Gastrointestinal Stromal Tumor
Gastrointestinal stromal tumor (GIST) is a rare mesenchymal neoplasm that arises predominantly in the gastrointestinal tract, with the stomach and small intestine being the most common sites. GISTs originate from the interstitial cells of Cajal or related stem cells, which serve as pacemaker cells regulating gut motility. The pathogenesis of GIST is closely associated with activating mutations in the KIT proto-oncogene or, less commonly, the platelet-derived growth factor receptor alpha (PDGFRA) gene, resulting in constitutive activation of tyrosine kinase signaling pathways that drive tumorigenesis. Health impacts of GIST vary depending on tumor size, location, and metastatic potential, but may include gastrointestinal bleeding, abdominal pain, obstruction, or, in advanced cases, metastatic disease primarily to the liver or peritoneum. The clinical course can range from indolent to highly aggressive, with a risk of recurrence even after complete surgical resection.
Sporadic GISTs represent the vast majority of cases and are characterized by isolated tumors without a hereditary component. These tumors typically harbor activating mutations in the KIT or PDGFRA genes, leading to uncontrolled cellular proliferation. Sporadic GISTs most commonly arise in adults over the age of 40 and are usually solitary lesions. The clinical behavior ranges from benign to malignant, with risk stratification based on tumor size, mitotic index, and anatomical location.
Familial GIST is a rare hereditary form of the disease caused by germline mutations in the KIT or PDGFRA genes. Patients with familial GIST often present with multiple primary tumors throughout the gastrointestinal tract and may have associated features such as skin hyperpigmentation or dysphagia. This form follows an autosomal dominant inheritance pattern, and affected individuals are at increased risk for developing GISTs at an earlier age compared to sporadic cases.
Pediatric GIST is a distinct subtype occurring predominantly in children and adolescents, particularly females. Unlike adult GISTs, pediatric cases rarely harbor KIT or PDGFRA mutations and may instead involve alterations in the succinate dehydrogenase (SDH) complex. These tumors frequently present as multifocal gastric lesions with a tendency for lymph node involvement and often exhibit an indolent clinical course despite metastatic potential.
Syndromic GISTs are associated with genetic syndromes such as neurofibromatosis type 1 (NF1). In these cases, patients may develop multiple GISTs, typically in the small intestine, and the tumors are usually wild-type for KIT and PDGFRA mutations. The pathogenesis is linked to loss of function of the NF1 gene, resulting in dysregulation of the RAS pathway. These tumors may have a less aggressive behavior compared to sporadic GISTs.
GISTs are the most common mesenchymal tumors of the gastrointestinal tract, although they account for less than 1% of all gastrointestinal malignancies. The estimated annual incidence is approximately 10 to 15 cases per million population worldwide. GISTs are predominantly diagnosed in adults, with a median age at diagnosis of 60 to 65 years, and there is a slight male predominance. The majority of tumors arise in the stomach (60–70%), followed by the small intestine (20–30%), with less frequent involvement of the colon, rectum, and esophagus. Pediatric GISTs represent less than 2% of all cases. The overall survival and prognosis depend on several factors, including tumor size, mitotic rate, location, and presence of metastases at diagnosis. Advances in molecular diagnostics and targeted therapies have significantly improved outcomes in recent years.
The diagnosis of GIST involves a combination of clinical evaluation, imaging studies, histopathological examination, and molecular testing. Patients may present with nonspecific symptoms such as abdominal pain, gastrointestinal bleeding, or a palpable mass, while some tumors are discovered incidentally. Imaging modalities, including contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI), are essential for assessing tumor size, location, and potential metastases. Endoscopic ultrasound (EUS) can provide detailed assessment of submucosal lesions and guide fine-needle aspiration for tissue diagnosis. Definitive diagnosis requires histological evaluation, typically demonstrating spindle cell, epithelioid, or mixed morphology. Immunohistochemical staining for KIT (CD117) and DOG1 is highly sensitive and specific, aiding in the distinction from other mesenchymal tumors. Molecular analysis for KIT and PDGFRA mutations is recommended for prognostication and therapeutic decision-making. Risk stratification systems, such as the NIH and AFIP criteria, incorporate tumor size, mitotic index, and anatomical site to estimate the likelihood of recurrence and guide management.
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