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.

Jemal
,
A.
,
R.
Siegel
, and
E.
Ward
.
et al
.
Cancer statistics, 2008.
CA Cancer J Clin
2008
.
58
:
71
96
.
Klein
,
A. P.
,
K. A.
Brune
, and
G. M.
Petersen
.
et al
.
Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.
Cancer Res
2004
.
64
:
2634
2638
.
Hruban
,
R. H.
,
M. I.
Canto
, and
C.
Griffin
.
et al
.
Treatment of familial pancreatic cancer and its precursors.
Curr Treat Options Gastroenterol
2005
.
8
:
365
375
.
Hruban
,
R. H.
,
N. V.
Adsay
, and
J.
Albores-Saavedra
.
et al
.
Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions.
Am J Surg Pathol
2001
.
25
:
579
586
.
Hruban
,
R. H.
,
K.
Takaori
, and
D. S.
Klimstra
.
et al
.
An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms.
Am J Surg Pathol
2004
.
28
:
977
987
.
Canto
,
M. I.
,
M.
Goggins
, and
R. H.
Hruban
.
et al
.
Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.
Clin Gastroenterol Hepatol
2006
.
4
:
766
781
.
Brentnall
,
T. A.
,
M. P.
Bronner
,
D. R.
Byrd
,
R. C.
Haggitt
, and
M. B.
Kimmey
.
Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer.
Ann Intern Med
1999
.
131
:
247
255
.
Shi
,
C.
,
J. A.
Daniels
, and
R. H.
Hruban
.
Molecular characterization of pancreatic neoplasms.
Adv Anat Pathol
2008
.
15
:
185
195
.
Zamboni
,
G.
and
G.
Klöppel
.
Miscellaneous carcinomas of the pancreas.
In: Hamilton SR, Aaltonen LA, eds. Pathology and Genetics of Tumours of the Digestive System. Lyon, France: IARC Press; 2000:249. World Health Organization Classification of Tumours.
.
Abraham
,
S. C.
,
D. S.
Klimstra
, and
R. E.
Wilentz
.
et al
.
Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations.
Am J Pathol
2002
.
160
:
1361
1369
.
Zamboni
,
G.
,
G.
Klöppel
,
R. H.
Hruban
,
D. S.
Longnecker
, and
G.
Adler
.
Mucinous cystic neoplasms of the pancreas.
In: Hamilton SR, Aaltonen LA, eds. Pathology and Genetics of Tumours of the Digestive System. Lyon, France: IARC Press; 2000: 234–236. World Health Organization Classification of Tumours.
.
Bassi
,
C.
,
C.
Procacci
,
G.
Zamboni
,
A.
Scarpa
,
G.
Cavallini
, and
P.
Pederzoli
.
Verona University Pancreatic Team
.
Intraductal papillary mucinous tumors of the pancreas.
Int J Pancreatol
2000
.
27
:
181
193
.
Adsay
,
N. V.
,
D. S.
Klimstra
, and
C. C.
Compton
.
Cystic lesions of the pancreas:.
introduction
.
Semin Diagn Pathol
2000
.
17
(
1
):
1
6
.
Rodriguez
,
J. R.
,
R.
Salvia
, and
S.
Crippa
.
et al
.
Branch-duct intraductal papillary mucinous neoplasms: observations in 145 patients who underwent resection.
Gastroenterology
2007
.
13
:
372
379
.
Tada
,
M.
,
T.
Kawabe
, and
M.
Arizumi
.
et al
.
Pancreatic cancer in patients with pancreatic cystic lesions: a prospective study in 197 patients.
Clin Gastroenterol Hepatol
2006
.
4
(
10
):
1265
1270
.
Tanno
,
S.
,
Y.
Nakano
, and
T.
Nishikawa
.
et al
.
Natural history of branch duct intraductal papillary-mucinous neoplasms of the pancreas without mural nodules: long-term follow-up results.
Gut
2008
.
57
(
3
):
339
343
.
Hahn
,
S. A.
,
M.
Schutte
, and
A. T.
Hoque
.
et al
.
DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.
Science
1996
.
271
:
350
353
.
Hruban
,
R. H.
,
C. A.
Iacobuzio-Donahue
,
R. E.
Wilentz
,
M.
Goggins
, and
S. E.
Kern
.
Molecular pathology of pancreatic cancer.
Cancer J
2001
.
7
(
4
):
251
258
.
Schutte
,
M.
,
R. H.
Hruban
, and
J.
Geradts
.
et al
.
Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas.
Cancer Res
1997
.
57
:
3126
3130
.
Brune
,
K. A.
,
T.
Abe
, and
M. I.
Canto
.
et al
.
Multifocal neoplastic precusor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer.
Am J Surg Pathol
2006
.
30
:
1067
1076
.
Laffan
,
T. A.
,
K. M.
Horton
,
A. P.
Klein
,
E. K.
Fishman
,
P. T.
Johnson
, and
R. H.
Hruban
.
Prevalence of unsuspected pancreatic cysts on MDCT.
Am J Roentgenol. In press
.
Adsay
,
N. V.
and
G.
Zamboni
.
Paraduodenal pancreatitis: a clinico-pathologically distinct entity unifying “cystic dystrophy of heterotopic pancreas”, “para-duodenal wall cyst”, and “groove pancreatitis.”.
Semin Diagn Pathol
2004
.
21
(
4
):
247
254
.
Zamboni
,
G.
,
J.
Lüttges
, and
P.
Capelli
.
et al
.
Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens.
Virchows Arch
2004
.
445
(
6
):
552
563
.

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)