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Logo of tghTranslational Gastroenterology and Hepatology
Transl Gastroenterol Hepatol. 2017; 2: 91.
Published online 2017 November 15. doi:  10.21037/tgh.2017.11.03
PMCID: PMC5723733

Understanding the critical role for surgery in the management of wild-type gastrointestinal stromal tumor (GIST)

Recently in the Journal of Clinical Oncology, Weldon and coworkers from the National Institutes of Health reported a retrospective single institution experience with patient outcomes following the surgical treatment of WT gastrointestinal stromal tumor (GIST). Main outcomes examined was the association of surgery with event free survival (EFS) (1). Overall, the study reported a 1-, 5-, and 10-year EFS of 73%, 24%, and 16% respectively. Tumor biology factors such as metastatic disease [adjusted hazard ratio (AHR) =2.3; confidence interval (CI): 1.0–5.1; P=0.04) and >5 mitoses per 50 high-power fields (AHR =2.5; CI: 1.1–6.0; P=0.03) had a significantly increased hazard of disease progression or recurrence. In contrast, surgical considerations such as microscopic resection margin and type of gastric resection (wedge vs. anatomic) were not significantly associated with EFS.

GIST is a neoplasm derived from the interstitial cells of Cajal (2). The cells of Cajal are the pacemaker cells of the gut that produce peristaltic contractions. They are located in the myenteric plexus of the gastrointestinal tract. This explains how GIST can develop anywhere along the gastrointestinal tract, with a propensity for the stomach (50–60%), followed by small intestine (30–35%), colon and rectum (5%), and esophagus (<1%) (3). Overall, one demographic study showed GIST to be affected in 53% men, 72.2% Caucasians, 15.6% African Americans and 9.1% Hispanics (4).

GIST without mutations in KIT or platelet-derived growth factor alpha (PDGFRA) have been commonly classified as KIT/PDGFRA wild type GIST or WT GIST (5). KIT and PDGFRA are both type III tyrosine kinases and in patients who develop GIST mutations appear to be mutually exclusive as either mutation can drive GIST proliferation and lead to malignancy (6). Stem-cell factor or platelet-derived growth factor are the normal ligands for KIT and PDGFRA, respectively; and when bound, kinase domains are activated for receptor dimerization (7). In the setting of patients who develop GIST, approximately 75–80% of GIST have KIT mutations, and this typically affects the juxtamembrane domain encoded by exon 11 resulting in ligand-independent receptor activation. Mutations in the juxtamembrane domain disrupt its normal function of dimerization regulation. KIT mutations can also be observed in the extracellular domain (typically exon 9, approximately 6%) and Kinase I and II domains (exons 13 and 17, approximately 2%) (8). Tumors with KIT exon 9 mutations predominantly originate in small intestines and PDGFRA exon 9 mutations in the stomach. When not mutated, kinsase II domains aid in the activation loop for conformational regulation of the ATP binding pocket of each kinase. Among the patients without KIT mutations, one-third have mutations in PDGFRA in domains similar to those observed in KIT mutations. Any one of these mutations of KIT and PDGFRA will promote oncogenic signaling via the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathway (9).

Although WT GIST represents 10–15% of all cases (10), WT GIST are very common in young patients who develop GIST. In up to 85% of patients, WT GIST appears to be present in patients 22 years of age or younger (11). WT GIST are known to affect a larger proportion of females as well as almost exclusively arising from the stomach (12,13). WT GIST has been noted to have a more indolent course when compared to KIT/PDGFRA mutated GIST (14,15). For patients with mutations in KIT or PDGFRA, small molecule inhibitors of the mutant KIT and PDGFRA receptor tyrosine kinases, imatinib and sunitinib, have proven to significantly prolong survival in these subset of GIST patients (16-19). For WT GIST patients, first line therapy drug therapy with imatinib is unfortunately less effective (20). As a result, surgery is a critically important facet of treating WT GIST overall (14,21).

Recently, comprehensive molecular analysis has elucidated KIT/PDGFRA WT GIST to be a more complex entity dividing into several different subtypes. 20–40% of WT GIST are characterized to be succinate dehydrogenate ubiquinone complex (SDH)-deficient GIST; more specifically, subunit B (SDHB) protein expression is lost typically due to germ-line and/or somatic loss-of-function mutations in any of the four SDH A, B, C, or D subunits. The remaining WT GIST are not SDH-deficient and are represented by a BRAF V600E mutation (22), neurofibromatosis (NF) type 1 mutation (23), or a quadruple WT GIST (24).

Among the patients tested, the NIH Pediatric and Wildtype GIST clinic reported 55% of participants to be SDH deficient and 35% SDH competent without another mutation. Ten percent (5 patients) were SDH competent and with other mutations (NF 1 tumor suppressor gene deficient, BRAF deficient, and CBL deficient). Furthermore, the analysis from Weldon et al. demonstrated that EFS was not significantly affected by tumor SDH-competent status (median SDH-deficient EFS, 4.6 years vs. SDH-competent, 2.8 years; P=0.10) or germline SDH-competent status (median SDH-deficient EFS, 4.6 years vs. SDH-competent, 2.8 years; P=0.20). Although this study represents the largest cohort of SDH deficient (germline SDH deficient, 27 patients; tumor SDH deficient, 23 patients) WT GIST patients to date, it still remains a significantly underpowered study that restricts the ability to definitively identify clinical meaningful determinations associated with the presence of SDH mutations.

For surgical management of WT GIST, Weldon et al. reported no association between extent of gastric resection and EFS (log-rank test, P=0.67). Furthermore, repeated resections after initial resection were identified to be significantly associated with decreasing postoperative EFS (P<0.01). Similarly, a difference in outcome of local recurrence was not seen between initial anatomic gastric resection vs. non-anatomic gastric resection.

In summary, the NIH Pediatric and Wildtype GIST clinic report a surgical experience with the treatment of WT GIST that demonstrated tumor biology factors to be most important in its treatment in contrast to surgical factors. Nonetheless, surgical resection remains an important component (21,25), likely the key component, in the treatment strategies for this disease. In particular, the role of debulking surgery in metastatic disease in efforts to delay time to drug resistance continues to be studied. WT GIST represents one subtype of GIST that will need specific agents and treatment strategies based on its unique biologic characteristics. More specifically, in spite of cost, KIT and PDGFRA sequencing should be recommended when WT GIST is suspected.



Provenance: This is a Guest Editorial commissioned by Editor-in-Chief Jia-Fu Ji, MD, FACS (Peking University School of Oncology & Beijing Cancer Hospital, Department of Gastrointestinal Surgery, Beijing, China).

Conflicts of Interest: The authors have no conflicts of interest to declare.


1. Weldon CB, Madenci AL, Boikos SA, et al. Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Pediatric and Wildtype GIST Clinic. J Clin Oncol 2016:JCO2016686733. [Epub ahead of print]. [PMC free article] [PubMed]
2. Miettinen M, Lasota J. Histopathology of gastrointestinal stromal tumor. J Surg Oncol 2011;104:865-73. 10.1002/jso.21945 [PubMed] [Cross Ref]
3. Joensuu H, Vehtari A, Riihimaki 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. 10.1016/S1470-2045(11)70299-6 [PubMed] [Cross Ref]
4. Cheung MC, Zhuge Y, Yang R, Koniaris LG. Disappearance of racial disparities in gastrointestinal stromal tumor outcomes. J Am Coll Surg 2009;209:7-16. 10.1016/j.jamcollsurg.2009.03.018 [PubMed] [Cross Ref]
5. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813-25. 10.1200/JCO.2004.05.140 [PubMed] [Cross Ref]
6. Joensuu H, Hohenberger P, Corless CL. Gastrointestinal stromal tumour. Lancet 2013;382:973-83. 10.1016/S0140-6736(13)60106-3 [PubMed] [Cross Ref]
7. Blume-Jensen P, Claesson-Welsh L, Siegbahn A, et al. Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis. EMBO J 1991;10:4121-28. [PubMed]
8. Lux ML, Rubin BP, Biase TL, et al. KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol 2000;156:791-5. 10.1016/S0002-9440(10)64946-2 [PubMed] [Cross Ref]
9. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer 2011;11:865-78. [PubMed]
10. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299:708-10. 10.1126/science.1079666 [PubMed] [Cross Ref]
11. Janeway KA, Liegl B, Harlow A, et al. Pediatric KIT wild-type and platelet-derived growth factor receptor alpha-wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors. Cancer Res 2007;67:9084-8. 10.1158/0008-5472.CAN-07-1938 [PubMed] [Cross Ref]
12. Prakash S, Sarran L, Socci N, et al. Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr Hematol Oncol 2005;27:179-87. 10.1097/01.mph.0000157790.81329.47 [PubMed] [Cross Ref]
13. 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. 10.1097/01.pas.0000172190.79552.8b [PubMed] [Cross Ref]
14. Demetri GD, Benjamin RS, Blanke CD, et al. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 2007;5 Suppl 2:S1-29; quiz S30. [PubMed]
15. Pappo AS, Janeway KA. Pediatric gastrointestinal stromal tumors. Hematol Oncol Clin North Am 2009;23:15-34, vii. 10.1016/j.hoc.2008.11.005 [PubMed] [Cross Ref]
16. Demetri GD, van Oosterom AT, Garrett CR, 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. 10.1016/S0140-6736(06)69446-4 [PubMed] [Cross Ref]
17. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-80. 10.1056/NEJMoa020461 [PubMed] [Cross Ref]
18. Perez EA, Livingstone AS, Franceschi D, et al. Current incidence and outcomes of gastrointestinal mesenchymal tumors including gastrointestinal stromal tumors. J Am Coll Surg 2006;202:623-9. 10.1016/j.jamcollsurg.2006.01.002 [PubMed] [Cross Ref]
19. Pedroso FE, Raut CP, Xiao H, et al. Has the survival rate for surgically resected gastric gastrointestinal stromal tumors improved in the tyrosine kinase inhibitor era? Ann Surg Oncol 2012;19:1748-58. 10.1245/s10434-012-2222-9 [PubMed] [Cross Ref]
20. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006;24:4764-74. 10.1200/JCO.2006.06.2265 [PubMed] [Cross Ref]
21. Valsangkar N, Sehdev A, Misra S, et al. Current management of gastrointestinal stromal tumors: Surgery, current biomarkers, mutations, and therapy. Surgery 2015;158:1149-64. 10.1016/j.surg.2015.06.027 [PubMed] [Cross Ref]
22. Agaimy A, Terracciano LM, Dirnhofer S, 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. 10.1136/jcp.2009.064550 [PubMed] [Cross Ref]
23. Bajor J. Gastrointestinal stromal tumors in neurofibromatosis type 1. Orv Hetil 2009;150:149-53. 10.1556/OH.2009.28478 [PubMed] [Cross Ref]
24. Pantaleo MA, Nannini M, Corless CL, et al. 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. 10.1002/cam4.325 [PMC free article] [PubMed] [Cross Ref]
25. Zhuge Y, Cheung MC, Yang R, et al. Pediatric intestinal foregut and small bowel solid tumors: a review of 105 cases. J Surg Res 2009;156:95-102. 10.1016/j.jss.2009.03.054 [PubMed] [Cross Ref]

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