Endoscopic diagnosis of pancreatic cancer using intraductal ultrasonography

BACKGROUND/AIMS: At present developed modalities are not sufficient for detecting early stage pancreatic cancer. We previously reported the clinical usefulness of intraductal ultrasonography in various pancreatobiliary diseases. In the present study we assessed the usefulness of intraductal ultrasonography in diagnosing pancreatic cancer. METHODOLOGY: Thirty-one patients with pancreatic cancer were examined by intraductal ultrasonography. We approached the main pancreatic duct (pancreatic duct-intraductal ultrasonography) in 24 of 31 patients and the bile duct (bile duct-intraductal ultrasonography) in 20 patients with pancreatic cancer. We compared the diagnostic ability of pancreatic duct-intraductal ultrasonography with that of extracorporeal ultrasonography, computed tomography, endoscopic ultrasonography or endoscopic retrograde pancreatography. We examined the usefulness of bile duct-intraductal ultrasonography in diagnosing tumor invasion to the bile duct. RESULTS: Pancreatic duct-intraductal ultrasonography was able to demonstrate a tumor in 22 of 24 patients. Extracorporeal ultrasonography, computed tomography, endoscopic ultrasonography or endoscopic retrograde pancreatography detected tumors in 26, 27, 29, 29 of 31 patients, respectively. In two patients, only intraductal ultrasonography could demonstrate a tumor, which was not detected by any other modalities. We examined bile duct invasion of the tumor according to our grading system. The overall accuracy rate was 90%. No complications were noted in any patients throughout the study period. CONCLUSIONS: Intraductal ultrasonography is useful to diagnose pancreatic cancer, and it is suggested that it should be actively performed after endoscopic retrograde pancreatography.     

A case of asymptomatic intraductal papillary neoplasm of the bile duct without hepatolithiasis

A 65-year-old woman was found to have dilatation of the intrahepatic bile duct in the right anterior segment during a general health. Laboratory data were within normal ranges and no solid mass was detected in her abdominal computer tomography （CT） or nuclear magnetic resonance imaging （MRI）. However, endoscopic retrograde cholangiopancreatography （ERCP） demonstrated an obstruction of the right bile duct. Intraoperative cholangiography showed stenosis of the intrahepatic bile duct in the anterior inferior segment （B5） and narrowness of the intrahepatic bile duct in the anterior superior segment （B8）, so that we strongly suspected intrahepatic cholangiocarcinoma （ICC）. Histologically, surgically resected liver specimens, without tumor mass by macroscopic observation, showed intraductal papillary proliferation with fibrovascular cores and intraductal spreading of carcinoma in situ throughout a considerable area, especially in bile ductules around the peripheral small portal area. Furthermore, the immunohistochemical profile of the tumor （MUC5AC＋/CK7＋） was compatible with an intraductal papillary neoplasm of the bile duct （IPN-B）. Consequently, this case was diagnosed as IPN-B with spreading CIS, stageⅠ（pT1, pN0, P0, H1, M0）. We report a case of IPN-B with interesting histopathologicalfindings and emphasize that cholangiography is especially helpful for the diagnosis of bile duct dilatation due to infiltration of carcinoma cells.     

Signet ring cell carcinoma of the bile duct: a case report

A 72-year-old man was admitted with obstructive jaundice. Computed tomography revealed a 4cm tumor with multiple cystic components obstructing the common bile duct. Endoscopic ultrasonography, endoscopic retrograde cholangiopancreatography and intraductal ultrasonography demonstrated the tumor, which derived from the lower bile duct, grew into the bile duct lumen. Peroral cholangioscopy revealed distended tumor vessels on the surface of the tumor. Signet ring cell carcinoma of the bile duct was diagnosed by biopsy. The patient died 3 months after the first hospital admission despite chemotherapy.     

Intraductal papillary neoplasm of the bile duct developing in a patient with primary sclerosing cholangitis: A case report

We report a case of intraductal papillary neoplasm of the bile duct (IPNB) that developed in a patient with primary sclerosing cholangitis. A 46-year-old woman was admitted to our hospital with obstructive jaundice. The liver function tests demonstrated increased serum liver enzyme levels. Computed tomography showed dilatation of the intrahepatic bile ducts. Abdominal ultrasonography revealed a highly echoic protruding lesion in the posterior bile duct near the right lobe of the liver. The lesion was suspected to be IPNB, but we were unable to confirm whether it was a carcinoma. A right hepatectomy was performed, and this showed that the dilated bile duct was filled with mucin and contained several yellowish papillary tumors. Histologically, the neoplastic biliary epithelium showed papillary growth in the dilated lumen. The tumor was diagnosed as IPNB, high-grade intraepithelial neoplasia secreting abundant mucin. No recurrence has been detected 3 years after surgery.     

Postoperative survival in intrahepatic cholangiocarcinoma showing intraductal growth

Clinicopathologic variables favoring recurrence after hepatic resection for intrahepatic cholangiocarcinoma showing intraductal growth remain unclear. We investigated various clinicopathologic features in three patients who underwent resection for this type of intrahepatic cholangiocarcinoma. All underwent extended left hepatectomy plus resection of the caudate lobe and lymph node dissection. Lymph nodes showed no pathologic involvement. Although no cancer cells were seen in the mucosal layer by intraoperative pathologic examination at the bile duct stump in any patient, pathologic examination of resected specimens showed cancer cells invading beyond the mucosal layer in connective tissues surrounding the bile duct stump (interstitial invasion) of the Glisson's sheath in 2 patients. One of them died of cancer recurrence near the bile duct stump, while the third patient, without interstitial invasion, has survived for 10.6 years. In the intraductal growth type of intrahepatic cholangiocarcinoma, absence of cancer cells should be confirmed by intraoperative pathologic examination of not only the mucosal layer of the bile duct but also the connective tissue surrounding the bile duct, since interstitial invasion may be a risk factor for cancer recurrence.     

Intraductal papillary neoplasm of the bile duct: A biliary equivalent to intraductal papillary mucinous neoplasm of the pancreas?

Intraductal papillary neoplasm of the bile duct (IPNB) is a variant of bile duct carcinoma characterized by intraductal growth and better outcome compared with the more common nodular-sclerosing type. IPNB is a recognized precursor of invasive carcinoma, but its pathogenesis and natural history are ill-defined. This study examines the clinicopathologic features and outcomes of IPNB. A consecutive cohort of patients with bile duct cancer (hilar, intrahepatic, or distal) was reviewed, and those with papillary histologic features identified. Histopathologic findings and immunohistochemical staining for tumor markers and for cytokeratin and mucin proteins were used to classify IPNB into subtypes. Survival data were analyzed and correlated with clinical and pathologic parameters. Thirty-nine IPNBs were identified in hilar (23/144), intrahepatic (4/86), and distal (12/113) bile duct specimens between 1991 and 2010. Histopathologic examination revealed 27 pancreatobiliary, four gastric, two intestinal, and six oncocytic subtypes; results of cytokeratin and mucin staining were similar to those of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Invasive carcinoma was seen in 29/39 (74%) IPNBs. Overall median survival was 62 months and was not different between IPNB locations or subtypes. Factors associated with a worse median survival included presence and depth of tumor invasion, margin-positive resection, and expression of MUC1 and CEA. Conclusion: IPNBs are an uncommon variant of bile duct cancer, representing approximately 10% of all resectable cases. They occur throughout the biliary tract, share some histologic and clinical features with IPMNs of the pancreas, and may represent a carcinogenesis pathway different from that of conventional bile duct carcinomas arising from flat dysplasia. Given their significant risk of harboring invasive carcinoma, they should be treated with complete resection. (HEPATOLOGY 2012).     

Cholangiocarcinoma after flow diversion surgery for congenital biliary dilatation: A case report and review of literature

BACKGROUND Pancreaticobiliary maljunction(PBM) can be classified into two categories, PBM with congenital biliary dilatation(CBD) or PBM without biliary dilatation, and the management of PBM is often controversial. The treatment for PBM with CBD is prophylactic flow diversion surgery, and some authors have reported that the incidence of cancer after extrahepatic bile duct excision is less than 1%. A very rare case of intrahepatic cholangiocarcinoma 6 years after flow diversion surgery for PBM with CBD is reported.CASE SUMMARY A 30-year-old man was diagnosed as having PBM with CBD, Todani classification type IVA, because of abnormal liver enzyme profiles. He underwent flow diversion surgery and cholecystectomy, and the specimen showed adenocarcinoma foci, p T1, p Stage IA. Five and a half years passed without any recurrence of bile duct cancer. However, 6 years after his operation, computed tomography showed a gradually growing nodule in the bile duct.Fluorodeoxyglucose positron emission tomography showed high uptake, and magnetic resonance imaging showed restricted diffusion signals. On double balloon enteroscopy, the nodule at the posterior bile duct-jejunum anastomosis was directly visualized, and its biopsy specimen showed adenocarcinoma. The patient underwent right lobectomy and biliary reconstruction. The pathological diagnosis was intraductal papillary neoplasm with high-grade intraepithelial neoplasia, p Tis, p N0, p Stage 0. The patient's postoperative course was uneventful, and he has had no recurrence up to the present time.CONCLUSION This case suggests the necessity of careful observation after flow diversion surgery, especially when PBM with CBD is detected in adulthood.     

Preoperative assessment of extrahepatic bile duct carcinoma using three-dimensional intraductal US.

BACKGROUND: We investigated the utility of a new imaging modality, three-dimensional intraductal ultrasonography (US), for staging bile duct cancer. METHODS: In eight patients with extrahepatic bile duct carcinoma, two- and three-dimensional intraductal US was used to assess tumor invasion of the right hepatic artery, portal vein, and pancreatic parenchyma before resection. The findings were correlated with histologic information from the resected specimen. RESULTS: Three-dimensional intraductal US enabled accurate assessment of tumor invasion of the right hepatic artery in 88% of cases, the portal vein in 100%, and pancreatic parenchyma in 100%. Two-dimensional intraductal US enabled accurate assessment of invasion of these structures in 88%, 88%, and 88% of cases. CONCLUSIONS: Three-dimensional intraductal US is useful in assessing tumor stage in bile duct carcinoma.     

Curative reoperation for recurrent cancer of the extrahepatic bile duct: report of two cases

Local recurrence, following a resection for cancer of the extrahepatic bile duct, is usually incurable with second curative surgery being almost impossible. To determine the feasibility and significance of second curative surgery, our experiences are presented in this study. The medical records and clinical outcomes of two patients that underwent a re-resection for recurrent cancer of the extrahepatic bile duct were retrospectively reviewed. A 50-year-old female patient that had a recurrent disease at the intrahepatic and intrapancreatic bile duct, 66 months after a segmental resection of the bile duct for common bile duct (CBD) cancer, underwent a hepatopancreatoduodenectomy. A 29-year-old female patient had a recurrent tumor mass in the distal CBD, 28 months after a right hemihepatectomy and Roux-en-Y hepaticojejenostomy for a type IIIa Klatskin tumor, and underwent a segmental resection of the bile duct. The gross type of the above two cases was a papillary tumor. There was no operative mortality or morbidity. All patients are still alive after 46 and 9 months, respectively, without recurrence after the reoperation. It is concluded that a surgical re-resection is possible in selected patients with recurrent bile duct cancer, mostly of the papillary type. A primary operation for bile duct cancer should be performed with a wide surgical margin, and secondary curative surgery should be considered whenever possible in cases of recurrence.     

A case of small cell carcinoma of the common bile duct

Small cell carcinoma occasionally occurs in the gastrointestinal tract, but rarely in the biliary tract. We report a case of small cell carcinoma which occurred in the common bile duct. A 66-year-old female complained of epigastralgia and weight loss. Computed tomography and ultrasonography showed a mass near the pancreas head and dilatation of the intrahepatic bile ducts. Endoscopic nasobiliary drainage was undertaken, and it revealed obstruction of the common bile duct. The patient was diagnosed preoperatively as having extrahepatic bile duct cancer. Upon laparotomy, a tumor was found to be located in the middle common bile duct. Pylorus-preserving pancreaticoduodenectomy was performed. The main trunk of the portal vein and the right hepatic artery were resected concomitantly because of tumor involvement. Postoperative pathological examination revealed well-differentiated papillary adenocarcinoma on the surface of the bile duct lumen, but a large part of the extraductal component was small cell carcinoma. Upon immunohistochemical examination, synaptophysin and chromogranin A were found to be focally positive in small cell carcinoma, but negative for L-26 and CEA. The patient then underwent two postoperative courses of systemic chemotherapy. Nevertheless, she died of cancer recurrence eight months after the operation, which showed that the tumor had a highly lethal nature, with rapid and widespread dissemination. Further therapeutic trials are needed to improve survival in such cases.     

Advanced cholangiocarcinoma in a patient with stage I primary sclerosing cholangitis

A 29‐year‐old woman presented with jaundice and fever in May 2001. Cholangiography showed multiple strictures and beading of the biliary tree, with a large stricture in the common bile duct and marked dilatation of the hilar bile ducts. Typical cholangiography findings and elevated hepatobiliary enzymes suggested primary sclerosing cholangitis (PSC). At the same time, computed tomography detected a 2‐cm tumor in the common bile duct, and angiography showed an encasement in the portal vein. Tumor markers, cytology, and biopsy were all negative for cancer. Although laparotomy showed a healthy liver and no lymph node metastasis was found, suggesting early‐stage PSC and a low likelihood of accompanying cholangiocarcinoma (CCA) reported so far, the tumor in the resected common bile duct was subsequently diagnosed as CCA. Therefore, pancreatoduodenectomy was performed combined with partial resection of the portal trunk. Histology also revealed invasion of the wall of the portal vein by cancer cells. The patient had a recurrence 5 months later and died 12 months after her operation. This is a rare case in which stage I PSC was complicated by advanced CCA.     

Distinctive expression of CD133 between intraductal papillary neoplasms of the bile duct and bile duct adenocarcinomas

Aim: Intraductal papillary neoplasm of the bile duct (IPNB), a novel entity of biliary disease, is recently advocated as the counterpart of pancreatic intraductal papillary mucinous neoplasm (IPMN) because both are in common with a large amount of mucin production and papillary growth. Based on our recent finding that expression of CD133, a cancer stem cell marker, is lacking in pancreatic IPMN, we herein focused on CD133 expression of IPNB in comparison with intrahepatic cholangiocellular carcinoma (IHCCC) or hilar bile duct cancer (HBDC). Methods: Expression of CD133 protein was immunohistochemically determined in patients with IPNB (n = 7), IHCCC (n = 16) or HBDC (n = 8). In addition, morphological and immunohistochemical mucin expression patterns were characterized in IPNB, and clinicopathological features including prognosis were compared between IPNB and other biliary tumors. Results: The IPNB group included significantly more females than the other two groups, and had a longer survival time. While no CD133 expression was observed in IPNB tumor, 16.4% of cancer cells in IHCCC and 17.2% of cells in HBDC expressed CD133. Among seven patients with IPNB, six (86%) were morphologically the pancreatobiliary type and four of six showed mucin expression pattern of the typical pancreatobiliary type (MUC1+/MUC2‐/MUC5AC+). Conclusion: Loss of CD133 expression supports the hypothesis that IPNB is a counterpart of pancreatic IPMN with a differing carcinogenesis from conventional bile duct adenocarcinomas.     

Photodynamic therapy with 5-aminolevulinic acid is not effective in bile duct cancer.

BACKGROUND: The results of preliminary studies of photodynamic therapy (PDT) for palliation of patients with bile duct cancer with hematoporphyrin derivative have been good. Rapid elimination of a photosensitizer could potentially shorten the time requirement for shielding from light. This would enhance the benefit of this form of palliative treatment. Therefore the feasibility of PDT was investigated for nonresectable bile duct cancer by using 5-aminolevulinic acid. METHODS: Four patients with nonresectable bile duct cancer underwent cholangiography, cholangioscopy, and intraductal US before PDT. Light activation was performed 5 to 7 hours after oral administration of 5-aminolevulinic acid. All patients had an endoprosthesis placed in the bile duct after PDT. RESULTS: Cholangioscopy 72 hours after PDT revealed superficial fibrinoid necrosis. However, 4 weeks after PDT there was no significant reduction in bile duct stenoses. Two patients had infectious complications develop, but phototoxicity was not observed. CONCLUSIONS: Although superficial tumor necrosis was evident, PDT with 5-aminolevulinic acid failed to significantly reduce malignant bile duct obstruction. Therefore 5-aminolevulinic acid-PDT cannot be recommended for the palliative treatment of bile duct cancer.     

Cystic micropapillary neoplasm of peribiliary glands with concomitant perihilar cholangiocarcinoma

We report a case of a 75-year-old man with cystic micropapillary neoplasm of peribiliary glands detected preoperatively by radiologic examination. Enhanced computed tomography showed a low-density mass 2.2 cm in diameter in the right hepatic hilum and a cystic lesion around the common hepatic duct. cholangiocarcinoma, right hepatectomy with caudate lobectomy and bile duct resection were performed. Pathological examination revealed perihilar cholangiocarcinoma mainly involving the right hepatic duct. The cystic lesion was multilocular and covered by columnar lining epithelia exhibiting increased proliferative activity and p53 nuclear expression; it also contained foci of micropapillary and glandular proliferation. Therefore, the lesion was diagnosed as a cystic micropapillary neoplasm of peribiliary glands and resembled flat branch-type intraductal papillary mucinous neoplasm of the pancreas. Histological examination showed the lesion was discontinuous with the perihilar cholangiocarcinoma. Immunohistochemistry showed the cystic neoplasm was strongly positive for MUC6 and that the cholangiocarcinoma was strongly positive for MUC5 AC and S100 P. These results suggest these two lesions have different origins. This case warrants further study on whether this type of neoplasm is associated with concomitant cholangiocarcinoma as observed in pancreatic intraductal papillary mucinous neoplasm with concomitant pancreatic duct adenocarcinoma.     

Local recurrence at hepaticojejunostomy 9 years after resection of bile duct cancer with superficial flat spread

We report a male patient aged 45 years, who in 1993 had been diagnosed as having middle bile duct cancer and had received a pancreatoduodenectomy. Histopathology showed a nodular tumor with the main lesion in the middle bile duct and superficial spreading in both proximal and distal directions (which was not observed macroscopically), and residual tumor in the epithelium of the cut edge near the liver. The patient underwent follow-up without postoperative adjuvant therapy. In 2002, 9 years after the operation, the patient developed jaundice and was diagnosed with recurrence of bile duct cancer in the anastomotic site, based on cholangiographic results. He underwent resection of the right hepatic and caudate lobes and the anastomotic region of the bile duct and jejunum. Pathological findings showed an invasive tumor in the anastomotic region, with continuous intraepithelial spread in the direction of the bile duct, which suggested that the residual tumor in the epithelium had grown to become an invasive cancer. In this patient, the recurrence required 9 years after resection. This case provides evidence for the clinical course that might be anticipated for a patient with a residual tumor in the epithelium of the bile duct stump and subsequent superficial spreading bile duct cancer.     

Intraductal neoplasm of the intrahepatic bile duct: clinicopathological study of 24 cases

AIM: To investigate the clinicopathological features of intraductal neoplasm of the intrahepatic bile duct (INihB). METHODS: Clinicopathological features of 24 cases of INihB, which were previously diagnosed as biliary papillomatosis or intraductal growth of intrahepatic biliary neoplasm, were reviewed. Mucin immunohistochemistry was performed for mucin (MUC)1, MUC2, MUC5AC and MUC6. Ki-67, P53 and β-catenin immunoreactivity were also examined. We categorized each tumor as adenoma (low grade), borderline (intermediate grade), and malignant (carcinoma in situ , high grade including tumors with microinvasion). RESULTS: Among 24 cases of INihB, we identified 24 tumors. Twenty of 24 tumors (83%) were composed of a papillary structure; the same feature observed in intraductal papillary neoplasm of the bile duct (IPNB). In contrast, the remaining four tumors (17%) showed both tubular and papillary structures. In three of the four tumors (75%), macroscopic mucin secretion was limited but microscopic intracellular mucin was evident. Histologically, 16 tumors (67%) were malignant, three (12%) were borderline, and five (21%) were adenoma. Microinvasion was found in four cases (17%). Immunohistochemical analysis revealed that MUC1 was not expressed in the borderline/adenoma group but was expressed only in malignant lesions (P = 0.0095). Ki-67 labeling index (LI) was significantly higher in the malignant group than in the borderline/adenoma group (22.2 ± 15.5 vs 7.5 ± 6.3, P 0.01). In the 16 malignant cases, expression of MUC5AC showed borderline significant association with high Ki-67 LI (P = 0.0622). Nuclear expression of β-catenin was observed in two (8%) of the 24 tumors, and these two tumors also showed MUC1 expression. P53 was negative in all tumors. CONCLUSION: Some cases of INihB have a tubular structure, and are subcategorized as IPNB with tubular structure. MUC1 expression in INihB correlates positively with degree of malignancy.     

Significance of mucin expression in pancreatobiliary neoplasms

Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis and tumor invasion. We have described, for the first time, that pancreatic ductal adenocarcinomas (PDACs) with an aggressive behavior and a poor outcome expressed MUC1 (pan-epithelial membrane-associated mucin) but did not express MUC2 (intestinal-type secreted mucin), whereas intraductal papillary mucinous neoplasms (IPMNs) with indolent behavior and a favorable outcome did not express MUC1 but did express MUC2. These expression profiles of MUC1 and MUC2 related to the prognoses of the patients were also observed in biliary neoplasms such as intrahepatic cholangiocarcinoma (ICC)-mass-forming type (MF), mucin-producing bile duct tumor (MPBT), and extrahepatic bile duct carcinoma (EHBDC). We also found recently that high expression of MUC4 (tracheobronchial membrane-associated mucin) in PDACs, ICCs-MF, and EHBDCs was a new independent poor prognostic factor, although MUC4 was not expressed in normal pancreatobiliary tissue. High de novo expression of MUC5AC (gastric-type secreted mucin) was observed in many types of pancreatobiliary neoplasms, including all grades of pancreatic intraepithelial neoplasia (PanIN) and biliary intraepithelial neoplasia (BilIN), and all types of IPMNs and MPBTs, as well as PDACs and ICCs-MF, although MUC5AC was not expressed in normal pancreatobiliary tissue. The combined status of MUC1, MUC2, MUC4, and MUC5AC expression may be useful for the early detection of pancreatobiliary neoplasms and evaluation of their malignancy. In regard to the mechanism of mucin expression, we have recently reported that MUC1, MUC2, MUC4, and MUC5AC gene expression is regulated by epigenetics (DNA methylation and histone H3 lysine 9 modification) in cancer cell lines, including PDAC cells. Translational research of mucin gene expression mechanisms, including epigenetics, in pancreatobiliary neoplasms may give us new tools for the early and accurate detection of these neoplasms.     

Laparoscopic resection of synchronous intraductal papillary mucinous neoplasms: A case report

We describe herein a 68-year-old woman who was diagnosed with a quite rare entity of intraductal papillary mucinous neoplasms (IPMNs) occurring simultaneously in the left lateral lobe of liver and the tail of pancreas. Abdominal computed tomography and magnetic resonance cholangiopancreatography showed a cystic dilatation of the pancreatic duct in the pancreatic tail, which suggested an IPMN, and multiple intrahepatic duct stones in the left lateral lobe. The patient underwent a laparoscopic left lateral hepatolobectomy and spleen-preserving distal pancreatectomy. Intra-operative finding of massive mucin in the dilated bile duct implied an intraductal mucinous tumor in the liver. The diagnosis of synchronous IPMNs in the liver and pancreas was confirmed by pathological examination. The patient was followed up for 6 mo without signs of recurrence. Although several cases of IPMN of liver without any pancreatic association have been reported, the simultaneous occurrence of IPMNs in the liver and pancreas is very rare. To the best of our knowledge, it is the first reported case treated by laparoscopic resection.     

Signet ring cell carcinoma of the extrahepatic bile duct

Most tumors affecting the extrahepatic bile duct are adenocarcinomas; the other histologic types occur only rarely. We herein report the extremely rare case of signet ring cell carcinoma (SRCC) originating from the extrahepatic bile duct. A 55-year-old man was hospitalized for jaundice and pruritus. Computed tomography and positron emission tomography suggested the presence of distal extrahepatic bile-duct cancer. He underwent a pylorus preserving pancreaticoduodenectomy. A histologic study confirmed a signet ring cell neoplasm of the distal common bile duct. Because the upper resection margin was invaded by the tumor, he received postoperative concurrent chemoradiotherapy and four cycles of chemotherapy. The patient has survived with no evidence of recurrence for 2 years. This is the second case of primary SRCC of the distal extrahepatic bile duct reported in the literature; further reports of cases are warranted to determine the nature of SRCC in the extrahepatic bile duct.