Potential conflict of interest: Nothing to report.
Recently, attention has been drawn to papillary neoplasm of the pancreatobiliary systems. In the pancreas, the disease entity of intraductal papillary mucinous neoplasm (IPMN-P) is widely recognized. In contrast, the pathological characteristics of biliary papillary tumors, such as biliary papilloma(tosis) and papillary cholangiocarcinoma, have not yet been well documented. In this study, we compared the pathological features and post-operative prognosis among biliary papillary tumors (10 cases of biliary papilloma(tosis) and 22 cases of papillary cholangiocarcinoma), conventional non-papillary cholangiocarcinoma (15 cases), and IPMN-P (31 cases). Macroscopically, all biliary papillary tumors were characterized by the prominent intraductal papillary proliferation, and macroscopic mucin-hypersecretion was seen in 9 of 32 cases (28%). Histologically, biliary papillary tumors consisted of three types of tumor cells (pancreaticobiliary, intestinal and gastric types), whereas only the pancreaticobiliary type was observed in non-papillary cholangiocarcinoma. Immunohistochemically, biliary papillary tumors were characterized by the common expression of MUC2, CDX2 and cytokeratin 20. In addition, biliary papillary tumors could be associated with two types of invasive lesions: tubular adenocarcinoma (9 cases) and mucinous carcinoma (5 cases). Patients with tubular adenocarcinoma had a poor prognosis compared to non-invasive papillary tumor or papillary tumor with mucinous carcinoma. These pathological characteristics and the survival status of biliary papillary tumors were different from those of non-papillary cholangiocarcinoma, and rather closely resembled those of IPMN-P. In conclusion, biliary papillary tumors may be the biliary counterpart (intraductal papillary neoplasm of the bile duct) of IPMN-P. (HEPATOLOGY 2006;44:1333–1343.)
Certain types of papillary tumors with different malignant potentials are known to occur in the intrahepatic and extrahepatic bile ducts.1 Biliary papilloma (papilloma adenoma) is a rare benign neoplasm composed of papillary proliferation of the dysplastic biliary epithelium with delicate fibrovascular stalks.1 Multiple recurring biliary papillomas are known as biliary papillomatosis. Some cases of biliary papillomatosis have multiple tumors at the same time, and others manifest asynchronous tumors at different sites of the biliary tract.1, 2 Biliary papilloma and papillomatosis are now thought to be pre-malignant lesions, and they have the potential to progress to invasive lesions via an adenoma-carcinoma sequence.3
Some cholangiocarcinomas show mainly papillary proliferation in the bile duct lumen, and those cases are designated as papillary cholangiocarcinoma (papillary-CC) or cholangiocarcinoma of the intraductal growth-type.4, 5 Papillary-CC accounts for only a small fraction of intrahepatic and extrahepatic cholangiocarcinoma compared to those of other major types, such as the mass-forming or periductal-infiltrating type of intrahepatic cholangiocarcinoma, and the nodular or ulcerative type of extrahepatic cholangiocarcinoma.6 Interestingly, according to carcinogenetic studies, papillary-CC is different from cholangiocarcinoma of other types in that p53 or K-ras mutation, the expression of matrix metalloproteinase-2 (MMP-2) and the aberrant expression of β-catenin were relatively rare events in papillary-CC.7–9 In addition, there is increasing evidence that a component of papillary-CC is related to a favorable prognosis.10, 11
So far, there have already been several reports that papillary tumors of the biliary tract pathologically resemble intraductal papillary mucinous neoplasm of the pancreas (IPMN-P), in that both tumors showed prominent intraductal papillary proliferation of tumor cells, the acquisition of gastrointestinal phenotypes, not infrequent mucin hyper-secretion and frequent progression to mucinous carcinoma.12, 13, 14 However, there have been no comparative studies on the clinicopathological features and post-operative prognosis of biliary papillary tumors and IPMN-P using a considerable number of cases.
In this study, we compared the clinicopathological characteristics and post-operative outcome among biliary papilloma, biliary papillomatosis, papillary-CC and non-papillary cholangiocarcinoma (non-papillary-CC), and also compared those features of biliary papillary tumors with IPMN-P. The goal of this study was to reveal whether or not these biliary papillary tumors and IPMN-P show similar clinicopathological features.
papillary-CC, papillary cholangiocarcinoma; BP, biliary papilloma(tosis); IPMN-P, intraductal papillary mucinous neoplasm of the pancreas; non-papillary-CC, non-papillary cholangiocarcinoma.
Materials and Methods
A total of 32 cases of biliary papillary tumors were obtained from the hepatobiliary disease files of the Department of Human Pathology, Kanazawa University Graduate School of Medicine and affiliated hospitals in Japan between 1984 and 2005. This study consisted of 5 cases of biliary papilloma, 5 cases of biliary papillomatosis, and 22 cases of papillary-CC. In this study, biliary papilloma and biliary papillomatosis were examined in the same group (BP group). All BP and papillary-CC were located in the extrahepatic bile duct (common bile duct), hilar bile ducts (hepatic ducts and their first branches), or intrahepatic large bile ducts (second or third branches of hepatic ducts). Any papillary lesions of Vater's ampulla or gall bladder were not included in this study. No cases had any preceding conditions for biliary tumors, such as primary sclerosing cholangitis or hepatolithiasis. Average ages, male/female ratios, tumor sizes, and tumor locations of the examined cases are shown in Table 1. We used 15 cases of non-papillary-CC and 31 cases of IPMN-P as disease controls. All non-papillary-CC formed nodular lesions with or without periductal infiltration, and histologically showed invasive tubular adenocarcinoma (Table 2). Intraductal papillary proliferation was not observed in the non-papillary-CC used in this study. IPMN-P consisted of 23 cases of the branch duct-type and 8 cases of the main pancreatic duct-type. Out of 31 cases of IPMN-P, 15 cases were associated with invasive lesions of tubular adenocarcinoma (7 cases) or mucinous carcinoma (8 cases) (Table 2). All cases used in this study were surgically-resected cases (15 cases of choledochectomy, 5 cases of choledochectomy with partial hepatectomy, 6 cases of left hepatectomy, 4 cases of right hepatectomy, 38 cases of pancreatoduodenectomy, 9 cases of distal pancreatectomy and 1 case of total pancreatectomy).
Table 1. Average Ages, Sexes, Tumor Sizes and Tumor Locations of Biliary Papilloma(tosis), Papillary Cholangiocarcinoma, Non-Papillary Cholangiocarcinoma and Intraductal Papillary Mucinous Neoplasm of the Pancreas
Average Age (Range)
Abbreviations: N, number of cases; IPMN-P, intraductal papillary mucinous neoplasm of the pancreas
intrahepatic (3), extrahepatic (5), hilar (2)
intrahepatic (3), extrahepatic (17), hilar (2)
intrahepatic (3), extrahepatic (11), hilar (1)
main pancreatic duct (8), branch duct (23)
Table 2. Histological Types of Biliary Papilloma(tosis), Papillary Cholangiocarcinoma, Non-Papillary Cholangiocarcinoma and Intraductal Papillary Mucinous Neoplasm of the Pancreas
NOTE. Phrases in parenthesis are tumor differentiations.
Abbreviations: N, number of cases; IPMN-P, intraductal papillary mucinous neoplasm of the pancreas; CIS, carcinoma in situ.
CIS (8), tubular ca [well (5), moderately (4)], mucinous ca (5)
tubular ca [well (5), moderately (8), poorly (2)]
adenoma (10), borderline (4), CIS (2), tubular ca [well (3), moderately (4)], mucinous ca (8)
Definition and Classification of Biliary Papillary Tumors.
Biliary papilloma was defined as a solitary and localized papillary lesion composed of papillary proliferation of atypical biliary epithelium along with delicate fibrovascular cores. Biliary papillomatosis was defined as having more than three papillomas at different sites of intrahepatic or extrahepatic bile ducts at the same time or asynchronously. The largest tumor in each case of biliary papillomatosis was examined in this study. Tumor cells of biliary papilloma(tosis) (BP) showed mild to moderate degrees of dysplastic changes (nuclear enlargement, high nuclear/cytoplasmic ratio, irregularity of the nuclear membrane, and nuclear pleomorphism). Those histological features were not completely benign, although they did not fulfill the criteria of carcinoma in situ. Because there is no classification system for those equivocal papillary lesions of the bile duct, we categorized BP cases as borderline tumors in this study (Supplementary Fig. 1; available at the HEPATOLOGY website: http://interscience. wiley.com/jpages/0270-9139/suppmat/index.html). None of the cases of BP used in this study were associated with invasive carcinoma.
Papillary-CC was defined as cholangiocarcinoma with predominantly intraductal papillary growth associated or not associated with invasive cancer. Intraductal components were composed of biliary epithelium with severe dysplastic changes corresponding to carcinoma in situ. Invasive lesions associated with papillary-CC were histologically classified into conventional tubular adenocarcinoma and mucinous carcinoma. In this study, mucinous carcinoma was defined as more than 80% of invasive elements consisting of mucinous carcinoma.15 The depth of the invasive lesions influences the survival rates.16 The cases examined in this study, the stage of non-papillary-CC and invasive papillary-CC with tubular adenocarcinoma or mucinous carcinoma was not different: 8 of 15 non-papillary-CC (53%), 4 of 9 invasive papillary-CC with tubular adenocarcinoma (44%) and 2 of 5 invasive papillary-CC with mucinous carcinoma (40%) were confined to the ductal wall, and the remaining cases extended into the pancreas, liver, and the serosal surface of the bile ducts.
Classification of Tumor-Cell Types.
According to the classification of tumor-cell types of IPMN-P,17–20 we classified the tumor cells into three types: (1) the pancreaticobiliary type, composed of columnar cells with eosinophilic cytoplasm and round nuclei; (2) the intestinal type, characterized by stratified tall columnar cells with some goblet cells, resembling intestinal adenoma or adenocarcinoma; (3) the gastric type, composed of columnar cells with abundant intracytoplasmic mucin. In addition, the oncocytic type, which is characterized by abundant eosinophilic cytoplasm and round nuclei, was thought to be a variant of the pancreaticobiliary type, according to previous reports.17, 21
Immunostainings of MUC1, MUC2, MUC5AC, CDX2, CK7 and CK20 were performed using the EnVision+ system (Dako Cytomation, Glostrup, Denmark). Deparaffinized sections used for MUC2, MUC5AC, CDX2, CK7 and CK20 were microwaved in 10 mM citrate buffer (pH 6.0) for 20 minutes. After the blocking of endogenous peroxidase and incubation in normal goat serum (1:10; Vector Laboratories, Burlingame, CA) for 20 minutes, the deparaffinized sections were incubated overnight at 4 °C with primary monoclonal antibodies: anti-MUC1 (clone DF3; 1:100; Toray Fuji Bionics, Tokyo, Japan), anti-MUC2 (clone Ccp58; 1:100; Novocastra Laboratories, Newcastle, UK), anti-MUC5AC (clone CLH2; 1:100; Novocastra Laboratories), anti-CDX2 (clone CDX2-88; 1:100; BioGenex, San Ramon, CA), anti-CK7 (clone OV-TL 12/30; 1:50; Dako Cytomation), and anti-CK20 (clone Ks20.8; 1:50 dilution; Dako Cytomation). The sections were then incubated at room temperature for 1 hour with goat anti-mouse immunoglobulins conjugated to peroxidase labeled-dextran polymer (EnVision+; Dako Cytomation). The reaction products were developed by immersing the section in a 3,3′-diaminobenzidine tetrahydrochloride (DAB) solution containing 0.03% hydrogen peroxide. Nuclei were lightly counterstained with hematoxylin.
The expression of MUC1, MUC2, MUC5AC, CDX2, CK7 and CK20 was evaluated as positive or negative, according to the percentage of positive cells in the individual lesion: positive, more than 25%, negative, less than 25%.
Double Immunostaining for CDX2 and MUC2.
Double immunohistochemical staining was performed to assess the simultaneous detection of CDX2 and MUC2 in neoplastic biliary and pancreatic epithelium using 25 cases with both MUC2 and CDX2 expression on single immunostainings. The deparaffinized sections were incubated with normal goat serum (1:10, Vector Laboratories) for 20 minutes, immersed in 10 mmol/L citrate buffer and heated in a microwave oven at 95°C for 20 minutes, and then incubated with mouse monoclonal antibody to CDX2 (same antibody mentioned above) and rabbit polyclonal antibody to MUC2 (clone H-300; 1:100; Santa Cruz Biotechnology, Santa Cruz, CA) overnight at 4°C. The reaction product was visualized with fluorescent goat anti-mouse or anti-rabbit IgG antibody (1:500, Molecular Probes Inc., Eugene, OR), and observed under fluorescent microscopy. No positive staining was obtained when the primary monoclonal antibody was omitted or replaced by normal mouse serum in the negative controls of the staining procedures.
Statistical analysis was performed using the Mann-Whitney U test. The survival of the patients was compared using the Kaplan-Meier method, and differences between the survival curves were tested using the log-rank test. A probability of P less than .05 was considered statistically significant.
Classification of Papillary-CC.
Among 22 cases of papillary-CC, 8 cases were papillary adenocarcinoma in situ (36%), and 14 cases were associated with invasive cancer (64%). Of 14 cases with invasive cancer, 5 cases were histologically mucinous carcinomas (23% of papillary-CC), whereas 9 were tubular adenocarcinomas (41% of papillary-CC). Papillary-CC with tubular adenocarcinoma were histologically of the well (5 cases) or moderately differentiated type (4 cases) (Table 2). Papillary-CC resembled IPMN-P in that these two tumors could be associated with two types of invasive carcinoma (tubular adenocarcinoma and mucinous carcinoma) (Table 2). In contrast, all non-papillary-CC cases were histologically conventional tubular adenocarcinoma.
Gross Findings of Biliary Papillary Tumors.
All biliary papillary tumors (BP and papillary-CC) were macroscopically characterized by prominent intraductal papillary growth. Local and peripheral bile ducts were dilated (Supplementary Fig. 2), although cystic dilatation corresponding to cystic biliary tumor was not observed in any of the cases used in this study. Five cases of BP had more than three discontinuous papillary lesions in the surgically-resected specimens (four cases, three lesions; one case, five lesions) (Fig. 1A-B). Among them, one case also had a surgical history of solitary papillary tumor of the cystic duct 6 years ago. In addition to intraductal papillary proliferation, papillary-CC with tubular adenocarcinoma was associated with nodular infiltrative growth within the bile duct wall or neighboring hepatic and pancreatic parenchyma (Fig. 1C), whereas papillary-CC with mucinous carcinoma showed a muconodular growth pattern (Fig. 1D). Macroscopically, mucin was observed on the surface of the papillary tumor in 3 cases of BP, one case of papillary-CC (carcinoma in situ), and all cases of papillary-CC with mucinous carcinoma (5 cases) (Fig. 1A,B,D).
Histological Findings of Biliary Papillary Tumors.
All biliary papillary tumors showed prominent intraductal papillary proliferation of dysplastic tumor cells with delicate fibrovascular cores (Fig. 2A-B). All cases of BP showed mild to moderate cellular dysplasia, without overt malignancy, corresponding to borderline tumor (Supplementary Fig. 1). In biliary papillomatosis, non-neoplastic biliary epithelium was observed between each lesion. A papillary tumor, which had been resected 6 years previously in a case of BP, was also biliary papilloma without any invasive growth. Tubular adenocarcinoma associated with papillary-CC showed ill-defined invasive growth with abundant fibrous stroma at the base of the papillary lesions, and was commonly associated with vascular invasion, lymphatic invasion, and perineural invasion (Fig. 2C). Mucinous carcinoma with papillary-CC consisted of extravasated abundant mucin and floating tumor cells, and mucinous carcinoma showed compressive growth (Fig. 2D).
Tumor-Cell Types of Biliary Papillary Tumors, Non-Papillary-CC and IPMN-P.
Tumor-cell types of BP, papillary-CC, non-papillary-CC and IPMN-P are summarized in Table 3. Similar to previous reports,17–20 IPMN-P could be classified into three types of epithelium: the gastric type was the commonest (48%), and pancreaticobiliary and intestinal types were observed in 26% of cases each. Three types of tumor cells were also observed in BP and papillary-CC (Fig. 3), although the gastric type occurred in only one case of papillary-CC. Papillary-CC with tubular adenocarcinoma consisted of 7 cases of the pancreaticobiliary type (78%) and 2 cases of the intestinal type (22%), whereas those with mucinous carcinoma involved one case of the pancreaticobiliary type (20%) and 4 cases of the intestinal type (80%). One case of papillary-CC with tubular adenocarcinoma and one case of IPMN-P (carcinoma in situ) consisted of oncocytic tumor cells (a variant of the pancreaticobiliary type, as described in the Materials and Methods section17, 21). In contrast, all non-papillary-CC cases were of the pancreaticobiliary type, and intestinal and gastric types were not observed in any cases of non-papillary-CC.
Table 3. Tumor-Cell Types and Their Relationship to Ck20 Expression in Biliary Papilloma(tosis), Papillary Cholangiocarcinoma, Non-Papillary Cholangiocarcinoma and Intraductal Papillary Mucinous Neoplasm of the Pancreas
Abbreviations: N, number of cases; CIS, carcinoma in situ; IPMN-P, intraductal papillary mucinous neoplasm of the pancreas.
The results of MUC1, MUC2 and MUC5AC expression in each tumor group are shown in Fig. 4. MUC1 was expressed mainly in the apical membrane and occasionally in the cytoplasm of tumor cells. The latter expression was more frequent in invasive lesions. MUC2 and MUC5AC were mostly expressed in the cytoplasm of tumor cells. CDX2 was expressed in tumor-cell nuclei.
All cases of non-papillary-CC showed MUC1 expression, although its expression was only focal in one case (less than 25% of tumor cells). In contrast, MUC1 expression was less frequently observed in BP (10%, P < .001), papillary-CC (41%, P = .001) and IPMN-P (29%, P < .001). Among the papillary-CC cases, MUC1 was more frequently expressed in cases associated with tubular adenocarcinoma (67%) compared to those with carcinoma in situ (25%, P = .096) or mucinous carcinoma (20%, P = .107). MUC1 was mainly expressed in invasive tumor cells, rather than non-invasive cells in papillary-CC with tubular adenocarcinoma (Supplementary Fig. 3). Among the BP and papillary-CC cases, MUC1 expression was more common in the pancreaticobiliary type (41%) compared to the intestinal (21%) or gastric types (0%), although their differences were not significant.
On the other hand, MUC2 expression was more frequently observed in BP (50%), papillary-CC (45%) and IPMN-P (42%) compared to non-papillary-CC (0%) (P = .003) (Fig. 5). Among the BP and papillary-CC cases, MUC2 was more commonly expressed in the intestinal type (71%) compared to the pancreaticobiliary (29%, P = .022) and gastric types (0%, P = .157). MUC5AC expression was common in all tumor groups: BP (90%), papillary-CC (82%), non-papillary-CC (87%) and IPMN-P (97%). Similar to MUC2, CDX2 was more frequently expressed in BP (50%), papillary-CC (50%) and IPMN-P (42%) compared to non-papillary-CC (0%) (P = .003, 0.001 and 0.003, respectively). One case of BP and two cases of papillary-CC without MUC2 expression showed focal CDX2 expression. Among the BP and papillary-CC cases, CDX2 expression was more common in the intestinal type (79%) compared to the pancreaticobiliary (29%, P = .007) and gastric types (0%, P = .097). Double immunostaining of MUC2 and CDX2 revealed double-positive tumor cells in all 25 cases with both MUC2 and CDX2 expression on single immunostainings (Fig. 6).
Expression of CK7 and CK20.
The results of CK7 and CK20 expression in each tumor group are shown in Fig. 4. CK7 and CK20 were expressed in the cytoplasm of tumor cells. CK7 expression was observed in all neoplastic lesions examined in this study, and also the surrounding non-neoplastic biliary and pancreatic ductal epithelium, although its expression was only focal (less than 25% of tumor cells) in three tumors examined in this study. In contrast, CK20, which was not expressed in non-neoplastic biliary and pancreatic duct epithelium, was more frequently expressed in BP (60%) and papillary-CC (55%) compared to non-papillary-CC (13%) (P = .003 and 0.001, respectively) (Fig. 7). CK20 expression in BP and papillary-CC were also more frequent compared to those of IPMN-P (26%) (P = .051 and P = .035, respectively), although the former difference (BP to IPMN-P) was not significant.
Relationship Between CK20 Expression and Tumor-Cell Types.
The CK20 expression in each type of tumor cell is shown in Table 3. The intestinal-type tumors commonly expressed CK20, whereas no cases of the gastric type had CK20 expression, irrespective of the tumor groups. In the pancreaticobiliary type, 13-50% of cases were associated with CK20 expression in each tumor group.
Lymph Node Metastasis.
The frequency of lymph node metastasis at the time of surgery is shown in Table 4. Non-invasive biliary papillary tumors (BP and carcinoma in situ of papillary-CC) were not associated with lymph node metastasis. Lymph node metastasis was more frequently observed in non-papillary-CC cases compared to papillary-CC (P = .019). In addition, lymph node metastasis was more common in tubular adenocarcinoma than mucinous carcinoma among papillary-CC cases, although it was not significant (P = .216). These tendencies were also true for IPMN-P with tubular adenocarcinoma and mucinous carcinoma.
Table 4. Frequency of Lymph Node Metastasis in Biliary Papilloma(tosis), Papillary Cholangiocarcinoma, Non-Papillary Cholangiocarcinoma and Intraductal Papillary Mucinous Neoplasm of the Pancreas
Lymph Node Metastasis
Abbreviations: N, number of cases; IPMN-P, intraductal papillary mucinous neoplasm of the pancreas.
Survival Rates in the Patients With Biliary Papillary Tumors, Non-Papillary-CC and IPMN-P.
The survival status of patients with BP, papillary-CC, non-papillary-CC and IPMN-P are shown in Fig. 8A. Clinical outcome data were available in all cases examined in this study, except for 2 patients with papillary-CC (carcinoma in situ), who missed medical follow-ups at 20 and 35 months after surgery. Among the 10 patients with BP, 9 patients were alive, whereas one patient died due to a non-hepatobiliary disease (cerebral infarction) 19 months after surgery. The 5-year survival rates of the patients with BP, papillary-CC, non-papillary-CC and IPMN-P were 90%, 50%, 0% and 58%, respectively. Patients with BP or papillary-CC showed a significantly better prognosis compared to patients with non-papillary-CC (P < .001). The survival rate of patients with BP was higher than that of patients with papillary-CC, although it was not significant (P = .066).
We compared the survival status between patients with biliary papillary tumors (BP and papillary-CC) and patients with IPMN-P (Fig. 8B-C). Patients with non-invasive biliary papillary tumors (BP or the carcinoma in situ type of papillary-CC) had better prognoses compared to patients with papillary-CC with tubular adenocarcinoma (P < .001) and mucinous carcinoma (P = .141). Among the patients with papillary-CC, the survival rate of patients with mucinous carcinoma was better than that of patients with tubular adenocarcinoma (P = .045). The survival curve of patients of papillary-CC with invasive tubular adenocarcinoma was almost identical to that of non-papillary-CC (P = .152) (Fig. 8A-B), suggesting that the presence of invasive tubular adenocarcinoma in papillary-CC indicates a worse prognosis, the same as in non-papillary-CC, independent of whether there was a preexisting papillary carcinoma component. These survival statuses of biliary papillary tumors resembled those of IPMN-P, as shown in Fig. 8C.
It was found in this study that biliary papillary tumors (BP and papillary-CC) shared several pathological characteristics, which were different from those of non-papillary-CC. BP and papillary-CC showed the frequent expression of MUC2, CDX2 and CK20, whereas non-papillary-CC was characterized by the common expression of MUC1. These results suggested that common phenotypic changes could occur in the tumorigenesis or tumor-progression of papillary-CC and BP, but not non-papillary-CC. Especially, these immunophenotypes of MUC2, CDX2 and CK20 expression are thought to relate to the acquisition of an intestinal phenotype. In addition, patients with BP or papillary-CC showed more favorable prognoses compared to patients with non-papillary-CC. There is now increasing evidence that the genetic alterations and phenotypic changes are different between papillary-CC and non-papillary-CC.7–9, 22–24 Among intrahepatic cholangiocarcinoma, the papillary type had a lower frequency of K-ras and p53 mutations compared to the periductal infiltrating or mass-forming types.7 The aberrant nuclear expression of β-catenin, which is one of the key events during tumorigenesis of various malignant tumors, was closely related to the tumor-growth type of cholangiocarcinoma.9 Non-papillary-CC showed the frequent nuclear expression of β-catenin, whereas this was a rare event in papillary-CC. Different frequencies of K-ras and p53 mutations or the aberrant expression of β-catenin might be dependent on the predominantly non-invasive nature of papillary-CC, although this study revealed the pathological differences, mainly the phenotypic differences of tumor cells, between biliary papillary tumors (BP and papillary-CC) and non-papillary-CC. Additional research will be mandatory to determine whether those different pathological characteristics might reflect different manifestations of a single malignant tumor, or biologically distinct malignant tumors.
Interestingly, the pathological characteristics of BP and papillary-CC were found to resemble those of IPMN-P. We summarized the pathological similarities and differences between biliary papillary tumors (BP and papillary-CC) and IPMN-P in Table 5. BP, papillary-CC and IPMN-P are similarly characterized by a macroscopic growth-pattern (intraductal papillary lesions) and microscopic features (papillary proliferation with delicate fibrovascular cores and 3 types of tumor cells). As with BP, it is well known that multiple lesions rarely occur in the pancreas with IPMN-P,25 although the IPMN-P used in this study were all solitary lesions. During progression of tumor, these papillary tumors could progress to two types of invasive cancers: tubular adenocarcinoma and mucinous carcinoma. Once invasive tubular carcinoma arises in papillary-CC, the post-operative prognosis of such patients was similar to non-papillary-CC and was worse than that of papillary-CC with mucinous carcinoma (Fig. 8B). The survival rate of IPMN-P with tubuar adenocarcinoma was also worse than that of IPMN-P with mucinous carcinoma (Fig. 8C). These data strongly suggest that the histological types of invasive lesions have a great influence on the survival rate of papillary-CC and IPMN-P. Based on these pathological similarities, we now speculate that biliary papillary tumors (BP and papillary-CC) may be biliary counterparts of IPMN-P.
Table 5. Pathological Similarities and Differences Between Biliary Papillary Tumors and Intraductal Papillary Mucinous Neoplasm of the Pancreas
Abbreviation: IPMN-P, intraductal papillary mucinous neoplasm of the pancreas
Macroscopic growth pattern of intraductal papillary proliferation
Occasional association with mucin hypersecretion
Microscopic feature of papillary proliferation with fibrovascular cores
Occurrence of three types of tumor cells
Occasional association with multiple lesions
Possible progression to tubular adenocarcinoma and mucinous carcinoma
Influence of histological types of invasive lesion on survival rate
Higher frequency of CK20 expression in biliary papillary tumors than IPMN-P
Lower percentage of gastric-type tumors in biliary papillary tumors than IPMN-P
Lower frequency of mucin hypersecretion in biliary papillary tumors than IPMN-P
On the other hand, several pathological differences existed between biliary papillary tumors (BP and papillary-CC) and IPMN-P. IPMN-P showed lower frequencies of CK20 expression and a higher percentage of gastric-type tumors compared to biliary papillary tumors. These differences might reflect the subtypes of IPMN-P. Among IPMN-P, it has been reported that the gastric type is more common in the branch-duct type, whereas the pancreaticobiliary or intestinal types frequently occur in the main pancreatic duct.26 Out of 15 cases of the gastric type of IPMN-P used in this study, 13 cases were the branch-duct type and all of those cases were negative for CK20 expression. That is, it might be plausible that biliary papillary tumors (BP and papillary-CC) resemble IPMN-P, especially the main pancreatic duct-type.
The other important difference between biliary papillary tumors and IPMN-P is about mucin hypersecretion (macroscopic mucin). Mucin was macroscopically identifiable on the tumor surface in 9 of 32 cases (28%) of biliary papillary tumors (BP and papillary-CC) used in this study, whereas abundant mucin-production, which is referred to as IPMN-P, is usually observed in most cases of IPMN-P.27 Although mucin was not macroscopically observed in 72% of biliary papillary tumors, the intestinal-type tumor has many goblet cells (one of the mucin producing cells) and biliary papillary tumors commonly expressed the secretory type of mucin core proteins, such as MUC2 and MUC5AC, the same as IPMN-P. This difference about mucin hypersecretion might be caused by the extent of mucin-production, although further studies are mandatory to elucidate the exact mechanism of mucin secretion in pancreaticobiliary tumors.
It seems important in clinical medicine that biliary papillary tumors could progress to two types of invasive carcinoma (tubular adenocarcinoma and mucinous carcinoma) because the histological types of invasive lesions were closely related to the survival status of those patients. In addition, the phenotypic changes of MUC occurring during tumor progression might influence the histological types of invasive lesions. MUC2 expression was frequently observed in biliary papillary tumors, including non-invasive tumors and both invasive lesions (tubular adenocarcinoma and mucinous carcinoma), whereas MUC1 expression was commonly found in tubular adenocarcinoma cases, and rarely in non-invasive tumors and mucinous carcinoma. That is, phenotypic changes in tumor progression to tubular adenocarcinoma and mucinous carcinoma are characterized as MUC1+/MUC2+ and MUC1-/MUC2+, respectively.28 Similarly, Adsay et al. reported that two types of tumor progression could occur in IPMN-P: the MUC1-positive pathway to tubular adenocarcinoma and the MUC2-positive pathway to mucinous carcinoma.29
There have been already several reports revealing close similarities between clinical, pathological and radiological characteristics of biliary papillary tumors and IPMN-P.12, 14, 30–34 This study, using a considerable number of biliary papillary tumors and IPMN-P, also showed sufficient evidence that biliary papilloma(tosis) and papillary-CC with or without mucus hypersecretion belong to a single tumor entity of intraductal papillary neoplasm of the bile duct, as a biliary counterpart of IPMN-P. Intraductal papillary neoplasm of the bile duct could manifest clinicopathologically as papilloma, papillomatosis and papillary adenocarcinoma (papillary-CC) (in situ and invasive). However, the distinction of papillary-CC in situ from biliary papilloma(tosis) is still controversial. Mucin-hypersecreting bile duct tumors could be also included in this biliary neoplasm.30
In conclusion, we showed in this study that biliary papillary tumors (BP and papillary-CC) and IPMN-P have similar clinicopathological characteristics and tumor-cell phenotypes. This study suggests that BP and papillary-CC could belong to a tumor group of intraductal papillary neoplasm of the bile duct as a biliary counterpart of IPMN-P.