Papillary Neoplasm Of Bile Duct Research Articles

Reappraisal of pathological features of intraductal papillary neoplasm of bile duct with respect to the type 1 and 2 subclassifications

The pathological spectrum of intraductal papillary neoplasm of bile duct (IPNB) remains to be clarified. A total of 186 IPNBs were pathologically examined using the type 1 and 2 subclassifications proposed by Japanese and Korean biliary pathologists incorporating a two-tiered grading system (low-grade and high-grade dysplasia), with reference to four subtypes (intestinal [i], gastric [g], pancreatobiliary [pb], and concocytic [o] subtype). IPNBs were classifiable into type 1 composed of low-grade dysplasia and 'high-grade dysplasia with regular structures' (69 IPNBs), and type 2 of 'high grade dysplasia with irregular structures and complicated lesions' (117 IPNBs). Type 1 was more common in the intrahepatic bile duct (78%), whereas type 2 was frequently located in the extrahepatic bile duct (58%). Mucin hypersecretion was more common in type 1 (61%) than in type 2 (37%). IPNBs were classifiable into the four subtypes: 86 iPNBs, 40 gIPNBs, 31 pbIPNBs, and 29 oIPNBs. The four subtypes were histologically evaluable with reference to the type 1 and 2 subclassifications. iIPNB and pbIPNBs were frequently classified as type 2, whereas types 1 and 2 were observed at similar rates in gIPNB and oIPNB. Stromal invasion was almost absent in type 1, irrespective of subtype, but was found in 66 of 117 type 2 IPNBs (P<.01), and postoperative outcome was favorable in IPNBs without invasion compared with IPNBs with invasion (P<.05). The type 1 and 2 subclassifications with reference to the four subtypes may provide useful information for understanding IPNB.

Intraductal Papillary Neoplasm of Bile Duct: Updated Clinicopathological Characteristics and Molecular and Genetic Alterations

Intraductal papillary neoplasm of the bile duct (IPNB), a pre-invasive neoplasm of the bile duct, is being established pathologically as a precursor lesion of invasive cholangiocarcinoma (CCA), and at the time of surgical resection, approximately half of IPNBs show stromal invasion (IPNB associated with invasive carcinoma). IPNB can involve any part of the biliary tree. IPNB shows grossly visible, exophytic growth in a dilated bile duct lumen, with histologically villous/papillary neoplastic epithelia with tubular components covering fine fibrovascular stalks. Interestingly, IPNB can be classified into four subtypes (intestinal, gastric, pancreatobiliary and oncocytic), similar to intraductal papillary mucinous neoplasm of the pancreas (IPMN). IPNBs are classified into low-grade and high-grade based on lining epithelial features. The new subclassification of IPNB into types 1 (low-grade dysplasia and high-grade dysplasia with regular architecture) and 2 (high-grade dysplasia with irregular architecture) proposed by the Japan–Korea pathologist group may be useful in the clinical field. The outcome of post-operative IPNBs is more favorable in type 1 than type 2. Recent genetic studies using next-generation sequencing have demonstrated the existence of several groups of mutations of genes: (i) IPNB showing mutations in KRAS, GNAS and RNF43 belonged to type 1, particularly the intestinal subtype, similar to the mutation patterns of IPMN; (ii) IPNB showing mutations in CTNNB1 and lacking mutations in KRAS, GNAS and RNF43 belonged to the pancreatobiliary subtype but differed from IPMN. IPNB showing mutation of TP53, SMAD4 and PIK3CA might reflect complicated and other features characterizing type 2. The recent recognition of IPNBs may facilitate further clinical and basic studies of CCA with respect to the pre-invasive and early invasive stages.

Serum IgG as a Marker for Opisthorchis viverrini-Associated Cholangiocarcinoma Correlated with HER2 Overexpression.

BackgroundSerum antibody for Opisthorchis viverrini (OV) is strong evidence for a history of OV infection in people. Currently, no studies have examined whether varying cholangiocarcinoma (CCA) prevalence levels are linked to previous OV infection nor have they provided comprehensive assessment and characterization of OV-associated CCA.ObjectiveOur study examined the prevalence of serum IgG antibodies for OV-positive CCA cases and determined whether there were correlations of IgG antibodies with histopathologic features, HER2, PD-L1, and FGFR2 expression, as well as their roles on the patients’ survival.MethodsThe study involved 221 CCA surgical patients at Khon Kaen University Hospital, Thailand, from 2005 to 2017. Serum specimens were tested for OV IgG by ELISA. CCA tissue microarrays were used to examined for HER2, PD-L1, and FGFR2 expression. Logistic regression was used to investigate an association between factors and IgG. Cox regression was used to determine factors that affected CCA patient survival.ResultsIgG for OV were positive in 162 cases, and the prevalence was 73.3% (95% CI=68.0–78.7). About three quarters (78.3%) had large duct type tumors and concomitant intraductal papillary neoplasm of bile ducts (IPNB) occurred in 92 (50%) cases. HER2 expression was positive in 94 (61.4%) cases. Positive PD-L1 and FGFR2 expression occurred in 125 (83.9%) and 100 (67.1%) cases. IgG for OV had no significant correlation to any histological feature but had significant correlation with HER2 overexpression with adjusted OR=2.32 (95% CI=1.09–4.96, P=0.03). Cases of CCA with OV IgG positive had a significantly poor prognosis with adjusted HR=1.66 (95% CI=1.13–2.43, P=0.01).ConclusionWe found a high prevalence of serum IgG for OV-positive CCA patients and a correlation with overexpression of HER2. Moreover, IgG for OV and HER2 expression indicated poor survival of CCA. Therefore, future clinical studies for anti-HER2 treatments should focus on OV-associated CCA.

ASO Author Reflections: Prognostic Factors for Surgically Resected Intraductal Papillary Neoplasm of Bile Duct.

ASO Author Reflections: Prognostic Factors for Surgically Resected Intraductal Papillary Neoplasm of Bile Duct.

Gastric subtype of intraductal papillary neoplasm of the bile duct: The pathologic spectrum.

Intraductal papillary neoplasms of bile duct (IPNBs) remain a challenging entity to manage. The pathologic spectrum of 34 gastric subtype of IPNB (gIPNB) cases was examined in consideration of the type 1 and 2 subclassification proposed by Japan-Korea consensus and compared with gastric subtype of pancreatic intraductal papillary mucinous neoplasm (gIPMN) (44 cases). Type 1 gIPNBs (17 cases) showed regular papillary foveola with variable tubular pyloric glands. Eight of the type 1 gIPNBs showed low-grade dysplasia. Type 2 cases (n=17) showed complicated papillary and tubular structures and high-grade dysplastic foveola and pyloric glands. Foveolas were predominant in 15 cases, while pyloric glands were predominant in 10 cases, and considerable areas of foveolas and pyloric glands in the remaining: these three were found similarly in type 1 and 2 gIPNB. gIPMNs showed central foveola with a peripheral pyloric gland. Such a pattern was recognizable in type 1 but vague in type 2. Type 1 was frequently found in the intrahepatic bile ducts and showed abundant mucin, as in gIPMNs, while type 2 also occurred in the extrahepatic bile ducts and were pathologically more malignant. Type 1 lesions shared features of gIPMN, while type 2 lesions differed from gIPMN and were more pathologically malignant.

Endoscopic US can accurately predict invasion of Intraductal Papillary Neoplasm of Bile duct (IPNB), a retrospective clinical-pathological analysis

Endoscopic US can accurately predict invasion of Intraductal Papillary Neoplasm of Bile duct (IPNB), a retrospective clinical-pathological analysis

Pathology of intraductal papillary neoplasm of bile duct with reference to four subtypes

Pathology of intraductal papillary neoplasm of bile duct with reference to four subtypes

Clinicopathologic analysis of intraductal papillary neoplasm of bile duct: Korean multicenter cohort study

BackgroundIPNB is very rare disease and most previous studies on IPNB were case series with a small number due to low incidence. The aim of this study is to validate previously known clinicopathologic features of intraductal papillary neoplasm of bile duct (IPNB) based on the first largest multicenter cohort. MethodsAmong 587 patients previously diagnosed with IPNB and similar diseases from each center in Korea, 387 were included in this study after central pathologic review. We also reviewed all preoperative image data. ResultsOf 387 patients, 176 (45.5%) had invasive carcinoma and 21 (6.0%) lymph node metastasis. The 5-year overall survival was 80.9% for all patients, 88.8% for IPNB with mucosal dysplasia, and 70.5% for IPNB with invasive carcinoma. According to the “Jang & Kim's modified anatomical classification,” 265 (68.5%) were intrahepatic, 103 (26.6%) extrahepatic, and 16 (4.1%) diffuse type. Multivariate analysis revealed that tumor invasiveness was a unique predictor for survival analysis. (p = 0.047 [hazard ratio = 2.116, 95% confidence interval 1.010–4.433]). ConclusionsThis is the first Korean multicenter study on IPNB through central pathologic and radiologic review process. Although IPNB showed good long-term prognosis, relatively aggressive features were also found in invasive carcinoma and extrahepatic/diffuse type.

Intraductal papillary neoplasm of bile ducts: report of a case and literature review

A 67 year old male with right upper quadrant abdominal pain diagnosed with intraductal papillary neoplasm of bile ducts (IPNB) by endoscopic biopsy. The patient was treated surgically and disease free on first year follow-up. Intraductal papillary neoplasm of bile duct (IPNB) is a rare entity with malignant counterparts and recently classified by The World Health Organization. The aim of this study is to present a case of IPNB and review the literature. Pubmed/MEDLINE was searched and articles were extracted. Twenty four case reports and 17 retrospective case series were evaluated. From 41 studies, 824 cases were included. There was slight male predominancy among patients and almost all cases were from eastern countries. Even though the etiology remains unclear, hepatolithiasis was the most common potential etiological association. Most cases were treated with surgical intervention. More than half of the 577 resected specimens had invasive component. Incidence rate of histopathological subtypes were as fallowed: Intestinal (35%), pancreaticobiliary (32%), gastric (19%) and oncocytic (12%). Intraductal papillary neoplasm of bile duct has an increased malignancy rates at postoperative pathological diagnosis, consequently early surgical management is important.

Intraductal papillary neoplasm of bile duct developed in a patient with IgG4-related sclerosing cholangitis, autoimmune pancreatitis, and myasthenia gravis

In the course of treatment for myasthenia gravis, enlargement of a cystic mass in the liver with peripheral bile duct dilation, diffuse pancreatic enlargement, and serum IgG4 level elevation was identified in a 65-year-old man. Following the diagnosis of autoimmune pancreatitis, a left hepatectomy was performed because of suspected malignancy of the cystic lesion. Analysis of the resected specimen revealed the cystic lesion to be a dilated bile duct. Intraductal papillary tumor comprising fibrovascular stalks covered by neoplastic epithelium was identified in the lesion. Infiltration of IgG4-positive plasma cells was discovered around the cystic lesion. Finally, a diagnosis of intraductal papillary neoplasm of bile duct with IgG4-related sclerosing cholangitis was made. Autoimmune diseases, including IgG4-related diseases, require careful observation because of their potential for malignancy.

Recurrence After Resection for Intraductal Papillary Neoplasm of Bile Duct (IPNB) According to Tumor Location

BackgroundNo studies have yet analyzed the characteristics of recurrence after resection for intraductal papillary neoplasm of bile duct (IPNB) based on tumor location. We analyzed the patterns, timing, and risk factors for recurrence. MethodsFrom 1994 to 2014, data from 103 patients who were diagnosed with IPNB were retrospectively reviewed. Among these, 44 were extrahepatic IPNB (E-IPNB) and 59 were intrahepatic IPNB (I-IPNB). ResultsCK20, pancreaticobiliary type, tumor invasion beyond ductal wall, tumor invasion to adjacent organs, and invasive disease were more frequently found in E-IPNB than in I-IPNB (22.7 vs. 8.5%; p = 0.043, 38.6 vs. 23.7%; p = 0.050, 20.5 vs. 11.9%; p < 0.001, 4.5 vs. 1.7%; p < 0.001 and 93.2 vs. 55.9%; p < 0.001). E-IPNB has poorer 5-year recurrence-free survival (RFS) compared to I-IPNB (51.7 vs. 91.4%; p < 0.001). There was no significant difference in the rate of initial isolated locoregional recurrence and initial distant recurrence according to tumor location (14.6 in E-IPNB vs. 3.0% in I-IPNB; p = 0.123, 19.5 in E = IPNB vs. 12.0% in I-IPNB; p = 0.136). Recurrence rate according to timing was different between E-IPNB and I-IPNB: within 1 year (33.3% vs. 83.3%; p = 0.061) and 1–3 years (50.0% vs. 0%; p = 0.052). The independent prognostic factors for RFS were tumor location (p = 0.034) and lymph node metastasis (p = 0.013). ConclusionsE-IPNB has a worse prognosis than I-IPNB. Different follow-up schedules for surveillance according to tumor location are needed after surgery.

A man with repeated cholangitis

A 67-year-old man, with a past medical history of remarkable left intrahepatic biliary stones and recurrent episodes of acute cholangitis, presented to our hospital with low-grade fever and epigastric dull aching followed by tea-colored urine for 1 week. Initial laboratory data were as follows: Hb 11.5 g/dL, WBC (white blood count) 17 700/mm3, CRP (C-Reactive Protein) 25.13 mg/dL, AST/ALT (aspartate transaminase/alanine transaminase) 39/45 IU/L, bilirubin (T/D) 7.5/4.6 mg/dL, alkaline phosphatase 596 IU/L, CEA (carcinoembryonic antigen) 1.92 ng/mL, AFP (Alpha-FetoProtein) 4.10 ng/mL, PSA (prostate specific antigen) 5.57 ng/mL, and CA 19-9 (Carbohydrate Antigen 19-9) 92.56 U/mL. Abdominal computed tomography demonstrated a new-onset mass lesion (10 cm in diameter) occupying the left lobe of liver. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the liver demonstrated a 10 cm liver mass with dilatation of adjacent IHDs (intrahepatic duct) in the left lobe (mainly in segment 4), indicating a malignant neoplasm (Figure 1). The preoperative diagnosis was ICC according to his clinical presentation and radiological images. He received an extended left hepatectomy after a thorough preoperative evaluation, including the ICG (Indocyanine green) test. The histopathological examination demonstrated intraductal papillary neoplasm of bile duct (IPNB) with low-grade dysplasia and marked chronic inflammation (Figure 2). His postoperative course was uneventful, and he was discharged 10 days after the operation. IPNB, formerly named biliary papillomatosis, is a rare biliary epithelial tumor with an exophytic nature exhibiting a papillary mass within the bile duct lumen and with a prominent intraductal growth pattern. It has been considered as a precursor lesion of invasive cholangiocarcinoma. The grade of intraepithelial neoplasia is defined as either low-intermediate, high, or invasive carcinoma according the World Health Organization's 2010 classification system.1 The clinical picture of IPNB consists of recurrent colicky abdominal pain and repeated episodes of acute cholangitis with fever and jaundice due to partial or intermittent biliary obstruction.2 Common radiological findings for IPNB are bile duct dilatation or intraductal masses, and liver solid tumors are rarely seen. It is difficult to distinguish IPNB from other inflammatory and neoplastic lesions based on radiological appearance alone, including DCE-MRI of liver.3 Patients with IPNB should be considered for treatment because of the high risk of recurrent cholangitis and malignant transformation. Resection is the treatment of choice when IPNB is localized according to preoperative imaging workup. The overall prognosis is better in patients with IPNB than ICC, and long-term survival is anticipated after curative resection.4 The author declares no conflict of interest.

Laparoscopic right hepatectomy and distal MHV resection after portal vein embolization for intraductal papillary neoplasm of bile duct

Summary Objectives: Laparoscopic right hepatectomy is technically demanding procedure particularly for liver tumor. The report of this procedure for cholangiocarcinoma is limited. Besides, following portal vein embolisation (PVE), parenchymal transection is more difficult because of shifting of parenchymal transection plane from atrophy-hypertrophy phenomenon of PVE. And also PVE may induced inflammation around right portal pedicle making individual inflow vascular control is more challenging. We present the case of pure laparoscopic right hepatectomy and distal MHV resection using individual inflow vascular control for patient with intraductal papillary neoplasm of bile duct that involved distal MHV. Preoperatively, the patient underwent portal vein embolization. Methods: After careful searching for intra- and extra-hepatic metastases, cholecystectomy was performed to facilitate right portal pedicle exposure. Individual dissection and ligation of right portal vein, right anterior hepatic artery and right posterior hepatic artery were performed sequentially. Limited liver mobilization was performed to facilitate parenchymal transection. Ultrasonic device and Cavitron Ultrasonic Surgical Aspirator were used for parenchymal transection. Intraoperative ultrasonography was used for identify the point that MHV will be transected. Right hepatic duct was encircled and then divided and sutured. After completed parenchymal transection, right hepatic vein was divided by using stapling devices. Right lobe liver was mobilized completely and placed in plastic bag and removed through Pfannelstiel incision. Results: Pure laparoscopic right hepatectomy was performed successfully without intra-operative complications or blood transfusion. Operative time was 360 minutes and estimated blood loss was 150 ml. Pathology revealed moderately differentiated-intrahepatic cholangiocarcinoma, papillary type, uninvolved all resection margins. Patient was discharged on postoperative day 6 without peri-operative complications. Conclusions: Pure laparoscopic right hepatectomy using individual inflow vascular control is feasible procedure for intraductal papillary neoplasm of bile duct following PVE.

Biliary Intraepithelial Neoplasia in Non-biliary Cirrhosis-Report From 100 Explanted Livers: A Single Center Experience.

Background:Intrahepatic cholangiocarcinoma is a highly malignant tumor with a very short 5-year survival. Multistep carcinogenesis has been suggested as the main pathway for the development of this tumor. Main suggested precursors have been (1) biliary intraepithelial neoplasia (BilIN) and (2) intraductal papillary neoplasm of bile duct (IPNB). The former is flat and does not produce grossly and radiologically detectable mass lesion, but the latter produces grossly identifiable lesion.Objectives:The development of bile duct dysplasia (BilIN) in chronic biliary diseases has been investigated and proved, but the incidence of BilIN in non-biliary causes of cirrhosis such as hepatitis B and non-alcoholic steatohepatitis has very rarely been investigated. In this study, we have tried to find out the prevalence of BilIN in non-biliary cirrhosis.Patients and Methods:During the study period (2017-2018) in 100 explanted livers with the diagnosis of non-biliary cirrhosis, thorough sampling (at least 20 sections) was performed, and pathologic sections were studied for the presence of BilIN.Results:In the 100 studied livers with different diagnoses of non-biliary causes of cirrhosis, 31% of cases showed BilIN-1 and 2% of cases showed BiliIN-2. No case of BilIN-3 has been identified.Discussion and Conclusions:Non-biliary causes of cirrhosis should be considered as precursors of cholangiocarcinoma (BilIN); however, the incidence of this occurrence is low.

Intraductal Papillary Neoplasm of the Bile Duct Progressing to Hepatic Mucinous Adenocarcinoma

Intraductal papillary neoplasm of the bile duct (IPNB) is a rare variant of bile duct cancer and represents about only 10% of all resectable cases. The most common abnormal preoperative findings are intraductal masses and bile duct dilation. The purpose of this case report is to distinguish IPNB from invasive carcinoma, discuss the case presentation, and assess the best treatment options. We present a case of a 58 yo female with history of hyperlipidemia that presented to gastroenterologist with right upper quadrant pain. She underwent cholecystectomy but continued to have persistent fatigue, weight loss, and then developed jaundice. Family history was significant for prostate cancer in father and hepatocellular carcinoma (HCC) in mother. Initial endoscopic retrograde cholangiopancreatograophy (ERCP) showed common bile duct (CBD) dilation; balloon sphincterotomy of distal CBD was then done. She then had endoscopic ultrasound (EUS) which showed no solid or cystic masses seen in the pancreas and dilated extra and intrahepatic biliary system. ERCP revealed frond-like tumor in hilar/left intrahepatic duct takeoff with mucin secretion concerning for biliary IPMN tumor vs cholangiocarcinoma. Patient had bile duct stent placement. Biopsy of duct lesion showed IPNB with intermediate to high-grade dysplasia with initially no signs of invasive carcinoma. She underwent left hepatectomy with Roux-en-Y hepaticojejunostomy and portal lymphadenectomy. Final pathology showed an invasive mucinous adenocarcinoma of the left hepatic duct T2b N0/8 lymph nodes and she was started on adjuvant chemotherapy. Early diagnosis of IPNB is crucial because it is regarded as a premalignant lesion towards invasive cholangiocarcinoma/adenocarcinoma and this determines a patient's prognosis and specific targeted therapy. Our patient had major hepatectomy and portal lymphadenectomy, as aggressive surgical resection is recommended as treatment of choice for IPNB due to relatively good prognosis after resection. IPNB is difficult to diagnose preoperatively and has a high risk of progression to invasive cholangiocarcinoma or adenocarcinoma. Diagnostic modalities must be utilized early as aggressive surgical resection early generally gives good prognosis. New treatment modalities, such as ERCP-guided radiofrequency ablation and self-expandable metal stents can be utilized in non-surgical cases to prevent further biliary obstruction and palliative treatment and should be further studied.1248_A.tif Figure 1: A) Intraductal papillary neoplasm of bile duct with high to intermediate grade dysplasia. B) Papillary architecture with nuclei loss of orientation and characteristic fibrovascular cores. Neutrophils presenting showing inflammation. C) Fibrovascular cores present with pseudostratified epithelium and crowded nuclei with hyperchromaticity1248_B.tif Figure 2: A) Left hepatic lobe biopsy showing fibrovascular cores and pseudostratified epithelium. B) Biopsy showing prominent nucleoli with loss of orientation in nuclei and high-intermediate grade dysplasia, especially in top right of image.1248_C.tif Figure 3: A) Intraductal papillary neoplasm (top right) and mucinous adenocarcinoma present. B) Grade 2 moderately differentiated carcinoma with >50% mucinous differentiation involved and cribriform architecture pattern present.

Synchronous Presentation of Three Distinct Pancreaticobiliary Tumors: Pancreatic Ductal Adenocarcinoma, Cholangiocarcinoma, and a Pancreatic Neuroendocrine Tumor

Introduction: Pancreatic ductal adenocarcinoma (PDAC) accounts for 3% of all cancers in the United States though it comprises approximately 85% of pancreatic cancers. Less common pancreaticobiliary tumors include cholangiocarcinoma and pancreatic neuroendocrine tumors, which have an incidence of approximately 8,000 and 1,000 cases annually in the United States, respectively. Case Presentation: We present a case of a 71 year-old female with a previous history of a cholecystectomy initially presenting with a suspicious mass in the body of the pancreas. CT imaging with pancreas protocol demonstrated a pancreatic neck mass that on EUS biopsy showed pancreatic adenocarcinoma. The CT also showed a second, ill-defined lesion near the common bile duct (CBD) that on ERCP was proximal to the cystic duct remnant. Brush biopsies demonstrated high-grade dysplasia. The patient was treated surgically with a total pancreatectomy including proximal resection of the CBD and portal lymphadenectomy. Her post-operative course was uneventful. Pathology demonstrated a poorly-differentiated PDAC of the neck (T3N1) and a moderately-differentiated cholangiocarcinoma arising from an intraductal papillary neoplasm of bile duct (T2N0). Incidentally, the removed pancreas also demonstrated a sub-centimeter, well-differentiated neuroendocrine tumor. Discussion: Synchronous primary tumors of the pancreas occur in up to 20% of cases, typically involving pancreatic ductal adenocarcinoma and intrapapillary mucinous neoplasms. Synchronous pancreaticobiliary cancer is much less common. After a literature review, we identified fewer than ten reported cases of synchronous pancreatic cancer and gallbladder/bile duct cancer and no prior case reports from patients in the United States. This case provides a unique synchronous presentation of three distinct neoplasms within the pancreaticobiliary region. Although this presentation is extremely rare, it should be considered when assessing multiple pancreaticobiliary lesions.1452.tif Figure 1: CT imaging of the abdomen with contrast using a three-phase pancreas protocol approach. Red circle demonstrates a 1.9 x 1.3 cm mass in the common biliary duct at the level of the upper pancreatic head. Yellow circle demonstrates a 2.9 x 1.9 cm mass in the body of the pancreas.

Clinicopathologic characteristics of intraductal papillary neoplasm of bile duct (ipnb) after central review: Korean multi-center collaboration study

Introduction: Intraductal papillary neoplasm of the bile duct (IPNB) is a recently defined concept and its clinicopathologic characteristics and diagnostic criteria have not been well established yet. We performed this study to clarify the clinicopathologic features of IPNB and to find out the optimal morphologic criteria. Methods: Between 1997 and 2016, 457 patients were included in this study with final diagnosis of IPNB from 23 tertiary referral centers of Korea. Every case was reconfirmed through central review by 3 specialized biliary-pancreas pathologists. We applied 'Japan Biliary Association (JBA) classification' and 'modified anatomical classification' to compare the morphological features. Results: Patient's mean age was 65.5 years. The 5-year overall survival rate of all the patients was 80.6% and 104 (24.6%) patients underwent recurrence during the follow-up periods. Patients with the intestinal type (n=237; 52.2%) was the majority in the histologic subtypes of IPNB. Among 457 patients, 451 (98.7%) had bile duct dilatation and 430 (94.1%) had intraductal mass on preoperative images. We found out that the extrahepatic type had a higher rate of intestinal type and the intrahepatic type had equally high proportions of intestinal and pancreatobiliary type. Conclusion: As one of the prevalent nations of cholangiocarcinoma, this is the first Korean multi-center collaboration study of IPNB, which is thought to be a precursor lesion of cholangiocarcinoma. The 'modified anatomical classification' is a simple and intuitive criteria which can help to determine the treatment strategy and show some correlations with histologic subtype and pathologic phenotypes.

A statement by the Japan-Korea expert pathologists for future clinicopathological and molecular analyses toward consensus building of intraductal papillary neoplasm of the bile duct through several opinions at the present stage.

Intraductal papillary neoplasm of bile duct (IPNB) was described as a preinvasive neoplastic lesion of the biliary tract in the 2010 World Health Organization (WHO) classification. Although a number of studies have since been conducted on IPNBs, controversy remains, particularly regarding the standardization of its definition. Meetings by Japanese and Korean expert pathologists were held twice to resolve the pathological diagnostic aspects of IPNB. Through round-table discussions and histological reviews, we reached the common understanding that IPNBs diagnosed according to the criteria of WHO 2010 are characterized by intraductal predominant papillary or villous biliary neoplasms covering delicate fibrovascular stalks and are classified into two types pathologically. One type (type 1 IPNB) is histologically similar to intraductal papillary mucinous neoplasms of pancreas, and typically develops in the intrahepatic bile ducts, while the other (type 2 IPNB) has a more complex histological architecture with irregular papillary branching or with foci of solid-tubular components and typically involves the extrahepatic bile ducts. This report states the diagnostic pathologic features of IPNB proposed by WHO 2010. Since currently, the concept of IPNB is still confusing, the proposed diagnostic pathologic features stated here will be of use for future clinicopathological and molecular analyses toward consensus building of IPNB.

Primary Liver Cancers-Part 1: Histopathology, Differential Diagnoses, and Risk Stratification.

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the 2 most common primary malignant liver tumors, with hepatocellular and bile ductular differentiation, respectively. This article reviews the key histopathological findings of these 2 primary liver cancers and includes a review of the role of ancillary testing for differential diagnosis, risk stratification according to the American Joint Committee on Cancer (AJCC) staging recommendation, and a review of precancerous lesions. A literature review was conducted to identify articles with information relevant to precancerous precursors, current histopathological classification, ancillary testing, and risk stratification of primary malignant liver tumors. The histomorphology of normal liver, preinvasive precursors, primary malignancies, and morphological variants, and the utilization of ancillary tests for the pathological diagnosis are described. Dysplastic nodules are the preinvasive precursors of HCC, and intraductal papillary neoplasms of bile ducts and biliary intraepithelial neoplasia are the preinvasive precursors of CC. Benign liver nodules including focal nodular hyperplasia and adenomas are included in this review, since some forms of adenomas progress to HCC and often they have to be differentiated from well-differentiated HCC. A number of morphological variants of HCC have been described in the literature, and it is necessary to be aware of them in order to render the correct diagnosis. Risk stratification is still dependent on the AJCC staging system. The diagnosis of primary liver carcinomas is usually straightforward. Application of the appropriate ancillary studies aids in the differential diagnosis of difficult cases. The understanding of the carcinogenesis of these malignancies has improved with the standardization of the pathological classification of preinvasive precursors and studies of the molecular pathogenesis. Risk stratification still depends on pathological staging.

KRAS mutation and immunohistochemical profile in intraductal papillary neoplasm of the intrahepatic bile ducts

Intraductal papillary neoplasm of bile duct (IPNB) is characterized by a spectrum of diseases ranging from low-grade intraepithelial neoplasia to invasive carcinoma. In the present study, we aimed to investigate immunophenotypic features and KRAS mutations in relation to pathological subtypes and grades in Chinese patients with IPNBs. A total of 46 patients with IPNBs and 11 invasive adenocarcinomas arising in IPNBs (invasive IPNBs) were enrolled and clinicopathological data were analyzed. It was found that CK7 was expressed in 42 of the 46 neoplastic lesions. HepPar1 was expressed in 11 of the 46 noninvasive IPNBs, but not in invasive IPNBs. Additionally, CK19 was frequently expressed in both noninvasive IPNBs and invasive IPNBs. The intestinal-type IPNBs had a significantly higher percentage of MUC2 expression relative to the pancreaticobiliary (P=0.015) and gastric-type IPNBs (P<0.001). High-grade IPNBs and invasive IPNBs showed increased expression of cyclin D1, Ki-67, p53, mCEA, and CA19-9. The rate of KRAS mutation was significantly higher in high-grade IPNBs (P=0.001) and invasive IPNBs (P=0.006) than that in low- to intermediate-grade IPNBs. Additionally, KRAS mutation was significantly associated with tumor size, and Ki-67 expression. In conclusion, the expression of cyclin D, Ki-67, p53, mCEA and CA19-9 and KRAS mutation status are significantly correlated with histological grades of IPNBs.