Brain metastases from adenoendocrine carcinoma of the common bile duct: a case report.

A 68-year-old man with metastatic brain tumors from adenoendocrine carcinoma of the common bile duct is reported. A common bile duct tumor and a metastatic liver tumor had been resected 6 years and 3 years prior to admission, respectively. Microscopically they showed two components; moderately differentiated tubular adenocarcinoma and neuroendocrine carcinoma. He presented with headache and vomiting and MRI revealed two metastatic brain tumors. They were successfully resected and radiotherapy was carried out. Histological diagnosis of the metastatic brain tumors was neuroendocrine carcinoma, but carbohydrate antigen (CA)-19-9 and carcinoembryonic antigen (CEA)-immunoreactive cells were observed without glandular pattern. Immunohistochemically serotonin and pancreatic polypeptide were detected, but somatostatin was not. As the endocrine cells demonstrated in the normal extrahepatic bile ducts are only somatostatin-containing D cells, these cells are considered to originate as part of a metaplastic process. To our knowledge, this represents the second case of adenoendocrine carcinoma of the common bile duct.     

Analysis of ras gene mutations in biliary and pancreatic tumors by polymerase chain reaction and direct sequencing

Ras gene is one of the oncogenes most commonly detected in human cancers and consists of three families (H-ras, K-ras, N-ras) that are converted to active oncogenes by point mutations occurring in codon 12, 13, or 61. The authors analyzed mutations of these codons in 12 extrahepatic bile duct carcinomas, nine gallbladder carcinomas, and 20 pancreatic tumors (18 pancreatic adenocarcinomas and two islet cell tumors) by a method to directly sequence nucleotides, using polymerase chain reaction and a direct sequencing method. Point mutations at K-ras codon 12 were found in all of 18 pancreatic adenocarcinomas and in one bile duct carcinoma, but there were no mutations in the remaining 11 bile duct carcinomas, in all of 9 gallbladder carcinomas, or in two islet cell tumors. A very high incidence of ras gene mutations may be used clinically for the diagnosis of debatable cases of pancreatic adenocarcinoma.     

Activation of telomerase and its diagnostic application in biopsy specimens from biliary tract neoplasms.

BACKGROUND: Telomerase activity has been reported to have potential as a useful diagnostic marker for cancer in various organs. The authors previously reported that telomerase activity in pancreatic juice differentiates pancreatic ductal carcinoma from adenoma and pancreatitis. In the current study, the usefulness of semiquantitatively determined telomerase activity in the diagnosis of malignant biliary tract neoplasms was investigated. METHODS: The samples examined included 61 surgically resected biliary tract tissues (11 gallbladder carcinomas, 5 bile duct carcinomas, 1 gallbladder adenoma, 30 cholecytitis cases, 7 cholesterol polyps, 1 normal gallbladder, and 6 normal common bile duct tissues), 42 bile samples from patients with biliary tract or pancreatic disease (19 cases of malignant biliary tract disease, 11 cases of benign biliary tract disease, 10 cases of malignant pancreatic disease, and 2 cases of benign pancreatic disease), and 14 bile duct biopsy specimens collected by percutaneous transhepatic choledochoscopy or endoscopic retrograde cholangiopancreatography (8 bile duct carcinoma specimens, 1 bile duct adenoma specimen, and 5 hepatolithiasis specimens). RESULTS: In biliary tract tissues, a telomerase ladder was detected in 73% of gallbladder carcinomas, 40% of bile duct carcinomas, and none of the other biliary tract tissues. One gallbladder adenoma showed a weak telomerase ladder. The telomerase ladder was detected in the bile sample from 1 patient (5.3%) with malignant biliary tract disease, none of the patients with benign biliary tract disease, 5 patients (50%) with malignant pancreatic disease, and none of the patients with benign pancreatic disease. In biopsy specimens, the telomerase ladder was detected in 75% of patients with bile duct carcinoma but not in any of the patients with hepatolithiasis. The median value of relative telomerase activity in the patients with bile duct carcinoma was significantly higher than that in the patients with hepatolithiasis. The diagnosis of bile duct carcinoma was confirmed preoperatively by histopathologic examination in only 25% of the biopsy specimens. CONCLUSIONS: The results of the current study indicate that telomerase is highly activated in biliary tract carcinomas and that the detection of a telomerase ladder in biopsy samples is an excellent tool for the diagnosis of bile duct carcinomas.     

Development and clinical pathology of carcinoma of the gallbladder and extrahepatic bile duct

We reported the causes of cancer development and clinical pathology of the gallbladder and extrahepatic bile duct carcinoma. Gallstone, secondary bile acid, and congenital malunion between the bile duct and the pancreatic duct are considered as causes of intestinal metaplasia of the mucosa of the biliary tract. The intestinal metaplasia has closely relationship with development of dysplasia and carcinoma. We treated 101 patients with gallbladder carcinoma and 85 patients with bile duct carcinoma. Sex ratios of the patients with gallbladder carcinoma and bile duct carcinoma were 1:1.8 and 1.7:1. Fifty-one of 101 patients with gallbladder carcinoma had gallstones, and 17 of them had congenital malunion between the bile duct and the pancreatic duct. In four of 23 patients with gallbladder carcinoma and 10 of 64 patients with bile duct carcinoma, superficial cancer spread was seen and it was very important for surgical operation clinically.     

Mucin-producing tumor of the pancreas

A new pancreatic tumor, called mucin-producing tumor, has received great attention in Japan. These tumors are found inside the pancreatic duct and produce large quantities of copious mucus. The authors examined 22 cases of these tumors histologically and histochemically. In 12 malignant cases, the tumors inside the ducts consisted of cancerous lesions over small areas along with papillary or atypical hyperplasia. Tumors in ten benign cases mainly consisted of papillary hyperplasia. Except for three patients with carcinoma in situ, cancerous tumors infiltrated the pancreatic parenchyma and, in some cases, were observed invading the bile duct or duodenum. A mucous histochemical study showed evidence of sialomucin in malignant cases; neutral mucin was dominant in benign cases. Characteristics of this disease were also compared with 13 cases of mucinous cystic neoplasm. From the results, it was concluded that these two diseases can be classified into the same conceptual category.     

Intensity-modulated radiotherapy in treatment of pancreatic and bile duct malignancies: toxicity and clinical outcome

PURPOSE: To assess the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) in pancreatic and bile duct (cholangiocarcinoma) malignancies. METHODS AND MATERIALS: Twenty-five patients with pancreatic and bile duct cancer were treated with IMRT. Twenty-three received concurrent 5-fluoruracil. One patient with a pancreatic primitive neuroectodermal tumor received concurrent etoposide and ifosfamide. Eight patients had resected tumors, and 17 had unresectable primary (n = 14) or recurrent (n = 3) tumors. Six patients underwent treatment planning with conventional three-dimensional four-field techniques for dosimetric comparison with IMRT. RESULTS: Compared with conventional RT, IMRT reduced the mean dose to the liver, kidneys, stomach, and small bowel. IMRT was well tolerated, with 80% experiencing Grade 2 or less acute upper GI toxicity. At a median follow-up of 10.2 months, no resected patients had local failure, and only 1 of 10 assessable patients with unresectable cancer had local progression. The median survival and distant metastasis-free survival of the 24 patients with adenocarcinoma was 13.4 and 7.3 months, respectively. Grade 4 late liver toxicity occurred in 1 patient surviving >5 years. The remainder of the assessable patients experienced no (n = 9) or Grade 1 (n = 4) late toxicity. CONCLUSION: In this hypothesis-generating analysis, the acute and chronic toxicity profile with IMRT in the treatment of pancreatic and bile duct cancer was encouraging. Local control was not compromised, despite efforts to increase conformality and avoid doses to normal structures. Distant failure remains a major obstacle in pancreatic cancer.     

Radiotherapy with multiple fractions per day in pancreatic and bile duct cancer

Twenty patients with pancreatic and bile duct cancer have been treated with external radiotherapy with multiple fractions per day (MFD). All patients had localized disease only. Sixteen patients have been treated with a split-course technique, to a dose of 60 to 70 Gy in 7-8 weeks, four patients had a continuous series of 44 Gy in 19 days. The mean survival was 7.9 months for patients with a pancreatic cancer. Four out of nine patients with pancreatic cancer in whom the tumour was evaluable showed a tumour regression, one out of nine reached a partial remission. The mean survival in the responders was 9.5 months. All patients with pancreatic cancer died of their tumour. Four out of eight patients with bile duct cancer died of their tumour, the mean survival was 10 months. Four patients with bile duct cancer are still alive (10+, 10+, 10+, 11+ months). No serious acute toxicity was seen. Six patients showed gastrointestinal toxicity at 1.5 to 9 months after the end of treatment. All of them could be treated in a conservative way. From the results obtained in this feasibility study, radiotherapy with MFD in pancreatic and bile duct cancer appears to achieve similar tumour response as conventionally fractionated radiotherapy and the observed toxicity of MFD can be considered as acceptable. MFD might be a more appropriate treatment scheme for combination with chemotherapy and radiosensitizers.     

Analysis of extrahepatic bile duct carcinomas according to the New American Joint Committee on Cancer staging system focused on tumor classification problems in 222 patients

BACKGROUND: Although the sixth edition of the American Joint Committee on Cancer (AJCC) staging system for extrahepatic bile duct carcinoma was updated, the system has a problem on T classification due to its ambiguous definition of T1 as "tumor confined to bile duct histologically" and T2 as "tumor invading beyond the bile duct." METHODS: The authors considered the outermost part of the muscle layer or fibrous tissue as within the extrahepatic bile duct and considered the area starting from large clusters of adipose tissue as beyond the extrahepatic bile duct. After designing a precise definition of the extrahepatic bile duct wall, they analyzed the new AJCC staging system in 222 patients with of extrahepatic bile duct carcinomas. Then, other clinicopathologic variables for prognosis were evaluated using univariate and multivariate analyses. RESULTS: The 5-year survival rates for patients with tumors that were classified as T1, T2, T3, and T4 were 53.1%, 29.7%, 24.9%, and 0%, respectively. There was a significant difference in survival between patients with T1 tumors and T2 tumors (P < 0.05), but not between patients with T2 tumors and T3 tumors. Significant prognostic factors included depth of invasion (P < 0.005), lymph node metastasis (P < 0.005), and patient age (P < 0.05). CONCLUSIONS: Based on a proposed histologic definition, depth of invasion was practical for evaluating the prognosis of patients with middle and upper extrahepatic bile duct carcinomas. Therefore, the authors recommended changing the current pT1 and pT2 classifications to more precise pathologic terminology.     

CT-guided percutaneous fine needle aspiration cytodiagnosis of pancreatic and periampullary tumors

CT guided percutaneous fine needle aspiration cytodiagnosis was performed on 30 patients with pancreatic and periampullary tumors in China-Japan Friendship Hospital from November 1984 to January 1986. In our series, 9 pancreatic head cancers, 4 pancreatic body and tail cancers, 5 ampullary cancers had positive cytodiagnosis (100%-18/18). 2 of 3 (67%) duodenal cancers and 6 of 7 (86%) the distal common bile duct cancers were positive by cytodiagnosis. 2 pancreatitis were negative (100%). The positive rate by CT guided diagnosis was 93.3% (28/30). In the same period, ultrasonically guided percutaneous fine needle aspiration cytodiagnosis was performed on 30 patients with pancreatic and periampullary tumors, a correction rate of diagnosis was 67%. CT guided procedure is more accurate than that ultrasonically guided.     

Early diagnosis of pancreatic cancer by routine CT scanning; significance of the pancreatic bile duct scanning

Early recognition of dilated tail-side pancreatic duct and liver-side bile duct is one of the main diagnostic goals for an early diagnosis of pancreatic cancer. In order to attain these objectives, a new scanning method involving Target Volume Scan for the pancreas as a routine CT scanning modality has been devised. The picturing capability of this imaging method for the pancreatic bile duct and its role in the early diagnosis of pancreatic cancer are discussed. In phantom experiments, clinical experiments and clinical applications, the pancreatic duct within the pancreas body and the intra-hepatic bile duct, which were expanded into a cylindrical form of pure circular cross section with a diameter greater than 2 mm, have been pictured as continuous, linear, low-density regions. Similarly, the pancreatic duct within the pancreas head and the choledoch duct with diameters greater than 3 mm have also been pictured as low-density circular areas. In healthy pancreatic bile ducts, the tail section of the pancreas head and the intra-hepatic bile duct do not appear in scans, and although 70% of healthy choledoch ducts have been pictured, many deformed lumens have been observed in cross section. The conditions for obtaining successful images of lumens depended upon the degree of intra-lumen filling with either pancreatic juice or bile rather than the diameter of the lumen. Consequently, pancreatic cancer, which causes changes in the pancreatic duct and bile duct lumen, can be detected as a discontinuity in the image of the lumen obtained in the Target Volume Scan, regardless of the cancer, suggesting that the Target Volume Scan could be an important diagnostic imaging tool for the early detection of pancreatic cancer.     

Effects of urokinase on the transfer of 1-hexylcarbamoyl-5-fluorouracil (HCFU) into the blood, bile and pancreatic juice

We studied effects of urokinase (Uronase) on the transfer of an oral anticancer agent, 1-hexylcarbamoyl-5-fluorouracil (HCFU) into blood, bile and pancreatic juice in 5 patients in whom pancreaticoduodenectomy has been performed for cancer of the periampullary region, and who had been simultaneously provided with drainage of the bile duct and pancreatic duct. Following oral administration of 500 mg of HCFU, HCFU and 5-FU concentrations in blood reached a peak at 2 hours, those in bile at 4 hours, and those in pancreatic juice at 4 to 6 hours. The administration of 24,000 IU of urokinase in combination with HCFU resulted in increased HCFU and 5-FU concentrations in blood, bile and pancreatic juice--the HCFU concentration in bile increased to 3 times and that in pancreatic juice, to about 5 times the level in the some counterparts in urokinase--untreated patients. These changes seemed to have resulted from the acceleration by urokinase of distribution of the anticancer agent into the organs.     

A case of intraductal mucinous neoplasms with the whole main pancreatic duct dilation treated via segment pancreatectomy

The patient was a 77-year-old woman. She was diagnosed as intraducal papillary mucinous neoplasms (IPMN). She refused an operation for 3 years. After all, a nodule in the main pancreatic duct was pointed out, she agreed and was referred to us. Her past history showed pacemaker implantation for third-degree atrioventricular block, and no impaired glucose tolerance. Abdominal CT showed a dilated whole pancreatic duct and a multilocular cystic tumor. Endoscopic retrograde pancreatography showed a marked dilation of the main pancreatic duct. We diagnosed as main duct IPMN. Intraoperative US showed no nodule in pancreatic duct, and there was no suspicious lesion of invasive cancer. We performed segmental pancreatectomy between the left side of common bile duct and the pancreas tail. The tumor was resected with clear margins. Both cut-ends of the main pancreatic duct were anastomosed to a jejunal loop. The postoperative course was excellent. She was discharged on day 16. The glycemic control was good, she needed no treatment for diabetes. Total pancreatectomy has many problems such as insulin and pancreatic polypeptide deficiency, hypoglycemia, malabsorption, diarrhea and liver dysfunction. We avoided total pancreatectomy so that her quality of life was maintained. Still a careful follow -up is required.     

Pancreatic duct cell carcinoma with positive 111In Octreotide uptake

Duct cell adenocarcinomas may produce neuroendocrine markers such as pancreatic polypeptide, gastrin and gastrin releasing hormones. A 53 year old patient, with a history of insulin dependent diabetes, was found to have a pancreatic mass which was later pathologically demonstrated to be a duct cell adenocarcinoma. The tumor produced elevated circulating neuroendocrine markers specifically gastrin and pancreatic polypeptides. An 111In Octreotide imaging showed definite uptake of Octreotide by the tumor. The patient was subsequently treated with Somatostatin analog which resulted in the reduction of some of the circulating endocrine markers. The patient had essentially six months of asymptomatic clinical remission but then she relapsed. Octreotide scanning could be useful for selected patients with pathologic diagnosis of duct cell adenocarcinoma, because some tumors may have neuroendocrine features and can be imaged, and might even respond to Somatostatin analog therapy.     

Interdisziplin?re Behandlung des Pankreaskarzinoms

Pancreatic cancer is currently the fourth most common fatal cancerous disease in Germany with 14,000 deaths every year. It is most frequently localized in the pancreatic head and characterized by aggressive growth behavior with early metastasis. Only 20% of patients present with resectable tumors at diagnosis which allow a curative R0 resection (e.g. Whipple procedure) followed by adjuvant chemotherapy. In cases of non-resectable or metastasizing pancreatic cancer, palliative treatment should be initiated in a interdisciplinary manner. In oncologic treatment gemcitabine is the most important medication in both adjuvant and palliative situations. Further palliative interventional and surgical measures comprise stenting of the common bile duct and operative bypass procedures. A small percentage of patients with primarily non-resectable tumors may benefit from neoadjuvant radiochemotherapy which can provide secondary resectability.     

Carcinoid tumors of the extrahepatic bile duct. A rare cause of malignant biliary obstruction

BACKGROUND: Carcinoid tumors of the extrahepatic bile duct are rare and account for 0.2-2% of all gastrointestinal carcinoids. Similar to other tumors of the bile duct, these lesions are difficult to diagnose preoperatively and nearly impossible to distinguish from cholangiocarcinoma. METHODS: The authors retrospectively analyzed all reported cases of carcinoid tumor of the bile duct and report on two additional cases. RESULTS: Thirty cases of carcinoid tumor of the bile duct have been reported. Among this group were 20 women and 9 men (female-to-male ratio, 2.2:1) with an overall mean age of 47 years (range, 19-79 years). The most common anatomic sites for extrahepatic carcinoid tumors were the common bile duct (58%), perihilar region (28%), cystic duct (11%), and common hepatic duct (3%). Jaundice was the most common presenting complaint (55%). Sixty-nine percent of patients with extrahepatic biliary carcinoids had disease confined to the bile duct, whereas 31% had evidence of distant metastases. All patients who presented with localized disease remain disease free with a mean follow-up of 32 months (range, 3 months to 20 years). CONCLUSIONS: Carcinoid tumor of the bile duct is a rare form of malignant biliary obstruction. Unlike cholangiocarcinoma, biliary carcinoids occur more commonly in younger patients and in women. Aggressive local invasion by the primary tumor is rare, and metastases occur in less than one-third of patients. All patients who underwent a curative surgical resection were alive and disease free at time of published report, implying a more favorable prognosis. Aggressive surgical resection is recommended.     

Gallbladder mucosa ornithine decarboxylase activity is increased in patients with anomalous arrangement of the pancreaticobiliary duct.

Ornithine decarboxylase (ODC) activity, which seems to increase in premalignant lesions, was studied in gallbladder mucosa from 32 patients with or without anomalous arrangement of the pancreaticobiliary duct (AAPBD). Mucosal ODC activity was significantly increased in 17 patients with AAPBD compared with 15 control subjects with normal biliary anatomy. Among the 17 patients with AAPBD, ODC activity was significantly increased in 7 in whom the major pancreatic duct joined the common bile duct (P-C type) compared with 8 in whom the common bile duct joined the pancreatic duct (C-P type). The increased ODC activity in gallbladder mucosa suggests that patients with the P-C type of AAPBD may have an increased risk of gallbladder cancer. These results are consistent with recent clinicopathologic studies of AAPBD that have demonstrated an association between AAPBD and biliary tract malignancy. Determination of the mechanism that induces mucosal ODC activity may provide a clue to the pathogenesis of gallbladder carcinoma in patients with AAPBD.     

Diagnostic p53 immunostaining of endobiliary brush cytology: preoperative cytology compared with the surgical specimen.

BACKGROUND: Endobiliary brush cytology is important in the distinction of malignant and benign causes of extrahepatic bile duct obstruction. The additional diagnostic value of p53 immunostaining on these cytology specimens was assessed. METHODS: All patients with extrahepatic bile duct obstruction who underwent endoscopic retrograde cholangiopancreatography (ERCP) with endobiliary brush cytology and subsequent surgery at the Academic Medical Center in Amsterdam during a 3-year period were studied. p53 Immunocytology was compared with the corresponding conventional light microscopic cytology and p53 immunostaining of the subsequent surgical specimen. RESULTS: Fifty-three patients with the following diagnoses were included: pancreatic carcinoma (23), bile duct carcinoma (15), ampullary carcinoma (5), lymph node metastases (2), carcinoma of unknown origin (4), chronic pancreatitis (3), and primary sclerosing cholangitis (1). Fifty-one percent of the carcinomas showed positive p53 immunostaining; all four surgical specimens without carcinoma were negative. The sensitivities of conventional light microscopic cytology, p53 immunocytology, and both tests combined were 29%, 24%, and 43%, respectively. These sensitivities were higher in cases of bile duct carcinoma (46%, 40%, and 66%) compared with cases of pancreatic carcinoma (13%, 9%, and 22%). Specificities of both tests were 100%. CONCLUSIONS: p53 Immunostaining on endobiliary brush cytology may be helpful in the diagnosis of malignant extrahepatic bile duct stenosis, especially in patients with bile duct carcinoma. Cancer (Cancer Cytopathol) Copyright 1999 American Cancer Society.     

Safety of biliary stent placement followed by definitive chemoradiotherapy in patients with pancreatic cancer with bile duct obstruction

BackgroundAlthough patients with malignant bile duct obstruction due to pancreatic cancer are often initially treated with biliary stent placement, concurrent chemoradiotherapy with stents poses a potential risk of increased toxicity. This retrospective study aimed to evaluate the safety of biliary stent placement followed by definitive concurrent chemoradiotherapy in patients with pancreatic cancer.MethodsPatients with pancreatic cancer who underwent either a plastic stent or a self-expanding metallic stent placement for malignant bile duct obstruction before definitive concurrent chemoradiotherapy were retrospectively reviewed. Radiotherapy was delivered in 1.8 Gy per fraction to a total dose of 50.4 Gy. Gemcitabine, TS-1 plus Gemcitabine, or TS-1 was the concurrent chemotherapy/regimen. The primary endpoint was the rate of biliary stent-related toxicities, defined as biliary bleeding, duodenal perforation, or bile duct perforation.ResultsThirty patients were included. Plastic stents were placed in 23 patients and self-expanding metallic stent in seven patients at the start of irradiation. The median follow-up time was 20 (range, 2–63) months, and 27 patients (90%) completed concurrent chemoradiotherapy. Biliary stent-related toxicity (grade 3 biliary bleeding) was confirmed in one patient (3%) with a plastic stent 9 months after concurrent chemoradiotherapy. The median duration of locoregional control, progression-free survival, and overall survival were 31.1, 7.3, and 10.5 months, respectively.ConclusionsStent placement followed by concurrent chemoradiotherapy was not associated with an apparent increase in toxicity and may be an appropriate treatment for patients with locally advanced pancreatic head cancer with bile duct obstruction.     

Clinical investigation of carbohydrate antigen CA-50

The CA-50 enzyme immunoassay kit (EIA kit) that has been developed with the use of C-50 monoclonal antibody prepared by L. Lindholm et al. was evaluated for diagnosis of human cancer. The levels of CA-50 in the sera were determined using this kit supplied from Mitsui Pharmaceuticals, Inc. Co. in 759 healthy donors, 728 patients with benign disease and 1,263 untreated patients with cancer. A CA-50 concentration of 40 U/ml of serum was used as the cut-off value. Patients with pancreatic cancer and patients with bile duct cancer had high positive incidence of 75% and 68%, respectively, compared with a low positive incidence of under 40% in patients with other cancers. On the other hand, positive rates in patients with benign disease were as low as 13%. Comparison of the serum levels of CA-50 with CA19-9 in the same samples did not exhibit complete positive correlation in patients with pancreatic cancer, patients with bile duct cancer and patients with liver cancer. These findings indicated that C-50 antibody reacted with two epitopes of CA19-9 and sialosyllactotetraose. From the above results, the usefulness of CA-50 as a tumor marker for pancreatic cancer and bile duct cancer was recognized with this EIA kit.