Gastrointestinal stromal tumor overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]
Overview
In medical oncology, gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal tract. GISTs are non-epithelial tumors and mostly occur in the stomach (70% of cases). In 1983, Mazur and Clark and Schaldenbrand and Appleman in 1984 were the first to describe gastrointestinal stromal tumors as an independent entity of intra-abdominal tumors that were neither carcinomas nor exhibit histologic features of smooth muscle or nerve cells. GISTs are thought to be derived from the interstitial cells of Cajal or undifferentiated precursor cells that finally develop into interstitial cells of Cajal. Genes involved in the pathogenesis of gastrointestinal stromal tumors include mutations in proto-oncogenes such as c-Kit gene and PDGFRA (platelet derived growth factor receptor-alpha) gene. The symptoms of GISTs depends upon the tumor size and location. Majority of the GISTs are asymptomatic. Patients with GIST who have symptoms (tumor size > 5cm) are generally non specific such as dysphagia, vague abdominal discomfort, jaundice and abdominal fullness. Common physical examination findings of gastrointestinal stromal tumors (GIST) include abdominal distension, palpable abdominal mass and in severe cases may present with signs of abdominal perforation and peritonitis. CT scan of the abdomen and pelvis is the imaging test of choice and an is important tool in the diagnosis of gastrointestinal stromal tumor (GIST). CT scan may be used to determine the size, location and staging of GIST. A CT scan may also accurately de-mark surrounding structures, multiple tumors and metastases. The predominant therapy for gastrointestinal stromal tumor (GIST) is surgical resection. Medical therapy with tyrosine kinase inhibitors are indicated in patients with unresectable lesions, to decrease tumor size prior to surgery and for prevention of recurrent disease. Imatinib 400 mg to 800 mg PO q24h is the drug of choice for patients with aforementioned conditions. Patients resistant to imatinib are treated with sunitinib 50 mg PO q24h. Medical therapy such as fluid resuscitation, antibiotics cover, deep venous thrombosis prophylaxis should also be given to decrease perioperative morbidity associated with resection of GIST. Patients with GIST on medical therapy, tend to have a recurrent course and must be evaluated on a periodic basis with a CT scan or PET scan for early identification of recurrent disease.
Historical Perspective
Prior to the advent and use of electron microscopy, gastrointestinal stromal tumors (GIST) were classified as smooth muscle tumors such as leiomyomas or leiomyosarcomas. In 1983, Mazur and Clark and Schaldenbrand and Appleman in 1984 were the first to describe gastrointestinal stromal tumors as an independent entity of intra-abdominal tumors that were neither carcinomas nor exhibit histologic features of smooth muscle or nerve cells. In 1998, Kindblom et al described the origin of GIST as pluripotential mesenchymal stem cells which were programmed to differentiate into the interstitial cell of Cajal. In 1998 Hirota and others were the first to describe c-kit (proto-oncogene) mutations as the cause of GIST. In 2001, Joensuu was the first to report successful treatment of patients with advanced GIST on molecular-targeted therapy (imatinib).
Pathophysiology
Gastrointestinal stromal tumors (GISTs) are rare but the most common mesenchymal (nonepithelial) tumors of the gastrointestinal tract. GISTs are derived from the interstitial cells of Cajal or undifferentiated precursor cells that finally develop into interstitial cells of Cajal. GIST tumors can either be benign tumors or massive malignant tumors with widespread metastasis. They can occur in any part of the gastrointestinal tract with the most common location as stomach. GIST (tumors) can grow as an endophytic or exophytic lesions. Genes involved in the pathogenesis of gastrointestinal stromal tumors include mutations in c-Kit gene and PDGFRA (platelet derived growth factor receptor-alpha) gene. Both Kit gene and PDGFRA are tyrosine kinase receptors and control cell proliferation. Mutation in c-Kit gene and PDGFRA leads to inhibition of apoptosis and uncontrolled cell proliferation. In some rare cases where the patient do not exhibit the typical mutation in c-Kit and PDGFRA, mutations in succinate dehydrogenase (SDH) have been reported. Conditions associated with GIST include urticaria pigmentosa, neurofibromatosis type 1, and Carney-Stratakis syndrome. On gross pathology, GISTs have a rounded appearance with areas of hemorrhage. On microscopic histopathological analysis, GISTs are cellular tumors arising from muscularis propria and composed of spindle cells (70%), epithelioid cells (20%) or either one of them.
Causes
Molecular genetics have drastically changed the understanding of gastrointestinal stromal tumors (GIST). Genetic mutations are considered the most identifiable cause of GIST. Around 95% of these mutations are sporadic with less than 5% occur as part of hereditary, familial, or idiopathic multi tumor syndromes. Common causes of gastrointestinal stromal tumor include mutation in c-Kit gene and PDGFRA gene. In other cases where the patient do not exhibit the typical mutation in c-Kit and PDGFRA , mutations in succinate dehydrogenase (SDH) have been reported. Rare genes involved include mutation in BRAF kinase, and protein kinase C.
Epidemiology and Demographics
The incidence of gastrointestinal stromal tumors (GIST) is approximately 1.0-1.60 cases per 100,000 individuals worldwide. The prevalence of GIST is approximately 12.9 cases per 100,000 individuals worldwide. GIST commonly affects individuals older than 40 years of age with the median age of 60s. Males are more commonly affected by GIST than females. A study based on the Surveillance, Epidemiology, and End Results (SEER) registry data found that GIST usually affects individuals of the white race (72.2%).
Risk factors
The most common risk factors in the development of gastrointestinal stromal tumors (GIST) include age and genetic syndromes. Age is considered as the most potent risk factor in the development of GIST with people in the age group of 50-80 believed to be at the highest risk. Genetic syndromes associated with GIST include neurofibromatosis type 1, Carney-Stratakis syndrome and familial gastrointestinal stromal tumor syndrome.
Screening
There is insufficient evidence to recommend routine screening for Gastrointestinal stromal tumor (GIST).
Differential Diagnosis
Around 75 % of the patients with gastrointestinal stromal tumors (GIST) are asymptomatic and the rest have non-specific symptoms such as vague abdominal pain and discomfort. Thus, GIST must be differentiated from other tumors on the basis of cell markers. GIST must be differentiated from other mesenchymal tumors such as gastrointestinal leiomyoma, gastrointestinal leiomyosarcoma, gastrointestinal carcinoma, gastrointestinal schwannoma and melanoma.
Natural History, Complications and Prognosis
If left untreated, patients with gastrointestinal stromal tumors (GIST) may progress to develop abdominal pain, abdominal distension and perforation. A benign GIST may remain unchanged for years before its progression into malignancy. A GIST may rupture and lead to intra-abdominal or gastrointestinal bleeding. Ultimately, the GIST may metastasize and turn fatal. Common complications of GIST include bowel obstruction, bowel perforation, and peritonitis. Depending on the extent of the tumor at the time of diagnosis, the prognosis of GIST may vary. Prognosis of GIST depends upon size, location, spread and mitotic rate of the tumor. A benign GIST treated with surgical resection has much more better outcome as compared to patients with malignant GIST.
Diagnosis
Staging
According to the American Joint Committee on Cancer, there are 4 stages of gastrointestinal stromal tumor based on the tumor spread.
History and Symptoms
Obtaining history is an important aspect in making a diagnosis of gastrointestinal stromal tumors (GIST). The areas of focus should be on onset, duration, and progression of symptoms such as abdominal pain, constipation, change in appetite, and black stools. The symptoms of GISTs depends upon the tumor size and location. Majority of the GISTs are asymptomatic. Patients with GIST who have symptoms (tumor size > 5cm) are generally non specific such as dysphagia, vague abdominal discomfort, jaundice and abdominal fullness.
Physical Examination
Common physical examination findings of gastrointestinal stromal tumors (GIST) include abdominal distension and palpable abdominal mass. Patients with severe and longstanding GIST may present with signs of abdominal perforation and peritonitis such as abdominal tenderness, rigidity and guarding. Other findings include those from tumor rupture and blood loss such as low blood pressure, tachycardia, and dyspnea.
Laboratory Examination
There are no diagnostic laboratory findings associated with gastrointestinal stromal tumor (GIST). However, patients who present with signs and symptoms of abdominal pain and obstruction and other features of GIST should be evaluated with complete blood cell count, electrolytes, renal function test, liver function tests, coagulation profile, serum amylase and lipase, blood group type and serum albumin levels.
Abdominal X-ray
Abdominal X ray is not routinely indicated in patients of gastrointestinal stromal tumor (GIST) as their findings are quite non-specific. However, they may be indicated in patients who present with severe abdominal pain indicating intestinal obstruction or perforation. On an abdominal X-ray, GIST appears as a large, soft tissue density displacing bowel loops. Depending upon the severity of the condition, signs of intestinal obstruction such as multiple air-fluid levels may be present.
CT scan
CT scan of the abdomen and pelvis is the imaging test of choice and an important tool in the diagnosis of gastrointestinal stromal tumor (GIST). CT scan may be used to determine the size, location and staging of GIST. CT scan may also accurately de-mark surrounding structures, multiple tumors and metastases. On a CT scan, a small GIST (< 5 cms) appears as homogeneous mass with clear boundaries, while a large GIST (>10cms) appears as a heterogeneous mass with irregular borders and have local or distant spread.
MRI
MRI is more accurate and sensitive than a CT scan for delineating rectal gastrointestinal stromal tumors (GISTs). For GISTs located at other locations MRI is as sensitive as a CT scan. However, a biopsy (endoscopic or CT guided) is the gold standard in diagnosing GIST. On a T1 weighted MRI, low signal intensity indicates solid component GIST whereas on a T2 weighted MRI, high signal intensity indicates solid component GISTs.
Ultrasound
An endoscopic ultrasound (EUS) may be done in patients of gastrointestinal stromal tumors (GIST) presenting with signs and symptoms of abdominal pain, bleeding or obstructive symptoms. EUS-guided biopsy can also be used for diagnosing and staging of GIST. An EUS can detemine the exact cell type and histopathological analysis associated with GIST. On EUS, GIST appears as smooth submucosal mass with areas of ulceration or bleeding.
Other Imaging Findings
Endoscopy may be helpful in the diagnosis of gastrointestinal stromal tumor (GIST).An endoscope can be used in conditions where GIST is located in accessible places such as stomach, esophagus and large intestine. On an endoscopy, GIST can appear as a smooth submucosal mass with areas of ulceration or bleeding.
Other Diagnostic studies
There are no other diagnostic studies associated with gastrointestinal stromal tumors (GIST).
Medical Therapy
The predominant therapy for gastrointestinal stromal tumor(GIST) is surgical resection. Medical therapy with tyrosine kinase inhibitors are indicated in patients with unresectable lesions, to decrease tumor size prior to surgery and for prevention of recurrent disease. Imatinib 400 mg to 800 mg PO q24h is the drug of choice for patients with aforementioned conditions. Patients resistant to imatinib are treated with sunitinib 50 mg PO q24h. Medical therapy such as fluid resuscitation, antibiotics cover, deep venous thrombosis prophylaxis should also be given to decrease perioperative morbidity associated with resection of GIST.
Surgical Therapy
The predominant therapy for gastrointestinal stromal tumor (GIST) is surgical resection. Surgical resection offers an opportunity to completely cure GIST. Laparoscopic and endoscopic resection are the most preferred route of surgery. Surgical resection of GIST include complete gross resection with an intact pseudocapsule and negative microscopic margins.
Prevention
Effective measures for the secondary prevention of gastrointestinal stromal tumors include regular follow ups including physical examination with laboratory and imaging evaluations. GIST on medical therapy tend to have a recurrent course and must be evaluated on a periodic basis with a CT scan or PET scan for early identification of recurrent disease.