Skip to main content
SpringerLink
Log in

Pancreatic Intraepithelial Neoplasia

  • Chapter
Pancreatic Cancer

Part of the book series: M. D. Anderson Solid Tumor Oncology Series ((MDA))

Most pancreatic cancers are not diagnosed until after the cancer has spread to other organs and is no longer curable. As a result, the death rate for pancreatic cancer in this country (34,290/year) is approximately equal to the incidence rate (37,680/year) (1). By contrast, many patients survive the diagnosis of breast cancer, and half of the decline in breast cancer mortality in the last quarter of a century has come from improved early detection (2). We believe that early detection of preinvasive lesions is the greatest hope for curing pancreatic neoplasia. This chapter discusses pancreatic intraepithelial neoplasia (PanIN), the most common precursor lesion in the pancreas (3).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Jemal A, Siegel R, Ward E, et al. Cancer Statistics, CA A Cancer Journal for Clinicians 2008, 58:71–96.

    Article  Google Scholar 

  2. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortal-ity from breast cancer. N Engl J Med 2005, 353(17):1784–1792.

    Article  CAS  PubMed  Google Scholar 

  3. Maitra A, Fukushima N, Takaori K, et al. Precursors to invasive pancreatic cancer. Adv Anat Pathol 2005, 12(2):81–91.

    Article  PubMed  Google Scholar 

  4. Hulst SPL. Zur kenntnis der Genese des Adenokarzinoms und Karzinoms des Pankreas. Virchows Arch (B) 1905, 180:288–316.

    Article  Google Scholar 

  5. Hruban RH, Adsay NV, Albores-Saavedra J, et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 2001, 25 (5):579–586.

    Article  CAS  PubMed  Google Scholar 

  6. Hruban RH, Takaori K, Klimstra DS, et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 2004, 28(8):977–987.

    Article  PubMed  Google Scholar 

  7. Hruban RH, Klimstra DS, Pitman MB. Atlas of tumor pathology. Tumors of the pancreas, 4th ed. Washington, DC: Armed Forces Institute of Pathology, 2007.

    Google Scholar 

  8. Furukawa T, Chiba R, Kobari M, et al. Varying grades of epithelial atypia in the pancreatic ducts of humans. Classification based on morphometry and multilvariate analysis and correlated with positive reactions of carcinoembryonic antigen. Arch Pathol Lab Med 1994, 118:227–234.

    CAS  PubMed  Google Scholar 

  9. Detlefsen S, Sipos B, Feyerabend B, et al. Pancreatic fibrosis associated with age and ductal papillary hyperplasia. Virchows Arch 2005, 447(5):800–805.

    Article  PubMed  Google Scholar 

  10. Brune KA, Abe T, Canto MI, et al. Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer. Am J Surg Pathol 2006, 30(9):1067–1076.

    PubMed  Google Scholar 

  11. Cubilla AL, Fitzgerald PJ. Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res 1976, 36:2690–2698.

    CAS  PubMed  Google Scholar 

  12. Kozuka S, Sassa R, Taki T, et al. Relation of pancreatic duct hyperplasia to carcinoma. Cancer 1979, 43:1418–1428.

    Article  CAS  PubMed  Google Scholar 

  13. Andea A, Sarkar F, Adsay NV. Clinicopathological correlates of pancreatic intraepithelial neoplasia: a comparative analysis of 82 cases with and 152 cases without pancreatic ductal adenocarcinoma. Mod Pathol 2003, 16(10):996–1006.

    Article  PubMed  Google Scholar 

  14. Lüttges J, Reinecke-Lüthge A, Mollmann B, et al. Duct changes and K-ras mutations in the disease-free pancreas: analysis of type, age relation and spatial distribution. Virchows Arch 1999, 435 (5):461–468.

    Article  PubMed  Google Scholar 

  15. Kimura W, Nagai H, Kuroda A, et al. Analysis of small cystic lesions of the pancreas. Int J Pancreatol 1995, 18(3):197–206.

    CAS  PubMed  Google Scholar 

  16. Lowenfels AB, Maisonneuve EP, Dimagno YE, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 1997, 89 (6):442–446.

    Article  CAS  PubMed  Google Scholar 

  17. Volkholz H, Stolte M, Becker V. Epithelial dysplasias in chronic pancreatitis. Virchows Arch A Pathol Anat Histopathol 1982, 396:331–349.

    Article  CAS  Google Scholar 

  18. Rosty C, Geradts J, Sato N, et al. p16 Inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis. Am J Surg Pathol 2003, 27(12):1495–1501.

    Article  PubMed  Google Scholar 

  19. Agoff SN, Crispin DA, Bronner MP, et al. Neoplasms of the ampulla of Vater with concurrent pancreatic intraductal neoplasia: a histological and molecular study. Mod Pathol 2001, 14(3):139–146.

    Article  CAS  PubMed  Google Scholar 

  20. Stelow EB, Adams RB, Moskaluk CA. The prevalence of pancreatic Intraepithelial neoplasia in pancreata with uncommon types of primary neoplasms. Am J Surg Pathol 2006, 30(1):36–41.

    Article  PubMed  Google Scholar 

  21. Yanagisawa A, Ohtake K, Ohashi K, et al. Frequent c-Ki- ras oncogene activation in mucous cell hyperplasias of pancreas suffering from chronic inflammation. Cancer Res 1993, 53:953–956.

    CAS  PubMed  Google Scholar 

  22. Tada M, Ohashi M, Shiratori Y, et al. Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease. Gastroenterology 1996, 110:227–231.

    Article  CAS  PubMed  Google Scholar 

  23. Moskaluk CA, Hruban RH, Kern SE. p16 and K-ras gene mutations in the intraductal precur-sors of human pancreatic adenocarcinoma. Cancer Res 1997, 57:2140–2143.

    CAS  PubMed  Google Scholar 

  24. Lüttges J, Schlehe B, Menke MA, et al. The K-ras mutation pattern in pancreatic ductal aden-ocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium. Cancer 1999, 85(8):1703–1710.

    Article  PubMed  Google Scholar 

  25. Hruban RH, van Mansfeld ADM, Offerhaus GJ, et al. K- ras oncogene activation in adenocar-cinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 1993, 143(2):545–554.

    CAS  PubMed  Google Scholar 

  26. Hruban RH, Goggins M, Parsons JL, et al. Progression model for pancreatic cancer. Clin Cancer Res 2000, 6:2969–2972.

    CAS  PubMed  Google Scholar 

  27. Caldas C, Hahn SA, da Costa LT, et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 1994, 8:27–32.

    Article  CAS  PubMed  Google Scholar 

  28. Schutte M, Hruban RH, Geradts J, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 1997, 57:3126–3130.

    CAS  PubMed  Google Scholar 

  29. Wilentz RE, Geradts J, Maynard R, et al. Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res 1998, 58:4740–4744.

    CAS  PubMed  Google Scholar 

  30. Fukushima N, Sato N, Ueki T, et al. Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Am J Pathol 2002, 160 (5):1573–1581.

    CAS  PubMed  Google Scholar 

  31. Yamano M, Fujii H, Takagaki T, et al. Genetic progression and divergence in pancreatic car-cinoma. Am J Pathol 2000, 156(6):2123–2133.

    CAS  PubMed  Google Scholar 

  32. Heinmöller E, Dietmaier W, Zirngibl H, et al. Molecular analysis of microdissected tumors and preneoplastic intraductal lesions in pancreatic carcinoma. Am J Pathol 2000, 157(1):83–92.

    PubMed  Google Scholar 

  33. Hustinx SR, Leoni LM, Yeo CJ, et al. Concordant loss of MTAP and p16/CDKN2A expres-sion in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion. Mod Pathol 2005, 18(7):959–963.

    Article  CAS  PubMed  Google Scholar 

  34. Lüttges J, Galehdari H, Brocker V, et al. Allelic loss is often the first hit in the biallelic inacti-vation of the p53 and DPC4 genes during pancreatic carcinogenesis. Am J Pathol 2001, 158 (5):1677–1683.

    PubMed  Google Scholar 

  35. Boschman CR, Stryker S, Reddy JK, et al. Expression of p53 protein in precursor lesions and adenocarcinoma of human pancreas. Am J Pathol 1994, 145:1291–1295.

    CAS  PubMed  Google Scholar 

  36. DiGiuseppe JA, Hruban RH, Goodman SN, et al. Overexpression of p53 protein in adenocar-cinoma of the pancreas. Am J Clin Pathol 1994, 101:684–688.

    CAS  PubMed  Google Scholar 

  37. McCarthy DM, Brat DJ, Wilentz RE, et al. Pancreatic intraepithelial neoplasia and infiltrating adenocarcinoma: analysis of progression and recurrence by DPC4 immunohistochemical labeling. Hum Pathol 2001, 32:638–642.

    Article  CAS  PubMed  Google Scholar 

  38. Wilentz RE, Iacobuzio-Donahue CA, Argani P, et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progres-sion. Cancer Res 2000, 60:2002–2006.

    CAS  PubMed  Google Scholar 

  39. van Heek NT, Meeker AK, Kern SE, et al. Telomere shortening is nearly universal in pancre-atic intraepithelial neoplasia. Am J Pathol 2002, 161(5):1541–1547.

    PubMed  Google Scholar 

  40. Hruban RH, Adsay NV, Albores-Saavedra J, et al. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res 2006, 66 (1):95–106.

    Article  CAS  PubMed  Google Scholar 

  41. Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003, 4(6):437–450.

    Article  CAS  PubMed  Google Scholar 

  42. Hingorani SR, Wang L, Multani AS, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005, 7(5):469–483.

    Article  CAS  PubMed  Google Scholar 

  43. Aguirre AJ, Bardeesy N, Sinha M, et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 2003, 17(24):3112–3126.

    Article  CAS  PubMed  Google Scholar 

  44. Bardeesy N, Morgan J, Sinha M, et al. Obligate roles for p16(Ink4a) and p19(Arf)-p53 in the suppression of murine pancreatic neoplasia. Mol Cell Biol 2002, 22(2):635–643.

    Article  CAS  PubMed  Google Scholar 

  45. Prasad NB, Biankin AV, Fukushima N, et al. Gene expression profiles in pancreatic intraepi-thelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. Cancer Res 2005, 65(5):1619–1626.

    Article  CAS  PubMed  Google Scholar 

  46. Heidenblut AM, Lüttges J, Buchholz M, et al. aRNA-longSAGE: a new approach to generate SAGE libraries from microdissected cells. Nucleic Acids Res 2004, 32(16):e131.

    Article  PubMed  Google Scholar 

  47. 47. Buchholz M, Braun M, Heidenblut A, et al. Transcriptome analysis of microdissected pancre-atic intraepithelial neoplastic lesions. Oncogene 2005.

    Google Scholar 

  48. Adsay NV, Merati K, Andea A, et al. 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. Mod Pathol 2002, 15(10):1087–1095.

    Article  PubMed  Google Scholar 

  49. Kim GE, Bae HI, Park HU, et al. Aberrant expression of MUC5AC and MUC6 gastric mucins and sialyl Tn antigen in intraepithelial neoplasms of the pancreas. Gastroenterology 2002, 123 (4):1052–1060.

    Article  CAS  PubMed  Google Scholar 

  50. Swartz MJ, Batra SK, Varshney GC, et al. MUC4 expression increases progressively in pan-creatic intraepithelial neoplasia. Am J Clin Pathol 2002, 117(5):791–796.

    Article  PubMed  Google Scholar 

  51. Maitra A, Ashfaq R, Gunn CR, et al. Cyclooxygenase 2 expression in pancreatic adenocarci-noma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with auto-mated cellular imaging. Am J Clin Pathol 2002, 118(2):194–201.

    Article  CAS  PubMed  Google Scholar 

  52. Duxbury MS, Matros E, Clancy T, et al. CEACAM6 is a novel biomarker in pancreatic adeno-carcinoma and PanIN lesions. Ann Surg 2005, 241(3):491–496.

    Article  PubMed  Google Scholar 

  53. Maitra A, Adsay NV, Argani P, et al. Multicomponent analysis of the pancreatic adenocarci-noma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol 2003, 16(9):902–912.

    Article  PubMed  Google Scholar 

  54. Brat DJ, Lillemoe KD, Yeo CJ, et al. Progression of pancreatic intraductal neoplasias to infil-trating adenocarcinoma of the pancreas. Am J Surg Pathol 1998, 22(2):163–169.

    Article  CAS  PubMed  Google Scholar 

  55. Brockie E, Anand A, Albores-Saavedra J. Progression of atypical ductal hyperplasia/carci-noma in situ of the pancreas to invasive adenocarcinoma. Ann Diagn Pathol 1998, 2 (5):286–292.

    Article  CAS  PubMed  Google Scholar 

  56. Brentnall TA, Bronner MP, Byrd DR, et al. Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Ann Intern Med 1999, 131(4):247–255.

    CAS  PubMed  Google Scholar 

  57. Canto MI, Goggins M, Yeo CJ, et al. Screening for pancreatic neoplasia in high-risk individu-als: An EUS-based approach. Clin Gastroenterol Hepatol 2004, 2(7):606–621.

    Article  PubMed  Google Scholar 

  58. Canto MI, Goggins M, Hruban RH, et al. Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. Clin Gastroenterol Hepatol 2006, 4(6):766–781.

    Article  PubMed  Google Scholar 

  59. Spinelli KS, Fromwiller TE, Daniel RA, et al. Cystic pancreatic neoplasms: observe or oper-ate. Ann Surg 2004, 239(5):651–657.

    Article  PubMed  Google Scholar 

  60. 60. Tada M, Kawabe T, Arizumi M, et al. Pancreatic cancer in patients with pancreatic cystic lesions: a prospective study in 197 patients. Clin Gastroenterol Hepatol 2006.

    Google Scholar 

  61. Allen PJ, D’Angelica M, Gonen M, et al. A selective approach to the resection of cystic lesions of the pancreas: results from 539 consecutive patients. Ann Surg 2006, 244(4):572–582.

    PubMed  Google Scholar 

  62. O’Shaughnessy JA, Kelloff GJ, Gordon GB, et al. Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res 2002, 8 (2):314–346.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Sol Goldman Pancreatic Cancer Research Center and the John Hopkins Medical Institutions, Baltimore, Maryland, USA

    Ralph H. Hruban MD, Kieran Brune BS & Anirban Maitra MBBS

  2. University of Tokyo, Tokyo, Japan

    Noriyoshi Fukushima MD

Authors
  1. Ralph H. Hruban MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kieran Brune BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noriyoshi Fukushima MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anirban Maitra MBBS
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of California San Diego, La Jolla, CA, USA

    Andrew M. Lowy

  2. School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Steven D. Leach

  3. Wayne State University, Detroit, MI, USA

    Philip A. Philip

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer Science + Business Media, LLC

About this chapter

Cite this chapter

Hruban, R.H., Brune, K., Fukushima, N., Maitra, A. (2008). Pancreatic Intraepithelial Neoplasia. In: Lowy, A.M., Leach, S.D., Philip, P.A. (eds) Pancreatic Cancer. M. D. Anderson Solid Tumor Oncology Series. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-69252-4_3

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-69252-4_3

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-387-69250-0

  • Online ISBN: 978-0-387-69252-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation