Naoki Mochidome

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.

‘Microcystic pattern’ should be recognised as part of the morphological spectrum of solid-pseudopapillary neoplasm of the pancreas

Solid pseudopapillary neoplasm (SPN) is an uncommon pancreatic tumour characterised by solid and pseudopapillary growth patterns. We have observed SPNs can show a microcystic pattern (microcystic SPN), which has been poorly described and may be confused with microcystic neoplasms. We conducted the present study to clarify the clinicopathological and immunohistochemical features of microcystic SPNs.

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.

Role of SpyGlass-DStm in the preoperative assessment of pancreatic intraductal papillary mucinous neoplasm involving the main pancreatic duct

BACKGROUND/OBJECTIVES It is often difficult to determine an adequate resection line during pancreatectomy for intraductal papillary mucinous neoplasm involving the main pancreatic duct during partial pancreatectomy. The aim of this study was to evaluate the usefulness of improved peroral pancreatoscopy using SpyGlass-DStm in the preoperative assessment of intraductal papillary mucinous neoplasm involving the main pancreatic duct. METHODS We collected and retrospectively analyzed clinicopathological data from seven consecutive patients who underwent preoperative assessment of intraductal papillary mucinous neoplasm involving the main duct using SpyGlass-DStm. RESULTS Good imaging quality of the intraductal protruding lesion was obtained in all seven patients, and only one adverse event was noted wherein a patient had mild pancreatitis. Six patients underwent pancreatectomy. In one patient, masked-type concomitant pancreatic ductal adenocarcinoma and low-length dysplastic lesion was found near the surgical margin, which was not detected by preoperative imaging modalities including SpyGlass-DStm. The sensitivity of targeting biopsy during SpyGlass-DStm to diagnose high-grade dysplasia was 0%. CONCLUSIONS SpyGlass-DStm can be safely performed in patients with intraductal papillary mucinous neoplasm involving the main duct, and has excellent visualization of the target lesion. However, challenges include poor diagnostic ability of targeting biopsy, and, therefore, intraoperative frozen section is still needed to obtain negative surgical margins.

Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix: Adipose tissue-derived stromal cells

Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue‐derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three‐dimensional (3‐D) organotypic fat invasion model using visceral fat from CAG‐EGFP mice, GFP‐positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3‐D collagen matrices produced by ASCs cultured in cancer cell‐conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4‐positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy.

Differential Diagnosis of Pancreatic Epidermoid Cyst Without a Solid Component (Residual Splenic Tissue) vs. Mucinous Cystic Neoplasm

PurposeThe purpose of this study was to clarify whether there are differences in imaging findings between pancreatic epidermoid cyst (EDC) without a solid component (residual splenic tissue) and mucinous cystic neoplasm (MCN).Materials and MethodsThe study group consisted of histologically proven EDC (eight cases) and MCN (20 cases). CT and MRI findings were compared on the following imaging findings: the shape of the cystic lesions and the presence or absence of septum, calcification, and high-intensity fluid on T1- and diffusion-weighted images (b factor = 1000). The degree of contact with the pancreatic tail was compared between the EDCs and six of the MCNs at the edge of the pancreatic tail.ResultsThe EDCs were round (n = 3) or oval (n = 5), while the MCNs consisted of three round, five oval, six pear-like, and six multilobulated lesions (P < 0.05). Septum was present in 4 of 8 (50%) EDCs and 19 of 20 (95%) MCNs (P < 0.05). The presence of calcification (2 of 8 [25%] EDCs vs. 8 of 20 [40%] MCNs), high-intensity fluid on T1-weighted images (2 of 7 [29%] EDCs vs. 5 of 20 [25%] MCNs), and high-intensity fluid on diffusion-weighted images (5 of 7 [71%] EDCs vs. 5 of 20 [25%] MCNs) were not significantly different. The degree of contact with the pancreatic parenchyma was similar between the two types of lesions.ConclusionAlthough the imaging findings for EDC without a solid component and MCN overlap, a pear-like or multilobulated shape may favor a diagnosis of MCN.

Mucinous nonneoplastic cyst of the pancreas: CT and MRI appearances

PurposeThe purpose of this retrospective study was to evaluate imaging features of mucinous nonneoplastic cyst (MNNC) of the pancreas.Materials and methodsThree (0.9%) patients with MNNC of the pancreas were found in 335 surgically resected pancreatic cystic lesions. Three MDCT and two MRI/MRCP studies were retrospectively reviewed.ResultsThree cases of MNNC were found in the pancreatic neck, body, and tail, respectively. All the three cases were multilocular without communication with the main pancreatic duct (MPD), although upstream MPD dilatation was seen in two of the three cases. The signal intensity of the cyst fluid was low on T1-weighted, high on T2-weighted, and low on diffusion-weighted images. Cyst wall was thin in two cases, and the remaining case with obstructive pancreatitis showed visible cyst wall enhancement.ConclusionImaging findings of MNNC of the pancreas were nonspecific without communication with the MPD. Cyst wall is typically thin without visible enhancement.

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.