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Pathologie und Molekularbiologie gastrointestinaler Stromatumoren (GIST)

Pathology and molecular biology of gastrointestinal stromal tumors (GIST)

Der Radiologe volume 49, pages 1104–1108 (2009)Cite this article

Zusammenfassung

Gastrointestinale Stromatumoren (GIST) zeigen in etwa 50% der Fälle einen aggressiven Phänotyp mit Rezidiven und Metastasen. Sie können immunhistochemisch sicher von anderen mesenchymalen Tumorentitäten unterschieden werden und tragen in bis zu 85% der Fälle aktivierende Mutationen in den Rezeptortyrosinkinasen KIT oder PDGFRA. Die Aufklärung ihrer molekularen Pathogenese hatte einen therapeutischen Paradigmenwechsel zur Folge. Bei inoperablen oder metastasierten GIST stellt die Behandlung mit Tyrosinkinaseinhibitoren heute den Goldstandard dar mit einer Ansprechrate von bis zu 80% bei vergleichsweise geringen Nebenwirkungen. Die Kenntnis der KIT- bzw. PDGFRA-Mutation ist dabei sowohl prognostisch als auch therapeutisch von zentraler Bedeutung.

Abstract

Gastrointestinal stromal tumors (GIST) show an aggressive behavior with metastases and recurrences in up to 50% of cases. They can be clearly distinguished from other mesenchymal tumors by immunohistochemistry in the vast majority of cases. Of the tumors 85% carry somatic activating mutations in the receptor tyrosine kinases KIT or PDGFRA. The detection of these molecular events has changed the treatment of inoperable and metastatic GISTs dramatically as up to 80% of tumors respond well to tyrosine kinase inhibitors. This treatment has become the gold standard in the last few years with only few side effects. Knowledge of the underlying KIT or PDGFRA mutation is both relevant for the prognosis and treatment response.

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Literatur

  1. Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM (1998) Gastrointestinal pacemaker cell tumor (GIPACT) – gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 152:1259–1269

    CAS  PubMed  Google Scholar 

  2. Hirota S, Isozaki K, Moriyama Y et al (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580

    Article  CAS  PubMed  Google Scholar 

  3. Wardelmann E, Neidt I, Bierhoff E et al (2002) c-kit mutations in gastrointestinal stromal tumors occur preferentially in the spindle rather than in the epithelioid cell variant. Mod Pathol 15:125–136

    Article  PubMed  Google Scholar 

  4. Wardelmann E, Pauls K, Merkelbach-Bruse S et al (2004) Gastrointestinale Stromatumoren mit PDGFRa-Mutationen treten bevorzugt im Magen auf und zeigen einen epitheloiden oder gemischten Phänotyp. Verh Dtsch Ges Pathol 88:174–183

    CAS  PubMed  Google Scholar 

  5. Bednar B, Mirejovsky P (1986) Histogenesis of benign pleomorphic mesenchymal tumors. Cesk Patol 22:241–244

    CAS  PubMed  Google Scholar 

  6. Liegl B, Hornick JL, Corless CL, Fletcher CD (2009) Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes. Am J Surg Pathol 33:437–446

    Article  PubMed  Google Scholar 

  7. Fletcher CD, Berman J, Corless CL (2002) Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 33:459–465

    Article  PubMed  Google Scholar 

  8. Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 23:70–83

    Article  PubMed  Google Scholar 

  9. Joensuu H (2008) Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 39(10):1411–1419

    Article  PubMed  Google Scholar 

  10. Corless CL, Mc Greevey L, Haley A et al (2002) KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 160:1567–1572

    CAS  PubMed  Google Scholar 

  11. Rubin BP, Singer S, Tsao C et al (2001) KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61:8118–8121

    CAS  PubMed  Google Scholar 

  12. Taniguchi M, Nishida T, Hirota S (1999) Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. Cancer Res 59:4297–4300

    CAS  PubMed  Google Scholar 

  13. Lasota J, Wozniak A, Sarlomo-Rikala M et al (2000) Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors. Am J Pathol 157:1091–1095

    CAS  PubMed  Google Scholar 

  14. Lux ML, Rubin BP, Biase TL et al (2000) KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol 156:791–795

    CAS  PubMed  Google Scholar 

  15. Heinrich MC, Corless CL, Duensing A et al (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710

    Article  CAS  PubMed  Google Scholar 

  16. Hirota S, Ohashi A, Nishida T et al (2003) Gain-of-function mutations in platelet-derived growth factor receptor a gene in gastrointestinal stromal tumors. Gastroenterology 125:660–667

    Article  CAS  PubMed  Google Scholar 

  17. Lasota J, Dansonka-Mieszkowska A, Sobin L, Miettinen M (2004) A great majority of GIST with PDGFRA mutations represent gastric tumors of low or no malignant potential. Lab Invest 84:874–883

    Article  CAS  PubMed  Google Scholar 

  18. Medeiros F, Corless CL, Duensing A et al (2004) KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications. Am J Surg Pathol 28:889–894

    Article  PubMed  Google Scholar 

  19. Lasota J, Stachura J, Miettinen M (2006) GIST with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology. Lab Invest 86:94–100

    Article  CAS  PubMed  Google Scholar 

  20. Andersson LJ, Sjögren H, Meis-Kindblom JM et al (2002) The complexity of KIT gene mutations and chromosome rearrangements and their clinical correlation in gastrointestinal stromal (pacemaker cell) tumors. Am J Pathol 160:15–22

    CAS  PubMed  Google Scholar 

  21. Bachet JB, Hostein I, Le Cesne A et al (2009) Prognosis and predictive value of KIT exon 11 deletion in GIST. Br J Cancer 101:7–11

    Article  CAS  PubMed  Google Scholar 

  22. Wardelmann E, Losen I, Hans V et al (2003) Deletion of Trp-557 and Lys-558 in the juxtamembrane domain of the c-kit protooncogene is associated with metastatic behavior of gastrointestinal stromal tumors. Int J Cancer 106:887–895

    Article  CAS  PubMed  Google Scholar 

  23. Martin J, Poveda A, Llombart-Bosch A et al (2005) Deletions affecting codons 557-558 of the c-KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors: a study by the Spanish Group for Sarcoma Research (GEIS). J Clin Oncol 23:6190–6198

    Article  CAS  PubMed  Google Scholar 

  24. Lasota J, Dansonka-Mieszkowska A, Stachura T et al (2003) Gastrointestinal stromal tumors with internal tandem duplications in 3‘ end of KIT juxtamembrane domain occur predominantly in stomach and generally seem to have a favorable course. Mod Pathol 16:1257–1264

    Article  PubMed  Google Scholar 

  25. Lasota J, Kopczynski J, Sarlomo-Rikala M (2003) KIT 1530ins6 mutation defines a subset of predominantly malignant gastrointestinal stromal tumors of intestinal origin. Hum Pathol 34:1306–1312

    Article  CAS  PubMed  Google Scholar 

  26. Antonescu C, Sommer G, Sarran L (2003) Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors. Clin Cancer Res 9:3329–3337

    CAS  PubMed  Google Scholar 

  27. Wardelmann E, Hrychyk A, Merkelbach-Bruse S (2004) Association of platelet-derived growth factor receptor alpha mutations with gastric primary site and epithelioid or mixed cell morphology in gastrointestinal stromal tumors. J Mol Diagn 6:197–204

    CAS  PubMed  Google Scholar 

  28. Heinrich MC, Corless CL, Demetri GD (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumors. J Clin Oncol 21:4342–4349

    Article  CAS  PubMed  Google Scholar 

  29. Debiec-Rychter M, Dumez H, Judson I (2004) Use of c-kit/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 40:689–695

    Article  CAS  PubMed  Google Scholar 

  30. Blanke C, Joensuu H, Demetri G (2004) Long-term follow up of advanced gastrointestinal stromal tumor (GIST) patients treated with imatinib mesylate. ASCO Annual Meeting 2004, abstract no. 2

  31. Debiec-Rychter M, Sciot R, Le Cesne A et al (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093–1103

    Article  CAS  PubMed  Google Scholar 

  32. Demetri GD, Desai J, Fletcher J et al (2004) SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST). ASCO Annual Meeting 2004, abstract no. 3001

  33. Ma Y, Zeng S, Metcalfe D et al (2002) The c-kit mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitory sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood 99:1741–1744

    Article  CAS  PubMed  Google Scholar 

  34. Debiec-Rychter M, Cools J, Dumez H et al (2005) Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against Imatinib-resistant mutants. Gastroenterology 128:270–279

    Article  CAS  PubMed  Google Scholar 

  35. Wardelmann E, Thomas N, Merkelbach-Bruse S (2005) Acquired resistance to imatinib in gastrointestinal stromal tumors caused by multiple KIT mutations. Lancet Oncol 6:249–251

    Article  CAS  PubMed  Google Scholar 

  36. Wardelmann E, Merkelbach-Bruse S, Pauls K et al (2006) Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 12:1743–1749

    Article  CAS  PubMed  Google Scholar 

  37. Prenen H, Cools J, Mentens N et al (2006) Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin Cancer Res 12:2622–2627

    Article  CAS  PubMed  Google Scholar 

  38. Demetri GD, Benjamin RS, Blanke CD et al (2007) management of patients with gastrointestinal stromal tumor (GIST) – update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 [suppl 2]:S1–S29; quiz S30. Review. Erratum in: J Natl Compr Canc Netw 5(7)

    Google Scholar 

  39. Casali PG, Jost L, Reichardt P et al (2009) ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 20 [suppl 4]:iv64–67

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Interessenkonflikt

Prof. Dr. Eva Wardelmann erhält Vortragshonorare und Studienunterstützung von der Firma Novartis.

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Authors and Affiliations

  1. Institut für Pathologie, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Deutschland

    H.-U. Schildhaus, S. Merkelbach-Bruse, R. Büttner &  E. Wardelmann

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  1. H.-U. Schildhaus
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  2. S. Merkelbach-Bruse
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  3. R. Büttner
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  4. E. Wardelmann
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Correspondence to E. Wardelmann.

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Schildhaus, HU., Merkelbach-Bruse, S., Büttner, R. et al. Pathologie und Molekularbiologie gastrointestinaler Stromatumoren (GIST). Radiologe 49, 1104–1108 (2009). https://doi.org/10.1007/s00117-009-1850-y

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  • DOI: https://doi.org/10.1007/s00117-009-1850-y

Schlüsselwörter

  • Gastrointestinale Stromatumoren (GIST)
  • KIT
  • PDGFRα
  • Mutationsstatus

Keywords

  • Gastrointestinal stromal tumors (GIST)
  • KIT
  • PDGFRα
  • Mutation status