Gastrointestinal stromal tumor overview: Difference between revisions
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{{Gastrointestinal stromal tumor}} | {{Gastrointestinal stromal tumor}} | ||
{{CMG}}{{AE}}{{ | {{CMG}}; {{AE}}{{Akshun}} | ||
==Overview== | ==Overview== | ||
In [[medicine|medical]] [[oncology]], '''gastrointestinal stromal tumors | In [[medicine|medical]] [[oncology]], '''gastrointestinal stromal tumors (GISTs)''' are [[rare disease|rare]] [[Tumor|tumors]] of the [[gastrointestinal tract]]. GISTs are non-[[epithelium|epithelial]] [[tumor]]s 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|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]]. [[Computed tomography|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 [[Cancer staging|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 [[Patient|patients]] with aforementioned conditions. [[Patient|Patients]] resistant to [[imatinib]] are treated with sunitinib 50 mg PO q24h. [[Medical]] [[therapy]] such as fluid resuscitation, [[Antibiotic|antibiotics]] cover, [[deep venous thrombosis]] prophylaxis should also be given to decrease [[perioperative]] [[morbidity]] associated with [[resection]] of GIST. [[Patient|Patients]] with GIST on [[medical]] [[therapy]], tend to have a recurrent [[Course (medicine)|course]] and must be evaluated on a periodic basis with a [[CT-scans|CT scan]] or [[PET scan]] for early identification of recurrent [[disease]]. | ||
==Historical Perspective== | ==Historical Perspective== | ||
Prior to the advent and use of [[electron microscopy]], gastrointestinal stromal tumors (GIST) were classified as [[smooth muscle]] [[tumors]] such as [[Leiomyoma|leiomyomas]] or [[Leiomyosarcoma|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|(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]]). | Prior to the advent and use of [[electron microscopy]], gastrointestinal stromal tumors (GIST) were [[Classification|classified]] as [[smooth muscle]] [[tumors]] such as [[Leiomyoma|leiomyomas]] or [[Leiomyosarcoma|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-[[Abdomen|abdominal]] [[Tumor|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 cell|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|(proto-oncogene]]) [[Mutation|mutations]] as the cause of GIST. In 2001, Joensuu was the first to report successful treatment of [[Patient|patients]] with advanced GIST on [[molecular]]-[[targeted therapy]] ([[imatinib]]). | ||
==Pathophysiology== | ==Pathophysiology== | ||
Gastrointestinal stromal tumors (GISTs) are rare but the most common [[mesenchymal]] ( | Gastrointestinal stromal tumors (GISTs) are rare but the most common [[mesenchymal]] (non[[epithelial]]) [[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]] [[Tumor|tumors]] or massive [[malignant]] [[Tumor|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 [[Lesion|lesions]]. [[Genes]] involved in the [[pathogenesis]] of gastrointestinal stromal tumors include [[mutations]] in c-Kit [[gene]] and PDGFRA ([[Platelet-derived growth factor receptor|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, [[mutation|mutations]] in [[succinate dehydrogenase]] ([[Succinate dehydrogenase|SDH]]) have been reported. Conditions associated with GIST include [[urticaria pigmentosa]], [[neurofibromatosis type 1]], and [[Carney syndrome|Carney-Stratakis syndrome]]. On [[gross pathology]], GISTs have a rounded appearance with areas of [[hemorrhage]]. On [[microscopic]] [[histopathological]] [[analysis]], GISTs are cellular [[tumor|tumors]] arising from [[muscularis]] propria and composed of [[spindle cells]] (70%), [[Epithelioid cell|epithelioid cells]] (20%) or either one of them. | ||
==Causes== | ==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 [[genetic disorder|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]]'' | Molecular genetics have drastically changed the understanding of gastrointestinal stromal tumors (GIST). [[Genetics|Genetic]] [[Mutation|mutations]] are considered the most identifiable cause of GIST. Around 95% of these [[Mutation|mutations]] are sporadic with less than 5% occur as part of [[genetic disorder|hereditary]], [[familial]], or [[idiopathic]] multi [[tumor]] [[Syndrome|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 , [[Mutation|mutations]] in [[succinate dehydrogenase]] ([[Succinate dehydrogenase|SDH]]) have been reported. Rare [[genes]] involved include [[mutation]] in ''[[BRAF]]'' [[kinase]], and [[protein kinase C]]. | ||
==Epidemiology and Demographics== | ==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 Program|the Surveillance, Epidemiology, and End Results]] ([[The Surveillance, Epidemiology, and End Results Program|SEER]]) registry data found that GIST usually affects individuals of the white race (72.2%). | 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 Program|the Surveillance, Epidemiology, and End Results]] ([[The Surveillance, Epidemiology, and End Results Program|SEER]]) registry data found that GIST usually affects individuals of the white [[race]] (72.2%). | ||
==Risk factors== | ==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. | The most common [[Risk factor|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. [[Genetics|Genetic]] [[Syndrome|syndromes]] associated with GIST include [[neurofibromatosis type 1]], [[Carney syndrome|Carney-Stratakis syndrome]] and [[familial]] gastrointestinal stromal tumor syndrome. | ||
==Screening== | ==Screening== | ||
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==Differential Diagnosis== | ==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]]. | Around 75 % of the [[Patient|patients]] with gastrointestinal stromal tumors (GIST) are [[asymptomatic]] and the rest have non-specific [[Symptom|symptoms]] such as vague [[Abdomen|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== | ==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|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. | 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|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 [[Patient|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 and Physical examination|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 [[Symptom|symptoms]] such as [[abdominal pain]], [[constipation]], change in [[appetite]], and black [[Human feces|stools]]. The [[Symptom|symptoms]] of GISTs depends upon the [[tumor]] size and location. Majority of the GISTs are [[asymptomatic]]. [[Patient|Patients]] with GIST who have [[Symptom|symptoms]] ([[tumor]] size > 5cm) are generally non specific such as [[dysphagia]], vague [[Abdominal discomfort|abdominal discomfort,]] [[jaundice]] and [[abdominal fullness]]. | |||
== | ===Physical Examination=== | ||
Common [[physical examination]] findings of gastrointestinal stromal tumors (GIST) include [[abdominal distension]] and palpable [[abdominal mass]]. [[Patient|Patients]] with severe and longstanding GIST may present with signs of [[Abdomen|abdominal]] [[perforation]] and [[peritonitis]] such as [[abdominal tenderness]], rigidity and [[Abdominal guarding|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, [[Patient|patients]] who present with [[Medical sign|signs]] and [[Symptom|symptoms]] of [[abdominal pain]] and [[obstruction]] and other features of GIST should be evaluated with [[complete blood cell count]], [[Electrolyte|electrolytes]], [[Renal function tests|renal function test]], [[liver function tests]], [[coagulation]] profile, [[serum]] [[amylase]] and [[lipase]], [[Blood type|blood group type]] and [[Serum albumin|serum albumin levels]]. | |||
== | ===Abdominal X-ray=== | ||
Abdominal [[X rays|X ray]] is not routinely indicated in [[Patient|patients]] of gastrointestinal stromal tumor (GIST) as their findings are quite non-specific. However, they may be indicated in [[Patient|patients]] who present with severe [[abdominal pain]] indicating [[intestinal obstruction]] or [[Intestinal perforation|perforation]]. On an [[Abdomen|abdominal]] [[X-rays|X-ray]], GIST appears as a large, [[soft tissue]] density displacing [[Intestine|bowel]] loops. Depending upon the severity of the condition, signs of [[intestinal obstruction]] such as multiple air-fluid levels may be present. | |||
== | ===CT scan=== | ||
[[ | [[Computed tomography|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 [[Cancer staging|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 (test)|gold standard]] in diagnosing GIST. On a T1 weighted MRI, low signal [[intensity]] indicates solid component GIST whereas on a T2 weighted [[Magnetic resonance imaging|MRI]], high signal intensity indicates solid component GISTs. | |||
== | ===Ultrasound=== | ||
An [[endoscopic ultrasound]] (EUS) may be done in [[patient]]<nowiki/>s of gastrointestinal stromal tumors (GIST) presenting with [[signs]] and [[Symptom|symptoms]] of [[abdominal pain]], [[bleeding]] or [[Obstruction|obstructive]] [[Symptom|symptoms]]. [[Endoscopic ultrasound|EUS]]-guided [[biopsy]] can also be used for [[Diagnosis|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 Diagnostic studies== | ===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 [[Diagnosis|diagnostic]] studies associated with gastrointestinal stromal tumors (GIST). | |||
==Medical Therapy== | ==Medical Therapy== | ||
The predominant therapy for gastrointestinal stromal tumor is surgical resection. | The predominant [[therapy]] for gastrointestinal stromal tumor(GIST) is surgical [[resection]]. [[Medical]] [[therapy]] with [[tyrosine kinase]] [[Inhibitor|inhibitors]] are indicated in [[Patient|patients]] with unresectable [[Lesion|lesions]], to decrease [[tumor]] size prior to [[surgery]] and for [[Prevention (medical)|prevention]] of recurrent [[disease]]. [[Imatinib]] 400 mg to 800 mg PO q24h is the drug of choice for patients with aforementioned [[conditions]]. [[Patient|Patients]] resistant to imatinib are treated with sunitinib 50 mg PO q24h. [[Medical]] [[therapy]] such as [[fluid]] [[resuscitation]], [[Antibiotic|antibiotics]] cover, [[deep venous thrombosis]] [[prophylaxis]] should also be given to decrease [[perioperative]] [[morbidity]] associated with [[resection]] of GIST. | ||
==Surgical Therapy== | ==Surgical Therapy== | ||
The predominant therapy for gastrointestinal stromal tumor is surgical resection. | 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== | ==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 (medicine)|course]] and must be evaluated on a periodic basis with a [[CT scan]] or [[PET scan]] for early identification of recurrent [[disease]]. | |||
==References== | ==References== | ||
Latest revision as of 15:46, 28 February 2019
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Gastrointestinal stromal tumor Microchapters |
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Differentiating Gastrointestinal stromal tumor from other Diseases |
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Diagnosis |
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Treatment |
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Case Studies |
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Gastrointestinal stromal tumor overview On the Web |
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American Roentgen Ray Society Images of Gastrointestinal stromal tumor overview |
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Directions to Hospitals Treating Gastrointestinal stromal tumor |
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Risk calculators and risk factors for Gastrointestinal stromal tumor overview |
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.