Medical Oncology

, Volume 27, Issue 2, pp 213–218 | Cite as

Analysis of a case with disappearance of the primary gastrointestinal stromal tumor and progressive liver metastases under long-term treatment with tyrosine kinase inhibitors

  • Silke Cameron
  • Theodoros Savvoukidis
  • Thomas Armbrust
  • Florian Haller
  • Julia Kitz
  • László Füzesi
  • Giuliano RamadoriEmail author
Original Paper


The response of gastrointestinal stromal tumors (GISTs) to tyrosine kinase receptor inhibitors (TKR-I) has been a breakthrough for small molecular therapy. We report here on the very different long-term outcome of a synchronous metastatic GIST with complete remission of the primary tumor and progressive liver metastases under TKR-I therapy. In 2003, a 52-year-old patient was diagnosed with gastric GIST and synchronous multiple liver metastases. Therapy with imatinib, 400 mg daily, was started immediately. Fifteen months later, the primary was no longer detectable by endoscopy. In 2006, progression of the liver metastases was observed. Mutation analysis of the initial biopsy specimen from the primary, as well as the biopsy from the three main liver metastases after 3 years of imatinib treatment, revealed the common KIT exon 11 deletion (W557_K558del) in all tumor samples. Two of the metastases had a separate secondary mutation in KIT exon 14 and 17, respectively, while the largest cystic metastatic lesion had no other mutation. Imatinib was then increased to a daily dose of 800 mg, and in April 2007 the treatment was changed to sunitinib. Fifty-two months after initial diagnosis, the patient died of liver failure. At no time point, relapse of the gastric primary tumor was observed. Whilst TKR-Is are commonly very effective in treating GISTs, the present case illustrates their varying effects regarding the clinical behavior and genetic variations within different tumors of the same patient after long-term treatment.


Gastrointestinal stromal tumor (GIST) Secondary mutations Mutation analysis Tyrosine kinase receptor inhibitor (TKR-I) Treatment response of primary GIST versus metastases 



We are thankful to all our colleagues who participated in the treatment of the patient.


  1. 1.
    Miettinen M, Lasotta J. Gastrointestinal stromal tumors—definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch. 2001;438:1–12. doi: 10.1007/s004280000338.CrossRefPubMedGoogle Scholar
  2. 2.
    Kindblom LG, et al. Incidence, prevalence, phenotype and biologic spectrum of gastrointestinal stromal cell tumors (GIST)—A population based study of 600 cases. Ann Oncol. 2002;13(Suppl 5):157. doi: 10.1093/annonc/mdf012.Google Scholar
  3. 3.
    Hirota S, et al. Gain-of-function mutations of c-Kit in human gastrointestinal stromal tumors. Science. 1998;279:577–80. doi: 10.1126/science.279.5350.577.CrossRefPubMedGoogle Scholar
  4. 4.
    Heinrich MC, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708–10. doi: 10.1126/science.1079666.CrossRefPubMedGoogle Scholar
  5. 5.
    Hirota S, Isozaki K. Pathology of gastrointestinal stromal tumors. Pathol Int. 2006;56:1–9. doi: 10.1111/j.1440-1827.2006.02036.x.CrossRefPubMedGoogle Scholar
  6. 6.
    DeMatteo RP, et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231:51–8. doi: 10.1097/00000658-200001000-00008.CrossRefPubMedGoogle Scholar
  7. 7.
    Pidhorecky I, Cheney RT, Kraybill WG, Gibbs JF. Gastrointestinal stromal tumors: current diagnosis, biologic behavior, and management. Ann Surg Oncol. 2000;7:705–12. doi: 10.1007/s10434-000-0705-6.CrossRefPubMedGoogle Scholar
  8. 8.
    Pierie JP, et al. The effect of surgery and grade on outcome of gastrointestinal stromal tumors. Arch Surg. 2001;136:383–9. doi: 10.1001/archsurg.136.4.383.CrossRefPubMedGoogle Scholar
  9. 9.
    DeMatteo RP, Heinrich MC, El-Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol. 2002;33:466–77. doi: 10.1053/hupa.2002.124122.CrossRefPubMedGoogle Scholar
  10. 10.
    Joensuu H, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344:1052–6. doi: 10.1056/NEJM200104053441404.CrossRefPubMedGoogle Scholar
  11. 11.
    DeMatteo RP, et al. Results of tyrosine kinase inhibitor therapy followed by surgical resection for metastatic gastrointestinal stromal tumor. Ann Surg. 2007;245:347–52. doi: 10.1097/01.sla.0000236630.93587.59.CrossRefPubMedGoogle Scholar
  12. 12.
    Haller F, et al. Surgical management after neoadjuvant imatinib therapy in gastrointestinal stromal tumours (GISTs) with respect to imatinib resistance caused by secondary KIT Mutations. Ann Surg Oncol. 2006;14:526–32. doi: 10.1245/s10434-006-9228-0.CrossRefPubMedGoogle Scholar
  13. 13.
    Joensuu H. Gastrointestinal stromal tumor (GIST). Ann Oncol. 2006;17(Suppl 10):280–6. doi: 10.1093/annonc/mdl274.CrossRefGoogle Scholar
  14. 14.
    Bümming P, et al. Neoadjuvant, adjuvant and palliative treatment of gastrointestinal stromal tumours (GIST) with imatinib: a centre-based study of 17 patients. Br J Cancer. 2003;89:460–4. doi: 10.1038/sj.bjc.6600965.CrossRefPubMedGoogle Scholar
  15. 15.
    Salazar M, et al. First report of a complete pathological response of a pelvic GIST treated with imatinib as neoadjuvant therapy. GUT. 2006;55:585–6. doi: 10.1136/gut.2005.086744.CrossRefPubMedGoogle Scholar
  16. 16.
    Bauer S, Lang H, Schütte J, Hartman JT. Complete remission with imatinib in metastatic gastrointestinal stromal tumors. J Clin Oncol. 2005;23:6800–1. doi: 10.1200/JCO.2005.02.1063.CrossRefPubMedGoogle Scholar
  17. 17.
    Chacon M, Roca E, Huertas E, Sanchez Loria F, Domenechini E. Pathologic complete remission of metastatic gastrointestinal stromal tumor after imatinib mesylate. J Clin Oncol. 2005;23:1580–2. doi: 10.1200/JCO.2005.03.194.CrossRefPubMedGoogle Scholar
  18. 18.
    Bauer S, et al. Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib. Int J Cancer. 2005;117:316–25. doi: 10.1002/ijc.21164.CrossRefPubMedGoogle Scholar
  19. 19.
    Heinrich MC, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008;26:5352–9. doi: 10.1200/JCO.2007.15.7461.CrossRefPubMedGoogle Scholar
  20. 20.
    van der Zwan S, DeMatteo RP. Gastrointestinal stromal tumor: 5 years later. Cancer. 2005;104:1781–8. doi: 10.1002/cncr.21419.CrossRefPubMedGoogle Scholar
  21. 21.
    Lim K-H, et al. Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors. Med Oncol. 2008;25:207–13. doi: 10.1007/s12032-007-9014-2.CrossRefPubMedGoogle Scholar
  22. 22.
    Rubin BP. Gastrointestinal stromal tumours: an update. Histopathol. 2006;48:83–96. doi: 10.1111/j.1365-2559.2005.02291.x.CrossRefGoogle Scholar
  23. 23.
    Heinrich MC, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. JCO. 2006;24:4764–74. doi: 10.1200/JCO.2006.06.2265.CrossRefGoogle Scholar
  24. 24.
    Fletcher CDM, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33:459–65. doi: 10.1053/hupa.2002.123545.CrossRefPubMedGoogle Scholar
  25. 25.
    Miettinen M, El-Rifai W, Sobin LH, Lasota J. Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol. 2002;33:478–83. doi: 10.1053/hupa.2002.124123.CrossRefPubMedGoogle Scholar
  26. 26.
    Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol. 2008;39:1411–9. doi: 10.1016/j.humpath.2008.06.025.CrossRefPubMedGoogle Scholar
  27. 27.
    Judson IR. Prognosis, imatinib dose, and benefit of sunitinib in GIST: knowing the genotype. J Clin Oncol. 2008;26:5322–5. doi: 10.1200/JCO.2008.17.7725.CrossRefPubMedGoogle Scholar
  28. 28.
    Ryu M-H, et al. Patterns of progression in gastrointestinal stromal tumor treated with imatinib mesylate. Jpn J Clin Oncol. 2006;36:17–24. doi: 10.1093/jjco/hyi212.CrossRefPubMedGoogle Scholar
  29. 29.
    Liegl B, et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol. 2008;216:64–74. doi: 10.1002/path.2382.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Silke Cameron
    • 1
  • Theodoros Savvoukidis
    • 1
  • Thomas Armbrust
    • 1
  • Florian Haller
    • 2
  • Julia Kitz
    • 2
  • László Füzesi
    • 2
  • Giuliano Ramadori
    • 1
    Email author
  1. 1.Department of Gastroenterology and EndocrinologyUniversity Clinic of GöttingenGöttingenGermany
  2. 2.Department of GastroenteropathologyUniversity Clinic of the Georg August UniversityGöttingenGermany

Personalised recommendations