Tsuneshi Fujii

Natural History of Branch Duct Intraductal Papillary-Mucinous Neoplasms of the Pancreas without Mural Nodules: Long-term Follow-up Results

Background and aim: Although branch duct intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas without mural nodules are frequently observed in asymptomatic subjects, the natural history of these lesions has never been studied. The aim of this study was to elucidate the natural history of branch duct IPMNs without mural nodules. Methods: Eighty-two patients who had no apparent mural nodules on initial examination were selected for follow-up. All subjects underwent examinations by imaging modalities including endoscopic retrograde pancreatography, and were followed-up by regular examinations once or twice a year. Serial changes of the maximum cystic diameter and the appearance of mural nodules were studied during the observation periods ranging from 14 to 148 months (median, 61 months). Results: Nine (11.0%) of 82 patients exhibited obvious progression of cystic dilatation (median, 59 months). Of these nine patients with cystic enlargement, six continued with regular follow-up examinations. Three cases underwent surgical resection, and were pathologically diagnosed as adenoma in two and borderline in one. Four patients (4.9%) showed newly developed mural nodules in dilated branch ducts (median, 105 months). Histological analysis revealed three cases classified as adenoma and one as carcinoma in situ. None of the remaining 69 patients (84.1%) showed any changes in dilated branch ducts (median, 57 months). Conclusions: Most branch duct IPMNs without mural nodules remained unchanged during long-term follow-up. Although follow-up with careful examination is required to detect newly developed mural nodules in dilated branch ducts, branch duct IPMNs without mural nodules can be followed-up without surgery.

Pancreatic ductal adenocarcinomas in long-term follow-up patients with branch duct intraductal papillary mucinous neoplasms.

Objective: Although branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) are slow-growing tumors with a favorable prognosis, the synchronous occurrence of pancreatic ductal adenocarcinomas (PDAs) in patients with BD-IPMNs has been reported. This study was aimed to elucidate the development of PDAs in long-term follow-up patients with BD-IPMNs. Methods: We investigated 89 BD-IPMN patients who had no mural nodules and followed them up conservatively at least 2 years (median follow-up, 64 months; range, 25-158 months). All subjects underwent examinations by imaging modalities including endoscopic retrograde pancreatography. We calculated the standardized incidence ratio (SIR) from the vital statistics compiled by the Ministry of Health, Labor, and Welfare of Japan. Results: Among the 89 patients, 4 cases of PDAs distant from BD-IPMN were observed in 552 patient-years of follow-up (7.2 per 1000 patient-years). The expected number was 0.25, and the SIR of PDAs was 15.8 (95% confidence interval [CI], 4.3-40.4; P = 0.00014). Subgroup analyses showed that the incidence of PDAs was significantly increased in patients 70 years or older (SIR 16.7; 95% CI, 3.4-48.7; P = 0.0008) and in women (SIR 22.5; 95% CI, 2.7-81.1; P = 0.0037). Conclusions: Patients with BD-IPMNs are at a high risk for PDAs. During the follow-up, careful examination is required to detect the development of PDAs in patients with BD-IPMNs.Abbreviations: IPMN - intraductal papillary mucinous neoplasm, PDA - pancreatic ductal adenocarcinoma, ERCP - endoscopic retrograde cholangiopancreatography, MRCP - magnetic resonance cholangiopancreatography, EUS - endoscopic ultrasonography, CT - computed tomography, SIR - standardized incidence ratio

Incidence of Synchronous and Metachronous Pancreatic Carcinoma in 168 Patients with Branch Duct Intraductal Papillary Mucinous Neoplasm

Background/Aims: Although branch duct intraductal papillary mucinous neoplasms of the pancreas (BD-IPMN) are being diagnosed with increasing frequency, the incidence of concomitant pancreatic carcinoma (PC) is not well known. We investigated the incidence and clinical features of synchronous and metachronous PC in patients with BD-IPMN. Methods: We studied 168 BD-IPMN patients diagnosed by various imaging modalities, including endoscopic retrograde pancreatography, between 1990 and 2008. We reviewed the medical records and clinical features in both patients developing and not developing PC. The diagnosis of PC was histologically verified in all patients. Results: PC was observed in 9 (5.4%) of 168 patients. Five were synchronously detected at the time of BD-IPMN diagnosis, whereas four were metachronously identified during the follow-up period. All PCs occurred in regions separate from the BD-IPMN lesion. All PCs represented histologically invasive ductal adenocarcinomas, whereas the BD-IPMN lesion was diagnosed as adenoma. Patients developing PC were significantly older than patients not developing PC (p = 0.017). The diameters of the BD-IPMN lesions and main pancreatic ducts were significantly smaller in patients developing PC than patients not developing PC (p = 0.013 and p < 0.001, respectively). Conclusions: It was not infrequent for PC to occur in the pancreas with BD-IPMN. Particular attention should therefore be paid to the development of PC, even in low-risk BD-IPMN, as well as to changes in BD-IPMN.

Long-term outcomes after endoscopic sphincterotomy versus endoscopic papillary balloon dilation for bile duct stones

OBJECTIVE Endoscopic sphincterotomy (ES) is a well-established standard method for treating common bile duct stones. However, biliary sphincter function is impaired after the treatment, and this may influence the long-term outcomes. In this study, we aimed to compare the long-term outcomes after ES with those after endoscopic papillary balloon dilation (EPBD) because the latter procedure is expected to preserve biliary sphincter function better than ES. DESIGN A prospective follow-up of the original cohort in a previously randomized, controlled trial to compare the early outcomes after ES and EPBD. SETTING Eleven centers, including 6 clinical practices and 5 academic institutions. PATIENTS A total of 282 patients with common bile duct stones were randomly selected to undergo ES (n = 144) or EPBD (n = 138) in the previous study. INTERVENTIONS ES or EPBD. MAIN OUTCOME MEASUREMENTS Complications after ES or EPBD occurring during long-term follow-up. RESULTS The patients were followed up annually after the treatment. The median duration of the follow-up was 6.7 years. Morbidity was observed in 36 (25.0%) and 14 (10.1%) of the patients who underwent ES and EPBD, respectively (P = .0016). Kaplan-Meier analysis revealed a significantly higher incidence of biliary complications in the ES group than in the EPBD group (P = .0011). Multivariate analysis showed that ES, periampullary diverticulum, and in situ gallbladder stones were independent risk factors for stone recurrence. CONCLUSIONS During long-term follow-up, patients who underwent ES had significantly more biliary complications than those who underwent EPBD. The biliary sphincter dysfunction after ES results in additional late complications.

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.

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.

Pancreatic duct obstruction caused by malignant islet cell tumors of the pancreas.

Islet cell tumors of the pancreas represent 1% to 2% of all pancreatic tumors.1 Although diagnosis is highly accurate with imaging modalities such as CT and EUS,2-4 it is difficult to differentiate preoperatively between malignant and benign variants unless metastases and/or invasion of adjacent organs are present.5-7 ERCP continues to play a major role in the diagnosis of pancreatic diseases despite recent advances in and the widespread use of noninvasive diagnostic imaging modalities. There is, however, limited information available about the pancreatograms of islet cell tumors including findings that suggest whether the tumor is benign or malignant.7 Partial obstruction (stenosis) and complete obstruction of the main pancreatic duct are common findings that suggest pancreatic cancer; these occur in most cases of pancreatic malignancy but are unusual with islet cell tumors.8,9 If available, a clinical imaging finding highly suggestive of malignancy of islet cell tumor would be important in the preoperative assessment of patients without apparent metastasis. We encountered 2 cases of malignant islet cell tumors in which complete obstruction of the main pancreatic duct was demonstrated by ERCP.

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.