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Risk Classification

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Gastrointestinal Stromal Tumor

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Abstract

Because postoperative recurrence or metastasis can occur even after complete resection of primary gastrointestinal stromal tumors (GISTs), adjuvant imatinib therapy with imatinib mesylate is recommended for patients who are at high risk of such recurrence. Classification of risk of GIST recurrence has recently become increasingly important in informing precise application of adjuvant therapy and prediction of overall outcome. Several risk-stratification systems, including the National Institutes of Health (NIH) consensus criteria, Armed Forces Institute of Pathology (AFIP) criteria, modified NIH criteria, contour maps, and prognostic nomograms, have been developed, based mainly on tumor size, mitotic counts, and primary site. Mutations in c-kit and PDGFRA genes and other genetic and epigenetic events appear to contribute to the malignant phenotype of GISTs. Of the currently available risk-stratification systems, the modified NIH criteria appear to be the best for selecting patients for whom postoperative adjuvant imatinib is indicated; however, even these criteria have some limitations and outstanding issues. Further studies aimed at improving available risk-stratification systems and thus enabling more precise identification of patients at high risk of recurrence for whom postoperative adjuvant imatinib is indicated are needed.

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References

  1. 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(5):1259–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. O’Leary T, Berman JJ. Gastrointestinal stromal tumors: answers and questions. Hum Pathol. 2002;33(5):456–8.

    Article  PubMed  Google Scholar 

  3. 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(5350):577–80.

    Article  CAS  PubMed  Google Scholar 

  4. Hirota S, Ohashi A, Nishida T, Isozaki K, Kinoshita K, Shinomura Y, et al. Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology. 2003;125(3):660–7.

    Article  CAS  PubMed  Google Scholar 

  5. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708–10.

    Article  CAS  PubMed  Google Scholar 

  6. Patil DT, Rubin BP. Gastrointestinal stromal tumor: advances in diagnosis and management. Arch Pathol Lab Med. 2011;135(10):1298–310.

    Article  CAS  PubMed  Google Scholar 

  7. Fletcher CD. Clinicopathologic correlations in gastrointestinal stromal tumors. Hum Pathol. 2002;33(5):455.

    Article  PubMed  Google Scholar 

  8. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006;23(2):70–83.

    Article  PubMed  Google Scholar 

  9. Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol. 2008;39(10):1411–9.

    Article  PubMed  Google Scholar 

  10. 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(1):51–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Roberts PJ, Eisenberg B. Clinical presentation of gastrointestinal stromal tumors and treatment of operable disease. Eur J Cancer. 2002;38(Suppl 5):S37–8.

    Article  PubMed  Google Scholar 

  12. 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(9669):1097–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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(12):1265–72.

    Article  CAS  PubMed  Google Scholar 

  14. Joensuu H, Eriksson M, Sundby Hall K, Reichardt A, Hartmann JT, Pink D, et al. adjuvant imatinib for high-risk GI stromal tumor: analysis of a randomized trial. J Clin Oncol. 2016;34(3):244–50.

    Article  CAS  PubMed  Google Scholar 

  15. 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(36):4276–83.

    Article  CAS  PubMed  Google Scholar 

  16. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005;29(1):52–68.

    Article  PubMed  Google Scholar 

  17. Miettinen M, Makhlouf H, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol. 2006;30(4):477–89.

    Article  PubMed  Google Scholar 

  18. 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(3):265–74.

    Article  PubMed  Google Scholar 

  19. Gold JS, Gonen M, Gutierrez A, Broto JM, Garcia-del-Muro X, Smyrk TC, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol. 2009;10(11):1045–52.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Rossi S, Miceli R, Messerini L, Bearzi I, Mazzoleni G, Capella C, et al. 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. 2011;35(11):1646–56.

    Article  PubMed  Google Scholar 

  21. Ernst SI, Hubbs AE, Przygodzki RM, Emory TS, Sobin LH, O’Leary TJ. KIT mutation portends poor prognosis in gastrointestinal stromal/smooth muscle tumors. Lab Invest. 1998;78(12):1633–6.

    CAS  PubMed  Google Scholar 

  22. Taniguchi M, Nishida T, Hirota S, Isozaki K, Ito T, Nomura T, et al. Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. Cancer Res. 1999;59(17):4297–300.

    CAS  PubMed  Google Scholar 

  23. Kim TW, Lee H, Kang YK, Choe MS, Ryu MH, Chang HM, et al. Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors. Clin Cancer Res. 2004;10(9):3076–81.

    Article  CAS  PubMed  Google Scholar 

  24. Singer S, Rubin BP, Lux ML, Chen CJ, Demetri GD, Fletcher CD, et al. Prognostic value of KIT mutation type, mitotic activity, and histologic subtype in gastrointestinal stromal tumors. J Clin Oncol. 2002;20(18):3898–905.

    Article  CAS  PubMed  Google Scholar 

  25. 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(25):6190–8.

    Article  CAS  PubMed  Google Scholar 

  26. Iesalnieks I, Rummele P, Dietmaier W, Jantsch T, Zulke C, Schlitt HJ, et al. Factors associated with disease progression in patients with gastrointestinal stromal tumors in the pre-imatinib era. Am J Clin Pathol. 2005;124(5):740–8.

    Article  PubMed  Google Scholar 

  27. Andersson J, Bumming P, Meis-Kindblom JM, Sihto H, Nupponen N, Joensuu H, et al. Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology. 2006;130(6):1573–81.

    Article  CAS  PubMed  Google Scholar 

  28. Lasota J, Miettinen M. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol. 2006;23(2):91–102.

    Article  PubMed  Google Scholar 

  29. Debiec-Rychter M, Cools J, Dumez H, Sciot R, Stul M, Mentens N, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology. 2005;128(2):270–9.

    Article  CAS  PubMed  Google Scholar 

  30. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21(23):4342–9.

    Article  CAS  PubMed  Google Scholar 

  31. Hasegawa T, Matsuno Y, Shimoda T, Hirohashi S. Gastrointestinal stromal tumor: consistent CD117 immunostaining for diagnosis, and prognostic classification based on tumor size and MIB-1 grade. Hum Pathol. 2002;33(6):669–76.

    Article  PubMed  Google Scholar 

  32. Liu X, Qiu H, Zhang P, Feng X, Chen T, Li Y, et al. Prognostic role of tumor necrosis in patients undergoing curative resection for gastric gastrointestinal stromal tumor: a multicenter analysis of 740 cases in China. Cancer Med. 2017;6(12):2796–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Folkman J. Angiogenesis in psoriasis: therapeutic implications. J Invest Dermatol. 1972;59(1):40–3.

    Article  CAS  PubMed  Google Scholar 

  34. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3(6):401–10.

    Article  CAS  PubMed  Google Scholar 

  35. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997;18(1):4–25.

    Article  CAS  PubMed  Google Scholar 

  36. Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002;2(10):795–803.

    Article  CAS  PubMed  Google Scholar 

  37. Harris AL. Hypoxia – a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.

    Article  CAS  PubMed  Google Scholar 

  38. Cummins EP, Taylor CT. Hypoxia-responsive transcription factors. Pflugers Arch Eur J Physiol. 2005;450(6):363–71.

    Article  CAS  Google Scholar 

  39. Takahashi R, Tanaka S, Kitadai Y, Sumii M, Yoshihara M, Haruma K, et al. Expression of vascular endothelial growth factor and angiogenesis in gastrointestinal stromal tumor of the stomach. Oncology. 2003;64(3):266–74.

    Article  CAS  PubMed  Google Scholar 

  40. Takahashi R, Tanaka S, Hiyama T, Ito M, Kitadai Y, Sumii M, et al. Hypoxia-inducible factor-1alpha expression and angiogenesis in gastrointestinal stromal tumor of the stomach. Oncol Rep. 2003;10(4):797–802.

    CAS  PubMed  Google Scholar 

  41. Imamura M, Yamamoto H, Nakamura N, Oda Y, Yao T, Kakeji Y, et al. Prognostic significance of angiogenesis in gastrointestinal stromal tumor. Mod Pathol. 2007;20(5):529–37.

    Article  CAS  PubMed  Google Scholar 

  42. Zhao Y, Wang Q, Deng X. Altered angiogenesis gene expression in gastrointestinal stromal tumors: potential use in diagnosis, outcome prediction, and treatment. Neoplasma. 2012;59(4):384–92.

    Article  CAS  PubMed  Google Scholar 

  43. Basilio-de-Oliveira RP, Pannain VL. Prognostic angiogenic markers (endoglin, VEGF, CD31) and tumor cell proliferation (Ki67) for gastrointestinal stromal tumors. World J Gastroenterol: WJG. 2015;21(22):6924–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gill AJ, Chou A, Vilain R, Clarkson A, Lui M, Jin R, et al. Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. Am J Surg Pathol. 2010;34(5):636–44.

    PubMed  Google Scholar 

  45. Miettinen M, Wang ZF, Sarlomo-Rikala M, Osuch C, Rutkowski P, Lasota J. Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol. 2011;35(11):1712–21.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Pantaleo MA, Lolli C, Nannini M, Astolfi A, Indio V, Saponara M, et al. Good survival outcome of metastatic SDH-deficient gastrointestinal stromal tumors harboring SDHA mutations. Genet Med. 2015;17(5):391–5.

    Article  CAS  PubMed  Google Scholar 

  47. 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(2):234–40.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kaifi JT, Wagner M, Schurr PG, Wachowiak R, Reichelt U, Yekebas EF, et al. Allelic loss of Hox11L1 gene locus predicts outcome of gastrointestinal stromal tumors. Oncol Rep. 2006;16(4):915–9.

    PubMed  Google Scholar 

  49. Yamaguchi U, Nakayama R, Honda K, Ichikawa H, Hasegawa T, Shitashige M, et al. Distinct gene expression-defined classes of gastrointestinal stromal tumor. J Clin Oncol. 2008;26(25):4100–8.

    Article  CAS  PubMed  Google Scholar 

  50. Suehara Y, Kondo T, Seki K, Shibata T, Fujii K, Gotoh M, et al. Pfetin as a prognostic biomarker of gastrointestinal stromal tumors revealed by proteomics. Clin Cancer Res. 2008;14(6):1707–17.

    Article  CAS  PubMed  Google Scholar 

  51. Hasegawa T, Asanuma H, Ogino J, Hirohashi Y, Shinomura Y, Iwaki H, et al. Use of potassium channel tetramerization domain-containing 12 as a biomarker for diagnosis and prognosis of gastrointestinal stromal tumor. Hum Pathol. 2013;44:1271–7.

    Article  CAS  PubMed  Google Scholar 

  52. Setoguchi T, Kikuchi H, Yamamoto M, Baba M, Ohta M, Kamiya K, et al. Microarray analysis identifies versican and CD9 as potent prognostic markers in gastric gastrointestinal stromal tumors. Cancer Sci. 2011;102(4):883–9.

    Article  CAS  PubMed  Google Scholar 

  53. Yen CC, Yeh CN, Cheng CT, Jung SM, Huang SC, Chang TW, et al. Integrating bioinformatics and clinicopathological research of gastrointestinal stromal tumors: identification of aurora kinase A as a poor risk marker. Ann Surg Oncol. 2012;19(11):3491–9.

    Article  PubMed  Google Scholar 

  54. Yeh CN, Yen CC, Chen YY, Cheng CT, Huang SC, Chang TW, et al. Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors. Oncotarget. 2014;5(12):4071–86.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Yamamoto H, Kohashi K, Fujita A, Oda Y. Fascin-1 overexpression and miR-133b downregulation in the progression of gastrointestinal stromal tumor. Mod Pathol. 2013;26(4):563–71.

    Article  CAS  PubMed  Google Scholar 

  56. Bertucci F, Finetti P, Ostrowski J, Kim WK, Kim H, Pantaleo MA, et al. Genomic Grade Index predicts postoperative clinical outcome of GIST. Br J Cancer. 2012;107(8):1433–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Namlos HM, Boye K, Mishkin SJ, Baroy T, Lorenz S, Bjerkehagen B, et al. Non-invasive detection of ctDNA reveals intratumour heterogeneity and is associated with tumour burden in gastrointestinal stromal tumour. Mol Cancer Ther. 2018;17:2473–80.

    Article  PubMed  Google Scholar 

  58. Joensuu H, Martin-Broto J, Nishida T, Reichardt P, Schoffski P, Maki RG. Follow-up strategies for patients with gastrointestinal stromal tumour treated with or without adjuvant imatinib after surgery. Eur J Cancer. 2015;51(12):1611–7.

    Article  CAS  PubMed  Google Scholar 

  59. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130(10):1466–78.

    CAS  PubMed  Google Scholar 

  60. Hara R, Kikuchi H, Setoguchi T, Miyazaki S, Yamamoto M, Hiramatsu Y, et al. Microarray analysis reveals distinct gene set profiles for gastric and intestinal gastrointestinal stromal tumors. Anticancer Res. 2015;35(6):3289–98.

    CAS  PubMed  Google Scholar 

  61. Kawanowa K, Sakuma Y, Sakurai S, Hishima T, Iwasaki Y, Saito K, et al. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol. 2006;37(12):1527–35.

    Article  PubMed  Google Scholar 

  62. 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(1):113–20.

    Article  PubMed  Google Scholar 

  63. Fukasawa T, Chong JM, Sakurai S, Koshiishi N, Ikeno R, Tanaka A, et al. Allelic loss of 14q and 22q, NF2 mutation, and genetic instability occur independently of c-kit mutation in gastrointestinal stromal tumor. Jpn J Cancer Res. 2000;91(12):1241–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wozniak A, Sciot R, Guillou L, Pauwels P, Wasag B, Stul M, et al. Array CGH analysis in primary gastrointestinal stromal tumors: cytogenetic profile correlates with anatomic site and tumor aggressiveness, irrespective of mutational status. Genes Chromosom Cancer. 2007;46(3):261–76.

    Article  CAS  PubMed  Google Scholar 

  65. Chen Y, Tzeng CC, Liou CP, Chang MY, Li CF, Lin CN. Biological significance of chromosomal imbalance aberrations in gastrointestinal stromal tumors. J Biomed Sci. 2004;11(1):65–71.

    Article  PubMed  Google Scholar 

  66. Assamaki R, Sarlomo-Rikala M, Lopez-Guerrero JA, Lasota J, Andersson LC, Llombart-Bosch A, et al. Array comparative genomic hybridization analysis of chromosomal imbalances and their target genes in gastrointestinal stromal tumors. Genes Chromosom Cancer. 2007;46(6):564–76.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

We thank Dr. Trish Reynolds, MBBS, FRACP, from Edanz Group (www.edanzediting.com/ac), for editing the English text of a draft of this chapter.

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Authors and Affiliations

  1. Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Hirotoshi Kikuchi & Hiroya Takeuchi

  2. Hamamatsu University School of Medicine, Hamamatsu, Japan

    Hiroyuki Konno

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  1. Hirotoshi Kikuchi
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Correspondence to Hirotoshi Kikuchi .

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  1. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

    Yukinori Kurokawa

  2. Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo, Hokkaido, Japan

    Yoshito Komatsu

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Kikuchi, H., Konno, H., Takeuchi, H. (2019). Risk Classification. In: Kurokawa, Y., Komatsu, Y. (eds) Gastrointestinal Stromal Tumor. Springer, Singapore. https://doi.org/10.1007/978-981-13-3206-7_5

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