World Journal ofGastrointestinal Surgery

World J Gastrointest Surg 2019 June 27; 11(6): 279-302

ISSN 1948-9366 (online)

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Contents Monthly Volume 11 Number 6 June 27, 2019

MINIREVIEWS279 Neoadjuvant therapy in the treatment of hilar cholangiocarcinoma: Review of the literature

Frosio F, Mocchegiani F, Conte G, Bona ED, Vecchi A, Nicolini D, Vivarelli M

287 Hepatocellular carcinoma – time to take the ticketMullath A, Krishna M

CASE REPORT296 Role of total pancreatectomy in the treatment of paraduodenal pancreatitis: A case report

Mikulić D, Bubalo T, Mrzljak A, Škrtić A, Jadrijević S, Kanižaj TF, Kocman B

WJGS https://www.wjgnet.com June 27, 2019 Volume 11 Issue 6I

ContentsWorld Journal of Gastrointestinal Surgery

Volume 11 Number 6 June 27, 2019

ABOUT COVER Associate Editor of World Journal of Gastrointestinal Surgery, Shefali Agrawal,MD, Associate Professor, Attending Doctor, Surgical Oncologist,Department of Surgical Oncology, Indraprastha Apollo Hospitals, NewDelhi 110076, India

AIMS AND SCOPE World Journal of Gastrointestinal Surgery (World J Gastrointest Surg, WJGS,online ISSN 1948-9366, DOI: 10.4240) is a peer-reviewed open accessacademic journal that aims to guide clinical practice and improve diagnosticand therapeutic skills of clinicians. The WJGS covers topics concerning micro-invasive surgery; laparoscopy;hepatic, biliary, pancreatic and splenic surgery; surgical nutrition; portalhypertension, as well as associated subjects. The current columns of WJGSinclude editorial, frontier, diagnostic advances, therapeutics advances, fieldof vision, mini-reviews, review, original articles, case report, etc. We encourage authors to submit their manuscripts to WJGS. We will givepriority to manuscripts that are supported by major national andinternational foundations and those that are of great basic and clinicalsignificance.

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Submit a Manuscript: https://www.f6publishing.com World J Gastrointest Surg 2019 June 27; 11(6): 279-286

DOI: 10.4240/wjgs.v11.i6.279 ISSN 1948-9366 (online)

MINIREVIEWS

Neoadjuvant therapy in the treatment of hilar cholangiocarcinoma:Review of the literature

Fabio Frosio, Federico Mocchegiani, Grazia Conte, Enrico Dalla Bona, Andrea Vecchi, Daniele Nicolini,Marco Vivarelli

ORCID number: Fabio Frosio(0000-0002-1706-9149); FedericoMocchegiani (0000-0003-0877-6535);Grazia Conte (0000-0002-3877-7355);Enrico Dalla Bona(0000-0002-9986-1083); AndreaVecchi (0000-0002-4626-6686);Daniele Nicolini(0000-0002-5477-3346); MarcoVivarelli (0000-0003-0500-9461).

Author contributions: Frosio Fcollected the majority of data andwrote the paper; Mocchegiani Frevised the manuscript; Conte Gand Dalla Bona E helped incollecting the data aboutneoadjuvant therapy beforeresection; Vecchi A and Nicolini Dfinalized the research concerningthe treatment prior totransplantation; Vivarelli M gavethe input in realizing this review.

Conflict-of-interest statement:There is no conflict of interestassociated with any of the seniorauthors or other coauthors whohave contributed to thismanuscript.

Open-Access: This article is anopen-access article which wasselected by an in-house editor andfully peer-reviewed by externalreviewers. It is distributed inaccordance with the CreativeCommons Attribution NonCommercial (CC BY-NC 4.0)license, which permits others todistribute, remix, adapt, buildupon this work non-commercially,and license their derivative workson different terms, provided theoriginal work is properly cited and

Fabio Frosio, Federico Mocchegiani, Grazia Conte, Enrico Dalla Bona, Andrea Vecchi, DanieleNicolini, Marco Vivarelli, Unit of Hepato-pancreato-biliary and Transplant Surgery, Departmentof Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona 60126,Italy

Corresponding author: Federico Mocchegiani, MD, Assistant Professor, Unit of Hepato-pancreato-biliary and Transplant Surgery, Department of Experimental and Clinical Medicine,Polytechnic University of Marche, Via Conca 71, Ancona 60126, Italy.federicomocchegiani@hotmail.comTelephone: +39-71-5964577Fax: +39-71-5965100

AbstractCholangiocarcinoma (CCA) is a malignant tumor of the biliary system andincludes, according to the anatomical classification, intra hepatic CCA (iCCA),hilar CCA (hCCA) and distal CCA (dCCA). Hilar CCA is the most challengingtype in terms of diagnosis, treatment and prognosis. Surgery is the onlytreatment possibly providing long-term survival, but only few patients areconsidered resectable at the time of diagnosis. In fact, tumor’s extension tosegmentary or subsegmentary biliary ducts, along with large lymph nodeinvolvement or intrahepatic metastases, precludes the surgical approach. Toachieve R0 margins is mandatory for the disease-free survival and overallsurvival. In case of unresectable locally advanced hCCA, radiochemotherapy(RCT) as neoadjuvant treatment demonstrated to be a therapeutic option beforeeither hepatic resection or liver transplantation. Before liver surgery, RCT isbelieved to enhance the R0 margins rate. For patients meeting the Mayo Cliniccriteria, RCT prior to orthotopic liver transplant (OLT) has proved to produceacceptable 5-years survivals. In this review, we analyze the current role ofneoadjuvant RCT before resection as well as before OLT.

Key words: Hilar cholangiocarcinoma; Klatskin tumor; Neoadjuvant treatement;Radiotherapy; Chemotherapy; Hepatic resection; Liver transplantation

©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.

Core tip: Surgery is the only potentially curative treatment for hilar cholangiorcinoma;however, most of the patients are considered not resectable because of the local extent.

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the use is non-commercial. See:http://creativecommons.org/licenses/by-nc/4.0/

Manuscript source: Invitedmanuscript

Received: March 26, 2019Peer-review started: March 28, 2019First decision: May 8, 2019Revised: May 29, 2019Accepted: June 10, 2019Article in press: June 10, 2019Published online: June 27, 2019

P-Reviewer: Aosasa S, Kato JS-Editor: Dou YL-Editor: AE-Editor: Wang J

Neoadjuvant radiochemotherapy is supposed to increase R0 margins rate, or even toallow radical resection for locally advanced tumors, but few studies are available.Moreover, for patients with early stage tumors meeting the Mayo Clinic criteria,neoadjuvant therapy before liver transplantation has produced very good survivals,gaining worldwide acceptance. This is the first review to consider the role ofneoadjuvant treatment for hilar cholangiocarcinoma, before resection as well as beforeliver transplantation.

Citation: Frosio F, Mocchegiani F, Conte G, Bona ED, Vecchi A, Nicolini D, Vivarelli M.Neoadjuvant therapy in the treatment of hilar cholangiocarcinoma: Review of the literature.World J Gastrointest Surg 2019; 11(6): 279-286URL: https://www.wjgnet.com/1948-9366/full/v11/i6/279.htmDOI: https://dx.doi.org/10.4240/wjgs.v11.i6.279

INTRODUCTIONCholangiocarcinoma (CCA) is a malignant tumor of the liver arising from the cholan-giocytes of the bile ducts and it represents the second most common primary hepaticmalignancy behind the hepatocellular carcinoma[1]. The cholangiocytes have differentfeatures in relation to their location in the biliary tree and this heterogeneity reflectsthe existence of different histological types of CCA[2], such as mucine producing,hepatocytic differentiated, etc. Established risk factors for CCA are primary sclerosingcholangitis (PSC), hepatobiliary parasites (Opisthorchis viverrini and Clonorchis sinensis,in Southest Asia especially), hepatolithiasis, Caroli’s disease and type I and IVcholedocal cysts; more recently, cirrhosis has emerged as an independent risk factortoo[3]; on the other hand, hepatitis B and C virus, diabetes mellitus and obesity arepossible risk factors to be confirmed. Nevertheless, in most patients with CCA, no riskfactor is identifiable. The current anatomical classification includes intra hepatic CCA(iCCA), hilar CCA (hCCA) and distal CCA (dCCA)[4]. hCCA notably refers to tumorslocated between the secondary branches of the right and left hepatic ducts and thecommon hepatic duct at the level of cystic duct origin[5]. The prognosis of CCA is quitemiserable and surgery is the only potentially curative treatment.

In case of hCCA, which is the most common type[6], diagnosis and treatment areextremely challenging. First of all, most of the patients are not eligible for surgery,since one of the following conditions occurs: Bilateral involvement of the second-order bile ducts, bilateral or contralateral vascular involvement, metastatic disease,underlying advanced hepatic disease and PSC[7]. An advanced preoperative work upis therefore needed: Along with magnetic resonance cholangiography and computedtomography scan, the histologic mapping of the biliary tree obtained through theSpyglass cholangioscopy system appears crucial to establish the resectability and toplan the right operative strategy. Secondly, if feasible, surgery for hCCA consists of amajor procedure, usually an extended lobar hepatic and bile duct resection, withregional lymphadenectomy and Roux-en-Y hepaticojejunostomy[8]; an accurateevaluation of the future liver remnant is always required, as preoperative portal veinembolization or staged hepatectomy as ALPPS are the available techniques to providefor its hypertrophy. Moreover, even when a R0 resection is accomplished, it can onlyproduce 5-years survivals up to 40%[9], being the lymph nodes involvement a well-known negative prognostic factor[10]. For R1 resected patients, a marked decrease indisease free survival (DFS) and overall survival (OS) has been observed. Patientspotentially at high risk of residual tumor (R1) after surgery are considered “borderlineresectable”. For them, neoadjuvant radiochemotherapy (RCT) has been advocated as apossible treatment to allow R0 resections. In “unresectable” early stage hCCApatients, RCT has already been validated prior to Orthotopic Liver Transplant (OLT)as part of the Mayo Clinic protocol. The aim of the present paper is to review thehistory and the current role of neoadjuvant RCT in both settings, hepatic resectionand OLT.

RCT BEFORE HEPATIC RESECTIONIn literature, only few studies are available, all with a small number of patientsincluded and a poor distinction between hCCA and dCCA; definition of “borderline

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resectable” and “unresectable” patients are often unclear as well.In 1997 McMasters et al[11] published the results of a prospective study applying

neoadjuvant RCT for extra hepatic CCA. Combined infusion of 5-FU (300 mg/m2 perday, from Monday to Friday) and external beam radiation (1.8 Gy per day, fromMonday to Friday, to a total dose of 50.4 Gy or 45 Gy) were used. Nine patients, fivewith hCCA and four with dCCA, were included. Six of them had an unresectabledisease, based on preoperative imaging or on surgical exploration performed inothers hospitals. R0 resection was achieved in all the nine patients (100%), comparedto 54% obtained in the group having received surgery alone. There were no majorcomplications. Among the five patients with hCCA, two displayed a pathologiccomplete response, the others a partial one. The authors concluded that hCCApatients treated with neoadjuvant RCT obtained 100% of R0 resection (5/5) with apathologic complete response in 40% (2/5). Despite the limited number and thequestionable selection of the patients (both hCCA and dCCA, unresectable andresectable), this study demonstrated the achievement of R0 resection after neao-djuvant RCT for hCCA patients primarily not elegible for surgery.

In 2000, Gerhards et al[12] demonstrated that preoperative radiotherapy (RT) at thetotal dose of 10.5 Gy (three fractions of 3.5 Gy on three consecutive days the weekbefore surgery) could decrease the risk of intra operative implantation metastases inpatients with resectable hCCA who had undergone ERCP or PTC for biliary drainage;that risk had been previously assessed at 20% by the same group[13].

In a retrospective study, Nelson et al[14] considered a cohort of twelve patients out offorty-five with hCCA and dCCA, either “borderline resectable” or “unresectable”,who had received neoadjuvant RCT at different doses. R0 resection could finally beperformed in 11/12 patients (91%); pathologic complete response was found in 3/12(25%). A complication requiring surgery was developed by 2/12 patients (16%),without any difference in terms of morbidity if compared to the thirty-three patientswho did not undergo neoadjuvant therapy. Definitely, the twelve patients with hCCAand dCCA showed a better trend in 5-years survival rate, 53% vs 23%, but notstatistically significant. Also, this study is limited by small sample size, unclear choiceof patients and different regimens of RCT.

More recently, a retrospective study about neoadjuvant RCT has been published bya South Korean group[15]. They focused on patients with locally advanced hCCA(Bismuth type III and IV, TNM stage III and IV). Twelve patients who had receivedvarious regimens of neoadjuvant RCT before surgery (neoadjuvant group) werecompared to a control group of forty-five patients, homogeneous in terms of age, sex,stage of the disease and biological values, who had undergone surgery without RCT.The neoadjuvant group showed a higher rate of downstaging of the tumor aftersurgery [91.7% (11/12) vs 51.1% (23/45), P = 0.01] and a higher rate of R0 resections[83.3% (10/12) vs 64.4% (30/45), P = 0.32]. On other hand, recurrence rate [83.3%(10/12) vs 68.9% (31/45), P = 0.48], DFS (26.0 mo vs 15.1, P = 0.91) and OS (32.9 mo vs27.1, P = 0.26) did not show any advantage for the neoadjuvant group.

In 2018, a Japanese group[16] reported a retrospective study of 8 patients whoreceived S-1 chemotherapy and 50 Gy RT as a neoadjuvant protocol for locallyadvanced hCCA. The authors defined as locally advanced a tumor for which a radicalsurgery was not technically feasible, not even by performing extreme surgery. Inparticular, three patients had broad extra-hepatic perineural invasion, three displayedbroad bile duct infiltration, one had bilateral portal vein invasion and one bilateralhepatic artery involvement. Six of the eight patients (75%) succeeded in beingreclassified as resectable after the neoadjuvant treatment and underwent left/righthemihepatectomy/trisegmentectomy with caudate lobectomy. Only one resectionturned out to be R1. Three patients were relapse-free 104, 37 and 7 mo later, whilethree died from primary disease at 37, 31 and 17 mo from surgery.

A phase I trial named NACRAC[17], carried out by the Sendai team, established at600 mg/m2 the recommended dose of gemcitabine (at day 1 and day 8, every threeweeks) to associate at external beam radiation (1.8 Gy daily, total dose 45 Gy) for theneoadjuvant treatment of CCA. The phase II trial of the NACRAC study[18], aimed atevaluating the pathological curability after RCT as well as DFS and OS, is currently inprogress. So far, twenty-five patients with advanced extrahepatic CCA have beenenrolled and treated with neoadjuvant RCT. Three were not operated (for livermetastases, progression of the tumor, heart failure), two were not resected (both dueto peritoneal carcinomatosis) and one patient was found to have a pancreatic cancer.Among the nineteen patients who were finally resected, seventeen (89.6%) got an R0resection. Considering all the twenty-four patients recruited with CCA, R0 resectionaccounted for 70.8%. Since there were no deaths nor severe complications, up to nowneoadjuvant RCT prior to surgery has proved to be safe and effective in enhancingfree-margins resection for advanced hCCA and dCCA. At the end of the study (40cases are necessary), once DFS and OS are known, proper indications for CCA will be

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defined.Few cases of R0 resection after neoadjuvant chemotherapy (CT) alone for unresecta-

ble hCCA have been reported. Tada et al[19] achieved an R0 resection after an extendedleft hepatectomy with partial resection of the portal vein and regional node dissectionin a patient with a Bismuth type III hCCA involving the portal bifurcation, treated bygemcitabine and S-1 combination chemotherapy in neoajduvant setting during fourmonths. The 52-year-old patient was alive and disease-free at 29 mo from surgery.Sano et al[20] described another case report of unresectable hCCA, in which R0resection required an arterial resection too, after neoadjuvant gemcitabine (twocourses) at the high dose of 1000 mg/m2.

Photodynamic therapy (PDT) has been evaluated as a neoadjuvant treatment beforesurgery for advanced hCCA, by a German group[21]. Seven patients were included andmanaged to undergo an R0 resection; on the specimens, no viable tumor cells werefound on the superficial layer of the bile duct into the depth of 4 mm. However, as theinitial resectability was not assessed, there was no evidence of the role of PDT ingetting negative margins. Thus, PDT is a low-risk procedure allowing destruction ofthe inner biliary epithelium, whose utility in neoadjuvant environs remains to bedetermined. (Table 1)

RCT PRIOR TO LIVER TRANSPLANTIATIONAs previously mentioned, many hCCA patients are considered “unresectable” atdiagnosis for a wide tumor extension at both hepatic lobes, for bilateral involvementof the segmental hepatic ducts or of the main vessels, for poor liver function in case ofPSC or other liver chronic disease. In such a complex setting, RCT is considered asneoadjuvant treatment before OLT with the aim to downstage the tumor burden andto confine that within the organ to replace.

The first experiences of OLT for CCA included both intra and extra hepatic CCA.The results were absolutely discouraging in terms of recurrence and survival andCCA was regarded as a contraindication to OLT. In particular, Meyer et al[22] reportedthe largest series, made up of 207 patients from the Cincinnati Transplant TumorRegistry (1968-1997): 5 years survival was 23%, 51% recurred - almost all within twoyears - and survival after recurrence was extremely poor. Robles et al[23] describedsimilar findings on a Spanish cohort of 59 patients, of which 36 with hCCA and 23with iCCA; 5 years survivals were respectively 30% and 42%, recurrence rate 53% and35%. OLT with incidentally found CCA did not show better intermediate and long-term survivals, according to a Canadian study[24].

The benefit of high dose combined external beam radiation and brachitherapy forextra hepatic CCA was already known thanks to the works published by Alden et al[25]

in 1994: 2 years survival was 48% for patients treated with 55 Gy or more, 0% withoutRT. Moreover, Foo et al[26] in 1997 had observed an improved survival with theconcomitant use of 5-FU chemotherapy. Following these findings, the NebraskaUniversity group[27] was the first to combine neoadjuvant RCT and OLT in a selectedcohort of seventeen patients with hCCA (Bismuth types III and IV) < 2 cm and nointra or extra-hepatic metastases. Neoadjuvant protocol provided only intra biliarybrachitherapy, delivered through percutaneous trans hepatic catheters to a total doseof 60 Gy, and intravenous infusion of 5-FU (300 mg/m2/d), given until the trans-plantation. An exploratory laparotomy was performed while on the waiting list, whena liver donor was available: an extended lymphadenectomy was carried out and inthe presence of extrahepatic involvement OLT was precluded. This happened to fourpatients, while two died from disease progression before the staging surgery. Elevenpatients finally underwent OLT, seven of which had PSC and ulcerative colitis.Recurrence was confirmed in two patients, 4 and 5 mo after the transplantation. Fourother patients died from post-operative complications while five patients (45%) weredefinitely alive and tumor-free with a median follow up of 7.5 (2.8-14.5) years fromOLT. Although the high rate of septic complications due to the brachiterapy, theNebraska University’s work did manage to achieve long term survivals in selectedpatients with unresectable hCCA.

The Mayo Clinic group proposed his original neoadjuvant protocol in 1993,combining irradiation and CT. Patients with early stage hCCA either judgedunresectable by an experienced hepatobiliary surgeon or developed in the context ofPSC were considered. Criteria for anatomic unresectability were well defined: Bila-teral segmental ductal extension, encasement of the main trunk of the portal vein,unilateral ductal extension with controlateral vascular encasement, unilateral liveratrophy in the presence of controlateral segmental ductal or vascular involvement.The first inclusion criteria embraced maximum tumor size of 3 cm, no extension

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Table 1 Papers about neoadjuvant therapy before resection considered in this review

Author Yr Type of studyPatientstreated withNA RCT

Resectability Neoadjuvantregimen

% of R0(R0/resected)

Resultsachieved Conclusions

McMasters atal[11]

1997 Nonrandomized,prospective

5 hCCA and 4dCCA

Allunresectable

5-FU at 300mg/m2, EBRTto 50.4 or 45 Gy

100% (9/9) Recurrence forhCCA: 0%

NA RCT cansafely allow R0resection.

Nelson et al[14] 2009 Retrospective 12 (hCCA anddCCA)

10 unresectable 5-FU, EBRT to50.4 Gy (11/12)± brachitherapy(5/12)

91% (11/12) Better trend in5-yr survivalrate for NARCT group

NA RCT cansafely allow R0resection.

Jung et al[15] 2015 Retrospective 12, all hCCA Allunresectable

5-FU/Gemcitabine, EBRT to 50.4or 45 Gy

83,3% (10/12) Better R0 ratefor NA RCTgroup; noadvantage inDFS and OS

NA RCT cansafely allow R0resection,withoutimproving DFSand OS.

Sumiyoshi etal[16]

2018 Retrospective 8 hCCA Allunresectable

S-1, EBRT to 50Gy

71,4% (5/7) Better DFS andOS for patientswho underwentsurgery afterdownstagingwith NA RCT

NA RCT cansafely allow R0resection,improved DFSand OS forpatientsoperated.

Katayose etal[18]

2015 Nonrandomized,prospective

24 (hCCA anddCCA)

All advanced,possiblyresectable

Gemcitabine600 mg/m2,EBRT to 45 Gy

80,9 % (17/21) R0 rate: 80.9%of patientsoperated, 70.8%of all patientsenrolled

NA RCTfollowed bysurgeryeffective andwell tolerated,DFS and OS yetto determine.

Tada et al[19] 2012 Case report 1 hCCA Unresectable Gemcitabine +S-1

1/1 R0 resectionwith portalresection, norecurrence at 29mo

NA CT canallow R0resection.

Sano et al[20] 2011 Case report 1 hCCA Unresectable Gemcitabine 1/1 R0 resectionwith portal andarterialresection, norecurrence at 18mo

NA CT canallow R0resection.

NA RCT: Neoadjuvant radiochemotherapy; hCCA: Hilar cholangiocarcinoma; dCCA: Distal cholangiocarcinoma; EBRT: External beam radiation therapy;5-FU: 5-Fluorouracil; DFS: Disease free survival; OS: Overall survival.

below the cystic duct for hCCA without PSC, absence of intra or extra-hepaticmetastases (including hepatic hilar lymph nodes metastases). Uncontrolled infections,previous RT or CT treatments or any attempts of surgery or percutaneous procedures(due to the risk of peritoneal tumor seeding) motivated the exclusion. Neoadjuvanttreatment involved firstly external beam radiation (1.5 Gy twice a day, five days aweek over three weeks, to a total of 45 Gy) followed by intra biliary brachitherapy (20-30 Gy, through iridium wires placed endoscopically or percutaneously). Intravenous5-FU was administered at the dose of 500 mg/m2/d for the first three days of RT; 225mg/m2/d were given later, from the beginning of the brachitherapy to the transplan-tation, with one-month pause for the staging surgery: An exploratory laparotomy wasperformed two to six weeks after the brachytherapy; a celiac and peripancreaticlymphadenectomy extended to the hepatic artery and distal common bile duct wasperformed, avoiding hepatic hilum dissection. Patients with no evidence ofperitoneal, hepatic or lymphatic metastases were listed for OLT. In the pilot studypublished in 2000[28] nineteen patients were enrolled for neoadjuvant RCT. Fourpatients experienced biliary complications, one of which died from uncontrolledsepsis. Of the eighteen patients who underwent the staging surgery, six had metastas-es (five lymphatic, one peritoneal) and one developed a malignant ascites. Elevenpatients were finally transplanted (of which one underwent retransplantation forearly arterial thrombosis). All patients were alive, three with a follow up < 12 mo, theremaining eight with a mean follow up of 44 mo. Only one patient recurred 40 moafter OLT.

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Since 1999, patients with tumor extension below the cystic duct were also included:In this case, a pancreatoduodenectomy had to be combined at OLT. In 2001, oralcapecitabine (2000 mg/m2 per day, two out of every three weeks) was adopted as themaintenance chemotherapy from the brachitherapy to the OLT. Furthermore, since2002, endoscopic US needle aspiration of the hepatic regional nodes before thebeginning of the neoadjuvant treatment was added to the protocol: If positive, thepatient was excluded and this did decrease the rate of positive staging laparotomy.

In 2006 Heimbach et al[29] updated the results of the Mayo Clinic (1993-2006): At thattime, one hundred and six patients had begun the neoadjuvant treatment, ninety-fourhad undergone the staging operation, of which eighteen (19%) had shown contrain-dication for OLT; for the sixty-five patients finally transplanted, 1-year and 5-yearssurvival were respectively 91% and 76% and 5-years DFS was 60%. Four patients (6%)died from complications of OLT and eleven (17%) recurred at the mean time of 29 moafter OLT. Recurrence was associated with older age, CA 19.9 > 100/mL before OLT,longer time on the waiting list; tumor grade, perineural invasion and residual tumor >2 cm on the explanted liver were correlated as well.

An exception MELD score for patients having completed the neoadjuvant protocolhad already been introduced by the United Network for Organ Sharing since 2002:From 2009 the score adopted was the same given for HCC, with additional pointsevery three months on the list. A multicenter study[30] conducted on 12 Americancenters including 287 patients confirmed the excellent results already known.Considering all the patients who had started the neoadjuvant treatment (intention-to-treat), 5-years and 10-years OS were respectively 53% and 42%. With specific regardsto the transplanted cohort of 214 patients, 5-years DFS was 65%, as in Heimbach’sprevious report, and 10-years DFS 59%. Seventy-one patients dropped-out with adrop-out rate attested at 11.5% every three months, which confirmed the suitability ofthe additional MELD points introduced. Post-transplant recurrence was 20% (n = 43),post-transplant mortality 22% (n = 62). No significant difference in terms of survivalwas detected between patients with or without underlying PSC.

All these studies definitely confirmed that for patients with unresectable early stagehCCA meeting the Mayo Clinic criteria, neoadjuvant RCT followed by OLT canprovide excellent long term DFS and OS. In terms of survival, the results arecomparable to those achieved with OLT for chronic (hepatitis C) or malignant(hepatocarcinoma) disease and seem to exceed those accomplished with resection.That is the reason why RCT prior to OLT has been advocated as a choice even forresectable hCCA; actually, a French prospective randomized multicenter trial namedTRANSPHIL[31] is currently in progress.

In the attempt to expand the strict Mayo Clinic criteria, the UCLA group hasproposed a protocol[32] for locally advanced iCCA and hCCA in the absence of distantmetastasis. They developed a prognostic risk score based on seven survival predic-tors, of which five were histological ones, to stratify patients in three different riskgroups: Low, intermediate and high risk. Tumor biopsy before the neoadjuvanttreatment to assess the predictive variables and to determine the risk class wasrequired. Low and intermediate patients underwent OLT after negative exploratorylaparotomy. A second biopsy was necessary after the staging surgery only for highrisk patients, in order to evaluated their response to the neoadjuvant treatment; incase of downstaging to intermediate or low risk class, OLT could be performed alsofor them. Adjuvant CT was eventually given based on the biological features of thepretreatment biopsy. For low risk group, a 5-years DFS at 78% was attested, while forintermediate 19%. Thus, this experience definitely showed that very good andacceptable 5-years DFS can be achieved respectively for low risk and for intermediaterisk patients with locally advanced iCCA or hCCA, by expanding the Mayo Cliniccriteria according to the UCLA stratification system.

RCT produces serious adverse-effects and technical issues. Before the transplant,hilar necrosis with intraductal debris can result in cholangitis, cholecystitis andhepatic abscesses, requiring hospitalization, antibiotics therapy and percutaneousprocedures. Fibrosis makes isolation of the pedicle challenging during the transplantsurgery. Above all, a high rate of post-transplant late vascular complications is due tothe neoadjuvant regimen: considering the Mayo Clinic series up to 2006, Mantel et al[33]

reported a 21% of arterial and a 22% of portal vein complications, as 40% of patientsexperienced a vascular impairment. In that series, the interposition of a donor iliacartery graft has reduced late complications only in deceased donor recipients as, onthe other side, it is associated with more early technical problems in living donorrecipients.

CONCLUSION

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Up to now, there is no general consensus regarding the effectiveness of RCT as aneoadjuvant treatement before liver resection. Anyway, considering all the limitationsof the studies cited, neaodjuvant RCT for patients with locally advanced hCCA isfeasible and seems to allow R0 resections for initially unresectable tumors. Thedefinitive results of the phase II trial of the NACRAC study will eventually confirmthat and they will suggest whether neoadjuvant RCT can affect survival or not. Aprospective multicenter trial based on a well-shared definition of unresectability ofhCCA is absolutely needed.

Combined RCT and OLT are nowadays the treatment of choice for patients withearly stage hCCA either unresectable or on underlying PSC who match the strictMayo Clinic criteria. For these patients such synergism appears to provide DFS andOS higher than resection for resectable tumors, so that RCT prior to OLT is beinginvestigated also for the latter ones. Protocols assessing the effectiveness of thecombination RCT - OLT even for selected patients with locally advance hCCA andiCCA are ongoing, too.

REFERENCES1 Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III: Liver, biliary tract, and

pancreas. Gastroenterology 2009; 136: 1134-1144 [PMID: 19245868 DOI: 10.1053/j.gastro.2009.02.038]2 Komuta M, Govaere O, Vandecaveye V, Akiba J, Van Steenbergen W, Verslype C, Laleman W, Pirenne

J, Aerts R, Yano H, Nevens F, Topal B, Roskams T. Histological diversity in cholangiocellular carcinomareflects the different cholangiocyte phenotypes. Hepatology 2012; 55: 1876-1888 [PMID: 22271564 DOI:10.1002/hep.25595]

3 Shaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA. Risk factors of intrahepaticcholangiocarcinoma in the United States: a case-control study. Gastroenterology 2005; 128: 620-626[PMID: 15765398 DOI: 10.1053/j.gastro.2004.12.048]

4 Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology2013; 145: 1215-1229 [PMID: 24140396 DOI: 10.1053/j.gastro.2013.10.013]

5 Blechacz B. Cholangiocarcinoma: Current Knowledge and New Developments. Gut Liver 2017; 11: 13-26[PMID: 27928095 DOI: 10.5009/gnl15568]

6 Blechacz B, Komuta M, Roskams T, Gores GJ. Clinical diagnosis and staging of cholangiocarcinoma. NatRev Gastroenterol Hepatol 2011; 8: 512-522 [PMID: 21808282 DOI: 10.1038/nrgastro.2011.131]

7 Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma - evolving concepts andtherapeutic strategies. Nat Rev Clin Oncol 2018; 15: 95-111 [PMID: 28994423 DOI:10.1038/nrclinonc.2017.157]

8 Nagorney DM, Kendrick ML. Hepatic resection in the treatment of hilar cholangiocarcinoma. Adv Surg2006; 40: 159-171 [PMID: 17163100 DOI: 10.1016/j.yasu.2006.05.009]

9 Hasegawa S, Ikai I, Fujii H, Hatano E, Shimahara Y. Surgical resection of hilar cholangiocarcinoma:analysis of survival and postoperative complications. World J Surg 2007; 31: 1256-1263 [PMID:17453285 DOI: 10.1007/s00268-007-9001-y]

10 Kitagawa Y, Nagino M, Kamiya J, Uesaka K, Sano T, Yamamoto H, Hayakawa N, Nimura Y. Lymphnode metastasis from hilar cholangiocarcinoma: audit of 110 patients who underwent regional andparaaortic node dissection. Ann Surg 2001; 233: 385-392 [PMID: 11224627 DOI:10.1097/00000658-200103000-00013]

11 McMasters KM, Tuttle TM, Leach SD, Rich T, Cleary KR, Evans DB, Curley SA. Neoadjuvantchemoradiation for extrahepatic cholangiocarcinoma. Am J Surg 1997; 174: 605-8; discussion 608-9[PMID: 9409582 DOI: 10.1016/S0002-9610(97)00203-1]

12 Gerhards MF, Gonzalez DG, ten Hoopen-Neumann H, van Gulik TM, de Wit LT, Gouma DJ. Preventionof implantation metastases after resection of proximal bile duct tumours with pre-operative low doseradiation therapy. Eur J Surg Oncol 2000; 26: 480-485 [PMID: 11016470 DOI: 10.1053/ejso.1999.0926]

13 ten Hoopen-Neumann H, Gerhards MF, van Gulik TM, Bosma A, Verbeek PC, Gouma DJ. Occurrenceof implantation metastases after resection of Klatskin tumors. Dig Surg 1999; 16: 209-213 [PMID:10436369 DOI: 10.1159/000018729]

14 Nelson JW, Ghafoori AP, Willett CG, Tyler DS, Pappas TN, Clary BM, Hurwitz HI, Bendell JC, MorseMA, Clough RW, Czito BG. Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma.Int J Radiat Oncol Biol Phys 2009; 73: 148-153 [PMID: 18805651 DOI: 10.1016/j.ijrobp.2008.07.008]

15 Jung JH, Lee HJ, Lee HS, Jo JH, Cho IR, Chung MJ, Park JY, Park SW, Song SY, Bang S. Benefit ofneoadjuvant concurrent chemoradiotherapy for locally advanced perihilar cholangiocarcinoma. World JGastroenterol 2017; 23: 3301-3308 [PMID: 28566890 DOI: 10.3748/wjg.v23.i18.3301]

16 Sumiyoshi T, Shima Y, Okabayashi T, Negoro Y, Shimada Y, Iwata J, Matsumoto M, Hata Y, Noda Y,Sui K, Sueda T. Chemoradiotherapy for Initially Unresectable Locally Advanced Cholangiocarcinoma.World J Surg 2018; 42: 2910-2918 [PMID: 29511872 DOI: 10.1007/s00268-018-4558-1]

17 Katayose Y, Rikiyama T, Motoi F, Yamamoto K, Yoshida H, Morikawa T, Hayashi H, Kanno A, HirotaM, Satoh K, Ariga H, Suzuki M, Ohyauchi M, Kondo Y, Ikeya S, Ogawa Y, Shimosegawa T, Egawa S,Unno M. Phase I trial of neoadjuvant chemoradiation with gemcitabine and surgical resection forcholangiocarcinoma patients (NACRAC study). Hepatogastroenterology 2011; 58: 1866-1872 [PMID:22234055 DOI: 10.5754/hge10106]

18 Katayose Y, Nakagawa K, Yoshida H, Morikawa T, Hayashi H, Okada T, Mizuma M, Sakata N, OhtsukaH, Fukase K, Yabuuchi S, Ishida M, Aoki T, Okada R, Masuda K, Kawaguchi K, Motoi F, Naitoh T, UnnoM. Neoadjuvant chemoradiation therapy for cholangiocarcinoma to improve R0 resection rate: The firstreport of phase II study. J Clin Oncol 2015; 33: 402-402 [DOI: 10.1200/jco.2015.33.3_suppl.402]

19 Tada S, Fujikawa T, Tanaka A, Abe T, Yoshimoto Y, Maekawa H, Shimoike N, Tanaka H, Kawashima T,Shiraishi K. [A case of unresectable hilar cholangiocarcinoma successfully treated by gemcitabine and S-1combination chemotherapy]. Gan To Kagaku Ryoho 2012; 39: 1279-1282 [PMID: 22902459]

20 Sano T, Shimizu Y, Senda Y, Hara K, Yamao K, Nimura Y. A resected case of initially unresectable hilar

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cholangiocarcinoma by left hepatic trisectionectomy, caudate lobectomy with simultaneous portal andhepatic arterial resection and reconstruction after systemic chemotherapy. HPB. 174–244 Conference: 3rdBiennial Congress of the Asian Pacific HPBA 2011 Melbourne, VIC Australia HPB 13, Suppl, P-1532011; 174-244

21 Wiedmann M, Caca K, Berr F, Schiefke I, Tannapfel A, Wittekind C, Mössner J, Hauss J, Witzigmann H.Neoadjuvant photodynamic therapy as a new approach to treating hilar cholangiocarcinoma: a phase IIpilot study. Cancer 2003; 97: 2783-2790 [PMID: 12767091 DOI: 10.1002/cncr.11401]

22 Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients.Transplantation 2000; 69: 1633-1637 [PMID: 10836374 DOI: 10.1097/00007890-200004270-00019]

23 Robles R, Figueras J, Turrión VS, Margarit C, Moya A, Varo E, Calleja J, Valdivieso A, Valdecasas JC,López P, Gómez M, de Vicente E, Loinaz C, Santoyo J, Fleitas M, Bernardos A, Lladó L, Ramírez P,Bueno FS, Jaurrieta E, Parrilla P. Spanish experience in liver transplantation for hilar and peripheralcholangiocarcinoma. Ann Surg 2004; 239: 265-271 [PMID: 14745336 DOI:10.1097/01.sla.0000108702.45715.81]

24 Ghali P, Marotta PJ, Yoshida EM, Bain VG, Marleau D, Peltekian K, Metrakos P, Deschênes M. Livertransplantation for incidental cholangiocarcinoma: analysis of the Canadian experience. Liver Transpl2005; 11: 1412-1416 [PMID: 16237695 DOI: 10.1002/lt.20512]

25 Alden ME, Mohiuddin M. The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer. Int J Radiat Oncol Biol Phys 1994; 28: 945-951 [PMID: 8138448DOI: 10.1016/0360-3016(94)90115-5]

26 Foo ML, Gunderson LL, Bender CE, Buskirk SJ. External radiation therapy and transcatheter iridium inthe treatment of extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys 1997; 39: 929-935 [PMID:9369143 DOI: 10.1016/S0360-3016(97)00299-X]

27 Sudan D, DeRoover A, Chinnakotla S, Fox I, Shaw B, McCashland T, Sorrell M, Tempero M, Langnas A.Radiochemotherapy and transplantation allow long-term survival for nonresectable hilarcholangiocarcinoma. Am J Transplant 2002; 2: 774-779 [PMID: 12243499 DOI:10.1034/j.1600-6143.2002.20812.x]

28 De Vreede I, Steers JL, Burch PA, Rosen CB, Gunderson LL, Haddock MG, Burgart L, Gores GJ.Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation forcholangiocarcinoma. Liver Transpl 2000; 6: 309-316 [PMID: 10827231 DOI: 10.1053/lv.2000.6143]

29 Heimbach JK, Gores GJ, Haddock MG, Alberts SR, Pedersen R, Kremers W, Nyberg SL, Ishitani MB,Rosen CB. Predictors of disease recurrence following neoadjuvant chemoradiotherapy and livertransplantation for unresectable perihilar cholangiocarcinoma. Transplantation 2006; 82: 1703-1707[PMID: 17198263 DOI: 10.1097/01.tp.0000253551.43583.d1]

30 Darwish Murad S, Kim WR, Harnois DM, Douglas DD, Burton J, Kulik LM, Botha JF, Mezrich JD,Chapman WC, Schwartz JJ, Hong JC, Emond JC, Jeon H, Rosen CB, Gores GJ, Heimbach JK. Efficacy ofneoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 UScenters. Gastroenterology 2012; 143: 88-98.e3; quiz e14 [PMID: 22504095 DOI:10.1053/j.gastro.2012.04.008]

31 Assistance Publique. Liver Resection Versus Radio-chemotherapy-Transplantation for HilarCholangiocarcinoma (TRANSPHIL). [accessedSep 11]. In ClinicalTrials.gov [Internet]. Bethesda (MD):U.S. National Library of Medicine. 2015; Available from:https://clinicaltrials.gov/ct2/show/NCT02232932 ClinicalTrials.gov Identifier: NCT02232932/

32 Hong JC, Petrowsky H, Kaldas FM, Farmer DG, Durazo FA, Finn RS, Saab S, Han SH, Lee P, MarkovicD, Lassman C, Hiatt JR, Busuttil RW. Predictive index for tumor recurrence after liver transplantation forlocally advanced intrahepatic and hilar cholangiocarcinoma. J Am Coll Surg 2011; 212: 514-20; discussion520-1 [PMID: 21463781 DOI: 10.1016/j.jamcollsurg.2010.12.005]

33 Mantel HT, Rosen CB, Heimbach JK, Nyberg SL, Ishitani MB, Andrews JC, McKusick MA, HaddockMG, Alberts SR, Gores GJ. Vascular complications after orthotopic liver transplantation after neoadjuvanttherapy for hilar cholangiocarcinoma. Liver Transpl 2007; 13: 1372-1381 [PMID: 17427173 DOI:10.1002/lt.21107]

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W J G SWorld Journal ofGastrointestinalSurgery

Submit a Manuscript: https://www.f6publishing.com World J Gastrointest Surg 2019 June 27; 11(6): 287-295

DOI: 10.4240/wjgs.v11.i6.287 ISSN 1948-9366 (online)

MINIREVIEWS

Hepatocellular carcinoma – time to take the ticket

Anju Mullath, Murali Krishna

ORCID number: Anju Mullath(0000-0003-0813-2203); MuraliKrishna (0000-0002-9590-5798).

Author contributions: Mullath Aand Krishna M contributed equallyto this work; Mullath A came upwith the idea and performed theliterature search; Krishna M wrotethe manuscript; All authors haveread and approved the finalmanuscript.

Conflict-of-interest statement: Theauthors declare that they have noconflict of interest.

Open-Access: This article is anopen-access article which wasselected by an in-house editor andfully peer-reviewed by externalreviewers. It is distributed inaccordance with the CreativeCommons Attribution NonCommercial (CC BY-NC 4.0)license, which permits others todistribute, remix, adapt, buildupon this work non-commercially,and license their derivative workson different terms, provided theoriginal work is properly cited andthe use is non-commercial. See:http://creativecommons.org/licenses/by-nc/4.0/

Manuscript source: Unsolicitedmanuscript

Received: May 9, 2019Peer-review started: May 10, 2019First decision: May 31, 2019Revised: June 13, 2019Accepted: June 20, 2019Article in press: June 21, 2019Published online: June 27, 2019

P-Reviewer: Huang XY, Zhu HS-Editor: Ma YJL-Editor: Filipodia

Anju Mullath, Department of Gastroenterology, Lakeshore Hospital and Research Centre, Kochi682040, Kerala, India

Murali Krishna, Department of Surgery, Military Hospital, Palampur 176061, HimachalPradesh, India

Corresponding author: Murali Krishna, DNB, MBBS, MD, Assistant Professor, Surgeon,Surgical Specialist, Department of Surgery, Military Hospital, Holta Camp, Palampur 176061,Himachal Pradesh, India. murali276@yahoo.comTelephone: 91-841-1066008

AbstractHepatocellular carcinoma is one of the leading malignancies worldwide. Earlydetection of hepatocellular carcinoma and its management in the form of livertransplantation offers an attractive treatment option. The Milan criteria, proposedby Mazzaferro et al, have been the standard for selecting patients withhepatocellular carcinoma for transplantation. Recently, several studies haveshown that even patients selected outside the Milan criteria can undergotransplantation with a relatively good outcome. This article examines thecurrently existing criteria other than the Milan criteria and also evaluates use ofalpha-fetoprotein and positron emission tomography scans to predict the chanceof recurrence.

Key words: Hepatocellular carcinoma; Milan; Alpha-fetoprotein; Positron emissiontomography

©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.

Core tip: The Milan criteria have been used extensively worldwide to select patients withhepatocellular carcinoma for liver transplantation. Over the years, it has been questionedwhether the Milan criteria are too restrictive and whether patients outside the Milancriteria could benefit from liver transplantation. Several other criteria have beenproposed and validated, and latest is the hepatocellular carcinoma Metroticket concept.This minireview evaluates the various current criteria that exist for liver transplantationfor hepatocellular carcinoma cases.

Citation: Mullath A, Krishna M. Hepatocellular carcinoma – time to take the ticket. World JGastrointest Surg 2019; 11(6): 287-295URL: https://www.wjgnet.com/1948-9366/full/v11/i6/287.htm

WJGS https://www.wjgnet.com June 27, 2019 Volume 11 Issue 6287

E-Editor: Liu JH DOI: https://dx.doi.org/10.4240/wjgs.v11.i6.287

INTRODUCTIONHepatocellular carcinoma (HCC) is one of the leading malignant diseases worldwide.It ranks third in terms of cancer-related mortality, and the incidence of HCC is on therise[1]. A range of management options are available for HCC and include excision,radiofrequency ablation, transarterial chemo embolization (TACE), and use ofbiological agents.

Liver transplantation offers a very unique treatment for HCC. Specifically, alongwith the lesion, it removes the tissue that is at risk for developing malignancy.However, there are certain risk factors associated with recurrence of tumor in thetransplanted liver and development of metastatic disease at a later date. Hence, not allcases of HCC are compatible with liver transplantation. Mazzaferro et al[2] came upwith criteria to select patients with HCC for liver transplantation. These criteria,which are widely known as the Milan criteria, suggest that patients with a single 5-cmtumor or with up to 3 tumors (each tumor not larger than 3 cm) can be eligible forliver transplantation. According to the Milan criteria, the outcome of transplantationis highly favorable, with an overall survival rate of 70%[3].

The rising incidence of HCC and a relatively easy availability of organs due to theliving donor liver transplantation (often referred to as LDLT) have led to the questionof whether the Milan criteria are too strict. Can patients outside the Milan criteria alsobenefit from liver transplantation? This problem has been addressed in two ways.First, advanced HCC patients are down-staged using locoregional therapy to fit intothe Milan criteria. Second, the criteria for transplantation were expanded to includepatients outside the Milan criteria.

Tumor down-stagingMajno et al[4] was the first to test the concept of HCC down-grading before trans-plantation. Preoperative TACE was applied in a cohort of 111 patients beforeorthotopic liver transplant (OLT). Majno et al[4] concluded that there was no beneficialeffect of preoperative TACE on recurrence-free survival after OLT. Another study byGraziadei et al[5] investigated a cohort of 15 patients with an HCC stage exceeding theT2 criteria, who underwent preoperative TACE. Among this cohort, 10 patientsunderwent OLT ultimately, and the 5-year survival rate after OLT was 41%. Thoughthe initial studies painted a dismal picture, the limiting factor in these studies was theabsence of well-defined criteria to select the patients for down-staging.

The seminal paper by Yao et al[6] looked into this problem. Those researchersdeveloped the modified UCSF down-staging inclusion criteria (Table 1). Initially, thestudy looked at a cohort of 30 patients, and the later follow-up paper expanded thiscohort to 61 patients. Successful down-staging was achieved in 70% of the cases, andamong those who underwent transplantation, the 4-year posttransplant survival ratewas 92%.

Lei et al[7] compared the overall survival and tumor-free survival in patients whounderwent transplantation according to the Milan criteria and those who were down-staged before transplantation. Out of the 112 patients included in the study, 58patients were outside the Milan criteria. The modified UCSF down-staging inclusioncriteria were used to include advanced HCC patients. TACE, “RAF”, “HIFU”,resection, etc were used as the down-staging therapies. The overall survival rate inpatients who underwent down-staging was 70.7% compared to 74.1% in patients whoinitially met the Milan criteria. The tumor recurrence rate was 20.7% in the down-staging group and 20.5% in the Milan criteria group.

The latest American Association for the Study of Liver Diseases (commonly knownas AASLD) guidelines[8] recommend that patients outside the Milan criteria should beconsidered for liver transplantation after successful down-staging. Though the highestoverall survival was noted for patients undergoing multimodal therapy, the optimalform of therapy is not known. TACE with stereotactic radiation therapy was initiallyused as a modality for treating inoperable HCC. Due to the treatment effectiveness,the same approach was extrapolated for use as a down-staging tool before trans-plantation. A limited case series of 12 patients, who underwent down-staging withTACE plus stereotactic radiation therapy, was published by Jacob et al[9]. Six patientsamong the twelve total underwent liver transplantation. There were no difficultiesduring the procedure, except for the effects of radiation. The explant pathologyshowed no viable tumor deposits at the 10 treated HCC sites in 6 patients.

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Table 1 Modified UCSF down-staging criteria

Extended criteria

UCSF[27] Single tumor ≤ 6.5 cm in diameter or no more than 3 lesions ≤ 4.5 cm indiameter, and total tumor diameter ≤ 8 cm

Asan criteria[28] ≤ 6 tumors, all ≤ 5 cm in diameter, and no gross vascular invasion

Valencia criteria[29] 1-3 tumors ≤ 5 cm and cumulative tumor burden ≤ 10 cm

Up-to-7 criteria[14] Sum of the sizes of the largest tumor (in cm) and the number of tumors ≤ 7

CUN criteria[30] Single tumor ≤ 6 cm or up to 3 nodules ≤ 5 cm

Mount-Sinai[31] Any number of lesions, each is 5-7 cm in diameter

Edmonton[32] Number of single tumors ≤ 7, tumor ≤ 5 cm in diameter

Dallas[33] Single tumor diameter ≤ 6 cm or 2-4 tumors each ≤ 5 cm in diameter

Tokyo[34] ≤ 5 tumors not exceeding 5 cm in diameter

Shanghai[35] Single tumor ≤ 9 cm in diameter or no more than 3 nodules with the largestnodule ≤ 5 cm in diameter, overall tumor diameter ≤ 9 cm withoutextrahepatic metastasis, lymph node or macrovascular invasion

The data from the global investigation of therapeutic decision in HCC and oftreatment with sorafenib (referred to as “GIDEON”)[10] have shown that thecombination of TACE and sorafenib has a beneficial effect on overall survival inpatients with advanced disease. The START trial[11] also supports the above-mentioned finding. The SPACE trial[12] tried this combination on the Barcelona stage BHCC and did not find any difference compared to using TACE alone. Even thoughfew of the latest studies[13] have shown benefit, further investigation is required, andfeasibility of this combination for down-staging needs to be evaluated.

EXTENDED CRITERIA FOR OLT IN HCCThe currently widely used Milan criteria were proposed by Mazzaferro et al[2] in 1996.Then, several studies ratified the utility of the Milan criteria by reporting 5-yearsurvival rates after liver transplantation ranging from 71% to 75%. This cemented theMilan criteria as a tool to select patients for OLT. However, the concept of limitingtransplantation based only on tumor size and number of nodules was originallydrawn from clinical experience. It is not known whether these are the ideal criteria.Several studies have shown that expanding the criteria in terms of the number ofnodules and size of lesion offers survival rates that are comparable to those of theMilan criteria. A list of currently used extended criteria (Table 2) and the relatedoverall survival (Figure 1) is presented below.

In 2009, Mazzaferro et al[14], who originally suggested the Milan criteria, developedan extended criteria, termed the Up-to-7 criteria (UTSC). Since then, the UTSC havebeen utilized in several studies. According to the UTSC, the 5-year survival rate aftera transplant is 71.2%. One of the latest studies, by Diaz et al (no reference available),reviewed the transplantations performed at their unit by dividing these trans-plantations into three groups: Patients within the Milan criteria; patients outside theMilan criteria but within the UTSC; and patients outside the UTSC. Out of the total 91patients, the maximum number of patients were within the Milan criteria (n = 74) andonly 12 patients were outside the Milan criteria but within the UTSC. The 5-yearsurvival was found to be 58.3% for the patients within the UTSC. Though this survivalrate was significantly lower than that in the earlier studies, the rate was still highcompared to the patients outside the UTSC.

However, the question remains as to how far can we push the envelope? Are wecausing more harm than good by expanding these criteria? What is the limit? In thepast, a 5-year post transplant survival of 50% was considered to be a cut-off. A studyconducted by the University of Michigan Health System compared the benefits inpatients with HCC undergoing transplantation beyond the Milan criteria versus theharm done to other patients on the organ waiting list[15]. The study concluded that theposttransplant 5-year survival rate should be at least 61% to avoid harm to otherpatients on the waiting list.

BIOMARKERS AS PREDICTORS OF RECURRENCE

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Figure 1

Figure 1 Overall 5-yr survival rates.1Denotes 4-yr survival rates.

The advantage of OLT for HCC is that it removes precancerous tissue and also helpsprevent recurrence. However, in approximately 20% of patients, there is recurrence ofHCC[16]. These patients have to undergo salvage transplantation or other treatments.An assessment to help estimate the risk of recurrence will help with better selection ofcandidates for transplantation.

Tumor biology helps with better predicting the risk of recurrence. The goldstandard remains biopsy of the tumor with histopathological examination. However,this invasive procedure is often fraught with dangers, such as bleeding and needletrack seeding. In addition, ascites in patients with decompensated cirrhosis is anothercontraindication for biopsy. To overcome this problem, other biomarkers are beingused to predict tumor behavior. These biomarkers include alpha-fetoprotein (AFP),des-gamma carboxy prothrombin, and positron emission tomography (PET) scan. Alist of criteria that use biomarkers (Table 3) and the associated survival rates (Figure 2)are presented below.

AFP is one of the earliest tumor markers for HCC. With the advent of betterimaging, the role of AFP has diminished. However, several studies have shown thatpreoperative levels of AFP can help predict recurrence. Several criteria have evolvedto include AFP for selecting patients for transplantation. A study conducted by Tosoet al[17] reviewed 6478 patients who underwent liver transplantation for HCC.According to this study, only the total tumor volume and AFP levels can predictpatient survival. Then, a composite score was created with a cut-off of total tumorvolume > 115 cm3 and AFP > 400 ng/mL. Patients who did not meet the scorerequirement had a 5-year survival rate below 50% at 3 years. Other similar AFP-basedcriteria include the “AFP-TTD” and Warsaw criteria.

Another study conducted by Ito et al[18] analyzed the results of 125 patients whounderwent liver transplantation for HCC, to determine the optimal criteria outsidethe Milan criteria. In their multivariate analysis, PIVKA-II level < 400 mAU/mL wasfound to significantly correlate with 5-year recurrence rates. A similar studyconducted by Kim et al[19] studied the factors involved in recurrence of HCC followingthe adult LDLT. Out of the cohort of 461 patients, 77 patients had a recurrence. Thestudy concluded that PIVKA-II level > 100 mAU/mL and AFP level > 150 ng/mLwere among the important deciding factors for tumor recurrence.

PET is being increasingly used in oncology treatment worldwide. This functionalscan is based on the utilization of glucose by metabolically active tissues, such astumors. The most commonly used tracer is 18-fluorodeoxyglucose (FDG). Othertracers that have been used include 11-C-acetate and 18-F-choline. The sensitivity of18FDG in HCC ranges from 50% to 70%[20]. Because hepatocytes have a physiologicaluptake of glucose, the ability to contrast between a well-differentiated tumor andnormal liver cells is difficult. Okazumi et al[21] have classified liver tumors based on theFDG uptake pattern into three types: Type I - greater accumulation of tracercompared to normal liver tissue; Type II - similar to normal liver tissue accumulationof tracer; and Type III – lower accumulation compared to normal liver tissue.

There have been several publications describing investigations into the utility ofPET scan in managing HCC. An article by Campos et al[22] reviewed the use of FDG-

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Table 2 Extended criteria currently in use

Inclusion criteria

a) 1 lesion > 5 cm and ≤ 8 cm

b) 2 or 3 lesions, at least one > 3 cm but ≤ 5 cm + the total tumor diameter ≤ 8 cm

c) 4 or 5 lesions, all ≤ 3 cm + the total tumor diameter ≤ 8 cm

d) No vascular invasion on imaging

Criteria for successful down-staging

Tumor size and number need to satisfy the UNOS T2 criteria

Complete tumor necrosis without contrast enhancement to suggest residual tumor, equivalent to obliteration of the tumor irrespective of the tumor size

Additional guidelines

1) A minimum observation period of 3 mo after down-staging is required before deceased donor liver transplantation, and if imaging studies meet theabove-mentioned criteria for successful down-staging

2) Patients can undergo live donor liver transplantation at 3 mo after down-staging, and if imaging studies satisfy the UCSF criteria

3) Those with acute hepatic decompensation after the down-staging procedure are not eligible for liver transplantation unless they satisfy theabovementioned criteria

Inclusion criteria

e) 1 lesion > 5 cm and ≤ 8 cm

f) 2 or 3 lesions, at least one > 3 cm but ≤ 5 cm + the total tumor diameter ≤ 8 cm

g) 4 or 5 lesions, all ≤ 3 cm + the total tumor diameter ≤ 8 cm

No vascular invasion on imaging

Criteria for successful down-staging

Tumor size and number need to satisfy the UNOS T2 criteria

1) Complete tumor necrosis without contrast enhancement to suggest presence of a residual tumor, equivalent to tumor obliteration irrespective of thetumor size

Additional guidelines

4) A minimum observation period of 3 mo after down-staging is required before deceased donor liver transplantation, and if imaging studies satisfy theabove-mentioned criteria for successful down-staging

5) Patients can undergo live donor liver transplantation at 3 mo after down-staging, and if imaging studies satisfy the UCSF criteria

6) Those with acute hepatic decompensation after the down-staging procedure are not eligible for liver transplantation unless they meet the above-mentioned criteria

PET in HCC patients undergoing transplantation. It was observed that the amount oftracer uptake had a significant association with the outcome after surgery. The traceruptake value is denoted by SUVmax, and tumors with a low tracer uptake had betterprognosis after transplantation even if tumors were outside the Milan criteria.Another value that is commonly used in studies is the ratio between SUVmax of thetumor and the normal liver tissue denoted as TSUVmax/LSUVmax. Studies haveshown that TSUVmax/LSUVmax < 1.15 indicates a disease-free survival of 97% at 2years compared to 42% in patients with a value > 1.15[23]. A recent study by Song etal[24] evaluated 123 HCC patients who underwent partial liver transplant. The studyshowed that the PET-transarterial chemolipiodolization and AFP levels, when usedtogether, had a better chance at predicting recurrence than the Milan criteria. The cut-off for the AFP level was 200 and the PET positivity was set at TSUVmax/LSUVmax >1.1.

CONCLUSIONHCC is one of the leading malignancies worldwide. HCC is also a leading cause ofmortality. Surgical management of HCC in the form of liver transplantation has avery good outcome when performed in the right candidates. The latest studiessupport the “HCC-Metroticket” concept[25] in which the criteria fulfilling a 5-yearsurvival of 60%-80% are acceptable. The Metroticket project has launched a website(http://www.hcc-olt-metroticket.org/), on which you can calculate the preoperative5-year survival rates using parameters such as the maximum tumor size, number ofnodules, and AFP level.

Ultimately, all of these protocols and criteria were created because we do not havea complete understanding of the genetic alterations that lead to carcinogenesis and theway that different mutations affect cancer biology. In the future, having a betterunderstanding of the genetic makeup of tumors and using new markers, such as longnoncoding RNAs[26], can make these criteria obsolete. Until then, we can strive to

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Figure 2

Figure 2 5-yr overall survival rates.1Denotes 3-yr survival rates.

achieve the best result possible without causing harm to other patients.

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Table 3 Criteria including tumor biomarkers

Biomarker criteria

TTV/AFP[17] Total tumor volume ≤ 115 cm3 and AFP ≤ 400 ng/mL

AFP-TTD[36] Total tumor diameter ≤ 8 cm and AFP ≤ 400 ng/mL

Warsaw[37] Outside the Milan criteria but within the UCSF/ Up-to-7 criteria with AFP <100 ng/mL

NCCK[38] Negative PET/CT findings and the total tumor size < 10 cm

Kyoto[18] ≤ 10 tumors, all of which ≤ 5 cm in diameter, and serum DCP ≤ 400mAU/mL

Kyushu university[39] Tumor diameter ≤ 5 cm and serum DCP ≤ 300 mAU/mL

Extended Toronto[40] No size-number limitation, no vascular invasion, no extrahepatic disease, nocancer-related symptoms, biopsy of the largest tumor not poorlydifferentiated

AFP: Alpha-fetoprotein; CT: Computed tomography; DCP: Des-gamma carboxy prothrombin; PET: Positron emission tomography; TTV: Total tumorvolume.

REFERENCES1 Rossi L, Zoratto F, Papa A, Iodice F, Minozzi M, Frati L, Tomao S. Current approach in the treatment of

hepatocellular carcinoma. World J Gastrointest Oncol 2010; 2: 348-359 [PMID: 21160806 DOI:10.4251/wjgo.v2.i9.348]

2 Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M,Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas inpatients with cirrhosis. N Engl J Med 1996; 334: 693-699 [PMID: 8594428 DOI:10.1056/NEJM199603143341104]

3 Jonas S, Bechstein WO, Steinmüller T, Herrmann M, Radke C, Berg T, Settmacher U, Neuhaus P.Vascular invasion and histopathologic grading determine outcome after liver transplantation forhepatocellular carcinoma in cirrhosis. Hepatology 2001; 33: 1080-1086 [PMID: 11343235 DOI:10.1053/jhep.2001.23561]

4 Majno P, Giostra E, Mentha G. Management of hepatocellular carcinoma on the waiting list before livertransplantation: time for controlled trials? Liver Transpl 2007; 13: S27-S35 [PMID: 17969086 DOI:10.1002/lt.21328]

5 Graziadei IW, Sandmueller H, Waldenberger P, Koenigsrainer A, Nachbaur K, Jaschke W, Margreiter R,Vogel W. Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedestumor progression while on the waiting list and leads to excellent outcome. Liver Transpl 2003; 9: 557-563[PMID: 12783395 DOI: 10.1053/jlts.2003.50106]

6 Yao FY, Mehta N, Flemming J, Dodge J, Hameed B, Fix O, Hirose R, Fidelman N, Kerlan RK, RobertsJP. Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumorswithin Milan criteria. Hepatology 2015; 61: 1968-1977 [PMID: 25689978 DOI: 10.1002/hep.27752]

7 Lei J, Wang W, Yan L. Downstaging advanced hepatocellular carcinoma to the Milan criteria may providea comparable outcome to conventional Milan criteria. J Gastrointest Surg 2013; 17: 1440-1446 [PMID:23719776 DOI: 10.1007/s11605-013-2229-y]

8 Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, Zhu AX, Murad MH, MarreroJA. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018; 67: 358-380[PMID: 28130846 DOI: 10.1002/hep.29086]

9 Jacob R, Saddekni S, Dover L, DuBay DA. Successful hepatocellular carcinoma downstaging withtransarterial chemoembolization followed by stereotactic radiotherapy. Liver Transpl 2016; 22: 547-551[PMID: 26785388 DOI: 10.1002/lt.24398]

10 Geschwind JF, Gholam PM, Goldenberg A, Mantry P, Martin RC, Piperdi B, Zigmont E, Imperial J,Babajanyan S, Foreman PK, Cohn A. Use of Transarterial Chemoembolization (TACE) and Sorafenib inPatients with Unresectable Hepatocellular Carcinoma: US Regional Analysis of the GIDEON Registry.Liver Cancer 2016; 5: 37-46 [PMID: 26989658 DOI: 10.1159/000367757]

11 Chung YH, Han G, Yoon JH, Yang J, Wang J, Shao GL, Kim BI, Lee TY, Chao Y. Interim analysis ofSTART: Study in Asia of the combination of TACE (transcatheter arterial chemoembolization) withsorafenib in patients with hepatocellular carcinoma trial. Int J Cancer 2013; 132: 2448-2458 [PMID:23129123 DOI: 10.1002/ijc.27925]

12 Lencioni R, Llovet JM, Han G, Tak WY, Yang J, Guglielmi A, Paik SW, Reig M, Kim DY, Chau GY,Luca A, Del Arbol LR, Leberre MA, Niu W, Nicholson K, Meinhardt G, Bruix J. Sorafenib or placeboplus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial. J Hepatol 2016;64: 1090-1098 [PMID: 26809111 DOI: 10.1016/j.jhep.2016.01.012]

13 Ren B, Wang W, Shen J, Li W, Ni C, Zhu X. Transarterial Chemoembolization (TACE) Combined withSorafenib <i>versus</i> TACE Alone for Unresectable Hepatocellular Carcinoma: A Propensity ScoreMatching Study. J Cancer 2019; 10: 1189-1196 [PMID: 30854128 DOI: 10.7150/jca.28994]

14 Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, Camerini T, Roayaie S, SchwartzME, Grazi GL, Adam R, Neuhaus P, Salizzoni M, Bruix J, Forner A, De Carlis L, Cillo U, Burroughs AK,Troisi R, Rossi M, Gerunda GE, Lerut J, Belghiti J, Boin I, Gugenheim J, Rochling F, Van Hoek B, MajnoP; Metroticket Investigator Study Group. Predicting survival after liver transplantation in patients withhepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol2009; 10: 35-43 [PMID: 19058754 DOI: 10.1016/S1470-2045(08)70284-5]

15 Yao FY. Liver transplantation for hepatocellular carcinoma: beyond the Milan criteria. Am J Transplant

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Mullath A et al. Alternatives to the Milan criteria for HCC

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2008; 8: 1982-1989 [PMID: 18727702 DOI: 10.1111/j.1600-6143.2008.02351.x]16 Yan WT, Quan B, Xing H, Wu MC, Yang T. Time to recurrence, but not recurrence-free survival, should

be the endpoint used to predict early recurrence after HCC resection. J Hepatol 2019; 70: 570-571 [PMID:30553526 DOI: 10.1016/j.jhep.2018.10.025]

17 Toso C, Asthana S, Bigam DL, Shapiro AM, Kneteman NM. Reassessing selection criteria prior to livertransplantation for hepatocellular carcinoma utilizing the Scientific Registry of Transplant Recipientsdatabase. Hepatology 2009; 49: 832-838 [PMID: 19152426 DOI: 10.1002/hep.22693]

18 Ito T, Takada Y, Ueda M, Haga H, Maetani Y, Oike F, Ogawa K, Sakamoto S, Ogura Y, Egawa H,Tanaka K, Uemoto S. Expansion of selection criteria for patients with hepatocellular carcinoma in livingdonor liver transplantation. Liver Transpl 2007; 13: 1637-1644 [PMID: 18044766 DOI: 10.1002/lt.21281]

19 Kim DY, Paik YH, Ahn SH, Youn YJ, Choi JW, Kim JK, Lee KS, Chon CY, Han KH. PIVKA-II is auseful tumor marker for recurrent hepatocellular carcinoma after surgical resection. Oncology 2007; 72Suppl 1: 52-57 [PMID: 18087182 DOI: 10.1159/000111707]

20 Cho KJ, Choi NK, Shin MH, Chong AR. Clinical usefulness of FDG-PET in patients with hepatocellularcarcinoma undergoing surgical resection. Ann Hepatobiliary Pancreat Surg 2017; 21: 194-198 [PMID:29264581 DOI: 10.14701/ahbps.2017.21.4.194]

21 Okazumi S, Isono K, Enomoto K, Kikuchi T, Ozaki M, Yamamoto H, Hayashi H, Asano T, Ryu M.Evaluation of liver tumors using fluorine-18-fluorodeoxyglucose PET: characterization of tumor andassessment of effect of treatment. J Nucl Med 1992; 33: 333-339 [PMID: 1311035]

22 Cascales-Campos PA, Romero PR, Schneider MA, Lopez-Lopez V, Navarro JL, Frutos L, Pons MiñanoJA, Paricio PP. Positron emission tomography/computed tomography in patients with hepatocellularcarcinoma undergoing liver transplantation. Useful, necessary or irrelevant? Eur J Radiol 2017; 91: 155-159 [PMID: 28629563 DOI: 10.1016/j.ejrad.2017.03.013]

23 Lee JW, Paeng JC, Kang KW, Kwon HW, Suh KS, Chung JK, Lee MC, Lee DS. Prediction of tumorrecurrence by 18F-FDG PET in liver transplantation for hepatocellular carcinoma. J Nucl Med 2009; 50:682-687 [PMID: 19372474 DOI: 10.2967/jnumed.108.060574]

24 Song MJ, Bae SH, Yoo IeR, Park CH, Jang JW, Chun HJ, Choi BG, Lee HG, Choi JY, Yoon SK.Predictive value of ¹F-fluorodeoxyglucose PET/CT for transarterial chemolipiodolization of hepatocellularcarcinoma. World J Gastroenterol 2012; 18: 3215-3222 [PMID: 22783045 DOI:10.3748/wjg.v18.i25.3215]

25 Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma.Semin Liver Dis 2005; 25: 181-200 [PMID: 15918147 DOI: 10.1055/s-2005-871198]

26 Krishna M, Mullath A. Role of lncRNAs in GI Cancer. J Cancer Therapy 2018; 9: 281-298 [DOI:10.4236/jct.2018.93026]

27 Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, Ascher NL, Roberts JP. Livertransplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impactsurvival. Hepatology 2001; 33: 1394-1403 [PMID: 11391528 DOI: 10.1053/jhep.2001.24563]

28 Lee SG, Hwang S, Moon DB, Ahn CS, Kim KH, Sung KB, Ko GY, Park KM, Ha TY, Song GW.Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one large-volume center. Liver Transpl 2008; 14: 935-945 [PMID: 18581465 DOI: 10.1002/lt.21445]

29 Silva M, Moya A, Berenguer M, Sanjuan F, López-Andujar R, Pareja E, Torres-Quevedo R, Aguilera V,Montalva E, De Juan M, Mattos A, Prieto M, Mir J. Expanded criteria for liver transplantation in patientswith cirrhosis and hepatocellular carcinoma. Liver Transpl 2008; 14: 1449-1460 [PMID: 18825681 DOI:10.1002/lt.21576]

30 Herrero JI, Sangro B, Quiroga J, Pardo F, Herraiz M, Cienfuegos JA, Prieto J. Influence of tumorcharacteristics on the outcome of liver transplantation among patients with liver cirrhosis andhepatocellular carcinoma. Liver Transpl 2001; 7: 631-636 [PMID: 11460231 DOI:10.1053/jlts.2001.25458]

31 Roayaie S, Frischer JS, Emre SH, Fishbein TM, Sheiner PA, Sung M, Miller CM, Schwartz ME. Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellularcarcinomas larger than 5 centimeters. Ann Surg 2002; 235: 533-539 [PMID: 11923610 DOI:10.1097/00000658-200204000-00012]

32 Kneteman NM, Oberholzer J, Al Saghier M, Meeberg GA, Blitz M, Ma MM, Wong WW, Gutfreund K,Mason AL, Jewell LD, Shapiro AM, Bain VG, Bigam DL. Sirolimus-based immunosuppression for livertransplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl 2004; 10:1301-1311 [PMID: 15376305 DOI: 10.1002/lt.20237]

33 Onaca N, Davis GL, Goldstein RM, Jennings LW, Klintmalm GB. Expanded criteria for livertransplantation in patients with hepatocellular carcinoma: a report from the International Registry ofHepatic Tumors in Liver Transplantation. Liver Transpl 2007; 13: 391-399 [PMID: 17318865 DOI:10.1002/lt.21095]

34 Sugawara Y, Tamura S, Makuuchi M. Living donor liver transplantation for hepatocellular carcinoma:Tokyo University series. Dig Dis 2007; 25: 310-312 [PMID: 17960065 DOI: 10.1159/000106910]

35 Fan J, Yang GS, Fu ZR, Peng ZH, Xia Q, Peng CH, Qian JM, Zhou J, Xu Y, Qiu SJ, Zhong L, Zhou GW,Zhang JJ. Liver transplantation outcomes in 1,078 hepatocellular carcinoma patients: a multi-centerexperience in Shanghai, China. J Cancer Res Clin Oncol 2009; 135: 1403-1412 [PMID: 19381688 DOI:10.1007/s00432-009-0584-6]

36 Lai Q, Avolio AW, Manzia TM, Sorge R, Agnes S, Tisone G, Berloco PB, Rossi M. Combination ofbiological and morphological parameters for the selection of patients with hepatocellular carcinomawaiting for liver transplantation. Clin Transplant 2012; 26: E125-E131 [PMID: 22192083 DOI:10.1111/j.1399-0012.2011.01572.x]

37 Grąt M, Kornasiewicz O, Lewandowski Z, Hołówko W, Grąt K, Kobryń K, Patkowski W, Zieniewicz K,Krawczyk M. Combination of morphologic criteria and α-fetoprotein in selection of patients withhepatocellular carcinoma for liver transplantation minimizes the problem of posttransplant tumorrecurrence. World J Surg 2014; 38: 2698-2707 [PMID: 24858191 DOI: 10.1007/s00268-014-2647-3]

38 Lee SD, Lee B, Kim SH, Joo J, Kim SK, Kim YK, Park SJ. Proposal of new expanded selection criteriausing total tumor size and (18)F-fluorodeoxyglucose - positron emission tomography/computedtomography for living donor liver transplantation in patients with hepatocellular carcinoma: The NationalCancer Center Korea criteria. World J Transplant 2016; 6: 411-422 [PMID: 27358787 DOI:10.5500/wjt.v6.i2.411]

39 Soejima Y, Taketomi A, Yoshizumi T, Uchiyama H, Aishima S, Terashi T, Shimada M, Maehara Y.Extended indication for living donor liver transplantation in patients with hepatocellular carcinoma.

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Transplantation 2007; 83: 893-899 [PMID: 17460559 DOI: 10.1097/01.tp.0000259015.46798.ec]40 Sapisochin G, Goldaracena N, Laurence JM, Dib M, Barbas A, Ghanekar A, Cleary SP, Lilly L, Cattral

MS, Marquez M, Selzner M, Renner E, Selzner N, McGilvray ID, Greig PD, Grant DR. The extendedToronto criteria for liver transplantation in patients with hepatocellular carcinoma: A prospectivevalidation study. Hepatology 2016; 64: 2077-2088 [PMID: 27178646 DOI: 10.1002/hep.28643]

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W J G SWorld Journal ofGastrointestinalSurgery

Submit a Manuscript: https://www.f6publishing.com World J Gastrointest Surg 2019 June 27; 11(6): 296-302

DOI: 10.4240/wjgs.v11.i6.296 ISSN 1948-9366 (online)

CASE REPORT

Role of total pancreatectomy in the treatment of paraduodenalpancreatitis: A case report

Danko Mikulić, Tomislav Bubalo, Anna Mrzljak, Anita Škrtić, Stipislav Jadrijević, Tajana Filipec Kanižaj,Branislav Kocman

ORCID number: Danko Mikulic(0000-0001-8103-6045); TomislavBubalo (0000-0003-1422-8439); AnnaMrzljak (0000-0001-6270-2305);Anita Škrtić (0000-0002-9275-7283);Stipislav Jadrijević(0000-0002-0565-0665); TajanaFilipec Kanizaj(0000-0002-9828-8916); BranislavKocman (0000-0003-1497-6031).

Author contributions: Mikulić Dand Bubalo T were the patient’soperator and assistant. Mikulić Dreviewed the literature andcontributed to manuscript drafting.Bubalo T contributed tomanuscript drafting. Mrzljak Areviewed the literature andcontributed to manuscript drafting.Škrtić A performed pathologyanalyzed and explained thepathology imagings findings.Jadrijević S, Filipec Kanižaj T andKocman B were responsible for therevision of the manuscript forimportant intellectual content. Allauthors issued final approval forthe version to be submitted.

Informed consent statement:Informed written consent wasobtained from the patient forpublication of this report and anyaccompanying images.

Conflict-of-interest statement: Theauthors declare that they have noconflict of interest.

CARE Checklist (2016) statement:The authors have read the CAREChecklist (2016), and themanuscript was prepared andrevised according to the CARE

Danko Mikulić, Tomislav Bubalo, Stipislav Jadrijević, Branislav Kocman - Division ofAbdominal Surgery and Organ Transplantation, Department of Surgery, University HospitalMerkur, Zagreb 10000, Croatia

Anna Mrzljak, Tajana Filipec Kanižaj - Division of Gastroenterology, Department of InternalMedicine, University of Zagreb, School of Medicine, University Hospital Merkur, Zagreb10000, Croatia

Anita Škrtić, Department of Pathology and Cytology, University of Zagreb, School ofMedicine, University Hospital Merkur, Zagreb 10000, Croatia

Corresponding author: Danko Mikulić, MD, PhD, FEBS, Division of Abdominal Surgery andOrgan Transplantation, Department of Surgery, University Hospital Merkur, Zajčeva 19,Zagreb 10000, Croatia. danko.mikulic@zg.t-com.hr

AbstractBACKGROUNDParaduodenal pancreatitis (PP) is a rare form of chronic pancreatitis presentingwith symptoms of duodenal obstruction. Conservative treatment is oftenunsuccessful and pancreaticoduodenectomy is the preferred surgical approach. Amini review of the outcomes of surgical therapy for PP shows that the results ofpancreaticoduodenectomy are predominantly favorable.

CASE SUMMARYIn our case report of PP, we describe an unusual course first presenting with thesymptoms of chronic pancreatitis and a pseudocyst of the pancreatic tail. Apseudocystojejunostomy was performed and the late postoperative course wascomplicated with the symptoms of duodenal obstruction. At laparotomy, PP wasfound and the patient was treated with a total pancreatectomy. The postoperativecourse was uneventful and good weight gain with resolution of pain wasdemonstrated at follow up visits.

CONCLUSIONSurgery is currently the optimal treatment option for PP. It is also the bestdiagnostic tool in distinguishing between pancreatitis and pancreaticadenocarcinoma.

Key words: Paraduodenal pancreatitis; Groove pancreatitis; Chronic pancreatitis; Total

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Checklist (2016).

Open-Access: This article is anopen-access article which wasselected by an in-house editor andfully peer-reviewed by externalreviewers. It is distributed inaccordance with the CreativeCommons Attribution NonCommercial (CC BY-NC 4.0)license, which permits others todistribute, remix, adapt, buildupon this work non-commercially,and license their derivative workson different terms, provided theoriginal work is properly cited andthe use is non-commercial. See:http://creativecommons.org/licenses/by-nc/4.0/

Manuscript source: Unsolicitedmanuscript

Received: April 17, 2019Peer-review started: April 18, 2019First decision: May 31, 2019Revised: June 6, 2019Accepted: June 21, 2019Article in press: June 21, 2019Published online: June 27, 2019

P-Reviewer: Fan Y, Jin C, Lieto ES-Editor: Ma YJL-Editor: AE-Editor: Wang J

pancreatectomy; Case report

©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.

Core tip: Paraduodenal pancreatitis (PP) is a rare form of chronic pancreatitis presentingwith symptoms of duodenal obstruction. Conservative treatment is often unsuccessfuland pancreaticoduodenectomy is the preferred surgical approach. Differential diagnosisfrom carcinoma of the pancreatic head can be quite difficult and it is often onlypostoperative pathology that provides the definitive diagnosis. In this case report wepresent an uncommon case where PP was associated with a necrotic pseudocyst of thetail of the pancreas and the patient was treated with total pancreatectomy.

Citation: Mikulić D, Bubalo T, Mrzljak A, Škrtić A, Jadrijević S, Kanižaj TF, Kocman B.Role of total pancreatectomy in the treatment of paraduodenal pancreatitis: A case report.World J Gastrointest Surg 2019; 11(6): 296-302URL: https://www.wjgnet.com/1948-9366/full/v11/i6/296.htmDOI: https://dx.doi.org/10.4240/wjgs.v11.i6.296

INTRODUCTIONParaduodenal pancreatitis (PP) is an often unrecognized form of chronic pancreatitisthat can present with diagnostic and therapeutic dilemmas. It is a rare form of focalpancreatitis involving the area of the paraduodenal groove, that is, the area betweenthe dorso-cranial portion of the pancreatic head, duodenum and the common bileduct. It was first described in 1970 and the authors proposed the term ’’duodenaldystrophy’’[1]. Several other synonyms for PP have appeared based on differentpathologic and imaging characteristics of this uncommon disease, including: Groovepancreatitis, paraduodenal wall cysts, cystic pancreatic heterotopic dystrophy,myoadenomatosis of the duodenum and pancreatic hamartoma of the duodenum[2].The exact incidence of PP is difficult to establish as it is often unrecognized, but isreported to be found in 12.8%-19.5% of surgical specimens after pancreaticoduo-denectomy for chronic pancreatitis[2,3]. PP is frequently associated with the presence ofheterotopic pancreatic tissue in the duodenal wall, therefore, the pathogenesis of PP isbelieved to be related to chronic inflammation of this tissue. Alcohol consumption isfound to be the culprit in most patients. In 15 retrospective reports, 79.68% patients(251 out of 305) with PP were alcohol abusers[4].

PP is clinically manifested by recurrent episodes of pancreatitis, chronic abdominalpain located mostly in the epigastrium, obstructive jaundice, weight loss, nausea andvomiting caused by duodenal stenosis [2 ,5]. Diagnosis is based on computertomography (CT) and magnetic resonance (MR) imaging and endoscopic ultrasound.Differential diagnosis from carcinoma of the pancreatic head can be quite difficult andit is often only postoperative pathology that provides the definitive diagnosis.

Different treatment modalities have been proposed for PP, ranging from medicalmanagement to endoscopic treatment to surgical resection. However, it seems thatsurgical therapy, namely pancreaticoduodenectomy (PD) offers the best long-termresults in patients with PP[6,7]. Apart from symptom resolution, it also provides fordefinitive pathologic diagnosis and prevents recurrence[8-10].

The purpose of this review is to summarize the cases of PP treated with PD thathave been published to date, to evaluate the results and analyze the role of surgicaltherapy. Also, we present an uncommon case where PP was associated with a necroticpseudocyst of the tail of the pancreas and the patient was treated by totalpancreatectomy (TP).

Literature searchA PubMed literature search was performed for studies dealing with surgicaltreatment for PP published between 2000 and 2018. Key words used were groovepancreatitis, PP, duodenal wall cyst, cystic pancreatic heterotopic dystrophy,myoadenomatosis of the duodenum, pancreatic hamartoma of the duodenum andsynonyms, surgical treatment, surgery and pancreaticoduodenectomy. Only studiespublished in English were analyzed (Table 1).

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Table 1 Studies in english dealing with outcomes of surgical treatment of paraduodenalpancreatitis

Ref. Study design Period No. of patients No. of operated patients

Rahman et al[9] Prospective 2000-2005 11 11

Egorov et al[6] Prospective 2004-2013 62 52

Casetti et al[10] Prospective 1990-2006 58 58

Oza et al[15] Case control 2000-2013 13 9

Jounnaud et al[16] Retrospective 1990-2004 23 14

Rebours et al[17] Retrospective 1995-2004 105 29

CASE PRESENTATION

Chief complaintsA 69-year old man presented with a history of chronic alcoholic pancreatitis and an 8cm x 6 cm pseudocyst of the pancreatic tail. He complained of long lasting symptomsincluding chronic abdominal pain, nausea and early satiety.

History of present illnessPreoperative upper endoscopy and multi-slice computer tomography (MSCT) showedno other pathological findings, with normal appearance of the duodenum and thepancreatic head. He underwent an uneventful surgical pseudocystojejunostomy witha normal operative and early postoperative course. Three months postoperatively hepresented to the emergency department with epigastric pain, intense nausea,vomiting, intolerance of solid food and profound weight loss. An urgent MSCTshowed a markedly enlarged pancreatic head with suspected tumor involvement ofthe pancreatico-duodenal complex and dilation of the intrahepatic and extrahepaticbile ducts (Figure 1). On upper endoscopy, obstruction of the duodenum wasapparent with duodenal biopsy showing nonspecific mucosal changes consistent withchronic inflammation. Upper gastrointestinal series also showed obstruction of theduodenum (Figure 2). A decision was made to perform a PD. At laparotomy, theoperation was extended into a TP since the pancreatic tail showed marked atrophywith necrotic debris filling the residual psudocyst. Both operative and postoperativecourses were uneventful. The patient was released on the 10th postoperative day andafter 6 months of follow-up, the patient was unremarkable, with no pain and a weightgain of 7 kg. The control of his diabetes is satisfactory with HbA1c value of 7%.

History of past illnessApart from chronic pancreatitis the patient had no significant past medical history.

Physical examinationPathology report showed a thickened duodenal mucosa with cysts ranging in dia-meter up to 0.9 cm containing clear fluid, permeating at the interface between theduodenum and the pancreas. Hyperplasia of Brunner's glands and smooth musclecells was visible with proliferation of connective tissue in lamina propria, submucosaland subserosal tissues. Pancreatic tissue in the paraduodenal area showed a reductionof the lobular arhitecture that was replaced with connective tissue. Epithelial changesin the pancreatic periferal small ducts were consistent with pancreatic intraepithelialneoplasia (PanIN) 2 and 3 in unaffected pancreatic tissue. Serial sectioning of thespecimen revealed the minor papilla proximal to the major papilla. Papilla wasaffected with the disease (Figure 3).

DISCUSSIONPP is described as an inflammatory process between the C-loop of the duodenum andthe head of the pancreas. It is mainly associated with male gender, smoking andalcohol consumption[3]. Duodenal stenosis and cystic lesions in the duodenum arecommon findings. It is clearly a distinct entity from chronic pancreatitis of thepancreas proper and from pancreatic pseudocysts. Cystic lesions of PP are lined withepithelium and they are located inside the duodenal wall with no connection to thepancreas proper[5]. On the other hand, in a number of patients, PP is associated withmore extensive chronic pancreatitis and pancreatic pseudocysts.

Two theories exist regarding the pathophysiology of the disease. First, PP may be

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Figure 1

Figure 1 Multi-slice computer tomography scan of abdominal cavity. A suspected tumor mass of thepancreatico-duodenal complex (yellow circle) and dilation of the intrahepatic and extrahepatic bile ducts (orangearrows).

the consequence of obstruction of small ducts of heterotopic pancreatic tissue in theduodenum leading to acute and chronic inflammation[11]. Second mechanismassociates the toxic effects of alcohol in heterotopic pancreas leading to chronicinflammation. The mechanisms of obstruction and alcohol toxicity in pancreatitis ofthe pancreaticoduodenal groove may even be synergistic[5].

In most series, patients with PP are first offered medical management. Conservativetreatment relies on analgetics, alcohol abstinence, octreotide and endoscopic fenestra-tion of the cysts. However, when conservative treatment fails, surgery is performedwith pancreaticoduodenectomy playing a central role in the surgical armamentarium.

In this mini-review, we have analyzed several reports focusing on surgical tre-atment of PP. Results of surgical treatment are overall good with 80% of patientsreporting complete relief of symptoms after surgery. The majority of patients in theanalyzed studies have been treated with pancreaticoduodenectomy. The proceduresthat are performed less often include bypass procedures, pancreas preservingduodenal resections and duodenum preserving pancreatic head resections (Table 2).Bypass procedures may relieve the symptoms but they can not prevent recurrentsbouts of pancreatitis. The efficiency of duodenum and pancreas preserving resectionsis limited by incomplete resection of the groove area[6]. On the other hand, pancrea-ticoduodenectomy is usually effective since all of the diseased tissue is removed.Literature analyzed in this mini-review provides evidence that suggests goodoutcomes after pancreaticoduodenectomy for PP. Most of the patients experience painrelief and weight gain. Even though it is a major procedure with significant morbidityand mortality, PD is still the best option both for diagnostic and for therapeutic mana-gement of PP.

In the literature, we have not found any reports of TP for PP. Our patient had anatypical course first presenting with a symptomatic pseudocyst of the pancreatic tailand chronic pancreatitis of the pancreas proper. At the time, he had no signs ofduodenal obstruction or other symptoms of PP. Only several months after pseudocy-stojejunostomy, there was an exacerbation of PP with complete duodenal obstructionthat prompted surgery. Due to necrosis and atrophy of the remaining body and tail ofthe pancreas, the decision was made to perform a TP. Despite being a more extensiveoperation than PD, TP today has similar postoperative outcomes without the risk of apancreatic fistula[12]. In the past, metabolic problems such as brittle insulin-dependentdiabetes mellitus and malabsorption due to loss of pancreatic exocrine secretion weredifficult to control. Weight loss, diarrhea and malabsorption often contributed tocachexia-like syndrome and to considerable loss of quality of life in patients after TP.Due to these reasons, TP was largely abandoned for a long time[13].

Significant improvements in the control of diabetes together with the pancreaticenzyme treatments for exocrine pancreatic insufficiency provide good options forovercoming postoperative consequences of TP[14]. Therefore, chronic pancreatitis withinvolvement of both the head and the body of pancreas can be one of the emergingindications for this operation.

CONCLUSIONThis report highlights good outcomes of surgical treatment for PP. Apart fromsymptom relief, it is frequently also the best diagnostic tool since differential

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Figure 2

Figure 2 Upper gastrointestinal series showing the obstruction of duodenum. The image shows the site ofobstruction with retrograde dilation of duodenum (orange arrow). A very small portion of contrast agent passedthrough the obstruction (yellow arrow).

diagnosis between PP and pancreatic head adenocarcinoma can often be quitedifficult. PD is the usual surgical approach, however, TP can also be a good choice ifthe body and tail of the pancreas are consumed with pseudocysts or chronic pancrea-titis.

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Table 2 Characteristics of operated patients and their outcomes in analyzed studies, n (%)

Characteristics of operated patients 173 (100)

PD 134 (77.5)

Pancreas preserving duodenal resection 10 (5.8)

Duodenum preserving pancreatic head resection 5 (2.9)

Bypass 16 (9.2)

Pseudocyst drainage 8 (4.6)

Outcome

Success 136 (78.6)

Partial success 35 (20.2)

Failure 2 (1.2)

PD: Pancreaticoduodenectomy.

Figure 3

Figure 3 Pathological changes in paraduodenal pancreatitis. A: Characteristic cysts and thickened duodenal mucosa; B: Hyperplasia of Brunner's glands andsmooth muscle cells; C: The minor duodenal papilla.

REFERENCES1 Potet F, Duclert N. [Cystic dystrophy on aberrant pancreas of the duodenal wall]. Arch Fr Mal App Dig

1970; 59: 223-238 [PMID: 5419209]2 Adsay NV, Zamboni G. Paraduodenal pancreatitis: a clinico-pathologically distinct entity unifying "cystic

dystrophy of heterotopic pancreas", "para-duodenal wall cyst", and "groove pancreatitis". Semin DiagnPathol 2004; 21: 247-254 [PMID: 16273943 DOI: 10.1053/j.semdp.2005.07.005]

3 Becker V, Mischke U. Groove pancreatitis. Int J Pancreatol 1991; 10: 173-182 [PMID: 1787332]4 Pezzilli R, Santini D, Calculli L, Casadei R, Morselli-Labate AM, Imbrogno A, Fabbri D, Taffurelli G,

Ricci C, Corinaldesi R. Cystic dystrophy of the duodenal wall is not always associated with chronicpancreatitis. World J Gastroenterol 2011; 17: 4349-4364 [PMID: 22110260 DOI:10.3748/wjg.v17.i39.4349]

5 Fléjou JF, Potet F, Molas G, Bernades P, Amouyal P, Fékété F. Cystic dystrophy of the gastric andduodenal wall developing in heterotopic pancreas: an unrecognised entity. Gut 1993; 34: 343-347 [PMID:8097180 DOI: 10.1136/gut.34.3.343]

6 Egorov VI, Vankovich AN, Petrov RV, Starostina NS, Butkevich ATs, Sazhin AV, Stepanova EA.Pancreas-preserving approach to "paraduodenal pancreatitis" treatment: why, when, and how? Experienceof treatment of 62 patients with duodenal dystrophy. Biomed Res Int 2014; 2014: 185265 [PMID:24995273 DOI: 10.1155/2014/185265]

7 Galloro G, Napolitano V, Magno L, Diamantis G, Nardone G, Bruno M, Mollica C, Persico G. Diagnosisand therapeutic management of cystic dystrophy of the duodenal wall in heterotopic pancreas. A casereport and revision of the literature. JOP 2008; 9: 725-732 [PMID: 18981555]

8 Pessaux P, Lada P, Etienne S, Tuech JJ, Lermite E, Brehant O, Triau S, Arnaud JP.Duodenopancreatectomy for cystic dystrophy in heterotopic pancreas of the duodenal wall. GastroenterolClin Biol 2006; 30: 24-28 [PMID: 16514378 DOI: 10.1016/s0399-8320(06)73073-1]

9 Rahman SH, Verbeke CS, Gomez D, McMahon MJ, Menon KV. Pancreatico-duodenectomy forcomplicated groove pancreatitis. HPB (Oxford) 2007; 9: 229-234 [PMID: 18333228 DOI:10.1080/13651820701216430]

10 Casetti L, Bassi C, Salvia R, Butturini G, Graziani R, Falconi M, Frulloni L, Crippa S, Zamboni G,Pederzoli P. "Paraduodenal" pancreatitis: results of surgery on 58 consecutives patients from a singleinstitution. World J Surg 2009; 33: 2664-2669 [PMID: 19809849 DOI: 10.1007/s00268-009-0238-5]

11 Leger L, Lemaigre G, Lenriot JP. [Cysts on heterotopic pancreas of the duodenal wall]. Nouv Presse Med1974; 3: 2309-2314 [PMID: 4456294]

12 Casadei R, Monari F, Buscemi S, Laterza M, Ricci C, Rega D, D'Ambra M, Pezzilli R, Calculli L, Santini

WJGS https://www.wjgnet.com June 27, 2019 Volume 11 Issue 6

Mikulić D et al. TP for paraduodenal pancreatitis

301

D, Minni F. Total pancreatectomy: indications, operative technique, and results: a single centre experienceand review of literature. Updates Surg 2010; 62: 41-46 [PMID: 20845100 DOI:10.1007/s13304-010-0005-z]

13 Barbier L, Jamal W, Dokmak S, Aussilhou B, Corcos O, Ruszniewski P, Belghiti J, Sauvanet A. Impactof total pancreatectomy: short- and long-term assessment. HPB (Oxford) 2013; 15: 882-892 [PMID:23458647 DOI: 10.1111/hpb.12054]

14 Epelboym I, Winner M, DiNorcia J, Lee MK, Lee JA, Schrope B, Chabot JA, Allendorf JD. Quality oflife in patients after total pancreatectomy is comparable with quality of life in patients who undergo apartial pancreatic resection. J Surg Res 2014; 187: 189-196 [PMID: 24411300 DOI:10.1016/j.jss.2013.10.004]

15 Oza VM, Skeans JM, Muscarella P, Walker JP, Sklaw BC, Cronley KM, El-Dika S, Swanson B, HintonA, Conwell DL, Krishna SG. Groove Pancreatitis, a Masquerading Yet Distinct Clinicopathological Entity:Analysis of Risk Factors and Differentiation. Pancreas 2015; 44: 901-908 [PMID: 25899649 DOI:10.1097/MPA.0000000000000351]

16 Jouannaud V, Coutarel P, Tossou H, Butel J, Vitte RL, Skinazi F, Blazquez M, Hagège H, Bories C,Rocher P, Belloula D, Latrive JP, Meurisse JJ, Eugène C, Dellion MP, Cadranel JF, Pariente A;Association Nationale des Hépato-Gastroentérologues des Hôpitaux généraux. Cystic dystrophy of theduodenal wall associated with chronic alcoholic pancreatitis. Clinical features, diagnostic procedures andtherapeutic management in a retrospective multicenter series of 23 patients. Gastroenterol Clin Biol 2006;30: 580-586 [PMID: 16733382 DOI: 10.1016/s0399-8320(06)73231-6]

17 Rebours V, Lévy P, Vullierme MP, Couvelard A, O'Toole D, Aubert A, Palazzo L, Sauvanet A, HammelP, Maire F, Ponsot P, Ruszniewski P. Clinical and morphological features of duodenal cystic dystrophy inheterotopic pancreas. Am J Gastroenterol 2007; 102: 871-879 [PMID: 17324133 DOI:10.1111/j.1572-0241.2007.01091.x]

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