Der Pathologe

, 32:224 | Cite as

Vorläuferläsionen pankreatobiliärer Karzinome

Hauptreferate

Zusammenfassung

Die Vorläuferläsionen der pankreatobiliären Karzinome sind entweder zystisch oder flach. Zu den zystischen Vorläufern des Pankreaskarzinoms gehören die muzinös zystische Neoplasie und die intraduktal papillär muzinöse Neoplasie (IPMN). Das Gegenstück im Gallengang stellt die intraduktal papilläre Neoplasie (IPN) dar. In den zystischen Vorläuferläsionen ist eine Adenom-Karzinom-Sequenz erkennbar, welche meistens auf dem Boden 4 histogenetisch unterschiedlicher Zelltypen entsteht: pankreatobiliär, onkozytär, intestinal und gastrisch. Diese Subtypen der IPMN/IPN sind morphologisch und immunhistochemisch gut charakterisiert und haben eine klinische Relevanz durch ihre unterschiedliche Prognose: Der gastrische Subtyp hat die beste Prognose, gefolgt vom intestinalen und onkozytären Typ, die schlechteste Prognose weist der pankreatobiliäre Typ auf. Die pankreatische intraepitheliale Neoplasie (PanIN) und die biliäre intraepitheliale Neoplasie (BilIN) repräsentieren die flachen Vorläuferläsionen. Die PanIN sind morphologisch und molekularbiologisch gut charakterisiert. PanIN mit lobulozentrischer Atrophie wurde vor Kurzem als eine weitere potenzielle Vorläuferläsion des Pankreaskarzinoms beschrieben. Die BilIN sind morphologisch gut definiert, allerdings sind die zugrunde liegenden molekularen Veränderungen nur wenig erforscht.

Schlüsselwörter

Vorläuferläsion Pankreaskarzinom, duktales Gallengangskarzinom Intraepitheliale Neoplasie Neoplasien, zystische, muzinöse und seröse 

Precursor lesions of pancreatobiliary cancer

Abstract

Precursor lesions of pancreatobiliary cancer can be divided into cystic and flat lesions. Mucinous cystic neoplasm and intraductal papillary mucinous neoplasm (IPMN) comprise the cystic precursors in the pancreas, while intraductal papillary neoplasm (IPN) represents their counterpart in the bile duct system. There is an adenoma-carcinoma sequence in the cystic precursors arising from four different types of epithelia: pancreatobiliary, oncocytic, intestinal and gastric. These subtypes of IPMN/IPN are morphologically and immunohistochemically well characterised and show clinical and prognostic relevance: the gastric subtype is associated with the best prognosis, followed by the oncocytic and intestinal subtypes, while the pancreatobiliary subtype is characterized by adverse clinical behaviour. Pancreatic intraepithelial neoplasia (PanIN) and biliary intraepithelial neoplasia (BilIN) represent the flat precursors. PanIN are morphologically and biologically well defined. PanIN with lobulocentric atrophy has recently been described as a putative precursor of pancreatic cancer. Despite well defined morphological features in BilIN, the molecular alterations seen during early tumor progression in the biliary tract are poorly understood.

Keywords

Precursor lesion Carcinoma, pancreatic ductal Bile duct neoplasm Intraepithelial neoplasm Neoplasms, cystic, mucinous, and serous 

Literatur

  1. 1.
    Abraham SC, Lee J-H, Boitnott JK et al (2002) Microsatellite instability in intraductal papillary neoplasms of the biliary tract. Mod Pathol 15:1309–1317PubMedCrossRefGoogle Scholar
  2. 2.
    Abraham SC, Lee J-H, Hruban RH et al (2003) Molecular and immunohistochemical analysis of intraductal papillary neoplasms of the biliary tract. Hum Pathol 34:902–910PubMedCrossRefGoogle Scholar
  3. 3.
    Adsay NV, Merati K, Basturk O et al (2004) Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an „intestinal“ pathway of carcinogenesis in the pancreas. Am J Surg Pathol 28:839–848PubMedCrossRefGoogle Scholar
  4. 4.
    Aguirre AJ, Bardeesy N, Sinha M et al (2003) Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 17:3112–3126PubMedCrossRefGoogle Scholar
  5. 5.
    Andea A, Sarkar F, Adsay VN (2003) Clinicopathological correlates of pancreatic intraepithelial neoplasia: a comparative analysis of 82 cases with and 152 cases without pancreatic ductal adenocarcinoma. Mod Pathol 16:996–1006PubMedCrossRefGoogle Scholar
  6. 6.
    Biankin AV, Biankin SA, Kench JG et al (2002) Aberrant p16(INK4 A) and DPC4/Smad4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma. Gut 50:861–868PubMedCrossRefGoogle Scholar
  7. 7.
    Le Borgne J, Calan L de, Partensky C (1999) Cystadenomas and cystadenocarcinomas of the pancreas: a multiinstitutional retrospective study of 398 cases. French Surgical Association. Ann Surg 230:152–161CrossRefGoogle Scholar
  8. 8.
    Brune K, Abe T, Canto M et al (2006) 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 30:1067–1076PubMedGoogle Scholar
  9. 9.
    Crippa S, Salvia R, Warshaw AL et al (2008) Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients. Ann Surg 247:571–579PubMedCrossRefGoogle Scholar
  10. 10.
    Detlefsen S, Sipos B, Feyerabend B, Klöppel G (2005) Pancreatic fibrosis associated with age and ductal papillary hyperplasia. Virchows Arch 447:800–805PubMedCrossRefGoogle Scholar
  11. 11.
    Duarte I, Llanos O, Domke H, Harz C, Valdivieso V (1993) Metaplasia and precursor lesions of gallbladder carcinoma. Frequency, distribution, and probability of detection in routine histologic samples. Cancer 72:1878–1884PubMedCrossRefGoogle Scholar
  12. 12.
    Fernández-del Castillo C, Adsay NV (2010) Intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology 139:708–713, 713.e1–2CrossRefGoogle Scholar
  13. 13.
    Fritz S, Fernandez-del Castillo C, Mino-Kenudson M et al (2009) Global genomic analysis of intraductal papillary mucinous neoplasms of the pancreas reveals significant molecular differences compared to ductal adenocarcinoma. Ann Surg 249:440–447PubMedCrossRefGoogle Scholar
  14. 14.
    Fukushima N, Sato N, Prasad N et al (2004) Characterization of gene expression in mucinous cystic neoplasms of the pancreas using oligonucleotide microarrays. Oncogene 23:9042–9051PubMedCrossRefGoogle Scholar
  15. 15.
    Furukawa T, Klöppel G, Volkan Adsay N et al (2005) Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study. Virchows Arch 447:794–799PubMedCrossRefGoogle Scholar
  16. 16.
    Furukawa T, Hatori T, Fujita I et al (2011) Prognostic relevance of morphological types of intraductal papillary mucinous neoplasms of the pancreas. Gut 60:509–516PubMedCrossRefGoogle Scholar
  17. 17.
    Goldin RD, Roa JC (2009) Gallbladder cancer: a morphological and molecular update. Histopathology 55:218–229PubMedCrossRefGoogle Scholar
  18. 18.
    Guerra C, Mijimolle N, Dhawahir A et al (2003) Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4:111–120PubMedCrossRefGoogle Scholar
  19. 19.
    Hingorani SR, Petricoin EF, Maitra A et al (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4:437–450PubMedCrossRefGoogle Scholar
  20. 20.
    Hingorani SR, Wang L, Multani AS et al (2005) Trp53R172 H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7:469–483PubMedCrossRefGoogle Scholar
  21. 21.
    Hoang MP, Murakata LA, Padilla-Rodriguez AL, Albores-Saavedra J (2001) Metaplastic lesions of the extrahepatic bile ducts: a morphologic and immunohistochemical study. Mod Pathol 14:1119–1125PubMedCrossRefGoogle Scholar
  22. 22.
    Hruban RH, Adsay NV, Albores-Saavedra J et al (2001) Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 25:579–586PubMedCrossRefGoogle Scholar
  23. 23.
    Hruban RH, Takaori K, Klimstra DS et al (2004) An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 28:977–987PubMedCrossRefGoogle Scholar
  24. 24.
    Hruban RH, Adsay NV, Albores-Saavedra J et al (2006) Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res 66:95–106PubMedCrossRefGoogle Scholar
  25. 25.
    Hruban RH, Maitra A, Goggins M (2008) Update on pancreatic intraepithelial neoplasia. Int J Exp Pathol 1:306–316Google Scholar
  26. 26.
    Iacobuzio-Donahue CA, Klimstra DS, Adsay NV 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 157:755–761PubMedCrossRefGoogle Scholar
  27. 27.
    Itatsu K, Zen Y, Ohira S et al (2007) Immunohistochemical analysis of the progression of flat and papillary preneoplastic lesions in intrahepatic cholangiocarcinogenesis in hepatolithiasis. Liver Int 27:1174–1184PubMedCrossRefGoogle Scholar
  28. 28.
    Jimenez RE, Warshaw AL, Z’graggen K et al (1999) Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy. Ann Surg 230:501–509; discussion 509–511PubMedCrossRefGoogle Scholar
  29. 29.
    Kaino M, Kondoh S, Okita S et al (1999) Detection of K-ras and p53 gene mutations in pancreatic juice for the diagnosis of intraductal papillary mucinous tumors. Pancreas 18:294–299PubMedCrossRefGoogle Scholar
  30. 30.
    Kang YK, Kim WH, Jang JJ (2002) Expression of G1-S modulators (p53, p16, p27, cyclin D1, Rb) and Smad4/Dpc4 in intrahepatic cholangiocarcinoma. Hum Pathol 33:877–883PubMedCrossRefGoogle Scholar
  31. 31.
    Kawahira H, Kobayashi S, Kaneko K, Asano T, Ochiai T (2000) p53 protein expression in intraductal papillary mucinous tumors (IPMT) of the pancreas as an indicator of tumor malignancy. Hepatogastroenterology 47:973–977PubMedGoogle Scholar
  32. 32.
    Kim YT, Kim J, Jang YH et al (2001) Genetic alterations in gallbladder adenoma, dysplasia and carcinoma. Cancer Lett 169:59–68PubMedCrossRefGoogle Scholar
  33. 33.
    Kim SG, Wu T-T, Lee JH et al (2003) Comparison of epigenetic and genetic alterations in mucinous cystic neoplasm and serous microcystic adenoma of pancreas. Mod Pathol 16:1086–1094PubMedCrossRefGoogle Scholar
  34. 34.
    Klimstra DS, Longnecker DS (1994) K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol 145:1547–1550PubMedGoogle Scholar
  35. 35.
    Kloek JJ, Gaag NA van der, Erdogan D et al (2011) A comparative study of intraductal papillary neoplasia of the biliary tract and pancreas. Hum Pathol 42:824–832PubMedCrossRefGoogle Scholar
  36. 36.
    Klöppel G, Kosmahl M (2006) Is the intraductal papillary mucinous neoplasia of the biliary tract a counterpart of pancreatic papillary mucinous neoplasm? J Hepatol 44:249–250PubMedCrossRefGoogle Scholar
  37. 37.
    Kosmahl M, Pauser U, Peters K et al (2004) Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a review of 418 cases and a classification proposal. Virchows Arch 445:168–178PubMedCrossRefGoogle Scholar
  38. 38.
    Longnecker DS, Adsay NV, Fernandez-del Castillo C et al (2005) Histopathological diagnosis of pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms: interobserver agreement. Pancreas 31:344–349PubMedCrossRefGoogle Scholar
  39. 39.
    Lüttges J, Reinecke-Lüthge A, Möllmann B et al (1999) Duct changes and K-ras mutations in the disease-free pancreas: analysis of type, age relation and spatial distribution. Virchows Arch 435:461–468PubMedCrossRefGoogle Scholar
  40. 40.
    Lüttges J, Zamboni G, Longnecker D, Klöppel G (2001) The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma. Am J Surg Pathol 25:942–948PubMedCrossRefGoogle Scholar
  41. 41.
    Mino-Kenudson M, Fernández-Del Castillo C, Baba Y et al (2011) Prognosis of invasive intraductal papillary mucinous neoplasm depends on histological and precursor epithelial subtypes. Gut: April 20, 2011 (Epub ahead of print) doi:10.1136/gut.2010.232272 Google Scholar
  42. 42.
    Moore PS, Orlandini S, Zamboni G et al (2001) Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but not in exocrine nonductal or endocrine tumorigenesis. Br J Cancer 84:253–262PubMedCrossRefGoogle Scholar
  43. 43.
    Mukawa K, Kawa S, Aoki Y, Zhai Y, Nikaido T (1999) Reduced expression of p53 and cyclin A in intraductal mucin-hypersecreting neoplasm of the pancreas compared with usual pancreatic ductal adenocarcinoma. Am J Gastroenterol 94:2263–2267PubMedCrossRefGoogle Scholar
  44. 44.
    Nishigami T, Onodera M, Torii I et al (2009) Comparison between mucinous cystic neoplasm and intraductal papillary mucinous neoplasm of the branch duct type of the pancreas with respect to expression of CD10 and cytokeratin 20. Pancreas 38:558–564PubMedCrossRefGoogle Scholar
  45. 45.
    Ohtsuka M, Kimura F, Shimizu H et al (2011) Similarities and differences between intraductal papillary tumors of the bile duct with and without macroscopically visible mucin secretion. Am J Surg Pathol 35:512–521PubMedCrossRefGoogle Scholar
  46. 46.
    Pai RK, Mojtahed K, Pai RK (2011) Mutations in the RAS/RAF/MAP kinase pathway commonly occur in gallbladder adenomas but are uncommon in gallbladder adenocarcinomas. Appl Immunohistochem Mol Morphol 19:133–140PubMedCrossRefGoogle Scholar
  47. 47.
    Sahin F, Maitra A, Argani P et al (2003) Loss of Stk11/Lkb1 expression in pancreatic and biliary neoplasms. Mod Pathol 16:686–691PubMedCrossRefGoogle Scholar
  48. 48.
    Sasatomi E, Tokunaga O, Miyazaki K (2000) Precancerous conditions of gallbladder carcinoma: overview of histopathologic characteristics and molecular genetic findings. J Hepatobiliary Pancreat Surg 7:556–567PubMedCrossRefGoogle Scholar
  49. 49.
    Sato N, Rosty C, Jansen M et al (2001) STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol 159:2017–2022PubMedCrossRefGoogle Scholar
  50. 50.
    Sato N, Ueki T, Fukushima N et al (2002) Aberrant methylation of CpG islands in intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology 123:365–372PubMedCrossRefGoogle Scholar
  51. 51.
    Schönleben F, Qiu W, Bruckman KC et al (2007) BRAF and KRAS gene mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) of the pancreas. Cancer Lett 249:242–248PubMedCrossRefGoogle Scholar
  52. 52.
    Sessa F, Solcia E, Capella C et al (1994) Intraductal papillary-mucinous tumours represent a distinct group of pancreatic neoplasms: an investigation of tumour cell differentiation and K-ras, p53 and c-erbB-2 abnormalities in 26 patients. Virchows Arch 425:357–367PubMedCrossRefGoogle Scholar
  53. 53.
    Shi C, Klein AP, Goggins M et al (2009) Increased Prevalence of Precursor Lesions in Familial Pancreatic Cancer Patients. Clin Cancer Res 15:7737–7743PubMedCrossRefGoogle Scholar
  54. 54.
    Shibahara H, Tamada S, Goto M et al (2004) Pathologic features of mucin-producing bile duct tumors: two histopathologic categories as counterparts of pancreatic intraductal papillary-mucinous neoplasms. Am J Surg Pathol 28:327–338PubMedCrossRefGoogle Scholar
  55. 55.
    Sipos B, Frank S, Gress T, Hahn S, Klöppel G (2009) Pancreatic intraepithelial neoplasia revisited and updated. Pancreatology 9:45–54PubMedCrossRefGoogle Scholar
  56. 56.
    Sohn TA, Yeo CJ, Cameron JL et al (2004) Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg 239:788–797; discussion 797–799PubMedCrossRefGoogle Scholar
  57. 57.
    Takaori K, Matsusue S, Fujikawa T et al (1998) Carcinoma in situ of the pancreas associated with localized fibrosis: a clue to early detection of neoplastic lesions arising from pancreatic ducts. Pancreas 17:102–105PubMedCrossRefGoogle Scholar
  58. 58.
    Terris B, Ponsot P, Paye F et al (2000) Intraductal papillary mucinous tumors of the pancreas confined to secondary ducts show less aggressive pathologic features as compared with those involving the main pancreatic duct. Am J Surg Pathol 24:1372–1377PubMedCrossRefGoogle Scholar
  59. 59.
    Thompson LD, Becker RC, Przygodzki RM, Adair CF, Heffess CS (1999) Mucinous cystic neoplasm (mucinous cystadenocarcinoma of low-grade malignant potential) of the pancreas: a clinicopathologic study of 130 cases. Am J Surg Pathol 23:1–16PubMedCrossRefGoogle Scholar
  60. 60.
    Volkan Adsay N (2007) Cystic lesions of the pancreas. Mod Pathol 20(Suppl 1):S71–S93CrossRefGoogle Scholar
  61. 61.
    Wilentz RE, Albores-Saavedra J, Zahurak M et al (1999) Pathologic examination accurately predicts prognosis in mucinous cystic neoplasms of the pancreas. Am J Surg Pathol 23:1320–1327PubMedCrossRefGoogle Scholar
  62. 62.
    Yanagisawa N, Mikami T, Saegusa M, Okayasu I (2001) More frequent beta-catenin exon 3 mutations in gallbladder adenomas than in carcinomas indicate different lineages. Cancer Res 61:19–22PubMedGoogle Scholar
  63. 63.
    Zamboni G, Scarpa A, Bogina G et al (1999) Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors. Am J Surg Pathol 23:410–422PubMedCrossRefGoogle Scholar
  64. 64.
    Zen Y, Adsay NV, Bardadin K et al (2007) Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria. Mod Pathol 20:701–709PubMedCrossRefGoogle Scholar
  65. 65.
    Zen Y, Fujii T, Itatsu K et al (2006) Biliary papillary tumors share pathological features with intraductal papillary mucinous neoplasm of the pancreas. Hepatology 44:1333–1343PubMedCrossRefGoogle Scholar
  66. 66.
    Z’graggen K, Rivera JA, Compton CC et al (1997) Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas. Ann Surg 226:491–498; discussion 498–500CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Abt. Allg. Pathologie und Pathologische Anatomie, Institut für Pathologie und NeuropathologieUniversitätsklinikum TübingenTübingenDeutschland

Personalised recommendations