Accuracy of Contrast-Enhanced Ultrasound in the Diagnosis of Bile Duct Obstruction

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1 E12 Originl Artile THIEME Aury of Contrst-Enhned Ultrsound in the Dignosis of Bile Dut Ostrution Authors F. J. P. Fontán 1, Á. R. Reoredo 2, A. R. Siso 1 Affilitions 1 Rdiology, Complejo Hospitlrio Universitrio de A Coruñ, A Coruñ, Spin 2 Rdiology, Complejo Hospitlrio Universitrio Arquiteto Mride, A Coruñ, Spin Key words domen iliry system ultrsound reeived epted Astrt Purpose: To investigte the ility of ontrstenhned ultrsound (CEUS) to differentite enign from mlignnt lesions using iliry dut ostrution. Mterils nd Methods: Between Novemer 2006 nd Deemer 2013, 59 ptients with ile dut ostrution of undetermined use in seline ultrsound underwent CEUS study. The enhnement nd posterior wshout were nlyzed in rel time ll long the study durtion (5 ). The finl dignosis suggested y CEUS ws ompred with histologi dignosis (47.5 %) or with rdiologi follow-up with TC, RM or ERCP. Results: Finl dignoses inluded 42 mlignnt lesions (holngiorinom n = 22, metstses n = 6, pnreti rinom n = 6, heptorinom n = 4, gllldder rinom n = 2, mpullry rinom n = 1 nd lymphom n = 1) nd 17 enign lesions (lithisis or iliry sludge n = 15, xnthogrnulomtous holeystitis n = 1 nd indeterminte n = 1). CEUS ury ompred with finl dignoses sed on omined referene stndrd ws 86.4 %. CEUS orretly identified 36 of 42 mlignnt lesions (sensiility 85.7 %) nd 15 of 17 enign lesions (speifiity 88.2 %). The positive preditive vlue of CEUS for mlignny ws 94.7 %, while the negtive preditive vlue ws 71.4 %. Conlusion: CEUS is useful to differentite etween enign nd mlignnt uses of ostrutive jundie. This tehnique improves the detetion of ile dut invsion in hepti neoplsms nd permits etter evlution of intr- nd extrdutl extension of hilr heptoiliry tumors. Biliogrphy DOI /s Pulished online: 2015 Ultrsound Interntionl Open 2015; 1: E12 E18 Georg Thieme Verlg KG Stuttgrt New York ISSN Correspondene Dr. Ángel Ríos Reoredo Rdiology Complejo Hospitlrio Universitrio Arquiteto Mride Avenid Resideni, s/n Ferrol A Coruñ A Coruñ Spin Tel.: + 34/658/ Angel.Rios.Reoredo@sergs.es Liense terms Introdution Conventionl ultrsound is the first-line imging method for investigting iliry diseses. One ile dut ostrution is deteted, it is neessry to determine oth the stop level nd its nture. Bseline sonogrphy my e le to lolize the intror extrhepti origin of holestsis ut, in generl, hs reltively low ury for this purpose [1, 2]. As onsequene, in mny ses it is neessry to omine ultrsound (US) with other noninvsive methods, inluding omputed tomogrphy (CT) or mgneti resonne (MR), or invsive imging tehniques, inluding endosopi retrogrde holngiopnretogrphy (ERCP) or eho-endosopy, to get the finl dignosis. Development of new sonogrphi ontrst medi nd improvements in detetion tehniques with low ousti power hve represented signifint dvnes in ultrsound dignosis. Seond-genertion ultrsound ontrst gents inlude gs miroule-sed sustnes, stilized y ioomptile thin shell, usully of lipid omposition. The resulting dimeter of 3 5 µm, smller thn red ells, is still muh igger thn the prtiles used with CT nd MR. For this reson, the ultrsound ontrst is onfined to the intrvsulr spe, nd does not ross to the extrellulr milieu, filitting thorough study of mirond mroirultion in the trget lesion [3]. Other dvntges of ontrst-enhned ultrsound (CEUS) over CT nd MR inlude its hypollergeni, non-nephrotoxi onditions [4], s well s gret verstility, euse it n e performed in lmost ny setting, involves no rdition nd permits rel-time dynmi study of enhnement. The utility of CEUS in the dignosis of liver tumors is widely epted. The Europen Federtion of Soieties of Ultrsound in Mediine nd Biology (EFSUMB) pulished the first guide of linil prtie for this tehnique in 2004 [5]. More reently, the use of intrvsulr nd intrvitry CEUS in different orgns hs resulted in

2 Originl Artile E13 new EFSUMB guidelines for non-hepti use in A more reent updte (2011) hs reognized the usefulness of CEUS for the dignosis of iliry diseses [6]. There re few studies in the literture exploring the enefits of CEUS in iliry diseses [7 9]. Moreover, ll of them evlute its use in gllldder nd iliry dut disese from generl point of view, ut do not investigte its dignosti vlue in iliry dut ostrution. The im of this study ws to determine the usefulness of CEUS to differentite mong enign nd mlignnt iliry dut ostrution. Mterils nd Methods Study popultion Between Novemer 2006 nd Deemer 2013, 59 ptients (33 men nd 26 women) underwent iliry CEUS under the following requisites: 1. intrhepti (dut dimeter > 40 % ove tht of the djent portl vein) or extrhepti ( > 7 mm) ile dut dilttion demonstrted y seline ultrsound in ptient with linil findings of ostrutive jundie, 2. Unknown use of iliry dut ostrution. Ptients were exluded if the dignosis ws strightforwrd fter seline ultrsound, s in ses of lithisis with ousti shdow or msses in the pnreti hed. We lso exluded ptients with known severe rdiopthy nd pregnnt or ltting women. The study fulfilled the ethil rules of our institution. In our unit, ontrst-enhned ultrsound is routinely indited in the se of suspeted neoplsti lesion. Considering tht the study protool did not require ny further invsive mneuvers, we did not request forml pprovl y the lol ethil ommittee of our enter. Ptients were speifilly informed of the nture nd onditions of the ongoing study nd verl informed onsent ws requested nd otined in ll ses. We used the histologi reports from smples otined y ERCP or surgery s the referene dignosis. When these were not ville, we used linil nd rdiologi follow-up dt provided y CT, MRI or ERCP. Lesions were lssified s enign, mlignnt or indeterminte, ording to these results. Ultrsound tehnique All ultrsound exmintions were performed y the sme rdiologist with more thn 8 yers of CEUS experiene. In ll studies seline US exmintions were the first pproh. After onfirmtion of ile dut ostrution, olus of 2.5 ml of Sonovue (Bro, Miln, Itly), omposed y sulfur hexfluoride miroules with phospholipid shell, ws injeted through the nteuitl vein, nd CEUS study ws performed in rel time long 5, with low ousti power ontrst-speifi imging tehnique. A simultneous disply of tissue nd ontrst signls ensured visuliztion of the dynmi enhnement nd wshout ptterns. Relevnt imges nd videos were reorded digitlly. Dt nlysis Imges were interpreted initilly y single rdiologist, with more thn 8 yers of CEUS experiene, who ws not wre of the results of the other imging test. Susequently, n interprettive onsensus ws rehed y ll uthors fter revisiting imges nd videos. Bsl ultrsound ws nlyzed nd then ompred with relevnt CEUS findings. Pthologi nd imging studies were reorded in dtse, nd the sme pplied for the ntomi lotions of the lesions in the iliry tree (intrhepti, hilr, ommon hepti dut, ommon iliry dut nd intrpnreti dut). Sensitivity ws lulted s the frtion of true positives over the numer of true positives plus flse negtives, i. e., the totl numer of mlignnt lesions, s demonstrted y the omined referene stndrd. Speifiity ws lulted s the frtion of true negtives over the numer of true negtives plus flse positives. Dignosti ury ws defined y the numer of true positives plus true negtives divided y the totl numer of ptients. Positive preditive vlue ws lulted y dividing the true positives y the totl positive results in CEUS. Negtive preditive vlue ws lulted y dividing the true negtives y the totl negtive results in CEUS. Results CEUS ws performed in 59 ptients (33 men nd 26 women, with men ge of 71.5 yers (rnge 48 90)). The finl dignoses inluded 42 mlignnt nd 17 enign lesions. A histologi nlysis ws possile in 28 ptients (47.5 %), while the dignosis ws sed on dt from the linil nd rdiologil follow-up in the remining 31 ses (52.5 %) ( Tle 1). Tle 2 shows the finl dignoses. Among mlignnies, the most frequent dignosis ws holngiorinom (22 ptients). In 6 ses of hilr holngiorinom, seline ultrsound dislosed intrhepti ile dut dilttion with possile hilr lesions, isoehoi to liver prenhym. CEUS demonstrted in ll ses infiltrting enhning lesions in the iliry onfluene with lter wshout nd disrete mrgins ( Fig. 1). Extrhepti holngiorinom presented s ommon hepti dut lesions in 7 ses nd ommon iliry dut lesions in 9 ses; ll ut one of these ses showed fol prietl thikening or intrdutl lesions of vrile ehogeniity. CEUS demonstrted hyperenhnement nd posterior wshout in intrdutl lesions, pointing to its tumorl nture ( Fig. 2, 3). In one se CEUS showed hypoehoi non-enhning ompletely neroti mss with portl mlignnt thromosis ( Fig. 4). Tle 1 Stndrd of referene for the finl dignosis of iliry lesions. Dignosti tehnique Numer of lesions (%) Pthologi nlysis 28 (47.5) Contrst-enhned CT 35 (59.3) Contrst-enhned MR 25 (42.4) ERCP 28 (47.4) Tle 2 Finl dignosis of iliry lesions (totl = 59). Finl dignosis Numer Benign 17 Biliry sludge/gllstones 15 Xnthogrnulomtous holeystitis 1 Inonlusive 1 Mlignnt 42 Cholngiorinom 22 Metstses 6 Pnreti rinom 6 Heptoellulr rinom 4 Gllldder rinom 2 Ampullry rinom 1 Lymphom 1

3 E14 Originl Artile Fig. 1 Kltskin tumor. Bseline ultrsound shows intrhepti ile dut dilttion with hilr mss isoehoi to liver prenhym (rrow). The lesion showed isoenhnement in the rteril nd portl phse (not shown), ut in the lte phse CEUS improves the definition of the mss nd its limits, showing disrete hypoehoi mss 2 min fter ontrst gent injetion in the wshout phse. Dynmi ontrst-enhned MR in the lte phse shows iliry dut dilttion ut fils to improve lesion definition. Fig. 2 Extrhepti holngiorinom. Bseline ultrsound shows mild ommon ile dut dilttion filled distlly with hyperehoi st. CEUS shows st enhnement with moderte wshout in lter phses. Coronl reformtted CT imge niely shows the neoplsti dutl wll thikening. d 4 ptients presented with heptoellulr rinom. In 2 ses, CEUS demonstrted mlignnt infiltrtion of the ile duts, presenting with erly rteril phse enhnement, followed y wshout in the portl nd lter phses. In 2 other ses, distnt metstti, ostrutive iliry lesions with similr ehvior to the Fig. 5). originl tumor in the dynmi study were deteted ( Fig. 3 Extension of extrhepti holngiorinom to the liver. Bseline ultrsound shows dilted ommon ile dut oupied y n isoehoi st. CEUS in the rteril phse shows peripherl enhnement of the lesion nd wshout with extension to the surrounding liver prenhym in the lte phse. The sme finding is visulized on portl phse ontrst-enhned CT d. 6 ses orresponded to ile dut metstses from gstri rinom (n = 3), oloni rinom (n = 2) nd renl rinom (n = 1). In 4 ses CEUS demonstrted intrdutl lesions in the hilr onfluene nd extrhepti iliry duts, while ile dut infiltrtion y ontiguous liver mlignny ws oserved in the Fig. 6). remining 2 ses (

4 Originl Artile E15 Fig. 4 Neroti holngiorinom. Bseline ultrsound shows dilted ommon ile dut filled with intrluminl st isoehoi to the liver prenhym (rrows). CEUS shows the sene of enhnement in the neroti vsulr mss nd thromosed portl vein (sterisk). Fig. 5 Metstti heptoellulr rinom to iliry duts in ptient treted with previous multiple rdiofrequeny ltions. Bseline ultrsound shows n intrdutl mss. CEUS shows enhnement in the rteril phse nd lte wshout tht prllels the ontrst ehvior of the originl mss. Fig. 6 Spred of liver metstsis to ile dut. Bseline ultrsound shows mild dilttion of intrhepti ile duts nd hyperehoi st in the ommon hepti dut. CEUS in the lte phse shows wshout in metstsi prenhymtous lesion extending to the ilry dut tht is not visulized on portl phse ontrst-enhned CT. CEUS identified 3 of 6 ses of pnreti rinom, dislosing hypoenhning mss in the rteril phse not visile on seline ultrsound. In one se, ile dut ostrution y lymphom presented s disrete hypoenhning mss in the pnreti hed with peripnreti denopthies. Regrding enign lesions, CEUS orretly identified 14 of 15 ses (93.3 %) orresponding to iliry sludge nd stones tht presented s intrluminl sts with vrile ehogeniity on seline ultrsound, with no enhnement fter ontrst dministrtion ( Fig. 7). One se of holngitis showed diffuse hyperenhnement in the dut wll during the rteril phse nd wsh-out in the portl nd lte phse. In nother se, seline ultrsound demonstrted dutl dilttion seondry to heterogeneous hilr mss, with lifition, extending to the gllldder nd engulfing iliry duts nd vessels. CEUS showed intense enhnement in the rteril phse, with posterior wshout. Pthologil study dislosed infiltrtive xnthogrnulomtous holeystitis ( Fig. 8). We lso studied 7 ptients with suspeted iliry prosthesis ostrution. CEUS showed no enhnement in 5 ses ( Fig. 7), whih me out to e sludge, nd enhnement in 2 other ses orresponding to holngiorinom relpse nd metstsi hypernephrom. In 6 ses the results of CEUS were indeterminte. In 4 of these ses, lesions ffeted the intrpnreti distl ommon iliry dut. The lotion of the lesions in the iliry tree is refleted in Tle 3. CEUS orretly identified 36 out of 42 mlignnt lesions nd 15 of 17 enign lesions, resulting in n overll sensitivity of 85.7 % nd speifiity of 88.2 %. Its positive preditive vlue ws 94.7 % while the negtive preditive vlue ws 71.4 %, with n overll dignosti ury of 86.4 % ( Tle 4). Disussion Bsl ultrsound is the first-line imging test in ptients with suspeted iliry dut ostrution, permitting differentition

5 E16 Originl Artile Fig. 7 Biliry sludge in ptient with ostrutive holngiorinom treted with dutl prosthesis. Bseline ultrsound shows stent (rrow) enirled y n ehogeni mss. CEUS shows the sene of enhnement in the mss, onfirming its inert nture. Fig. 8 Xntogrnulomtous mss. Bseline ultrsound shows heterogeneous, predominntly hyperehoi hilr mss with ile dut dilttion (rrows) nd lifition (rrow in ). CEUS shows signifint rteril enhnement with posterior wshout (not shown) tht orreltes with portl phse ontrst-enhned CT d. d Tle 3 Lotion of lesions in the iliry tree. Tle 4 CEUS dignosti performne. Lesion lotion Numer CEUS Pthologi result/ct/mr/ercp Intrhepti 3 Hilr 9 Common hepti dut 12 Common iliry dut 17 Intrhepti 11 Biliry prosthesis 7 Totl 59 etween intr- nd extrhepti holestsis. However, this tehnique offers low sensitivity t the time of estlishing the nture of the lesion. In the present study, we hve demonstrted tht CEUS improves dignosis, differentiting enign from mlignnt lesions in the mjority of ses. We elieve tht CEUS represents n pproprite first-line dignosti proedure following initil identifition of iliry ostrution y non-enhned ultrsound llowing segregtion of ptients who require CT or MR for stging nd surgil plnning from those who n proeed diretly to ERCP. Performing CEUS during the sme session n sve time nd is finnilly prudent. Mlignnt Benign Totl Mlignnt Benign The omprison of CEUS nd ontrst-enhned ross-setionl imging is sometimes prolemti. CEUS offers rel-time dynmi study without gps in dt quisition, while CT nd MR hve sn delys nd, onsequently, my miss the erly initil enhnement in the rteril phse. Moreover, the use of purely intrvsulr ontrst medium n void some prolemti effets hppening with the interstitil diffusion in MR nd CT ontrst gents, suh s msquerding of some lesions during the portl nd lte phse produed y the persistent enhnement [10]. Alterntively the lk of interstitil enhnement in CEUS n theoretilly limit differentition etween neoplsti proesses with or without n importnt interstitil omponent.

6 Originl Artile E17 In CEUS imges, intrhepti ile dut diltion is more onspiuous, due to prenhyml enhnement, improving the detetion of intrluminl lesions, whether mlignnt or orresponding to sludge or iliry stones. In ptients with neoplsti jundie, sertining extly the use, level nd extension of the lesion is neessry, in order to selet ndidtes for surgil resetion. Similrly to CT nd MR, CEUS llows more preise determintion of neoplsi prenhymtous extension in tumors of dutl origin, s lso dutl extension of lesions originted in the liver prenhym. Cholngiorinom is the most frequent iliry neoplsm, lssified s intrhepti (peripherl nd hilr) or extrhepti. Hilr holngiorinom origintes in the ile dut ifurtion, nd tends to infiltrte the djent liver prenhym. Bsl ultrsound shows intrhepti dilttion with norml extrhepti dut, ut hs low pity to estlish the nture of the ostrution, due to the frequent isoehogeniity of these lesions with norml liver prenhym nd its infiltrtive nture [7 9]. In our experiene, Kltskin tumors show vrile enhnement in erly phses with onstnt wshout in lte phses whih niely delinetes the limits of the lesion. These fetures re onsistent with those desried in the literture. Xu et l. [11] studied the dynmi ehvior of hilr holngiorinom in CEUS, demonstrting hyperenhnement, isoenhnement nd hypoenhnement in the rteril phse in 43.8, 43.8 nd 12.6 % of ses, respetively, with ring, homogeneous enhnement pttern or heterogeneous enhnement pttern in 9.4, 34.4 nd 56.2 % of ses, respetively. In the portl nd lte phses, 93.8 % of the ses presented wshout, whih improved the delimittion of the tumor mrgins. Extrhepti holngiorinom n lso show vrile enhnement in the CEUS rteril phse, with wshout in lte phses in most ses. The essentil ontriution of CEUS is differentition mong tumors nd non-enhning, inert mteril, inluding lithisis without ousti shdow, lood lots or detritus [7, 10, 12]. Bile dut infiltrtion is rre omplition of heptoellulr rinoms nd n present with ontiguous diret invsion or emoliztion of n oult prenhymtous lesion [9]. Both presenttions were oserved in this study, with n enhnement pttern similr to the originl tumor, hyperenhnement in the rteril phse nd ontrst wsh-out in the lte phse [13]. CEUS is lso useful to tegorize intriliry metstsi lesions of non-hepti origin. These re infrequent lesions with diffiult differentil dignosis with mlignnt primry lesions. They n present s fully intrdutl lesions or s seondry invsive lesions from djent liver metstses. Different primry tumors n use iliry metstti ostrution ut gstrointestinl mlignnies, prtiulrly oloni ner, re most frequent [9]. In our study, gstri ner ws most ommon. CEUS improves the detetion of pnreti hed tumors not deteted y sl ultrsound. The pnres enhnes homogeneously in the rteril phse nd presents trnsient venous phse, filitting detetion of rinom, whih presents typilly with hypoenhnement in ll phses [6]. Fn et l. [14] reported sensitivity, speifiity nd ury of 91.7, 97.2 nd 87 %, respetively, t the time of detetion of pnreti denorinoms with CEUS. The results re similr to those otined with ontrst-enhned CT. Benign lesions show no enhnement on CEUS, due to the inert nture of intrdutl ontents (iliry sludge, lithisis, lood lots or detritus), llowing differentition from tumorl sts in most ses. Even if no enhnement is the rule in enign lesions, there re exeptions, whih inlude inflmmtory onditions suh s xnthogrnulomtous lesions or the fint pttion of the dutl wll in ses of holngitis. These exmples emphsize tht enhnement is not synonymous with mlignnt lesion. Alterntively, extensive neroti mlignnt lesions n present without ontrst enhnement in rre instnes. CEUS shres some limittions with sl ultrsound, inluding opertor dependene. Oesity nd owel gs re importnt ostles in some ses, prtiulrly during the evlution of the distl ile dut. This limittion ws ehind most indeterminte ses in this study. Importnt limittions of the study re its retrospetive design nd the sene of unitry referene test, due to the impossiility of otining pthologi dignosis in some ses. In the ltter ses we used CT, MR nd follow-up to set referene dignosis. Prospetive studies re neessry to vlidte our onlusions, s re omprtive investigtions out greement mong CEUS, on one side, nd CT or MR, on the other. Conlusion CEUS is useful to differentite the enign or mlignnt nture of iliry dut ostrution. It my offer omined pproh with CT nd MR, sving the indition of these tehniques in unequivol ses of enignity nd represents n lterntive in those ses in whih these tehniques re hzrdous or ontrindited, inluding instnes of ontrst llergy or kidney filure. In ddition, CEUS is le to dislose tumorl invsion of iliry duts y liver tumors nd helps to define the lol extension of hilr heptoiliry neoplsms. Referenes 1 Rogovenu I, Gheone DI, Sftoiu A et l. The role of imging methods in identifying the uses of extrhepti holestsis. J Gstrointestin Liver Dis 2006; 15: Blkourne LH, Ernhrdt RC, Sistrom CL et l. The sensitivity nd role of ultrsound in the evlution of iliry ostrution. Am Surg 1994; 60: Wilson SR, Burns PN. Miroule-enhned US in Body Imging: Wht Role? Rdiology 2010; 257: Pisgli F, Bolondi L. The sfety of Sonovue in dominl pplitions: retrospetive nlysis of investigtions. Ultrsound Med Biol 2006; 32: Cludon M, Dietrih CF, Choi BI et l. Guidelines nd good linil prtie reommendtions for ontrst enhned ultrsound (CEUS) in the liver updte 2012: WFUMB-EFSUMB inititive in oopertion with representtives of AFSUMB, AIUM, ASUM, FLAUS nd ICUS. Ultrshll Med 2013; 34: Pisgli F, Nolsøe C, Dietrih CF et l. 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7 E18 Originl Artile 10 Dietrih CF, Cui XW, Boozri B et l. Contrst-enhned ultrsound (CEUS) in the dignosti lgorithm of heptoellulr nd holngioellulr rinom, omments on the AASLD guidelines. Ultrshll Med 2012; 33: S57 S66 11 Xu H-X, Chen L-D, Xie X-Y et l. Enhnement pttern of hilr holngiorinom: ontrst-enhned ultrsound versus ontrst-enhned omputed tomogrphy. Eur J Rdiol 2010; 75: Liu LN, Xu HX, Zheng SG et l. Ultrsound Findings of Intrdutl Ppillry Neoplsm in Bile Dut nd the Added Vlue of Contrst-Enhned Ultrsound. Ultrshll Med 2014; DOI: /s Wildner D, Berntik T, Greis C et l. CEUS in Heptoellulr Crinom nd Intrhepti Cholngioellulr Crinom in 320. Ptients-Erly or Lte Wshout Mtters: A Sunlysis of the DEGUM Multienter Tril. Ultrshll Med 2015; 36: Fn Z, Li Y, Yn K et l. Applition of ontrst-enhned ultrsound in the dignosis of solid pnreti lesions A omprison of onventionl ultrsound nd ontrst-enhned CT. Eur J Rdiol 2013; 82: