An association of gastrointestinal stromal tumors (GISTs) with other malignancies is not new (1-5). In 2006, Agaimy et al. (1) reported on secondary cancer diagnoses in 486 GIST patients, including cases from the literature. They found 228 GIST patients with gastrointestinal cancers (46.9%), of which 19.5% were of gastric origin and 22.4% were of colorectal origin. Esophageal carcinoma, gastric MALT lymphoma and small bowel adenocarcinoma were less common. Two hundred ninety GIST patients had secondary cancers outside the gastrointestinal tract. They included prostate cancer (8.8%), cancers of the lymphoreticular system (7.4%), breast cancer (7%), renal cell carcinoma (5.5%), lung cancer (5.3%), cancer of the female genital tract (5.1%), soft tissue and bone sarcoma (3.1%), carcinoid tumors (2.7%), malignant melanoma (2.5%), pancreas cancer (2.3%), urinary bladder cancer (2%), seminoma (1.2%), hepatocellular carcinoma (0.8%), thyroid cancer (0.8%), cancer of the gallbladder and biliary tract (0,8%), paraganglioma (0.6%), squamous cell carcinoma of the head and neck (0.4%), and others.
The current article of Mendonca et al. (6) entitled “The association of renal cell carcinoma with gastrointestinal stromal tumors” describes 9 patients with renal cell carcinoma in a collective of 405 patients with GIST (2.2%). In 2000, the same center (Memorial Sloan-Kettering Cancer Center) (2), reported in at the time 200 GIST patients: four patients with breast cancer (2%), two patients with prostate cancer (1%), and one patient (0.5%) each with skin, uterine, lung and renal cancer. In our own collective of 172 GIST patients, about 20% had a secondary malignancy, one of which had renal cell carcinoma (0.6%) (7).
Whilst micro-GIST of the stomach are frequent incidental findings in gastrointestinal or pancreaticobiliary tumor surgery (20–30/100) (8,9), the incidence of overt GIST is rare (0.2% of gastrointestinal tumors, 1–2/100,000) (10,11). The incidence of renal cancer varies from 1–10/100,000 within the different countries (12). The co-occurrence of GIST with other malignancies is not uncommon and seems to vary between 0.5% and 20%. As shown above, the likelihood of a patient presenting with GIST and another specific type of tumor however is small. Common environmental factors, such as smoking, obesity and hypertension (as in renal cancer) (13) do not seem to play a role, as these factors are not relevant in GIST (14). Nevertheless, there seems to be correlation with specific malignancies, such as prostate or renal cancer. It is possible to hypothesize that mechanisms involving protein tyrosine kinases are influenced by their cognate growth factors in the microenvironment (15). This would also explain, why the receptor tyrosine kinase cMET (whose ligand is hepatocyte growth factor) seems to be involved in renal cell cancer, however, association with hepatocellular cancer is extremely rare (16).
Both, renal cancer and GIST are highly vascularized tumors, and profit from anti-VEGFR treatment, such as sunitinib (17-19). Furthermore, in subgroups of GIST and renal cell cancer, the occurrence of germline mutations in succinate dehydrogenase (SDH) A, SDHC, and mutations of the Von-Hippel-Lindau (VHL) gene have been described (20-26). These mutations are involved in the energy metabolism of tumors. SDH is an enzyme complex found in the inner mitochondrial membrane. It participates in both, the citric acid cycle and the electron transport chain (27). In wildtype (WT) GIST, loss of the subunit SDHB has been described (28). This leads to accumulation of succinate, the substrate of succinate dehydrogenase and stabilizes Hypoxia-inducible factor alpha (HIFα) which is being degraded under physiological conditions (29). The consequence is pseudo-hypoxia, which induces genes, which are involved in the survival of cells under hypoxic conditions such as angiogenesis, apoptosis resistance, and oxygen-independent ATP-synthesis, and lead to tumor progression (30).
The occurrence of XP11 translocation-associated renal carcinoma and GIST seems to be rare. The resulting gene fusions involve the transcription factor E3 (TFE3), which also is involved in mitochondrial energy balance and alterations which lead to abnormalities of glucose and lipid metabolism (31).
Is the development of RCC and GIST really associated or co-occurring? In the manuscript of Mendonca et al. (6), RCC and GIST were synchronous in 5/9 (55.6%) of the cases. Most RCC were pT1 8/9 (88.9%), half were clear cell RCC (4/9), half papillary RCC (4/9).
GISTs were not characterized according to their tumor stage. Their initial size was 7.6 cm with 4/9 (44.4%) being small bowel GIST, where the classification for risk of recurrence would at least be intermediate. 5/9 GIST (55.6%) were metastatic. Thus, GISTs were rather advanced compared to RCC. The authors argue that RCC diagnosis might be aided by serial imaging in the follow-up care of GIST. As RCC were detected early, operation could be curative with a mean follow-up of 9.2 (range 3.8–28.4) years. The question of concomitant treatment of RCC and GIST does thus not occur. Other articles however showed that not only tyrosine kinase inhibitor monotherapy, but also combination of i.e., sunitinib and cytotoxic chemotherapy (gemcitabine) are an active and well-tolerated combination in patients with aggressive RCC (32). This also conforms with our own experience of concomitant tyrosine kinase inhibitor treatment (imatinib) and systemic gemcitabine in GIST and urinary bladder cancer.
From the different available studies, it can be concluded that whilst we should generally be aware of other tumors in the follow-up care of GIST patients, some tumors co-occur more often than others, such as renal cancer. The association between these malignancies warrants further genetic testing to help identify specific mutations. Different pathways, such as tyrosine-kinase receptor pathways and an anti-inflammatory microenvironment (33) seem to be a common denominator. The current manuscript as a clinical report opens a glimpse into these complex mechanisms.
Conflicts of Interest: The author has no conflicts of interest to declare.
- Agaimy A, Wunsch PH, Sobin LH, et al. Occurrence of other malignancies in patients with gastrointestinal stromal tumors. Semin Diagn Pathol 2006;23:120-9. [Crossref] [PubMed]
- DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51-8. [Crossref] [PubMed]
- Murphy JD, Ma GL, Baumgartner JM, et al. Increased risk of additional cancers among patients with gastrointestinal stromal tumors: A population-based study. Cancer 2015;121:2960-7. [Crossref] [PubMed]
- Sevinc A, Seker M, Bilici A, et al. Co-existence of gastrointestinal stromal tumors with other primary neoplasms. Hepatogastroenterology 2011;58:824-30. [PubMed]
- Vassos N, Agaimy A, Hohenberger W, et al. Coexistence of gastrointestinal stromal tumours (GIST) and malignant neoplasms of different origin: prognostic implications. Int J Surg 2014;12:371-7. [Crossref] [PubMed]
- Mendonca SJ, Sanchez A, Blum KA, et al. The association of renal cell carcinoma with gastrointestinal stromal tumors. J Surg Oncol 2018;117:1716-20. [Crossref] [PubMed]
- Krüsmann O, Cameron S. Langzeitüberleben von Patienten mit gastrointestinalen Stromatumoren (GIST). Available online: https://www.researchgate.net/publication/319240804_Langzeituberleben_von_Patienten_mit_gastrointestinalen_Stromatumoren_GIST
- Agaimy A, Wunsch PH, Hofstaedter F, 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. [Crossref] [PubMed]
- Kawanowa K, Sakuma Y, Sakurai S, et al. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol 2006;37:1527-35. [Crossref] [PubMed]
- Blackstein ME, Blay JY, Corless C, et al. Gastrointestinal stromal tumours: consensus statement on diagnosis and treatment. Can J Gastroenterol 2006;20:157-63. [Crossref] [PubMed]
- Nilsson B, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden. Cancer 2005;103:821-29. [Crossref] [PubMed]
- Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol 2010;7:245-57. [Crossref] [PubMed]
- Navai N, Wood CG. Environmental and modifiable risk factors in renal cell carcinoma. Urol Oncol 2012;30:220-4. [Crossref] [PubMed]
- Joensuu H, Eriksson M, Hall KS, et al. Risk factors for gastrointestinal stromal tumor recurrence in patients treated with adjuvant imatinib. Cancer 2014;120:2325-33. [Crossref] [PubMed]
- Gallick GE, Corn PG, Zurita AJ, et al. Small-molecule protein tyrosine kinase inhibitors for the treatment of metastatic prostate cancer. Future Med Chem 2012;4:107-19. [Crossref] [PubMed]
- Shetty GS, Bhalla P, Desai SM, et al. Synchronous hepatocellular carcinoma with renal cell carcinoma: a case report and review of literature of multiple synchronous primary malignancies. Indian J Surg 2013;75:290-2. [Crossref] [PubMed]
- 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. [Crossref] [PubMed]
- Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006;295:2516-24. [Crossref] [PubMed]
- Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:16-24. [Crossref] [PubMed]
- Gill AJ, Lipton L, Taylor J, et al. Germline SDHC mutation presenting as recurrent SDH deficient GIST and renal carcinoma. Pathology 2013;45:689-91. [Crossref] [PubMed]
- Hsieh JJ, Le VH, Oyama T, et al. Chromosome 3p Loss-Orchestrated VHL, HIF, and Epigenetic Deregulation in Clear Cell Renal Cell Carcinoma. J Clin Oncol 2018. [Epub ahead of print]. [Crossref] [PubMed]
- Jiang Q, Zhang Y, Zhou YH, et al. A novel germline mutation in SDHA identified in a rare case of gastrointestinal stromal tumor complicated with renal cell carcinoma. Int J Clin Exp Pathol 2015;8:12188-97. [PubMed]
- Kang G, Yun H, Sun CH, et al. Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors. Oncotarget 2016;7:6538-51. [PubMed]
- Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993;260:1317-20. [Crossref] [PubMed]
- Torous VF, Su A, Lu DY, et al. Adult Patient with Synchronous Gastrointestinal Stromal Tumor and Xp11 Translocation-Associated Renal Cell Carcinoma: A Unique Case Presentation with Discussion and Review of Literature. Case Rep Urol 2015;2015:814809. [Crossref] [PubMed]
- Wang J, Xi Z, Xi J, et al. Somatic mutations in renal cell carcinomas from Chinese patients revealed by whole exome sequencing. Cancer Cell Int 2018;18:159. [Crossref] [PubMed]
- Oyedotun KS, Lemire BD. The quaternary structure of the Saccharomyces cerevisiae succinate dehydrogenase. Homology modeling, cofactor docking, and molecular dynamics simulation studies. J Biol Chem 2004;279:9424-31. [Crossref] [PubMed]
- Huss S, Elges S, Trautmann M, et al. Classification of KIT/PDGFRA wild-type gastrointestinal stromal tumors: implications for therapy. Expert Rev Anticancer Ther 2015;15:623-8. [Crossref] [PubMed]
- King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 2006;25:4675-82. [Crossref] [PubMed]
- Cameron S. Gastrointestinaler Stromatumor (GIST); Stuttgart, Georg Thieme Verlag, 2015;119-33.
- Pastore N, Vainshtein A, Klisch TJ, et al. TFE3 regulates whole-body energy metabolism in cooperation with TFEB. EMBO Mol Med 2017;9:605-21. [Crossref] [PubMed]
- Michaelson MD, McKay RR, Werner L, et al. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer 2015;121:3435-43. [Crossref] [PubMed]
- Wang D, DuBois RN. Immunosuppression associated with chronic inflammation in the tumor microenvironment. Carcinogenesis 2015;36:1085-93. [Crossref] [PubMed]
Cite this article as: Cameron S. The search for a common denominator of gastrointestinal stromal tumors and renal cell carcinoma. Gastrointest Stromal Tumor 2018;1:3.