Gastrointestinal stromal tumor


Gastrointestinal stromal tumors are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs arise in the smooth muscle pacemaker interstitial cell of Cajal, or similar cells. They are defined as tumors whose behavior is driven by mutations in the KIT gene, PDGFRA gene, or BRAF kinase. 95% of GISTs stain positively for KIT. Most occur in the stomach and gastric GISTs have a lower malignant potential than tumors found elsewhere in the GI tract.

Classification

GIST was introduced as a diagnostic term in 1983. Until the late 1990s, many non-epithelial tumors of the gastrointestinal tract were called "gastrointestinal stromal tumors". Histopathologists were unable to specifically distinguish among types now known to be dissimilar molecularly. Subsequently, CD34, and later CD117, were identified as markers that could distinguish the various types.
Additionally, in the absence of specific therapy, the diagnostic categorization had only a limited influence on prognosis and therapy.
The understanding of GIST biology changed significantly with identification of the molecular basis of GIST, particularly c-KIT. Historically, literature reviews prior to the molecular definition of GIST, and for a short time thereafter, asserted that 70-80% of GISTs were benign. The identification of a molecular basis for GIST led to the exclusion of many tumors that had been considered as GIST previously, and also the incorporation of a much larger number of tumors that had been labeled as other types of sarcomas and undifferentiated carcinomas. For example, some previous diagnoses of stomach and small bowel leiomyosarcomas would be reclassified as GISTs on the basis of immunohistochemical staining. All GIST tumors are now considered to have malignant potential, and no GIST tumor can be definitively classified as "benign". Hence, all GISTs are eligible for cancer staging in the AJCC / UICC. Nonetheless, different GISTs have different risk assessments of their tendency to recur or to metastasize, dependent on their site of origin, size, and number of mitotic figures.
A multi-omics study introduced a new molecular classification of GIST and identifies YLPM1, a potential tumor suppressor gene.  The study categorised KIT/PDGFRA-mutated GISTs into 4 molecular subtypes. The C2 subtype, enriched with CD8+ T cells, shows potential responsiveness to immunotherapy. The C3 subtype, with frequent CDKN2A aberrations, could benefit from a combination of KIT and CDK4/6 inhibitors, showing strong synergistic effects. Additionally, C1 and C4 subtypes align with established risk classifications, supporting existing therapeutic strategies and prognostic outcomes.  This new molecular classification provides new insights that guide personalized treatments.
Due to the change in definition, clinical pathways of care before the year 2000 are largely uninformative in the current era.

Signs and symptoms

GISTs may present with trouble swallowing, gastrointestinal bleeding, or metastases. Intestinal obstruction is rare, due to the tumor's outward pattern of growth. Often, there is a history of vague abdominal pain or discomfort, and the tumor has become rather large by time the diagnosis is made.

Pathophysiology

GISTs are tumors of connective tissue, i.e. sarcomas; unlike most gastrointestinal tumors, they are nonepithelial. About 70% occur in the stomach, 20% in the small intestine and less than 10% in the esophagus. Small tumors are generally not aggressive, especially when cell division rate is slow. GIST tumors commonly metastasize to the liver and/or to the greater omentum, lesser omentum, or mesentery. Less common areas of metastasis include the lungs, subcutaneous tissue, lymph nodes or bones.
GISTs are thought to arise from interstitial cells of Cajal, that are normally part of the autonomic nervous system of the intestine. They serve a pacemaker function in controlling motility.

Genetics

Most GISTs are sporadic. Less than 5% occur as part of hereditary familial or idiopathic multitumor syndromes. These include, in descending order of frequency, neurofibromatosis Recklinghausen, Carney's triad, germline gain-of-function mutations in c-KIT/PDGFRA, and the Carney-Stratakis syndrome. The Carney-Stratakis syndrome is a dyad of hereditary GIST and paraganglioma, that is caused by germline mutations in the mitochondrial tumor suppressor gene pathway involving the succinate dehydrogenase subunits SDHD, SDHC and SDHB.

c-KIT mutations

Approximately 85% GISTs are associated with an abnormal c-KIT pathway. c-KIT is a gene that encodes for a transmembrane receptor for a growth factor termed stem cell factor. The abnormal c-KIT pathway most commonly arises from mutation of the gene itself; a smaller subset of c-KIT-associated GISTs are associated with constitutive activity of the KIT enzymatic pathway, found by immunoblotting. The c-KIT product/CD117 is expressed on ICCs and a large number of other cells, mainly bone marrow cells, mast cells, melanocytes and several others. In the gut, however, a mass staining positive for CD117 is likely to be a GIST, arising from ICC cells.
The c-KIT molecule comprises a long extracellular domain, a transmembrane segment, and an intracellular part. Mutations generally occur in the DNA encoding the intracellular part, which acts as a tyrosine kinase to activate other enzymes. Mutations make c-KIT function independent of activation by scf, leading to a high cell division rate and possibly genomic instability. Additional mutations are likely "required" for a cell with a c-KIT mutation to develop into a GIST, but the c-KIT mutation is probably the first step of this process.
Mutations in the exons 11, 9 and rarely 13 and 17 of the c-KIT gene are known to occur in GIST. The tyrosine kinase function of c-KIT is important in the medical therapy for GISTs, as described below.
  • KIT-D816V point mutations in c-KIT exon 17 are responsible for resistance to targeted therapy drugs like imatinib mesylate, a tyrosine kinase inhibitor.
  • KIT-p.D419del — A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8.

    PDGFRA mutations

Most GIST cells with wildtype c-KIT instead have a mutation in another gene, PDGFR-α, which is a related tyrosine kinase. Mutations in c-KIT and PDGFrA are mutually exclusive .

Wild-type tumors

Lesser numbers of GISTs appear to be associated with neither c-KIT nor PDGFR-α abnormalities. About 10-15% of gastrointestinal stromal tumors carry wild-type sequences in all hot spots of KIT and platelet-derived growth factor receptor alpha . These tumors are currently defined by having no mutations in exons 9, 11, 13, and 17 of the KIT gene and exons 12, 14, and 18 of the PDGFRA gene.

Diagnosis

is often undertaken.
Negative immunohistochemistry staining for β-catenin in cell nuclei is a consistent finding in uterine leiomyomas, and helps in distinguishing such tumors from β-catenin positive spindle cell tumors.
The definitive diagnosis is made with a biopsy, which can be obtained endoscopically, percutaneously with CT or ultrasound guidance or at the time of surgery. A biopsy sample will be investigated under the microscope by a pathologist physician. The pathologist examines the histopathology to identify the characteristics of GISTs. Smaller tumors can usually be confined to the muscularis propria layer of the intestinal wall. Large ones grow, mainly outward, from the bowel wall until the point where they outstrip their blood supply and necrose on the inside, forming a cavity that may eventually come to communicate with the bowel lumen.
When GIST is suspected—as opposed to other causes for similar tumors—the pathologist can use immunohistochemistry. 95% of all GISTs are CD117-positive. Other cells that show CD117 positivity are mast cells.
If the CD117 stain is negative and suspicion remains that the tumor is a GIST, the newer antibody DOG1 can be used. Also, sequencing of KIT and PDGFRA can be used to prove the diagnosis.

Imaging

The purpose of radiologic imaging is to locate the lesion, evaluate for signs of invasion and detect metastasis. Features of GIST vary depending on tumor size and organ of origin. The diameter can range from a few millimeters to more than 30 cm. Larger tumors usually cause symptoms in contrast to those found incidentally which tend to be smaller and have better prognosis. Large tumors tend to exhibit malignant behavior but small GISTs may also demonstrate clinically aggressive behavior.
File:CT image of a GIST tumor in the gastric cardia.jpg|thumb|CT image of a GIST in the gastric cardia. The lesion appears submucosal, is hypervascular and protrudes intraluminally. Upper GI bleeding led to endoscopy, finding an ulcerated mass.
Plain radiographs are not very helpful in the evaluation of GISTs. If an abnormality is seen, it will be an indirect sign due to the tumor mass effect on adjacent organs. On abdominal x-ray, stomach GISTs may appear as a radiopaque mass altering the shape of the gastric air shadow. Intestinal GISTs may displace loops of bowel and larger tumors may obstruct the bowel and films will show an obstructive pattern. If cavitations are present, plain radiographs will show collections of air within the tumor. Calcification is an unusual feature of GIST but if present can be visible on plain films.
Barium fluoroscopic examinations and CT are commonly used to evaluate the patient with abdominal complaints. Barium swallow images show abnormalities in 80% of GIST cases. However, some GISTs may be located entirely outside the lumen of the bowel and will not be appreciated with a barium swallow. Even in cases when the barium swallow is abnormal, an MRI or CT scan must follow since it is impossible to evaluate abdominal cavities and other abdominal organs with a barium swallow alone. In a CT scan, abnormalities may be seen in 87% of patients and it should be made with both oral and intravenous contrast. Among imaging studies, MRI has the best tissue contrast, which aids in the identification of masses within the GI tract. Intravenous contrast material is needed to evaluate lesion vascularity.
Preferred imaging modalities in the evaluation of GISTs are CT and MRI, and, in selected situations, endoscopic ultrasound. CT advantages include its ability to demonstrate evidence of nearby organ invasion, ascites, and metastases. The ability of an MRI to produce images in multiple planes is helpful in determining the bowel as the organ of origin, facilitating diagnosis.
File:Beta-catenin immunohistochemistry in gastrointestinal stromal tumor.jpg|thumb|Immunohistochemistry for β-catenin in GIST, which is negative as there is only staining of cytoplasm but not of cell nuclei. Negative nuclear β-catenin staining is seen in approximately 95% of GIST cases, and helps in distinguishing such tumors from β-catenin positive spindle cell tumors.