Hilar cholangiocarcinoma accompanied by pancreaticobiliary maljunction without bile duct dilatation 20 years after cholecystectomy : report of a case
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1 169 CASE REPORT Hilr cholngiocrcinom ccompnied y pncreticoiliry mljunction without ile duct dilttion 20 yers fter cholecystectomy : report of cse Shinichiro Ymd, Mitsuo Shimd, Tohru Utsunomiy, Yuji Morine, Storu Imur, Tetsuy Ikemoto, Hiroki Mori, Mmi Knmoto, Jun Hnok, Shuichi Iwhshi, Yu Sito, nd Hiroki Ishishi The Deprtment of Surgery, the University of Tokushim, Kurmoto-cho, Tokushim City, Tokushim, , Jpn Astrct : Pncreticoiliry mljunction (PBM) is ssocited with the occurrence of iliry cncer due to pncretoiliry reflux. From the perspective of crcinogenesis, the tretment for PBM is controversil. We herein report cse of hilr cholngiocrcinom 20 yers fter the occurrence of gllldder cncer. A 75-yer-old mn ws referred to our hospitl regrding n ostructive jundice nd ile duct tumor. A cholecystectomy ws performed for cholelithisis on this ptient 20 yers go, nd cncer in situ ws detected. Computed tomogrphy (CT) nd endoscopic retrogrde cholngiopncretogrphy (ERCP) reveled tumor of the portl heptic region nd PBM without dilttion of the ile duct. Adenocrcinom ws detected from ile cytology, nd we dignosed hilr cholngiocrcinom. Despite the iliry decompression, jundice ws prolonged nd the ptient pssed wy. Our cse suggests tht not only cholecystectomy ut lso iliry diversion is needed for PBM regrdless of the existence of ile duct dilttion. J. Med. Invest. 60 : , Ferury, 2013 Keywords : pncreticoiliry mljunction, hilr cholngiocrcinom, cholecystectomy INTRODUCTION Pncreticoiliry mljunction (PBM) is congenitl nomly defined s union of the pncretic nd iliry ducts outside of the duodenl wll (1-3). The most importnt clinicl feture is the frequent ssocition of PBM with iliry cncers. As the norml sphincter muscle cnnot functionlly ffect the union, two-wy regurgittion (pncretoiliry nd iliopncretic reflux) occurs, resulting in vrious pthologicl conditions in the Received for puliction Novemer 6, 2012 ; ccepted Ferury 1, Address correspondence nd reprint requests to Mitsuo Shimd, M.D. FACS, Deprtment of Digestive nd Trnsplnt Surgery, Institute of Helth Bioscience, Grdute School of Medicine, the University of Tokushim, Kurmoto, Tokushim, , Jpn nd Fx : iliry trct nd pncres (1-3). As the hydropressure in the pncretic duct is usully higher thn in the ile duct (4), pncretic juice frequently refluxes into the ile duct through the nomlous junction, resulting in high incidence of crcinogenesis in the iliry trct. From the perspective of crcinogenesis, the tretment of PBM especilly without ile duct dilttion is controversil ; either only cholecystectomy should e performed, in which cse n extrheptic iliry duct resection would e unnecessry, or oth n extrheptic iliry duct resection nd hepticojejunostomy should e undertken. We herein report cse of hilr cholngiocrcinom tht occurred 20 yers fter cholecystectomy for incidentl gllldder cncer, with PBM. The Journl of Medicl Investigtion Vol
2 170 S. Ymd, et l. Hilr cholngiocrcinom with pncreticoiliry mljunction CASE REPORT A 75-yer-old mle ws referred to our institute for jundice nd tumor of the common ile duct. He ws performed cholecystectomy for cholelithisis 20 yers go t nery hospitl, nd the histologicl finding reveled tht the gllldder hd well-differentited denocrcinom in situ. As further exmintions of the iliry trct were not undertken, the existence of pncretoiliry mljunction (PBM) ws not found t tht time. In Decemer 2010, the ptient went to the hospitl for generl mlise nd ws dignosed with jundice. MRCP reveled tumor in the heptic portl region nd dilttion of the intrheptic ile duct. He ws dmitted to our institute, nd exmintions of the tumor were performed. Adominl computed tomogrphy (CT) showed spce occupied with lesions from the hilr to middle ile duct, with enhncement nd intrheptic ile duct dilttion (Figure 1). Endoscopic retrogrde cholngiopncretogrphy (ERCP) reveled stenosis of the hilr middle ile duct ecuse of the tumor (Figure 1). ERCP lso showed tht the min pncretic duct joined the ile duct ove the ppill of Vter (clssifiction of PBM type B, Figure 1). The dimeter of the common ile duct ws 10 mm. In light of the dilttion cused y the ile duct ostruction resulting from the tumor, we dignosed PBM without dilttion of the ile duct. We performed endoscopic retrogrde iliry dringe nd denocrcinom ws detected from ile cytology. We dignosed hilr cholngiocrcinom with PBM. As the dominl CT showed swelling of the prortic lymph nodes, we decided tht the opertion could not e performed. For iliry decompression, n endoscopic retrogrde iliry dringe (ERBD) tue ws plced in the right heptic duct. However, iliry decompression ws not chieved with complete success due to the tumor in the heptic portl region. The ptient s generl condition grdully worsened, nd he pssed wy three months fter dmission. The dignosis from the utopsy ws hilr cholngiocrcinom nd pncretoiliry mljunction (Figure 2, ). In the specimen otined from the utopsy, HE stining showed tht the tumor in the heptic Figure 1. Findings of liver nd ile duct. () findings of contrst enhnced CT. There is tumor from the heptic portl region to the middle ile duct with enhncement nd intrheptic ile duct dilttion. () findings of ERCP. Tumor cuses stenosis of the heptic portl region middle ile duct, nd the min pncretic duct joined the ile duct ove the ppill of Vter (clssifiction of PBM type B). Figure 2. Specimen of utopsy. () totl imge of the liver. () findings of tumor invsion to middle ile duct nd pncreticoiliry mljunction. Scle rs, 2 cm. Dignosis ws hilr cholngiocrcinom nd pncretoiliry mljunction.
3 The Journl of Medicl Investigtion Vol. 60 Ferury portl region extended to the middle of the common ile duct (Figure 3, ). K-rs nd HDAC ntiody stining were positive oth in the cncerous prt nd non-cncerous prt (Figure 4-d). DISCUSSION The pthologicl condition of PBM is such tht the mixing of phospholipse A2 in pncretic juice Figure 3. HE stining of cncerous prt. () common ile duct, 200 () heptic portl region, 200 c d Figure 4. Immunohistochemicl findings for k-rs nd HDAC (, : k-rs, c,d : HDAC). () cncerous prt, 100 () non cncerous prt, 200 (intrheptic ile duct) (c) cncerous prt, 100 (d) non cncerous prt, 200 (intrheptic ile duct)
4 172 S. Ymd, et l. Hilr cholngiocrcinom with pncreticoiliry mljunction nd ile will produces lysolecithin, which hs severe cell toxicity. Repeted dmge to, nd restortion of, the iliry epithelium produces vrint ccompnied y cellulr typicl chnge (5), displying hyperplsi-dysplsi-crcinom sequence (6, 7). From the perspective of crcinogenesis, the tretment of PBM, especilly without ile duct dilttion, is controversil ; either only cholecystectomy should e performed, in which cse n extrheptic iliry duct resection would e unnecessry, or oth n extrheptic iliry duct resection nd hepticojejunostomy should e performed. It ws reported tht the cncer development rtes of PBM in dults with dilttion of ile duct re 13.4% in the gllldder, 7.0% in the ile duct, nd 1.0% in the gllldder+ile duct (8). Those of PBM without dilttion of the ile duct re 37.4% in the gllldder, 3.1% in the ile duct, nd 1.8% in the gllldder+ile duct (8). This report hs reveled tht PBM hs ckground of iliry trct crcinogenesis regrdless of whether it is with or without ile duct dilttion, nd tht we should py ttention to the crcinogenesis of the gllldder in prticulr. Although the crcinogenesis rte of n undilted ile duct with PBM ws the lowest mong these dt (3.1%), this rte is 200 times higher thn tht seen in usul crcinogenesis of the ile duct in Jpn (9). These fcts suggest tht iliry diversion is necessry in the light of crcinogenesis. In terms of compliction of iliry diversion, cute pncretitis, pncretic fistul, gstrointestinl leeding nd ileus cn occur s erly compliction. However, these complictions occur with low frequency nd most of them recover y conservtive mngement. Cholngitis nd heptolithisis re reported to occur s lte compliction, nd induced minly y ile duct stenosis (10). As these complictions cn occur repetedly, creful, long-term follow-up is importnt. Aout the moleculr mechnism of crcinogenesis, K-rs re minly discussed s gene normlity of mucosl epithelium. The genetic muttion of K-rs in the cncerous prts of erly gllldder cncer with PBM is seen t level of 50%, higher thn tht of usul erly gllldder cncer (6%) (11). In terms of ile duct cncer, it ws reported tht K-rs muttion with PBM ws detected t % in cncerous prts nd t 40% in the noncncerous prts with or without dilttion of the ile duct (12, 13). In our cse, since K-rs ntiody stining ws positive oth in the cncerous nd non-cncerous prts, there could hve een high potentil for crcinogenesis in the ile duct. From n epigenetic perspective, the sttus of histone cetyltion, which is controlled y histone cetyltrnsferse (HAT) nd histone decetylse (HDAC), plys n importnt role in vrious gene expressions through the chromtin remodeling. Specificlly, the errnt ctivtion of HDAC in tumor cells leds to diverse trnscriptionl gene repression, minly involving the regultion of differentition, ngiogenesis, prolifertion, migrtion, nd metstsis (14, 15). Furthermore, it ws reported tht HDAC inhiitor decrese the expression of k-rs (16), nd HDAC my influence on k-rs ctivity in mechnism of crcinogenesis. In our cse, HDAC stining ws positive oth in the cncerous nd non cncerous prts. Repeted dmge to, nd restortion of, the iliry epithelium, cn led to errnt ctivtion of HDAC, nd relte to the overexpression of k-rs nd potentil for crcinogenesis. In conclusion, we experienced cse of hilr cholngiocrcinom with PBM 20 yers fter the occurrence of gllldder cncer, nd we suggest tht surgery to seprte the pncretic juice nd ile long with cholecystectomy is needed for PBM, regrdless of the existence or otherwise of ile duct dilttion. CONFLICT OF INTEREST STATEMENT Shinichiro Ymd nd other co-uthors hve no conflict of interest. REFERENCES 1. Bitt DP : Congenitl choledochl cyst : new etiologicl concept sed on nomlous reltionships of common ile duct nd pncretic ul. Ann Rdiol 12 : , Mtsumoto Y, Fujii H, Itkur J, Mtsud M, Noukw B, Sud K : Recent dvnces in pncreticoiliry mljunction. J Heptoilily Pncret Surg 9 : 45-54, Wistu II, Alores-Svedr J : Genetic normlities involved in the pthogenesis of gllldder crcinom. J Heptoilily Pncret Surg 6 : , Kmel D, Pkko P, Nuorv K, Vhkngs K, Soini Y : p53 nd epithelil dysplsis of the gllldder. J Clin Pthol 170 : 67-72, Kmisw T : Clinicl implictions nd pthophysiology of pncretoiliry nd iliopncretic
5 The Journl of Medicl Investigtion Vol. 60 Ferury reflux. Journl of Jpn Biliry Assocition 21 : , Shimd K, Yngisw J, Nkym F : Incresed lysophosphtidylcholine nd pncretic enzyme content in ile of ptients with nomlous pncreticoiliry ductl junction. Heptology 13 : , Tsuchid A, Itoi T : Crcinogenesis nd chemoprevention of iliry trct cncer in pncreticoiliry mljunction. World J Gstrointest Oncol 2 : , Morine Y, Mori H, Utsunomiy T, Imur S, Ikemoto T, Ishishi H : Epidemiology nd Clinicl fetures of Pncreticoiliry Mljunction. Journl of Jpn Biliry Assocition 25 : , Mtsud T, Mrugme T, Kmo K, Ktnod K, Ajiki W, Soue T : The Jpn Cncer Surveillnce Reserch Group. : Cncer incidence nd incidence rtes in Jpn in 2003 :sed on dt from 13 popultion-sed cncer registries in the Monitoring of Cncer Incidence in Jpn (MCIJ) project. Jpnese Journl of Clinicl Oncology 39 : , Todni T, Wtne Y, Urushihr N, Nod T, Morotomi Y : Biliry complictions fter excisionl procedure for choledochl cyst. J Peditr Surg 30 : , Hnd K, Itoh M, Fujii K, Tsuchid A, Ooishi H, Kjiym G : K-rs nd p53 muttions in stge I gllldder crcinom with n nomlous junction of the pncreticoiliry duct. Cncer 77 : , Motojim K, Tsunod T, Knemtsu T, Ngt Y, Urno T, Shiku H : Distinguishing pncretic crcinom from other perimpullry crcinoms y nlysis of muttions in the Kirstenrs oncogene. Ann Surg 214 : , Wtne M, Ask M, Tnk J, Kurosw M, Ksi M, Miyzki T : Point muttion of K- rs gene codon 12 in iliry trct tumors. Gstroenterology 107 : , Glozk MA, Seto E : Histone decetylses nd cncer. Oncogene 26 : , Weichert W : HDAC expression nd clinicl prognosis in humn mlignncies. Cncer Lett 280 : , Birn A, Brownstein M, Hkli R, Kloog Y : Downregultion of survivin nd uror A y histone decetylse nd RAS inhiitors : new drug comintion for cncer therpy. Int J Cncer 128 : , 2011
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