Pancreatic cancer is one of the most lethal of all the solid malignancies. Less than 5% of patients in whom pancreatic cancer is diagnosed today will be alive in 5 years.1 Few therapies are effective, and until recently, painfully little was known about this disease. Today, a number of advances have made pancreatic pathology an exciting and rapidly advancing field. First, it is now clear that pancreatic cancer aggregates in some families, and some of the genes responsible for the familial aggregation of pancreatic cancer have been discovered.2,3 Second, a number of precursor lesions, such as pancreatic intraepithelial neoplasia, which can give rise to invasive pancreatic cancer, have been described and are now well characterized.4,5 Third, preliminary attempts to detect pancreatic neoplasia early in asymptomatic individuals show promise of success.6,7 Fourth, a number of variants of pancreatic cancer with differing genetic and clinical features have been described.8–10 Fifth, we have a much better understanding of the subtypes and natural biology of cystic lesions of the pancreas, including intraductal papillary mucinous neoplasm and mucinous cystic neoplasm.11–13 These cystic neoplasms are important because they represent a real opportunity to cure pancreatic neoplasia before an invasive cancer develops.14–16 Finally, there has been a revolution in our understanding of the genetic changes and gene expression patterns that characterize pancreatic cancer.17–19 The time is ripe to apply these advances to improve patient care. In this special issue of the Archives, an international panel of experts presents a comprehensive review of the most important pancreatic diseases that pathologists are likely to encounter in their practices. The full spectrum of these diseases is discussed—from modern molecular understandings to easy-to-follow algorithms for clinical diagnoses.

This issue leads off with a comprehensive review of endocrine neoplasms of the pancreas by Capelli et al. They deftly integrate modern molecular biology with a description of up-to-date diagnostic and prognostic indicators, and thereby bring the reader to a deeper understanding of these less aggressive, but nonetheless malignant neoplasms of the pancreas. Next, Dr Klein and colleagues review familial pancreatic cancer. They define the clinical syndromes associated with an increased risk of pancreatic cancer and show how family history of cancer can be used to predict a patient's risk of developing pancreatic cancer. Dr Offerhaus and colleagues then comprehensively describe pancreatic intraepithelial neoplasia, the earliest precursors to invasive pancreatic cancer. They illustrate the histologic and genetic progression from normal tissue to precursor to invasive cancer in both humans and mouse models. An understanding of these precursors is obviously critically important to early detection efforts.20 Drs Klöppel and Adsay then discuss the next step in the progression of pancreatic cancer and review the differential diagnosis in pancreas pathology—invasive pancreatic cancer versus chronic pancreatitis. The distinction between these two entities is not only critically important for the patient, but, in our experience, is also one of the most difficult in surgical pathology. The guidelines presented by Klöppel and Adsay are therefore critically important. Cytology is growing in importance, and Drs Stelow and Bellizzi next present an extremely user-friendly algorithmic approach to the evaluation of cytologic specimens from the pancreas.

Although morphology is currently used to diagnose invasive pancreatic cancer, global gene expression studies have led to the discovery of a host of genes that are overexpressed in pancreatic cancer and are therefore potential new markers for this disease. Dr Pandey and colleagues provide a comprehensive and in-depth state-of-the-art review of gene expression studies of the pancreas. They show how these markers have been discovered and describe the potential application of new markers to the early detection and diagnosis of pancreatic cancer.

Having progressed from precursor lesion to invasive carcinoma, the next article, by Drs Iacobuzio-Donahue and Yachida, reviews recent developments in our understanding of metastatic pancreatic cancer. This field is particularly important when considering that most patients with pancreatic cancer do not receive a diagnosis until after the disease has spread. This review is followed by an article on cystic neoplasms of the pancreas by Dr Adsay and colleagues. Cystic neoplasms of the pancreas are important for two reasons. First, they represent an opportunity to cure pancreatic neoplasia before an invasive cancer develops. Second, more and more of these neoplasms are being diagnosed as the use and resolution of imaging increases.21 Dr Zamboni and colleagues then review nonneoplastic mimickers of pancreatic neoplasms, including autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis) and paraduodenal pancreatitis (groove pancreatitis).22,23 These entities have only recently been characterized and are growing in importance with the increasing volume of pancreatic surgery.

This special issue ends with an algorithmic approach to the diagnosis of pancreatic tumors. This review by Dr Klimstra and colleagues integrates many of the findings from the other reviews into a single user-friendly guide to pancreatic pathology.

We appreciate the opportunity to assemble this issue for the Archives. It is our hope that the reader will find this issue useful in the daily practice of diagnostic pathology and that the issue will provide insight into recent molecular advances in our understanding of pancreatic neoplasia.

Ralph H. Hruban, MDRalph H. Hruban, MD, is a professor of pathology and oncology at The Johns Hopkins University School of Medicine. He received his undergraduate degree from the University of Chicago and his Doctor of Medicine from The Johns Hopkins University. He continued at Johns Hopkins for his residency training, spent 1 year as a fellow at Memorial Sloan-Kettering Cancer Center in New York, and then returned to Johns Hopkins to join the faculty in 1990. Dr Hruban is currently the director of The Sol Goldman Pancreatic Cancer Research Center, and director of the Division of Gastrointestinal/Liver Pathology. The pancreatic cancer research team at Johns Hopkins has made many of the fundamental advances in our understanding of pancreatic cancer during the last decade, including demonstrating that pancreatic cancer is fundamentally a genetic disease. Dr Hruban's research focuses on the precursor lesions that give rise to invasive pancreatic cancer. In addition to his research efforts, he founded the National Familial Pancreas Tumor Registry at Johns Hopkins and helped create The Johns Hopkins Pancreatic Cancer Web site (http://pathology.jhu.edu/pancreas). This Web site serves as a resource to patients and their families, and the users of this Web site founded the national pancreatic cancer advocacy group PanCAN. He is recognized by the Institute for Scientific Information as a highly cited researcher and by Essential Science Indicators as the most highly cited pancreatic cancer scientist. Dr Hruban has received a number of awards including the Arthur Purdy Stout Prize, the Young Investigator Award from the United States and Canadian Academy of Pathology, the PanCAN Medical Visionary Award, and 5 teaching awards from The Johns Hopkins School of Medicine. Dr Hruban is a member of the scientific advisory board of PanCAN, the Joseph C. Monastra Foundation, and the Michael Rolfe Pancreatic Cancer Foundation. He is also the director of science for The Lustgarten Foundation and chair of the advisory committee for The Johns Hopkins Alan Mason Chesney Medical Archives.

Ralph H. Hruban, MDRalph H. Hruban, MD, is a professor of pathology and oncology at The Johns Hopkins University School of Medicine. He received his undergraduate degree from the University of Chicago and his Doctor of Medicine from The Johns Hopkins University. He continued at Johns Hopkins for his residency training, spent 1 year as a fellow at Memorial Sloan-Kettering Cancer Center in New York, and then returned to Johns Hopkins to join the faculty in 1990. Dr Hruban is currently the director of The Sol Goldman Pancreatic Cancer Research Center, and director of the Division of Gastrointestinal/Liver Pathology. The pancreatic cancer research team at Johns Hopkins has made many of the fundamental advances in our understanding of pancreatic cancer during the last decade, including demonstrating that pancreatic cancer is fundamentally a genetic disease. Dr Hruban's research focuses on the precursor lesions that give rise to invasive pancreatic cancer. In addition to his research efforts, he founded the National Familial Pancreas Tumor Registry at Johns Hopkins and helped create The Johns Hopkins Pancreatic Cancer Web site (http://pathology.jhu.edu/pancreas). This Web site serves as a resource to patients and their families, and the users of this Web site founded the national pancreatic cancer advocacy group PanCAN. He is recognized by the Institute for Scientific Information as a highly cited researcher and by Essential Science Indicators as the most highly cited pancreatic cancer scientist. Dr Hruban has received a number of awards including the Arthur Purdy Stout Prize, the Young Investigator Award from the United States and Canadian Academy of Pathology, the PanCAN Medical Visionary Award, and 5 teaching awards from The Johns Hopkins School of Medicine. Dr Hruban is a member of the scientific advisory board of PanCAN, the Joseph C. Monastra Foundation, and the Michael Rolfe Pancreatic Cancer Foundation. He is also the director of science for The Lustgarten Foundation and chair of the advisory committee for The Johns Hopkins Alan Mason Chesney Medical Archives.

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Giuseppe Zamboni, MDGiuseppe Zamboni, MD, has been a professor of pathology at the Medical School of the University of Verona since 1998 and chief of the Pathology Department of the Sacro Cuore-Don Calabria Hospital in Negrar, Verona, Italy, since 2000. He graduated in 1980 from the University of Padua, defending his thesis on “Adenomatous Polyps of the Colon” under the guidance of Professor Luciano Fiore-Donati. He obtained his specialization in pathology from the University of Parma in 1984. He spent 2 years as a general surgical pathologist at Vicenza Hospital before being invited to the University of Verona to focus his diagnostic ability on gastrointestinal pathology and collaborate in scientific studies with the Verona Group. He is one of the founding members of the pancreatic research team at the University of Verona. His clinical expertise and knowledge of pathology were instrumental in identifying novel pancreatic tumor types, that is, perivascular epithelioid cell tumor (PEComa) (clear cell “sugar” tumor) and acinar cystadenoma of the pancreas, and in defining inflammatory conditions of the pancreas such as autoimmune pancreatitis. He is the keystone in the renowned Verona Pancreas Group— the most important group in its field in Italy, and among the first in the world for patient volume and number of scientific publications— and a pioneer in the study of molecular anomalies associated with diverse pancreatic types. As part of this group of collaborating clinicians and pathologists, Dr Zamboni has provided vast knowledge in the field of pancreatic tumors, which has been vital to European scientific research and has led, in the last 20 years, to a definition of clinicopathologic standards that encompass valid tools for diagnosis and prognostic stratification of diverse pancreatic tumor types. In 2000, as a member of the World Health Organization International Committee for the Classification of the Tumours of the Gastrointestinal Tract, Liver and Pancreas, he wrote a chapter on mucinous cystic neoplasms of the pancreas. Dr Zamboni is on the board of Virchows Archive, the official journal of the European Society of Pathology.

Giuseppe Zamboni, MDGiuseppe Zamboni, MD, has been a professor of pathology at the Medical School of the University of Verona since 1998 and chief of the Pathology Department of the Sacro Cuore-Don Calabria Hospital in Negrar, Verona, Italy, since 2000. He graduated in 1980 from the University of Padua, defending his thesis on “Adenomatous Polyps of the Colon” under the guidance of Professor Luciano Fiore-Donati. He obtained his specialization in pathology from the University of Parma in 1984. He spent 2 years as a general surgical pathologist at Vicenza Hospital before being invited to the University of Verona to focus his diagnostic ability on gastrointestinal pathology and collaborate in scientific studies with the Verona Group. He is one of the founding members of the pancreatic research team at the University of Verona. His clinical expertise and knowledge of pathology were instrumental in identifying novel pancreatic tumor types, that is, perivascular epithelioid cell tumor (PEComa) (clear cell “sugar” tumor) and acinar cystadenoma of the pancreas, and in defining inflammatory conditions of the pancreas such as autoimmune pancreatitis. He is the keystone in the renowned Verona Pancreas Group— the most important group in its field in Italy, and among the first in the world for patient volume and number of scientific publications— and a pioneer in the study of molecular anomalies associated with diverse pancreatic types. As part of this group of collaborating clinicians and pathologists, Dr Zamboni has provided vast knowledge in the field of pancreatic tumors, which has been vital to European scientific research and has led, in the last 20 years, to a definition of clinicopathologic standards that encompass valid tools for diagnosis and prognostic stratification of diverse pancreatic tumor types. In 2000, as a member of the World Health Organization International Committee for the Classification of the Tumours of the Gastrointestinal Tract, Liver and Pancreas, he wrote a chapter on mucinous cystic neoplasms of the pancreas. Dr Zamboni is on the board of Virchows Archive, the official journal of the European Society of Pathology.

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The authors have no relevant financial interest in the products or companies described in this article.

Author notes

Reprints: Ralph H. Hruban, MD, The Sol Goldman Pancreatic Cancer Research Center, Weinberg 2242, 401 N Broadway, Baltimore, MD 21231 (rhruban@jhmi.edu)