Daniel S. Longnecker

Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions.

Proliferative epithelial lesions in the smaller caliber pancreatic ducts and ductules have been the subject of numerous morphologic, clinical, and genetic studies; however, a standard nomenclature and diagnostic criteria for classifying these lesion have not been established. To evaluate the uniformity of existing systems for grading duct lesions in the pancreas, 35 microscopic slides with 35 representative duct lesions were sent to eight expert pathologists from the United States, Canada, and Europe. Kappa values for interobserver agreement could not be calculated initially because more than 70 different diagnostic terms were used by the eight pathologists. In several cases, the diagnoses rendered for a single duct lesion ranged from “hyperplasia,” to “metaplasia,” to “dysplasia,” to “carcinoma in situ.” This review therefore demonstrated the need for a standard nomenclature and classification system. Subsequently, during a working group meeting, the pathologists agreed to adopt a single standard system. The terminology pancreatic intraepithelial neoplasia (or PanIN) was selected, and diagnostic criteria for each grade of PanIN were established (http://pathology.jhu.edu/pancreas_panin). This new system was then evaluated by having the eight pathologists rereview the original 35 cases. Only seven different diagnoses were rendered, and kappa values of 0.43, 0.14, and 0.42 were obtained for PanINs 1, 2, and 3 respectively. Cases assigned other diagnoses (e.g., squamous metaplasia) collectively had a kappa value of 0.41. These results show both the potential of the classification system, and also the difficulty of classifying these lesions even with a consistent nomenclature. However, even when there is lack of consensus, having a restricted set of descriptions and terms allows a better understanding of the reasons for disagreement. It is suggested that we adopt and apply this system uniformly, with continued study of its reliability and use, and possibly further refinement. The acceptance of a standard classification system will facilitate the study of pancreatic duct lesions, and will lead ultimately to a better understanding of their biologic importance.

An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms

Invasive pancreatic ductal adenocarcinoma is an almost uniformly fatal disease. Several distinct noninvasive precursor lesions can give rise to invasive adenocarcinoma of the pancreas, and the prevention, detection, and treatment of these noninvasive lesions offers the potential to cure early pancreatic cancers. Noninvasive precursors of invasive ductal adenocarcinoma of the pancreas include pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Diagnostic criteria, including a distinct ovarian-type stroma, and a consistent nomenclature are well established for mucinous cystic neoplasms. By contrast, consistent nomenclatures and diagnostic criteria have been more difficult to establish for PanINs and IPMNs. Because both PanINs and IPMNs consist of intraductal neoplastic proliferations of columnar, mucin-containing cells with a variable degree of papilla formation, the distinction between these two classes of precursor lesions remains problematic. Thus, considerable ambiguities still exist in the classification of noninvasive neoplasms in the pancreatic ducts. A meeting of international experts on precursor lesions of pancreatic cancer was held at The Johns Hopkins Hospital from August 18 to 19, 2003. The purpose of this meeting was to define an international acceptable set of diagnostic criteria for PanINs and IPMNs and to address a number of ambiguities that exist in the previously reported classification systems for these neoplasms. We present a consensus classification of the precursor lesions in the pancreatic ducts, PanINs and IPMNs.

Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study

Now that more than two decades have passed since the first reports of intraductal papillary-mucinous neoplasms (IPMNs), it has become clear that IPMN consists of a spectrum of neoplasms with both morphological and immunohistochemical variations. At a meeting of international experts on pancreatic precursor lesions held in 2003, it was agreed that a consensus classification of IPMN subtypes should be established to enable a more detailed analysis of the clinicopathological significance of the variations. Based on our experience and on information from the literature, we selected representative histological examples of IPMNs and defined a consensus nomenclature and criteria for classifying variants as distinctive IPMN subtypes including gastric type, intestinal type, pancreatobiliary type, and oncocytic type. These definitions can be used for further analyses of the clinicopathological significance of the variations of IPMN.

Pathology of Genetically Engineered Mouse Models of Pancreatic Exocrine Cancer: Consensus Report and Recommendations

Several diverse genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These mouse models have a spectrum of pathologic changes; however, until now, there has been no uniform nomenclature to characterize these changes. An international workshop, sponsored by The National Cancer Institute and the University of Pennsylvania, was held from December 1 to 3, 2004 with the goal of establishing an internationally accepted uniform nomenclature for the pathology of genetically engineered mouse models of pancreatic exocrine neoplasia. The pancreatic pathology in 12 existing mouse models of pancreatic neoplasia was reviewed at this workshop, and a standardized nomenclature with definitions and associated images was developed. It is our intention that this nomenclature will standardize the reporting of genetically engineered mouse models of pancreatic exocrine neoplasia, that it will facilitate comparisons between genetically engineered mouse models and human pancreatic disease, and that it will be broad enough to accommodate newly emerging mouse models of pancreatic neoplasia.

The Dichotomy in the Preinvasive Neoplasia to Invasive Carcinoma Sequence in the Pancreas: Differential Expression of MUC1 and MUC2 Supports the Existence of Two Separate Pathways of Carcinogenesis

Emerging evidence suggests a dichotomy in the dysplasia–CIS-invasive carcinoma sequence in the pancreas. Pancreatic intraepithelial neoplasms (PanINs; small, incidental duct lesions) progress to invasive ductal adenocarcinomas (5-y survival of <15%), whereas intraductal papillary mucinous neoplasms (large, intraductal tumors with ductal dilatation) are often associated with colloid carcinoma (5-y survival of >55%). We explored the relationship of these lesions by examining the expression of MUC1 and MUC2, glycoproteins reportedly reflecting “aggressive” and “indolent” phenotypes in pancreas cancer, respectively. Immunohistochemical labeling with MUC1 (clone Ma695) and MUC2 (clone Ccp58) antibodies was performed on PanINs (n = 43), intraductal papillary mucinous neoplasms (n = 74), ductal adenocarcinomas (n = 136), and colloid carcinomas (n = 15). Fifty-four percent of the intraductal papillary mucinous neoplasms expressed MUC2, whereas none of the PanINs did. In contrast, PanINs, especially higher grade lesions, were often positive for MUC1 (61% of PanIN 3), whereas the expression of this glycoprotein was infrequent in intraductal papillary mucinous neoplasms (20%). This dichotomy was further accentuated in the invasive carcinomas with which these two preinvasive pathways are respectively associated: all colloid carcinomas were MUC2+ (100%) and MUC1− (0%), whereas the labeling pattern was the reverse for ductal adenocarcinomas: 63% were MUC1+ and only 1% were MUC2+. These results support a dichotomy in the dysplasia–CIS sequence in the pancreas. Because these two pathways often lead to different types of invasive carcinomas, this is an invaluable model for the study of carcinogenesis. The findings here also support the previous impression that MUC2 (the mucin associated with gel formation) is a marker of the “indolent” pathway (intraductal papillary mucinous neoplasm and colloid carcinoma), whereas MUC1 (the glycoprotein known to have an inhibitory role in cell–cell and cell–stroma interactions as well as in immunoresistance of tumor cells) is a marker of the “aggressive” pathway (PanIN to ductal adenocarcinoma).

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.

Autoimmune Pancreatitis : Pathological, Clinical, and Immunological Features

Introduction In recent years a type of chronic pancreatitis has been described that is clearly distinct from alcoholic chronic pancreatitis. It is characterized by its special pathology, immunologic features, clinical presentation, and steroid responsiveness. Because of its histologic hallmarks, i.e., ductal and periductal infiltration by lymphocytes, plasma cells, and granulocytes, it has been called duct-destructive chronic pancreatitis. The frequent association of this type of pancreatitis with other autoimmune diseases such as Sjögrens disease and a number of other immune phenomena has led to the concept that it is an autoimmune disease. Hence, the term autoimmune pancreatitis has been introduced and will be used in this review. Aims This review focuses on the pathology and related clinical and immunologic features of this new type of pancreatitis. Conclusions As the ability to diagnose autoimmune pancreatitis on the basis of clinical, imaging, and laboratory findings improves, it seems likely that fewer patients with this diagnosis will undergo resection. Thus, there is a need to accumulate and study additional retrospective series of patients undergoing resection because of mass-forming chronic pancreatitis.

Pancreatic Cancer and Precursor Pancreatic Intraepithelial Neoplasia Lesions Are Devoid of Primary Cilia

Primary cilia have been proposed to participate in the modulation of growth factor signaling pathways. In this study, we determined that ciliogenesis is suppressed in both pancreatic cancer cells and pancreatic intraepithelial neoplasia (PanIN) lesions in human pancreatic ductal adenocarcinoma (PDAC). Primary cilia were absent in these cells even when not actively proliferating. Cilia were also absent from mouse PanIN cells in three different mouse models of PDAC driven by an endogenous oncogenic Kras allele. Inhibition of Kras effector pathways restored ciliogenesis in a mouse pancreatic cancer cell line, raising the possibility that ciliogenesis may be actively repressed by oncogenic Kras. By contrast, normal duct, islet, and centroacinar cells retained primary cilia in both human and mouse pancreata. Thus, arrested ciliogenesis is a cardinal feature of PDAC and its precursor PanIN lesions, does not require ongoing proliferation, and could potentially be targeted pharmacologically.

Ras Activity Levels Control the Development of Pancreatic Diseases

BACKGROUND & AIMS Differentiated pancreatic acinar cells expressing endogenous levels of mutant K-Ras do not spontaneously develop pancreatic ductal adenocarcinoma (PDAC). However, we hypothesized that acinar cells would develop PDAC in the presence of Ras activity levels mimicking those of human tumor cells. METHODS We measured Ras activity in PDAC cells from mice and humans using a Raf pull-down assay. We compared the effects of acinar cell expression of mutant K-Ras at endogenous and elevated levels on Ras activity and on the development of PDAC. RESULTS Ras activity was greatly elevated in PDAC cells compared with nontransformed cells expressing endogenous levels of mutant K-Ras. Expression of endogenous levels of mutant K-Ras in differentiated acinar cells resulted in moderately elevated Ras activity and in sparse murine pancreatic intraepithelial neoplasias (mPanINs) that did not spontaneously advance to PDAC unless the tumor suppressor p53 was simultaneously deleted. In contrast, expression of mutant K-Ras at higher levels generated Ras activity equal to that in PDAC. High Ras activity mimicking levels in PDAC led to acinar cell senescence and generated inflammation and fibrosis resembling the histologic features of chronic pancreatitis. With higher Ras activity in acinar cells, abundant mPanINs formed and spontaneously progressed to both cystic papillary carcinoma and metastatic PDAC. CONCLUSIONS There is an important relationship between Ras activity levels and the progression of PDAC. Sufficient Ras activity in pancreatic acinar induces several important pancreatic disease manifestations not previously reported and supports a potential direct linkage between chronic pancreatitis, cystic papillary carcinoma, and PDAC.

A Revised Classification System and Recommendations From the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas.

International experts met to discuss recent advances and to revise the 2004 recommendations for assessing and reporting precursor lesions to invasive carcinomas of the pancreas, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other lesions. Consensus recommendations include the following: (1) To improve concordance and to align with practical consequences, a 2-tiered system (low vs. high grade) is proposed for all precursor lesions, with the provision that the current PanIN-2 and neoplasms with intermediate-grade dysplasia now be categorized as low grade. Thus, “high-grade dysplasia” is to be reserved for only the uppermost end of the spectrum (“carcinoma in situ”–type lesions). (2) Current data indicate that PanIN of any grade at a margin of a resected pancreas with invasive carcinoma does not have prognostic implications; the clinical significance of dysplasia at a margin in a resected pancreas with IPMN lacking invasive carcinoma remains to be determined. (3) Intraductal lesions 0.5 to 1 cm can be either large PanINs or small IPMNs. The term “incipient IPMN” should be reserved for lesions in this size with intestinal or oncocytic papillae or GNAS mutations. (4) Measurement of the distance between an IPMN and invasive carcinoma and sampling of intervening tissue are recommended to assess concomitant versus associated status. Conceptually, concomitant invasive carcinoma (in contrast with the “associated” group) ought to be genetically distinct from an IPMN elsewhere in the gland. (5) “Intraductal spread of invasive carcinoma” (aka, “colonization”) is recommended to describe lesions of invasive carcinoma invading back into and extending along the ductal system, which may morphologically mimic high-grade PanIN or even IPMN. (6) “Simple mucinous cyst” is recommended to describe cysts >1 cm having gastric-type flat mucinous lining at most minimal atypia without ovarian-type stroma to distinguish them from IPMN. (7) Human lesions resembling the acinar to ductal metaplasia and atypical flat lesions of genetically engineered mouse models exist and may reflect an alternate pathway of carcinogenesis; however, their biological significance requires further study. These revised recommendations are expected to improve our management and understanding of precursor lesions in the pancreas.