Hitoshi Ura

Multicentric development of pancreatic intraductal carcinoma through atypical papillary hyperplasia

We report a case of multiple intraductal carcinomas of the pancreas associated with diffuse atypical papillary hyperplasia. A 67-year-old Japanese man with a complaint of epigastric pain was examined by endoscopic retrograde pancreatography, which demonstrated multiple dilated branches of the pancreatic duct in the body and tail of the pancreas. Histologic examination on the resected pancreas showed diffuse atypical papillary hyperplasia in multiple dilated ducts associated with multiple intraductal carcinomas. Histologic features are described and multicentric carcinogenesis through atypical papillary hyperplasia is discussed.

Solitary true cyst of the pancreas in two adults: analysis of cyst fluid and review of the literature

Solitary true cyst of the pancreas in adults is extremely rare. We report two adult cases of solitary true cyst of the pancreas. In a 53-yr-old woman there was discovered, incidentally, a unilocular cyst of 7.0 × 6.5 cm in size in the tail of the pancreas that was noted on abdominal US and CT scan. A 16-yr-old boy presented with abdominal pain, and an abdominal US and CT scan revealed a 6.5 cm cystic mass located in the tail of the pancreas. Both patients underwent distal pancreatectomy. Histologically, the cyst was lined with flattened cuboidal and squamous epithelium without morphological alterations. Analysis of the cyst fluid revealed high CA 19-9 (>100,000 U/L) and Span-1 levels (>60,000 U/L) in both cases. Immunohistochemically, the lining epithelial cells of true cyst were positive for CA 19-9 staining. The clinicopathological features of solitary true cyst of the pancreas in adults are briefly reviewed.

Cytotoxicity of Simvastatin to Pancreatic Adenocarcinoma Cells Containing Mutant ras Gene

Simvastatin (SV), a 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor, inhibits the synthesis of mevalonic acid. The dose‐dependent (0.1–100 μg/ml) cytotoxicity of SV towards human (MIAPaCa‐2, Panc‐1, HPC‐1, HPC‐3, HPC‐4, PK‐1, PK‐9) and hamster (T2) pancreatic carcinoma cell lines was determined by MTT assay. At up to 20 μg/ml of SV, the effect was reversible and was restored by 60 μg/ml mevalonic acid. Point mutation of Ki‐ras at codon 12 in each cell line was detected by means of the modified polymerase chain reaction. The concentration of SV necessary to achieve 50% cytotoxicity was about 10 μg/ml, and at this concentration of SV, DNA synthesis assayed in terms of [3H]thymidine uptake, isoprenylation of p21ras examined by Western blotting and cell progression from G1 to S phase of the cell cycle analyzed by flow cytometry were all inhibited. Isoprenylation inhibitors of p21ras, such as SV, are expected to be useful for the treatment of pancreatic cancer.

α-Fetoprotein-producing adenocarcinoma of the pancreas presenting focal hepatoid differentiation

SummaryWe report a rare case of pancreatic carcinoma producing α-fetoprotein (AFP), showing focal hepatoid differentiation in metastatic lymph nodes. A 65-yr-old female was admitted because of abdominal pain. The serum AFP was measured at 16,170 ng/mL. Radiological examinations revealed a mass measuring 6 cm in diameter in the body and tail of the pancreas. A right supraclavicular lymphadenopathy was found and biopsied. Light microscopy showed a tumor consisting of a portion of a hepatoid area and well-differentiated adenocarcinoma, which was suggestive of a hepatoid adenocarcinoma. Immunohistochemical analysis showed that the tumor cells expressed AFP, α1-antitrypsin (AT) and albumin. Although the pathological diagnosis of the primary pancreatic tumor was not obtained, this appears to be the first case of hepatoid adenocarcinoma of the pancreas.

Selective cytotoxicity of farnesylamine to pancreatic carcinoma cells and Ki-ras–transformed fibroblasts

Farnesyl protein transferase (FPTase) catalyses the post‐translational modification of proteins by a farnesyl pyrophosphate. One of the substrates of this enzyme is p21ras, the product of the ras oncogene. We examined whether farnesylamine, one of the FPTase inhibitors (FTI), is selectively cytotoxic in pancreatic carcinoma cells and Ki‐ras–transformed fibroblasts. Furthermore, we investigated whether the cytotoxicity of farnesylamine is caused by the induction of apoptosis in these cells. Using the FPTase assay, we found that farnesylamine inhibited FPTase in vitro. Immunoprecipitation showed that farnesylamine inhibited farnesylation of p21ras in vivo. In addition, 24 and 5 μM farnesylamine were required to achieve 50% cytotoxicity in pancreatic carcinoma cells containing activated Ki‐ras and Ki‐ras–transformed NIH/3T3 cells, respectively. The parental NIH/3T3 cells were resistant to the cytotoxic effect of farnesylamine at concentrations less than 100 μM. After incubation with farnesylamine, DNA fragmentation was observed in both pancreatic carcinoma cells and Ki‐ras–transformed fibroblasts at cytotoxic doses of this compound but not in NIH/3T3 cells. These results indicate that the mechanism of cell death induced by farnesylamine is apoptosis, and this apoptosis occurred specifically in pancreatic carcinoma cells containing mutated Ki‐ras and the Ki‐ras–transformed cells. Because raf is downstream of ras (p21ras) in the ras–raf–mitogen‐activated protein kinase signaling pathway, we used c‐raf‐1–transformed fibroblasts, which proved to be resistant to apoptosis induced by farnesylamine. This supports the theory that inhibition of ras signaling may be related to the induction of apoptosis. These data further suggest that farnesylamine could be useful as a chemotherapeutic agent in cancers that very frequently contain a Ki‐ras oncogene mutation, e.g., pancreatic cancer. Mol. Carcinog. 21:93–99, 1998.

Association between anomalous pancreaticobiliary ductal union and adenomyomatosis of the gall‐bladder

A frequent association of biliary tract carcinoma and anomalous pancreaticobiliary ductal union (APBD) is well recognized, especially gall‐bladder carcinoma in undilated type APBD. However, little is known about the presence and incidence of adenomyomatosis (AMT) of the gall‐bladder, a presumed premalignant lesion, in patients with APBD. This retrospective study was conducted to elucidate the clinical features and incidence of AMT in APBD patients with relation to undilated type and dilated type APBD. We reviewed the clinicopathological records of 30 patients with APBD (28 women and two men) encountered during the past 10 years. Among them, 22 patients underwent cholecystectomy and the resected specimens were subjected to histopathological examinations. Eleven cases of APBD patients were undilated type and 11 cases were dilated type. Adenomyomatosis was found in six (55%) of 11 undilated type and one (9%) of 11 dilated type, and fundal type was predominantly observed in six (86%) of seven AMT. An overall incidence of AMT in APBD patients was 32%. An undilated type of APBD is frequently associated with AMT and we believe, therefore, that clinicians should be aware of a possible coexistence of APBD and AMT.

Splenic hamartoma associated with thrombocytopenia

A case of splenic hamartoma associated with thrombocytopenia is reported. A 70-year-old man was referred to our hospital because of carcinoma of the body of the pancreas. Hematological examination disclosed thrombocytopenia and elevated serum CA19-9 and Span-1 levels. In addition to typical findings of pancreatic carcinoma, a solid mass was observed in the spleen by imaging procedures. On ultrasonography, the splenic mass was well demarcated and slightly hypoechoic. Computed tomography demonstrated a homogeneous low-density mass 5 cm in diameter. On T1- and T2-weighted magnetic resonance images, the splenic mass was demonstrated as low intensity and high intensity, respectively. On selective angiography, the tumor was hypervascular. Distal pancreatectomy plus splenectomy was performed. Microscopically, the splenic tumor consisted of red pulp tissue and was diagnosed as splenic hamartoma.

α-Fetoprotein producing mucin-producing carcinoma of the pancreas: A case report with immunohistochemical study and lectin-affinity profile

a -Fetoprote in (AFP) is a fetal serum protein produced mainly in the fetal live r, yolk sac and, in small amounts, in the fetal gastrointe stinal tract (1). After birth, AFP rapidly disappe ars and is not detected in the serum of healthy persons. However, AFP often reappears in the serum of patients with live r cancer, germ-cell tumors such as yolk sac tumor, and some other malignancie s (2, 3). Along with live r cancer, cancers of the digestive organs are reported to produce AFP. However, pancreatic cancer with elevated serum AFP is rare (4 ± 11) . Mucin-producing tumor (MPT) of the pancreas has recently been increasingly recognize d as a clinical entity that is characte rized by unique clinicopathologic feature s distinct from those of a commono pancreatic ductal cell carcinoma (12± 14) . Dilation of the main pancreatic duct (MPD) and/or branch ducts with ® lling defects of mucin demonstrable by endoscopic retrograde pancreatography (ERP), as well as excretion of mucin through the patulous ori® ce of an enlarge d papilla of Vater, are diagnostic features of MPT, and this disease has a favorable prognosis following pancreatectomy. These feature s are attribute d to the excessive secretion of mucin by the tumor cells and, histopathologica lly, tumors consisted, for the most part, of intraductal papillary carcinoma and adenoma in the MPT and/or large branch ducts (13, 14) . Recently, we experienced a patient with mucinproducing carcinoma of the pancreas who had a high leve l of serum AFP. Mucin-producing carcinoma of the pancreas is seldom reported as an AFP-producing cancer. We reported a case of AFP-producing, mucin-producing carcinoma of the pancreas and used a immunohistochemical approach to determine the AFP-producing site in the resected specimen. In addition to these clinicopathologic characteristics, the bioche mical prope rty of AFP in the patient’ s serum, lectin-af® nity analysis, was also investigated. The literature of the pancreatic ductal cell carcinoma producing AFP is reviewed.

Proliferative potential and K-ras mutation in epithelial hyperplasia of the gallbladder in patients with anomalous pancreaticobiliary ductal union

BACKGROUND Recent studies have shown that anomalous pancreaticobiliary ductal union (APBD) is an important risk factor for the development of gallbladder carcinoma. Epithelial hyperplasia of the gallbladder is one of the characteristic changes, but it is not clear whether epithelial hyperplasia is a premalignant lesion that could lead to cancer in APBD patients. METHODS Twenty-four APBD patients were classified into two types: patients with bile duct dilation (dilated type) (n 13) and patients without dilation (undilated type) (n = 11). Resected gallbladders obtained from APBD patients and control patients without APBD were examined histologically and with immunohistochemical techniques for the detection of p53 and Ki-67 (as a cell proliferation marker). K-ras mutations were examined using polymerase chain reaction-restriction fragment length polymorphism and direct DNA sequence analysis. The patients were also classified, according to extent of epithelial hyperplasia, as having high grade or low grade hyperplasia. RESULTS Fifteen (63%) of 24 APBD patients had epithelial hyperplasia of the gallbladder, whereas no patients without APBD exhibited this lesion. The incidence of epithelial hyperplasia was significantly higher in the gallbladders of undilated-type APBD patients (91%) than in those of dilated-type patients (38%) (P < 0.01). Three of 24 APBD patients (13%) had gallbladder carcinoma, and 2 of the 3 gallbladder carcinomas (67%) were accompanied by diffuse epithelial hyperplasia of the gallbladder. Among 21 nonneoplastic gallbladders, diffuse epithelial hyperplasia was observed in all (100%) of the undilated-type APBD and in 4 (33%) of 12 dilated-type APBD (P < 0.001). High grade hyperplasia was observed in 7 of 11 patients (64%) with undilated-type APBD and 2 of 13 patients (15%) with dilated-type APBD (P < 0.05). The incidence of high grade hyperplasia increased with age among patients older than 35 years. Ki-67 labeling index (LI) was significantly higher in hyperplastic mucosa than in control gallbladder mucosa. High grade hyperplasia had a significantly higher Ki-67 LI than low grade hyperplasia (P < 0.001). Two (22%) of 9 high grade hyperplasia cases had K-ras mutations, whereas none of 6 low grade hyperplasia cases had. The types of K-ras mutations in codon 12 were GTT (Val) and GAT (Asp) in each case of hyperplasia; these were identical to those of concomitant carcinomas. Neither hyperplastic nor normal mucosa exhibited p53 overexpression. CONCLUSIONS The results of this study suggest that hyperplasia of the gallbladder mucosa in APBD patients is an early change that, because of the increased proliferative activity and presence of K-ras mutations, could be considered a premalignant lesion of the gallbladder. An increased cell population of epithelial hyperplasia may predispose the mucosa to mutational events, resulting in an increased risk for the development of gallbladder carcinoma in APBD patients.

Multifocal serous cystadenoma of the pancreas. A case report and review of the literature.

SummarySerous cystadenoma of the pancreas is usually unifocal; multifocal tumors are rare. We report a case of multifocal serous cystadenoma of the pancreas in a 48-yr-old female complaining of general malaise. Serum tumor markers, such as CA 19-9, DUPAN-2, and Span-1, were elevated. Abdominal ultrasound (US) and computed tomography (CT) scans revealed two distinct cystic masses in the head and body of the pancreas, respectively. The patient underwent total pancreatectomy. The resected pancreas contained two discrete cystic masses in the head and body; no solid components were observed. Microscopically, the inner surfaces of the cysts were evenly lined by a single layer of low cuboidal or significantly attenuated epithelial cells containing clear cytoplasm and abundant glycogen without other morphological alterations. The histogenesis of serous cystadenoma is not clear; multicentric tumors may be helpful in understanding histogenesis.