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Pathophysiology, diagnosis, and treatment of gastrointestinal stromal tumors

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Abstract

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.

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References

  1. MT Mazur HB Clark (1983) ArticleTitleGastric stromal tumors. Reappraisal of histogenesis Am J Surg Pathol 7 507–19 Occurrence Handle6625048

    PubMed  Google Scholar 

  2. H Maeda A Yamagata S Nishikawa K Yoshinaga S Kobayashi K Nishi et al. (1992) ArticleTitleRequirement of c-kit for development of intestinal pacemaker system Development 116 369–75 Occurrence Handle1283735

    PubMed  Google Scholar 

  3. JD Huizinga L Thuneberg M Kluppel J Malysz HB Mikkelsen A Bernstein (1995) ArticleTitleW/kit gene required for intestinal cells of Cajal and for intestinal pacemaker activity Nature 373 347–9 Occurrence Handle10.1038/373347a0 Occurrence Handle7530333

    Article  PubMed  Google Scholar 

  4. K Isozaki S Hirota A Nakama J Miyagawa Y Shinomura Z Xu et al. (1995) ArticleTitleDisturbed intestinal movement, bile reflux to the stomach, and deficiency of c-kit-expressing cells in Ws/Ws mutant rats Gastroenterology 109 456–64 Occurrence Handle10.1016/0016-5085(95)90333-X Occurrence Handle7542218

    Article  PubMed  Google Scholar 

  5. S Hirota K Isozaki Y Moriyama K Hashimoto T Nishida S Ishiguro et al. (1998) ArticleTitleGain-of-function mutations of c-kit in human gastrointestinal stromal tumors Science 279 577–80 Occurrence Handle10.1126/science.279.5350.577 Occurrence Handle9438854

    Article  PubMed  Google Scholar 

  6. M Nakahara K Isozaki S Hirota J Miyagawa N Hase-Sawada M Taniguchi et al. (1998) ArticleTitleA novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors Gastroenterology 115 1090–5 Occurrence Handle9797363

    PubMed  Google Scholar 

  7. MC Heinrich CL Corless A Duensing L McGreevey CJ Chen N Joseph et al. (2003) ArticleTitlePDGFRA activating mutations in gastrointestinal stromal tumors Science 299 708–10 Occurrence Handle10.1126/science.1079666 Occurrence Handle12522257

    Article  PubMed  Google Scholar 

  8. S Hirota A Ohashi T Nishida K Isozaki K Kinoshita Y Shinomura et al. (2003) ArticleTitleGain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors Gastroenterology 125 660–7 Occurrence Handle10.1016/S0016-5085(03)01046-1 Occurrence Handle12949711

    Article  PubMed  Google Scholar 

  9. DA Tuveson NA Willis T Jacks JD Griffin S Singer CD Fletcher et al. (2001) ArticleTitleSTI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications Oncogene 20 5054–8 Occurrence Handle10.1038/sj.onc.1204704 Occurrence Handle11526490

    Article  PubMed  Google Scholar 

  10. P Besmer JE Murphy PC George FH Qiu PJ Bergold L Lederman et al. (1986) ArticleTitleA new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family Nature 320 415–21 Occurrence Handle10.1038/320415a0 Occurrence Handle3007997

    Article  PubMed  Google Scholar 

  11. MC Heinrich BP Rubin BJ Longley JA Fletcher (2002) ArticleTitleBiology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations Hum Pathol 33 484–95 Occurrence Handle10.1053/hupa.2002.124124 Occurrence Handle12094373

    Article  PubMed  Google Scholar 

  12. A Duensing F Medeiros B McConarty NE Joseph D Panigrahy S Singer et al. (2004) ArticleTitleMechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs) Oncogene 23 3999–4006 Occurrence Handle10.1038/sj.onc.1207525 Occurrence Handle15007386

    Article  PubMed  Google Scholar 

  13. ML Lux BP Rubin TL Biase CJ Chen T Maclure G Demetri et al. (2000) ArticleTitleKIT extracellular and kinase domain mutations in gastrointestinal stromal tumors Am J Pathol 156 791–5 Occurrence Handle10702394

    PubMed  Google Scholar 

  14. J Lasota A Wozniak M Sarlomo-Rikala J Rys R Kordek A Nassar et al. (2000) ArticleTitleMutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors. A study of 200 cases Am J Pathol 157 1091–5 Occurrence Handle11021812

    PubMed  Google Scholar 

  15. S Hirota T Nishida K Isozaki M Taniguchi J Nakamura T Okazaki et al. (2001) ArticleTitleGain-of-function mutation at the extracellular domain of KIT in gastrointestinal stromal tumours J Pathol 193 505–10 Occurrence Handle10.1002/1096-9896(2000)9999:9999<::AID-PATH818>3.0.CO;2-E Occurrence Handle11276010

    Article  PubMed  Google Scholar 

  16. S Sakurai S Oguni M Hironaka M Fukayama S Morinaga K Saito (2001) ArticleTitleMutations in c-kit gene exons 9 and 13 in gastrointestinal stromal tumors among Japanese Jpn J Cancer Res 92 494–8 Occurrence Handle11376557

    PubMed  Google Scholar 

  17. BP Rubin S Singer C Tsao A Duensing ML Lux R Ruiz et al. (2001) ArticleTitleKIT activation is a ubiquitous feature of gastrointestinal stromal tumors Cancer Res 61 8118–21 Occurrence Handle11719439

    PubMed  Google Scholar 

  18. K Kinoshita K Isozaki S Hirota T Nishida H Chen M Nakahara et al. (2003) ArticleTitlec-kit gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumors J Gastroenterol Hepatol 18 147–51 Occurrence Handle10.1046/j.1440-1746.2003.02911.x Occurrence Handle12542597

    Article  PubMed  Google Scholar 

  19. MC Heinrich CL Corless GD Demetri CD Blanke M von Mehren H Joensuu et al. (2003) ArticleTitleKinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor J Clin Oncol 21 4342–9 Occurrence Handle14645423

    PubMed  Google Scholar 

  20. HJ Kang SW Nam H Kim H Rhee NG Kim H Kim et al. (2005) ArticleTitleCorrelation of KIT and platelet-derived growth factor receptor alpha mutations with gene activation and expression profiles in gastrointestinal stromal tumors Oncogene 24 1066–74 Occurrence Handle10.1038/sj.onc.1208358 Occurrence Handle15690055

    Article  PubMed  Google Scholar 

  21. T Nishida S Hirota M Taniguchi K Hashimoto K Isazaki H Nakamura et al. (1998) ArticleTitleFamilial gastrointestinal stromal tumors with germline mutation of the KIT gene Nat Genet 19 323–4 Occurrence Handle10.1038/1209 Occurrence Handle9697690

    Article  PubMed  Google Scholar 

  22. S Hirota T Okazaki Y Kitamura (2000) ArticleTitleCause of familial and multiple gastrointestinal autonomic nerve tumors with hyperplasia of interstitial cells of Cajal is germline mutation of the c-kit gene Am J Surg Pathol 24 326–7 Occurrence Handle10.1097/00000478-200002000-00045 Occurrence Handle10680913

    Article  PubMed  Google Scholar 

  23. H Maeyama E Hidaka H Ota S Minami M Kajiyama A Kuraishi et al. (2001) ArticleTitleFamilial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit gene Gastroenterology 120 210–5 Occurrence Handle11208730

    PubMed  Google Scholar 

  24. A Beghini M Tibiletti G Roversi A Chiaravalli G Serio C Capella et al. (2001) ArticleTitleGermline mutation in the juxtamembrane domain of the kit gene in a family with urticaria pigmentosa Cancer 92 658–62 Occurrence Handle10.1002/1097-0142(20010801)92:3<657::AID-CNCR1367>3.0.CO;2-D

    Article  Google Scholar 

  25. M Carballo I Roig F Aguilar MA Pol MJ Gamundi I Hernan et al. (2005) ArticleTitleNovel c-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentation Am J Med Genet 132 361–4 Occurrence Handle10.1002/ajmg.a.30388

    Article  Google Scholar 

  26. K Isozaki B Terris J Belgiti S Schiffmann S Hirota JM Vanderwinden (2000) ArticleTitleGermline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors Am J Pathol 157 1581–5 Occurrence Handle11073817

    PubMed  Google Scholar 

  27. S Hirota T Nishida K Isozaki M Taniguchi K Nishikawa A Ohashi et al. (2002) ArticleTitleFamilial gastrointestinal stromal tumors associated with dysphasia and novel type germline mutation of KIT gene Gastroenterology 122 1493–9 Occurrence Handle10.1053/gast.2002.33024 Occurrence Handle11984533

    Article  PubMed  Google Scholar 

  28. A Chompret C Kannengiesser M Barrois P Terrier P Dahan T Tursz et al. (2004) ArticleTitlePDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor Gastroenterology 126 318–21 Occurrence Handle10.1053/j.gastro.2003.10.079 Occurrence Handle14699510

    Article  PubMed  Google Scholar 

  29. B Wehrle-Haller (2003) ArticleTitleThe role of Kit-ligand in melanocyte development and epidermal homeostasis Pigment Cell Res 16 287–96 Occurrence Handle10.1034/j.1600-0749.2003.00055.x Occurrence Handle12753403

    Article  PubMed  Google Scholar 

  30. BJ Longley DD Metcalfe M Tharp X Wang L Tyrrell SZ Lu et al. (1999) ArticleTitleActivating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis Proc Natl Acad Sci U S A 96 1609–14 Occurrence Handle10.1073/pnas.96.4.1609 Occurrence Handle9990072

    Article  PubMed  Google Scholar 

  31. X Tang M Boxer A Dummond P Ogston M Hodgins AD Burden (2004) ArticleTitleA germline mutation in KIT in familial diffuse cutaneous mastocytosis J Med Genet 41 e88 Occurrence Handle10.1136/jmg.2003.015156 Occurrence Handle15173254

    Article  PubMed  Google Scholar 

  32. H Chen S Hirota K Isozaki H Sun A Ohashi K Kinoshita et al. (2002) ArticleTitleInterstitial cells of Cajal in patients with familial and multiple gastrointestinal stromal tumours Gut 51 793–6 Occurrence Handle10.1136/gut.51.6.793 Occurrence Handle12427778

    Article  PubMed  Google Scholar 

  33. ME Zoller B Rembeck A Oden M Samuelsson L Angervall (1997) ArticleTitleMalignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population Cancer 79 2125–31 Occurrence Handle10.1002/(SICI)1097-0142(19970601)79:11<2125::AID-CNCR9>3.0.CO;2-N Occurrence Handle9179058

    Article  PubMed  Google Scholar 

  34. K Kinoshita S Hirota K Isozaki A Ohashi T Nishida Y Kitamura et al. (2004) ArticleTitleAbsence of c-kit gene mutations in gastrointestinal stromal tumors from neurofibromatosis type 1 patients J Pathol 202 80–5 Occurrence Handle10.1002/path.1487 Occurrence Handle14694524

    Article  PubMed  Google Scholar 

  35. Y Takazawa S Sakurai Y Sakuma T Ikeda J Yamaguchi Y Hashizume et al. (2005) ArticleTitleGastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen’s disease) Am J Surg Pathol 29 755–63 Occurrence Handle10.1097/01.pas.0000163359.32734.f9 Occurrence Handle15897742

    Article  PubMed  Google Scholar 

  36. AE Rader A Avery CL Wait LS McGreevey D Faigel MC Heinrich (2001) ArticleTitleFine-needle aspiration biopsy diagnosis of gastrointestinal stromal tumors using morphology, immunocytochemistry, and mutational analysis of c-kit Cancer 93 269–75 Occurrence Handle10.1002/cncr.9041 Occurrence Handle11507701

    Article  PubMed  Google Scholar 

  37. SQ Li TJ O’Leary LH Sobin YS Erozan DL Rosenthal RM Przygodzki (2000) ArticleTitleAnalysis of KIT mutation and protein expression in fine needle aspirates of gastrointestinal stromal/smooth muscle tumors Acta Cytol 44 981–6 Occurrence Handle11127756

    PubMed  Google Scholar 

  38. K Kinoshita K Isozaki S Tsutsui S Katamura S Hiraoka K Watabe et al. (2003) ArticleTitleEndoscopic ultrasonography-guided fine needle aspiration biopsy in follow-up patients with gastrointestinal stromal tumors Eur J Gastroenterol Hepatol 15 1189–93 Occurrence Handle10.1097/00042737-200311000-00007 Occurrence Handle14560152

    Article  PubMed  Google Scholar 

  39. N Ando H Goto Y Niwa Y Hirooka N Ohmiya T Nagasaka et al. (2002) ArticleTitleThe diagnosis of GI stromal tumors with EUS-guided fine needle aspiration with immunohistochemical analysis Gastrointest Endosc 55 37–43

    Google Scholar 

  40. K Okubo K Yamao T Nakamura M Tajika A Sawaki K Hara et al. (2004) ArticleTitleEndoscopic ultrasound-guided fine-needle aspiration biopsy for the diagnosis of gastrointestinal stromal tumors in the stomach J Gastroenterol 39 747–53 Occurrence Handle10.1007/s00535-004-1383-0 Occurrence Handle15338368

    Article  PubMed  Google Scholar 

  41. CD Fletcher JJ Berman C Coreless F Gorstein J Lasota BJ Longley et al. (2002) ArticleTitleDiagnosis of gastrointestinal stromal tumors: a consensus approach Hum Pathol 33 459–65 Occurrence Handle12094370

    PubMed  Google Scholar 

  42. N Fukuta M Kitano K Maekawa T Chikugo M Kudo (2005) ArticleTitleEstimation of the malignant potential of gastrointestinal stromal tumors: the value of contrast-estimated coded phase-inversion harmonics US J Gastroenterol 40 247–55 Occurrence Handle10.1007/s00535-004-1531-6 Occurrence Handle15830283

    Article  PubMed  Google Scholar 

  43. JY Bray S Bonvalot P Casali H Choi M Debiac-Richter AP DeiTos et al. (2005) ArticleTitleConsensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST consensus conference of 20–21 March 2004, under the auspices of ESMO Ann Oncol 16 566–78 Occurrence Handle10.1093/annonc/mdi127 Occurrence Handle15781488

    Article  PubMed  Google Scholar 

  44. HL Cheng WJ Lee IR Lai RH Yuan SC Yu (1999) ArticleTitleLaparoscopic wedge resection of benign gastric tumor Hepatogastroenterology 46 2100–4 Occurrence Handle10430405

    PubMed  Google Scholar 

  45. M Kimata T Kubota Y Otani M Ohgami Y Ishikawa T Yokoyama et al. (2000) ArticleTitleGastrointestinal stromal tumors treated by laparoscopic surgery: report of three cases Surg Today 30 177–80 Occurrence Handle10.1007/s005950050038 Occurrence Handle10664344

    Article  PubMed  Google Scholar 

  46. H Joensuu PJ Roberts M Sarlomo-Rikala LC Andersson P Tervahartiala D Tuveson et al. (2001) ArticleTitleEffect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor N Engl J Med 344 1052–6 Occurrence Handle11287975

    PubMed  Google Scholar 

  47. GD Demetri M von Mehren CD Blanke AD Van den Abbeele B Eisenberg PJ Roberts et al. (2002) ArticleTitleEfficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors N Engl J Med 347 472–80 Occurrence Handle10.1056/NEJMoa020461 Occurrence Handle12181401

    Article  PubMed  Google Scholar 

  48. J Verweij A van Oosterom J-Y Blay I Judson S Rodenhuis W van der Graaf et al. (2003) ArticleTitleImatinib 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 39 2006–11 Occurrence Handle10.1016/S0959-8049(02)00836-5 Occurrence Handle12957454

    Article  PubMed  Google Scholar 

  49. J Verweij PG Casali J Zalcberg A LeCesne P Reichardt J-Y Blay et al. (2004) ArticleTitleProgression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial Lancet 364 1127–34 Occurrence Handle10.1016/S0140-6736(04)17098-0 Occurrence Handle15451219

    Article  PubMed  Google Scholar 

  50. U De Giorgi J Verweij (2005) ArticleTitleImatinib and gastrointestinal stromal tumors: where do we go from here? Mol Cancer Ther 4 495–501 Occurrence Handle15767559

    PubMed  Google Scholar 

  51. CL Corless JA Fletcher MC Heinrich (2004) ArticleTitleBiology of gastrointestinal stromal tumors J Clin Oncol 22 3813–25 Occurrence Handle15365079

    PubMed  Google Scholar 

  52. E Tamborini L Bonadiman A Greco V Albertini T Negri A Gronchi et al. (2004) ArticleTitleA new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient Gastroenterology 127 294–9 Occurrence Handle10.1053/j.gastro.2004.02.021 Occurrence Handle15236194

    Article  PubMed  Google Scholar 

  53. LL Chen JC Trent EF Wu GN Fuller L Ramdas W Zhang et al. (2004) ArticleTitleA missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors Cancer Res 64 5913–9 Occurrence Handle15342366

    PubMed  Google Scholar 

  54. M Debiec-Rychter J Cools H Dumez R Sciot M Stul N Mentens et al. (2005) ArticleTitleMechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants Gastroenterology 128 270–9 Occurrence Handle10.1053/j.gastro.2004.11.020 Occurrence Handle15685537

    Article  PubMed  Google Scholar 

  55. H Chen K Isozaki K Kinoshita A Ohashi Y Shinomura Y Matsuzawa et al. (2003) ArticleTitleImatinib inhibits various types of activating mutant kit found in gastrointestinal stromal tumors Int J Cancer 105 130–5 Occurrence Handle10.1002/ijc.11025 Occurrence Handle12672043

    Article  PubMed  Google Scholar 

  56. MJ Frost PT Ferrao TP Hughes LK Ashman (2002) ArticleTitleJuxtamembrane mutant V560GKit is more sensitive to imatinib (STI571) compared with wild-type c-kit, whereas the kinase domain mutant D816VKit is resistant Mol Cancer Ther 1 1115–24 Occurrence Handle12481435

    PubMed  Google Scholar 

  57. GD Demetri J Desai JA Fletcher JA Morgan CDM Fletcher A Kazanovicz et al. (2004) ArticleTitleSUI1248, 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 Proc Am Soc Clin Oncol 23 195

    Google Scholar 

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Authors and Affiliations

  1. First Department of Internal Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan

    Yasuhisa Shinomura

  2. Department of Gastroenterology and Hepatology, Osaka University Medical School, Suita, Japan

    Kazuo Kinoshita & Shusaku Tsutsui

  3. Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan

    Seiichi Hirota

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  1. Yasuhisa Shinomura
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  2. Kazuo Kinoshita
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  3. Shusaku Tsutsui
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  4. Seiichi Hirota
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Shinomura, Y., Kinoshita, K., Tsutsui, S. et al. Pathophysiology, diagnosis, and treatment of gastrointestinal stromal tumors. J Gastroenterol 40, 775–780 (2005). https://doi.org/10.1007/s00535-005-1674-0

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