Immunohistochemical study of genetic alterations in intraductal and invasive ductal tumors of the pancreas.

BACKGROUND/AIMS: Multiple genetic alterations are involved in the development of pancreatic neoplasm. Here we investigated the incidence of p53, ras, bcl-2 and c-erbB-2 gene alterations in intraductal papillary-mucinous tumors and invasive ductal adenocarcinoma of the pancreas by immunohistochemical method to identify and analyze their relationship in terms of these genetic alterations. METHODOLOGY: Fifty-four pancreatic lesions, including 18 benign (hyperplasia (3) and intraductal papillary adenoma (15)), and 16 malignant (carcinoma in situ (2) and intraductal papillary adenocarcinoma (14)) cases of intraductal papillary-mucinous tumor; and 20 cases of invasive ductal adenocarcinoma, were immunostained by avidin-biotin peroxidase conjugate method. RESULTS: p53 and rasp21 expressions were significantly greater in malignant intraductal (P < 0.01, P < 0.05) and invasive ductal (P < 0.01, P < 0.01) tumors than in benign intraductal papillary-mucinous tumors; while bcl-2 and c-erbB-2 expressions were significantly greater in invasive ductal adenocarcinoma than both benign (P < 0.01, P < 0.05) and malignant (P < 0.05, P < 0.05) intraductal papillary-mucinous tumors. CONCLUSIONS: Different groups of genetic alterations are involved in different phases of pancreatic tumorigenesis. p53 and ras gene alterations occur at an early stage during the development of intraductal papillary-mucinous tumor, while additional alterations of bcl-2 and c-erbB-2 occur during the development of invasive ductal adenocarcinoma of the pancreas.     

p53 protein expression in intraductal papillary mucinous tumors (IPMT) of the pancreas as an indicator of tumor malignancy

BACKGROUND/AIMS: Intraductal papillary mucinous tumors, as a cystic disease in the pancreas, clinically has a more indolent and favorable course than invasive ductal pancreas carcinoma. However, some cases of intraductal papillary mucinous tumors show invasive and rapid progression like ductal pancreas carcinoma and the prognosis of such patients is sometimes poor. In the current study, we carried out immunohistochemical staining of intraductal papillary mucinous tumor tissues for p53 and investigated whether positive staining indicates tumor malignancies and has a prognostic value for intraductal papillary mucinous tumors. METHODOLOGY: Nineteen (19) patients who underwent pancreatic resection under the diagnosis of intraductal papillary mucinous tumors at the Chiba University Hospital between April 1992 and December 1996 were studied. We performed immunohistochemical staining of p53 as well as of PCNA, Ki-67 and Bcl-2 using their respective antibodies. Pathological findings revealed that 9 cases were intraductal papillary adenoma, 9 were intraductal papillary adenocarcinoma, and one was invasive ductal papillary adenocarcinoma. RESULTS: p53 expression could only be detected in the 1 case with invasive ductal papillary adenocarcinoma. Significant association could not be found between histological features and immunohistochemical staining of PCNA, Ki-67 and Bcl-2. CONCLUSIONS: p53 protein expression could be detected after progression to invasive type of intraductal papillary mucinous tumors. The present results demonstrate that p53 expression might be an indicator of invasive progression in intraductal papillary mucinous tumors, and might represent a surgical indicator of intraductal papillary mucinous tumors.     

Ki-ras codon 12 point mutation and p53 mutation in pancreatic diseases.

BACKGROUND/AIMS: The Ki-ras gene located at 12p, encodes the GTP binding protein involving the signal transduction system and concerns cell proliferation and differentiation. METHODOLOGY: Pancreatic tissues were obtained from 37 patients with various pancreatic diseases. Ki-ras codon 12 point mutation and p53 (exon 5-8) mutation were examined in 3 patients with chronic pancreatitis, 9 mucinous adenoma of the pancreas (2 with mucinous cystadenoma and 7 with intraductal papillary-mucinous adenoma), 22 pancreatic ductal carcinoma, and 3 serous cystadenoma. RESULTS: On usual pancreatic exocrine ductal lesions, Ki-ras point mutation was evident in 0% (0/3) of chronic pancreatitis, in 56% (5/9) of mucinous adenoma, and in 57% (12/21) of ductal carcinoma, the mutation being located in the second letter in 18 and in the 1st letter in 2. One Ki-ras codon 12 positive pancreatic cancer showed Ki-ras codon 12 point mutation in the surrounding pancreas (2nd letter mutation in both areas). p53 mutation was present in 0% (0/1) of chronic pancreatitis, in 0% (0/8) of mucinous adenoma, while it was evident in 29% (6/21) of pancreatic ductal carcinoma, the mutation being situated in exon 5 in 3, in exon 6 in 1, and in exon 7 in 2. In 3 patients with serous cystadenoma, there was no mutation in Ki-ras codon 12 or p53 (exon 5-8). CONCLUSIONS: These findings suggest that Ki-ras point mutation is involved in the early events of pancreatic ductal carcinoma, while p53 mutation is intricated in the late phase of pancreatic ductal carcinogenesis and the histogenesis of serous cystadenoma is different from that of pancreatic exocrine ductal lesions including mucinous adenoma and ductal carcinoma.     

P53 mutation but not p16/MTS1 mutation occurs in intraductal papillary mucinous tumors of the pancreas

BACKGROUND/AIMS: Intraductal papillary mucinous tumors of the pancreas are rare lesions, which typically show a benign clinical course. However, some of these tumors have a malignant nature and grow in an invasive manner. The purpose of the study was to determine the prevalence of p53-, p16/MTS1- and K-ras mutations in benign and malignant intraductal papillary mucinous tumors with intent to value their importance for tumor progression. METHODOLOGY: Thirteen different archival tumor specimens were obtained at the Department of Pathology, University of Ulm. Three cases showed an invasive component of the tumor. Genomic DNA was extracted after laser capture microdissection of tumor cells from paraffin-embedded tissue sections. The corresponding sequences of p53 (exon 5, 6, 7, 8) and p16/MTS1 (exon 2) were amplified by polymerase chain reaction and subjected to single strand conformation polymorphism analysis. Codon 12 of K-ras was analyzed by the enrichment polymerase chain reaction-restriction fragment length polymorphism method. Positive samples were further investigated by sequencing. RESULTS: K-ras mutations occurred in benign and malignant intraductal papillary mucinous tumors (4/13), whereas an alteration of the coding p53 gene sequence could only be detected in the intraductal and invasive component of one malignant tumor. None of the tissue specimens revealed mutations in exon 2 of p16/MTS1. CONCLUSIONS: In contrast to K-ras mutations, alterations in the p53 gene may characterize ductal papillary mucinous carcinomas, which could be of major interest for their early diagnosis. The lack of mutations in the p16/MTS1 gene suggests that other genes may be involved in the formation of intraductal papillary mucinous neoplasias.     

Clinical importance of precursor lesions in the pancreas

Three distinct noninvasive precursor lesions to invasive ductal adenocarcinoma of the pancreas have been described. These include the mucinous cystic neoplasm, intraductal papillary mucinous neoplasm, and pancreatic intraepithelial neoplasia. The early detection and treatment of these lesions can interrupt the progression of a curable noninvasive precursor to an almost uniformly deadly invasive cancer.     

Ras activation in myelodysplastic syndromes: clinical and molecular study of the chronic phase of the disease

We studied N-ras and Ki-ras point mutations respectively at codons 12-13 and 12 in 15 patients with myelodysplastic syndromes (MDS) using the polymerase chain reaction (PCR) method for DNA amplification, and slot blot hybridization to allele specific oligonucleotide (ASO) probes. We analysed peripheral blood and bone marrow samples collected at diagnosis and repeatedly during the chronic phase of the disease to define when the activation occurred and in which haemopoietic cell populations, in order to establish possible relationships between clinical and molecular features. In three cases the N-ras oncogene was mutated at codon 12 in every cell population, both at diagnosis and throughout the chronic phase. Point mutations were not seen at the 12 codon of the Ki-ras oncogene. In patients lacking activated ras oncogene at diagnosis, mutations were not discovered during the entire period of observation. Therefore in our cases disease progression and leukaemic transformation did not correlate with the presence of the activated N-ras. Our data suggest that ras activation occurs early in the pathogenesis of MDS and involves a haemopoietic progenitor with multiple differentiative capacity, without however conferring an apparent proliferative advantage on its progeny.     

Detection of c-Ki-ras gene codon 12 mutations from pancreatic duct brushings in the diagnosis of pancreatic tumours.

Differential diagnosis of pancreatic cancer and chronic pancreatitis is sometimes difficult and cytological examination of brushings or aspirated material collected during endoscopic retrograde cholangiopancreatography (ERCP) remains disappointing. As point mutations in codon 12 of the c-Ki-ras 2 gene are found in most pancreatic adenocarcinoma and not in chronic pancreatitis, this study analysed prospectively the presence of these mutations in brushing samples collected during ERCP in 45 patients (26 males, 19 females) showing a dominant stricture of the main pancreatic duct at pancreatography: 24 with pancreatic adenocarcinoma, 16 with chronic pancreatitis, and five intraductal mucin hypersecreting neoplasms. Twenty of 45 patients presented equivocal ERCP findings that did not permit a definite diagnosis. Ki-ras mutations at codon 12 were detected using a rapid and sensitive method based on polymerase chain reaction mediated restriction fragment length polymorphism analysis and confirmed by direct sequencing of polymerase chain reaction products. Results were compared with those provided by routine brush cytology. A definitive diagnosis was established for each patient. Mutations were detected in 20 of 24 patients with pancreatic adenocarcinoma (83%), but in none of the chronic pancreatitis patients and intraductal mucin hypersecreting neoplasms, irrespective of their location. By contrast, only 13 of 24 pancreatic adenocarcinoma (54%) were detected by conventional cytological examination, which yielded four false negative and seven non-contributive results. Sensitivity, specificity, and accuracy of molecular biological and cytological methods were 83%-76%, 100-83%, and 90%-58%, respectively. Notably the mutations could be detected in six patients with small tumour size (< or = 2 cm). In conclusion, Ki-ras analysis performed on pancreatic brushing samples is an efficient procedure, more accurate than cytology in the diagnosis of pancreatic adenocarcinoma, and highly specific in the differentiation between neoplastic and chronic inflammatory ductal changes, especially in patients showing inconclusive ERCP findings.     

A mucous histochemical and immunohistochemical study of precancerous and neoplastic lesions in the human pancreas

Summary A total of 44 cases of pancreatic lesions, including hyperplasia (six) cases, adenoma (mucinous cystadenomas [eight] and intraductal papillary adenoma [eight]), noninvasive intraductal papillary tumors (five), and invasive ductal carcinomas (17) were investigated possibly to establish a diagnostic marker. We examined the type of mucin secreted and immunoreactivities of antibodies toras-p21 and c-erbB-2 oncogene products. A significant decrease in the amount of mucin was found in invasive lesions, and this was associated with a shift toward production of neutral mucins and especially sialomucins. Hyperplasia and adenoma, in contrast, demonstrated a predominance of neutral mucin. The sulfated mucins found in normal epithelium were only very weakly stained in any of the tumor types. Thirty-three percent of non-invasive intraductal papillary tumors and 88% of invasive ductal adenocarcinomas demonstrated strong binding of theras-p21 antibody. In contrast no obvious differences in expression of c-erbB-2 were evident between the groups. In conclusion, a combined mucin histochemical/immunohistochemical approach may facilitate accurate diagnosis.     

Invasive ductal adenocarcinoma of the pancreas may originate from the larger pancreatic duct: a study of 13 tumors less than 2 cm in diameter

Background/Purpose

We aimed to elucidate the origin/primary site of invasive ductal adenocarcinoma of the pancreas, based on the distribution of intraductal carcinoma components. These components were identified by a mural elastic fiber cuff.

Methods

Thirteen specimens from patients with invasive ductal adenocarcinoma (microscopically, less than 2?cm in diameter) of the pancreas were studied histopathologically. Variants of invasive ductal adenocarcinoma and intraductal papillary-mucinous carcinoma were excluded.

Results

Intraductal carcinoma components of invasive ductal adenocarcinoma were found in 12 of the specimens 13 (92%), and were observed within the tumor mass and/or on its boundary, or outside the tumor mass. Intraductal components were characterized by low papillary projections lacking a fibrovascular core, with/without surrounding tubular structures, or by irregular stratification and pleomorphism of the epithelial cells. Invasive components mostly showed a tubular pattern with desmoplasia. The distribution of the intraductal components in the 12 specimens was as follows: in 9 (75%), they were in both the main pancreatic duct and large branch ducts; and in 3, they were in the smaller branch ducts only.

Conclusions

Invasive ductal adenocarcinomas of the pancreas may originate most frequently from the main pancreatic duct or larger branch ducts, while the smaller ducts are less often the site of cancer origin.

     

The prognosis of intraductal papillary mucinous tumors of the pancreas

BACKGROUND/AIMS: Intraductal papillary mucinous tumors of the pancreas have been recognized as a distinct clinical entity. However, their biological behavior has not been clearly defined. The aim of this study was to examine the prognosis of this tumor, to clarify the biological behavior and determine the most appropriate treatment. METHODOLOGY: Correlations between prognosis of operated cases and histopathologic features were investigated. RESULTS: In 105 patients with characteristic clinical features of intraductal papillary mucinous tumors, the lesions were classified as hyperplasias in 21%, intraductal tumors in 48% and invasive carcinomas in 31%. Minimal invasion was apparent in 25%, lymph node metastasis in 21%, and fistula formation in 31% of the invasive lesions. Non-invasive and minimally invasive intraductal papillary mucinous tumors were essentially free from risk of tumor recurrence. Other invasive intraductal papillary mucinous tumors showed a significantly poor prognosis. CONCLUSIONS: Because of the variation in pathological characteristics, patient outcome and the possibility of differential diagnosis, the treatment might be recommended as follows: the case of hyperplasia can be followed-up with close surveillance. Non-invasive and minimally invasive intraductal papillary mucinous tumors should be operated with function-preserving minimal pancreatectomy. For patients with invasive intraductal papillary mucinous tumors evident with preoperative imaging modalities, radical operations with lymph node dissection might be needed.     

Invasive carcinoma of the pancreas derived from intraductal papillary adenocarcinoma without mucin hypersecretion but with changes in the pancreatic duct on pancreatography

We present a case of invasive carcinoma of the pancreas derived from intraductal papillary adenocarcinoma without mucin hypersecretion in a 65‐year‐old man with a 45‐year history of alcohol abuse and a 2‐year follow‐up of chronic pancreatitis. Two years previously, in May 1998, he was admitted for investigation of abdominal pain. Computed tomography (CT) showed diffuse dilation of the main pancreatic duct with atrophy of the pancreatic parenchyma. Endoscopic retrograde pancreatography (ERP) showed a diffusely dilated main pancreatic duct with irregular side branches in the head of the pancreas. Chronic alcoholic pancreatitis was diagnosed on the basis of the pancreatography findings. The patient was readmitted for investigation of progressive weight loss in August 2000. Serum CA19‐9 levels were markedly elevated (750U/ml) and CT showed enlargement of the head and body of the pancreas. ERP showed irregularity of the main pancreatic duct in the head of the pancreas, and the distal main pancreatic duct (which was dilated on initial ERP examination) was interrupted in the body of the pancreas. Suspected pancreatic carcinoma was diagnosed, and pylorus‐preserving pancreatoduodenectomy was performed. Frozen section examination of the cut end of the pancreas revealed ductal carcinoma, and total pancreatoduodenectomy with portal vein resection was performed. Histologically, the resected tumor was diagnosed as an invasive carcinoma derived from intraductal papillary adenocarcinoma without mucin hypersecretion. We recommend observing changes in the pancreatic duct on pancreatography to diagnose invasive carcinoma of the pancreas derived from intraductal papillary adenocarcinoma in a resectable state.     

Common features between neoplastic and preneoplastic lesions of the biliary tract and the pancreas

the bile duct system and pancreas show many similarities due to their anatomical proximity and common embryological origin.Consequently,preneoplastic and neoplastic lesions of the bile duct and pancreas share analogies in terms of molecular,histological and pathophysiological features.Intraepithelial neoplasms are reported in biliary tract,as biliary intraepithelial neoplasm(BilIN),and in pancreas,as pancreatic intraepithelial neoplasm(PanIN).Both can evolve to invasive carcinomas,respectively cholangiocarcinoma(CCA)and pancreatic ductal adenocarcinoma(PDAC).Intraductal papillary neoplasms arise in biliary tract and pancreas.Intraductal papillary neoplasm of the biliary tract(IPNB)share common histologic and phenotypic features such as pancreatobiliary,gastric,intestinal and oncocytic types,and biological behavior with the pancreatic counterpart,the intraductal papillary mucinous neoplasm of the pancreas(IPMN).All these neoplastic lesions exhibit similar immunohistochemical phenotypes,suggesting a common carcinogenic process.Indeed,CCA and PDAC display similar clinic-pathological features as growth pattern,poor response to conventional chemotherapy and radiotherapy and,as a consequence,an unfavorable prognosis.The objective of this review is to discuss similarities and differences between the neoplastic lesions of the pancreas and biliary tract with potential implications on a common origin from similar stem/progenitor cells.     

Mucinous cystic neoplasms of the pancreas: pathology and molecular genetics

Mucinous cystic neoplasm (MCN) of the pancreas is a distinct clinicopathological entity characterized by mucin-producing epithelial and cyst-forming neoplasm with “ovarian-type” stroma beneath the epithelial component. It is clearly distinguished from ductal adenocarcinoma and intraductal papillary mucinous neoplasm (IPMN). However, MCN can progress to infiltrating carcinoma, and frequently shows a similar histological pattern to ductal adenocarcinoma. Several genetic alterations such as K-ras oncogene mutation, and epigenetic alterations such as hypermethylation of p16 in the invasive component of MCN are also common with ductal adenocarcinoma. Furthermore, recent technologies, including a laser-assisted microdissection system for histological slides and global gene expression profilings using DNA microarrays, made possible to identify more information about molecular abnormalities of MCNs. It is important to diagnose the lesions before they progress to an invasive carcinoma. MCN is one of the precursors of invasive pancreatic carcinoma.     

Endoscopic ultrasound characteristics of mucinous cystic neoplasms of the pancreas

OBJECTIVE: Mucinous cystic neoplasms of the pancreas have a more favorable prognosis than ductal adenocarcinoma. Management of a subgroup, intraductal papillary-mucinous neoplasms, is controversial. Endoscopic ultrasound (EUS) with fine-needle aspiration biopsy may emerge as the imaging modality of choice. There are few studies describing the EUS features of these tumors. METHODS: A total of 35 consecutive cases of cystic tumors of the pancreas with an established pathological diagnosis were analyzed for characteristic EUS features. RESULTS: Mucinous cystadenocarcinomas (n = 14) were more likely to be characterized by hypoechoic cystic/solid mass or complex cyst and were frequently associated with a dilated main pancreatic duct. Benign mucinous duct ectasia (n = 6) were characterized by a dilated main pancreatic duct in conjunction with hyperechoic thickening of the duct wall. The two cases of intraductal mucinous hyperplasia additionally showed a hypoechoic mass. Intraductal papillary carcinoma (n = 11) had features in common with mucinous cystadenocarcinoma but also had echogenic foci in the mass and intraductal hyperechoic lesions. The two cases of microcystic cystadenoma showed either a mixed hypoechoic solid/cystic mass or a complex cyst without the additional features seen in mucinous cystadenocarcinoma. CONCLUSIONS: EUS features seem to exist that may help to differentiate cystic neoplasms from adenocarcinoma of the pancreas and, thus, to establish the preoperative diagnosis of cystic tumors of the pancreas.     

Atypical ductal hyperplasia of the pancreas associated with a stricture of the main pancreatic duct

Atypical ductal hyperplasia of the pancreas is thought to be a precancerous lesion. We report a case of atypical ductal hyperplasia associated with a stricture of the main pancreatic duct. A 70-year-old man was admitted to our hospital because of abdominal pain with an elevated serum pancreatic isoamylase level. Endoscopic retrograde cholangiopancreatography disclosed a stricture of the main pancreatic duct in the body of the pancreas. Cytological evaluation of endoscopic brushings suggested adenocarcinoma. Distal pancreatec-tomy was performed. Microscopic examination of the stenotic pancreatic duct showed a hyperplastic epithelium without atypia. Atypical hyperplasia, however, was found in the distal portion of the main pancreatic duct in close proximity to the stricture. Atypical hyperplasia extended along the main pancreatic duct into the ductal branches of the pancreatic tail. In contrast to the vast majority of patients with atypical hyperplasia, the atypical hyperplasia seen in the present patient had no histological features suggestive of intraductal extension of the invasive carcinoma or intraductal papillary-mucinous tumor, thus representing a sporadic precancerous lesion, and it may have been equivalent to carcinoma in situ. Pancreatic duct stricture and the resultant stasis of the pancreatic juice may have promoted the atypical changes in the ductal cells upstream of the stricture. Received: August 20, 2001 / Accepted: February 8, 2002 Reprint requests to: M. Kogire Editorial on page 311     

A case of minimal invasive carcinoma from intraductal papillary mucinous neoplasm with invasive ductal carcinoma of the pancreas]

A 69-year-old man was referred to our hospital for epigastralgia. He was found to have elevation of serum amylase and CA19-9. Ultrasonography, abdominal CT, MRCP, ERCP and EUS showed the cystic lesion and a possibility of an other tumor. There was a stenosis of the main pancreatic duct (MPD) at the pancreas head and dilatation of the MPD from the body to the tail. Intraductal papillary mucinous neoplasm (IPMN) of the branch pancreatic duct was diagnosed, and there was a likelihood of ductal carcinoma of the pancreas. We therefore performed pancreatoduodenectomy. Pathological finding showed invasive carcinoma from an intraductal papillary mucinous neoplasm with invasive ductal carcinoma of the pancreas.     

Different amounts of K-ras mutant epithelial cells in pancreatic carcinoma and mass-forming pancreatitis

Clinically, differential diagnosis of pancreatic carcinoma (PC) and so-called "mass-forming pancreatitis (MFP)" is difficult. We analyzed the amount, ductal level, and K-ras mutation of ductal hyperplasia and intraductal carcinoma in surgically resected cases of MFP (n = 18) and PC (n = 16). DNAs extracted from microdissected epithelial foci were analyzed for K-ras codon 12 mutation by nested polymerase chain reaction and restriction fragment length polymorphism. The histology of MFP showed severe destruction of exocrine tissue and pancreatic stones and/or protein plugs (72%, 13 of 18 cases) in mostly peripheral ducts. The average basal membrane lengths of nonpapillary and papillary hyperplasia in cases of carcinoma were about 4 and 15 times more than those of MFP, respectively. The frequency of K-ras mutation in hyperplastic foci increased from nonpapillary [six (27%) of 22] to papillary foci [16 (64%) of 25] in K-ras mutant PCs, but there was no difference between nonpapillary [one (6%) of 18] and papillary foci (none of 19) in K-ras wild-type PCs, and also between nonpapillary (none of 24) and papillary foci [one (7%) of 14] in MFPs.     

Clinical results of extended lymphadenectomy and intraoperative radiotherapy for pancreatic adenocarcinoma

BACKGROUND/AIMS: The efficacy of extended lymphadenectomy and intraoperative radiotherapy for resectable pancreatic cancer is controversial. The objective of this study was to clarify the surgical outcome after pancreatic resection with extended lymphadenectomy or intraoperative radiotherapy in patients with pancreatic adenocarcinoma. METHODOLOGY: Between 1992 and 2002, 105 patients with pancreatic adenocarcinoma undergoing surgical resection were retrospectively analyzed. Eighty-eight patients had invasive ductal adenocarcinoma and 17 had invasive intraductal papillary mucinous adenocarcinoma. Seventy-six patients underwent pancreatic resection with extended lymphadenectomy and 44 received 20 Gy intraoperative radiotherapy. RESULTS: Patients with invasive intraductal papillary mucinous adenocarcinoma had a similar prognosis to those with invasive ductal adenocarcinoma. There was no significant difference in survival (p = 0.86) between patients with and without extended lymphadenectomy. There was no significant difference in survival (p = 0.053) between patients with and without intraoperative radiotherapy. Patients without lymph node metastasis had a significantly better prognosis (p = 0.0015) than those with nodal involvement. CONCLUSIONS: Neither extended lymphadenectomy nor intraoperative radiotherapy showed a survival advantage in patients with resectable pancreatic adenocarcinoma. Pancreatic cancer patients without nodal involvement had a significantly better prognosis than those with nodal involvement.     

Current understanding of precursors to pancreatic cancer

Precursors to pancreatic cancer have been investigated for a century. Previous studies have revealed three distinct precursors,i.e. mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), and pancreatic intraepithelial neoplasia (PanIN), harboring identical or similar genetic alterations as does invasive pancreatic carcinoma. The current understanding of precursors to pancreatic cancer can be illustrated by progressive pathways from noninvasive MCN, IPMN, and PanIN toward invasive carcinoma. MCNs consist of ovarian‐type stroma and epithelial lining with varying grades of atypia, and are occasionally associated with invasive adenocarcinoma. The epithelium of noninvasive IPMNs shows a variety of different directions of differentiation, including gastric, intestinal, pancreatobiliary (PB), and oncocytic types. IPMNs can also harbor varying grades of architectural and cytologic atypia. IPMNs confined to branch ducts are mostly the gastric type, and IPMNs involving the main ducts are often intestinal type, while PB and oncocytic types are rare. Small (<1 cm) IPMNs of the gastric type are not always morphologically distinguishable from low‐grade PanINs. Mucin expression profiles suggest intestinal‐type IPMNs progress to mucinous noncystic (colloid) carcinoma, while PB‐type IPMNs progress toward ductal adenocarcinoma. It is a well‐described paradigm that PanIN lesions progress toward ductal adenocarcinoma through step‐wise genetic alterations. The activation of Hedgehog and Notch signaling pathways in PanIN lesions as well as in pancreatic adenocarcinoma suggest that developmental pathways may be disregulated during carcinogenesis of the pancreas. Further study is needed to elucidate the pathways from precursors toward invasive carcinoma of the pancreas.     

Pancreatic Intraepithelial Neoplasia Revisited and Updated

Most pancreatic neoplasms are classified as ductal adenocarcinoma because they show a ductal phenotype, making a ductal origin very likely. The duct lesions that may give rise to pancreatic ductal adenocarcinoma have been called pancreatic intraepithelial neoplasia (PanIN). A classification system for these lesions distinguishes between three grades of PanIN. Molecular studies revealed that PanIN-2 and PanIN-3 lesions represent a distinct step towards invasive carcinoma. While high-grade PanINs are extremely rare in the normal pancreas, low-grade PanINs are common in individuals older than 40 years and may be associated with lobular fibrosis and intraductal papillary mucinous neoplasms of the gastric type. This disease spectrum has also been described in members of kindreds with familial pancreatic cancer. The natural history and cause of PanINs are unknown. As PanIN-1 lesions entail little risk, while PanIN-3 lesions are high-risk lesions, it would be of interest to target PanIN-2 lesions, which can be regarded as the starting point of progressive neoplastic changes that lead to invasive pancreatic ductal adenocarcinoma. Global gene expression analysis identified several differentially expressed genes which show enhanced expression in PanINs and may be used as potential biomarkers to facilitate diagnosis and therapy.