Noriyoshi Fukushima

Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study

Now that more than two decades have passed since the first reports of intraductal papillary-mucinous neoplasms (IPMNs), it has become clear that IPMN consists of a spectrum of neoplasms with both morphological and immunohistochemical variations. At a meeting of international experts on pancreatic precursor lesions held in 2003, it was agreed that a consensus classification of IPMN subtypes should be established to enable a more detailed analysis of the clinicopathological significance of the variations. Based on our experience and on information from the literature, we selected representative histological examples of IPMNs and defined a consensus nomenclature and criteria for classifying variants as distinctive IPMN subtypes including gastric type, intestinal type, pancreatobiliary type, and oncocytic type. These definitions can be used for further analyses of the clinicopathological significance of the variations of IPMN.

Real‐time identification of liver cancers by using indocyanine green fluorescent imaging

We have often encountered difficulties in identifying small liver cancers during surgery. Fluorescent imaging using indocyanine green (ICG) has the potential to detect liver cancers through the visualization of the disordered biliary excretion of ICG in cancer tissues and noncancerous liver tissues compressed by the tumor.

Clinicopathological features and prognosis of mucinous cystic neoplasm with ovarian-type stroma: a multi-institutional study of the Japan pancreas society.

Objective: The aim of this study was to elucidate the clinicopathological features and prognosis of mucinous cystic neoplasms (MCNs). Materials and Methods: We performed a multi-institutional, retrospective study on a collected series of patients with MCN pathologically defined by ovarian-type stroma. Clinicopathological features and prognosis were investigated. Result: Mucinous cystic neoplasm was confirmed in 156 cases, including 129 adenomas (82.7%) and 21 noninvasive (13.4%) and 6 invasive carcinomas (3.9%). Patients with MCN were exclusively women (98.1%) with the mean age of 48.1 years. All but 1 MCN were in the pancreatic body/tail region with a mean size of 65.3 mm. Communication between the cyst and the pancreatic duct was found in 18.1%. The 3-, 5-, and 10-year survival rates were 97.6%, 96.6%, and 96.6%, respectively. A significant difference in the survival rates was observed between adenomas and carcinomas and between minimally invasive carcinomas and invasive carcinomas. Cyst diameter and presence of mural nodule were predictive of malignant MCN. Conclusions: Mucinous cystic neoplasm is a rare but distinctive pancreatic cystic neoplasm with a favorable overall prognosis. All MCNs should be resected to prevent malignant changes but can be observed for an appropriate time when the lesion is small without the presence of mural nodules.

Multicenter study of serous cystic neoplasm of the Japan pancreas society.

Objectives There have been only a few reports on follow-up results of serous cystic neoplasm (SCN) of the pancreas. The frequency of malignancy and surgical indication of SCN are not determined yet. Methods In this multi-institutional study of the Japan Pancreas Society, a total of 172 patients with SCN were enrolled. The mean follow-up period was 4.5 years. Surgical resection was performed in 90 patients, whereas the remaining 82 were simply observed. Results Of all patients, 20% were symptomatic. The tumor was located in the pancreatic head (39%), body (35%), and tail (22%). The mean diameter of the tumor was 4.1 cm. None of the patients showed distant or lymph node metastasis except for liver metastasis found in 2 patients (1.2%). No patient died during the follow-up. The preoperative diagnosis did not correctly identify SCN in 57 (63%) of 90 resected cases. A honeycomb appearance, which is one of the most characteristic findings of SCN, could be diagnosed better by endoscopic ultrasonography than by other imaging diagnostic modalities. Conclusions Surgical resection should be considered only when clear distinction from other surgical diseases is difficult, when symptoms or mass effects are present, and when the tumor size is large.

Pancreatic adenocarcinoma: update on the surgical pathology of carcinomas of ductal origin and PanINs

Pancreatic cancer is the fourth leading cause of cancer death in the US. Most pancreatic cancers are infiltrating ductal adenocarcinomas. The careful application of well-defined morphologic criteria can be used to differentiate between infiltrating ductal adenocarcinoma and reactive glands. While most pancreatic cancers are ductal adenocarcinomas, a number of histologically defined variants have been described. These are important to recognize because they have distinct clinical pathologic features. Pancreatic intraepithelial neoplasia (PanIN) is the presumed precursor lesion to infiltrating ductal adenocarcinoma, and PanIN lesions can mimic infiltrating cancer.

Diagnosing Pancreatic Cancer Using Methylation Specific PCR Analysis

The aim of this study was to determine the utility of detecting methylated ppENK and p16 in pancreatic juice by methylation specific PCR as a marker of pancreatic adenocarcinoma. Pancreatic juice samples were collected either intraoperatively, from 92 patients undergoing pancreaticoduodenectomy for benign (n = 20) and malignant periampullary disease (n = 72) or endoscopically (by duodenal aspiration after secretin infusion), from 13 patients undergoing investigation for pancreatic disease. Methylated ppENK was detected in the pancreatic juice of 30 (66.7%) of 45 patients with pancreatic ductal adenocarcinoma, in 4 (44.4%) of 9 patients with intraductal papillary-mucinous adenocarcinoma, and in 7 (41.2%) of 17 patients with other periampullary carcinomas, using methylation specific PCR. Methylated p16 was detected in a lower percentage of these patients (11.1%, 11.1% and 23.5%, respectively). In contrast, methylated ppENK and p16 were not detected in 21 patients with non-malignant disease including 12 patients with chronic pancreatitis. Methylated ppENK was detected in 30 of 33 (90.9%) primary pancreatic adenocarcinoma and methylated p16 was in 6/33 (18.2%). Despite the absence of ppENK and p16 methylation in normal pancreas, methylated ppENK and p16 was present in the duodenum of 90.5% and 28.6%, respectively of patients without cancer. Further, methylated ppENK and p16 was seen in 88.9% and 11.1%, respectively of pancreatic juice samples obtained by duodenal aspiration from patients without cancer. We conclude that since ppENK and p16 are not normally methylated in pancreatic secretions, detection of methylated ppENK and p16 in pure pancreatic juice obtained by direct cannulation of the pancreatic duct to avoid duodenal secretions may suggest the presence of pancreatic adenocarcinoma Key Words: Pancreatic juice, Methylation, ppENK, Pancreatic adenocarcinoma

Less aggressive features of colorectal cancer with liver metastases showing macroscopic intrabiliary extension

We have previously reported the frequent occurrence of bile duct invasion by liver metastases from colorectal cancer. We found that patients with macroscopic intrabiliary cancer growth survive longer after hepatectomy than those without this feature. In the present study, we analyzed the clinicopathological features of primary colorectal cancer showing macroscopic intrabiliary extension of liver metastases. We reviewed 217 patients who underwent initial hepatic resection for colorectal liver metastasis between 1992 and 1998, and analyzed the corresponding primary colorectal cancers clinicopathologically. Microscopic bile duct invasion was found in 89 of 217 cases (40.6%) and, of these cases, 23 (10.6%) had macroscopic intrabiliary extension. Histological sections of the corresponding primary colorectal cancer were available in eight (group A) of these 23 cases. These were compared with 20 cases, selected randomly, of colorectal cancer that did not show bile duct invasion and were diagnosed as liver metastases. These patients underwent hepatectomy during the same period as group A and were used as a control (group B). The histology of the primary tumors revealed well‐differentiated adenocarcinoma in 100% of group A and in 25% of group B. The average maximum diameter of the primary tumor was 5.32 cm in group A and 3.61 cm in group B. Venous invasion was detected in 25% of group A and in 90% of group B (P < 0.01), while the incidences of lymphatic vessel invasion and lymph node metastases were similar between the groups. These data suggest that macroscopic intrabiliary extension could be a good indicator of a unique subgroup of colorectal cancers showing less aggressive features even though they develop liver metastases. Careful histological evaluation is important even for metastatic tumors.

Abdominal Pain in Patients with Resectable Pancreatic Cancer with Reference to Clinicopathologic Findings

Abdominal and/or back pain is one of the most common symptoms in patients with pancreatic cancer. However, the cause of the pain and the clinicopathologic features of patients with pain have not been fully elucidated. We retrospectively determined the factors related to preoperative abdominal and/or back pain in 95 patients with resectable pancreatic cancer. Pancreatic tumor size, invasion of the intrapancreatic nerves, invasion of the anterior pancreatic capsule, and lymph node metastasis were determined to be variables related to the pain. Pancreatic tumor size, invasion of anterior pancreatic capsule, and lymph node metastasis were also variables significantly correlating to pain intensity. Survival also correlated with pain intensity: the median survival periods were 29 months in patients without pain, 19 months in those with mild pain, and 9 months in those with severe pain who required analgesics. Larger pancreatic tumors, invasion of the intrapancreatic nerves, and invasion of the anterior pancreatic capsule may cause abdominal and/or back pain in patients with resectable pancreatic cancer. This study also suggests clinical implications of the pain intensity as a prognostic factor in patients with resectable pancreatic cancer.

‘Ovarian‐type’ stroma of pancreatic mucinous cystic tumor expresses smooth muscle phenotype

‘Ovarian‐type’ stroma of nine mucinous cystic tumors (MCT) of the pancreas, six cystadenomas and three cystadenocarcinomas, were studied immunohistochemically. Most of the spindle cells of the ‘ovarian‐type’ stroma were positive for smooth muscle actin and desmin, but were negative for S‐100 cytochrome p450 19 and CD34. Similar stroma with smooth muscle differentiation has been described in hepatobillary MCT. Embryologic similarity between the pancreas and liver suggests a closely related origin of MCT In both organs.

Claudin-18 Is an Early-Stage Marker of Pancreatic Carcinogenesis:

Pancreatic ductal neoplasms exhibit gastric epithelium–like characteristics. In this study, we evaluated the expression of claudin-18 (CLDN18), a gastric epithelium–associated claudin, in pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and pancreatic ductal adenocarcinomas (PDACs) using immunohistochemistry. We observed a high level of expression of CLDN18 in PanINs (31/32, 97%), IPMNs (61/65, 95%), and MCNs (4/5, 80%) using ordinary tissue section analysis. Furthermore, we observed a high level of CLDN18 expression in PDACs (109/156, 70%) using tissue microarray analysis. However, the normal pancreatic duct or the ductal metaplasia of the acinar cells was not immunoreactive. Comparative analysis of CLDN18 and phenotypic markers in IPMNs revealed that simultaneous expression of CLDN18 and intestinal markers frequently occurred, even in intestinal-type IPMNs. CLDN18 variant 2 mRNA was expressed and was similarly upregulated by phorbol 12–myristate 13–acetate (PMA) treatment in pancreatic cancer cell lines and in a gastric cancer cell line. An inhibitor of pan-PKC (GF109203X) completely suppressed this upregulation in pancreatic cancer cells. These results indicate that CLDN18, a marker for the early carcinogenetic process, is commonly expressed in precursor lesions of PDAC. Activation of the PKC pathway might be involved in CLDN18 expression associated with pancreatic carcinogenesis.