Identification and Analysis of Precursors to Invasive Pancreatic Cancer

Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 980)

Abstract

Precursor lesions of pancreatic cancer have been recognized about a century ago. The development of a consistent reproducible nomenclature and classification system for these lesions has been a major advance in the study of these noninvasive precursors. Pancreatic intraepithelial neoplasia (PanIN) as microscopic precursor lesions can be distinguished from mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMN) that are cystic and can often be recognized on imaging. Since precursor lesions harbor the unique chance to treat a patient before a fatal pancreatic cancer can arise a molecular characterization is essential to understand the biology and to find diagnostic and therapeutic targets to fight this disease of near uniform lethality. In order to study precursor lesions on a molecular level a meticulous isolation of the neoplastic cells is inevitable. We present the salient histopathologic and molecular features of precursor lesions of pancreatic cancer as well as methods that have proved to be useful within experimental studies.

Key words

Precursor lesions PanIN IPMN MCN Microdissection 

Notes

Acknowledgements

Anirban Maitra is supported by the Sol Goldman Pancreatic Cancer Research Center and the Michael Rolfe Foundation for Pancreatic Cancer Research. Hanno Matthaei is supported by a fellowship grant by Deutsche Krebshilfe (German Cancer Aid), Bonn, Germany. We are grateful to Dr. Ralph Hruban at Johns Hopkins for his contributions to an earlier edition of this chapter.

References

  1. 1.
    Vincent A, Herman J, Schulick R, Hruban RH, Goggins M (2011) Pancreatic cancer. Lancet 378(9791):607–620 (in eng)PubMedCrossRefGoogle Scholar
  2. 2.
    Yachida S et al (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467(7319):1114–1117 (in eng)PubMedCrossRefGoogle Scholar
  3. 3.
    Jones S et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321(5897):1801–1806 (in eng)PubMedCrossRefGoogle Scholar
  4. 4.
    Matthaei H, Schulick RD, Hruban RH, Maitra A (2011) Cystic precursors to invasive pancreatic cancer. Nat Rev Gastroenterol Hepatol 8(3):141–150 (in eng)PubMedCrossRefGoogle Scholar
  5. 5.
    Klimstra DS, Longnecker DS (1994) K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol 145(6):1547–1550PubMedGoogle Scholar
  6. 6.
    Hruban RH et al (2001) Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 25(5):579–586PubMedCrossRefGoogle Scholar
  7. 7.
    Hruban RH et al (2004) An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 28(8):977–987PubMedCrossRefGoogle Scholar
  8. 8.
    Fernandez-del Castillo C, Adsay NV (2010) Intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology 139(3):708–713, 713 e701–702PubMedCrossRefGoogle Scholar
  9. 9.
    Longnecker DS et al (2005) Histopathological diagnosis of pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms: interobserver agreement. Pancreas 31(4):344–349 (in eng)PubMedCrossRefGoogle Scholar
  10. 10.
    Wu J et al (2011) Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med 3(92):92ra66 (in eng)PubMedCrossRefGoogle Scholar
  11. 11.
    Hruban RH, Klimstra DS, Pitman MB (2006) Tumors of the pancreas. American Registry of Pathology, Washington, DCGoogle Scholar
  12. 12.
    Basturk O, Coban I, Adsay NV (2009) Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications. Arch Pathol Lab Med 133(3):423–438 (in eng)PubMedGoogle Scholar
  13. 13.
    Biankin AV et al (2001) Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia. Cancer Res 61(24):8830–8837PubMedGoogle Scholar
  14. 14.
    Luttges J et al (2001) Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis. Am J Pathol 158(5):1677–1683PubMedCrossRefGoogle Scholar
  15. 15.
    Jansen M et al (2002) Aberrant methylation of the 5′ CpG island of TSLC1 is common in pancreatic ductal adenocarcinoma and is first manifest in high-grade PanlNs. Cancer Biol Ther 1(3):293–296PubMedGoogle Scholar
  16. 16.
    Fukushima N et al (2002) Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Am J Pathol 160(5):1573–1581PubMedCrossRefGoogle Scholar
  17. 17.
    Maitra A et al (2002) Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging. Am J Clin Pathol 118(2):194–201PubMedCrossRefGoogle Scholar
  18. 18.
    Maitra A et al (2003) Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol 16(9):902–912PubMedCrossRefGoogle Scholar
  19. 19.
    Takaori K, Kobashi Y, Matsusue S, Matsui K, Yamamoto T (2003) Clinicopathological features of pancreatic intraepithelial neoplasias and their relationship to intraductal papillary-mucinous tumors. J Hepatobiliary Pancreat Surg 10(2):125–136PubMedCrossRefGoogle Scholar
  20. 20.
    Brat DJ, Lillemoe KD, Yeo CJ, Warfield PB, Hruban RH (1998) Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol 22(2):163–169PubMedCrossRefGoogle Scholar
  21. 21.
    Moskaluk CA, Hruban RH, Kern SE (1997) p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 57(11):2140–2143PubMedGoogle Scholar
  22. 22.
    Maitra A, Wistuba II, Gazdar AF (2001) Microdissection and the study of cancer pathways. Curr Mol Med 1(1):153–162PubMedCrossRefGoogle Scholar
  23. 23.
    Maitra A et al (1999) Enrichment of epithelial cells for molecular studies. Nat Med 5(4):459–463PubMedCrossRefGoogle Scholar
  24. 24.
    Wilentz RE et al (2000) Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas: a new marker of DPC4 inactivation. Am J Pathol 156(1):37–43PubMedCrossRefGoogle Scholar
  25. 25.
    Wilentz RE et al (2000) Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 60(7):2002–2006PubMedGoogle Scholar
  26. 26.
    Iacobuzio-Donahue CA et al (2000) Dpc-4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas: comparison with conventional ductal adenocarcinomas. Am J Pathol 157(3):755–761PubMedCrossRefGoogle Scholar
  27. 27.
    Iacobuzio-Donahue CA et al (2000) Dpc4 protein in mucinous cystic neoplasms of the pancreas: frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am J Surg Pathol 24(11):1544–1548PubMedCrossRefGoogle Scholar
  28. 28.
    Dhanasekaran SM et al (2001) Delineation of prognostic biomarkers in prostate cancer. Nature 412(6849):822–826PubMedCrossRefGoogle Scholar
  29. 29.
    Rubin MA et al (2002) alpha-Methylacyl coenzyme A racemase as a tissue biomarker for prostate cancer. JAMA 287(13):1662–1670PubMedCrossRefGoogle Scholar
  30. 30.
    van Heek NT et al (2002) Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. Am J Pathol 161(5):1541–1547PubMedCrossRefGoogle Scholar
  31. 31.
    Rexhepaj E et al (2010) Validation of cytoplasmic-to-nuclear ratio of survivin as an indicator of improved prognosis in breast cancer. BMC Cancer 10:639 (in eng)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Hanno Matthaei
    • 1
  • Marco Dal Molin
    • 2
    • 3
  • Anirban Maitra
    • 4
  1. 1.Department of Pathology and OncologyThe Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical InstitutionsBaltimoreUSA
  2. 2.Department of PathologyThe Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical InstitutionsBaltimoreUSA
  3. 3.Department of OncologyThe Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical InstitutionsBaltimoreUSA
  4. 4.Departments of Pathology and OncologyThe Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical InstitutionsBaltimoreUSA

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