intraductal papillary neoplasms of the bile duct ( ipnbs ) are recognized as a distinct type of biliary tumor ( 1,2 ) . this entity includes previous categories , such as biliary papillomatosis and mucin - producing bile duct tumors ( 3 ) . ipnbs share clinicopathological characteristics with intraductal papillary mucinous neoplasms ( ipmns ) of the pancreas , as they both typically present with dilatation of the affected ducts , predominantly intraductal papillary masses and the overproduction of mucin ( 3,4 ) . the development of multiple separate tumors is a characteristic feature potentially associated with either condition . an index report of ipnbs included a case of multiple ipnbs , in which three separate tumors developed in the intrapancreatic bile duct 6 years after the initial tumor in the cystic duct was resected ( 1 ) . however , multiple ipnbs have only been described in a small number of reports , suggesting that a presentation with multiple biliary tumors is less common compared with pancreatic ipmns . the rarity of multiple ipnbs has restricted the discussion on clinicopathological characteristics and developmental mechanisms . we herein describe another case of metachronous multiple ipnbs and review the literature in order to establish whether these cases represent true multicentric tumors or intrabiliary tumor dissemination . a 64-year - old woman with no particular previous medical history presented with fever lasting for 1 week . the serological tests revealed elevated levels of c - reactive protein ( 13.4 mg / dl ; normal range , < 0.5 mg / dl ) , alanine aminotransferase ( 62 iu / l ; normal range , 536 iu / l ) , alkaline phosphatase ( 816 iu / l ; normal range , 110370 iu / l ) . the leukocyte count and serum levels of aspartate aminotransferase , total bilirubin , carcinoembryonic antigen and carbohydrate antigen 199 were within the normal range . on computed tomography ( ct ) , a 75-mm cystic mass in the right hepatic lobe and dilatation of the intrahepatic bile duct were detected ( fig . 1a ) . following aspiration due to a suspected infectious liver cyst , the patient underwent endoscopic retrograde cholangiography ( erc ) , which revealed filling defects within the dilated common hepatic duct ( fig on peroral cholangioscopy ( pocs ) , a papillary mucin - producing tumor was identified around the orifice of the right hepatic duct , while no obvious tumor was present in the left hepatic and common bile ducts ( fig . although the small bile duct biopsy from the papillary tumor was not conclusive , extended right hepatectomy was performed for suspected ipnb . on intraoperative frozen section examination , the common hepatic duct margin was tumor - free , while the left hepatic duct appeared to be positive for an intraepithelial tumor with high - grade dysplasia . despite additional resection of the left hepatic duct , on macroscopic examination , the main tumor was located in the right hepatic duct and exhibited mucin overproduction . microscopically , the biliary neoplasm consisted of atypical epithelial cells arranged in a high papillary architecture along thin fibrovascular stalks ( fig . the tumor cells exhibited intestinal - type morphology ( e.g. , nuclear stratification and goblet cells ) , with enlarged nuclei and loss of polarity , characteristics consistent with high - grade dysplasia . the cells were diffusely positive for mucin core protein ( muc)2 and muc5ac ( fig . 3 ) , focally positive for muc1 , muc6 and cytokeratin ( ck)20 , and negative for ck7 . based on the histological findings , the tumor was diagnosed as intestinal - type ipnb with high - grade dysplasia . since the left hepatic duct margin was positive for tumor cells , gemcitabine 1,000 mg / m was administered every 2 weeks for a total of 15 courses . twenty - six months later , the patient underwent a follow - up ct , which revealed no recurrence in the left hepatic duct , but detected a papillary tumor in the common bile duct ( fig . , the tumor appeared to be a mucin - producing neoplasm with abundant mucus secreted from the dilated ampulla of vater ( fig . the histological appearance of the tumor was nearly identical to that of the original neoplasm , with a similar immunohistochemical phenotype ( fig . the postoperative course was uneventful , with no signs of recurrence at the time of writing of this manuscript ( follow - up of 12 months ) . in the present case , two separate ipnbs developed over a ~2-year period . although the left hepatic duct margin in the initial surgery was focally positive for intraepithelial neoplasia , the second tumor developed in the lower common bile duct . the recurrent tumor was surrounded by non - neoplastic epithelium , suggesting that the two ipnbs were separate , with no tumor cells between them . however , we also hypothesized that the second tumor represented intrabiliary tumor dissemination , as both tumors had a nearly identical histological appearance , and the second tumor developed in the lower part of the bile duct compared with the primary tumor . since intrabiliary dissemination is not considered as progression in ipnbs , a literature review was performed to investigate this possibility . large studies were first reviewed , in which > 20 cases of ipnbs were investigated , in terms of how often multiple tumors develop in patients with ipnbs . among ~10 large studies reported to date from asia , europe and the usa , two provided detailed descriptions of patients with multiple biliary tumors ( 5,6 ) . in a study by paik et al ( 5 ) , 4 of the 25 investigated cases with ipnbs were found to have tumor recurrence after complete resection with negative surgical margins . two patients had recurrence in the liver parenchyma and lymph nodes , representing remote metastasis of the invasive components . in the remaining 2 patients , the primary ipnbs were located in the intrahepatic bile ducts , whereas the recurrent tumors developed in the distal bile duct , similar to our patient . kang et al ( 6 ) also reported multifocal tumors in 43 of 84 ( 51% ) patients with ipnbs ; however , this number appears to be markedly higher compared with that in other studies , which leads us to question the definition of multiple ipnbs used in that study . no or limited information was available in terms of multiple tumors in the remaining studies ( 710 ) . the pubmed database was searched using the terms  ipnb ,  mucin - producing bile duct tumor , biliary papillomatosis ,  multiple ,  multiplicity and  recurrence , and the selected manuscripts were reviewed . a similar search was also conducted through ichushi ( http://login.jamas.or.jp/ ) , which enables searching for medical literature and abstracts written in japanese . cases of recurrent tumors at the anastomotic site were excluded , as they were most likely to be local recurrence rather than multiple tumors . a total of 9 additional case reports describing multiple separate ipnbs were eventually retrieved ( 1119 ) . the clinicopathological characteristics of these cases and our patient are summarized in table i. of the 10 patients , 8 initially underwent liver resection for ipnbs that developed in the hilar or intrahepatic bile duct , while the remaining 2 received bile duct resection for a cystic duct neoplasm or cholecystectomy for a gallbladder ipnb . multiple tumors were identified in the original resected specimens in 2 patients ( cases 4 and 9 , table i ) . recurrent tumors developed in more distal parts of the bile duct compared with the primary tumors in 8 of the 10 patients . although the majority of the patients had a single episode of tumor recurrence , 2 patients had multiple episodes ( cases 3 and 7 in table i ) ( 13,17 ) . a 66-year - old woman originally had ipnb in the left hepatic lobe and underwent left hepatectomy with a negative surgical margin . fifteen months later , a recurrent tumor was detected in the upper common bile duct , which was surgically resected . although the bile duct margin in the second surgery was also tumor - free , another papillary tumor was detected in the intrapancreatic bile duct 35 months later , requiring the whipple procedure . the literature review clearly demonstrated that recurrent tumors typically develop in the lower bile duct compared with the primary ipnbs . of note , 84% of primary ipnbs develop in the intrahepatic or hilar bile duct ( 20 ) , in contrast to recurrent ipnbs , 80% of which developed in the common bile duct ( table i ) . these findings suggest that intrabiliary dissemination is a more likely mechanism for multiple ipnbs , rather than true multicentricity in the majority of the patients . however , multicentric ipnbs remain a possibility in a specific proportion of patients , particularly those with risk factors for this biliary neoplasm , such as hepatolithiasis . future molecular studies comparing gene abnormalities in multiple ipnbs are required to elucidate the frequency of true multicentric ipnbs developing in the biliary tree . matsubara et al ( 21 ) recently reported a case of papillary adenocarcinoma of the ampulla of vater , which was subsequently complicated by retrograde intraductal dissemination in the pancreas . although this is the only report raising the possibility of cancer cells possibly disseminating along the pancreatobiliary duct system , we have observed similar cases , in which ampullary cancers or intrapancreatic cholangiocarcinomas were intraductally disseminated to the pancreas . to the best of our knowledge , the present study is the first report suggesting that a similar pattern of tumor extension may also occur in the bile duct . multiple ipmns , particularly of the branch - duct type , are common ; however , the majority are suspected to represent true multicentric tumors . one reason is that the majority of branch - duct type ipmns are low - grade , with a low propensity for dissemination . another potential factor is that the pancreatic duct is located horizontally , in contrast to the bile duct , which is positioned vertically . in conclusion , the results of our case indicate that multiple ipnbs may be attributed to the biliary dissemination of tumor cells . true multicentric ipnbs appear to be less common than initially considered , given that the extrahepatic lower bile duct is typically affected by recurrent ipnbs .
intraductal papillary neoplasms of the bile duct ( ipnbs ) are recognized as a distinct type of biliary tumor . 
 we herein discuss the possible mechanisms underlying the development of multiple tumors in patients with ipnbs through a case presentation and literature review . 
 a 64-year - old woman initially underwent extended right hepatectomy for ipnb in the right hepatic duct . 
 although the surgical margin of the common bile duct was tumor - free , recurrence was detected in the intrapancreatic bile duct 26 months later . 
 both tumors had similar histopathological characteristics ( intestinal - type ipnb with high - grade dysplasia , but no invasive cancer ) . 
 a literature review identified 9 additional cases of multiple ipnbs . unlike conventional ipnbs , which typically affect the intrahepatic or hilar bile duct , 80% of recurrent multiple tumors developed in the extrahepatic bile duct . 
 although multicentric tumors have been suggested in such cases , the intrabiliary dissemination of tumor cells appears to be more likely , as the majority of recurrent tumors develop in more distal parts of the bile duct compared with the primary tumor .