência deum aci-dentevascularcerebralisquémico,aparentementeem relac¸ãocomaparagempor24horas da terapêutica anti-coagulante com heparina de baixo peso molecular para realizac¸ão de biópsia hepática e pancreática guiadas por exame de imagem. A síndrome de Trousseau define-se por tromboses venosas recorrentes ou migratórias, embolias arteriais causadas por endocardite trombótica não-bacteriana,ou ambas,em doentescom neoplasiamaligna

∗_{Correspondingauthor.}

E-mailaddresses:amurinello@gmail.com,amurinello@iol.pt,antoniomurinello@yahoo.com(A.Murinello).

0872-8178/$–seefrontmatter©2012SociedadePortuguesadeGastrenterologiaPublishedbyElsevierEspaña,S.L.Allrightsreserved. http://dx.doi.org/10.1016/j.jpg.2012.09.006

interrupc¸ão_−aindaquebreve₋podeproporcionarnovoepisódiodetrombose.

©2012SociedadePortuguesadeGastrenterologia.PublicadoporElsevierEspaña,S.L.Todosos direitosreservados.

Introduction

Trousseau’ssyndrome(TS), namedafter theFrench physi-cian Armand Trousseau who first described it in 1865, referstorecurrentormigratoryspontaneousvenous throm-bosis, arterial embolism due to non-bacterial thrombotic endocarditis, or both, in a patient with known or occult malignancywhich is usually difficult todiagnose and may even remain elusive until it is disclosed in an autopsy.1

Thrombosis can occur from months to years before can-cerisknown,andanegativethoroughinitialwork-updoes notforgotheneed forcontinuedevaluationthatwill ulti-matelyallowanearlierdiagnosis.2,3_{Cryptogenicthrombosis}

prevented by heparin but not oral anticoagulants should prompt doctors to investigate the possibility of underly-ingmalignancy.PatientswithTSshowpersistentlow-grade intravascularcoagulation,thusaccountingforthe needto treatthemwithfulllargedoselowmolecularweightheparin onalifelongbasis.4

These patients show thrombotic diathesis that can be devastatingwhenleftuntreated,andthemostseverecases may lead to limb amputation in just a few hours, as a resultofseveredisseminatedintravascularcoagulation(DIC) thatcan happenbeforeanactual thrombosisensues. Par-ticularforms ofthissyndromearephlegmasia albadolens

andphlegmasiaceruleadolens,5_{andavariantofclassicTS}

hasbeenidentified,combiningmultiplearterialandvenous thrombiwithDICpronetobleeding.6

Malignant neoplasms are pro-thrombotic, and anoma-liesare possible in each point of Virchow’s triad --- blood flow(stasis),components(hypercoagulability)orvesselwall (endothelial injury). These surely are synergistic forces behind this, and many other factors such asconcomitant diseases, medications and decreased motility have a role as contributing factors.7,8 _{TS involves marked changes in}

the clotting cascade, brought about by the production andreleaseofprocoagulantsubstancesfromtumourcells. Althoughitmaybeassociatedwithanykindofneoplasm,TS ismostoftenrelatedtopancreatic,lung,prostate,gastric, colorectal,ovarianandbreastcancer.9

Clinical

report

Presentillness

A58-year-oldman,electronicstechnician,wasadmittedin ourInternalMedicinewardwithdeepvenousthrombosisof therightlowerlimb.HepresentedtotheEmergency Depart-ment with a 3-day course of right calf pain worsened by walking,followedbyswellingandincreasedtemperaturein

thesamelimb.Throughoutthewholeperiodhefelt increas-ingfatigueandhad anepisode of fainting.Justfour days beforethecurrent symptomsstarted hehadarrived from a vacation in Ecuador, during which his right upper limb hadbecomeswollen, redandhot.He wasdiagnosed with rightarmcellulitisandwasstartedonantibioticand anti-inflammatory therapy, improving subsequently. He denied fever, sweating, weight loss or coughing, as well as any digestive,urinaryorothermusculoskeletalsymptoms. Pastmedicalhistory

Pastmedicalhistorywaspositiveforsomechildhood infec-tious diseases (measles, mumps, chicken pox), grade I arterialhypertension(knownfor21yearsandwithout med-ication),smokinghabits(20pack-yearunits),mild alcohol intake(20gdaily),chroniclumbardisc disease,left varic-ocele surgery (at the age of 21) and benign prostatic hypertrophy.

Familydiseases

His father deceased, with a history of chronic renal fail-ure.Therewerenodiscernibleaccountsofcancerinclose relatives.

Physicalexamination

His physical examination revealed great overall condi-tionand stable vital signs (BP 113/70mmHg, HR 70bpm, RR 20bpm, apyrexia); no skin lesions, lymphadenopathy or thyromegaly; normal cardiac and respiratory sounds; soft,nontender,nondistendedabdomenwithnormalbowel sounds,nomassesonabdominalexamination,andno hep-atosplenomegaly;noevidenceofinfectioninhisrightupper limb;slightswellingandincreasedtemperatureinhisright leg,withpositiveHomans’sign;normalneurologicexamand fundusobservationwithinnormallimits.

Labtests

Laboratory tests showed the following: haemoglobin 14.6g/dl; WBC 10.9×109_{/l (68.1%N---20.3%L---7.1%M---4%E);} platelets258.0×109_{/l; ESR13mm; CRP 3.5mg/dl (N<1);} transferrin 195mg/dl (N: 215---365); ferritin 344.9ng/ml (26.0---388.0);glucose84mg/dl;creatinine0.6mg/dl; albu-min 3.7g/dl; normal serum electrophoresis; AST 42U/l (17---59); ALT 65U/l (21---72); GGT 168U/l (N: 15---73); ALP 209U/l (N: 38---126); total bilirubin 0.4mg/dl; amy-lase 591U/l (N: 30---110); lipase 6356U/l (N: 23---300);

Figure1 Contrast-enhancedabdominalCTscan,axialview: hypovascularlesions of theliver compatiblewith metastatic infiltration.

LDH 704U/l (N: 303---618); total cholesterol 180mg/dl; triglycerides 122mg/dl; total calcium9.5mg/dl; INR 1.1; aPTT 38.0; factor V 130.5%; factor VIII 152.2%; protein C 97%; protein S 92.8%; antithrombin III 107%; resistance toactivated protein C 3.14 (within normal limits); Lupus anticoagulant1.94ratio(1.6---2.0),Silicaclottingtime1.26 ratio(>1.16:positive);negativeantinuclearantibodiesand anti ␤2-glycoprotein; negative VDRL; normal TSH; nega-tiveserologiesforbothhepatitisBandC.Humanchorionic gonadotropin116(N<5)andCA15.3=74.4U/ml(N<31);all othertumourmarkers(PSA,␣-fetoprotein,CA19.9andCEA) withinnormalrange.Normalurinalysis.

Cardiactests

Cardiactestsshowedthefollowing: (1)EKG---normal;(2) cardiacultrasounddisplayinggoodleftventricleglobal sys-tolicfunction;diastolicdysfunction;novalveabnormalities; mildbiatrialdilation;dilatedrightventriclewithpreserved systolicfunction;IVCwithinnormallimits,preserved inspi-ratorycollapse;nointra-chamberthrombiortumour. Radiologicexams

Radiologicexamsrevealed:(1)chestradiograph---normal; (2)venousultrasound andDopplerof thelowerlimbs;(3) thoracicCT-angiogramand(4)abdominalandpelvicCTscan. The lastthreeexamslead tothefollowing diagnoses:(A) residualsuperficial venous thrombosis of the right basilic vein,maintainingdeepvenous(humeralandaxillary)system permeability;(B)deepvenousthrombosisoftheright pos-teriortibialandcalfveins,withnormalpopliteal,common femoral,superficialfemoralvein,greatsaphenousandsmall saphenousveinpermeability;leftlowerlimbvenoussystem withnolesions;(C)anteriorsegmentalpulmonaryembolism intherightupperlobeandtheinternalsegmentalbranchof theipsilateralinferiorlobe;(D)enlargedliverwithseveral imagescompatiblewithmetastases(Fig.1);and(E) infiltra-tivelesionofthepancreaticuncinateprocess,involvingthe

Figure 2 Contrast-enhanced abdominal CT scan, axial

view: hypovascularlesionofthe pancreatic uncinateprocess (2.5cmØ),withinvolvementofthesuperiormesentericvessels.

superior mesentericvesselsandthusbecoming inoperable (Fig.2).

Treatment

He was treated with subcutaneous enoxaparin 60mg bid, q12h,withsubsequentimprovement.

Outcome

ThepatientwasthentransferredtotheLisbonPortuguese OncologyInstitute,wherehehadanendoscopicultrasound guided fine-needle aspirationbiopsy ofthe liver and pan-creasthatconfirmedapancreaticadenocarcinoma(Fig.3) withhepaticmetastases(Fig.4).Inordertosafelyundergo thesebiopsiesenoxaparinwaswithheldduring24h.About 3 days after low-molecular-weight heparin (LMWH) was stoppedthepatientsufferedasevereischaemicstroke

leav-Figure3 Pancreaticaspirationcytology,Papanicolaoustain 10×40:smalltridimensionalaggregateshowingatypicalcellsof adenocarcinoma,displayingnuclearpleomorphism and hyper-chromasia.

Figure 4 Hepatic aspiration cytology, May---Grünwalds---Giemsa stain 10×40: small aggregate of atypicalcellswithacoarselypapillaryconfigurationandwith distinctnuclearpleomorphism.

inghimwithright-sidehemiplegia.Progressivedeterioration inneurologicstatusquicklyensuedandthepatient eventu-allydiedafewdaysafterwards.Noautopsywasmade.

Discussion

The combination of conventional tumour markers, endo-scopic methods and the most recent radiologic means includingpositron-emittingtomography(PETscan)allowus to correctly diagnose the malignancy behind TS in about 85---95% of cases.9 _{We stress the pivotal need --- as we}

approachthesepatientsinmedicalwards---toquicklyand correctlyidentifytheoriginandhistologyoftheunderlying neoplasm,becauseTSisaquiteseriousclinicalcondition, andeventhoughitisusuallyassociatedwithadvanced-stage cancer,therearealsorareeventswhenithelpstouncover cancer in an early phaseandtreat it, allowing for a bet-ter prognosis.10,11 _{Lifelong anticoagulation withheparinis}

mandatory,withaninitialperiodofhighdosagerangingfrom 15to90 daysaccordingtodifferentauthors.12,13 _Abruptly

interruptingheparinwithoutprevioustumourregressioncan be catastrophic, because procoagulating substances con-tinuetobereleasedbycancercells,thusmaintainingtheir prothrombotic effect. Withholdingheparin for just a few hourscan reactivate theclotting cascadeand precipitate thromboticevents.2,14_{VitaminKantagonistsarenot}

effec-tiveinpreventingtheseepisodes,sincetheprocoagulants releasedbyneoplasticcellsdonotdependonthisvitamin, andshouldnotbeusedinthiscontext.2

There areseveral explanations, probablytrue tosome degree and most likely intertwined,15 _{to these}

prothrom-botic effects in TS. Some of these are: (1) high serum levels of tissue factor, a primary cellular initiator of bloodclotting, primarilyconvertingfactorVII toitsactive form which then actives other proteases related to this process, particularly factor X; (2) intratumour secretion of a cystein-proteinase, activating factor X even in the absenceof factor VII; (3) cancer cell hypoxia, the subse-quent microenvironmental stress leading to the secretion ofprocoagulantandangiogenicfactors,notonlyincreasing

thromboticprocessesandmetastaticdisease;(4) platelet-richmicrothromboticprocesses;(5)activationofoncogenes thatinduce clotting; (6)toxicityfromhigh environmental levelsof iron, possibly contributingto the start and pro-motion of the tumour process while also instigating lipid oxidativelesions,resultinginanincreasedexpressionof tis-suefactorandadown-regulationofitsinhibitorypathway; (7)indirect effectof inflammatory cytokines,encouraged bytumourcells,abletoworsenTSbyactivatingendothelial cells andsubsequently increasingthe expression of adhe-sionmolecules includingP-selectin;(8)putative action of mucinesproducedbysomeneoplasms,possiblyconnecting toP-selectinandL-selectinwhichthenwouldpromotethe formationofplateletmicrothrombi.15

In a nutshell one might say that some structural or biochemical property of the tumour lesion that allows continuousexposureofbloodtocancercellsandtheir pro-coagulantsubstancesappearstobeanessentialcomponent ofTSpathophysiology.

Conclusion

This report’s goal was to relate a case of Trousseau’s syndromeassociatedwithpancreaticadenocarcinoma diag-nosed during the patient’s stay in our Internal Medicine ward. Our patient displayed recurrent migratory venous thromboses, beginning in his extremities, and pulmonary embolism.HewasplacedonLMWHandsubsequentlyshowed clinical improvementregarding the thrombotic processes. Theauthorsconsiderthatthe24-hhiatusinheparin admin-istrationaroundthetimeoftheliverandpancreaticbiopsies mayhavetriggered aboostofthromboticactivity,leading tothemanifestation ofanischaemic stroke,whichshould alertustothemassiveriskofsuspendingheparininthese settings.

Ethical

disclosures

Protection of human and animal subjects.The authors declarethatnoexperimentswereperformedonhumansor animalsforthisinvestigation.

Confidentialityofdata.Theauthorsdeclarethattheyhave followedthe protocols oftheir work centre onthe publi-cation of patientdata and that all the patients included inthestudyhavereceivedsufficientinformationandhave giventheirinformedconsentinwritingtoparticipateinthat study.

Right to privacy and informed consent.The authors declarethatnopatientdataappearinthisarticle.

Conflicts

of

interest

Theauthorshavenoconflictsofinteresttodeclare.

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