Virchows Archiv

, Volume 463, Issue 4, pp 481–487 | Cite as

GISTogram: a graphic presentation of the growing GIST complexity

  • Riccardo Ricci
  • Angelo Paolo Dei Tos
  • Guido Rindi
Review and Perspectives


Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They have represented a paradigm of molecular-targeted therapies for solid tumors since the discovery of KIT mutations and KIT expression in GIST in 1998, which opened the way to the use of imatinib, a tyrosine kinase inhibitor able to inhibit the growth of cells expressing KIT-mutant isoforms. Since then, accumulating evidence revealed the rather heterogeneous nature of GIST, implying possible different diagnostic and therapeutic approaches for each specific case, leading to the development of drugs alternative to imatinib. In this brief commentary, we graphically represent the historical growing of genotype and phenotype evidence on GIST since 1998 in its increasing complexity by building up a graph, which we have called “GISTogram”, that visually conveys most of GIST-characterizing features and the probability for each of them, either alone or in combination, to be observed in a single GIST case.


GIST Genotype Immunophenotype Graph 



This work was in part supported by line D1 grants 2010 and 2011 to RR and GR.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Supplementary material

428_2013_1467_Fig4_ESM.jpg (7 kb)

JPEG 7 kb

428_2013_1467_MOESM1_ESM.tif (10.4 mb)
High-resolution image TIFF 10,689 kb
428_2013_1467_Fig5_ESM.jpg (12 kb)

JPEG 12 kb

428_2013_1467_MOESM2_ESM.tif (10.4 mb)
High-resolution image TIFF 10,689 kb
428_2013_1467_Fig6_ESM.jpg (85 kb)

JPEG 84 kb

428_2013_1467_MOESM3_ESM.tif (10.4 mb)
High-resolution image TIFF 10,689 kb
428_2013_1467_Fig7_ESM.jpg (87 kb)

JPEG 87 kb

428_2013_1467_MOESM4_ESM.tif (10.4 mb)
High-resolution image TIFF 10,689 kb
428_2013_1467_Fig8_ESM.jpg (102 kb)

JPEG 102 kb

428_2013_1467_MOESM5_ESM.tif (10.4 mb)
High-resolution image TIFF 10,689 kb
428_2013_1467_Fig9_ESM.jpg (105 kb)

JPEG 104 kb

428_2013_1467_MOESM6_ESM.tif (10.4 mb)
High-resolution image TIFF 10,690 kb
428_2013_1467_Fig10_ESM.jpg (107 kb)

JPEG 107 kb

428_2013_1467_MOESM7_ESM.tif (10.4 mb)
High-resolution image TIFF 10,690 kb
428_2013_1467_Fig11_ESM.jpg (109 kb)

JPEG 108 kb

428_2013_1467_MOESM8_ESM.tif (10.4 mb)
High-resolution image TIFF 10,690 kb


  1. 1.
    Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580PubMedCrossRefGoogle Scholar
  2. 2.
    Sarlomo-Rikala M, Kovatich AJ, Barusevicius A, Miettinen M (1998) CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol 11:728–734PubMedGoogle Scholar
  3. 3.
    Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM (1998) Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 152:1259–1269PubMedGoogle Scholar
  4. 4.
    Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman S, Capdeville R, Dimitrijevic S, Druker B, Demetri GD (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056PubMedCrossRefGoogle Scholar
  5. 5.
    Emile JF, Brahimi S, Coindre JM, Bringuier PP, Monges G, Samb P, Doucet L, Hostein I, Landi B, Buisine MP, Neuville A, Bouché O, Cervera P, Pretet JL, Tisserand J, Gauthier A, Le Cesne A, Sabourin JC, Scoazec JY, Bonvalot S, Corless CL, Heinrich MC, Blay JY, Aegerter P (2012) Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population-based study differ from those of advanced GISTs. Med Oncol 29:1765–1772PubMedCrossRefGoogle Scholar
  6. 6.
    Steigen SE, Eide TJ, Wasag B, Lasota J, Miettinen M (2007) Mutations in gastrointestinal stromal tumors—a population-based study from Northern Norway. APMIS 115:289–298PubMedCrossRefGoogle Scholar
  7. 7.
    Corless CL, Barnett CM, Heinrich MC (2011) Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer 11:865–878PubMedGoogle Scholar
  8. 8.
    Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710PubMedCrossRefGoogle Scholar
  9. 9.
    Liegl-Atzwanger B, Fletcher JA, Fletcher CD (2010) Gastrointestinal stromal tumors. Virchows Arch 456:111–127PubMedCrossRefGoogle Scholar
  10. 10.
    West RB, Corless CL, Chen X, Rubin BP, Subramanian S, Montgomery K, Zhu S, Ball CA, Nielsen TO, Patel R, Goldblum JR, Brown PO, Heinrich MC, van de Rijn M (2004) The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutational status. Am J Pathol 165:107–113PubMedCrossRefGoogle Scholar
  11. 11.
    Miettinen M, Lasota J (2011) Histopathology of gastrointestinal stromal tumor. J Surg Oncol 104:865–873PubMedCrossRefGoogle Scholar
  12. 12.
    Novelli M, Rossi S, Rodriguez-Justo M, Taniere P, Seddon B, Toffolatti L, Sartor C, Hogendoorn PC, Sciot R, Van Glabbeke M, Verweij J, Blay JY, Hohenberger P, Flanagan A, Dei Tos AP (2010) DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours. Histopathology 57:259–270PubMedCrossRefGoogle Scholar
  13. 13.
    Yamamoto H, Kojima A, Nagata S, Tomita Y, Takahashi S, Oda Y (2011) KIT-negative gastrointestinal stromal tumor of the abdominal soft tissue: a clinicopathologic and genetic study of 10 cases. Am J Surg Pathol 35:1287–1295PubMedCrossRefGoogle Scholar
  14. 14.
    Maertens O, Prenen H, Debiec-Rychter M, Wozniak A, Sciot R, Pauwels P, De Wever I, Vermeesch JR, de Raedt T, De Paepe A, Speleman F, van Oosterom A, Messiaen L, Legius E (2006) Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet 15:1015–1023PubMedCrossRefGoogle Scholar
  15. 15.
    Fuller CE, Williams GT (1991) Gastrointestinal manifestations of type 1 neurofibromatosis (von Recklinghausen's disease). Histopathology 19:1–11PubMedCrossRefGoogle Scholar
  16. 16.
    Kinoshita K, Hirota S, Isozaki K, Ohashi A, Nishida T, Kitamura Y, Shinomura Y, Matsuzawa Y (2004) Absence of c-kit gene mutations in gastrointestinal stromal tumours from neurofibromatosis type 1 patients. J Pathol 202:80–85PubMedCrossRefGoogle Scholar
  17. 17.
    Rossi S, Miceli R, Messerini L, Bearzi I, Mazzoleni G, Capella C, Arrigoni G, Sonzogni A, Sidoni A, Toffolatti L, Laurino L, Mariani L, Vinaccia V, Gnocchi C, Gronchi A, Casali PG, Dei Tos AP (2011) Natural history of imatinib-naive GISTs: a retrospective analysis of 929 cases with long-term follow-up and development of a survival nomogram based on mitotic index and size as continuous variables. Am J Surg Pathol 35:1646–1656PubMedCrossRefGoogle Scholar
  18. 18.
    Agaimy A, Hartmann A (2010) Hereditäre und nichtereditäre syndromale gastrointestinale Stromaltumoren. Pathologe 31:430–437PubMedCrossRefGoogle Scholar
  19. 19.
    Lasota J, Miettinen M (2006) KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol 23:91–102PubMedCrossRefGoogle Scholar
  20. 20.
    Miettinen M, Wang ZF, Sarlomo-Rikala M, Osuch C, Rutkowski P, Lasota J (2011) Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 35:1712–1721PubMedCrossRefGoogle Scholar
  21. 21.
    Chou A, Chen J, Clarkson A, Samra JS, Clifton-Bligh RJ, Hugh TJ, Gill AJ (2012) Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression. Modern Pathol 25:1307–1313CrossRefGoogle Scholar
  22. 22.
    Pappo AS, Janeway K, Laquaglia M, Kim SY (2011) Special considerations in pediatric gastrointestinal tumors. J Surg Oncol 104:928–932PubMedCrossRefGoogle Scholar
  23. 23.
    McWhinney SR, Pasini B, Stratakis CA, International Carney Triad and Carney–Stratakis Syndrome Consortium (2007) Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 357:1054–1056PubMedCrossRefGoogle Scholar
  24. 24.
    Pantaleo MA, Astolfi A, Indio V, Moore R, Thiessen N, Heinrich MC, Gnocchi C, Santini D, Catena F, Formica S, Martelli PL, Casadio R, Pession A, Biasco G (2011) SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. J Natl Cancer Inst 103:983–987PubMedCrossRefGoogle Scholar
  25. 25.
    Celestino R, Lima J, Faustino A, Máximo V, Gouveia A, Vinagre J, Soares P, Lopes JM (2012) A novel germline SDHB mutation in a gastrointestinal stromal tumor patient without bona fide features of the Carney–Stratakis dyad. Fam Cancer 11:189–194PubMedCrossRefGoogle Scholar
  26. 26.
    Janeway KA, Kim SY, Lodish M, Nosé V, Rustin P, Gaal J, Dahia PL, Liegl B, Ball ER, Raygada M, Lai AH, Kelly L, Hornick JL, Pediatric NIH, Wild-Type GIST, Clinic O'SM, de Krijger RR, Dinjens WN, Demetri GD, Antonescu CR, Fletcher JA, Helman L, Stratakis CA (2011) Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A 108:314–318PubMedCrossRefGoogle Scholar
  27. 27.
    Doyle LA, Nelson D, Heinrich MC, Corless CL, Hornick JL (2012) 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 61:801–809PubMedCrossRefGoogle Scholar
  28. 28.
    Lasota J, Wang Z, Kim SY, Helman L, Miettinen M (2013) 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 37:114–119PubMedCrossRefGoogle Scholar
  29. 29.
    Agaram NP, Wong GC, Guo T, Maki RG, Singer S, Dematteo RP, Besmer P, Antonescu CR (2008) Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 47:853–859PubMedCrossRefGoogle Scholar
  30. 30.
    Miranda C, Nucifora M, Molinari F, Conca E, Anania MC, Bordoni A, Saletti P, Mazzucchelli L, Pilotti S, Pierotti MA, Tamborini E, Greco A, Frattini M (2012) KRAS and BRAF mutations predict primary resistance to imatinib in gastrointestinal stromal tumors. Clin Cancer Res 18:1769–1776PubMedCrossRefGoogle Scholar
  31. 31.
    Daniels M, Lurkin I, Pauli R, Erbstösser E, Hildebrandt U, Hellwig K, Zschille U, Lüders P, Krüger G, Knolle J, Stengel B, Prall F, Hertel K, Lobeck H, Popp B, Theissig F, Wünsch P, Zwarthoff E, Agaimy A, Schneider-Stock R (2011) Spectrum of KIT/PDGFRA/BRAF mutations and phosphatidylinositol-3-kinase pathway gene alterations in gastrointestinal stromal tumors (GIST). Cancer Lett 312:43–54PubMedCrossRefGoogle Scholar
  32. 32.
    Agaimy A, Märkl B, Arnholdt H, Wünsch PH, Terracciano LM, Dirnhofer S, Hartmann A, Tornillo L, Bihl MP (2009) Multiple sporadic gastrointestinal stromal tumours arising at different gastrointestinal sites: pattern of involvement of the muscularis propria as a clue to independent primary GISTs. Virchows Arch 455:101–108PubMedCrossRefGoogle Scholar
  33. 33.
    Hostein I, Faur N, Primois C, Boury F, Denard J, Emile JF, Bringuier PP, Scoazec JY, Coindre JM (2010) BRAF mutation status in gastrointestinal stromal tumors. Am J Clin Pathol 133:141–148PubMedCrossRefGoogle Scholar
  34. 34.
    Falchook GS, Trent JC, Heinrich MC, Beadling C, Patterson J, Bastida CC, Blackman SC, Kurzrock R (2013) BRAF mutant gastrointestinal stromal tumor: first report of regression with BRAF inhibitor dabrafenib (GSK2118436) and whole exomic sequencing for analysis of acquired resistance. Oncotarget 4:310–315PubMedGoogle Scholar
  35. 35.
    Jakob JA, Bassett RL Jr, Ng CS, Curry JL, Joseph RW, Alvarado GC, Rohlfs ML, Richard J, Gershenwald JE, Kim KB, Lazar AJ, Hwu P, Davies MA (2012) NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 118:4014–4023PubMedCrossRefGoogle Scholar
  36. 36.
    Kim J, Lazar AJ, Davies MA, Homsi J, Papadopoulos NE, Hwu WJ, Bedikian AY, Woodman SE, Patel SP, Hwu P, Kim KB (2012) BRAF, NRAS and KIT sequencing analysis of spindle cell melanoma. J Cutan Pathol 39:821–825PubMedCrossRefGoogle Scholar
  37. 37.
    Blair SL, Al-Refaie WB, Wang-Rodriguez J, Behling C, Ali MW, Moossa AR (2005) Gastrointestinal stromal tumors express ras oncogene: a potential role for diagnosis and treatment. Arch Surg 140:543–547PubMedCrossRefGoogle Scholar
  38. 38.
    Jakob JA, Bassett RL Jr, Ng CS, Curry JL, Joseph RW, Alvarado GC, Rohlfs ML, Richard J, Gershenwald JE, Kim KB, Lazar AJ, Hwu P, Davies MA (2012) NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 118:4014–4023PubMedCrossRefGoogle Scholar
  39. 39.
    Sakamoto A, Oda Y, Adachi T, Tamiya S, Matsuda S, Tanaka K, Iwamoto Y, Tsuneyoshi M (2001) H-ras oncogene mutation in dedifferentiated liposarcoma. Polymerase chain reaction-restriction fragment length polymorphism analysis. Am J Clin Pathol 115:235–242PubMedCrossRefGoogle Scholar
  40. 40.
    Sakamoto A, Oda Y, Adachi T, Oshiro Y, Tamiya S, Tanaka K, Matsuda S, Iwamoto Y, Tsuneyoshi M (2001) H-ras oncogene mutation in dedifferentiated chondrosarcoma: polymerase chain reaction-restriction fragment length polymorphism analysis. Mod Pathol 14:343–349PubMedCrossRefGoogle Scholar
  41. 41.
    Weihrauch M, Bader M, Lehnert G, Koch B, Wittekind C, Wrbitzky R, Tannapfel A (2002) Mutation analysis of K-ras-2 in liver angiosarcoma and adjacent nonneoplastic liver tissue from patients occupationally exposed to vinyl chloride. Environ Mol Mutagen 40:36–40PubMedCrossRefGoogle Scholar
  42. 42.
    Wong NACS, Deans ZC, Ramsden SC (2012) The UK NEQAS for molecular genetic scheme for gastrointestinal stromal tumour: findings and recommendations following four rounds of circulation. J Clin Pathol 65:786–790PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Riccardo Ricci
    • 1
  • Angelo Paolo Dei Tos
    • 2
  • Guido Rindi
    • 1
  1. 1.Department of PathologyUniversità Cattolica del Sacro CuoreRomaItaly
  2. 2.Department of PathologyTreviso Regional HospitalTrevisoItaly

Personalised recommendations