Synchronous primary gallbladder and pancreatic cancer associated with congenital biliary dilatation and pancreaticobiliary maljunction
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1 Mori et l. Surgicl Cse Reports (2017) 3:113 DOI /s x CASE REPORT Open Access Synchronous primry gllldder nd pncretic cncer ssocited with congenitl iliry dilttion nd pncreticoiliry mljunction Hruki Mori *, Hiroy Iid, Hiromitsu Mehir, Nomi Kitmur, Tomohru Shimizu nd Msji Tni Astrct Introduction: Synchronous doule cncer of the gllldder nd pncres tht is ssocited with congenitl iliry dilttion (CBD) nd pncreticoiliry mljunction (PBM) is extremely rre. PBM is frequently reported in Asi, prticulrly in Jpn. We report surgicl cse of synchronous doule cncer in ptient with primry gllldder nd pncretic cncer. Presenttion of cse: A 72-yer-old womn with epigstrlgi underwent sutotl stomch-preserving pncreticoduodenectomy nd gllldder ed resection for synchronous primry gllldder nd pncretic hed cncer. Histopthologicl exmintion reveled modertely differentited ductl denocrcinom of the pncretic hed nd well-differentited tuulr denocrcinom t the ottom of the gllldder. Conclusion: Synchronous gllldder nd pncretic cncer is extremely rre. It is necessry to determine the optiml surgicl course tking into considertion the degree of tumor progression. This is the second cse of synchronous primry gllldder nd pncretic cncer ssocited with CBD ccompnied y PBM. Keywords: Congenitl iliry dilttion, Gllldder cncer, Pncretic cncer Bckground Congenitl iliry dilttion (CBD) is congenitl mlformtion involving oth extrheptic ile duct dilttion nd pncreticoiliry mljunction (PBM) [1]. It is well known tht PBM is frequently ssocited with crcinom of the iliry trct [2, 3]. PBM includes norml connection etween the pncretic duct nd the common ile duct outside of the duodenl wll, which leds to the reciprocl reflux of pncretic juices nd ile. The norml intr-pncretic pressure is higher thn in the ile duct [4], nd pncretic juice reflux into the iliry trct is confirmed y the presence of ctivted pncretic enzymes mylse nd lipse [5]. It is thought tht the reflux of pncretic juice into the ile duct nd the repeted cycle of iliry epithelium rekdown nd regenertion leds to crcinogenesis [6, 7]. Anorml * Correspondence: hmori@elle.shig-med.c.jp Deprtment of Surgery, Shig University of Medicl Science, Settsukinow-chou, Ootsu, Shig , Jpn expression nd/or muttion of some oncogenes nd cncer suppressor genes occurs during ech step of crcinogenesis [8]. Continuous chronic inflmmtion cuses muttions in genes, such s K-rs nd p53, tht re ssocited with crcinogenesis nd gllldder cncer [9 11]. As result, ptients with CBD hve high rte of iliry trct cncers. In Western countries, the rte of iliry trct cncer concurrent with CBD is 20%, ut this rte is sed on very few cses (n = 20) [12]. In Jpn, lrge-scle survey of 2561 ptients ws undertken tht looked t the incidence of iliry trct cncer concurrent with CBD. The survey found tht iliry trct cncer occurs in 21.6% of dult ptients with CBD [13]. The min mlignncies re gllldder cncer (62.3%), ile duct cncer (32.1%), nd gllldder plus ile duct cncer (4.7%), indicting tht gllldder cncer is the most frequently found in ssocition with this condition [13]. On the other hnd, the evidence for crcinogenesis in pncretic crcinom ssocited with PBM is still lcking. The Author(s) Open Access This rticle is distriuted under the terms of the Cretive Commons Attriution 4.0 Interntionl License ( which permits unrestricted use, distriution, nd reproduction in ny medium, provided you give pproprite credit to the originl uthor(s) nd the source, provide link to the Cretive Commons license, nd indicte if chnges were mde.
2 Mori et l. Surgicl Cse Reports (2017) 3:113 Pge 2 of 5 Furthermore, there hs een only one other pulished cse of synchronous doule cncer consisting of gllldder cncer nd pncretic cncer ssocited with CBD. We report herein n interesting nd rre cse of the ove. Cse presenttion In June 2016, 72-yer-old womn ws dmitted to the hospitl complining of epigstrlgi; however, physicl exmintion did not revel ny normlities. Her lortory tests reveled norml complete lood count nd norml liver function. The serum crcinoemryonic ntigen level ws 9.3 ng/ml (norml rnge, < 5 ng/ml), the crohydrte ntigen 19-9 (CA19-9) level ws 1084 U/mL (norml rnge, < 37 U/mL), nd the duke pncretic monoclonl ntigen type 2 (DUPAN-2) level ws 140 U/mL (norml rnge, < 150 U/mL). The ptient hd no history of pncretitis, pncretic stone, nd cholngitis. Computed tomogrphy (CT) showed low-density mss in the pncretic hed nd thickness in the wll djoining the gllldder (Fig. 1, ). Furthermore, lymph nodes round the pncres were swelling nd multiple cystic lesions with murl nodule were found in the hed of the pncres. Mgnetic resonnce imging (MRI) showed prtilly cystic dilttion of the common ile duct, 32 mm in dimeter, reveling tht the pncretic duct joined the common ile duct 24 mm ove the ppill of Vter. The cystic dilttion of the common ile duct ws clssified s type I using the Todni system [14], nd cystic lesion in the hed of the pncres ws confirmed s rnch duct-type intrductl ppillry mucinous neoplsm (IPMN) (Fig. 2, ). Positron emission tomogrphy (PET)-CT showed n norml ccumultion of 18-fluorodeoxyglucose (FDG) in the pncretic hed nd gllldder. The ptient rejected invsive exmintion: therefore, we did not performed endoscopic ultrsonogrphy (EUS) or Endoscopic retrogrde cholngiopncretogrphy (ERCP) preopertively. The ptient ws dignosed with synchronous primry gllldder nd intrductl ppillry mucinous crcinom (IPMC) ecuse 9-mm murl nodule ws found in prt of the cystic lesion y CT. Sutotl stomch-preserving pncreticoduodenectomy nd gllldder ed resection were performed. The ptient s postopertive course ws complictedygrdebpncreticfistul,sgrdedy the Interntionl Study Group of Postopertive Pncretic Fistul (ISGPF) criteri, which ws treted y percutneous dringe. The ptient ws dischrged on the 47th postopertive dy. Histopthologicl exmintion reveled modertely differentited ductl denocrcinom ( cm) in the pncretic hed with retroperitonel nd plexus nerve invsion (Fig. 3), well-differentited tuulr denocrcinom ( cm) t the ottom of the gllldder with liver serosl invsion (Fig. 3), nd intrductl ppillry mucinous denom (IPMA) of the pncres. There were signs of lymphovsculr invsion nd perineurl invsion in the oth pncretic nd gllldder cncer. The cystic lesion detected preopertively ws mtch to the IPMA in histopthologicl exmintion. Concomitnt pncretic cncer did not originte from the IPMA. There ws no continuity in histopthologicl exmintion etween pncretic cncer nd IPMA (Fig. 3c). A totl of 16 lymph nodes were hrvested nd exmined. Lymph node metstses were detected in two of infrpyloric lymph nodes, three of lymph nodes long the common heptic rtery, two of lymph nodes in the heptoduodenl ligment, two of lymph nodes long the superior mesenteric vein, nd one of the lymph nodes on the nterior surfce of the pncretic hed. However, lymph node metstsis ws oserved nd it ws not known whether it originted from the pncretic cncer or gllldder cncer. Upon these findings, the stge of pncretic cncer ws pt3n1m0 (pstge IIB), nd the gllldder cncer ws pt3n1m0 (pstge IIIB). Postopertive djuvnt chemotherpy ws not performed ecuse of the nticipted impct on qulity of life fter surgery. Eight months fter surgery, she died due to peritonel dissemintion recurrence. Discussion CBD is thought to occur in the development of PBM; however, the pthogenesis of CBD is unknown [1]. The Fig. 1 Adominl computed tomogrphy (CT). Low-density mss nd cystic lesions in the pncretic hed. Thickness in the wll djoining the ottom of the gllldder
3 Mori et l. Surgicl Cse Reports (2017) 3:113 Pge 3 of 5 Fig. 2, Mgnetic resonnce imging (MRI) showed pncreticoiliry mljunction with cystic dilttion of the common ile duct (type I [Todni clssifiction]). GB gllldder, CBD common ile duct, MPD min pncretic duct, PBM pncreticoiliry mljunction incidence of CBD ppers to e higher in Orientl thn in Occidentl popultions [15]. Approximtely, one in every 1000 persons is ffected y this disese in Jpn [16]. In Western countries, CBD occurs in one of every two million irths nd in every 50, ,000 individuls [17 19]. It is importnt to dignose ile duct diltion tking into ccount ile duct dimeter, dilted site, nd expnded form. Since ile duct dimeter vries with ge, it is necessry to refer to the upper limit vlue of the ile duct dimeter y ge [20]. In our cse, the dimeter of the ile duct ws 32 mm, which extended eyond the upper limit of ge. Todni et l. [21] reported tht the reflux of ile my ctivte pncretic enzymes, which cn cuse chronic inflmmtion nd metplstic epithelil chnge in the pncretic duct, nd pncretic cncer my eventully develop. In our cse, pncretic ductl denocrcinom developed independently of IPMN in the pncretic duct, which is n importnt considertion for future cses. Brnch duct type IPMN (BD-IPMN) is ssocited with concomitnt pncretic crcinogenesis [22 24]. However, the exct dignosis etween pncretic cncer derived from IPMN nd concomitnt pncretic cncer with IPMN is difficult, when IPMN is close to pncretic cncer histopthologiclly. Ymguchi et l. [24] reported c Fig. 3 Histologicl exmintion. Modertely differentited ductl denocrcinom of the pncres. Well-differentited tuulr denocrcinom of the gllldder. c There ws no continuity in histopthologicl exmintion etween pncretic cncer nd IPMA
4 Mori et l. Surgicl Cse Reports (2017) 3:113 Pge 4 of 5 Tle 1 Chrcteristics of reported ptients with pncretoiliry mljunction nd doule cncer of the pncres nd gllldder Author Yer Age/sex Dignosis CBD PBM Surgery Survivl time (month) 1 Ued [25]) /M Synchronous (GBC, PC, BDC) + TP 30 months 2 Minmi [3]) /F Metchronous (GBC then PC) + + PD 78 months 3 Lhmr [26]) /F Metchronous (GBC then PC) + + PD 12 months 4 Rungskulkij [27]) /F Synchronous (GBC, PC) + + PD 12 months 5 Our cse /F Synchronous (GBC, PC) + + SSPPD 8 months, deth BDC ile duct cncer, GBC gllldder cncer, F femle, M mle, PC pncretic cncer, PD pncreticoduodenectomy, SSPPD sutotl stomch-preserving pncreticoduodenectomy, TP totl pncretectomy, CBD congenitl iliry dilttion, PBM pncreticoiliry mljunction tht pproximtely one third of pncretic cncers derived from IPMN re mucinous crcinom, nd most pncretic cncers concomitnt with IPMN re tuulr denocrcinom, which re similr to ordinry pncretic cncers. We reviewed litertures in PuMed using the terms pncretoiliry mljunction, congenitl iliry dilttion, pncretic cncer, nd gllldder cncer until To the est of our knowledge, only four cses of PBM with synchronous gllldder nd pncres cncer hve een reported worldwide (Tle 1) [3, 25 27]. Four out of five cses were femles nd presented with CBD. Furthermore, our cse is the second to present with synchronous doule cncer nd CBD. Three cses including ours underwent enlrged cholecystectomy in ddition to pncretectomy. Due to ntomicl fetures, gllldder cncer develops under the serous memrne in the heptoduodenl mesoderm nd infiltrtes eyond the musculris propri. It directly invdes the liver cross the liver ed through the cystic duct in dvnced cncer with extrcpsulr invsion; vrious locl progression into the duodenum nd/or colon is lso oserved. In our cse, we performed gllldder ed resection in ddition to sutotl stomch-preserving pncreticoduodenectomy. This procedure hs possiility to decrese the qulity of life; therefore, the ptient could not receive postopertive djuvnt chemotherpy in our cse. When choosing the degree of heptectomy for gllldder cncer, it is necessry to select the est surgicl procedure considering the progression of the tumor nd the generl condition of ech ptient. Conclusions In summry, pncretic crcinom ssocited with PBM is rre event. PBM is closely relted to chronic pncretitis, ut the ctul reltionship etween pncretic crcinom nd CBD ccompnied y PBM is uncler, due to lck of sufficient dt [3, 26]. Funiki et l. [28] reported tht the incidence of pncretic cncer is higher in ptients with PBM thn in ptients without PBM. They suspected tht the reflux of ile into the pncretic duct my cuse chronic inflmmtion nd cncer of the pncres. The frequency of pncretic cncer with PBM is 0.8%, which is reltively lower thn iliry trct cncer. However, the incidence of pncretic cncer in Jpn is 16.2 per 100,000 of the popultion; therefore, 0.8% is 49.4 times higher thn the crcinogenic risk in the generl popultion [29]. The present cse suggests tht ptients with CBD ccompnied y PBM should e monitored for synchronous cncer of the pncreticoiliry system nd the pproprite surgicl procedure should e selected on per ptient sis. Authors contriutions HM is the first uthor of this mnuscript nd the corresponding uthor. HI, HM, nd NK collected the clinicl dt. TS nd MT revised the mnuscript. All uthors red nd pproved the finl mnuscript. Funding The uthors received no finncil support for the preprtion of this cse report. Authors informtion All uthors re memers of the Jpn Surgicl Society nd the Division of Deprtment of Surgery, Shig University of Medicl Science, Shig, Jpn, Settsukinow-chou, Ootsu, Shig , Jpn. Ethics pprovl nd consent to prticipte Not pplicle. Consent for puliction The ptient hs consented to the puliction of these fetures of her cse, nd her identity hs een protected. Competing interests The uthors declre tht they hve no competing interests. Pulisher s Note Springer Nture remins neutrl with regrd to jurisdictionl clims in pulished mps nd institutionl ffilitions.
5 Mori et l. Surgicl Cse Reports (2017) 3:113 Pge 5 of 5 Received: 28 August 2017 Accepted: 27 Octoer 2017 References 1. The Jpnese Study Group on Pncreticoiliry Mljunction (JSPBM), The Committee of JSPBM for Dignostic Criteri for Pncreticoiliry Mljunction. Dignostic criteri for congenitl iliry dilttion JJBA. 2015;29: Seki M, Yngw A, Ninomiy E, Ninomiy Y, Oht H, Siur A, et l. Clinicopthology of pncreticoiliry mljunction: reltionship etween ltertion in ckground iliry epithelium nd neoplstic development. J Hepto-Biliry-Pncret Surg. 2005;12: Minmi Y, Hsuike Y, Tked Y, Tsujink T. Metchronous doule cncer of the gllldder nd pncres ssocited with pncreticoiliry mljunction. J Hepto-Biliry-Pncret Surg. 2008;15: Tnk M, Iked S, Kwkmi K, Nkym F. The presence of positive pressure grdient from pncretic duct to choledochl cyst demonstrted y duodenoscopic microtrnsducer mnometry: clue to pncreticoiliry reflux. Endoscopy. 1982;14: Tshiro S, Imizumi T, Ohkw H, Okd A, Ktoh T, Kwhrd Y, et l. Pncreticoiliry mljunction: retrospective nd ntionwide survey in jpn. J Hepto-Biliry-Pncret Surg. 2003;10: Nkmur T, Okd A, Higki J, Tojo H, Okmoto M. Pncreticoiliry mljunction-ssocited pncretitis: n experimentl study on ctivtion of pncretic phospholipse A2. World J Surg. 1996;20: Tnno S, Or T, Fujii T, Mizukmi Y, Shudo R, Nishino N, et l. Prolifertive potentil nd k-rs muttion in epithelil hyperplsi of the gllldder in ptients with nomlous pncreticoiliry ductl union. Cncer. 1998;83: Resende V, Rod R, Pedros MS. Gllldder ppillry neoplsi ssocited with intrheptic crcinom nd pncreticoiliry mlformtion. Gstroenterology Res. 2012;5(6): Hnd K, Itoh M, Fujii K, Tsuchid A, Hirt M, Ishimru S, et l. Pthology nd cellulr kinetics of gllldder with n nomlous junction of the pncreticoiliry duct. Am J Gstroenterol. 1996;91: Mtsur T, Skuri Y, Ssym Y, Hori H, Ochii M, Funiki T, et l. K-rs point muttions in cncerous nd noncncerous iliry epithelium in ptients with pncreticoiliry mljunction. Cncer. 1996;77: Nod Y, Fujit N, Koyshi G, Ito K, Horguchi J, Tksw O, et l. Histologicl study of gllldder nd ile duct epitheli in ptients with nomlous rrngement of the pncreticoiliry ductl system: comprison etween those with nd without dilted common ile duct. J Gstroenterol. 2007;42: Rossi RL, Silvermn ML, Brsch JW, Munson JL, ReMine SG. Crcinoms rising in cystic conditions of the ile ducts. A clinicl nd pthologic study. Ann Surg. 1987;205: Morine Y, Shimd M, Tkmtsu H, Arid T, Endo I, Kuot M, et l. Clinicl fetures of pncretico iliry mljunction: updte nlysis of 2nd Jpn-ntionwide survey. J Heptoiliry Pncret Sci. 2013;20: Todni T, Wtne Y, Nruse M, et l. Congentil ile duct cysts: clssifiction, opertive procedures, nd review of thirty-seven cses including cncer rising from choledochl cyst. Am J Surg. 1977;134: Ymguchi M. Congenitl choledochl cyst. Anlysis of 1,433 ptients in the Jpnese literture. Am J Surg. 1980;140: Miyno T, Ymtk A. Choledochl cysts. Curr Opin Peditr. 1997;9: Olourne NA. Choledochl cysts. A review of the cystic nomlies of the iliry tree. Ann R Coll Surg Engl. 1975;56: Lenriot JP, Gigot JF, Segol P, Fgniez PL, Fingerhut A, Adloff M. Bile duct cysts in dults: multi-institutionl retrospective study. French ssocitions for surgicl reserch. Ann Surg. 1998;228: Howell CG, Templeton JM, Weiner S, Glssmn M, Betts JM, Witzleen CL. Antentl dignosis nd erly surgery for choledochl cyst. J Peditr Surg. 1983;18: Hmd Y, Ando H, Kmisw T, et l. Dignostic criteri for congentitl iliry dilttion JHBPS. 2016;23: Todni T, Wtne Y, Urushihr N, Nod T, Morotomi Y. Choledochl cyst, pncreticoiliry mljunction, nd cncer. J Hepto-Biliry-Pncret Surg. 1994;1: Ymguchi K, Nkmur K, Yokoht K, et l. Pncretic cyst s sentinel of in situ crcinom of the pncres. Report of two cses. Int J Pncretol. 1997;22(3): Ymguchi K, Ohuchid J, Ohtsuk T, et l. Intrductl ppillry-mucinous tumor of the pncres concomitnt with ductl crcinom of the pncres. Pncretology. 2002;2(5): Ymguchi K, Knemitsu S, Htori T, et l. Pncretic ductl denocrcinom derived from IPMN nd pncretic ductl denocrcinom concomitnt with IPMN. Pncres. 2011;40(4): Ued N, Ngkw T, Oht T, Kyhr M, Ueno K, Konishi I, Izumi R, Miyzki I. Synchronous cncer of the iliry trct nd pncres ssocited with nomlous rrngement of the pncreticoiliry ductl system. J Clin Gstroenterol. 1992;15: Lhmr A, Aid SB, Arf MN, Byr R, Khlfllh MT, Mzi-Regy S. Metchronous cncer of gllldder nd pncres with pncretoiliry mljunction. World J Gstrointest Surg. 2010;2: Rungsklkij N, Boonskn P. Synchronous gllldder nd pncretic cncer ssocited with pncreticoiliry mljunction. World J Gstroenterol. 2014;20(39): Funiki T, Mtsur T, Miykw S, Ishihr S. Pncreticoiliry mljunction nd crcinogenesis to iliry nd pncretic mlignncy. Lngeneck's Arch Surg. 2009;394: Mrugme T, Mtsud T, Kmo K, Ktnod K, Ajiki W, Soue T, Jpnese cncer surveillnce reserch group. Cncer incidence rtes in Jpn in 2001 sed on the dt from 10 popultion-sed cncer registries. Jpn J Clin Oncol. 2007;37:
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