The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma.

Intraductal papillary-mucinous neoplasms of the pancreas seem to comprise various types, whose relationship to ductal adenocarcinoma and mucinous noncystic carcinoma is unclear. We analyzed the mucin immunophenotype and the DPC4/SMAD4 expression in intraductal papillary-mucinous neoplasms, ductal carcinomas, and mucinous noncystic carcinomas to define features that may help to distinguish between different types of intraductal papillary-mucinous neoplasms and to establish their relationship to other neoplasms of the exocrine pancreas. A series of 51 intraductal papillary-mucinous neoplasms, three mucinous noncystic carcinomas (two with an intraductal component), and 35 ductal adenocarcinomas were screened immunohistochemically for their expression of MUC1, MUC2, MUC5, and DPC4/SMAD4. All intraductal papillary-mucinous neoplasms and mucinous noncystic carcinomas were positive for MUC5. Thirty-two intraductal papillary-mucinous neoplasms and three mucinous noncystic carcinomas abundantly expressed MUC2 but no (or only little) MUC1. The remaining intraductal papillary-mucinous neoplasms showed either mainly MUC1 expression or focal MUC1 and MUC2 expression. All ductal carcinomas but one were MUC2 negative and MUC1 and MUC5 positive. DPC4 was not expressed in two intraductal papillary-mucinous neoplasms that showed a tubular invasion pattern. Twelve of 23 ductal adenocarcinomas were DPC4 positive. Intraductal papillary-mucinous neoplasms can be divided into at least three different mucin immunophenotypes. The first and largest group of intraductal papillary-mucinous neoplasms and mucinous noncystic carcinomas is MUC1 negative and MUC2 positive and probably forms one tumor entity. The second group seems to be related to ductal carcinoma because of its MUC1 positivity in the absence or very weak MUC2 staining. The third group shows focal MUC1/MUC2 expression and is characterized by oncocytic histology.     

Pancreatic intraepithelial neoplasia in chronic pancreatitis]

Chronic pancreatitis causes destruction of the pancreatic gland which leads to tissue fibrosis and regenerative hyperplasia of the epithelium of pancreatic ducts and ductules. Morphological studies revealed distinct proliferative lesions in the pancreatic ducts and ductules adjacent to infiltrating adenocarcinomas of the pancreas. A stepwise progression from mild to severe dysplasia in these hyperplastic lesions has been reported. These lesions, called Pancreatic Intraepithelial Neoplasia (PanIN), harbour a number of well-characterised genetic alterations. Therefore, PanINs were defined as true clonal neoplastic lesions with minimal to moderate and severe cytological and architectural atypia. Almost all of the genetic alterations that have been identified in pancreatic adenocarcinomas have also been identified in PanIN lesions. The prevalence of genetic changes increases as the degree of cytological atypia and histological dysplasia in the PanIN lesions increases. However, some genetic abnormalities have also been found in chronic pancreatitis and normal pancreas, e. g. K-ras mutations. However, due to intratumorous heterogeneity of the genetic changes, further studies are necessary to search for more specific and homogeneous expressed molecular markers. A better understanding of the molecular genetic changes occurring during neoplastic progression in the pancreas will form the basis for future strategies of early tumour detection and improved therapy.     

The mucin profile of noninvasive and invasive mucinous cystic neoplasms of the pancreas

Recently, it was shown that ductal adenocarcinomas and intraductal papillary-mucinous neoplasms of the pancreas differ in their expression of the mucin markers MUC1 and MUC2 while both tumors express MUC5AC. It is not known whether mucinous cystic neoplasms of the pancreas have their own mucin profile. To clarify this issue, 22 mucinous cystic neoplasms were examined immunohistologically for their expression of MUC1, MUC2, MUC5AC, and MUC6 and also for the protein products of the tumor suppressor genes p53 and DPC4 and the mismatch repair genes. Noninvasive mucinous cystic neoplasms, regardless of the degree of cellular atypia, were all positive for MUC5AC and negative for MUC1, with the exception of the cyst-lining epithelium of a single case with eosinophilic cytology (case no. 16). Only in cases with an invasive component was MUC1 expression observed. MUC2 expression was restricted to goblet cells scattered within the epithelium of the mucinous cystic neoplasms and was often accompanied by endocrine cells, a further indication of intestinal differentiation. DPC4 expression was maintained in all tumors, except for three invasive carcinomas. p53 nuclear reactivity was found in one borderline tumor and four invasive mucinous cystic carcinomas. The results suggest that the epithelium of noninvasive mucinous cystic neoplasms does not differ in its expression of MUC5AC from ductal adenocarcinomas, intraductal papillary-mucinous neoplasms, and metaplastic pancreatic duct epithelium. The fact that noninvasive mucinous cystic neoplasms lack MUC1 expression (except for an eosinophilic variant) but express it when they become invasive might be used as a marker indicating the step of progression from noninvasiveness to invasiveness.     

Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model

Pancreatic duct glands (PDGs) have been hypothesized to give rise to pancreatic intraepithelial neoplasia (PanIN). Treatment with the glucagon-like peptide (GLP)-1 analog, exendin-4, for 12 weeks induced the expansion of PDGs with mucinous metaplasia and columnar cell atypia resembling low-grade PanIN in rats. In the pancreata of Pdx1-Cre; LSL-Kras(G12D) mice, exendin-4 led to acceleration of the disruption of exocrine architecture and chronic pancreatitis with mucinous metaplasia and increased formation of murine PanIN lesions. PDGs and PanIN lesions in rodent and human pancreata express the GLP-1 receptor. Exendin-4 induced proproliferative signaling pathways in human pancreatic duct cells, cAMP-protein kinase A and mitogen-activated protein kinase phosphorylation of cAMP-responsive element-binding protein, and increased cyclin D1 expression. These GLP-1 effects were more pronounced in the presence of an activating mutation of Kras and were inhibited by metformin. These data reveal that GLP-1 mimetic therapy may induce focal proliferation in the exocrine pancreas and, in the context of exocrine dysplasia, may accelerate formation of neoplastic PanIN lesions and exacerbate chronic pancreatitis.     

Multicentric pancreatic intraepithelial neoplasias (PanINs) presenting with the clinical features of chronic pancreatitis

A 46-year-old woman was readmitted to our hospital in August 2005 because of severe abdominal pain and nausea. Computed tomography demonstrated a huge cystic lesion in the retroperitoneal space behind the hepatoduodenal ligament and lesser peritoneal cavity. Endoscopic retrograde pancreatography revealed communication between the dilated main pancreatic duct and a pseudocyst. The condition was preoperatively diagnosed as chronic pancreatitis associated with a pseudocyst or an intraductal papillary mucinous neoplasm without mucin hypersecretion. The patient underwent a distal pancreatectomy with splenectomy. The pathologic diagnosis was multicentric pancreatic intraepithelial neoplasia (PanIN), and histological examination revealed a positive surgical margin around the remnant pancreas. Four months after the surgery, the patient underwent a total pancreatectomy. Macroscopic observation revealed diffuse fibrosis of the pancreatic parenchyma compatible with chronic pancreatitis. Histological examination revealed a constellation of noninvasive intraductal neoplasias with high-grade atypia, diffusely distributed in the small pancreatic ducts of the resected pancreas. Localized fibrosis and cystic dilation of the small ducts were detected in a lobule of exocrine glands draining into a ductule involved by PanIN lesions in the head of the pancreas. In summary, multicentric PanIN lesions are associated with lobular atrophy of the pancreatic parenchyma and chronic pancreatitis-like changes that follow. Total pancreatectomy may be recommended for patients with multicentric precursor lesions throughout the entire pancreas.     

Mucinous cystic neoplasm of the pancreas or intraductal papillary-mucinous tumour of the pancreas.

OBJECTIVE: To compare clinicopathological findings in patients with mucinous cystic neoplasms and intraductal papillary-mucinous tumours. DESIGN: Retrospective study. SETTING: University department of surgery, Japan. SUBJECTS: 21 patients with mucinous cystic neoplasms (group 1) and 48 with intraductal papillary-mucinous tumours (group 2). RESULTS: The mean age was younger in group 1 (53(3.4) years) than in group 2 (65(1) years, p < 0.0001). The male:female ratio was smaller in group 1 than in group 2, being 0.17 (3/18) and 1.4 (28/20), respectively, (p = 0.0007). The main sites of the lesions were also significantly different: in group 1 four (19%) were located in the head and 17 in the body or tail, while 32 (67%) were in the head of the pancreas and 16 (33%) in the body or tail in group 2 (p = 0.0007). A unique endoscopic finding, excretion of mucin from the patulous orifice of the papilla, was present in two (9%) of the 21 mucinous cystic tumours and in 21 (45%) of the 47 intraductal papillary-mucinous tumours examined (p = 0.006). Metachronous or synchronous malignant diseases were found in the pancreas or other organs in one (5%) of the 21 patients with mucinous cystic neoplasm and in 13 (27%) of the 48 with intraductal papillary-mucinous tumours (p = 0.03). The three- and five-year survival rates of 11 patients with mucinous cystadenocarcinoma were 45% and 27%, while those of 15 with intraductal papillary-mucinous carcinoma were 85% and 42%. CONCLUSIONS: These findings suggest that mucinous cystic neoplasm and intraductal papillary-mucinous tumours are different clinicopathological entities. Aggressive surgery with peripancreatic lymph node dissection is recommended, particularly for mucinous cystadenocarcinoma, and postoperative follow-up with attention given to the presence of other malignancy is necessary as well as to local recurrence and haematogenous spread.     

Intraductal papillary-mucinous tumor of the pancreas: assessing the grade of malignancy from natural history

Intraductal papillary-mucinous tumor of the pancreas is a spectrum of conditions ranging from benign to malignant, and very few papers have referred to the natural history of this disease. In this communication the indicators of malignancy were examined from a viewpoint of natural history. Follow-up computed tomographies (CTs) more than 6 months after the diagnosis were reviewed in 17 Japanese patients with intraductal papillary-mucinous tumor of the pancreas. They were divided into two groups by the presence or absence of morphological progressive changes by the follow-up CTs, and the clinicopathological features were compared between the two groups to examine possible malignant indicators. The 17 patients consisted of seven patients in the no-change group and ten in the progressive group. The distribution of the patients was not different with regard to age; gender; or presence or absence of pancreatitis, diabetes mellitus, or unique findings of the ampulla of Vater between the two groups. The dilatation of the main pancreatic duct (> or = 3 mm) was more frequent in the progressive group: (eight of ten patients; 80%) than in the no-change group (two of seven patients; 29%) (P = 0.03). Six (86%) of the seven tumors in the no-change group were located in the branch duct, whereas five (50%) of the ten in the progressive group were situated in the main pancreatic duct. Histopathologic diagnoses of the resected specimens of the four in the no-change group examined were intraductal papillary-mucinous adenoma in three and adenoma with moderate dysplasia in one, whereas the diagnoses in the six in the progressive group examined were adenoma in two, adenoma with moderate dysplasia in two, and carcinoma (invasive) in two. The patients with intraductal papillary-mucinous tumor of the pancreas with a dilatation of the main pancreatic duct at the time of diagnosis should be followed up more carefully than those without dilatation. Once progressive morphological changes are detected by the follow-up CTs surgical resection should be considered because of possible malignancy.     

Familial fibrocystic pancreatic atrophy with endocrine cell hyperplasia and pancreatic carcinoma

Understanding the pathology of familial pancreatic carcinoma may provide important insights into pancreatic tumorigenesis. We now describe in detail the pancreatic pathology of an autosomal dominant pancreatic carcinoma kindred with distinct clinical, genetic, and pathologic manifestations differing from all other reported forms of sporadic or familial pancreatic neoplasia. Affected individuals develop a prodrome of diabetes mellitus, pancreatic exocrine insufficiency, and characteristic pancreatic imaging abnormalities. Eleven family members have undergone total pancreatectomy, revealing a unique and characteristic fibrocystic, lobulocentric pancreatic atrophy. This was patchy to diffuse in distribution and was invariably associated with a nesidioblastosis-like endocrine cell hyperplasia. All but one resected pancreas demonstrated glandular epithelial dysplasia: 10 had low-grade dysplasia (pancreatic intraductal neoplasia grade II of III or PanIN II) and seven also had high-grade dysplasia (pancreatic intraductal neoplasia grade III of III or PanIN III). Dysplasia was multifocal in small-to medium-sized duct-like structures within areas of acinar atrophy, microcystic change, and mucinous hyperplasia. Two pancreata had carcinomas of multiple and unusual histologic subtypes, including small cell undifferentiated carcinoma and giant cell anaplastic carcinoma. The findings in this kindred yield important information on a distinctive and previously unrecognized pancreatic cancer precursor. Recognition of this entity may help identify additional kindreds and perhaps the underlying genetic defect. As is the case for other familial cancers, the as yet unknown specific genetic defect may have wider implications for pancreatic cancer in general.     

p16(INK4a) alterations in chronic pancreatitis-indicator for high-risk lesions for pancreatic cancer

BACKGROUND. p16(INK4a) alterations are considered to be an early event in pancreatic tumorigenesis and have been described in duct lesions adjacent to pancreatic cancers. This study evaluates whether duct lesions in chronic pancreatitis tissues of patients without pancreatic cancer also harbor genetic alterations in the p16(INK4a) tumor-suppressor gene, and thus represent high-risk precursors for pancreatic cancer. METHODS. Tissues were obtained from 20 pancreatic specimens taken from patients operated on for histologically verified chronic pancreatitis. Pancreatic intraductal neoplasias (PanIN) were identified in hematoxylin-and-eosin-stained slides. p16 protein expression was investigated immunohistochemically in all specimens. DNA from PanIN and non-PanIN tissue was analyzed genetically for p16(INK4a) mutations by single-strand conformation variation analysis and direct sequencing of the encoding region. Additionally, p16(INK4a) promoter methylation was analyzed by a methylation specific polymerase test. RESULTS. PanIN-1a lesions were identified in 10 of the 20 chronic pancreatitis specimens. Four of these 10 PanIN specimens (40%), but none of the 20 non-PanIN tissues, revealed a loss of p16 expression in immunohistochemistry. The mutational analysis of the p16(INK4a) gene showed 1 known polymorphism (c.442G > A; A148T) but no mutations. Two of the 10 specimens with PanIN revealed an inactivating hypermethylation of the p16(INK4a) promoter. CONCLUSIONS. This study shows for the first time that p16(INK4a) alterations can be observed in a considerable number of PanIN1 in chronic pancreatitis tissues not associated with pancreatic cancer. Therefore, p16(INK4a) alterations, especially promoter methylation, might indicate high-risk precursors in chronic pancreatitis that might progress to cancer.     

Systematic review of the utility of 18-FDG PET in the preoperative evaluation of IPMNs and cystic lesions of the pancreas

BackgroundThe aim of this systematic review is to assess the role of 18-fluorodeoxyglucose positron emission tomography in the preoperative evaluation of intraductal papillary mucinous neoplasms and cystic lesions of the pancreas.MethodsA computerized PubMed search was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify studies evaluating positron emission tomography in the preoperative evaluation of pancreatic cystic lesions.ResultsA total of 14 studies evaluated the role of 18-fluorodeoxyglucose positron emission tomography/positron emission tomography-computed tomography, 9 of which evaluated only intraductal papillary mucinous neoplasms and 5 evaluated all pancreatic cystic lesions, including intraductal papillary mucinous neoplasms. Pooled analysis was carried out for studies evaluating intraductal papillary mucinous neoplasms only and studies evaluating all cystic lesions. Imaging with 18-fluorodeoxyblucose positron emission tomography had a positive predictive value, negative predictive value, sensitivity, specificity, and accuracy of 90%, 91%, 85%, 95%, and 91% in identifying malignancy (defined as either invasive and/or high-grade dysplasia) in intraductal papillary mucinous neoplasms and a positive predictive value, negative predictive value, sensitivity, specificity, and accuracy of 85%, 81%, 79%, 86%, and 88% in identifying malignancy in other cystic lesions. Pooled analysis reported the positive predictive value, negative predictive value, sensitivity, specificity, and accuracy of Sendai consensus guidelines (SCG) criteria as 69%, 69%, 68%, 55%, and 58%. The Fukuoka consensus guidelines (FCG) only had sensitivity, specificity, and accuracy reported as 61%, 52%, and 52%, respectively.ConclusionThe 18-fluorodeoxyblucose positron emission tomography had a high degree of accuracy of detecting malignancy in intraductal papillary mucinous neoplasm and cystic lesion of the pancreas. Comparison of the utility of positron emission tomography with the Fukuoka consensus guidelines and the Sendai consensus guidelines suggest that positron emission tomography is superior to present guidelines in detecting malignant intraductal papillary mucinous neoplasm and cystic lesion of the pancreas. Further studies in larger patient cohorts may be required to corroborate these findings and to determine the place of positron emission tomography in the management of intraductal papillary mucinous neoplasm and cystic lesions of the pancreas.     

Cells of origin of pancreatic neoplasms

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant disease associated with poor prognosis, despite recent medical advances. It is of great importance to understand the initial events and cells of origin of pancreatic cancer to prevent the development and progression of PDAC. There are three distinct precursor lesions that develop into PDAC: pancreatic intraepithelial neoplasms (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms (MCNs). Studies on genetically engineered mouse models have revealed that the initiation and development of these lesions largely depend on genetic alterations. These lesions originate from different populations in the pancreas. PanIN development seems to be the result of the transdifferentiation of acinar cells, whereas IPMNs most likely arise from the progenitor niche of the pancreatic ductal epithelium. Pancreatic carcinogenesis is dependent on various events, including gene alterations, environmental insults, and cell types. However, further studies are needed to fully understand the initial processes of pancreatic cancer.     

Analysis of Pancreatic Cyst Fluid

Pancreatic cysts are extremely common, and are identified in between 2% to 13% on abdominal imaging studies. Most pancreatic cysts are pseudocysts, serous cystic neoplasms, mucinous cystic neoplasms, or intraductal papillary mucinous neoplasms. The management of pancreatic cysts depends on whether a cyst is benign, has malignant potential, or harbors high-grade dysplasia or invasive carcinoma. The diagnosis of pancreatic cysts, and assessment of risk of malignant transformation, incorporates clinical history, computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound, and fine-needle aspiration of cyst fluid. This article reviews the cyst fluid markers that are currently used, as well as promising markers under development.     

Total pancreatectomy: indications, operative technique, and results

The aims of this study were to identify the indications to perform a total pancreatectomy and to evaluate the outcome and quality of life of the patient who underwent this operation. A retrospective analysis of a prospective database, regarding all the patients who underwent total pancreatectomy from January 2006 to June 2009, was carried out. Perioperative and outcome data were analyzed in two different groups: ductal adenocarcinoma (group 1) and non-ductal adenocarcinoma (group 2). Twenty (16.9%) total pancreatectomies out of 118 pancreatic resections were performed. Seven (35.0%) patients were affected by ductal adenocarcinoma (group 1) and the remaining 13 (65.0%) by pancreatic diseases different from ductal adenocarcinoma (group 2) [8 (61.5%) intraductal pancreatic mucinous neoplasms, 2 (15.4%) well-differentiated neuroendocrine carcinomas, 2 (15.4%) pancreatic metastases from renal cell cancer and, finally, 1 (7.7%) chronic pancreatitis]. Eleven patients (55%) underwent primary elective total pancreatectomy; nine (45%) had a completion pancreatectomy previous pancreaticoduodenectomy. Primary elective total pancreatectomy was significantly more frequent in group 2 than in group 1. Early and long-term postoperative results were good without significant difference between the two groups except for the disease-free survival that was significantly better in group 2. The follow-up examinations showed a good control of the apancreatic diabetes and of the exocrine insufficiency without differences between the two groups. In conclusion, currently, total pancreatectomy is a standardized and safe procedure that allows good early and late results. Its indications are increasing because of the more frequent diagnose of pancreatic disease that involved the whole gland as well as intraductal pancreatic mucinous neoplasm, neuroendocrine tumors and pancreatic metastases from renal cell cancer.     

Totale Pankreatektomie

Permanent reduction of morbidity and death in centers for pancreatic surgery has led to a change in the indication for total pancreatectomy from rescue pancreatectomy for complications of pancreatic surgery increasingly to elective surgery, especially in the management of advanced intraductal papillary mucinous neoplasms. We discuss the indication for oncologic total pancreatectomy, rescue pancreatectomy, and removal of the whole pancreas for chronic pancreatitis. Furthermore we describe technical and metabolic aspects following total pancreatectomy.     

The prevalence of pancreatic intraepithelial neoplasia in pancreata with uncommon types of primary neoplasms

Pancreatic ductal adenocarcinoma is thought to develop through a series of genetic events through its purported precursor lesion, pancreatic intraepithelial neoplasia (PanIN). Little, however, is known regarding the role of possible precursor lesions in the development of other primary neoplasms of the pancreas. This study investigated the prevalence of PanIN, as defined by recent consensus statements, in pancreata with uncommon types of primary neoplasms. All pancreata resected at the University of Virginia from June 1, 1991 to March 1, 2005 for neoplasia not diagnosed as conventional ductal adenocarcinoma were reviewed and classified according to the World Health Organization's classification schema for tumors of the exocrine and endocrine pancreas. All slides from these cases were then assessed for PanIN, which was classified according to the criteria of the most recent consensus statement. Three acinar cell carcinomas (ACCs), 18 mucinous cystic neoplasms (MCNs), 24 pancreatic endocrine tumors (PETs), 12 serous cystadenomas (SCs), and 3 solid-pseudopapillary tumors (SPTs) were identified. PanIN was identified in the pancreata of 3 of 3 ACCs, 17 of 18 MCNs, 16 of 24 PETs, 10 of 12 SCs, and 2 of 3 SPTs. The degree of PanIN was noted to trend with patient age. Although the high prevalence of PanIN in pancreata concomitantly harboring certain uncommon neoplasms of the pancreas could signify its role as a precursor lesion for those neoplasms, its high prevalence throughout our series may simply be the result of a coincidental, prevalent finding seen in all pancreata, especially with aging. Because of the ubiquitous nature of PanIN, it should not be used histologically to assist in the diagnosis and subclassification of pancreatic neoplasia.     

An acute necrotic pancreatitis as a complication of cystic pancreatic tumor

The peculiarities of the cystic pancreatic tumor morphogenesis were studied up. Possibility and probability of the anastomosis existence between mucinous cystic tumor and pancreatic duct with its secondary mucinous dilatation were confirmed, causing the complications occurrence, an acute pancreatitis in particular. Selecting the surgical tactic in mucinous cystic tumor it is necessary to take into account the probability of the intraductal malignization foci formation, what precludes application of extended pancreatic resection using adjuvant chemotherapy and the postoperative serological control conduction.     

Strategies for screening for pancreatic adenocarcinoma in high-risk patients: the place of endoscopic ultrasound

Screening high-risk individuals with imaging tests, such endoscopic ultrasound and computed tomography, can lead to the detection and treatment of predominantly asymptomatic premalignant lesions. These pancreatic lesions consist of resectable, mostly branch-type non invasive intraductal papillary mucinous neoplasms. Endoscopic ultrasound features of chronic pancreatitis are highly prevalent in high-risk individuals and these directly correlate with multifocal lobulocentric parenchymal atrophy due to pancreatic intraepithelial neoplasia. Long-term, multi-prospective studies are needed to determine if screening for early pancreatic adenocarcinoma and timely intervention results in decreased pancreatic cancer incidence and mortality in high-risk individuals.