Seminars in Oncology
Volume 36, Issue 4 , Pages 290-301 , August 2009

Gastrointestinal Stromal Tumors I: Pathology, Pathobiology, Primary Therapy, and Surgical Issues

  • Peter Reichardt

      Affiliations

    • Sarcoma Center Berlin-Brandenburg, HELIOS Klinikum Bad Saarow, Bad Saarow, Germany
    • These authors contributed equally to this work.
    • ,
  • Pancras C.W. Hogendoorn

      Affiliations

    • Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
    • These authors contributed equally to this work.
    • ,
  • Elena Tamborini

      Affiliations

    • Laboratory of Experimental Molecular Pathology, IRCCS Foundation, Istituto Nazionale Tumori, Milan, Italy
    • These authors contributed equally to this work.
    • ,
  • Massimo Loda

      Affiliations

    • Dana-Farber Cancer Institute, Boston, MA
    • These authors contributed equally to this work.
    • ,
  • Alessandro Gronchi

      Affiliations

    • Department of Surgery, Istituto Nazionale Tumori, Milan, Italy
    • These authors contributed equally to this work.
    • ,
  • Andrés Poveda

      Affiliations

    • Instituto Valenciano de Oncología, Valencia, Spain
    • These authors contributed equally to this work.
    • ,
  • Patrick Schöffski

      Affiliations

    • University Hospitals Leuven, Department of General Medical Oncology and Laboratory of Experimental Oncology Leuven Cancer Institute, Catholic University Leuven, Leuven, Belgium
    • These authors contributed equally to this work.
    • Corresponding Author InformationAddress correspondence to Patrick Schöffski, MD, MPH, University Hospitals Leuven, Department of General Medical Oncology and Laboratory of Experimental Oncology, Leuven Cancer Institute, Catholic University Leuven, Herestraat 49, B-3000 Leuven, Belgium

References 

  1. Goettsch WG, Bos SD, Breekveldt-Postma N, Casparie M, Herings RM, Hogendoorn PC. Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer. 2005;41:2868–2872
  2. Miettinen M, Lasota J. Gastrointestinal stromal tumors—definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch. 2001;438:1–12
  3. Corless CL, Heinrich MC. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol. 2008;3:557–586
  4. Nilsson B, Bumming P, Meis-Kindblom JM, Oden A, Dortok A, Gustavsson B, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden. Cancer. 2005;103:821–829
  5. Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CD, et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene. 2001;20:5054–5058
  6. Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344:1052–1056
  7. van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato di Paola E, Dimitrijevic S, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet. 2001;358:1421–1423
  8. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–480
  9. Verweij J, van Oosterom A, Blay JY, Judson I, Rodenhuis S, van der Graaf W, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target (Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study). Eur J Cancer. 2003;39:2006–2011
  10. Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26:626–632
  11. Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364:1127–1134
  12. Benjamin RS, Choi H, Macapinlac HA, Burgess MA, Patel SR, Chen LL, et al. We should desist using RECIST, at least in GIST. J Clin Oncol. 2007;25:1760–1764
  13. Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753–1759
  14. Blay JY, Le Cesne A, Ray-Coquard I, Bui B, Duffaud F, Delbaldo C, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol. 2007;25:1107–1113
  15. Le Cesne A, Ray-Coquard I, Bui B, Rios M, Adenis A, Bertucci F, et al. Continuous versus interruption of imatinib in responding patients with advanced GIST after three years of treatment: a prospective randomized phase III trial of the French Sarcoma Group [abstract]. J Clin Oncol. 2007;25:10005
  16. Van Glabbeke MM, Owzar K, Rankin C, Simes J, Crowley J. Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): a meta-analyis based on 1,640 patients [abstract]. J Clin Oncol. 2007;25:10004
  17. Demetri GD, Benjamin RS, Blanke CD, Blay JY, Casali P, Choi H, et al. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)—update of the NCCN clinical practice guidelines. J Natl Compr Cancer Netw. 2007;5(Suppl 2):S1–S29
  18. Zalcberg JR, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay JY, et al. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer. 2005;41:1751–1757
  19. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329–1338
  20. DeMatteo R, Owzar K, Maki R, Pisters P, Blackstein M, Antonescu C, et al. Adjuvant imatinib mesylate increases recurrence free survival in patients with completely resected localized primary gastrointestinal stromal tumor: North American Intergroup phase III trial ACOSOG Z9001 [abstract]. J Clin Oncol. 2007;25:10079
  21. Fiore M, Palassini E, Fumagalli E, Pilotti S, Tamborini E, Stacchiotti S, et al. Preoperative imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumors (GIST). Eur J Surg Oncol. 2009;35:739–745
  22. Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol. 2009;99:42–47
  23. McAuliffe JC, Hunt KK, Lazar AJ, Choi H, Qiao W, Thall P, et al. A randomized, phase II study of preoperative plus postoperative imatinib in GIST: evidence of rapid radiographic response and temporal induction of tumor cell apoptosis. Ann Surg Oncol. 2008;
  24. Kitamura Y, Hirota S, Nishida T. Molecular pathology of c-kit proto-oncogene and development of gastrointestinal stromal tumors. Ann Chir Gynaecol. 1998;87:282–286
  25. Sciot R, Debiec-Rychter M, Daugaard S, Fisher C, Collin F, van Glabbeke M, et al. Distribution and prognostic value of histopathologic data and immunohistochemical markers in gastrointestinal stromal tumours (GISTs): an analysis of the EORTC phase III trial of treatment of metastatic GISTs with imatinib mesylate. Eur J Cancer. 2008;44:1855–1860
  26. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–580
  27. Fletcher CD. Clinicopathologic correlations in gastrointestinal stromal tumors. Hum Pathol. 2002;33:455
  28. Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33:459–465
  29. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol. 2002;33:484–495
  30. Graadt van Roggen JF, van Velthuysen ML, Hogendoorn PC. The histopathological differential diagnosis of gastrointestinal stromal tumours. J Clin Pathol. 2001;54:96–102
  31. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708–710
  32. Hoeben A, Schöffski P, Debiec-Rychter M. Clinical implications of mutational analysis in gastrointestinal stromal tumours. Br J Cancer. 2008;98:684–688
  33. Isozaki K, Hirota S. Gain-of-function mutations of receptor tyrosine kinases in gastrointestinal stromal tumors. Curr Genomic. 2006;7:469–475
  34. Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 2008;53:245–266
  35. Mol CD, Dougan DR, Schneider TR, Skene RJ, Kraus ML, Scheibe DN, et al. Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem. 2004;279:31655–31663
  36. Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher A, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620–625
  37. Keun Park C, Lee EJ, Kim M, Lim HY, Choi DI, Noh JH, et al. Prognostic stratification of high-risk gastrointestinal stromal tumors in the era of targeted therapy. Ann Surg. 2008;247:1011–1018
  38. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22:3813–3825
  39. Gold JS, van der Zwan SM, Gonen M, Maki RG, Singer S, Brennan MF, et al. Outcome of metastatic GIST in the era before tyrosine kinase inhibitors. Ann Surg Oncol. 2007;14:134–142
  40. Casali PG, Jost L, Reichardt P, Schlemmer M, Blay JY. Gastrointestinal stromal tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008;19(Suppl 2):ii35–ii38
  41. Debiec-Rychter M, Dumez H, Judson I, Wasag B, Verweij J, Brown M, et al. 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. 2004;40:689–695
  42. Agaram NP, Besmer P, Wong GC, Guo T, Socci ND, Maki RG, et al. Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors. Clin Cancer Res. 2007;13:170–181
  43. Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11:4182–4190
  44. Desai J, Shankar S, Heinrich MC, Fletcher JA, Fletcher CD, Manola J, et al. Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors. Clin Cancer Res. 2007;13:5398–5405
  45. Nishida T, Kanda T, Nishitani A, Takahashi T, Nakajima K, Ishikawa T, et al. Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor. Cancer Sci. 2008;99:799–804
  46. Tamborini E, Bonadiman L, Greco A, Albertini V, Negri T, Gronchi A, et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology. 2004;127:294–299
  47. Wardelmann E, Thomas N, Merkelbach-Bruse S, Pauls K, Speidel N, Buttner R, et al. Acquired resistance to imatinib in gastrointestinal stromal tumours caused by multiple KIT mutations. Lancet Oncol. 2005;6:249–251
  48. DeMatteo RP, Maki RG, Singer S, Gonen M, Brennan MF, Antonescu CR. Results of tyrosine kinase inhibitor therapy followed by surgical resection for metastatic gastrointestinal stromal tumor. Ann Surg. 2007;245:347–352
  49. Gronchi A, Fiore M, Miselli F, Lagonigro MS, Coco P, Messina A, et al. Surgery of residual disease following molecular-targeted therapy with imatinib mesylate in advanced/metastatic GIST. Ann Surg. 2007;245:341–346
  50. Raut CP, Posner M, Desai J, Morgan JA, George S, Zahrieh D, et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol. 2006;24:2325–2331
  51. Rutkowski P, Nowecki Z, Nyckowski P, Dziewirski W, Grzesiakowska U, Nasierowska-Guttmejer A, et al. Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol. 2006;93:304–311
  52. Van Glabbeke M, Verweij J, Casali PG, Le Cesne A, Hohenberger P, Ray-Coquard I, et al. Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study. J Clin Oncol. 2005;23:5795–5804
  53. Scaife CL, Hunt KK, Patel SR, Benjamin RS, Burgess MA, Chen LL, et al. Is there a role for surgery in patients with “unresectable” cKIT+ gastrointestinal stromal tumors treated with imatinib mesylate?. Am J Surg. 2003;186:665–669
  54. Bauer S, Hartmann JT, de Wit M, Lang H, Grabellus F, Antoch G, et al. Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib. Int J Cancer. 2005;117:316–325
  55. Sym SJ, Ryu MH, Lee JL, Chang HM, Kim TW, Kim HC, et al. Surgical intervention following imatinib treatment in patients with advanced gastrointestinal stromal tumors (GISTs). J Surg Oncol. 2008;98:27–33

Disclosures P. Reichardt: Pfizer, Novartis (honoraria); research funding (Novartis)A. Gronchi: Novartis (honoraria)P. Schöffski: Pfizer (honoraria and research funding); Novartis (honoraria and research funding)Other authors: no significant relationships

PII: S0093-7754(09)00102-X

doi: 10.1053/j.seminoncol.2009.06.002

Seminars in Oncology
Volume 36, Issue 4 , Pages 290-301 , August 2009

Article Tools

* Image Usage & Resolution