A Comparison of Hepatic Mucinous Cystic Neoplasms with Biliary Intraductal Papillary Neoplasms

中国科技论文在线 http://www.paper.edu.cn CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:586–593

A Comparison of Hepatic Mucinous Cystic Neoplasms With Biliary Intraductal Papillary Neoplasms

TAO LI,* YUAN JI,‡ XU–TING ZHI,* LU WANG,§ XIN–RONG YANG,§ GUO–MING SHI,§ WEI ZHANG,§ and ZHAO–YOU TANG§

*Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China; ‡Department of Pathology and §Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China

Background & Aims:: There is controversy regarding pattern, commonly an overproduction of mucin and an asso- the term biliary intraductal papillary neoplasms (IPN-B) ciation with invasive adenocarcinoma.7–10 Therefore, some in- and their pathology, which frequently are confused with vestigators recommended the term biliary intraductal papillary hepatic mucinous cystic neoplasms (MCN). We aimed to neoplasms to be adopted in the study of biliary cystic tu- summarize the clinicopathologic features of IPN-B and dif- mors,7,11 in analogy to their pancreatic counterpart, to avoid ferentiate them from MCN. Methods: From January 1998 confusion with hepatic MCN. As in the pancreas, the presence to December 2007, there were 19 patients with intrahepatic of ovarian-like stroma is required to establish the diagnosis of IPN-B and 13 patients with MCN who underwent surgical hepatic MCN and its distinction from IPN-B.10 That is, biliary treatment at Zhongshan Hospital. Multiple demographic cystadenoma or cystadenocarcinoma should be restricted to and clinicopathologic parameters were reviewed retrospec- true cystic neoplasms with ovarian-like stroma, and most cases tively and compared between the groups. Results: The previously reported as biliary cystadenoma or cystadenocarci- mean ages of patients with IPN-B and MCN were 59.5 ؎ noma without ovarian-like stroma,12 which is considered to .the arise from bile ducts,13 are now thought to be IPN-B ;(0004. ؍ and 44.4 ؎ 9.7 years, respectively (P 11.1 ,Currently, great attention is being drawn to IPN-B. However .(028. ؍ male:female ratios also differed (11:8 vs 2:11; P with only a few cases of IPN-B reported, there continues to be (006. ؍ Tumors were significantly smaller (6.0 vs 11.2 cm; P in patients with IPN-B than in those with MCN. More inadequate knowledge available to understand the tumor and patients with IPN-B also had hepatolithiasis (47.4% vs 0%, to distinguish its intrahepatic form from other biliary cystic cholangiectasis and communication between tumors, especially MCN. In the current study we present a ;(004. ؍ P the cyst and main bile duct were more frequent in pa- single-institution, retrospective analysis of the clinical and ra- tients with IPN-B than in those with MCN (P < .001). diologic presentation, treatment, pathologic features, and long- The IPN-B consisted of 4 subtypes—the gastric subtype term outcomes of patients with intrahepatic IPN-B. was the least invasive. Malignant lesions were more common in patients with IPN-B than in those with MCN Patients and Methods The overall 5-year survival rates A retrospective review was made of the medical records .(03. ؍ vs 38.5%; P 78.9%) of patients with IPN-B and MCN were 82% and 100%, of all patients seen from January 1998 to December 2007 with respectively. Conclusions: Intrahepatic IPN-B repre- histologically proven IPN-B in Zhongshan Hospital, Fudan sents a distinct clinicopathologic entity that differs clini- University. IPN-B was defined microscopically as an intraductal cally, histologically, and radiologically from MCN. Curative papillary growth of neoplastic biliary epithelia with fine fibro- resection has a favorable prognosis for patients with IPN-B, vascular cores in the lumen of the biliary tree,8 and the absence but further studies of its subtype are required. of an ovarian-type stroma.10 Noninvasive tumors were classified as adenoma, borderline, or carcinoma in situ depending on the de- gree of epithelial dysplasia within the specimen. Invasive tumors ntraductal papillary neoplasms (adenocarcinoma/adenoma) were classified as tubular, colloid, or mixed-type carcinoma. Iand mucinous cystic neoplasms (MCNs) (cystadenocarcinoma/ Information including demographics, clinical history and cystadenoma) are 2 types of mucin-producing neoplasms of the presentation, diagnostic work-up, type of surgical procedure, bile duct. In contrast to the well-known MCN, biliary intraduc- details of histology, hospital course, and follow-up evaluation tal papillary neoplasm (IPN-B), which has been reported previ- were obtained and compared with those of 13 concurrent pa- ously in the literature under various terms, such as biliary papillomatosis,1 bile duct papillomatosis,2 mucin-hypersecreting cholangiocarcinoma,3 or mucin-hypersecreting bile duct Abbreviations used in this paper: CA 19-9, carbohydrate antigen tumor,4 is a newly recognized entity and its intrahepatic form 19-9; CT, computed tomography; ERCP, endoscopic retrograde cholan- usually is confused with MCN. giopancreatography; IDUS, intraductal ultrasonography; IPN-B, biliary Recent studies have revealed that IPN-B has striking similar- intraductal papillary neoplasm; IPMN-P, pancreatic intraductal papillary mucinous neoplasms; MCN, mucinous cystic neoplasm; MRCP, ities with pancreatic intraductal papillary mucinous neoplasms magnetic resonance cholangiopancreatography; MRI, magnetic reso- (IPMN-P), which can be distinguished from pancreatic MCN by nance imaging; US, ultrasound. the absence of ovarian-like stroma and communication with © 2009 by the AGA Institute the pancreatic duct.5,6 Both IPN-B and IPMN-P arise within the 1542-3565/09/$36.00 duct system and show a predominantly intraductal growth doi:10.1016/j.cgh.2009.02.019 转载中国科技论文在线 http://www.paper.edu.cn May 2009 BILIARY INTRADUCTAL PAPILLARY NEOPLASM 587

Table 1. Demographics and Clinical Characteristics of IPN-B Results and MCN Clinical Characteristics Characteristics IPN-B (n ϭ 19) MCN (n ϭ 13) P value There were 19 cases of intrahepatic IPN-B and 13 cases of Demographic data MCN. Clinical characteristics are described in Table 1. The mean Mean age, y 59.5 Ϯ 11.1 44.4 Ϯ 9.7 .0004 age of patients with IPN-B was 59.5 Ϯ 11.1 years (median, 60 y; Median age, y 60 43 range, 30–76 y) and the male:female ratio was 11:8, which was Sex, male:female 11:8 2:11 .028 quite different from those patients with MCN, for whom the mean Clinical manifestations age was 44.4 Ϯ 9.7 years (median, 43 y; range, 28–60 y; P ϭ .0004), Abdominal pain 6 (31.6%) 5 (38.5%) NS and female predominance was marked (M:F ratio, 2:11; P ϭ .028). Jaundice 1 (5.3%) 0 NS Overall, more than half of the patients of both groups were Weight loss 1 (5.3%) 0 NS asymptomatic and the neoplasms were discovered incidentally. Acute cholangitis 1 (5.3%) 0 NS There were no significant differences between IPN-B and MCN No symptoms 10 (52.6%) 8 (61.5%) NS ϭ Associated diseases with respect to clinical presentation (P NS), and the most Hepatolithiasis 9 (47.4%) 0 .004 common clinical manifestation at admission was epigastric Clonorchiasis 1 (5.3%) 0 NS pain. But IPN-B was associated more commonly with hepato- Hepatitis 0 2 (15.4%) NS lithiasis than MCN (47.4% vs 0%; P ϭ .004). Cirrhosis 1 (5.3%) 1 (7.7%) NS Both IPN-B and MCN seldom happened in patients with None 8 (42.1%) 10 (76.9%) NS hepatitis or cirrhosis, and serum carcinoembryonic antigen and Mean serum CA 19-9 50.2 (2.8–159) 251.3 (0.6–1434) NS ␣-fetoprotein levels were normal, except that the serum carbo- level, U/mL (range) hydrate antigen 19-9 (CA 19-9) level was increased in 42.1% of IPN-B patients and in 46.2% of MCN patients. However, the increase of CA 19-9 level was correlated to neither the progres- ϭ tients with MCN. All patients had follow-up evaluations con- sion nor the prognosis of both tumors (P NS). sisting of a clinical examination, serologic assessment of tumor markers and imaging, which included abdominal ultrasound Radiologic Findings (US), computed tomography (CT), magnetic resonance imaging US was performed in all IPN-B and MCN patients and (MRI), or magnetic resonance cholangiopancreatography (MRCP). revealed multilocular or unilocular lesions. Papillary projections or In all patients, recurrences were confirmed histologically. masses along the walls were detected in 18 IPN-B patients (Figure All continuous data are presented at mean Ϯ standard devia- 1A), including 3 hypoechoic, 9 hyperechoic, and 6 hyperechoic and tion. Categoric variables were compared using the Pearson chi- hypoechoic mixed masses, but were not detected in most MCN square test and the Fisher exact test when cell counts were less patients (94.7% vs 30.8%; P ϭ .0002), which usually were misdiag- than 5. The Student t test was used for all comparisons among nosed as simple cysts. Marked dilatation of the intrahepatic bile continuous variables. Significance was accepted at the 5% level. duct was detected in 14 IPN-B patients (Figure 1B), but in none of

Figure 1. US ﬁndings of IPN-B. (A) Cystic lesion with echogenic projections along the cyst walls on US. (B) US showed multilocular cystic lesions with marked dilatation of the bile duct (arrows). (C) US showed unilocular cystic lesion communicated with bile ducts (arrows). (D) On cholangiography, the dilated right bile ducts revealed multiple, amorphous ﬁlling defects (arrows) and ragged irregularity of the bile duct wall. (E) Choledocho- scope showed pinkish or red multiple papillary masses scattered within the bile duct. Panels D and E are from the same IPN-B patient. 中国科技论文在线 http://www.paper.edu.cn 588 LI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 5

Figure 2. CT ﬁndings of IPN-B. (A) Contrast-enhanced CT showed enhancement of the lesion. (B) Multiloc- ular cystic lesions with slightly enhanced projections along the walls. (C) Slight enhancement of the wall (arrow) with projections. (D) Cystic lesion without enhancement in the arterial phase.

the MCN patients (73.7% vs 0%; P Ͻ .0001). Communication with Ten patients with IPN-B underwent CT scans, and 9 of the bile ducts could be detected by US in some IPN-B (Figure 1C). On neoplasms appeared as a hypoattenuated or isoattenuated cholangiography, the dilated bile ducts of IPN-B lesions showed mass, 7 of which showed enhancement of the mass (Figure 2A multiple amorphous ﬁlling defects and ragged irregularity of the and B) or cyst wall (Figure 2C) in the arterial phase, and 2 were bile duct wall (Figure 1D), and choledochoscopy showed pinkish not enhanced (Figure 2D). In 2 patients, the bile duct walls were or red multiple papillary masses covered with mucin and scattered thickened and enhanced. Ten patients underwent MRI scan; 9 within the bile duct lumen (Figure 1E). lesions were all hypointense on T1-weighted images (Figure 3A)

Figure 3. MRI ﬁndings of IPN-B. (A) Contrast T1-weighted MRI showed hypointense lesions with nodular enhancement (arrow). (B) The lesion was hyperintense on T2-weighted image. (C) On the precontrast T1-weighted MRI, the cystic lesion was hyperintense and multiseptated. (D)Onthe enhanced T2-weighted MRI, the lesion was hyperintense compared with the surrounding liver parenchyma. 中国科技论文在线 http://www.paper.edu.cn May 2009 BILIARY INTRADUCTAL PAPILLARY NEOPLASM 589

Table 2. Comparison of Pathologic Features Between IPN-B 4A). In 10 cases of IPN-B, tumor appeared grossly as well- and MCN defined cystic masses. The cyst contents were mucoid and IPN-B MCN hemorrhagic, namely cystic type. The cyst walls and septa were (n ϭ 19) (n ϭ 13) P value lined with soft and friable papillary tumor masses with focal nodular, more solid areas, which was different from that of Mean tumor diameter, cm 6.0 Ϯ 3.9 11.2 Ϯ 5.6 .006 MCN, which usually was smooth and glistening. Tumor was Location of the lesions .030 identified grossly within dilated bile duct in 9 of the patients, Right lobe 4 8 namely ductectatic type. The intraductal mass was solitary in 3 Left lobe 15 5 patients, but in 6 lesions several smaller nodules were scattered Histologic diagnosis .030 Benign, adenoma ϩ BN 3 ϩ 16ϩ 2 in the duct around the main intraductal mass (Figure 4B). A Malignant, CIS ϩ carcinoma 5 ϩ 10 1 ϩ 4 large amount of mucin was present in 7 patients in dilated Communication with bile ducts 19 0 Ͻ.0001 intrahepatic bile ducts (Figure 4C). Luminal communication between cystic tumors and bile ducts was detected using probes BN, borderline neoplasm; CIS, carcinoma in situ. on all surgically resected IPN-B (Figure 4D), which was significantly different from MCN (100% vs 0%; P Ͻ .0001). and hyperintense on T2-weighted images (Figure 3B), except 1 Histologic grading of the tumors is described in Table 2. lesion was hyperintense on the T1-weighted image (Figure 3C) Malignant lesions (carcinoma or carcinoma in situ) were more ϭ and hypointense on the T2-weighted image. On enhanced MRI, common in IPN-B than in MCN (78.9% vs 38.5%; P .03). the lesion was hyperintense compared with the surrounding Based on a tumor-cell classification of IPMN-P mentioned in liver parenchyma (Figure 3D). Dilatation of bile duct also was the literature,14 19 IPN-B patients were classified into 4 sub- detected in most patients on CT (8 of 10) or MRI (7 of 10) scan. types: gastric type (5 patients), composed of columnar cells with However, in 2 patients who were diagnosed preoperatively with abundant intracytoplasmic mucin (Figure 5A); intestinal type (7 biliary stones, only dilatation of the bile duct was detected patients), characterized by stratified tall columnar cells with whereas the intraductal masses were not found. some goblet cells (Figure 5B); pancreaticobiliary type (5 patients), composed of columnar cells with eosinophilic cyto- Pathologic Findings plasm and round nuclei (Figure 5C); and oncocytic type (2 The pathologic features of the tumors are described in patients), characterized by abundant eosinophilic cytoplasm Table 2. The mean diameter of the IPN-B was 6.0 cm (range, and round nuclei (Figure 5D). Most gastric-type IPN-B were 2–13 cm), much smaller than that of the MCN (mean, 11.2 cm; adenoma or borderline neoplasm, which is more benign than range, 6–22 cm; P ϭ .006). The location of the mass differed, the other 3 subtypes (60% vs 7.1%; P ϭ .037). Compared with with IPN-B usually occurring in the left lobe, whereas MCN the other 3 subtypes, the intestinal type was the most common occurred in the right lobe (P ϭ .03). type associated with hepatolithiasis or cholangitis (85.7% vs Grossly, IPN-B growth was confined within the duct wall 50%; P ϭ .057). All 4 subtypes of IPN-B lacked the ovarian-like without any evidence of invasion into the adjacent liver (Figure stroma that was present in all MCN (Figure 6).

Figure 4. Macroscopic appearances of IPN-B. (A) Tumor was conﬁned within the duct wall without invasion into the adjacent liver. (B) A grayish fungating mass with smaller nodules scattered in the duct around it. (C) The intrahepatic duct was lined by a mas- sive papillary proliferation of epithelial cells and bile duct lumen was partly obstructed by mucin. (D) Cystic tumor ﬁlled with mucin and soft brown mural nodules. Direct communication with the bile ducts can be seen easily. 中国科技论文在线 http://www.paper.edu.cn 590 LI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 5

Figure 5. Subtypes of IPN-B. (A) Gastric type showed numerous papillary structures that project into the lumen (H&E staining, 100ϫ). (B) Intes- tinal type showed papillovillous proliferations of biliary lining cells (H&E staining, 200ϫ). (C) Pancreaticobiliary type showed multiple papillary and vil- lous proliferations of epithelial lining cells. The nuclei are mildly hyperchro- matic and the ﬁbrovascular core is thin (H&E staining, 40ϫ). (D) Oncocytic type showed the most predominant cells of the lining epithelium were columnar cells with oncocytic features showing abundant eosinophilic gran- ular cytoplasm and centrally located nuclei with prominent nucleoli (H&E staining, 40ϫ).

Perioperative Course and 1 patient underwent laparoscopic drainage before com- Treatment for IPN-B and MCN is summarized in plete resection was performed because their neoplasms were Table 3. Eighteen IPN-B patients underwent curative surgical diagnosed initially as a simple cyst. The other 2 patients resection with negative resection margin, and 1 patient had received palliative treatment, among which 1 patient under- a positive resection margin after a left lateral segmentec- went local resection and hepatic artery ligation, and the tomy. Of 13 MCN patients, 11 patients were treated cura- other patient underwent only hepatic artery ligation because tively, but 2 of the patients underwent US-guided puncture of multifocal lesions.

Figure 6. MCN case. (A) Precontrast CT showed one huge round cyst with a small papillary projection (arrow). (B) Contrast-enhanced CT showed no enhancement of the wall. (C) Macro- scopic picture showed a more granu- lar appearance and a solid compo- nent (arrow); part of the cyst wall appeared thicker. (D) Histologically, the tall columnar epithelial cells lining a mucinous cystadenoma showed no signiﬁcant atypia with the ovarian-like stroma beneath the epithelium. 中国科技论文在线 http://www.paper.edu.cn May 2009 BILIARY INTRADUCTAL PAPILLARY NEOPLASM 591

Table 3. Types of Surgeries Performed in Patients hepatolithiasis, moderate to marked chronic proliferative IPN-B (n ϭ 19) MCN (n ϭ 13) cholangitis, and peripheral bile duct obliteration were found more frequently in the affected liver with IPN-B. Because these Right hemihepatectomy 2 0 lesions may lead to the development of periductal inflamma- Left hemihepatectomy 9 4 tion, mucosal epithelial drop-out, and reparative hyperplasia, Left lateral segmentectomy 2 0 and may be followed by biliary dysplasia, papillary hyperplasia Local resection ϩ CHJ 5 0 with dysplasia, and in situ or invasive cholangiocarcinoma,17 Local resection 0 7 they are suggested to be related to the origin of IPN-B.8 Fur- ϩ Local resection HAL 0 1 thermore, the prevalence of tumor locations differed, with HAL 0 1 IPN-B usually located in the left intrahepatic bile duct, which is Liver transplantationa 10 the frequent location of hepatolithiasis, and might suggest the HAL, hepatic artery ligation; CHJ, cholangiojejunostomy. correlation between them as well. aInitial treatment was right lobectomy ϩ choledochectomy ϩ CHJ. Preoperative diagnosis by means of conventional imaging studies is not always easy for IPN-B or MCN. Although they both usually appeared as a cystic mass on imaging, small pap- The median postoperative length of stay was 11.7 days illomas may not be detected by US or CT. In the study by Lee (range, 8–19 d) and 9.3 days (range, 6–17 d) for the IPN-B and et al,1 intraductal papilloma and mucin secretion can be de- Ͼ MCN groups, respectively (P .05). There were no surgical tected in less than 50% of patients with IPN-B at CT and US, deaths or surgical re-explorations. All patients were followed and in our series nearly 70% of MCN were misdiagnosed pre- Ϯ up. The mean duration of follow-up evaluation was 35.0 31.0 operatively as a simple hepatic cyst and some IPN-B were months (median, 24 mo; range, 4–127 mo) for the IPN-B group, diagnosed as biliary stones. Imaging studies also do not allow Ϯ and 47.5 37.8 months (median, 27 mo; range, 11–115 mo) for the distinction of the presence or absence of ovarian-like the MCN group. stroma.18 Therefore, the most common abnormal radiologic find- All 13 MCN patients survived at the end of the study period ing of IPN-B to differentiate it from MCN was intrahepatic bile including the 2 patients who had tumor that recurred within 12 duct dilatation. Communication with the bile duct contributes months after the initial resection and underwent resection to the diagnosis of IPN-B, but it is difficult to detect by con- again. Of the 19 IPN-B patients, 16 patients remain alive at the ventional radiologic modalities. Endoscopic retrograde cholan- time of this writing and 14 of them are free of disease. After a giopancreatography (ERCP) is helpful for the diagnosis of mean follow-up period of 30.8 months (range, 12–74 mo) after IPN-B because of its characteristic cholangiographic findings of the initial resection, 5 patients developed recurrence, 2 of whom diffuse bile duct dilatation and amorphous filling defects in the were treated by liver transplantation and radiotherapy, and still bile duct.19 However, a large amount of mucin secretion and were alive. The other 3 patients all died as a consequence of obstruction by the tumor prevent complete opacification of the tumor recurrence. All 3 cases were invasive carcinomas and the entire biliary tract.20 Thus, small papillomas, which usually are presence of neural or muscular invasion was detected in all of remote from main tumors, may not be detected and may be the them. The 1-, 3-, and 5-year overall and tumor-free survival rates foci of recurrence.21 From this point of view, MRCP is superior of IPN-B patients were 100%, 82.0%, and 82.0%, and 93.8%, to ERCP because intraductal papilloma can be better identified 65.6%, and 65.6%, respectively. on MRCP, for the reason that mucin and bile juice can enhance the contrast between these fluids and papilloma. However, Discussion MRCP cannot take the place of ERCP completely; during ERCP In our study, IPN-B and MCN share some common therapeutic biliary drainage and stent insertion and biopsy characteristics, such as rare incidence, mucin production, and through the papilla are valuable in some patients with unre- cystic mass. However, there are unique clinical findings for each sectable disease or comorbid conditions, or in patients who type. IPN-B develops most commonly in patients between 50 need preoperative biliary drainage. and 70 years of age, which is much later than MCN. Although In the study by Lee et al,1 percutaneous transhepatic cholan- female predominance was noted in the MCN group, there was gioscopy revealed additional lesions in nearly one third of no marked sex preponderance in the IPN-B group. These data IPN-B patients after a radiologic imaging examination, includ- were similar to that of IPMN-P,15,16 but different from the data ing ERCP and MRCP. Therefore, percutaneous transhepatic of INP-B in Japan and Taiwan,8,11 in which female predomi- cholangioscopy is suggested to be essential, it can visualize the nance also was noted in the IPN-B group. There were no bile duct directly and confirm the histology and extent of the significant differences between the IPN-B and MCN groups lesions to ensure that appropriate treatment is provided. It is with respect to clinical presentation, but IPN-B usually was more useful in patients with mucin secretion because mucin is associated with hepatolithiasis, and sometimes with uncom- observed as filling defects on direct cholangiography and the mon presentation of jaundice and acute cholangitis. Although detection of mucin secretion may be difficult with CT and US.1 the serum CA 19-9 level was increased in about half of the Endoscopic US and intraductal ultrasonography (IDUS) repre- patients in both groups, in the current study there was no sent a major advance in endoscopic imaging for biliary tumors. evidence that the increase in CA 19-9 level was correlated to They not only allow a clear visualization of the neoplasia, but tumor progression or prognosis. Therefore, the increase might also accurate local tumor staging.22,23 However, IDUS exceeds just be owing to the cholestasis or cholangitis associated with conventional endoscopic US in terms of depiction of bile duct mucin overproduction.1 obstruction, diagnostic accuracy, and sensitivity and in the Both IPN-B and MCN usually occurred in normal liver prediction of surgical tumor resectability.24 It was especially without hepatitis or cirrhosis in the current study. However, useful for the differential diagnosis of advanced and early tu- 中国科技论文在线 http://www.paper.edu.cn 592 LI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 5

mors and was essential to determine the appropriate surgery traluminal therapy38 also are safe and useful adjuvant therapies plan.25 Furthermore, IDUS is useful for assessing the histologic for a better survival rate. type of bile duct cancer.26 The accuracy, sensitivity, and speci- The prognosis of IPN-B seems to be worse than that of ficity of IDUS in predicting papillary adenocarcinoma were MCN, but this needs to be verified further by a large number of 90%, 89%, and 90%, respectively.26 It also makes up for percu- cases and a relatively long follow-up evaluation. Because intra- taneous transhepatic cholangioscopy, the sensitivity of which ductal papilloma and mucin can be better identified on MRCP can be improved from 93% to 100%.27 Biopsy or aspiration than US and CT, and is less invasive than ERCP, it is more through percutaneous transhepatic cholangioscopy or IDUS useful for follow-up evaluation to evaluate changes in the size may provide useful data for the diagnosis, but we seldom and extent of tumors and to determine if new lesions appear.21 perform that because of the invasiveness, the time required to Therefore, to detect recurrences, we recommend that after re- complete the procedure, the high frequency of false-negative section patients from both groups undergo a surveillance pro- findings, and the risk of malignant seeding of the tract. gram with follow-up appointments scheduled for every 3 Our results confirm that both IPN-B and MCN comprise a months for the first year and for every 6 months beginning in wide range of histopathologic atypia, and carcinoma, either in the second year, by evaluations consisting of a clinical exami- situ or invasive, but IPN-B was more invasive in our series than nation, serologic assessment of tumor markers, and imaging, MCN. Furthermore, IPN-B is heterogeneous on the basis of among which MRCP is recommended. This policy should be their histology. Some researchers have suggested that parallel applied to patients not only with invasive carcinoma, but also to IPMN-P, there are 4 subtypes of IPN-B, including intestinal, with noninvasive neoplasms, which also can recur owing to pancreatobiliary, gastric, and oncocytic types.7 According to metachronous multifocal tumors or positive transection mar- their criteria, in the present study, 5 patients were classified as gins, and, in these cases, further resection can be attempted. pancreatobiliary type, 5 patients were classified as gastric type, In summary, IPN-B should be regarded as a unique clinical 7 patients were classified as intestinal type, and only 2 patients entity, and is different from MCN in terms of clinicopathologic were classified as oncocytic type, which was thought to be a and radiologic features. Aggressive surgical procedures should variant of the pancreaticobiliary type.9,28 Similar to IPMN-P,29 be attempted for these 2 mucin-producing neoplasms with adenoma or borderline neoplasm is more common in the gas- favorable prognosis. Further studies on the subtypes of IPN-B tric type, whereas the other 3 types mostly are associated with are necessary and may provide a better understanding of its carcinoma. In addition, the intestinal type of our series is the genesis and the outcome of the patients. most common in IPN-B associated with hepatolithiasis or cholangitis. It is possible that the tumor cell type of IPN-B References might reflect the preceding condition, affect the growth types of 1. Lee SS, Kim MH, Lee SK, et al. Clinicopathologic review of 58 tumors, or influence the outcome of the patients.10 However, patients with biliary papillomatosis. Cancer 2004;100:783–793. additional research on the subtype of IPN-B is necessary to 2. Hubens G, Delvaux G, Willems G, et al. Papillomatosis of the clarify this issue. intra- and extrahepatic bile ducts with involvement of the pancre- Currently, IPN-B is considered to be a premalignant disease atic duct. Hepatogastroenterology 1991;38:413–418. with high malignant potential and must be treated aggressi- 3. Chen MF, Jan YY, Chen TC. Clinical studies of mucin-producing vely.1 Although there were case reports of nonresectional therapy cholangiocellular carcinoma: a study of 22 histopathology-proven cases. Ann Surg 1998;227:63–69. that were followed by long-term patient survival,30 resection 4. Kim HJ, Kim MH, Lee SK, et al. Mucin-hypersecreting bile duct still provides the best chance for cure. Surgical resection is tumor characterized by a striking homology with an intraductal proposed when IPN-B is localized according to the preoperative papillary mucinous tumor (IPMT) of the pancreas. Endoscopy imaging work-up and with the support of intraoperative US or 2000;32:389–393. cholangioscopy.31 All our patients underwent surgical resection, 5. Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary muci- and the prognosis was favorable. The overall 5-year survival rate nous neoplasms of the pancreas: an updated experience. Ann was 82%, which was similar to the previous studies.1,32 For Surg 2004;239:788–797. patients with multicentricity or a diffuse pattern of IPN-B, the 6. Salvia R, Crippa S, Falconi M, et al. Branch-duct intraductal recurrence rate is high after surgical resection. Thus, liver trans- papillary mucinous neoplasms of the pancreas: to operate or not to operate? Gut 2007;56:1086–1090. plantation has been suggested to be the only ultimate curative 7. Kloppel G, Kosmahl M. Is the intraductal papillary mucinous approach to avoid recurrence and guarantee long-term survi- neoplasia of the biliary tract a counterpart of pancreatic papillary 33,34 val. One patient in our series underwent liver transplanta- mucinous neoplasm? J Hepatol 2006;44:249–250. tion because of recurrence 2 years after initial resection and still 8. Chen TC, Nakanuma Y, Zen Y, et al. Intraductal papillary neopla- is alive without any evidence of recurrence after 18 months of sia of the liver associated with hepatolithiasis. Hepatology 2001; follow-up evaluation. In case major surgery is not indicated, 34:651–658. adjuvant or palliative procedures are recommended. Palliative 9. Zen Y, Fujii T, Itatsu K, et al. Biliary papillary tumors share intrahepatic tubing or percutaneous transhepatic biliary drain- pathological features with intraductal papillary mucinous neo- age can alleviate jaundice and cholangitis to prolong survival.35 plasm of the pancreas. Hepatology 2006;44:1333–1343. Venu et al36 introduced intraluminal radiation therapy as pal- 10. Zen Y, Fujii T, Itatsu K, et al. Biliary cystic tumors with bile duct communication: a cystic variant of intraductal papillary neoplasm liative treatment for biliary tree neoplasms. It can be performed of the bile duct. Mod Pathol 2006;19:1243–1254. using an endoscopic approach or by the percutaneous transhe- 11. Zen Y, Sasaki M, Fujii T, et al. Different expression patterns of mucin patic route and has been proved to be effective by tumor core proteins and cytokeratins during intrahepatic cholangiocarcino- disappearance or improvement in symptoms. Recently, new genesis from biliary intraepithelial neoplasia and intraductal papil- alternatives such as percutaneous choledochoscopic laser abla- lary neoplasm of the bile duct—an immunohistochemical study of tion,37 cholangioscopic electrocoagulation, and iridium-192 in- 110 cases of hepatolithiasis. J Hepatol 2006;44:350–358. 中国科技论文在线 http://www.paper.edu.cn May 2009 BILIARY INTRADUCTAL PAPILLARY NEOPLASM 593

12. Akiyoshi T, Yamaguchi K, Chijiiwa K, et al. Cystadenocarcinoma 27. Tamada K, Ueno N, Tomiyama T, et al. Characterization of biliary of the liver without mesenchymal stroma: possible progression strictures using intraductal ultrasonography: comparison with from a benign cystic lesion suspected by follow-up imagings. J percutaneous cholangioscopic biopsy. Gastrointest Endosc Gastroenterol 2003;38:588–592. 1998;47:341–349. 13. Akwari OE, Tucker A, Seigler HF, et al. Hepatobiliary cystadenoma 28. Adsay NV, Conlon KC, Zee SY, et al. Intraductal papillary- with mesenchymal stroma. Ann Surg 1990;211:18–27. mucinous neoplasms of the pancreas: an analysis of in situ 14. Furukawa T, Kloppel G, Volkan Adsay N, et al. Classification of and invasive carcinomas in 28 patients. Cancer 2002;94: types of intraductal papillary-mucinous neoplasm of the pan- 62–77. creas: a consensus study. Virchows Arch 2005;447:794–799. 29. Nakamura A, Horinouchi M, Goto M, et al. New classification of 15. Shyr YM, Su CH, Tsay SH, et al. Mucin-producing neoplasms of pancreatic intraductal papillary-mucinous tumour by mucin ex- the pancreas. Intraductal papillary and mucinous cystic neo- pression: its relationship with potential for malignancy. J Pathol plasms. Ann Surg 1996;223:141–146. 2002;197:201–210. 16. D’Angelica M, Brennan MF, Suriawinata AA, et al. Intraductal 30. Lai R, Freeman ML, Mallery S. EUS in multiple biliary papilloma- papillary mucinous neoplasms of the pancreas: an analysis of tosis. Gastrointest Endosc 2002;55:121–125. clinicopathologic features and outcome. Ann Surg 2004;239: 31. Cox H, Ma M, Bridges R, et al. Well differentiated intrahepatic 400–408. cholangiocarcinoma in the setting of biliary papillomatosis: a 17. Koga A, Ichimiya H, Yamaguchi K, et al. Hepatolithiasis associ- case report and review of the literature. Can J Gastroenterol ated with cholangiocarcinoma. Possible etiologic significance. 2005;19:731–733. Cancer 1985;55:2826–2829. 32. Suh KS, Roh HR, Koh YT, et al. Clinicopathologic features of the 18. Buetow PC, Buck JL, Pantongrag-Brown L, et al. Biliary cystade- intraductal growth type of peripheral cholangiocarcinoma. Hepa- noma and cystadenocarcinoma: clinical-imaging-pathologic corre- tology 2000;31:12–17. lations with emphasis on the importance of ovarian stroma. 33. Imvrios G, Papanikolaou V, Lalountas M, et al. Papillomatosis of Radiology 1995;196:805–810. intra- and extrahepatic biliary tree: successful treatment with liver 19. D’Abrigeon G, Blanc P, Bauret P, et al. Diagnostic and therapeutic transplantation. Liver Transpl 2007;13:1045–1048. aspects of endoscopic retrograde cholangiography in papilloma- 34. Charre L, Boillot O, Goffette P, et al. Long-term survival after tosis of the bile ducts: analysis of five cases. Gastrointest En- isolated liver transplantation for intrahepatic biliary papillomato- dosc 1997;46:237–243. sis. Transpl Int 2006;19:249–252. 20. Hoang TV, Bluemke DA. Biliary papillomatosis: CT and MR find- 35. Okuda K, Kubo Y, Okazaki N, et al. Clinical aspects of intrahe- ings. J Comput Assist Tomogr 1998;22:671–672. patic bile duct carcinoma including hilar carcinoma: a study of 57 21. Chung DJ, Lee SK, Ha HK, et al. Multiple biliary papillomatosis: autopsy-proven cases. Cancer 1977;39:232–246. comparison of MR cholangiography with endoscopic retrograde 36. Venu RP, Geenen JE, Hogan WJ. Intraluminal radiation therapy for cholangiography. J Comput Assist Tomogr 2002;26:968–974. biliary tract malignancy—an endoscopic approach. Gastrointest 22. Dancygier H, Nattermann C. The role of endoscopic ultrasonog- Endosc 1987;33:236–238. raphy in biliary tract disease: obstructive jaundice. Endoscopy 37. Meng WC, Lau WY, Choi CL, et al. Laser therapy for multiple 1994;26:800–802. biliary papillomatosis via choledochoscopy. AustNZJSurg 23. Awad SS, Fagan S, Abudayyeh S, et al. Preoperative evaluation of 1997;67:664–666. hepatic lesions for the staging of hepatocellular and metastatic 38. Gunven P, Gorsetman J, Ohlsen H, et al. Six-year recurrence free liver carcinoma using endoscopic ultrasonography. Am J Surg survival after intraluminal iridium-192 therapy of human bilobar 2002;184:601–604. biliary papillomatosis. A case report. Cancer 2000;89:69–73. 24. Menzel J, Poremba C, Dietl KH, et al. Preoperative diagnosis of bile duct strictures—comparison of intraductal ultrasonography with conventional endosonography. Scand J Gastroenterol 2000; 35:77–82. Reprint requests 25. Tamada K, Ueno N, Ichiyama M, et al. Assessment of tumor Address requests for reprints to: Zhao-You Tang, MD, Professor and extent in extrahepatic bile duct cancers—utility of intraductal Chairman, Liver Cancer Institute (Zhongshan Hospital), Fudan Univer- ultrasonography. Nippon Shokakibyo Gakkai Zasshi 1994;91: sity, 136 Yi Xue Yuan Road, Shanghai, China. e-mail: zytang@fudan. 863–874. ac.cn; fax: (86) 21-6403-7181. 26. Tamada K, Kanai N, Tomiyama T, et al. Prediction of the histologic type of bile duct cancer by using intraductal ultrasonogra- Conflicts of interest phy. Abdom Imaging 1999;24:484–490. The authors disclose no conflicts.