Skip to main content

Advertisement

SpringerLink
Log in

Gastrointestinal stromal tumors (GISTs): SEAP–SEOM consensus on pathologic and molecular diagnosis

  • Special Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

An Erratum to this article was published on 30 January 2017

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, with an incidence of 1.1 cases/100,000 inhabitants/year. A group of experts from the Spanish Society of Pathology and the Spanish Society of Oncology met to discuss a brief update on GISTs and agree on aspects relating to the pathological and molecular diagnosis of these tumors. GISTs are generally solitary, well-circumscribed lesions of variable size (<10 mm–35 cm) that may present with intra- or extra-luminal parietal growth or a mixed-type (hourglass) growth pattern. Histologically, they are unencapsulated neoplasms displaying expansive growth and spindle-shaped (70%), epithelioid (20%), or mixed cellularity (10%). Mitotic activity is generally moderate or low and should be evaluated only in areas with high cellularity or higher mitotic frequency. The great majority of GISTs harbour mutually exclusive activating mutations in genes coding for the type III receptor tyrosine kinases KIT and PDGFRA; less commonly, GISTs have also been reported to display mutations elsewhere, including BRAF and NF1 and SDH-complex genes. The method most widely used to detect KIT and PDGFRA mutations is amplification of the exons involved by polymerase chain reaction followed by direct sequencing (Sanger method) of these amplification products. Molecular analyses should always specify the type of analysis performed, the region or mutations evaluated, and the sensitivity of the detection method employed.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

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

    Article  PubMed  Google Scholar 

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

    Google Scholar 

  3. Coindre JM, Emile JF, Monges G, Ranchere-Vince D, Scoazec JY. Gastrointestinal stromal tumors: definition, histological, immunohistochemical, and molecular features, and diagnostic strategy. Ann Pathol. 2005;25:358–85.

    Article  PubMed  Google Scholar 

  4. 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;279:577–80.

    Article  CAS  PubMed  Google Scholar 

  5. Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998;152:1259–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708–10.

    Article  CAS  PubMed  Google Scholar 

  7. Agaram NP, Wong GC, Guo T, Maki RG, Singer S, Dematteo RP, et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2008;47:853–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. McWhinney SR, Pasini B, Stratakis CA. Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med. 2007;357:1054–6.

    Article  CAS  PubMed  Google Scholar 

  9. 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;344:1052–6.

    Article  CAS  PubMed  Google Scholar 

  10. Rubio J, Marcos-Gragera R, Ortiz MR, Miro J, Vilardell L, Girones J, et al. Population-based incidence and survival of gastrointestinal stromal tumours (GIST) in Girona, Spain. Eur J Cancer. 2007;43:144–8.

    Article  CAS  PubMed  Google Scholar 

  11. Agaimy A, Wunsch PH, Hofstaedter F, Blaszyk H, Rummele P, Gaumann A, et al. Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am J Surg Pathol. 2007;31:113–20.

    Article  PubMed  Google Scholar 

  12. Joensuu H, Vehtari A, Riihimaki J, Nishida T, Steigen SE, Brabec P, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol. 2012;13:265–74.

    Article  PubMed  Google Scholar 

  13. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231:51–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, 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;26:620–5.

    Article  CAS  PubMed  Google Scholar 

  15. Pink D, Schoeler D, Lindner T, Thuss-Patience PC, Kretzschmar A, Knipp H, et al. Severe hypoglycemia caused by paraneoplastic production of IGF-II in patients with advanced gastrointestinal stromal tumors: a report of two cases. J Clin Oncol. 2005;23:6809–11.

    Article  PubMed  Google Scholar 

  16. Agaimy A, Dirnhofer S, Wunsch PH, Terracciano LM, Tornillo L, Bihl MP. Multiple sporadic gastrointestinal stromal tumors (GISTs) of the proximal stomach are caused by different somatic KIT mutations suggesting a field effect. Am J Surg Pathol. 2008;32:1553–9.

    Article  PubMed  Google Scholar 

  17. Otto C, Agaimy A, Braun A, Radecke J, Hoeppner J, Illerhaus G, et al. Multifocal gastric gastrointestinal stromal tumors (GISTs) with lymph node metastases in children and young adults: a comparative clinical and histomorphological study of three cases including a new case of Carney triad. Diagn Pathol. 2011;6:52.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Corless CL, Heinrich MC. Molecular pathobiology of gastrointestinal stromal sarcomas. Ann Rev Pathol. 2008;3:557–86.

    Article  CAS  Google Scholar 

  19. Kalkmann J, Zeile M, Antoch G, Berger F, Diederich S, Dinter D, et al. Consensus report on the radiological management of patients with gastrointestinal stromal tumours (GIST): recommendations of the German GIST Imaging Working Group. Cancer Imaging. 2012;12:126–35.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Poveda A, del Muro XG, Lopez-Guerrero JA, Martinez V, Romero I, Valverde C, et al. GEIS 2013 guidelines for gastrointestinal sarcomas (GIST). Cancer Chemother Pharmacol. 2014;74:883–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Group ESESNW. Gastrointestinal stromal tumours: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii21–6.

    Article  Google Scholar 

  22. Ando N, Goto H, Niwa Y, Hirooka Y, Ohmiya N, Nagasaka T, et al. The diagnosis of GI stromal tumors with EUS-guided fine needle aspiration with immunohistochemical analysis. Gastrointest Endosc. 2002;55:37–43.

    Article  PubMed  Google Scholar 

  23. 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;33:459–65.

    Article  PubMed  Google Scholar 

  24. Rubin BP. Gastrointestinal stromal tumours: an update. Histopathology. 2006;48:83–96.

    Article  CAS  PubMed  Google Scholar 

  25. Liegl-Atzwanger B, Fletcher JA, Fletcher CD. Gastrointestinal stromal tumors. Virchows Arch. 2010;456:111–27.

    Article  PubMed  Google Scholar 

  26. Sobin LH, Gospodarowicz MK, Wittekind C, International Union against Cancer. TNM classification of malignant tumours. Chichester, Hoboken: Wiley-Blackwell; 2010.

    Google Scholar 

  27. The ESMO/European Sarcoma Network Working Group. Gastrointestinal stromal tumours: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii21–6.

    Article  Google Scholar 

  28. Diaz Delgado M, Hernandez Amate A, Pereira Gallardo S, Jaramillo S, Virizuela Echaburu JA, Gonzalez-Campora RJ. Gastrointestinal stromal tumors: morphological, immunohistochemical and molecular changes associated with kinase inhibitor therapy. Pathol Oncol Res. 2011;17:455–61.

    Article  CAS  PubMed  Google Scholar 

  29. Miettinen M, Killian JK, Wang ZF, Lasota J, Lau C, Jones L, et al. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol. 2013;37:234–40.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Patil DT, Rubin BP. Gastrointestinal stromal tumor: advances in diagnosis and management. Arch Pathol Lab Med. 2011;135:1298–310.

    Article  CAS  PubMed  Google Scholar 

  31. Liegl B, Hornick JL, Corless CL, Fletcher CD. Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes. Am J Surg Pathol. 2009;33:437–46.

    Article  PubMed  Google Scholar 

  32. Miettinen M, Wang ZF, Lasota J. DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: a study of 1840 cases. Am J Surg Pathol. 2009;33:1401–8.

    Article  PubMed  Google Scholar 

  33. Rios-Moreno MJ, Jaramillo S, Pereira Gallardo S, Vallejo A, Mora M, Garcia-Escudero A, et al. Gastrointestinal stromal tumors (GISTs): CD117, DOG-1 and PKCtheta expression. Is there any advantage in using several markers? Pathol Res Pract. 2012;208:74–81.

    Article  CAS  PubMed  Google Scholar 

  34. Gonzalez-Campora R, Delgado MD, Amate AH, Gallardo SP, Leon MS, Beltran AL. Old and new immunohistochemical markers for the diagnosis of gastrointestinal stromal tumors. Anal Quant Cytol Histol. 2011;33:1–11.

    PubMed  Google Scholar 

  35. Lasota J, Wang Z, Kim SY, Helman L, Miettinen M. Expression of the receptor for type i insulin-like growth factor (IGF1R) in gastrointestinal stromal tumors: an immunohistochemical study of 1078 cases with diagnostic and therapeutic implications. Am J Surg Pathol. 2013;37:114–9.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lee HE, Kim MA, Lee HS, Lee BL, Kim WH. Characteristics of KIT-negative gastrointestinal stromal tumours and diagnostic utility of protein kinase C theta immunostaining. J Clin Pathol. 2008;61:722–9.

    Article  CAS  PubMed  Google Scholar 

  37. Parkkila S, Lasota J, Fletcher JA, Ou WB, Kivela AJ, Nuorva K, et al. Carbonic anhydrase II. A novel biomarker for gastrointestinal stromal tumors. Mod Pathol. 2010;23:743–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Patil DT, Ma S, Konishi M, Carver PD, Pukay M, Beadling C, et al. Utility of BRAF V600E mutation-specific immunohistochemistry in detecting BRAF V600E-mutated gastrointestinal stromal tumors. Am J Clin Pathol. 2015;144:782–9.

    Article  CAS  PubMed  Google Scholar 

  39. Doyle LA, Nelson D, Heinrich MC, Corless CL, Hornick JL. Loss of succinate dehydrogenase subunit B (SDHB) expression is limited to a distinctive subset of gastric wild-type gastrointestinal stromal tumours: a comprehensive genotype-phenotype correlation study. Histopathology. 2012;61:801–9.

    Article  PubMed  Google Scholar 

  40. Martin-Broto J, Rubio L, Alemany R, Lopez-Guerrero JA. Clinical implications of KIT and PDGFRA genotyping in GIST. Clin Transl Oncol. 2010;12:670–6.

    Article  CAS  PubMed  Google Scholar 

  41. Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 2008;53:245–66.

    Article  CAS  PubMed  Google Scholar 

  42. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22:3813–25.

    Article  CAS  PubMed  Google Scholar 

  43. Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005;23:5357–64.

    Article  CAS  PubMed  Google Scholar 

  44. Agaimy A, Terracciano LM, Dirnhofer S, Tornillo L, Foerster A, Hartmann A, et al. V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours. J Clin Pathol. 2009;62:613–6.

    Article  CAS  PubMed  Google Scholar 

  45. Pantaleo MA, Astolfi A, Urbini M, Nannini M, Paterini P, Indio V, et al. Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST. Eur J Hum Genet. 2014;22:32–9.

    Article  CAS  PubMed  Google Scholar 

  46. Miettinen M, Lasota J. Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review. Int J Biochem Cell Biol. 2014;53:514–9.

    Article  CAS  PubMed  Google Scholar 

  47. Killian JK, Miettinen M, Walker RL, Wang Y, Zhu YJ, Waterfall JJ, et al. Recurrent epimutation of SDHC in gastrointestinal stromal tumors. Sci Transl Med. 2014;6:268ra177.

    Article  PubMed  Google Scholar 

  48. Pauls K, Merkelbach-Bruse S, Thal D, Buttner R, Wardelmann E. PDGFRalpha- and c-kit-mutated gastrointestinal stromal tumours (GISTs) are characterized by distinctive histological and immunohistochemical features. Histopathology. 2005;46:166–75.

    Article  CAS  PubMed  Google Scholar 

  49. Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol. 2008;39:1411–9.

    Article  PubMed  Google Scholar 

  50. Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, Ganjoo KN, Maki RG, et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. Natl Compr Cancer Netw. 2010;8(Suppl 2):S1–41.

    CAS  Google Scholar 

  51. Martin J, Poveda A, Llombart-Bosch A, Ramos R, Lopez-Guerrero JA, Garcia del Muro J, et al. Deletions affecting codons 557-558 of the c-KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors: a study by the Spanish Group for Sarcoma Research (GEIS). J Clin Oncol. 2005;23:6190–8.

    Article  CAS  PubMed  Google Scholar 

  52. Wozniak A, Rutkowski P, Piskorz A, Ciwoniuk M, Osuch C, Bylina E, et al. Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumours (GIST): Polish Clinical GIST Registry experience. Ann Oncol. 2012;23:353–60.

    Article  CAS  PubMed  Google Scholar 

  53. Martin-Broto J, Gutierrez A, Garcia-del-Muro X, Lopez-Guerrero JA, Martinez-Trufero J, de Sande LM, et al. Prognostic time dependence of deletions affecting codons 557 and/or 558 of KIT gene for relapse-free survival (RFS) in localized GIST: a Spanish Group for Sarcoma Research (GEIS) Study. Ann Oncol. 2010;21:1552–7.

    Article  CAS  PubMed  Google Scholar 

  54. Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:1097–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schutte J, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307:1265–72.

    Article  CAS  PubMed  Google Scholar 

  56. Casali PG, Le Cesne A, Poveda Velasco A, Kotasek D, Rutkowski P, Hohenberger P, et al. Time to definitive failure to the first tyrosine kinase inhibitor in localized GI stromal tumors treated with imatinib as an adjuvant: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas. J Clin Oncol. 2015;33:4276–83.

    Article  CAS  PubMed  Google Scholar 

  57. Wozniak A, Rutkowski P, Schoffski P, Ray-Coquard I, Hostein I, Schildhaus HU, et al. Tumor genotype is an independent prognostic factor in primary gastrointestinal stromal tumors of gastric origin: a European multicenter analysis based on ConticaGIST. Clin Cancer Res. 2014;20:6105–16.

    Article  CAS  PubMed  Google Scholar 

  58. 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;364:1127–34.

    Article  CAS  PubMed  Google Scholar 

  59. 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;26:626–32.

    Article  CAS  PubMed  Google Scholar 

  60. Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 2006;42:1093–103.

    Article  CAS  PubMed  Google Scholar 

  61. 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;368:1329–38.

    Article  CAS  PubMed  Google Scholar 

  62. Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:295–302.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Fernando Rico-Villademoros (COCIENTE SL, Madrid, Spain) for editorial assistance in the preparation of this manuscript. SEOM and SEAP are grateful for financial support for this project in the form of unrestricted Grants from Bayer and Pfizer.

Author information

Authors and Affiliations

  1. Instituto de Biomedicina de Sevilla, IBIS, Medical Oncology, Virgen del Rocío University Hospital, Seville, Spain

    J. Martin-Broto & N. Hindi

  2. Medical Oncology, La Paz University Hospital, Madrid, Spain

    V. Martinez-Marín

  3. Sarcoma Translational Research Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona, Spain

    C. Serrano

  4. Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain

    J. A. López-Guerrero

  5. Pathology Department, Son Espases University Hospital, Palma de Mallorca, Spain

    R. Ramos-Asensio

  6. Pathology Department, Virgen Macarena University Hospital, Seville, Spain

    A. Vallejo-Benítez & R. González-Cámpora

  7. Pathology Department, Virgen del Rocío University Hospital, Seville, Spain

    D. Marcilla-Plaza

Authors
  1. J. Martin-Broto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. Martinez-Marín
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Serrano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. Hindi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. A. López-Guerrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R. Ramos-Asensio
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Vallejo-Benítez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D. Marcilla-Plaza
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R. González-Cámpora
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Martin-Broto.

Ethics declarations

Conflict of interest

The authors declare that, when writing and revising the text, they did not know the names of the pharmaceutical companies that provided financial support for this project, so this support has not influenced the content of this article.

Ethical statement

The manuscript does not contain clinical studies or patient data

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s12094-017-1619-0.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martin-Broto, J., Martinez-Marín, V., Serrano, C. et al. Gastrointestinal stromal tumors (GISTs): SEAP–SEOM consensus on pathologic and molecular diagnosis. Clin Transl Oncol 19, 536–545 (2017). https://doi.org/10.1007/s12094-016-1581-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-016-1581-2

Keywords

Search

Navigation