Abstract
The discovery of KIT gene mutation in gastrointestinal stromal tumor (GIST) has provided a paradigm shift in the classification, diagnosis, and molecular-targeted therapy of gastrointestinal mesenchymal tumors. According to a recent concept, GIST is considered a spindle or epithelioid cell neoplasm which basically expresses KIT protein and has KIT or platelet-derived growth factor receptor-alpha (PDGFRA) gene mutation. Exceptional cases are immunohistochemically negative or weakly positive for KIT (often with PDGFRA mutation), and minor subset has another gene alteration such as succinate dehydrogenase (SDH), RAS, NF1, or BRAF. There are growing evidences of phenotype–genotype correlations in GIST. Risk stratification based on mitotic counts, tumor size, and rupture is useful for the prognostication and management of patients with GIST. GISTs should be distinguished from various types of neoplasms such as leiomyoma, schwannoma, and inflammatory myofibroblastic tumor, although leiomyosarcoma of the gastrointestinal tract has become a very rare entity in the “KIT” era. Both histopathological procedures and molecular investigations are important for the evolution of diagnosis and treatment of GIST and mimics.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–80.
Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006;23:70–83.
Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33:459–65.
Miettinen MM, Corless CL, Debiec-Rychter M, et al. Gastrointestinal stromal tumours. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO classification of tumours of soft tissue and bone. Lyon: IARC Press; 2013. p. 164–7.
Yamamoto H, Oda Y. Gastrointestinal stromal tumor: recent advances in pathology and genetics. Pathol Int. 2015;65:9–18.
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.
Lasota J, Miettinen M. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol. 2006;23:91–102.
Corless CL. Gastrointestinal stromal tumors: what do we know now? Mod Pathol. 2014;27(Suppl 1):S1–16.
Yamamoto H, Oda Y, Kawaguchi K, et al. c-kit and PDGFRA mutations in extragastrointestinal stromal tumor (gastrointestinal stromal tumor of the soft tissue). Am J Surg Pathol. 2004;28:479–88.
Yamamoto H, Kojima A, Nagata S, Tomita Y, Takahashi S, Oda Y. KIT-negative gastrointestinal stromal tumor of the abdominal soft tissue: a clinicopathologic and genetic study of 10 cases. Am J Surg Pathol. 2011;35:1287–95.
Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors presenting as omental masses – a clinicopathologic analysis of 95 cases. Am J Surg Pathol. 2009;33:1267–75.
Yamamoto H, Miyamoto Y, Nishihara Y, et al. Primary gastrointestinal stromal tumor of the liver with PDGFRA gene mutation. Hum Pathol. 2010;41:605–9.
Long KB, Butrynski JE, Blank SD, et al. Primary extragastrointestinal stromal tumor of the pleura: report of a unique case with genetic confirmation. Am J Surg Pathol. 2010;34:907–12.
Sakurai S, Hishima T, Takazawa Y, et al. Gastrointestinal stromal tumors and KIT-positive mesenchymal cells in the omentum. Pathol Int. 2001;51:524–31.
Doyle LA, Hornick JL. Gastrointestinal stromal tumours: from KIT to succinate dehydrogenase. Histopathology. 2014;64:53–67.
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;35:1712–21.
Boikos SA, Pappo AS, Killian JK, et al. Molecular subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors: a report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol. 2016;2:922–8.
Janeway KA, Kim SY, Lodish M, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 2011;108:314–8.
Andersson J, Bümming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology. 2006;130:1573–81.
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342–9.
Antonescu CR. The GIST paradigm: lessons for other kinase-driven cancers. J Pathol. 2011;223:251–61.
Miettinen M, Lasota J, Sobin LH. Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. Am J Surg Pathol. 2005;29:1373–81.
Rege TA, Wagner AJ, Corless CL, Heinrich MC, Hornick JL. “Pediatric-type” gastrointestinal stromal tumors in adults: distinctive histology predicts genotype and clinical behavior. Am J Surg Pathol. 2011;35:495–504.
Dwight T, Benn DE, Clarkson A, et al. Loss of SDHA expression identifies SDHA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors. Am J Surg Pathol. 2013;37:226–33.
Pantaleo MA, Astolfi A, Urbini M, 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.
Mason EF, Hornick JL. Conventional risk stratification fails to predict progression of succinate dehydrogenase-deficient gastrointestinal stromal tumors: a clinicopathologic study of 76 cases. Am J Surg Pathol. 2016;40:1616–21.
Carney JA, Sheps SG, Go VL, Gordon H. The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med. 1977;296:1517–8.
Carney JA, Stratakis CA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet. 2002;108:132–9.
Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med. 2009;266:43–52.
Antonescu CR. Gastrointestinal stromal tumor (GIST) pathogenesis, familial GIST, and animal models. Semin Diagn Pathol. 2006;23:63–9.
Patil DT, Rubin BP. Gastrointestinal stromal tumor: advances in diagnosis and management. Arch Pathol Lab Med. 2011;135:1298–310.
Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol. 2006;30:90–6.
Pantaleo MA, Nannini M, Corless CL, Heinrich MC. Quadruple wild-type (WT) GIST: defining the subset of GIST that lacks abnormalities of KIT, PDGFRA, SDH, or RAS signaling pathways. Cancer Med. 2015;4:101–3.
Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol. 2008;39:1411–9.
Joensuu H, Vehtari A, Riihimäki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol. 2012;13:265–74.
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.
Agaimy A, Haller F, Gunawan B, Wünsch PH, Füzesi L. Distinct biphasic histomorphological pattern in gastrointestinal stromal tumours (GISTs) with common primary mutations but divergent molecular cytogenetic progression. Histopathology. 2009;54:295–302.
Yamamoto H, Kojima A, Miyasaka Y, et al. Prognostic impact of blood vessel invasion in gastrointestinal stromal tumor of the stomach. Hum Pathol. 2010;41:1422–30.
Antonescu CR, Romeo S, Zhang L, et al. Dedifferentiation in gastrointestinal stromal tumor to an anaplastic KIT-negative phenotype: a diagnostic pitfall: morphologic and molecular characterization of 8 cases occurring either de novo or after imatinib therapy. Am J Surg Pathol. 2013;37:385–92.
Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753–9.
Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11:4182–90.
Miettinen M, Sarlomo-Rikala M, Sobin LH, Lasota J. Esophageal stromal tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 17 cases and comparison with esophageal leiomyomas and leiomyosarcomas. Am J Surg Pathol. 2000;24:211–22.
Miettinen M, Kopczynski J, Makhlouf HR, et al. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases. Am J Surg Pathol. 2003;27:625–41.
Deshpande A, Nelson D, Corless CL, et al. Leiomyoma of the gastrointestinal tract with interstitial cells of Cajal: a mimic of gastrointestinal stromal tumor. Am J Surg Pathol. 2014;38:72–7.
Heidet L, Boye E, Cai Y, et al. Somatic deletion of the 5′ ends of both the COL4A5 and COL4A6 genes in a sporadic leiomyoma of the esophagus. Am J Pathol. 1998;152:673–8.
Yamamoto H, Handa M, Tobo T, et al. Clinicopathological features of primary leiomyosarcoma of the gastrointestinal tract following recognition of gastrointestinal stromal tumours. Histopathology. 2013;63:194–207.
Miettinen M, Sobin LH, Lasota J. True smooth muscle tumors of the small intestine: a clinicopathologic, immunohistochemical, and molecular genetic study of 25 cases. Am J Surg Pathol. 2009;33:430–6.
Lasota J, Wasag B, Dansonka-Mieszkowska A, et al. Evaluation of NF2 and NF1 tumor suppressor genes in distinctive gastrointestinal nerve sheath tumors traditionally diagnosed as benign schwannomas: a study of 20 cases. Lab Investig. 2003;83:1361–71.
Yamamoto H, Kohashi K, Tsuneyoshi M, Oda Y. Heterozygosity loss at 22q and lack of INI1 gene mutation in gastrointestinal stromal tumor. Pathobiology. 2011;78:132–9.
Gleason BC, Hornick JL. Inflammatory myofibroblastic tumours: where are we now? J Clin Pathol. 2008;61:428–37.
Coffin CM, Fletcher JA. Inflammatory myofibroblastic tumor. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO classification of tumours of soft tissue and bone. Lyon: IARC Press; 2013. p. 83–4.
Mano H. ALKoma: a cancer subtype with a shared target. Cancer Discov. 2012;2:495–502.
Yamamoto H, Yoshida A, Taguchi K, et al. ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours. Histopathology. 2016;69:72–83.
Goldblum JR, Fletcher JA. Desmoid-type fibromatosis. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO classification of tumours of soft tissue and bone. Lyon: IARC Press; 2013. p. 72–3.
Lucas DR, Al-Abbadi M, Tabaczka P, et al. c-Kit expression in desmoid fibromatosis. Comparative immunohistochemical evaluation of two commercial antibodies. Am J Clin Pathol. 2003;119:339–45.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Yamamoto, H. (2019). Histology. In: Kurokawa, Y., Komatsu, Y. (eds) Gastrointestinal Stromal Tumor. Springer, Singapore. https://doi.org/10.1007/978-981-13-3206-7_2
Download citation
DOI: https://doi.org/10.1007/978-981-13-3206-7_2
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-13-3205-0
Online ISBN: 978-981-13-3206-7
eBook Packages: MedicineMedicine (R0)