Journal of Gastroenterology

, Volume 40, Issue 8, pp 775–780

Pathophysiology, diagnosis, and treatment of gastrointestinal stromal tumors

  • Yasuhisa Shinomura
  • Kazuo Kinoshita
  • Shusaku Tsutsui
  • Seiichi Hirota


Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Activating mutations of KIT or the platelet-derived growth factor receptor alpha gene (PDGFRA) have been identified in the vast majority of GISTs. The respective oncoproteins exhibit constitutive tyrosine kinase activity and promote cell growth. KIT and PDGFRA mutations are rarely found in GISTs in patients with neurofibromatosis type 1 (NF1) suggesting that the pathogenesis of GIST in NF1 patients is different from that in non-NF1 patients. Endoscopic diagnosis of GIST is usually difficult. Endoscopic ultrasonography (EUS)-guided fine-needle aspiration biopsy (EUS-FNAB) is a useful method for the diagnosis of GIST and for the detection of KIT or PDGFRA mutations. Imatinib mesylate, a tyrosine kinase inhibitor known to inhibit the activities of BCR-ABL, KIT, and PDGFR, is currently being used for the treatment of both chronic myeloid leukemia and metastatic GIST. The clinical response to imatinib therapy correlates with the types of mutations of KIT and PDGFRA, and the determination of KIT and PDGFRA mutations is useful for predicting the effect of imatinib. Resistance to imatinib after an initial response has been reported; secondary point mutations in KIT or PDGFRA that confer imatinib resistance are the most common mechanisms responsible for acquired resistance to imatinib. The continued development of target-specific therapies should increase the probability of cure in most patients with GISTs.

Key words

KIT PDGFR NF1 tyrosine kinase inhibitor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Mazur, MT, Clark, HB 1983Gastric stromal tumors. Reappraisal of histogenesisAm J Surg Pathol750719PubMedGoogle Scholar
  2. 2.
    Maeda, H, Yamagata, A, Nishikawa, S, Yoshinaga, K, Kobayashi, S, Nishi, K,  et al. 1992Requirement of c-kit for development of intestinal pacemaker systemDevelopment11636975PubMedGoogle Scholar
  3. 3.
    Huizinga, JD, Thuneberg, L, Kluppel, M, Malysz, J, Mikkelsen, HB, Bernstein, A 1995W/kit gene required for intestinal cells of Cajal and for intestinal pacemaker activityNature3733479CrossRefPubMedGoogle Scholar
  4. 4.
    Isozaki, K, Hirota, S, Nakama, A, Miyagawa, J, Shinomura, Y, Xu, Z,  et al. 1995Disturbed intestinal movement, bile reflux to the stomach, and deficiency of c-kit-expressing cells in Ws/Ws mutant ratsGastroenterology10945664CrossRefPubMedGoogle Scholar
  5. 5.
    Hirota, S, Isozaki, K, Moriyama, Y, Hashimoto, K, Nishida, T, Ishiguro, S,  et al. 1998Gain-of-function mutations of c-kit in human gastrointestinal stromal tumorsScience27957780CrossRefPubMedGoogle Scholar
  6. 6.
    Nakahara, M, Isozaki, K, Hirota, S, Miyagawa, J, Hase-Sawada, N, Taniguchi, M,  et al. 1998A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumorsGastroenterology11510905PubMedGoogle Scholar
  7. 7.
    Heinrich, MC, Corless, CL, Duensing, A, McGreevey, L, Chen, CJ, Joseph, N,  et al. 2003PDGFRA activating mutations in gastrointestinal stromal tumorsScience29970810CrossRefPubMedGoogle Scholar
  8. 8.
    Hirota, S, Ohashi, A, Nishida, T, Isozaki, K, Kinoshita, K, Shinomura, Y,  et al. 2003Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumorsGastroenterology1256607CrossRefPubMedGoogle Scholar
  9. 9.
    Tuveson, DA, Willis, NA, Jacks, T, Griffin, JD, Singer, S, Fletcher, CD,  et al. 2001STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implicationsOncogene2050548CrossRefPubMedGoogle Scholar
  10. 10.
    Besmer, P, Murphy, JE, George, PC, Qiu, FH, Bergold, PJ, Lederman, L,  et al. 1986A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene familyNature32041521CrossRefPubMedGoogle Scholar
  11. 11.
    Heinrich, MC, Rubin, BP, Longley, BJ, Fletcher, JA 2002Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterationsHum Pathol3348495CrossRefPubMedGoogle Scholar
  12. 12.
    Duensing, A, Medeiros, F, McConarty, B, Joseph, NE, Panigrahy, D, Singer, S,  et al. 2004Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs)Oncogene2339994006CrossRefPubMedGoogle Scholar
  13. 13.
    Lux, ML, Rubin, BP, Biase, TL, Chen, CJ, Maclure, T, Demetri, G,  et al. 2000KIT extracellular and kinase domain mutations in gastrointestinal stromal tumorsAm J Pathol1567915PubMedGoogle Scholar
  14. 14.
    Lasota, J, Wozniak, A, Sarlomo-Rikala, M, Rys, J, Kordek, R, Nassar, A,  et al. 2000Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors. A study of 200 casesAm J Pathol15710915PubMedGoogle Scholar
  15. 15.
    Hirota, S, Nishida, T, Isozaki, K, Taniguchi, M, Nakamura, J, Okazaki, T,  et al. 2001Gain-of-function mutation at the extracellular domain of KIT in gastrointestinal stromal tumoursJ Pathol19350510CrossRefPubMedGoogle Scholar
  16. 16.
    Sakurai, S, Oguni, S, Hironaka, M, Fukayama, M, Morinaga, S, Saito, K 2001Mutations in c-kit gene exons 9 and 13 in gastrointestinal stromal tumors among JapaneseJpn J Cancer Res924948PubMedGoogle Scholar
  17. 17.
    Rubin, BP, Singer, S, Tsao, C, Duensing, A, Lux, ML, Ruiz, R,  et al. 2001KIT activation is a ubiquitous feature of gastrointestinal stromal tumorsCancer Res61811821PubMedGoogle Scholar
  18. 18.
    Kinoshita, K, Isozaki, K, Hirota, S, Nishida, T, Chen, H, Nakahara, M,  et al. 2003c-kit gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumorsJ Gastroenterol Hepatol1814751CrossRefPubMedGoogle Scholar
  19. 19.
    Heinrich, MC, Corless, CL, Demetri, GD, Blanke, CD, von Mehren, M, Joensuu, H,  et al. 2003Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumorJ Clin Oncol2143429PubMedGoogle Scholar
  20. 20.
    Kang, HJ, Nam, SW, Kim, H, Rhee, H, Kim, NG, Kim, H,  et al. 2005Correlation of KIT and platelet-derived growth factor receptor alpha mutations with gene activation and expression profiles in gastrointestinal stromal tumorsOncogene24106674CrossRefPubMedGoogle Scholar
  21. 21.
    Nishida, T, Hirota, S, Taniguchi, M, Hashimoto, K, Isazaki, K, Nakamura, H,  et al. 1998Familial gastrointestinal stromal tumors with germline mutation of the KIT geneNat Genet193234CrossRefPubMedGoogle Scholar
  22. 22.
    Hirota, S, Okazaki, T, Kitamura, Y 2000Cause of familial and multiple gastrointestinal autonomic nerve tumors with hyperplasia of interstitial cells of Cajal is germline mutation of the c-kit geneAm J Surg Pathol243267CrossRefPubMedGoogle Scholar
  23. 23.
    Maeyama, H, Hidaka, E, Ota, H, Minami, S, Kajiyama, M, Kuraishi, A,  et al. 2001Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit geneGastroenterology1202105PubMedGoogle Scholar
  24. 24.
    Beghini, A, Tibiletti, M, Roversi, G, Chiaravalli, A, Serio, G, Capella, C,  et al. 2001Germline mutation in the juxtamembrane domain of the kit gene in a family with urticaria pigmentosaCancer9265862CrossRefGoogle Scholar
  25. 25.
    Carballo, M, Roig, I, Aguilar, F, Pol, MA, Gamundi, MJ, Hernan, I,  et al. 2005Novel c-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentationAm J Med Genet1323614CrossRefGoogle Scholar
  26. 26.
    Isozaki, K, Terris, B, Belgiti, J, Schiffmann, S, Hirota, S, Vanderwinden, JM 2000Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumorsAm J Pathol15715815PubMedGoogle Scholar
  27. 27.
    Hirota, S, Nishida, T, Isozaki, K, Taniguchi, M, Nishikawa, K, Ohashi, A,  et al. 2002Familial gastrointestinal stromal tumors associated with dysphasia and novel type germline mutation of KIT geneGastroenterology12214939CrossRefPubMedGoogle Scholar
  28. 28.
    Chompret, A, Kannengiesser, C, Barrois, M, Terrier, P, Dahan, P, Tursz, T,  et al. 2004PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumorGastroenterology12631821CrossRefPubMedGoogle Scholar
  29. 29.
    Wehrle-Haller, B 2003The role of Kit-ligand in melanocyte development and epidermal homeostasisPigment Cell Res1628796CrossRefPubMedGoogle Scholar
  30. 30.
    Longley, BJ, Metcalfe, DD, Tharp, M, Wang, X, Tyrrell, L, Lu, SZ,  et al. 1999Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosisProc Natl Acad Sci U S A96160914CrossRefPubMedGoogle Scholar
  31. 31.
    Tang, X, Boxer, M, Dummond, A, Ogston, P, Hodgins, M, Burden, AD 2004A germline mutation in KIT in familial diffuse cutaneous mastocytosisJ Med Genet41e88(Online report)CrossRefPubMedGoogle Scholar
  32. 32.
    Chen, H, Hirota, S, Isozaki, K, Sun, H, Ohashi, A, Kinoshita, K,  et al. 2002Interstitial cells of Cajal in patients with familial and multiple gastrointestinal stromal tumoursGut517936CrossRefPubMedGoogle Scholar
  33. 33.
    Zoller, ME, Rembeck, B, Oden, A, Samuelsson, M, Angervall, L 1997Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish populationCancer79212531CrossRefPubMedGoogle Scholar
  34. 34.
    Kinoshita, K, Hirota, S, Isozaki, K, Ohashi, A, Nishida, T, Kitamura, Y,  et al. 2004Absence of c-kit gene mutations in gastrointestinal stromal tumors from neurofibromatosis type 1 patientsJ Pathol202805CrossRefPubMedGoogle Scholar
  35. 35.
    Takazawa, Y, Sakurai, S, Sakuma, Y, Ikeda, T, Yamaguchi, J, Hashizume, Y,  et al. 2005Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen’s disease)Am J Surg Pathol2975563CrossRefPubMedGoogle Scholar
  36. 36.
    Rader, AE, Avery, A, Wait, CL, McGreevey, LS, Faigel, D, Heinrich, MC 2001Fine-needle aspiration biopsy diagnosis of gastrointestinal stromal tumors using morphology, immunocytochemistry, and mutational analysis of c-kitCancer9326975CrossRefPubMedGoogle Scholar
  37. 37.
    Li, SQ, O’Leary, TJ, Sobin, LH, Erozan, YS, Rosenthal, DL, Przygodzki, RM 2000Analysis of KIT mutation and protein expression in fine needle aspirates of gastrointestinal stromal/smooth muscle tumorsActa Cytol449816PubMedGoogle Scholar
  38. 38.
    Kinoshita, K, Isozaki, K, Tsutsui, S, Katamura, S, Hiraoka, S, Watabe, K,  et al. 2003Endoscopic ultrasonography-guided fine needle aspiration biopsy in follow-up patients with gastrointestinal stromal tumorsEur J Gastroenterol Hepatol15118993CrossRefPubMedGoogle Scholar
  39. 39.
    Ando, N, Goto, H, Niwa, Y, Hirooka, Y, Ohmiya, N, Nagasaka, T,  et al. 2002The diagnosis of GI stromal tumors with EUS-guided fine needle aspiration with immunohistochemical analysisGastrointest Endosc553743Google Scholar
  40. 40.
    Okubo, K, Yamao, K, Nakamura, T, Tajika, M, Sawaki, A, Hara, K,  et al. 2004Endoscopic ultrasound-guided fine-needle aspiration biopsy for the diagnosis of gastrointestinal stromal tumors in the stomachJ Gastroenterol3974753CrossRefPubMedGoogle Scholar
  41. 41.
    Fletcher, CD, Berman, JJ, Coreless, C, Gorstein, F, Lasota, J, Longley, BJ,  et al. 2002Diagnosis of gastrointestinal stromal tumors: a consensus approachHum Pathol3345965PubMedGoogle Scholar
  42. 42.
    Fukuta, N, Kitano, M, Maekawa, K, Chikugo, T, Kudo, M 2005Estimation of the malignant potential of gastrointestinal stromal tumors: the value of contrast-estimated coded phase-inversion harmonics USJ Gastroenterol4024755CrossRefPubMedGoogle Scholar
  43. 43.
    Bray, JY, Bonvalot, S, Casali, P, Choi, H, Debiac-Richter, M, DeiTos, AP,  et al. 2005Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST consensus conference of 20–21 March 2004, under the auspices of ESMOAnn Oncol1656678CrossRefPubMedGoogle Scholar
  44. 44.
    Cheng, HL, Lee, WJ, Lai, IR, Yuan, RH, Yu, SC 1999Laparoscopic wedge resection of benign gastric tumorHepatogastroenterology4621004PubMedGoogle Scholar
  45. 45.
    Kimata, M, Kubota, T, Otani, Y, Ohgami, M, Ishikawa, Y, Yokoyama, T,  et al. 2000Gastrointestinal stromal tumors treated by laparoscopic surgery: report of three casesSurg Today3017780CrossRefPubMedGoogle Scholar
  46. 46.
    Joensuu, H, Roberts, PJ, Sarlomo-Rikala, M, Andersson, LC, Tervahartiala, P, Tuveson, D,  et al. 2001Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumorN Engl J Med34410526PubMedGoogle Scholar
  47. 47.
    Demetri, GD, von Mehren, M, Blanke, CD, Van den Abbeele, AD, Eisenberg, B, Roberts, PJ,  et al. 2002Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumorsN Engl J Med34747280CrossRefPubMedGoogle Scholar
  48. 48.
    Verweij, J, van Oosterom, A, Blay, J-Y, Judson, I, Rodenhuis, S, van der Graaf, W,  et al. 2003Imatinib 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 studyEur J Cancer39200611CrossRefPubMedGoogle Scholar
  49. 49.
    Verweij, J, Casali, PG, Zalcberg, J, LeCesne, A, Reichardt, P, Blay, J-Y,  et al. 2004Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trialLancet364112734CrossRefPubMedGoogle Scholar
  50. 50.
    De Giorgi, U, Verweij, J 2005Imatinib and gastrointestinal stromal tumors: where do we go from here?Mol Cancer Ther4495501PubMedGoogle Scholar
  51. 51.
    Corless, CL, Fletcher, JA, Heinrich, MC 2004Biology of gastrointestinal stromal tumorsJ Clin Oncol22381325PubMedGoogle Scholar
  52. 52.
    Tamborini, E, Bonadiman, L, Greco, A, Albertini, V, Negri, T, Gronchi, A,  et al. 2004A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patientGastroenterology1272949CrossRefPubMedGoogle Scholar
  53. 53.
    Chen, LL, Trent, JC, Wu, EF, Fuller, GN, Ramdas, L, Zhang, W,  et al. 2004A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumorsCancer Res6459139PubMedGoogle Scholar
  54. 54.
    Debiec-Rychter, M, Cools, J, Dumez, H, Sciot, R, Stul, M, Mentens, N,  et al. 2005Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutantsGastroenterology1282709CrossRefPubMedGoogle Scholar
  55. 55.
    Chen, H, Isozaki, K, Kinoshita, K, Ohashi, A, Shinomura, Y, Matsuzawa, Y,  et al. 2003Imatinib inhibits various types of activating mutant kit found in gastrointestinal stromal tumorsInt J Cancer1051305CrossRefPubMedGoogle Scholar
  56. 56.
    Frost, MJ, Ferrao, PT, Hughes, TP, Ashman, LK 2002Juxtamembrane mutant V560GKit is more sensitive to imatinib (STI571) compared with wild-type c-kit, whereas the kinase domain mutant D816VKit is resistantMol Cancer Ther1111524PubMedGoogle Scholar
  57. 57.
    Demetri, GD, Desai, J, Fletcher, JA, Morgan, JA, Fletcher, CDM, Kazanovicz, A,  et al. 2004SUI1248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GISTProc Am Soc Clin Oncol23195(abstr 3001)Google Scholar

Copyright information

© Springer-Verlag Tokyo 2005

Authors and Affiliations

  • Yasuhisa Shinomura
    • 1
  • Kazuo Kinoshita
    • 2
  • Shusaku Tsutsui
    • 2
  • Seiichi Hirota
    • 3
  1. 1.First Department of Internal MedicineSapporo Medical University School of MedicineSapporoJapan
  2. 2.Department of Gastroenterology and HepatologyOsaka University Medical SchoolSuitaJapan
  3. 3.Department of Surgical PathologyHyogo College of MedicineNishinomiyaJapan

Personalised recommendations