Gastrointestinal Stromal Tumor (GIST)


Gastrointestinal stromal tumor (GIST) is a rare tumor of digestive tract representing 1-3% of gastrointestinal malignancies. It can develop from any part of the gastrointestinal tract from the esophagus to the anus and from the adjacent structure to the intestine within abdominal cavity. GIST is a type of sarcoma which arises from connective tissues of gut wall also called interstitial cells of Cajal (ICC). The ICCs are known as "pacemaker cells of the gut" because they send signals to trigger peristalsis. GIST tumor arise from the GI tract wall can grow outside of the involved organ called exophytic and those grow inward in the lumen of intestinal tract called endophytic.

Incidence of GIST in gastrointestinal tract -

Stomach - approximately 55%, the most common site
Duodenum and small intestine - approx. 30%,
Esophagus - approx. 5%
Rectum - approx. 5%
Colon - approx. 2%
GISTs may also develop in the supporting membranes of the abdominal organs like peritoneum, mesentery, omentum, the liver, the pancreas, the ovaries, the uterus, and the prostate. Because these types of GISTs do not arise directly from the GI tract, they are called extragastrointestinal stromal tumors. When a GIST grows in a location where it is not encased in the peritoneal membranes, it is said to be retroperitoneal. GISTs are most commonly metastasize to liver, peritoneum, mesentery and omentum. GIST rarely spreads to lymph nodes.

Types of GIST -

Histologically, GISTs can be classified as
Spindle cell tumors - 70%
Epithelioid cell tumor - 20%
Pleomorphic/mixed morphology tumors - 10%
Immunohistochemistry - GISTs are typically CD117-positive in 85-95%, CD34- positive in 60-70% and S100 -positive in10% of cases. Characteristics of GISTs that are predictive of aggressive behavior are mitotic rate greater than 5 per 10 high-power fields (HPF), size larger than 5 cm and 10 cm, and location (small bowel more aggressive than gastric GISTs). However, tumors with low mitotic index (< 5 per 50 HPF) and smaller size (2-5 cm) can also metastasize.

Risk Factors -

No known environmental, behavioral, diet or lifestyle risk factors
Age - most commonly affects older people, usually over age of 50 years. Children are affected very rarely. Persons with inactivation of the neurofibromatosis 1 gene (NF1) are more likely to develop GIST at younger ages. Familial GIST also develops in younger or middle-aged adults.

Sex - incidence of GIST is similar in men and women. Pediatric GISTs are more common in girls and young women. Genetic mutations - The majority of GISTs show mutations in cell-surface proteins called tyrosine kinase receptors. Most GISTs show mutations in a gene that produces a growth factor receptor called KIT. A few GISTs show mutations in the gene for a closely related receptor for platelet derived growth factor receptor alpha (PDGFR a or PDGFRA). Lesser numbers of GISTs appear to be associated with neither c-kit nor PDGFR-a abnormalities. About 10-15% of gastrointestinal stromal tumors (GISTs) carry wild-type sequences in all hot spots of KIT and platelet-derived growth factor receptor alpha (PDGFRA).

Heritability -

Almost all GISTs are sporadic, meaning that the mutations are random occurrences affecting a single individual. Less than 5% occur as part of hereditary familial or idiopathic. These include, in descending order of frequency, neurofibromatosis (NF-1), Carney's triad (gastric GIST, pulmonary chondroma and extra-adrenal paraganglioma), germline gain-of-function mutations in c-Kit / PDGFRA, and the Carney-Stratakis syndrome.

Symptoms and signs

Symptoms of a GIST vary depending on the size and location of the tumor.
Patients with smaller tumors have no symptoms.
Larger tumors may cause symptoms include -
Vague, nonspecific abdominal pain or discomfort
A painless lump in abdomen
Vomiting or diarrhea
Bowel obstruction
Bleed into the GI tract, resulting in black or tarry stools, or occasionally in vomiting of blood.
Very rarely a GIST may rupture, making its presence known with a medical emergency
Anemia may result from chronic bleeding, leading to fatigue
Weight loss
Diagnosis

Diagnosis is based on detailed evaluation of history, physical examination, endoscopy and some radiological investigations.

History and Physical examination-

The detailed clinical history of the patient is evaluated. A through abdominal examination is done to check abdominal lumps or anything else that seems unusual.

Ultrasound scan

For large size tumor ultrasound is the primary investigation

Barium and air (double-contrast) series-

It can detect GISTs that have grown to a size sufficient to produce symptoms. Barium swallow is done for patients with dysphagia while barium enema for patients with constipation, decreased stool caliber, or colonic manifestations. On X-ray GIST appears as an elevated, sharply demarcated filling defect. The overlying mucosa typically has a smooth contour unless ulceration has developed.

Endoscopy

A thin, flexible endoscope is introduced into mouth, down the esophagus and into stomach and small bowel. GIST arises from these structures can be easily seen. Endoscopic features of GISTs include submucosal mass displacing the overlying mucosa. Ulceration or bleeding of the overlying mucosa from pressure necrosis may be present.

Endoscopic ultrasound

For smaller size GIST and when the tumor is exophytic then an endoscopic ultrasound may be used to show the size and position of a GIST. An ultrasound probe is attached at the end of the scope and it produces an image of the intestine containing the tumor and surrounding structures. Fine-needle aspiration biopsy specimens may be obtained under sonographic guidance.

Computerized tomography (CT) scan

CT scan Provides comprehensive information regarding the size and location of the tumor and its relationship to adjacent structures. It can also be used to detect the presence of multiple tumors and of metastatic spread.

Magnetic resonance imaging (MRI) scan

MRI can detect tumors and its surrounding structures.

PET (positron emission tomography) scan

It is used for the assessment of metastatic disease. It is also used in monitoring of response to adjuvant therapy.

Treatment of GISTs

The treatment for GIST depends on a number of factors, including general health of the patients, the size and position of the tumor, local infiltration and distant spread of the tumor. The most common treatment for GIST is surgery to remove the tumor.

Tumors of big size that can't be removed with surgery, local involvement and those with distal spread, targeted chemotherapy also known as growth inhibitors are used.

Resectable GISTs can be completely removed by surgery. A clinical trial of targeted therapy with imatinib mesylate is given following surgery, to decrease the recurrence.

Unresectable GIST cannot be completely removed by surgery because they are too large or in a place where there would be too much damage to nearby organs if the tumor is removed. Treatment is usually targeted therapy with imatinib mesylate to shrink the tumor, followed by surgery to remove as much of the tumor as possible.

Metastatic GIST may include the targeted therapy with imatinib mesylate or sunitinib if the tumor begins to grow during imatinib mesylate therapy or if the side effectsare too bad. Surgery is planned if tumor shrinks.

Surgery

Surgery is performed by either open or minimal invasive methods. Minimal invasive methods has less post operative morbidities, less pain, short hospital stay and less wound complication. Preference of the methods of surgery depends on the size of tumor and the availability of the expert. Surgery is the best treatment for GIST. In localized, resectable adult GISTs, if anatomically and physiologically feasible, surgery is the primary treatment of choice. Lymph node metastases are rare, and routine removal of lymph nodes is typically not necessary.

The tumor is resected along with some surrounding healthy tissue. If the tumor has begun to grow into other tissues close by, these are also removed.
If the GIST has begun to spread, it is sometimes possible to remove the secondary tumors.

Surgery may also be performed to treat recurrent GISTs after targeted chemotherapy therapy.

For gastric GIST, depending upon the size, location a part or most of the stomach is removed.

For small bowel GIST, the loop containing the GIST is resected and the continuity of bowel is restored.

Surgery is done to remove tumors when there are serious complications, such as bleeding, a hole in the gastrointestinal tract, a blocked GI tract, or infection.

Targeted Chemotherapy (Growth inhibitors)

In about 85% of people with a GIST, the tumor cells have a change (mutation) in KIT. Treatment with growth inhibitors can block these signals. This may make the cancer shrink or stop it from growing. Growth inhibitors may be used to treat GISTs that can't be completely removed with an operation. These are imatinib and sunitinib.

The side effects of imatinib include tiredness, feeling sick (nausea), diarrhoea, swollen ankles and puffy eyes, and an itchy rash. Common side effects of sunitinib include a skin rash and soreness, tiredness, mouth ulcers and high blood pressure. These side effects can usually be well controlled with medicines.

Follow-up

Follow-up for GISTs that were removed by surgery may include CT scan of whole abdomen to see the local recurrence as well as distal metastasis. For GISTs that are treated with tyrosine kinase inhibitors, follow-up tests, such as CT, MRI, or PET scans, may be done to check how well the targeted therapy is working.