Modification of pancreatic carcinogenesis in the hamster model. 2. The effect of partial pancreatectomy.

The effect of partial pancreatectomy (PP) on the pancreatic carcinogenicity of N-nitrosobis (2-oxopropyl)amine (BOP) was investigated in Syrian golden hamsters by subcutaneous injection of a single dose of BOP (20 mg/kg, body weight) given 30 minutes after (Group 1), 1 week after (Group 2), or 1 week before 70% PP (Group 3). Additional groups consisted of animals with PP alone (Group 4), sham operation (laparotomy) followed 30 minutes later by BOP treatment (Group 5), and BOP treatment only (Group 6). The experiment was terminated 46 weeks after BOP administration in each group. The pancreas and extrahepatic bile ducts, including the common duct and gallbladder, were examined histologically. Tumor patterns were compared in hamsters with PP and in the corresponding segments of the pancreas in BOP-treated control groups. The pancreatic cancer incidence was highest (31%) in Group 2 and lowest in Group 1 (3%), a difference that was statistically significant (P less than 0.01). Also, a statistically highly significant larger number of tumors occurred in Group 2, compared with group 1, 3, or 5 (P less than 0.0005). In a comparison of the number of carcinomas per tumor-bearing hamster, there were greater numbers of carcinomas in Group 2 (2.6 carcinomas) than in Groups 1, 3, 5, and 6 (1.0, 1.0, 1.3, and 2.6 tumors, respectively). Moreover, pancreatic tumors in Group 2 hamsters were larger (average diameter, 10 mm) than in Group 1 (4 mm), Group 3 (3.5 mm), Group 5 (4 mm), and Group 6 (average, 9mm). The incidence of extrapancreatic tumors did not vary among the PP groups but was equally lower than those in BOP-treated control groups. The data indicated BOP carcinogenesis was inhibited by surgery (regardless of whether PP was per formed) when the carcinogen was given 30 minutes after the surgery but was significantly enhanced when BOP was administered 1 week after PP. The possible reasons for these conflicting results are discussed. Morphologically all tumors were of ductular, ductal, and mixed ductular-insular patterns and most developed at the resected margins, where proliferation of islets, ducts, and ductules, but not of acinar cells, occurred. The results confirm our view that the ductal and ductular cells are the progenitor cells for BOP-induced pancreatic tumors in hamsters.     

Characteristics of Endocrine Pancreas in Chronic Pancreatitis,as Revealed by Simultaneous Immunocytochemical Demonstration of Hormone Production

Abstract

Cells producing insulin, glucagon, somatostatin, and pancreatic polypeptide (PP) were demonstrated by simultaneous immunocytochemical detection in human pancreatic sections of 3 patients with chronic pancreatitis (CP) and diabetes mellitus (DM), 2 patients with CP and normal glucose tolerance, and 2 patients with normal morphology (3 sections each). The triple and quadruple labeling protocol involved the sequential use of immunogold silver staining (IGSS), indirect immunoalkaline phosphatase (IAP), the indirect immunoperoxidase (IPO), and the peroxidase-antiperoxidase (PAP) methods. This approach proved useful for the recognition of some topo-morphological features of the endocrine pancreas at a glance in normal and CP tissues.

In the process of islet cell neoformation (ductoendocrine proliferation), the A cells seemed to occur first within the ducts and ductules, followed by the B and D cells. Additionally, in some islets of Langerhans damaged by intraislet peliosis in DM patients, the A cells were found to be very resistant, whereas the number B cells was seriously reduced. (The J Histotechnol 13:213, 1990)     

Scanning electron microscopic study of precancerous and cancerous pancreatic lesions induced by N-nitrosobis (2-oxopropyl) amine in Syrian golden hamsters

Sequential alteration of Syrian golden hamster pancreatic ducts and ductules was investigated by scanning electron microscope during and subsequent to 10 weekly subcutaneous injections of N-nitrosobis (2-oxopropyl) amine (BOP). By examining surface morphology of ductal cells and resin casts of the secretory branches arising from the common duct, a series of lesions ranging from slight derangement of the luminal dimensions and loss of cilia to marked projections of "finger-like" processes accompanied by pleomorphism at the cellular and microvilli levels and increase in numbers of goblet cells could be established. A ductal histogenesis is proposed on the basis of the present scanning electron microscopic and earlier light microscopic findings.     

Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging

We immunohistochemically examined material from 36 pancreata (adenocarcinomas, 30 lesions; pancreatic intraepithelial neoplasia [PanIN], 65; normal pancreatic ducts, 30) for cyclooxygenase 2 (COX-2) with an automated platform. We analyzed 7 to 10 discrete foci and generated an average percentage of positive cells and average staining intensity for each lesion. These 2 values were then multiplied to create an overall "HistoScore" for each lesion. COX-2 demonstrated considerable heterogeneity of expression between and within cases. The overall average percentage of positive cells in adenocarcinomas was 47.3%; in PanINs, 36.3%; and in normal ducts, 19.2%. COX-2 was expressed in more than 20% of cells in 23 adenocarcinomas (77%), 42 PanINs (65%), and 12 normal ducts (40%). The overall average HistoScore for adenocarcinomas was 6.1; for PanINs, 5.4; and for normal ducts, 3.5. Significant differences in COX-2 expression were demonstrable in adenocarcinomas vs normal ducts, PanINs vs normal ducts, and PanIN 2/3 vs PanIN 1a/1b. In general, the pattern of COX-2 expression increased from normal to PanIN to adenocarcinoma. The up-regulation of COX-2 in a subset of noninvasive precursor lesions makes it a potential target for chemoprevention with selective COX-2 inhibitors.     

Histogenesis of pancreatic carcinomas: a study based on 248 cases

Primary pancreatic carcinomas were studied histologically and histochemically, to assess the frequency of ductal hyperplasia in tissue adjacent to malignant neoplasms. Hyperplasia was divided into four types: simple, papillary, atypical and ductular, affecting large, medium and small ducts (ductules). All types of hyperplasia were frequently seen in areas adjacent to carcinomas, including ductal, pleomorphic, mucinous, adenosquamous, small and spindle cell and cystadenocarcinomas. In contrast, acinar cell carcinoma and microadenocarcinoma were less frequently associated with ductal hyperplasia. Mucin histochemistry revealed differences in types of mucin between the normal ducts and hyperplastic pancreatic ducts and carcinomas. The former group contained small amounts of sulphated mucin while the latter showed a marked increase in neutral and sialomucins. Our study also suggests that both papillary and atypical hyperplasia are precancerous lesions, supporting an hypothesis of ductal origin of pancreatic carcinomas.     

SCANNING ELECTRON MICROSCOPIC STUDY OF PRECANCEROUS and CANCEROUS PANCREATIC LESIONS INDUCED BY N-NITROSOBIS (2-OXOPROPYL) AMINE IN SYRIAN GOLDEN HAMSTERS

Sequential alteration of Syrian golden hamster pancreatic ducts and ductules was investigated by scanning electron microscope during and subsequent to 10 weekly subcutaneous injections of N-nitrosobis (2-oxopropyl) amine (BOP). By examining surface morphology of ductal cells and resin casts of the secretory branches arising from the common duct, a series of lesions ranging from slight derangement of the luminal dimensions and loss of cilia to marked projections of "finger-like" processes accompanied by pleomorphism at the cellular and microvilli levels and increase in numbers of goblet cells could be established. A ductal histogenesis is proposed on the basis of the present scanning electron microscopic and earlier light microscopic findings. ACTA PATHOL. JPN. 36: 1359–1366, 1986.     

Argyrophilic and hormone immunoreactive cells in normal and hyperplastic pancreatic ducts and exocrine pancreatic carcinoma

Summary Scattered argyrophil cells were present in normal, large, medium-sized and small pancreatic ducts (ductules). There was marked increase in argyrophil cells in ducts with hyperplastic epithelium. Argyrophil cells were also found in 67.7% of all exocrine pancreatic carcinomas. In a well differentiated group including cystadenocarcinoma, mucinous carcinoma and well differentiated ductal adenocarcinoma argyrophil cells were found in all cases examined. Using four antisera (against insulin, glucagon, somatostatin and gastrin), insulin, glucagon and somatostatin cells were identified in 2.65%, 0.001% and 1.2% of normal ducts, and 7.5%, 2.4% and 4.6% of ducts with hyperplastic epithelium respectively and were also greatly increased in numbers in the latter group. Immunoreactive cells were present in 66.7% of exocrine carcinomas. Cells reactive for insulin were found in 7/15 cases; glucagon in 6/15 cases; somatostatin in 5/15 cases and gastrin in 2/15 cases. Eight cases contained two or more than two types of immunoreactive cells. The presence of argyrophil and hormone immunoreactive cells in pancreatic ducts and carcinomas is indicative of the close developmental relationship between endocrine and exocrine parts of the pancreas. The inter-relationship of response in the different cell types following stimulus suggests that injury to a common precursor may be involved.     

Characterization and isolation of ductular cells coexpressing neural cell adhesion molecule and Bcl-2 from primary cholangiopathies and ductal plate malformations

It has recently been shown that reactive bile ductules display neuroendocrine features, including immunoreactivity for the neural cell adhesion molecule (NCAM). In this study we have compared the immunohistochemical expression of NCAM with that of HEA-125 (biliary specific) and LKM-1 (hepatocyte specific) and other markers relevant to morphogenesis (Bcl-2, EMA) and cell proliferation (Ki-67) in cryostat sections from different chronic liver diseases and from fetal livers at different gestational ages. In parallel, viable NCAM-positive ductular cells were purified from collagenase digests of cirrhotic livers by immunomagnetic separation and characterized by immunocytochemistry and transmission electron microscopy. We demonstrated that reactive ductules with atypical morphology coexpressed NCAM and Bcl-2 and were found mainly in congenital diseases associated with ductal plate malformation and in primary cholangiopathies. On the contrary, reactive ductules with typical morphology were negative for NCAM/Bcl-2 and positive for EMA. Reactive ductules coexpressing NCAM/Bcl-2 were negative for the proliferation marker Ki-67 and appeared to be directly connected with periportal hepatocytes. In fetal livers NCAM/Bcl-2 was transiently expressed during the early developmental stages of ductal plate (10-16 weeks) and started to disappear as the ductal plate began duplicating. NCAM-positive ductal plate cells were Ki-67 negative, becoming positive in duplicated segments. Thus the histogenesis of ductular reactive cells seems to recapitulate the early stages of biliary ontogenesis. In primary cholangiopathies and ductal plate malformations, these cells do not appear to maturate further, and thus abundant ductular structures coexist with vanishing mature ducts. These NCAM-positive ductular cells were immunopurified from patients with chronic cholestatic liver diseases and showed ultrastructural features consistent with a less differentiated phenotype than mature cholangiocytes. These isolated cells represent a useful model for in vitro studies.     

Effects of dimethylnitrosamine on organ-cultured adult human pancreas

Portions of adult human pancreas from 20 donors were organ-cultured in a chemically defined medium in the absence or presence of DMNA for up to 12 weeks. In the absence of DMNA, necrosis of some acini occurred during the first week, while some clusters of well-preserved acini were maintained for up to 3 weeks. Proliferation of the epithelial linings of main and smaller ducts and ductules was noted during the first 2 weeks of culture. Ductal epitheliums thereafter showed some degeneration but remained viable during the 12 weeks of culture. In contrast to controls, the DMNA-treated explants showed better preservation of both acinar and ductal cells. DMNA induced both ductal hyperplasia and atypia of the epithelial linings of main ducts, smaller ducts, and ductules within 6 weeks, and carcinoma by the tenth week of culture. At the end of the first week cells devoid of zymogen within the acinar complex proliferated and progressively replaced necrotic cells. During the ninth and tenth weeks, foci of atypical cells developed among these cells. Cells derived from 10-week-old DMNA-treated explants produced multiple nodules of carcinoma when injected subcutaneously into nude mice.     

MUC4 expression increases progressively in pancreatic intraepithelial neoplasia

Pancreatic adenocarcinoma is believed to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs) that undergo a series of architectural, cytologic, and genetic changes, a progression model similar to the adenoma-carcinoma sequence in the colon. The apomucin MUC4 has been implicated in invasive pancreatic adenocarcinoma. MUC4 expression is not detectable at the RNA level in normal pancreas but is detectable at high levels in invasive pancreatic adenocarcinoma. We documented the pattern of expression of MUC4 in PanINs by studying a series of 71 PanIN lesions immunohistochemically using a new monoclonal antibody to MUC4. Five (17%) of 30 PanIN-1 lesions, 10 (36%) of 28 PanIN-2 lesions, 11 (85%) of 13 PanIN-3 lesions, and 25 (89%) of 28 invasive adenocarcinomas labeled with the MUC4 antibody used in the study. In addition, afew nonneoplastic lesions labeled with the MUC4 antibody, including reactive ducts in chronic pancreatitis, atrophic ducts filled with inspissated secretions, and ducts showing squamous metaplasia. Our data help establish the patterns of MUC4 expression in neoplastic precursors in the pancreas and add further support to the progression model for pancreatic adenocarcinoma.     

Intermediate cells in the pancreas and cell transformation

The paper reviews the medical literature concerning the occurrence and several possible explanations of the origin nature of pancreatic intermediate cells present. Electron microscopic studies of the human pancreas and results of animal experiments in the last years strongly suggest that cells in the wall of small pancreatic ducts (ductules) may develop into duct cells, exocrine pancreatic cells (acinar cells), endocrine islet cells, and hepatocytes even in the adult organism. This suggests that transitional cells arise from the known types of pancreatic intermediate cells during this process. The development of the different cells may start from a pool of omnipotent cells (entodermal stem cells of the foregut) present in the walls of the ductules, or from undifferentiated cells, reflecting their embryonic potential as a result of proliferation of duct cells (i.e. indirect cellular transformation = metaplasia of duct cells).     

Effect of All‐Trans Retinoic Acid on the Pancreas of Streptozotocin‐Induced Diabetic Rat

All‐trans Retinoic acid (atRA) is instructive for the development of endocrine pancreas and is an integral component of β‐cell induction protocols. We showed that atRA induces glucose‐responsive endocrine transdifferentiation of pleomorphic pancreatic ductal adenocarcinoma cells in vitro. This study aimed to detect the role of atRA in improving the histological changes of the pancreas in diabetic rats. Forty young male Wistar rats were used and divided into three groups. Group I: normal vehicle control (N = 5). Group II: streptozotocin‐induced diabetic rats (N = 20) were followed up at 0.0, 1, 2, and 4 weeks. Group III: streptozotocin‐induced diabetic rats (N = 15) treated with atRA (2.5 mg/kg/day), were followed up at 1, 2, and 4 weeks. Specimens from the pancreas were processed for light, electron microscopy and pancreatic insulin mRNA expression. Blood samples were assayed for the levels of glucose, insulin, and total peroxides. In the atRA‐treated group, the number of the islets and the islet area significantly increased. Strong insulin‐immunoreactive endocrine‐like cells were observed nearby the pancreatic acini and the interlobular ducts. Interestingly, insulin‐positive cells seemed to arise from pancreatic acinar and ductal epithelium. Ultrastructurally, ß‐cells, acinar, and ductal cells restored their normal appearance. Pancreatic insulin mRNA and blood indices were almost normalized. AtRA improved the histological changes of the pancreas and the blood indices in diabetic rats. Anat Rec, 299:334–351, 2016. © 2015 Wiley Periodicals, Inc.     

Incidence and diagnostic significance of minor pathologic changes in the adult pancreas at autopsy: a systematic study of 112 autopsies in patients without known pancreatic disease

In 112 unselected autopsies of adult patients without known pancreatic disease (except adult-onset diabetes mellitus), the pancreas was examined to establish the incidence and degree of such minor pancreatic lesions as lipomatosis, fibrosis, alterations of ducts and ductal epithelium, inflammatory infiltrates, focal necrosis, acinar dilation, and vascular changes. Each lesion was then tested for statistically significant correlations with the age of the patient and a number of clinical conditions, including cholelithiasis, adult-onset diabetes mellitus, adiposity, generalized severe atherosclerosis, chronic alcoholism, severe bacterial infection prior to death, and generalized malignant tumor. This was done in the hope of finding associated or predisposing factors for the pancreatic lesions. The results show, in addition to the unexpectedly high incidence of the various pancreatic lesions, a clear increase of lipomatosis, fibrosis, and both ductal and ductal epithelial alterations with increasing age; these conditions were accompanied by a steady decrease in the mean weight of the gland, starting at the age of about 40 years, except in cases of advanced lipomatosis. The latter condition was associated with adult-onset diabetes mellitus. Severe generalized atherosclerosis was correlated with lipomatosis and fibrosis, but the two latter conditions were found together only rarely. Acute (terminal) lesions, including focal necrosis and acinar dilation, were associated with severe bacterial disease prior to death. Other statistically significant correlations were rare, indicating the lack of specificity of these minor pancreatic lesions rather than offering a clue as to their pathogenesis. The diagnostic significance and the relations of these lesions to clinically relevant chronic pancreatitis are discussed briefly.     

Histologic characteristics of pancreatic intraepithelial neoplasia associated with different pancreatic lesions

Pancreatic intraepithelial neoplasia (PanIN) has been found in association with pancreatic ductal adenocarcinoma, intraductal papillary-mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other pancreatic lesions, but the characteristics of PanINs associated with these lesions are not well characterized. In this study, 185 partial or total pancreatectomy specimens were collected, and 173 had complete slides for reviewed, which included 74 pancreatic ductal adenocarcinomas, 28 IPMNs, 7 mucinous cystic neoplasms, 44 other nonductal tumors, and 20 nontumorous lesions. Differences in grade, extent, and duct involvement among PanINs associated with different lesions were analyzed. Patients with PanINs were older than those without, regardless of associated tumor or lesions. No sex predilection was noted. PanINs were found in 89%, 96%, 86%, 64%, and 55% pancreata with ductal adenocarcinomas, IPMNs, mucinous cystic neoplasm, other nonductal tumors, and nontumorous lesions, respectively. PanIN 1 and 2 were commonly associated with all types of lesions, but high-grade PanIN 3 was more frequently associated with ductal adenocarcinomas. Ductal involvement of PanINs was more extensive in association with ductal adenocarcinomas than in any other types of pancreatic tumors or lesions. PanINs associated with pancreatic ductal adenocarcinomas affected both the main and branched ducts, whereas PanINs associated with other types of pancreatic tumors or lesions were mainly present in the branch ducts. No statistical differences were observed in distribution, extent, and grade of PanINs among IPMNs, mucinous cystic neoplasms, other nonductal tumors, and nontumorous lesions. Our study demonstrated a high concurrence between PanINs and other precancerous lesions and histologic features of PanINs associated with different pancreatic diseases.     

A comparison of different challenge methods for induction of atrophic rhinitis in pigs

Transmission and development of atrophic rhinitis (AR) was studied in 5- to 15-week-old pigs (Groups 2-7) originating from a herd free of AR, and compared to unexposed healthy pigs (Group 1), and pigs from a herd with endemic AR (Group 8). At the start of the trial, pigs in Groups 2-5 were challenged intranasally twice a week for 3 weeks with pure cultures of bacteria originating from the endemic AR herd: Nontoxigenic Pasteurella multocida type A (PmA) plus Bordetella bronchiseptica phase I (Bb) (Group 2); PmA + toxigenic Pm type D (PmD) (Group 3); PmD only (Group 4); and PmD + Bb (Group 5). Group 6 pigs were challenged with nasal wash of pigs from the endemic AR herd, and Group 7 pigs were challenged by being housed together in the same pen with Group 8 pigs throughout the study. Nasal swabs of all pigs were cultured 5 times during the study. Serum was collected at 6 weeks post challenge. Average daily gain (ADG) and turbinate lesions (turbinate gross lesions by visual scoring and by Turbinate Perimeter Ratio, TPR, scoring, and histopathological lesions) were measured at the time of slaughter at 15 weeks of age. Mean TPR value for the Group 1 pigs was 1.64, which was significantly (P less than 0.05) different from the mean TPR value of 0.58 for the pigs from the endemic AR herd (Group 8), the 0.79 value for Group 6 pigs, and 1.03 value for Group 7 pigs. Of pigs challenged with pure bacterial cultures, only Group 5 (PmD + Bb) developed significant AR (mean TPR = 1.24). Only one pig in each of Groups 2 and 3, and two pigs in Group 4 showed TPR values indicative of AR (TPR less than 1.30). However, histopathological examination showed that those pigs were recovering from the infection 7 weeks post challenge. Constant exposure to certain bacteria or other factors in nasal washings, stress of crowding or poor environmental conditions might be required to experimentally produce AR in 5-week and older pigs similar to that in naturally infected pigs. There was no relationship between turbinate lesions and the isolation frequency or quantity of PmA, PmD, or Bb. Antibody levels against PmA or PmD had moderate to high correlation with TPR values (r = -0.694 and -0.503 respectively). ELISA values also corresponded well with the type of bacteria inoculated in each group of pigs and appeared to be a sensitive test for PmA, PmD, and Bb infections in pigs.(ABSTRACT TRUNCATED AT 400 WORDS)     

The foamy variant of pancreatic intraepithelial neoplasia

Foamy gland adenocarcinoma is a variant of pancreatic ductal carcinoma, whose precursor has not been described. We describe here the morphologic and immunohistochemical features of the pancreatic intraepithelial neoplasia (PanIN) lesions associated with invasive foamy pancreatic adenocarcinoma. The staining properties and morphologic and immunohistochemical features of 3 foamy PanIN lesions were compared with those of 7 pancreatic foamy gland adenocarcinomas. Hematoxylin and eosin, Mayer mucicarmine, periodic acid-Schiff, and Alcian blue stains were available for review in all cases. Immunohistochemical labeling for cytokeratin (CK)7, CK20, carcinoembryonic antigen polyclonal, MUC1, MUC2, CDX2, p53, and cyclin D1 was performed. The PanIN-1 lesions were found in the nonneoplastic pancreas and were similar to the PanIN-1 lesions of ordinary pancreatic ductal carcinoma. The PanIN-2 and -3 lesions were recognized immediately adjacent to or within the invasive foamy gland carcinoma. In these lesions, small or markedly dilated ducts were lined by cuboidal and columnar dysplastic nonfoamy cells and foamy cells. Hobnail cells were present in 2 cases. The PanIN-1, 2, and 3 lesions and the invasive foamy gland adenocarcinomas stained with mucicarmine, periodic acid-Schiff, and Alcian blue. The 3 PanIN-2 and -3 lesions and all 7 invasive foamy adenocarcinomas labeled with CK7, carcinoembryonic antigen polyclonal, and MUC1, whereas only 2 PanIN-2 and -3 lesions and 5 invasive adenocarcinomas showed immunoreactivity for cyclin D1 and p53. Three distinctive foamy PanIN lesions were identified within 7 invasive foamy gland pancreatic adenocarcinomas. The gradual progression of cytological and architectural abnormalities of the PanIN lesions from PanIN-1 to PanIN-3 excludes neoplastic ductal spread. These foamy PanIN lesions probably represent cancer precursors.     

Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia

A multistep model of carcinogenesis has recently been proposed for pancreatic ductal adenocarcinomas. In this model, noninvasive precursor lesions in the pancreatic ductules accumulate genetic alterations in cancer-associated genes eventually leading to the development of an invasive cancer. The nomenclature for these precursor lesions has been standardized as pancreatic intraepithelial neoplasia or PanIN. Despite the substantial advances made in understanding the biology of invasive pancreatic adenocarcinomas, little is known about the initiating genetic events in the pancreatic ductal epithelium that facilitates its progression to cancer. Telomeres are distinctive structures at the ends of chromosomes that protect against chromosomal breakage-fusion-bridge cycles in dividing cells. Critically shortened telomeres can cause chromosomal instability, a sine qua non of most human epithelial cancers. Although evidence for telomeric dysfunction has been demonstrated in invasive pancreatic cancer, the onset of this phenomenon has not been elucidated in the context of noninvasive precursor lesions. We used a recently described in situ hybridization technique in archival samples (Meeker AK, Gage WR, Hicks JL, Simon I, Coffman JR, Platz EA, March GE, De Marzo AM: Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining. American Journal of Pathology 2002, 160:1259-1268) for assessment of telomere length in tissue microarrays containing a variety of noninvasive pancreatic ductal lesions. These included 82 PanIN lesions of all histological grades (24 PanIN-1A, 23 PanIN-1B, 24 PanIN-2, and 11 PanIN-3) that were selected from pancreatectomy specimens for either adenocarcinoma or chronic pancreatitis. Telomere fluorescence intensities in PanIN lesions were compared with adjacent normal pancreatic ductal epithelium and acini (62 of 82 lesions, 76%), or with stromal fibroblasts and islets of Langerhans (20 of 82 lesions, 24%). Telomere signals were strikingly reduced in 79 (96%) of 82 PanINs compared to adjacent normal structures. Notably, even PanIN-1A, the earliest putative precursor lesion, demonstrated a dramatic reduction of telomere fluorescence intensity in 21 (91%) of 23 foci examined. In chronic pancreatitis, reduction of telomere signal was observed in all PanIN lesions, whereas atrophic and inflammatory ductal lesions retained normal telomere length. Telomere fluorescence intensity in PanIN lesions did not correlate with proliferation measured by quantitative Ki-67-labeling index or topoisomerase IIalpha expression. Thus, telomere shortening is by far the most common early genetic abnormality recognized to date in the progression model of pancreatic adenocarcinomas. Telomeres may be an essential gatekeeper for maintaining chromosomal integrity, and thus, normal cellular physiology in pancreatic ductal epithelium. A critical shortening of telomere length in PanINs may predispose these noninvasive ductal lesions to accumulate progressive chromosomal abnormalities and to develop toward the stage of invasive carcinoma.     

Duct‐obstructive pancreatitis with granulocytic epithelial lesion in a patient with ulcerative colitis: An atypical manifestation of type 2 autoimmune pancreatitis?

Type 2 autoimmune pancreatitis (AIP) typically presents with diffuse or focal enlargement of the pancreas; however, its diverse clinical presentation has not yet been clarified. We herein described a 46‐year‐old man with a 1‐month history of ulcerative colitis who presented with imaging features of a mass‐like lesion in the pancreatic body with upstream duct dilatation and serum CA19‐9 elevation. He underwent laparoscopic distal pancreatectomy with splenectomy for suspected malignancy. Histologically, the area radiologically suspected to be duct dilatation consisted of necrotic tissue, in which the disrupted main pancreatic duct was involved. The area radiologically suspected to be the mass lesion showed features of pancreatitis without discrete mass. In addition, several ducts showed neutrophilic duct injury similar to granulocytic epithelial lesions observed in type 2 AIP. Immunohistochemistry revealed the aberrant expression of IL‐8 in the pancreatic ductules and infiltrating CD3‐positive T‐lymphocytes, findings recently identified in type 2 AIP. The present case is not typical for either type 2 AIP or other known conditions, but extreme examples of type 2 AIP may present with ductal obstruction because of severe neutrophilic duct injury. IL‐8 immunostaining may also assist in establishing a diagnosis of type 2 AIP with an atypical presentation.