Advertisement

Pancreatic Intraepithelial Neoplasia

  • Ralph H. Hruban
  • Kieran Brune
  • Noriyoshi Fukushima
  • Anirban Maitra
Part of the M. D. Anderson Solid Tumor Oncology Series book 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).

Keywords

Pancreatic Cancer Chronic Pancreatitis Intraductal Papillary Mucinous Neoplasm Invasive Adenocarcinoma Prostate Stem Cell Antigen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Jemal A, Siegel R, Ward E, et al. Cancer Statistics, CA A Cancer Journal for Clinicians 2008, 58:71–96.CrossRefGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 3.
    Maitra A, Fukushima N, Takaori K, et al. Precursors to invasive pancreatic cancer. Adv Anat Pathol 2005, 12(2):81–91.CrossRefPubMedGoogle Scholar
  4. 4.
    Hulst SPL. Zur kenntnis der Genese des Adenokarzinoms und Karzinoms des Pankreas. Virchows Arch (B) 1905, 180:288–316.CrossRefGoogle Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 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. 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.PubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.PubMedGoogle Scholar
  11. 11.
    Cubilla AL, Fitzgerald PJ. Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res 1976, 36:2690–2698.PubMedGoogle Scholar
  12. 12.
    Kozuka S, Sassa R, Taki T, et al. Relation of pancreatic duct hyperplasia to carcinoma. Cancer 1979, 43:1418–1428.CrossRefPubMedGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 17.
    Volkholz H, Stolte M, Becker V. Epithelial dysplasias in chronic pancreatitis. Virchows Arch A Pathol Anat Histopathol 1982, 396:331–349.CrossRefGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 26.
    Hruban RH, Goggins M, Parsons JL, et al. Progression model for pancreatic cancer. Clin Cancer Res 2000, 6:2969–2972.PubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 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.CrossRefPubMedGoogle Scholar
  34. 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.PubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.CrossRefPubMedGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. 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.CrossRefPubMedGoogle Scholar
  44. 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.CrossRefPubMedGoogle Scholar
  45. 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.CrossRefPubMedGoogle Scholar
  46. 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.CrossRefPubMedGoogle 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. 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.CrossRefPubMedGoogle Scholar
  49. 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.CrossRefPubMedGoogle Scholar
  50. 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.CrossRefPubMedGoogle Scholar
  51. 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.CrossRefPubMedGoogle Scholar
  52. 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.CrossRefPubMedGoogle Scholar
  53. 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.CrossRefPubMedGoogle Scholar
  54. 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.CrossRefPubMedGoogle Scholar
  55. 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.CrossRefPubMedGoogle Scholar
  56. 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.PubMedGoogle Scholar
  57. 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.CrossRefPubMedGoogle Scholar
  58. 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.CrossRefPubMedGoogle Scholar
  59. 59.
    Spinelli KS, Fromwiller TE, Daniel RA, et al. Cystic pancreatic neoplasms: observe or oper-ate. Ann Surg 2004, 239(5):651–657.CrossRefPubMedGoogle 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. 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.PubMedGoogle Scholar
  62. 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.PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2008

Authors and Affiliations

  • Ralph H. Hruban
    • 1
  • Kieran Brune
    • 1
  • Noriyoshi Fukushima
    • 2
  • Anirban Maitra
    • 1
  1. 1.The Sol Goldman Pancreatic Cancer Research Center and the John Hopkins Medical InstitutionsBaltimoreUSA
  2. 2.University of TokyoTokyoJapan

Personalised recommendations