Search

Background/aim: Mutations of the adenomatous polyposis coli (APC) tumor suppressor gene have been described in a subset of pancreatic carcinomas. The APC gene modulates the beta-catenin-Tcf pathway. The major player in this pathway is the beta-catenin protein encoded by the beta-catenin gene. A variety of different tumors, including colon, prostate, endometrial, and hepatocellular carcinomas, carry mutations in exon 3 of the beta-catenin gene. The aim of this study was to determine the role of the beta-catenin gene in the genesis of exocrine and endocrine tumors of the pancreas., Methods: 78 ductal pancreatic adenocarcinomas, 14 ductal pancreatic cancer cell lines, and 33 endocrine pancreatic tumors were evaluated for mutations in exon 3 of the beta-catenin gene by single-strand conformation polymorphism analysis and direct DNA sequencing. In addition, 40 ductal pancreatic adenocarcinomas were analyzed for intracellular beta-catenin accumulation by immunohistochemistry, indicating alterations of the beta-catenin gene., Results: Neither the 111 exocrine and endocrine pancreatic tumors nor the 14 pancreatic cancer cell lines carried mutations in exon 3 of the beta-catenin gene. Intracellular beta-catenin accumulation was not identified in any of the 40 pancreatic adenocarcinomas., Conclusion: These data suggest that the beta-catenin gene as the major player of the beta-catenin-Tcf pathway does not play an important role in the genesis of pancreatic tumors.

Background: Malignant fibrous histiocytoma (MFH) is the most common type of soft tissue sarcoma in adults; it occurs frequently in the extremities, the trunk, or retroperitoneal tissues. MFH rarely is detected in digestive organs, such as the liver or stomach., Methods: The authors report a patient with MFH of the pancreas who was treated with surgery alone. The tumor was studied for genetic alterations in the p53, p16ink4a, and DPC4 tumor suppressor genes as well as the K-ras oncogene by immunohistochemistry, single strand conformation variant (SSCV) analysis, and direct DNA sequencing., Results: The authors believe that this is the 13th report of primary pancreatic MFH in the world literature and the first genetic analysis of this rare tumor. The patient is alive with no evidence of recurrence 34 months after surgery. Immunohistochemistry revealed no abnormal accumulation of the p53 protein and normal nuclear p16 expression. Mutation analysis of the p53, p16, DPC4, and K-ras genes showed only a polymorphism at codon 72 of the p53 gene and no mutations in any of the genes., Conclusions: Genotypically, MFH of the pancreas is clearly different from other malignant pancreatic tumors, which further supports the hypothesis that this tumor is a rare but distinct entity.

The tumor suppressor gene DPC4/Smad4 at 18q21.1 is inactive in about 50% of pancreatic carcinoma xenografts and cell lines. However, the role of DPC4 in the multistep carcinogenesis of primary pancreatic adenocarcinomas remains uncertain. Therefore, we examined 45 primary human pancreatic adenocarcinomas and 12 pancreatic cancer cell lines for DPC4 alterations by single-strand conformational variant (SSCV) analysis and a PCR-based deletion assay. DPC4 was inactivated by either homozygous deletion or point mutation in 6 of 12 cell lines (50%). None of the primary pancreatic carcinomas carried a DPC4 mutation, although 66% revealed LOH of 18q21 sequences. These findings suggest that inactivation of DPC4 occurs more frequently in tumor-derived cell lines than in primary pancreatic adenocarcinomas. In addition, another, yet unidentified, tumor suppressor gene(s) may be linked with the frequent LOH of 18q21 in primary pancreatic adenocarcinomas.

Tumors of the endocrine pancreas are extremely rare, and molecular mechanisms leading to their development are not well understood. A candidate tumor suppressor gene, DPC4, located at 18q21, has recently been shown to be inactivated in half of pancreatic adenocarcinoma xenografts. The close anatomical relationship of the exocrine and endocrine pancreas prompted us to determine the role of DPC4 in the tumorigenesis of 25 pancreatic islet cell tumors (11 insulinomas, nine non-functioning endocrine carcinomas, three gastrinomas, two vipomas). A mutation screening of the highly conserved COOH-terminal domain of DPC4 (exons 8-11) was performed by single-strand conformational variant (SSCP) analysis and a PCR-based deletion assay. Five of nine (55%) non-functioning endocrine pancreatic carcinomas revealed either point mutations, small intragenic deletions or homozygous deletion of DPC4 sequences compared to none of the insulinomas, gastrinomas or vipomas. These results suggest that DPC4 is an important target gene promoting tumorigenesis of non-functioning neuroendocrine pancreatic carcinomas.

Objective: To evaluate clinical parameters, presurgical diagnostic tests, histologic findings, and the presence of K-ras oncogene mutations in cystic tumors of the pancreas to determine which best predict malignancy., Summary Background Data: Because presurgical, intraoperative, and final pathologic differentiation is difficult in cystic tumors of the pancreas, it would be a major benefit to identify markers that accurately predict malignancy in these rare tumors. The role of K-ras oncogene mutations as an indicator of malignancy has not been determined in these tumors., Methods: Nineteen patients with cystic tumors of the pancreas were evaluated, including K-ras mutation analysis based on polymerase chain reaction and restriction digestion assays and direct DNA sequencing, to screen for parameters that accurately predict malignancy., Results: All malignant cystic pancreatic tumors (five cystadenocarcinomas and three mucin-producing adenocarcinomas) harbored K-ras mutations at codon 12 or 13. K-ras mutations were also detected in the percutaneous fine-needle aspirates of two of these patients. In contrast, none of nine benign cystadenomas or the solid-papillary neoplasm had K-ras mutations. None of the patients with a benign tumor carrying K-ras wild-type sequences developed recurrent disease after a mean follow-up of 50 months. Seven of the 8 malignant cystic pancreatic tumors, but none of the 11 benign tumors, showed dilatation of the main pancreatic duct on computed tomography or endoscopic retrograde cholangiopancreatography., Conclusions: K-ras mutation analysis seems to be a powerful tool to determine the malignant potential of cystic pancreatic tumors before and after surgery. Dilatation of the main pancreatic duct on computed tomography or endoscopic retrograde cholangiopancreatography is highly suggestive for malignancy in these rare tumors.

In this prospective study we evaluated the presence and importance of hepatic micrometastases at the time of operation in patients with resectable pancreatic carcinoma. In 13 patients with pancreatic carcinoma and 5 patients with chronic pancreatitis Truecut-Needle biopsies of the liver were obtained during operation. K-ras mutation analysis was done by the PCR/restriction digestion assay with HphI, followed by an ultrasound of the liver in 3 monthly intervals. Four of 13 (30%) pancreatic cancer patients had K-ras gene mutations in the liver and had a mean survival of 6 months after resection. All chronic pancreatitis patients and 8 of the 9 remaining pancreatic cancer patients without K-ras mutations in the liver biopsies are alive without evidence of liver metastases after a mean follow-up of 9 months. Detection of micrometastases in the liver by K-ras mutation analysis might be a powerful tool to identify occult clinical relevant liver metastases.

Objective: The most effective way to localize the mostly small ( < 2 cm), benign and solitary insulinomas is still under discussion. Especially the evaluation of the different preoperative localization methods is not clarified. The aim of our study was to support the ongoing discussion in that matter., Patients and Methods: In total 25 patients have been included in our study since 1987. All showed sporadic insulinomas and underwent surgery. The following preoperative localization methods had been used: ultrasonography (US): 25 patients, computed tomography (CT): 23 patients, somatostatin receptor scintigraphy (SRS): four patients since 1990, angiography: six patients, endosonography (ES): five patients since 1995, selective portal venous sampling (PVS): two patients, magnetic resonance imaging (MRI): four patients since 1993. All 25 patients underwent a bidigital palpation in combination with intraoperative ultrasonography (IOUS). Four of the 25 patients were reoperated and had a prior unsuccessful operation elsewhere., Results: Preoperatively 19 of 25 insulinomas were localized (76%). The following sensitivity rates had been found: ultrasonography: 56%, computed tomography: 43%, endosonography: 100%, angiography: 66%, magnetic resonance imaging: 25%, selective portal venous sampling: 100%, somatostatin receptor scintigraphy: 0%. All 25 insulinomas were detected during operation, 100% by palpation in combination with intraoperative ultrasonography and 92% by palpation on its own., Conclusion: After an insulinoma is biochemically proven and after exclusion of a malignant metastasizing tumor by ultrasonography, all patients should be operated on. Intraoperative ultrasonography should be performed in any case. As other preoperative localization methods did not prove a convincing cost-utility-relation, one should not consider the usage of these methods before the initial operations. Before re-operations one should consider the use of costly pre-operative methods to localize insulinomas. Here endosonography and selective portal venous sampling are recommended as the first procedures of choice.