|Year : 2012 | Volume
| Issue : 1 | Page : 11-17
Gastrointestinal stromal tumor of the stomach: Evaluation and treatment in a poor-resource setting
Dauda M Mohammed1, Adamu Ahmed1, Ukwenya A Yahaya1, Khalid Lawal1, Liman A Almustapha2, Sani M Shehu2
1 Department of Surgery, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
2 Department of Pathology, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
|Date of Web Publication||22-Sep-2012|
Dauda M Mohammed
Department of Surgery, Ahmadu Bello University Teaching Hospital, Zaria, Kaduna State
Source of Support: None, Conflict of Interest: None
Background: Gastrointestinal stromal tumors (GISTs) represent mesenchymal tumors arising from the gastrointestinal wall, mesentery, omentum, or retroperitoneum that express the c-kit proto-oncogene. In low-income countries, facilities for diagnosis are limited and the patients present late with large tumors. We present the evaluation and treatment of gastric GIST and highlight the difficulties in management of these patients in a setting of limited resources.
Materials and Methods: We retrospectively reviewed patients who were managed for gastric GIST from January 2001 to December 2010 in the Department of Surgery, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria. Information recorded included patient's demographic characteristics, clinical presentation, treatment, operative findings, and outcome.
Results: There were 13 patients with histological diagnosis of gastric GIST. Their age ranged 31-67 years, with a mean of 48 years. All the patients were symptomatic and had palpable abdominal masses at presentation. Tumor size ranged 13.4-39.5 cm. Six patients had preoperative diagnosis of GIST, including two with immunohistochemical confirmation. Overall, seven patients had complete resection of their tumors. Four patients presented with gastric outlet obstruction and both peritoneal and liver metastasis. Five patients were on imatinib which they had taken for 3-13 months. Three patients had tumor recurrence 1-3 years after complete resection. Follow-up ranged from 1 month to 4.5 years. Five patients were followed up for more than 1 year.
Conclusion: Due to lack of facilities for endoscopic ultrasound guided biopsy and immunohistochemistry, preoperative diagnosis was based on clinical and radiological features. Despite the large tumor size, complete resection is associated with good control of symptoms and prolonged survival.
Keywords: CD117, gastrointestinal stromal tumors, outcome, treatment
|How to cite this article:|
Mohammed DM, Ahmed A, Yahaya UA, Lawal K, Almustapha LA, Shehu SM. Gastrointestinal stromal tumor of the stomach: Evaluation and treatment in a poor-resource setting. Arch Int Surg 2012;2:11-7
|How to cite this URL:|
Mohammed DM, Ahmed A, Yahaya UA, Lawal K, Almustapha LA, Shehu SM. Gastrointestinal stromal tumor of the stomach: Evaluation and treatment in a poor-resource setting. Arch Int Surg [serial online] 2012 [cited 2019 Sep 20];2:11-7. Available from: http://www.archintsurg.org/text.asp?2012/2/1/11/101256
| Introduction|| |
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract.  Presently, GISTs represent a distinct clinicopathologic entity that consists of mesenchymal tumors arising from the gastrointestinal wall, mesentery, omentum, or retroperitoneum that express the c-kit proto-oncogene protein, a cell membrane receptor with tyrosine kinase activity. , The c-kit protein, also known as CD117, is a very sensitive and specific marker for GISTs, which differentiates them from other gastrointestinal mesenchymal tumors such as leiomyomas, and leiomyosarcomas which do not express CD117.  Histologically GISTs display features of smooth muscle and neural differentiation which support their origin from interstitial (pacemaker) cell of Cajal.  However, the presence of c-kit protein in omental, mesenteric, and retroperitoneal tumors has raised doubts about the exclusivity of their origin from pacemaker cells of Cajal. 
GIST' pathogenesis is related to c-kit protein and platelet-derived growth factor receptor alpha (PDGFR alpha) mutation. , The gain-of-function mutations in the c-kit proto-oncogene, which result in the constitutive activation of the c-kit tyrosine kinase receptor ligand, lead to uncontrolled cell proliferation and inhibition of normal apoptotic cell death resulting in autonomous cell growth and malignant transformation. , The knowledge of this pathogenesis led to the discovery of the drug imatinib that acts by inhibiting the c-kit receptor, resulting in significant therapeutic effects on inoperable or metastatic GIST.  Discovered on GIST (DOG) 1, also known as ANO1, has emerged in recent years as a promising biomarker for GIST, since recent studies documented that DOG1 antibodies are more sensitive than c-kit antibodies in detecting gastric GIST and tumors carrying PDGFR alpha mutations. 
GIST usually occurs in older patients with an incidence of 10-20 new cases per million/year.  It represents 80% of mesenchymal gastrointestinal tumors and 0.1-3% of all gastrointestinal malignancies. , Although GISTs can occur in any part of the gastrointestinal tract, the stomach accounts for 50-70%. , In the stomach, the presentation of the patient is nonspecific and defends on the size, site, and biological behavior of the tumor. Therefore, preoperative diagnosis based on clinical and radiologic features is difficult. The size of the tumor is one of the factors that determine its malignant potential. Miettinen et al, reported that small gastric GISTs less than 2 cm have a 100% cure rate after complete surgical resection.  Therefore, early diagnosis and surgical resection while the tumor is still small are important determinants of outcome of this disease. In high-income countries, a high proportion of patients are asymptomatic, the disease being discovered incidentally during the course of investigations or operation for unrelated diseases. , Symptomatic GISTs tend to be large, with an average size of 6 cm, compared to 2 cm for asymptomatic tumors and 1.5 cm for those detected at autopsy.  In contrast, in low-income countries, facilities for diagnosis are limited and the patients present late with large tumors that are frequently complicated by severe gastrointestinal hemorrhage or spontaneous rupture. , These impart negatively on the outcome of treatment.
We present a case series of 13 patients with gastric GIST that presented over a 10-year period in a tertiary health center in Zaria, Nigeria. The objective of this study was to discuss the presentation, evaluation, and treatment of GISTs of the stomach and highlight the difficulties in the management of these patients in a setting of limited resources.
| Materials and Methods|| |
This study was carried out in the Department of Surgery, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria. All patients who had histological diagnosis of GIST of the stomach from January 2001 to December 2010 were reviewed retrospectively. Information recorded included patient's demographic characteristics, clinical presentation, treatment, operative findings, and outcome.
Following clinical examination, the patients were evaluated with barium meal and esophagogastroduodenoscopy (OGD). Abdominal ultrasound and CT scan were also carried out. Other investigations performed included complete blood count, serum urea, electrolytes, and creatinine, and liver function tests. Chest X-ray and ECG were also performed in appropriate cases. Endoscopic ultrasound (EUS) and ultrasound-guided percutaneous biopsy were not done. Surgical treatment of the tumor was planned based on clinical and radiological features. Surgery was aimed at complete resection of the tumor with negative resection margins (R0), sparing the stomach whenever possible. Microscopic residual tumor at resection margins was considered as R1, while macroscopic tumor left at operation was R2 resection.
All tumors were reviewed by experienced pathologists for histological confirmation of the diagnosis of GIST. The malignant potential of the tumor was categorized into very low risk, low risk, intermediate, and high risk, based on tumor size and mitotic activity, as previously described by Fletcher et al, [Table 1].  Morphologic appearance and cellular descriptions referred to standard descriptions as epithelioid, spindle, and mixed cells. Mitotic Index (MI) was obtained by counting mitotic features in 50 consecutive microscopic high-powered fields (HPF), 400×. Five patients had immunohistochemical confirmation of GIST.
|Table 1: Risk categorization of malignant potential of gastrointestinal stromal tumor|
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Patient's treated from 2008 to 2010 were started on imatinib (Gleevec® ; Novartis, Basel, Switzerland) at a daily dose of 400 mg postoperatively. Patients were followed up at one to three monthly intervals for 1 year and at three to six monthly intervals thereafter. Follow-up evaluation included history and physical examination at every visit and abdominopelvic ultrasound at 3-6 months intervals.
| Results|| |
There were 13 patients with histological diagnosis of gastric GIST, of whom five were seen from 2001 to 2005 while eight were seen from 2006 to 2010. Their age ranged from 31 to 67 years; means ± SD was 48 ± 3.6. Seven patients were males while six were females. Duration of symptoms ranged from 3 months to 4 years, with a median of 9 months. All the patients were symptomatic and had palpable abdominal masses at presentation. The most common symptom was abdominal pain seen in 10 (76.9%) patients. Tumor size ranged from 13.4 to 39.5 cm, with a median of 27.2 cm. Most tumors were located on the greater curvature of the stomach [Figure 1]. Other clinical features are given in [Table 2]. Only two patients had immunohistochemical diagnosis of GIST preoperatively through upper gastrointestinal endoscopic biopsy. Four other patients had a clinical diagnosis of GIST preoperatively based on radiological and ultrasound evaluation. The remaining seven patients were explored with a preoperative diagnosis of gastric adenocarcinoma (4 cases), retroperitoneal sarcoma (2 cases), and unspecified abdominal tumor (1 patient).
|Figure 1: Large exophytic tumor located on the greater curvature of the stomach|
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|Table 2: Demographic and clinical characteristics of patients with gastrointestinal stromal tumor|
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The tumor characteristics and surgical procedures performed are given in [Table 3]. All the patients had large fleshy endophytic (4) or exophytic (9) tumors that originated from the stomach. Overall, 7 (53.8%) patients had R0 resection while 2 had R1 resections. Of the remaining four patients, two presented with gastric outlet obstruction and had peritoneal metastasis and were offered gastrojejunostomy and biopsy. The remaining two had both liver and peritoneal metastasis and only biopsy was performed. Regional (D2) lymphadenectomy was done in five patients because of grossly enlarged lymph nodes, all of which were negative histologically. Intraoperatively, all the patients were given blood transfusion ranging from 2 to 5 units, with a median of 2. Postoperatively, two patients developed surgical site infection that was controlled by local wound care. One patient died postoperatively. This patient, a 58-year-old lady had a wedge resection of a large tumor on the greater curvature of the stomach. She died on the fifth postoperative day following pulmonary embolism. She was treated for pulmonary tuberculosis 10 years prior to operation. Three patients had tumor recurrence 1-3 years after complete resection. Two of these patients had re-exploration and resection of the tumors. Five patients were on imatinib which they had taken for 3-13 months. Overall, the follow-up ranged from 1 month to 4.5 years. Five patients were followed-up for more than 1 year.
| Discussion|| |
GISTs were first defined by Mazur and Clark after they detected a subgroup of gastrointestinal mesenchymal tumors that did not originate from smooth muscle or have neurogenic basis.  The annual incidence of GIST is estimated to be 10-20 per million.  In Egypt, the relative incidence reported by the National Cancer Institute is 2.5% of all gastrointestinal tumors and 0.3% of all malignancies.  In Western countries, GIST occurs in people after the fourth decade of life, with a mean age at diagnosis of 60 years. , The mean age of our patients was 48 years, which agrees with 43-50 years reported in our sub-region, probably due the younger age of our population. , The equal distribution in both sexes is also consistent with our data. ,
In high-income countries, 10-30% of cases of GIST are discovered incidentally during the course of investigation or operation for unrelated disease.  All our patients were symptomatic at presentation, with a median duration of 9 months. This is similar to 9-12 months reported from our sub-region. , The most common presentation of GISTs in our patients was abdominal pain. Gastrointestinal bleeding from mucosal ulceration was also a common feature.  Gastrointestinal bleeding is produced by pressure necrosis and ulceration of the overlying mucosa with resulting hemorrhage from disrupted vessels. Our patients presented with hematemesis, melena, or signs and symptoms of anemia caused by occult bleeding. Other signs and symptoms included nausea, vomiting, weight loss, and abdominal distention. In four of our patients, large GISTs formed externally bulging masses, whose extensive extragastric component masked the tumor origin from the stomach. These tumors are often centrally necrotic and cystic containing hemorrhagic-necrotic material or fluid with viable tumor only in a narrow peripheral zone. In the present study, every tumor was larger than 10 cm in diameter and of high-risk category according to previously defined criteria.  This agrees with 70-100% reported from low-income countries. , It is generally accepted that tumors greater than 5 cm have higher risk of metastasis or recurrence. , Similarly, a mitotic count greater than 5 mitoses per 50 HPF is considered to be associated with malignant behavior.  Studies from high-income countries show much lower prevalence of high-risk GIST, with 44% reported from Finland and 30% from UK. , In addition, GIST in our patients occurred sporadically with no clinical findings suggestive of familial GIST which can be seen in patients with neurofibromatosis type 1 or in the Carney-Stratakis triad (gastric GIST, paraganglioma, pulmonary chondroma). 
No laboratory test can specifically confirm or rule out the presence of GIST. Abdominal radiography may show a nonspecific soft-tissue mass indenting or displacing the gastric air shadow. Rarely, calcification may occur and be visible on abdominal radiographs [Figure 2]. In double-contrast barium meal, tumors can be visualized as submucosal masses with smooth and intact surface when coated with barium, but these findings are inconsistent and do not have considerable diagnostic value. Specific investigation in our patients was limited to endoscopy and biopsy. However, due to the submucosal or intramural location of these tumors, the ability to obtain adequate material for histological diagnosis via endoscopic forceps biopsy is limited. Therefore, most cases are preoperatively diagnosed as suspected GIST using imaging modalities only. , Although six of our patients had preoperative diagnosis of gastric GIST based on clinical and radiological features, only two of them had immunohistochemical diagnosis based on endoscopic biopsy of ulcerated tumors. Other studies reported that most gastric GISTs are diagnosed by surgical resection. , Recent studies have shown that EUS-guided fine needle aspiration (FNA) cytology appears to be of great value in the evaluation of GISTs.  By performing immunohistochemical analysis of specimens obtained by EUS-FNA, CD117 expression can be determined, which is necessary for making the diagnosis of GIST.  The reported diagnostic rate for tumors less than 2 cm, 2-4 cm, and more than 4 cm was 71%, 86%, and 100%, respectively.  This accurate preoperative pathological proof of GIST using EUS-FNA facilitates the surgeon's and oncologist's decision making for early local resection and early start of imatinib treatment. However, the degree of mitotic activity cannot be reliably determined on FNA specimen, hence the malignant potential of the tumor may not be determined.  The addition of immunohistochemical staining for Ki-67, a labeling index that denotes mitotic activity and cell proliferation, may be helpful in overcoming this problem.  Similar to Unalp and colleagues and Gold and Dematteo, we do not favor performing a preoperative percutaneous biopsy because of the risk of peritoneal seeding or tumor rupture. ,
|Figure 2: Barium meal and follow-through of a large antral tumor with a rim of calcification|
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CT scan is an important adjunct in the diagnosis of GIST and assists in both staging and grading of the tumor for preoperative planning. An exophytic pattern of growth in a large tumor, together with the absence of associated lymphadenopathy, helps to differentiate GISTs from other gastric tumors such as adenocarcinomas or lymphomas.  Other potentially useful diagnostic evaluations are magnetic resonance imaging and positron emission tomography which are appropriate for staging and determination of organ invasion.  Although conventional radiographs such as barium meal are readily available in low-income countries, CT scan and MRI cannot be performed by most patients due to high cost. In addition, while EUS guided FNA cytology may not be available in most centers, our laboratories do not have facilities for immunohistochemistry and those that do have probably may not stock the antibodies against the KIT receptor (CD117) because of the rarity of GIST in this environment. These factors make preoperative immunopathological diagnosis of GIST very difficult in our patients.
The aim of surgery is complete resection of visible and microscopic disease, possibly avoiding tumor rupture and achieving negative margins. However, DeMatteo et al, demonstrated that tumor size and not negative microscopic surgical margins determine the survival.  Therefore, complete resection with gross negative margins is also considered safe and effective. , Given this, wedge resection has been advocated by many investigators for the majority of gastric GISTs. ,, However, in accordance with the established principles of cancer surgery, more recent studies have shown that completeness of resection is an important factor that affects survival in patients with GISTs. , In addition, our patients present with large tumors that may necessitate a more extensive surgery, including partial or total gastrectomy. , In the present study, 38.5% of the patients underwent a wedge resection and 46.2% underwent a gastrectomy. A combined adjacent organ resection was performed in 15.4% of our patients, which agrees with 10-29.5% reported in other studies. ,, In high-income countries where patients present early and the tumors are comparatively small, complete resection with microscopic negative margins is achieved in 75.6-82.9% of patients. , Seven of our patients had R0 resection, of whom five were alive at 3 years. The effects of incomplete resection on survival rates in patients with advanced-stage GISTs are controversial. Wu and Bucher reported that debulking of large tumors could increase the effectiveness of chemotherapy even if negative margin was not achieved.  On the contrary, Langer and colleagues concluded that incomplete resection was useful only in controlling symptoms such as pain or hemorrhage and that it did not affect survival.  DeMatteo and co-workers reported 5-year survival rates after incomplete resection of 9% compared to 42% in patients who had complete resection.  Recent reports have demonstrated 42-88% 5-year overall survival following R0 resection compared to 0% following palliative care. , Unlike gastric adenocarcinoma, regional lymph nodes including perigastric and mesenteric lymph node metastasis of GIST is unusual. Lymph node involvement has been reported in 1.1-3.4% patients with GIST, hence lymphadenectomy is warranted only for evident nodal involvement. , Lymphadenectomy was performed in five of our patients who had perigastric node enlargement, all of whom were shown not to contain tumor histologically. Lymph node involvement is unusual even in the presence of liver metastasis.  This was the finding in two of our patients.
GISTs have a high risk of metastatic relapse, specifically in the liver and peritoneum, after initial surgery for localized disease. , The stratification of malignant potential is the most important predictor of the risk of relapse. The division of GIST into very low risk, low-risk, intermediate-risk, and high-risk groups accurately predicted outcome with regard to both recurrent tumor and survival. , In our setting where many patients present with obviously malignant tumors, the addition of an "overtly malignant group" as proposed by Nilsson et al, is important.  Additional risk factors associated with recurrence include presence of necrosis, infiltration of neighboring structures, high cellularity, serosal invasion, and high vascularity. 
Radiotherapy and conventional chemotherapy are known to be ineffective in the management of GISTs of the stomach. Imatinib, a tyrosine kinase inhibitor, antagonizes the effects of the KIT and PDGFRA proteins and has revolutionized the treatment of advanced and unresectable GISTs. , Several studies comparing the survival of patients with advanced GISTs before and after the approval of imatinib have shown that it prolongs the survival of such patients. , In the Surveillance, Epidemiology and End Results database, overall survival was 12 months in the pre-imatinib era compared to 33 months in the imatinib era.  Recent studies indicate that responsiveness to imatinib and other tyrosine kinase inhibitors is dependent on the type and site of mutation, with deletions appearing to be more aggressive than point mutations and exon 9 mutations being less responsive to imanitib therapy than exon 11 lesions. , Other factors that independently predict shorter progression-free survival for patients treated with imatinib as first-line therapy include male sex, low hemoglobin, high neutrophil count, poor performance status, and serum protein level. ,, Patients with a large or high-grade tumor, or margin-positive resection are most likely to benefit from adjuvant imatinib treatment. , All our patients had high-risk tumors including many whose tumors were overtly malignant. Only five of these patients could afford imatinib, albeit at irregular periods. In our institution, a month's supply of a 400 mg daily dose of imatinib costs about $300, indeed beyond the reach of most of our patients. The potential for development of imatinib resistance following irregular treatment cannot be overemphasized. The retrospective nature of our data is a limitation in this study. The current definition of histological criteria for the diagnosis of GIST is a spindled or epithelioid mesenchymal tumor of the gastrointestinal tract with unequivocal immunoreactivity to CD117. Therefore, lack of immunohistochemical assessment for CD117 in most of our patients is an important limitation.
In conclusion, our patients are younger than 60 years and present with high-grade tumors larger than 10 cm in diameter. Because we do not have facilities for EUS-FNA and immunohistochemistry against CD117, preoperative diagnosis was based on clinical and radiological features. In patients with gastrointestinal bleeding, upper endoscopy is a very helpful diagnostic tool which should be combined with EUS if such facility is available. Abdominal CT scan is usually the test of choice to further delineate the location and size of the lesion and to look for direct or metastatic spread. Despite the large tumor size and high mitotic activity, complete resection of the tumor is associated with good control of the symptoms and prolonged survival, and can be safely achieved by wedge or more radical resection of the stomach.
Paper presented in part at the West African College of Surgeons Conference held in Cotonou, Benin Republic, 2005.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]