Immunohistochemical analysis and in situ hybridization of cyclooxygenase-2 expression in intraductal papillary-mucinous tumors of the pancreas

BACKGROUND: The objective of this study was to investigate COX-2 expression in intraductal papillary-mucinous tumor of the pancreas (IPMT) using immunohistochemical staining (IH) and in situ hybridization (ISH). METHODS: Immunohistochemical staining of COX-2 was performed using samples from 42 patients with IPMT (hyperplasia, 10; adenoma, 13; noninvasive adenocarcinoma, 13; invasive adenocarcinoma, 6) and from 10 patients with ductal pancreatic adenocarcinoma, 10 with chronic pancreatitis, and 6 normal pancreatic tissues as controls. Also, COX-2 was determined in five patients with IPMT noninvasive adenocarcinoma, in whom all histologic types, hyperplasia, adenoma, and adenocarcinoma were observed in the same excised specimens. Furthermore, IH of proliferating cell nuclear antigen (PCNA) was performed, and the labeling index (LI) was calculated to investigate the correlation with COX-2. To confirm COX-2 mRNA, the authors performed ISH in 20 IPMT patients. RESULTS: COX-2 was positive in 0%, 0%, and 10% of pancreatic duct epithelial cells from normal pancreatic tissue, chronic pancreatitis, and IPMT hyperplasia, respectively. Whereas it was positive in 69%, 77%, 67%, and 80% of IPMT adenoma, IPMT noninvasive adenocarcinoma, IPMT invasive adenocarcinoma, and ductal pancreatic adenocarcinoma, respectively, showing significant differences between IPMT hyperplasia and IPMT adenoma or IPMT adenocarcinoma (noninvasive and invasive adenocarcinoma). In the same patient, COX-2 was negative in the hyperplasia region but positive in adenoma and adenocarcinoma regions, showing results reflecting the progression of the disease. In the COX-2 negative group, PCNA-LI was 19.2 +/- 17.9%, and 33.5 +/- 15.7% in the positive group, a significant difference. On ISH, COX-2 mRNA was expressed in three of four and seven of eight COX-2 positive patients with IPMT adenoma and adenocarcinoma, respectively. CONCLUSIONS: COX-2 was highly expressed in adenoma and adenocarcinoma in IPMT, showing a relation to the histologic grade of IPMT.     

Expression of cripto in Human Pancreatic Tumors

The expression of cripto gene product was examined immunohistochemically in 45 surgically resected pancreatic tumors, including 32 invasive ductal carcinomas, 4 intraductal papillary adenocarcinomas, 4 intraductal papillary adenomas, 2 mucinous cystadenomas, 2 islet cell tumors, and one solid and cystic tumor, and compared with that in 32 areas of accompanying chronic pancreatitis present in the cases of invasive ductal carcinomas and 5 non-tumorous areas of pancreas without pancreatitis. All pancreatic ductal tumors including adenomas and carcinomas showed positive staining with no difference in terms of staining intensity among intraductal tumors and invasive carcinomas with or without mucin hypersecretion. Islet cell tumors were positively stained but the solid and cystic tumor was negative. Duct epithelial cells and acinar cells were negative but islet cells were positive in the pancreas tissues without pancreatitis. Cells arranged in duct-like structures in areas of accompanying chronic pancreatitis were positively stained. The results suggest that cripto expression might be associated with a growth advantage of tumor cells and also with differentiation to form duct-like structures.     

Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers.

PURPOSE: Patients with pancreatic ductal adenocarcinoma usually present with advanced-stage disease and a dismal prognosis. One effective strategy likely to improve the morbidity and mortality from pancreatic cancer would be the identification of accurate, noninvasive diagnostic markers that would enable earlier diagnosis of symptomatic patients and earlier detection of cancer in asymptomatic individuals at high risk for developing pancreatic cancer. In this study, we evaluated serum macrophage inhibitory cytokine-1 (MIC-1) as a marker of pancreatic cancer. EXPERIMENTAL DESIGN: MIC-1 expression in primary pancreatic cancers, intraductal papillary mucinous neoplasms, and pancreatic cancer cell lines was determined using the National Center for Biotechnology Information serial analysis of gene expression database, oligonucleotide microarrays analysis, in situ hybridization, and immunohistochemistry. Serum MIC-1 levels were determined by ELISA in 80 patients with pancreatic adenocarcinomas, in 30 patients with ampullary and cholangiocellular carcinomas, in 42 patients with benign pancreatic tumors, in 76 patients with chronic pancreatitis, and in 97 healthy control subjects. The diagnostic performance of serum MIC-1 as a marker of pancreatic cancer was compared with that of serum CA19-9. RESULTS: Oligonucleotide microarray and serial analysis of gene expression data demonstrated that MIC-1 RNA levels were higher in primary pancreatic cancers, intraductal papillary mucinous neoplasms, and pancreatic cancer cell lines than in nonneoplastic pancreatic ductal epithelium. MIC-1 expression was localized to the malignant epithelium in pancreatic adenocarcinomas by in situ hybridization. MIC-1 protein was expressed in 14 of 16 primary pancreatic adenocarcinomas (88%) by immunohistochemistry and was also expressed in some pancreata affected by pancreatitis but not in normal pancreas. Serum MIC-1 levels were significantly higher in patients with pancreatic ductal adenocarcinoma (mean +/- SD, 2428 +/- 2324 pg/ml) and in patients with ampullary and cholangiocellular carcinomas (2123 +/- 2387 pg/ml) than in those with benign pancreatic neoplasms (940 +/- 469 pg/ml), chronic pancreatitis (1364 +/- 1236 pg/ml), or in healthy controls (546 +/- 262 pg/ml). An elevated serum MIC-1 (defined as 2 SD above the mean for healthy controls) performed as well as CA19-9 (area under the receiver operating characteristic curve, 0.81 and 0.77, respectively), and the combination of MIC-1 and CA19-9 significantly improved diagnostic accuracy (P < 0.05; area under the receiver operating characteristic curve, 0.87; sensitivity, 70%; specificity, 85%). CONCLUSION: Serum MIC-1 measurement can aid in the diagnosis of pancreatic adenocarcinoma.     

Pancreatic juice cytology in the diagnosis of intraductal papillary mucinous neoplasm of the pancreas: significance of sampling by peroral pancreatoscopy

BACKGROUND: The examination of pancreatic juice cytology could hypothetically contribute to the establishment of a definite diagnosis of malignant intraductal papillary mucinous neoplasm of the pancreas (IPMN), but to the authors' knowledge, its significance has not been confirmed to date. The current study was conducted to assess the diagnostic value of pancreatic juice cytology in IPMN and to examine the usefulness of peroral pancreatoscopy (POPS) in sampling pancreatic juice. METHODS: The study subjects were comprised of 103 patients with IPMN who underwent surgical resection of pancreatic tumors (adenoma in 29 patients, borderline in 17 patients, carcinoma in situ in 25 patients, and invasive carcinoma in 32 patients). Pancreatic juice was collected with a catheter in 71 patients and by POPS in 32 patients. Patients with pancreatic carcinoma (n = 81) and chronic pancreatitis (n = 76) also were investigated. RESULTS: The cytologic diagnosis was found to be of nondiagnostic value in only one patient with an IPMN, whereas it was of no diagnostic value in 14 of the patients with pancreatic carcinoma (17.3%), a difference that was statically significant (P < 0.001). The location of the IPMN (either in the pancreas or the pancreatic ducts) was not found to significantly affect the diagnostic value of the test. The sensitivity for IPMN was 62.2% when pancreatic juice was collected by POPS, and was 38.2% when it was collected using a catheter. In the case of pancreatic carcinoma, the sensitivity of pancreatic juice cytology was found to be 25.4%, which was significantly lower than that for IPMN when the pancreatic juice was collected by POPS (P < 0.001). CONCLUSIONS: Pancreatic juice cytology was found to have better diagnostic value in the patients with IPMNs compared with those with pancreatic carcinoma. POPS was found to be useful for the collection of pancreatic juice.     

Clinical significance of magnetic resonance cholangiopancreatography for the diagnosis of cystic tumor of the pancreas compared with endoscopic retrograde cholangiopancreatography and computed tomography.

BACKGROUND: Cystic tumor of the pancreas has been investigated by a variety of imaging techniques. Magnetic resonance cholangiopancreatography (MRCP) is being widely used as a non-invasive diagnostic modality for investigation of the biliary tree and pancreatic duct system. The purpose of this study was to compare MRCP images with those of endoscopic retrograde cholangiopancreatography (ERCP) and computed tomography (CT) in order to clarify the diagnostic efficacy of MRCP for cystic tumor of the pancreas. METHODS: We retrospectively studied 15 patients with cystic tumor of the pancreas that had been surgically resected and histopathologically confirmed. There were five cases of intraductal papillary adenocarcinoma, five of intraductal papillary adenoma, two of serous cyst adenoma, two of retention cyst associated with invasive ductal adenocarcinoma and one of solid cystic tumor. RESULTS: In all cases MRCP correctly identified the main pancreatic duct (MPD) and showed the entire cystic tumor and the communication between the tumor and the MPD. On the other hand, the detection rate by ERCP of the cystic tumor and the communication between the cystic tumor and the MPD was only 60%. Although the detection rates by CT for the septum and solid components inside the cystic tumor were 100 and 90.0%, respectively, those of MRCP for each were 58.3 and 20.0%. CONCLUSION: MRCP is capable of providing diagnostic information superior to ERCP for the diagnosis of cystic tumor of the pancreas. Although MRCP may provide complementary information about the whole lesion of interest, the characteristic internal features of cystic tumor of the pancrease should be carefully diagnosed in combination with CT.     

DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease

Molecular markers of pancreatic neoplasia could aid in the evaluation of visible pancreatic lesions and indicate neoplasia invisible to imaging. We evaluated methylation-specific PCR (MSP) assays that detect aberrantly methylated DNA for their use as markers of pancreatic neoplasia. Methylation analysis was done on pancreatic juice collected endoscopically or surgically from 155 individuals with suspected pancreatic disease: 56 patients had pancreatic ductal adenocarcinoma, 17 had intraductal papillary mucinous neoplasms, 26 had symptomatic chronic pancreatitis, 12 controls lacked evidence of pancreatic disease, and 44 were asymptomatic individuals at increased risk of developing familial pancreatic cancer undergoing screening for pancreatic neoplasia. Pancreatic juice DNA was analyzed for promoter methylation using conventional MSP assays for 17 genes. For six genes, pancreatic juice methylation was quantified using real-time quantitative MSP (QMSP; Cyclin D2, FOXE1, NPTX2, ppENK, p16, and TFPI2). Quantifying pancreatic juice methylation using QMSP with a cutoff of >1% methylated DNA could better predict pancreatic cancer than detecting methylation using conventional MSP. In the endoscopic group, 9 of 11 patients with pancreatic cancer, but none of 64 individuals without neoplasia had > or =1% methylation for two or more of the best five QMSP assays (82% sensitivity and 100% specificity; P < 0.0001). The prevalence of pancreatic juice methylation in patients with chronic pancreatitis was less than in patients with pancreatic cancer but higher than in controls and similar to high-risk individuals. The detection and quantification of aberrantly methylated DNA in pancreatic juice is a promising approach to the diagnosis of pancreatic cancer.     

Adenocarcinoma and concomitant intraductal papillary adenoma in the pancreas.

A 72-year-old man was found to have a 12 mm solid lesion in the pancreatic tail and an 8 mm cystic lesion in the body of the pancreas by computed tomography carried out during a routine follow-up study of his adult-onset diabetes mellitus. A distal pancreatectomy was performed revealing the pancreas to have an adenocarcinoma in the tail and a conglomeration of intraductal papillary adenoma in the body. A review of the literature disclosed similar coexistences of cystadenoma and carcinoma in four patients, none of which was documented with preoperative imaging features such as we had.     

Preoperative diagnosis of intraductal papillary-mucinous tumors of the pancreas with attention to telomerase activity

BACKGROUND: It has been reported that, in patients with intraductal papillary-mucinous tumor (IPMT) of the pancreas, it is difficult to distinguish adenoma from carcinoma preoperatively. Recently, it has also been reported that telomerase activity was detected in many patients with carcinoma. In this report, the authors used the method of telomerase repeat amplification protocol (TRAP) assay on pancreatic juice retrieved by endoscopic retrograde pancreatic juice aspiration (ERP aspiration). METHODS: Pancreatic juice was collected from 28 patients (13 with intraductal carcinoma and 15 with adenoma) using ERP aspiration at either Hiroshima University Hospital or its affiliated hospitals. Two samples of pancreatic juice were collected from each patient. Each sample was examined by cytology for Papanicolaou staining and TRAP assay. RESULTS: Four of 13 IPMT patients (31%) with intraductal carcinoma were diagnosed accurately by cytology. Seven of nine patients who were classified with benign tumors by cytologic assessment had tumors that expressed telomerase activity. Overall, 11 of 13 IPMT patients (85%) with intraductal carcinoma were diagnosed correctly by cytology associated with telomerase activity. All of the IPMT patients with adenoma were classified with benign tumors by cytologic assessment, and telomerase activity was not expressed. CONCLUSIONS: In this study, the authors found that telomerase activity was expressed with a comparatively high probability in intraductal carcinoma. These results suggest that telomerase activity in pancreatic juices may be used as an adjunct to cytologic diagnosis and may aid further in distinguishing between benign IPMT and malignant IPMT of the pancreas preoperatively.     

De novo expression of the Muc2 gene in pancreas carcinoma cells is triggered by promoter demethylation.

It has been established that mucin-producing variants of different subtypes of pancreatic carcinomas, including the intraductal papillary and ductal mucinous tumors, have usually a more favorable prognosis. Intraductal papillary and ductal mucinous tumors have also been shown to ectopically express the intestinal mucin gene MUC2. The mechanism of the de novo expression of this gene in tumors may have potential implications for the modulation of its behavior. We studied, therefore, the mechanism of the de novo expression of MUC2 in pancreas carcinoma cells in vitro. The MUC2 gene promoter is methylated in the nonexpressing pancreatic cell line PANC-1 and is not methylated in the expressing cell line BxPC-3. The promoter is silenced by methylation as shown by reporter expression assays. De novo expression of MUC2 in PANC-1 cells is triggered by treating the cells with a pharmacological inhibitor of DNA methylation (5-aza-2'-deoxycytidine). There was no decrease or loss of expression of the methyltransferase DNMT1 in the MUC2-producing cells. These data show that the de novo expression of the MUC2 gene in pancreas carcinoma cells is associated with promoter demethylation. They warrant further investigations on the relationship between MUC2 promoter demethylation in pancreatic cancer and the prognosis of carcinoma patients.     

ErbB2 oncogene antibodies differentiate between the normal and diseased pancreas, and between chronic pancreatitis and pancreatic cancer

Histological differentiation between chronic pancreatitis and pancreatic cancer, especially in biopsy material, remains challenging and the frequent association of 'secondary' chronic pancreatitis (due to ductal obstruction) with pancreatic cancer causes additional diagnostic problems. Our study, using anti-ErbB2 antibodies from Santa Cruz and Dako in tissues from the normal pancreas, chronic pancreatitis and pancreatic cancer showed that these antibodies discriminate between primary chronic pancreatitis and 'secondary' chronic pancreatitis due to pancreatic cancer. Tissues from 28 pancreatic cancer patients, 15 chronic pancreatitis patients and 12 organ donors or early autopsy cases were subjected to immunohistochemical studies using polyclonal ErbB2 antibodies from Santa Cruz and Dako. The Santa Cruz antibody immunoreacted with islet cells in all tissues from the normal pancreas and pancreatic cancer but not in any chronic pancreatitis specimen. The Dako antibody showed a membrane staining of ductal and ductular cells only in chronic pancreatitis cases but in none of the normal or cancer specimens. Moreover, in chronic pancreatitis cases, ductular cells were stained with the Santa Cruz antibody only in the severe form, but not in the mild or moderate form of the disease. The utilized ErbB2 antibodies discriminate between the normal pancreas, chronic pancreatitis and pancreatic cancer. Hence, these antibodies seem to present an additional useful aid in the surgical pathology of pancreatic diseases.     

Fine-needle aspiration cytology of mucinous tumors of the pancreas

BACKGROUND: Tumors of the pancreas associated with extracellular mucin production include mucin-producing ductal adenocarcinoma, mucinous cystic neoplasm (MCN), and intraductal papillary mucinous tumor (IPMT). Fine-needle aspiration (FNA) is used as an adjunct to radiologic analysis for the preoperative categorization of these tumors. The current study was designed to identify distinctive cytomorphologic features that would be useful for the categorization of mucinous tumors of the pancreas. METHODS: The authors evaluated Papanicolaou smears and Diff-Quik-stained smears of specimens obtained by computed tomography-guided and endoscopic ultrasound-guided FNA of the pancreas in 51 cases of mucinous tumors. In the 19 cases in which the patients underwent surgical excision after FNA, the cytologic features were compared with the histopathologic findings. The remaining cases were categorized as one of the three above-mentioned types of mucinous tumors on the basis of cytomorphologic features identified as indicative of subtype among the cases in which a cytologic-histologic correlation was performed. RESULTS: Among the 19 cases with cytologic-histologic correlation, 2 cases of serous cystadenoma and 2 cases of gastrointestinal duplication cyst were misdiagnosed on cytologic analysis as low-grade MCN. Among the remaining 15 cases, cytologic features by histologic diagnosis were as follows: ductal adenocarcinoma (n = 4): moderate to high cellularity, mild to moderate background mucin, three-dimensional clusters, high nuclear cytoplasmic ratios, and mild to moderate nuclear membrane irregularities; low-grade MCN (n = 5): mild to moderate cellularity, abundant background mucin, small clusters, and flat sheets of relatively bland glandular cells; mucinous cystadenocarcinoma (n = 1): similar to ductal adenocarcinoma but more abundant background mucin; and IPMT (n = 5): moderate to high cellularity, abundant background mucin, and prominent papillary arrangement of tall columnar cells with mild to moderate nuclear atypia. The remaining 32 cases were categorized based on cytology alone as adenocarcinoma with mucin production (n = 24) and low-grade MCN (n = 8). CONCLUSIONS: IPMT and low-grade MCN possess distinctive cytologic features that can be used to diagnose them correctly and distinguish them from one another and from other cystic tumors. Duplication cysts closely mimic low-grade MCN, which can lead to false-positive diagnoses. Because of substantial overlap in cytologic features, mucin-producing ductal adenocarcinoma was unable to be distinguished from mucinous cystadenocarcinoma cytologically.     

Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juice

The aim of this study was to determine the utility of detecting methylated ppENK and pi6 in pancreatic juice by methylation specific PCR as a marker of pancreatic adeno-carcinoma. 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 pi6 was detected in a lower percentage of these patients (11.1%, 11.1% and 23.5%, respectively). In contrast, methylated ppENK and pi6 were not detected in 20 patients with non-malignant periampullary disease including 12 patients with chronic pancreatitis. Methylated ppENK was detected in 30 of 33 (90.9%) primary pancreatic adenocarcinoma and methylated pi6 was in 6/33 (1 8.2%). Despite the absence of ppENKand pi6 methylation in normal pancreas, methylated ppENK and pi6 was present in the duodenum of 90.5% and 28.6%, respectively of patients without cancer. Further, methylated ppENK and pi6 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 pi6 are not normally methylated in pancreatic secretions, detection of methylated ppENK and pi6 in pure pancreatic juice obtained by direct cannulation of the pancreatic duct to avoid duodenal secretions may suggest the presence of pancreatic adenocarcinoma     

p53 Mutations in Two Patients with Intraductal Papillary Adenoma of the Pancreas

There has been no report on p53 gene mutation in benign human pancreatic intraductal tumors. We examined pancreatic juice and tissue specimens from two patients with intraductal papillary adenoma of the pancreas by polymerase chain reaction-single-strand conformation polymorphism analysis and direct sequencing and found point mutations of p53 gene resulting in amino acid substitutions in exons 6 and 8. Thus, p53 gene mutation may be an early event in the neoplastic process of some pancreatic intraductal tumors and may play an important role in tumorigenesis.     

胰腺导管内乳头状黏液肿瘤的CT诊断

目的 探讨胰腺导管内乳头状黏液肿瘤的CT和MRI表现,分析其诊断要点。方法 回顾性分析12例经手术切除和病理学证实的胰腺导管内乳头状黏液肿瘤的临床、CT和MRI资料。结果 （1）分支胰管型7例,均位于胰头和钩突,CT和MRI主要表现为分叶状或葡萄串样囊性病变,其间可见分隔,增强后囊性区域无强化,囊壁和分隔可强化。（2）混合型5例,4例为胰头或钩突分支胰管扩张合并主胰管扩张;1例同时伴有胰体分支胰管扩张,扩张的主胰管直径为4～7mm。（3）该病多发于老年人,临床主要表现为腹痛和胰腺炎。结论 胰腺导管内乳头状黏液肿瘤有相对特征性的影像学表现,CT和MRI对其诊断有重要价值。     

Main-duct intraductal papillary mucinous adenoma of the pancreas with a large mural nodule

Intraductal papillary mucinous neoplasm (IPMN) is an increasingly recognized entity representing a spectrum of benign and malignant neoplasms of the pancreas. Preoperative distinction between benign and malignant IPMNs remains difficult. Reported predictive factors for malignancy are size of the main pancreatic duct, cystic neoplasm, and mural nodule. We report herein the case of a 50-year-old woman in whom a large mural nodule (30 mm) in the dilated main pancreatic duct (16 mm in diameter) was detected by ultrasonography, computed tomography, and endoscopic retrograde cholangiopancreatography. Because the large mural nodule and dilatation of the main pancreatic duct were also detected by endoscopic ultrasonography (EUS) and intraductal ultrasonography (IDUS), the main-duct IPMN was considered to have malignant potential. Thus, pylorus-preserving pancreaticoduodenectomy with lymph node dissection was performed. The resected intraductal tumor appeared polypoid with a broad stalk and comprised a proliferation of mucin-containing columnar epithelial cells with papillary structures without malignant features. The final diagnosis was intraductal papillary mucinous adenoma of the pancreas. The size of the mural nodule and the final diagnosis in this case suggest that the introduction of a novel molecular-biological approach might be necessary for the precise preoperative diagnosis of main-duct IPMN and adequate surgical treatment.     

Differential roles of alterations of p53, p16, and SMAD4 expression in the progression of intraductal papillary-mucinous tumors of the pancreas

Intraductal papillary-mucinous tumors (IPMTs) of the pancreas are characterized by dilated pancreatic ducts and ductules that are lined by tall columnar mucin-producing neoplastic epithelial cells. IPMTs have been suggested to be distinct neoplasms with a less aggressive phenotype than that of conventional ductal adenocarcinomas of the pancreas. Molecular mechanisms underlying tumorigenesis of IPMTs are beginning to be characterized. Allelic losses have frequently been detected at 9p, 17p, and 18q, suggesting that inactivation of tumor suppressor genes at these loci play a role in tumorigenesis of IPMTs. Using immunohistochemistry, we analyzed 38 IPMTs, including 9 hyperplasia, 16 adenoma, and 13 carcinoma tissues, for expression of p53, Ki-67, p16, and SMAD4. Nuclear p53 expression was observed in 5 (38%) of 13 carcinoma tissues but not in hyperplasia or adenoma tissues. Partial loss of p16 expression was observed in 9 (56%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively. Partial loss of p16 expression was observed even in adenomas with mild atypia. Partial loss of SMAD4 expression was observed in 6 (38%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively. The SMAD4 negative index was significantly higher in invasive carcinomas than in non-invasive carcinomas. Our results suggest that loss of p16 is an early event and p53 alteration is a late event during the progression of IPMTs. SMAD4 inactivation appears to be an early event but also involved in invasive tumor growth. Our results suggest that these alterations accumulate during the progression of IPMTs, reflecting results of analysis of allelic losses that showed a stepwise accumulation of genetic changes during progression.     

Intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND/AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are neoplasms of the pancreatic duct epithelium characterized by intraductal papillary growth and thick mucin secretion. Quantities of mucin fill the main and/or branches of pancreatic ducts and cause ductal dilatation. This review encompasses IPMNs, including symptoms, diagnosis, management, and prognosis. METHODS: A Pubmed database search was performed. All abstracts were reviewed and all articles in which cases of IPMNs could be identified were further scrutinized. Further references were extracted by cross-referencing. RESULTS: Only one-third of all patients are symptomatic. According to the site of involvement, IPMNs are classified into three types: main duct type, branch duct type, and combined type. Most branch type IPMNs are benign, while the other two types are frequently malignant. The presence of large mural nodules increases the possibility of malignancy in all types. Presence of a large branch type IPMN and marked dilatation of the main duct indicate the existence of adenoma at least. Synchronous or metachronous malignancies may be developed in various organs. Endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography, and intraductal ultrasonography clearly demonstrate ductal dilatation and mural nodules, while magnetic resonance pancreatography best visualizes the entire outline of IPMNs. CONCLUSIONS: Prognosis is excellent after complete resection of benign and non-invasive malignant IPMNs. The extent of pancreatic resection and the intraoperative management of resection margins remain controversial. Total pancreatectomy should be reserved for patients with resectable but extensive IPMNs involving the whole pancreas; its benefits, however, must be balanced against operative and postoperative risks. Regular monitoring for disease recurrence is important after surgery.     

Fas (CD95/APO-1) and Fas ligand expression in normal pancreas and pancreatic tumors. Implications for immune privilege and immune escape

BACKGROUND: Fas (CD95/APO-1) and Fas ligand (FasL) play key roles in immunologic homeostasis and immune privilege and may regulate normal cell turnover. Earlier studies had suggested that FasL-positive pancreatic carcinoma cell lines can induce apoptosis in T cells, thereby evading host immune surveillance. In the current study the authors have characterized the expression of Fas and FasL in the normal pancreas and in pancreatic neoplasia. METHODS: Pancreatic resection specimens with ductal-type adenocarcinoma or intraductal dysplasia (n = 41), nonductal pancreatic neoplasms (n = 5), and chronic pancreatitis (n = 4) were examined for Fas and FasL expression by immunohistochemistry. The results in invasive adenocarcinoma were compared to those for benign ducts and intraductal dysplasia, and correlated with clinicopathologic features of the tumors and with patient survival. RESULTS: Fas was expressed in the normal pancreatic ducts and in intraductal dysplasia in a mixed membrane/cytoplasmic pattern. In all cases of invasive ductal-type adenocarcinoma, membranous Fas could not be detected; cytoplasmic Fas staining was reduced or completely lost. Loss of Fas expression in pancreatic ductal-type adenocarcinomas significantly correlated with poorer differentiation and extrapancreatic spread of the tumors and was associated with a shorter overall survival. FasL expression was present in the normal pancreatic ducts as well as in islet cells and was maintained in all pancreatic tumors. CONCLUSIONS: These results implicate the Fas pathway in the regulation of physiologic cell turnover and immune privilege in the normal pancreas and indicate that loss of Fas expression is correlated with malignant transformation and biologic aggressiveness in pancreatic adenocarcinomas. This may represent a mechanism by which pancreatic tumor cells become resistant to apoptosis and escape immune surveillance in vivo.