J. Coloproctol. (Rio J.) vol.35 número1

w w w . j c o l . o r g . b r

Journal

of

Coloproctology

Case

Report

Diagnostic

difficulty

in

Peutz–Jeghers

syndrome

夽

Jenifer

Loureiro

_,

_Gian

_Luigi

_Menegazzo

_,

_Lucas

_Vergamini

_,

Roberto

Carmagnani

Pestana

_,

_Fernanda

_Bellotti

_Formiga

,

Marcella

Guilherme

Carolino

de

Sousa

_,

_Thais

_Yuka

_Takahashi

_,

_Felipe

_Silveira

_,

Paulo

de

Azeredo

Passos

Candelária

_,

_Dino

_Martini

_Filho

_,

_Fang

_Chia

_Bin

b_{DepartmentofSurgery,IrmandadedaSantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil}

c_{IrmandadedaSantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil}

d_{DepartmentofPathology,IrmandadedaSantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil}

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Articlehistory:

Received19November2013 Accepted11August2014 Availableonline29January2015

Keywords:

Peutz–Jegherssyndrome Intestinalpolyps Diagnosis

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A case of diagnostic difficulty facing the patient with colonic polyposis secondary to Peutz–Jegherssyndrome,butwithoutfamilyhistoryandpathognomonicclinicalfeatures ofthedisease,isillustrated.Theexams,includingbiopsy,ledtodiagnosticuncertaintyand thedefinitivediagnosiswascharacterizedintherapeuticofexception.

©2014SociedadeBrasileiradeColoproctologia.PublishedbyElsevierEditoraLtda.All rightsreserved.

Dificuldade

diagnóstica

na

Síndrome

de

Peutz-Jeghers

Palavras-chave:

SíndromedePeutz-Jeghers Póliposintestinais Diagnóstico

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Ilustra-se um casode dificuldade diagnóstica frente à paciente compolipose colônica secundáriaaSíndromedePeutz-Jeghers,semhistóriafamiliaresemcaracterísticas clíni-caspatognomônicasdadoenc¸a.Osexames,incluindobiópsia,geraramdúvidadiagnóstica, sendoodiagnósticodefinitivocaracterizadoemterapêuticadeexcec¸ão.

©2014SociedadeBrasileiradeColoproctologia.PublicadoporElsevierEditoraLtda. Todososdireitosreservados.

夽

StudyconductedatFaculdadedeCiênciasMédicasdaSantaCasadeSãoPaulo(FCMSCSP)andDepartmentofSurgeryandPathology, IrmandadedaSantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,Brazil.

∗ _{Correspondingauthor.}

E-mail:[email protected](F.B.Formiga).

http://dx.doi.org/10.1016/j.jcol.2014.08.012

ordercharacterizedbymultiplehamartomatouspolypsinthe gastrointestinal tract, generally associatedwith mucocuta-neous hyperpigmentation.1,2 _{This isa rare condition, with}

prevalencebetween1:8300and1:280,000.2

PatientswithPJSare predisposedtothedevelopmentof benignandmalignantneoplasmsofthegastrointestinaltract, breast,ovary,uterus,cervixandtestis.2,3

Inthespectrumofcolonicpolyposes,histologyisdecisive toestablishtheetiologicdiagnosisanddefinethe therapeu-ticconduct.Thus,themotivationofthisworkistopresenta caseofPeutz–Jegherssyndromeinwhichtherewasdiagnostic difficulty.

Case

report

Man,44,previouslyhealthy,beganhematocheziathatevolved intoanintermittentminorenterorrhagiaayearago.Denied changeinbowelhabits,abdominaloranalpain,adynamiaor weightloss.Alsodeniedfamilyhistoryofintestinaldisease, butthepatientdidnotkeepintouchwithfamilymembers.

Onexamination,thepatientwasruddyandingood gen-eralcondition,theabdominalexaminationwasnormaland nomucocutaneouschangeswereobserved.Thedigital rec-talexaminationrevealedpolypslocatedapproximately5cm fromtheanalmargin,especiallyontheposteriorwall,with nobleeding.

Thecolonoscopyrevealedmultiplepolyps(approximately 50)throughoutthecolon,reachingdistalrectum.Thebiggest polypsintherightcolonwereabout3cminsize.Therectum containedapproximately 14polyps(Fig. 1). The chromoen-doscopywithmagnificationrevealedtypeII,IIILandIVcrypts, according to Kudo4 _{classification. Incisional biopsies were}

performedinthreeseparatepolypsthatwerehistologically characterizedashyperplasticpolyps(Fig.2).

Triple-contrast computerized tomography (CT) of the abdomenandpelvisrevealedonlya5-cmpolypintheright colon.

Ourpatientunderwenttotalcolectomywithvideo-assisted ileo-rectalanastomosis,withoutcomplicationsandwithgood postoperativeevolution.

Macroscopically,62polypoidinjurieswereobserved,some of them pedunculated, measuring from 3mm to 6cm (Fig. 3). The microscopic exam revealed hamartomatous polypscompatiblewithPeutz–Jegherssyndrome,seeninboth hematoxylin–eosinandinMasson’strichrome(Fig.2).

Currently, the patient evacuates soft feces five times a day and shows no fecal incontinence. There is an ongoing investigation of the rest of the gastrointestinal tract,in search ofpolyps and cancers associated withthe syndrome.

Discussion

Peutz–Jeghers syndrome (PJS) is characterized clinically by the presence of multiple hamartomatous polyps in the

describedbyJeghers.1,3

This is a rare autosomal dominant disease with high penetrance.2 _{The defect identified in patients with}

PJS is a mutation in the gene LKB1/STK11, encoding a serine–threoninekinaseandlocatedintheregion133_ofthe

shortarmofchromosome19.3_{Thisgeneregulatesapoptosis,}

thusthelossofitsfunctionisrelatedtoanunregulatedcell proliferation.6,7

It is believed that a great genetic heterogeneity occurs amongpatients withPJS.8 _{Onestudy evaluated33 patients}

withPJSandshowedthatonly52%ofthemhadamutationin theLKB1/STK11gene,suggestingthatabouthalfofthecases arenotcausedbymutationinthisgene.8

Malignant degeneration of these injuries occurs only rarely.2_{Thepatientdescribedinthispaperhadnosuch}

hyper-pigmentationandwasunawareofsuchmanifestationduring childhood.

In association with hyperpigmentation, the presenceof multiplehamartomatouspolypsinthegastrointestinaltract ismandatory;thesepolypsarecharacterizedbyasingle cen-tralbundleofsmoothmusclefibersfrommuscularismucosa, withbranchesinatree-shapedformandcoveredbynormal mucosaofthearea.1,2,7

Inastudyof202patients,52ofthemhadtheirdiagnosis basedonskinlesions,whilein150othersthediagnosiswas basedonintestinalpolyps.6

Approximately 25% of patients have no family history, as was the case with our patient. In the absence of mucocutaneousmanifestationsandofafamilyhistory, the diagnosticconfusioninthedescribedcaseoccurredbecause thecolonoscopystudysuggestedhyperplastic(typeIIcrypts) and adenomatous(cryptsIIILandIV)polyps,withabiopsy showinghyperplasticfeatures.

Histologically,hyperplasticfeaturesmaybepresentonthe surfaceofanypolyp,asshowninFig.2.Thus,tobelievethat theendoscopicappearance,chromoendoscopyandincisional biopsies willbesufficient forthe diagnosis could,actually, hinderitsestablishment.

Theresultinginformationonthediagnosticmethodused led themedicalstaff tothinkinasurgicaltreatment, sup-posing a mixed hereditary polyposis with an associated adenomatous component, besidesthe possibility of hyper-plasticpolyposis.

In the cited polyposes, colectomy is an option widely regarded, because of a greater chance of polyp maligniza-tion. Mixed adenomatous polyposes with an adenomatous componentmustnecessarilybetreatedbyresectivesurgery,3

and hyperplastic polyposes can be treated both with a short-term follow-up and with a prophylactic colectomy, since theircarcinogenesis isfastand can surprise interval tumors.3,9

Right colon

Transverse colon

Sigmoid

Rectum

Fig.1– Colonoscopywithmorethan50polypsscatteredthroughoutthecolonandrectum.

In1987,Giardielloproposed,forthefirsttime,criteriafor establishingthediagnosisofPJS.Thisauthorputinplacethree points:family history consistentwithautosomal dominant inheritance, mucocutaneous hyperpigmentation and small intestinepolyposis.10

Currently, the diagnosis of PJS is established by the presence ofthree or more hamartomatous polyps already characterizedand histologically confirmed, or any number ofpolyps inassociation withfamily history, or mucocuta-neoushyperpigmentationinassociationwithfamilyhistory, or even any number of polypsassociated with a mucocu-taneousmanifestation.3 _{Thus, the diagnosis ofPJSmay be}

characterizedforthepatientdescribed,whichalonehad62 hamartomatouscolonicpolyps.

Evenwiththepossibilityofcarrying outgeneticteststo identifytheLBK1/STK11gene,negativeresultsdonotexclude the diagnosis, because not all of the genetic mechanisms involvedinthissyndromewerediscoveredtillnow.8

Hamartomatousgastrointestinalpolypsarepredominant in the small intestine.2 _{A series of cases showed the}

fol-lowingfrequencyofpolyps:64%inthesmallintestine,53% inthecolon, 49%inthestomach,and 32%intherectum.6

It is important to underscore that, initially, this growth hasnotmalignantpotential,becausehamartomasare com-posed of elements of the gastrointestinal tract itself, but withitsarchitecturedistorted.11_{Itisimpossibleto}

differen-tiate endoscopically a characteristic hamartomatous polyp inacaseofSPJfrom otherpolyps,requiring amicroscopic study.12

The polyps grow in the first decade of life, and most patientsbecomesymptomaticbetween10–30yearsofage.In aseriesofcases,themostcommongastrointestinal symp-tomswere:obstructioncausedbyintussusception,orluminal occlusion by polyps (43%), abdominal pain (23%), acute or chronicrectalbleeding(14%)andpolypextrusionthrough rec-tum(7%).6_{Inupto69%ofpatientsintussusceptionwilloccur}

duringtheir life,andthis problemismorecommon inthe smallintestine.

Giventheimportanceofthesmallintestineinthe char-acterizationofthedisease,ourpatientwillbesubmitted,in additiontotheCTstudyalreadyheld,toanupperdigestive endoscopyandastudywithanendoscopycapsuleinsearch ofsmallpolypsthatwerenotidentifiedintheprevious laparo-scopicsurgery.

Peutz–Jeghers syndrome is associated with an increased risk of gastrointestinal and non-gastrointestinal malignancies.2 _{A meta-analysis involving six studies and}

210patientsshowedacumulativeriskof93%from15to64 yearsforalltypesofmalignancies.Thus,therelativeriskof an individual with SPJ to present neoplasia inany region, compared with the general population, is up to 15 times higher.13

ThemostfrequentneoplasminpatientswithPJSisthe colonictumor(57%),followedbybreast(45%),pancreas(36%), stomach(29%),ovary(21%),smallintestine(13%)anduterus (10%)tumors.3

3 4 Tree-like

muscularis mucosae proliferation

"Cystic"glandular dilation, with capillary projections

into lumen

Tree-like muscularis

mucosae proliferation

"Cystic" glandular dilation

Masson tricrome

Fig.2–Histologicalstudy:biopsyofpolypwithhyperplasticaspect(1).Hamartomatouspolyp(2and3).Thewhitesquare

representsthehyperplasticcomponentinahamartomatouspolyp.Massontrichromestainingshowingmusclefiberbundle

(4).

Fig.3–Productofatotalcolectomy:62hamartomatous polyps.

greaterthan5mm.14,15_{Theuseofcapsuleendoscopyis}

con-sideredasagoodmethodforsearchingthesmallintestine.16

AnotherlessexpensivebutlesssensitiveoptionistheCTscan withoralcontrast.17_{Thedouble-balloonenteroscopyisagreat}

option,whentherapeuticallyassociated;butthisprocedureis tooinvasiveforcontrolorscanningprocedures.2

Inaddition,asearchforothercancersisdeemednecessary, although there is still no established consensus concern-ing the periodicity and on what tests should be ordered. Colonoscopy, endoscopy, CT scan, MRI or pancreatic ultra-sound,chestX-ray,mammographyandpelvicultrasoundin women,testicularexaminationinmen,andCA-19-9and CA-125dosingarerecommended.3,8,13,18,19

Inanuncomplicateddisease,therecommendationisserial polypectomy, double-balloon enteroscopy, or colonoscopy. Youcanalsomakeuseofintraoperativeenteroscopy,butwith thetechnologicaladvancementsthismethodisbecomingless andlesssuitable.2_{Incasesinwhichthediseaseiscomplicated}

withinvagination, apartialbowel resection,or enterotomy withpolypectomy,willbeneeded.

There is evidence that the removal of polyps prevents emergencylaparotomyandprogressiontoneoplasia,andalso increasesthetimefreeofsurgery.2,20

Westilldonothaveapharmacologicaltreatment.Studies suggesttheroleofchemoprophylaxiswithuseofrapamycin orofanon-steroidalanti-inflammatorydrug(becauseofthe strongactivityofCOX-2inpolyps).10

Final

considerations

Non-adenomatous colonic polypoid syndromes are not rare and are difficult to diagnose. Representative polypectomies are required for diagnosis and therapeutic management.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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1. JeghersH,McKusickVA,KatzKH.Generalizedintestinal polyposisandmelaninspotsoftheoralmucosa,lipsand digits:asyndromeofdiagnosticsignificance.NEnglJMed. 1949;241:1031.

2. KopacovaM,TacheciI,RejchrtS,BuresJ.Peutz–Jeghers syndrome:diagnosticandtherapeuticapproach.WorldJ Gastroenterol.2009;15:5397–408.

3. StojcevZ,BorunP,HermannJ,KrokowiczP,CichyW, KubaszewskiL,etal.Hamartomatouspolyposissyndromes. HeredCancerClinPract.2013;11:4.

4. KudoS,TamuraS,NakajimaT,YamanoH,KusakaH, WatanabeH.Diagnosisofcolorectaltumorouslesions bymagnifyingendoscopy.GastrointestEndosc.1996; 44:8.

5. PeutzJL.Overeenzeermerkwaardige,gecombineerde familiairepollyposisvandesligmliezenvandentractus intestinalismetdievandeneuskeelholteengepaardmet eigenaardigepigmentatiesvanhuid-enslijmvliezen.Ned MaandschrvGen.1921;10:134.

6. UtsunomiyaJ,GochoH,MiyanagaT,HamaguchiE,Kashimure A.Peutz–Jegherssyndrome:itsnaturalcourseand

management.JohnsHopkinsMedJ.1975;136:71.

7.TaheriD,Afshar-MoghadamN,MahzoniM,EftekhariA, HashemiSM,EmamiMH,etal.Cancerproblemin Peutz–Jegherssyndrome.AdvBiomedRes.2013;2:35.

8.LimW,HearleN,ShahB,MurdayV,HodgsonSV,LucassenA, etal.FurtherobservationsonLKB1/STK11statusandcancer riskinPeutz–Jegherssyndrome.BrJCancer.2003;89:308.

9.HoriiJ,KatoJ,NagasakaT,HiraokaS,SunDS,WatanabeK, etal.Developmentofinvasivecoloncancerwith

microsatelliteinstabilityinapatientwithhyperplastic polyposissyndrome.JpnJClinOncol.2012;42:451–4.

10.GiardielloFM,WelshSB,HamiltonSR,OfferhausGJA, GittelsohnAM,BookerSV,etal.Increasedriskofcancerin thePeutz–Jegherssyndrome.NEnglJMed.1987;316:1511.

11.ChenHM,FangJY.Geneticsofthehamartomatouspolyposis syndromes:amolecularreview.IntJColorectalDis. 2009;24:865–74.

12.BurkartAL,SheridanT,LewinM,FentonH,AliNJ, MontgomeryE.DosporadicPeutz–Jegherspolypsexist? Experienceofalargeteachinghospital.AmJSurgPathol. 2007;31:1209–14.

13.GiardielloFM,BrensingerJD,TersmetteAC,GoodmanSN, PetersenGM,BookerSV.Veryhighriskofcancerinfamilial Peutz–Jegherssyndrome.Gastroenterology.2000;119:1447–53.

14.OncelM,RemziFH,ChurchJM,ConnorJT,FazioVW.Benefits of‘cleansweep’inPeutz–Jegherspatients.ColorectalDis. 2004;6:332–5.

15.VidalI,PodevinG,PiloquetH,LeRhunM,FrémondB,Aubert D,etal.Follow-upandsurgicalmanagementofPeutz–Jeghers syndromeinchildren.JPediatrGastroenterolNutr.

2009;48:419–25.

16.GayG,DelvauxM,FredericM.Capsuleendoscopyin non-steroidalanti-inflammatorydrugs-enteropathyand miscellaneous,rareintestinaldiseases.WorldJGastroenterol. 2008;14:5237–44.

17.GammonA,JaspersonK,KohlmannW,BurtRW.

Hamartomatouspolyposissyndromes.BestPractResClin Gastroenterol.2009;23:219–31.

18.HearleN,SchumacherV,MenkoFH,OlschwangS,Boardman LA,GilleJJP,etal.Frequencyandspectrumofcancersinthe Peutz–Jegherssyndrome.ClinCancerRes.2006;12:3209–15.

19.BoardmanLA,ThibodeauSN,SchaidDJ,LindorNM, McDonnellSK,BurgartLJ,etal.Increasedriskforcancerin patientswiththePeutz–Jegherssyndrome.AnnInternMed. 1998;128:896–9.