Bunsei Nobukawa

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.

Pancreatic ductal adenocarcinoma derived from IPMN and pancreatic ductal adenocarcinoma concomitant with IPMN.

Objectives: Pancreatic ductal adenocarcinoma (PDAC) may derive from an intraductal papillary mucinous neoplasm (IPMN) of the pancreas or may develop in the pancreatic duct apart from IPMN. The purpose of this study was to define the clinicopathological features of these 2 entities and compare them with those of ordinary PDAC. Methods: Of 765 patients who had surgical resection for IPMN, 122 were diagnosed as having PDAC derived from IPMN and 31 with PDAC concomitant with IPMN. In addition, 7605 patients with PDAC who were registered in the Japan Pancreas Society pancreatic cancer registry were compared with the above patients. Results: Pancreatic ductal adenocarcinomas derived from IPMN and concomitant with IPMN were significantly smaller, less invasive, and less extensive than ordinary PDAC. The median survival of patients with the 2 conditions was significantly longer than for those with ordinary PDAC when compared overall or when limited to TS2 (2.0 cm < tumor size ≤ 4.0 cm) or TS3 (4.0 cm < tumor size ≤ 6.0 cm) cases. Conclusions: These findings suggest that PDAC concomitant with IPMN and PDAC derived from IPMN may have more favorable biological behaviors or be diagnosed earlier than ordinary PDAC.

Pancreaticobiliary maljunction: pathophysiological and clinical aspects and the impact on biliary carcinogenesis

BackgroundPancreaticobiliary maljunction (PBM) is frequently associated with congenital choledochal cyst (CCBD), but differs in embryonic cause and clinical features. It is thought to develop as a misarrangement of the embryonic connections in the pancreaticobiliary ductal system, with the terminal bile duct joined to one of the ducts of the ventral pancreas. Clinical aspects are intermittent abdominal pain, relapsing acute pancreatitis, jaundice, cholangitis, and gallbladder cancer. In patients with PBM and CCBD, primary bile duct stones, acute cholangitis, and bile duct cancer are considered to result from cholestasis, regurgitation of pancreatic juice, and reciprocal reflux of bile and pancreatic juice. The mixture of bile and pancreatic juice due to recipocal reflex very likely plays an important role in biliary carcinogenesis.Patients and methodsWe reviewed the pathophysiological and clinical aspects and biliary carcinogenesis in 250 PBM patients (169 with benign hepatobiliary and pancreatic disease, 81 with malignancy).ResultsPBM patients show elevated cellular proliferation activity in the gallbladder epithelia. A number of oncogenes and tumor suppressor genes have been identified and implicated in carcinogenesis, particularly the K-ras oncogene and the p53 suppressor gene. Some K-ras mutations do not appear essential for hyperplasia but may be an early event in carcinogenesis. The p53 mutations are involved in carcinogenesis in the biliary epithelium in PBM patients.

Management of branch duct-type intraductal papillary mucinous tumor of the pancreas based on magnetic resonance imaging

Background: We assessed the usefulness of magnetic resonance imaging (MRI) in identifying nonmalignant intraductal papillary mucinous tumors (IPMTs) of the pancreas.Methods: Thirty-three patients with branch duct-type IPMT diagnosed by endoscopic retrograde cholangiopancreatography were prospectively examined with magnetic resonance cholangiopancreatography followed by dynamic gadolinium-enhanced MRI examinations, and patients with no findings suggestive of malignancy, including a solid mass, mural nodules, a main pancreatic duct wider than 5 mm in diameter, and stenosis of the main pancreatic duct, were prospectively followed up with sequential MRI examinations once or twice a year.Results: Twenty-six (79%) patients showed no findings suggestive of malignancy in the initial MRI examination. The diameter (mean ± standard error) of the main pancreatic duct was 3.9 ± 0.7 mm and that of the ectatic branch pancreatic duct was 36.0 ± 9.1 mm. Twenty-three patients were prospectively followed for more than 36 months and 22 of them showed no findings suggestive of malignancy during follow-up periods ranging from 39 to 77 months (mean = 55 months).Conclusion: MRI was useful to identify nonmalignant IPMTs of the branch duct type, and close follow-up observation with serial MRI examinations may be appropriate in the management of such patients.

Different patterns of p16INK4A and p53 protein expressions in intraductal papillary-mucinous neoplasms and pancreatic intraepithelial neoplasia.

Objectives: To examine aberrations and differences of cell cycle regulatory proteins between intraductal papillary-mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasias (PanINs). Methods: In total, 47 IPMN lesions and 42 PanIN lesions were obtained from 26 patients with IPMN and 16 patients who underwent pancreatic surgery for invasive pancreatic ductal cancer or other diseases. They were subjected to conventional hematoxylin-eosin staining and immunostaining for p16INK4A and p53. The percentages of immunohistochemical positivity or negativity were compared between IPMN and PanIN, in accordance with the same histological grade of atypia. The Ki-67 labeling index was also counted in each lesion. Results: Either the loss of p16INK4A expression or the overexpression of p53 was much more frequently observed among PanIN-3 than among carcinoma in situ in IPMN (P = 0.046 and 0.008, respectively). The Ki-67 labeling index was correlated with the histological grades of both PanINs and IPMNs (P = 0.0001 and P = 0.0001, respectively). Conclusions: There are different immunohistochemical expression patterns of p16INK4A and p53 between IPMNs and PanINs. These may substantiate their different genetic progressions to invasive carcinoma.Abbreviations: IPMN - intraductal papillary-mucinous neoplasia, PanIN - pancreatic intraepithelial neoplasia

Precancerous mucosal changes in the gallbladder of patients with occult pancreatobiliary reflux

BACKGROUND Pancreatobiliary reflux can occur even if the pancreaticobiliary junction is normal (occult pancreatobiliary reflux), and it may be associated with gallbladder carcinoma. The aim of the present study was to examine precancerous mucosal changes in the gallbladder from patients with occult pancreatobiliary reflux. METHODS The mucosa of the gallbladder from 13 patients who underwent cholecystectomy was examined histopathologically. These patients had an anatomically normal pancreatobiliary junction and a biliary amylase concentration greater than 10,000 IU/L. The gallbladder of patients without carcinoma was further examined by using immunohistochemical techniques to detect Ki-67, and the results were compared with those from control patients. RESULTS Of the 13 patients, 5 (38%) had gallbladder carcinoma and 8 (62%) did not. Of the 8 patients without carcinoma, 4 (50%) had dysplasia accompanied by hyperplasia, and 2 (25%) had hyperplasia alone of the gallbladder mucosa. The Ki-67 labeling index was significantly higher in hyperplastic and dysplastic mucosa than in control gallbladder mucosa (p < 0.0004). CONCLUSIONS Occult pancreatobiliary reflux could be associated with precancerous mucosal changes in the gallbladder, such as hyperplasia and dysplasia with increased cellular proliferation, and could be a possible risk factor for gallbladder carcinoma.

Intraductal Spread of Pancreatic Cancer

Background: Invasive ductal adenocarcinoma of the pancreas (IDAP) also spreads through the pancreatic ductal tree. The aim of this study was to clarify the clinicopathologic features of IDAP with intraductal spread. Methods: We studied the intraductal spread of IDAP and its correlation with clinicopathologic parameters in a surgical series of 54 patients. The pancreatic ducts were analyzed by confirmation of mural elastic fibers with elastica van Gieson stain. Results: Intraductal spread of carcinoma was identified in 37 patients (69%). Such spread was frequent in well-differentiated IDAP (93%), and the number of intraductal carcinoma foci was correlated with the grade of tumor differentiation (p < 0.001). The large branch ducts were the main route of intraductal spread (64.1%). The proliferation index, evaluated using Ki67, was lower in the intraductal carcinoma components than in the associated infiltrating carcinoma components (p < 0.001). The presence or absence of intraductal spread was not correlated with age, sex, tumor location, tumor size, or stage. IDAP with intraductal spread showed a tendency, although it was not significant (p = 0.092), to be associated with longer survival compared with IDAP without intraductal spread. Conclusion: IDAP, especially of the well-differentiated type, has a tendency to spread intraductally. The difference between the Ki67 labeling indexes in the intraductal and associated infiltrating carcinoma components suggests that these components show different biological behaviors.

Breast carcinoma diverging to aberrant melanocytic differentiation: a case report with histopathologic and loss of heterozygosity analyses.

A case of primary breast cancer showing differentiation to malignant melanoma is reported. To obtain insight into the clonal relationship between the two components of the tumor, polymerase chain reaction-based microsatellite analysis to detect loss of heterozygosity on chromosome arms 1p, 1q, 3q, 4q, 6q, 8p, 9p, 10q, 11q, 13q, 16q, 17p, 17q, and 18q with microdissected tissues of both components was performed in addition to histologic, histochemical, immunohistochemical, and ultrastructural techniques. The tumor consisted of a combination of carcinoma and melanoma with morphologic transition. Metastases in the lymph nodes and thoracic spinal bone marrow showed dual tissue structure. One of the metastatic lung tumors showed melanomatous tissue structure. The abundant pigment in the cells was positive for Fontana-Masson staining and bleached with potassium permanganate. The carcinoma component was positive for epithelial membrane antigen and CA19-9, but the melanoma component was negative. Conversely, the melanoma component was positive for HMB45 and vimentin, but the carcinoma component was negative. Electron microscopic analysis showed premelanosomes and melanosomes in the melanoma component. Microsatellite analysis showed the same genetic alterations with loss of heterozygosity on chromosome arms 1p, 3q, 4q, 6q, 9p, 10q, 11q, 13q, 16q, 17p, and 17q in in situ, invasive, and metastatic foci. We concluded that the carcinoma and melanoma components had arisen from the same clone and that this breast carcinoma might have diverged to aberrant malignant melanoma through multiple genetic alterations in the early period of ductal carcinoma in situ.

Development and Congenital Anomalies of the Pancreas

Understanding how the pancreas develops is essential to understand the pathogenesis of congenital pancreatic anomalies. Recent studies have shown the advantages of investigating the development of frogs, mice, and chickens for understanding early embryonic development of the pancreas and congenital anomalies, such as choledochal cysts, anomalous pancreaticobiliary junction, annular pancreas, and pancreas divisum. These anomalies arise from failure of complete rotation and fusion during embryogenesis. There are many theories in the etiology of congenital anomalies of the pancreas. We review pancreas development in humans and other vertebrates. In addition, we attempt to clarify how developmental failure is related to congenital pancreatic anomalies.

Pancreatic, hepatic, splenic, and mesenteric mucinous cystic neoplasms (MCN) are lumped together as extraovarian MCN

Mucinous cystic neoplasms (MCN) of the pancreas are mucin‐producing cystic tumors with an ovarian‐like stroma (OLS). In the present study MCN were obtained from 27 patients. These MCN were derived from 22 pancreas, three livers, spleen, and mesentery. MCN in various organs have common clinicopathological profiles, being unilocular or multilocular cystic tumors, with a fibrous capsule and lined by mucin‐secreting epithelium associated with an underlying subepithelial OLS. The OLS showed strong positivity for α‐smooth muscle actin (α‐SMA) and vimentin and weak, focal positivity for desmin. Both estrogen receptors and progesterone receptors were expressed in the nuclei of OLS cells. In addition, 20 ovarian MCN and 13 normal ovaries were studied with particular attention to the stroma. The stroma of ovarian MCN was strongly immunopositive for α‐SMA and vimentin and focally positive for desmin, whereas normal ovarian stroma was immunonegative for both α‐SMA and desmin. The OLS of MCN mentioned here was similar to the septa of ovarian MCN but not to ovarian stroma. In conclusion, MCN in various organs should be lumped together as ‘extraovarian’ MCN. The OLS was identified on the basis of myofibroblastic proliferation both in response to neoplastic development and dependent on hormones.