The stomach is involved in multiple common ailments, including gastroesophageal reflux disease, gastric ulcers, and cancer, the latter of which can take many forms. One type of cancer that presents a management challenge is gastrointestinal stromal tumors or GIST tumors for short. Originally, these are tumors that arise from the connective tissue, or stroma, of the stomach, rather than the lining, from which the more common and more deadly gastric adenocarcinoma finds its origin. However, over time, studies revealed that GIST arises from a very specific cell, called the interstitial cells of Cajal, that are responsible for the timing of contraction in the stomach and small intestine. GIST masses generally behave more indolently than gastric adenocarcinoma, with distant or lymph node metastases a rare feature, although involvement of the liver and peritoneum has been described. Due to this indolent nature, certain masses, once they have been identified as GIST through endoscopic biopsy, are candidates for surveillance. However, larger masses (as identified through evidence of necrosis on imaging) and rapidly growing masses are treated primarily with surgical resection. While in the past surgical resection would have involved a large abdominal incision and a lengthy postoperative recovery, laparoscopic techniques have allowed gastric resection to become a short procedure necessitating only an overnight stay.
Most patients presenting with GIST are symptomatic, with the common complaints being vague abdominal pain and evidence of gastrointestinal bleeding, either through melena, or stool with digested blood, or hematochezia. In situations where metastases exist at the time of presentation, signs of liver failure, although this is rare. GIST can also occur in the setting of endocrine syndromes such as von Hippel-Lindau disease or neurofibromatosis, but the majority are isolated findings. A small, but, due to the overall increase in imaging studies, an increasing number of patients are being diagnosed via abdominal imaging and are thus asymptomatic.
Patients with GIST have little in the way of physical findings, unless the tumor is markedly advanced, at which time a palpable abdominal mass overlying the stomach may be identified. Patients also may have pain to palpation of the abdomen, and, if the liver is involved, findings of jaundice.
The nature of the history of gastric GIST is variable, with some tumors behaving indolently while others exhibit local and distant metastasis, but two variables, in particular, have been identified as predictive of metastasis. The first is the size of the tumor, with greater than 10 centimeters in the greatest dimension being a poor prognostic sign. Greater than 5 mitoses per high power field on histologic analysis of the tumor is also a harbinger of metastasis.
Options for Treatment
In masses, less than 2 centimeters, that do not demonstrate increased mitotic activity on endoscopic biopsy, the natural history is uniformly benign and nothing further needs to be done. In tumors that are either between 2 and 5 centimeters with no increased mitotic activity, or tumors less than 2 centimeters but with increased mitotic activity, a watchful waiting strategy with surveillance CT may be adopted. However, in larger tumors (>5 centimeters) that are accompanied by increased mitotic activity or signs of necrosis on imaging, resection of the mass is the mainstay of treatment.
Rationale for Treatment
In this particular patient, a stomach mass was discovered after an endoscopy was performed secondary to abdominal pain. Due to the small size and lack of mitotic activity on biopsy, surveillance was elected initially. However, the mass grew over the course of a year, and repeat biopsy showed an increase in mitotic activity, as well as positive c-KIT staining. After discussion with the patient, the decision was made to proceed with resection of the mass.
Contraindications to the procedure would be the general ones of systemic illness precluding general anesthesia.
While GIST is the most common sarcomatous tumor of the gastrointestinal tract, it is still rare cancer, comprising only one percent of all GI tumors.1 Due to this, effective screening strategies have proven elusive. Most patients with gastric GIST present with symptoms, most commonly abdominal pain, although an increasing number are discovered incidentally. Almost one-third of GIST masses carry a high risk for malignant potential or are frankly malignant, and the poor state of adjuvant therapy associated with GIST is reflected in the high mortality rates associated with these high-risk and frankly malignant tumors.2
Diagnosis of gastric GIST is based on histologic analysis of tissue obtained at the time of endoscopy. This is due to two specific defects that have been identified as giving rise to GIST. The most common is found in the c-KIT gene of the affected cells. The c-KIT gene encodes for a transmembrane receptor, which is thought to play a crucial role in cellular apoptosis.3 In affected cells, the c-KIT tyrosine kinase is constitutively active, causing deregulation of cellular growth.1 Another, and mutually exclusive, gene defect is the one found in the gene responsible for platelet-derived growth factor-alpha (PDGFR-α).4 Presence of either of these mutations are diagnostic of GIST; however, they do not predict the malignant potential of the mass. Rather, the combination of the number of mitoses, or actively dividing cells, that are seen during histologic analysis, combined with the size of the tumor itself, is highly predictive of metastatic potential.5 In one large pathologic review of patients identified as having GIST, 86% of patients with greater than 5 mitoses per fifty high-powered field on microscopy, combined with a tumor mass of greater than 10 centimeters had eventual metastasis of GIST, while only two to three percent of patients who had neither found.5
If a GIST is detected and found to have concerns for increased malignant potential, removal of the mass via surgical resection is the mainstay of treatment. With the advent of laparoscopy, in otherwise uncomplicated patients, resection of gastric masses has become a much less morbid procedure, with patients returning home within twenty-four hours, as well as returning to regular diets soon postoperatively. This is especially the case for tumors located on the greater curvature of the stomach, where the mass is relatively simple to access and may be removed simply by stapling across the base of the mass with an endoscopic gastrointestinal stapler.
In the setting of metastatic or unresectable disease,6 or patients with high risk for recurrence based on primary tumor characteristics7, adjuvant therapy with imatinab, a tyrosine kinase inhibitor, may be considered. In fact, response to imatinib has been so positive that its continuous use in patients with GIST has been approved by the Federal Food and Drug Administration.8
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- Judson I, Demetri G. Advances in the treatment of gastrointestinal stromal tumours. Ann Oncol. 2007;18(suppl 10):x20-x24. doi:10.1093/annonc/mdm410.
- Nilsson B, Bümming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era. Cancer. 2005;103(4):821-829. doi:10.1002/cncr.20862.
- D'Amato G, Steinert DM, McAuliffe JC, Trent JC. Update on the biology and therapy of gastrointestinal stromal tumors. Cancer Control. 2005;12(1):44-56. doi:10.1177/107327480501200106.
- 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(23):4342-4349. doi:10.1200/JCO.2003.04.190.
- 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. doi:10.1097/01.pas.0000146010.92933.de.
- Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26(4):626-632. doi:10.1200/JCO.2007.13.4452.
- DeMatteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9669):1097-1104. doi:10.1016/S0140-6736(09)60500-6.
- Mahvi DM, Krantz SB. Stomach. In: Townsend CM Jr, Beauchamp RD, Evers BM, Mattox KL, eds. Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 19th ed. Philadelphia, PA: Saunders; 2012:1182-1226.