Skip to main content
SpringerLink
Log in

Gastrointestinale Stromatumoren

Evolution eines Tumorkonzepts von unklassifizierbaren Neoplasien zur zielgerichteten molekularen Therapie

Gastrointestinal stromal tumors

Evolution of a tumor concept from unclassifiable neoplasms to targeted molecular therapy

  • Schwerpunkt
  • Published:
Der Pathologe Aims and scope Submit manuscript

Zusammenfassung

Die Entdeckung onkogener C-KIT- und PDGFRA-Mutationen in gastrointestinalen Stromatumoren (GIST) legte die Grundlagen für eine innovative zielgerichtete molekulare Therapie mit den Tyrosinkinaseinhibitoren (TKI) Imatinib (Glivec®), Sunitinib und anderen Substanzen. Dies setzt eine präzise histopathologische Diagnose voraus, ergänzt durch eine Risikostratifizierung zur Abschätzung des malignen Potenzials. Zudem zeigen neuere Erkenntnisse, dass der Nachweis von Mutationen in C-KIT und PDGFRA sowie deren Art und auch die Lokalisation der Mutation innerhalb der Gensequenz von großer Bedeutung für Therapie (Substanzauswahl, Dosisbestimmung, Evaluation sekundärer Resistenz) und Prognose sind. In diesem Artikel wird eine Übersicht über aktuelle Entwicklungen in der histopathologischen und molekularen Diagnostik von GIST und die Relevanz der Mutationsanalyse für die Therapieoptimierung vermittelt.

Abstract

The discovery of activating oncogenic C-KIT and PDGFRA mutations in gastrointestinal stromal tumors (GIST) represented the key for the development of innovative targeted molecular therapy using the tyrosine kinase inhibitors (TKI) Imatinib (Glivec®), Sunitinib and other substances. This makes a precise histopathological diagnosis a major prerequisite, supplemented by appropriate risk stratification for the assessment of the expected biological behavior of individual tumors. Current knowledge demonstrates that the presence of kinase mutations in C-KIT and PDGFRA and their localization within the gene sequence as well as the mutation type are of great importance for planning appropriate treatment (drug selection and dose recommendation), but also for the assessment of prognosis and explanation of secondary resistance to TKI after initial response. This article gives an overview on current developments in the histopathological and molecular diagnostics of GIST and the role of kinase mutation analysis for optimizing patient treatment.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4
Abb. 5

Literatur

  1. Abraham SC, Krasinskas AM, Hofstetter WL et al (2007) Seedling mesenchymal tumors (gastrointestinal stromal tumors and leiomyomas) are common incidental tumors of the esophagogastric region. Am J Surg Pathol 31:1629–1635

    Article  PubMed  Google Scholar 

  2. Agaimy A, Wünsch PH (2006) Gastrointestinal stromal tumours: a regular origin in the muscularis propria, but an extremely diverse gross presentation. A review of 200 GISTs to critically re-evaluate the concept of so-called extra-gastrointestinal stromal tumours. Langenbecks Arch Surg 391:322–329

    Article  PubMed  Google Scholar 

  3. Agaimy A, Wünsch PH, Hofstaedter F et al (2007) Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am J Surg Pathol 31:113–120

    Article  PubMed  Google Scholar 

  4. Agaimy A, Wünsch PH (2009) Lymph node metastasis in gastrointestinal stromal tumours (GIST) occurs preferentially in young patients ≤40 yrs: An overview based on our case material and the literature. Langenbecks Arch Surg 394:375–381

    Article  PubMed  Google Scholar 

  5. Agaimy A, Terracciano LM, Dirnhofer S, et al (2009) V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumors (GISTs). J Clin Pathol 62:613–616

    Article  PubMed  CAS  Google Scholar 

  6. Agaimy A, Märkl B, Arnholdt H et al (2009) Multiple sporadic gastrointestinal stromal tumours arising at different gastrointestinal sites: Pattern of involvement of the muscularis propria as a clue to independent primary GISTs. Virchows Arch 455:101–108

    Article  PubMed  CAS  Google Scholar 

  7. Agaram NP, Wong GC, Guo T et al (2008) Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 47:853–859

    Article  PubMed  CAS  Google Scholar 

  8. Casali PG, Jost L, Reichardt P et al (2009) Gastrointestinal stromal tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 20 (Suppl 4):64–67

    PubMed  Google Scholar 

  9. Corless CL, McGreevey 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

    PubMed  CAS  Google Scholar 

  10. Daimaru Y, Kido H, Hashimoto H, Enjoji M (1988) Benign schwannoma of the gastrointestinal tract: a clinicopathologic and immunohistochemical study. Hum Pathol 19:257–264

    Article  PubMed  CAS  Google Scholar 

  11. Fletcher CDM, Berman JJ, Corless C et al (2002) Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 33:459–465

    Article  PubMed  Google Scholar 

  12. Goettsch WG, Bos SD, Breekveldt-Postma N et al (2005) Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer 41:2868–2872

    Article  PubMed  Google Scholar 

  13. Golden T, Stout AP (1941) Smooth muscle tumors of the gastrointestinal tract and retroperitoneal tissues. Surg Gynecol Obstet 73:784–810

    Google Scholar 

  14. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA (2002) Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol 33:484–495

    Article  PubMed  CAS  Google Scholar 

  15. 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  PubMed  CAS  Google Scholar 

  16. Joensuu H, Roberts PJ, Sarlomo-Rikala M et al (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056

    Article  PubMed  CAS  Google Scholar 

  17. Kawanowa K, Sakuma Y, Sakurai S et al (2006) High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol 37:1527–1535

    Article  PubMed  Google Scholar 

  18. Kindblom L-G, 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

    PubMed  CAS  Google Scholar 

  19. Lasota J, Kopczynski J, Sarlomo-Rikala M et al (2003) KIT 1530Ins6 mutation defines a subset of predominantly malignant gastrointestinal stromal tumors of intestinal origin. Hum Pathol 34:1306–1312

    Article  PubMed  CAS  Google Scholar 

  20. Lasota J, Miettinen M (2006) KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol 23:91–102

    Article  PubMed  Google Scholar 

  21. Lee JR, Joshi V, Griffin JW et al (2001). Gastrointestinal autonomic nerve tumor. Immunohistochemical and molecular identity with gastrointestinal stromal tumor. Am J Surg Pathol 25:979–987

    Article  PubMed  CAS  Google Scholar 

  22. Mazur MT, Clark HB (1983) Gastric stromal tumors: reappraisal of histogenesis. Am J Surg Pathol 7:507–519

    Article  PubMed  CAS  Google Scholar 

  23. 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 

  24. Miettinen M, Virolainen M, Sarlomo-Rikala M (1995) Gastrointestinal stromal tumors: value of CD34 antigen in their identification and separation from true leiomyoma and schwannoma. Am J Surg Pathol 19:207–216

    PubMed  CAS  Google Scholar 

  25. Miettinen M, Sobin LH, Lasota J (2005) Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 29:52–68

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  27. Miettinen M, Wang ZF, Lasota J (2009) DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: a study of 1840 cases. Am J Surg Pathol 33:1401–1408

    Article  PubMed  Google Scholar 

  28. Nilsson B, Bümming P, Meis-Kindblom JM et al (2005) Gastrointestinal stromal tumors: The incidence, prevalence, clinical course, and prognostication in the preimatinib era. A population-based study in Western Sweden. Cancer 103:821–829

    Article  PubMed  Google Scholar 

  29. Reith JD, Goldblum JR, Lyles RH, Weiss SW (2000) Extragastrointestinal (soft tissue) stromal tumors: An analysis of 48 cases with emphasis on histologic predictors of outcome. Mod Pathol 13:577–585

    Article  PubMed  CAS  Google Scholar 

  30. Sciot R, Debiec-Rychter M (2006) GIST under Imatinib therapy. Semin Diagn Pathol 23:84–90

    Article  PubMed  Google Scholar 

  31. Stout AP (1962) Bizarre smooth muscle tumors of the stomach. Cancer 25:400–409

    Article  Google Scholar 

  32. Verweij J, Casali PG, Zalcberg J et al (2004) Progression-free survival in gastrointestinal stomal tumours with high-dose imatinib: randomised trial. Lancet 364:1127–1134

    Article  PubMed  CAS  Google Scholar 

  33. Wardelmann E, Hrychyk A, Merkelbach-Bruse S et al (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

    PubMed  CAS  Google Scholar 

Download references

Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehungen hin: Priv.-Doz. Dr. Agaimy und Prof. Dr. Schneider-Stock erhielten Vortragshonorare von der Firma Novartis.

Author information

Authors and Affiliations

  1. Pathologisches Institut, Universitätsklinikum Erlangen, Krankenhausstr. 12, 91054, Erlangen, Deutschland

    A. Agaimy & R. Schneider-Stock

Authors
  1. A. Agaimy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. Schneider-Stock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Agaimy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Agaimy, A., Schneider-Stock, R. Gastrointestinale Stromatumoren. Pathologe 31, 115–122 (2010). https://doi.org/10.1007/s00292-009-1247-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00292-009-1247-8

Schlüsselwörter

Keywords

Search

Navigation