Kenjiro Date

Distinction of Invasive Carcinoma Derived From Intraductal Papillary Mucinous Neoplasms From Concomitant Ductal Adenocarcinoma of the Pancreas Using Molecular Biomarkers.

Objectives To clarify the usefulness of molecular biomarkers for distinguishing invasive carcinoma derived from intraductal papillary mucinous neoplasms (IPMNs [Inv-IPMN]) from concomitant pancreatic ductal adenocarcinoma (PDAC). Methods Data from 19 patients with resected concomitant PDAC were retrospectively reviewed. KRAS/GNAS mutations and immunohistochemical (IHC) expression of p53 and p16/CDKN2A were assessed in both IPMN and distinct PDAC. As controls, KRAS/GNAS mutations and IHC labeling were assessed between invasive and noninvasive components in 1 lesion of 22 independent patients. Results KRAS/GNAS mutation status of invasive and noninvasive components in Inv-IPMN was consistent in 18 (86%) of 21 patients. Conversely, mutational patterns in IPMN and distinct PDAC in the same pancreas differed from each other in 17 (89%) of 19. There were 10 (53%) and 8 (42%) of 19 patients who showed the same p53 and p16/CDKN2A staining between concomitant PDAC and distinct IPMN. In the Inv-IPMN cohort, 19 (86%) of 22 patients showed the same IHC expression pattern between the noninvasive and invasive components. Conclusions It may be possible to distinguish Inv-IPMN from concomitant PDAC by assessing these molecular biomarkers. More precise distinction of Inv-IPMN and concomitant PDAC will lead to adequate recognition of the natural history of IPMNs and hence optimal management.

Molecular Evidence for Monoclonal Skip Progression in Main Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas

Objective: To clarify clonality of distinct multisegmental main duct (MD)-intraductal papillary mucinous neoplasms (IPMNs) using microarray analysis. Background: IPMNs represent a pancreatic ductal cell field defect, which causes multiple occurrences of lesions. In addtion, it has been speculated that MD-IPMNs display features of monoclonal skip progression. Methods: Total RNA was extracted from fresh-frozen tissue samples of metachronous MD-IPMNs and nonneoplastic pancreas tissue from the same pancreas from two individuals, and whole human genome microarray analysis was performed. Formalin-fixed paraffin-embedded tissue specimens from 28 distinct IPMNs were then collected from 12 patients, genomic DNA was extracted, and GNAS/KRAS mutational status was investigated. Immunohistochemical analysis was performed to validate the expression pattern of the indicated proteins. Results: Microarray analysis revealed that metachronous MD-IPMNs from the same individual displayed pair-wise correlation coefficients of 0.9523 and 0.9512. In contrast, MD-IPMNs of the same histological grade from different individuals displayed coefficients of 0.8092 and 0.8211. Scatter plot analysis revealed that metachronous MD-IPMNs from the same individual displayed a closer linear relationship. Furthermore, heat map and hierarchical cluster analyses revealed that metachronous MD-IPMNs from the same individual were classified in the same branch, and the gene expression patterns were similar. The GNAS/KRAS mutational statuses of distinct MD-IPMNs were consistent with each other. Immunohistochemical assessment of five specific proteins demonstrated that the same expression pattern between two lesions was observed in 95% of the samples. Conclusions: These findings using molecular analyses indicate that MD-IPMNs might display features of monoclonal skip progression.

GNAS and KRAS mutational analyses of intraductal papillary neoplasms of the pancreas and bile duct developing in the same individual: A case report.

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas and intraductal papillary neoplasm of the bile duct (IPNB) are considered as counterparts of each other, and it is suggested that these two entities have similar molecular alteration pathways. However, the occurrence of IPMN of the pancreas and IPNB in the same patient is rare. We report a surgical case of a 69-year-old woman who developed invasive IPMN of the pancreas and underwent pancreatectomy, 6 months after hepatic resection of invasive IPNB. Molecular analysis revealed GNAS/KRAS mutation in both invasive IPMN of the pancreas and IPNB. This is believed to be the first case report investigating GNAS/KRAS mutational status in both IPMN of the pancreas and IPNB developing in the same patient, and these two entities may show similar molecular alternations.

Elevated bile amylase level without pancreaticobiliary maljunction is a risk factor for gallbladder carcinoma

Elevated bile amylase level in patients with pancreaticobiliary maljunction (PBM) or high confluence of pancreaticobiliary ducts (HCPBD) is well known as a risk factor for gallbladder carcinoma (GBC) development. However, the effects of occult pancreaticobiliary reflux (OPR), a condition characterized by high bile amylase level in the presence of an anatomically normal pancreaticobiliary junction, on GBC development remain unclear. The aim of this study was to assess the relationship between OPR and GBC.

Surveillance of patients with intraductal papillary mucinous neoplasm with and without pancreatectomy with special reference to the incidence of concomitant pancreatic ductal adenocarcinoma

Background The presence of an intraductal papillary mucinous neoplasm is important in the detection of concomitant pancreatic ductal adenocarcinoma. The aim of this study was to elucidate the incidence and timing of development of concomitant pancreatic ductal adenocarcinoma in patients with and without pancreatectomy for intraductal papillary mucinous neoplasm. Methods We reviewed retrospectively the surveillance data for 22 patients who underwent pancreatectomy for pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm (pancreatic ductal adenocarcinoma‐resection group), 180 who underwent pancreatectomy for intraductal papillary mucinous neoplasm (intraductal papillary mucinous neoplasm‐resection group), and 263 whose intraductal papillary mucinous neoplasms were left untreated (nonresection group). The incidence and timing of the development of a concomitant pancreatic ductal adenocarcinoma during the surveillance of patients with and without partial pancreatectomy for intraductal papillary mucinous neoplasm were investigated using the Kaplan‐Meier method. Results During a median surveillance period of 40 months (range 6–262 months), 5 patients in the pancreatic ductal adenocarcinoma‐resection group, 6 in the intraductal papillary mucinous neoplasm‐resection group, and 8 in the nonresection group developed concomitant pancreatic ductal adenocarcinoma. The estimated 5‐year (17%) and 10‐year (56%) cumulative incidences of secondary pancreatic ductal adenocarcinoma in the pancreatic ductal adenocarcinoma‐resection group were significantly greater than those in the other two groups (P < .01). Conversely, the difference in the estimated cumulative incidence of concomitant pancreatic ductal adenocarcinoma between the intraductal papillary mucinous neoplasm‐resection and nonresection groups was not significant (5‐year, 5.0% vs 2.2%; 10‐year, 5.0% vs 8.7%; P = .87). Conclusion Long‐term (≥5‐year) surveillance in patients with intraductal papillary mucinous neoplasm is necessary and important because of the potential for development of concomitant pancreatic ductal adenocarcinoma. Those with a history of resection of concomitant pancreatic ductal adenocarcinoma at the time of the initial operation are at quite high risk for the development of secondary pancreatic ductal adenocarcinoma.

Different Hormonal Expression Patterns Between Primary Pancreatic Neuroendocrine Tumors and Metastatic Sites.

Objectives Pancreatic neuroendocrine tumors (PNETs) are known to have heterogeneity in terms of their ability to produce multiple hormones. The aim of this study was to evaluate the heterogeneity of PNETs from the viewpoint of hormonal expression. Methods The expressions of 4 representative hormones, gastrin, insulin, glucagon, and somatostatin, in both primary and metastatic lesions, were analyzed by immunohistochemical staining in 20 patients with metastatic PNETs (6 gastrinomas, 1 insulinoma, 1 glucagonoma, and 12 nonfunctioning PNETs [NF-PNETs]). Metastatic sites included lymph nodes in all 20 patients and liver metastasis in 7 patients (2 gastrinomas and 5 NF-PNETs). Results There were 6 PNETs with multiple hormone secretion (30%), and positive expression of 1 or more hormones was found in 9 of 12 patients whose primary tumors were diagnosed as NF-PNETs. The positive concordance rate of the hormonal expression pattern between primary tumors and metastatic lymph nodes and between primary tumors and hepatic metastasis were 50% and 11%, respectively. Three patients had metastatic lesions with positive hormonal expression, whereas their primary tumors were negative. Conclusions Hormonal expressions are often different between the primary tumors and metastatic sites of PNETs.

Expression of Bcl-2 19-kDa interacting protein 3 predicts prognosis after ampullary carcinoma resection.

An adequate management strategy for ampullary carcinoma (AC), a rare neoplasm, has yet to be determined. The aim of this study was to identify specific molecular markers allowing for the adequate management of AC.