Gastrointestinal Stromal Tumor Treatment

Gastrointestinal Stromal Tumour (GIST)

• Earlier called leiomyoma and leiomyosarcoma, they occur in jejunum or ileum. These are uncommon mesenchymal tumours .
• The stomach is the most common site. GISTs are rare in the oesophagus, whereas leiomyoma is more common.
• They constitute 20% of malignant neoplasms of the small bowel.
• More common in the 5th and 6th decades of life.
• They arise from interstitial cells of Cajal which are pacemaker cells that regulate motility and peristalsis.
• GISTs arise from muscularis propriThey tend to grow extramurally.

Gastrointestinal Stromal Tumour Clinical Features;

• They present as bleeding/mass/perforation.
• Very often massive bleeding may be the only presentation.
• Carney’s triad: It consists of three components:
  • GIST
  • Pulmonary chondromas
  • Extra-adrenal paragangliomas
• A palpable, mobile large nodular mass suggests GIST.

Gastrointestinal Stromal Tumour Spread:

• Spread is mainly locoregional. In malignant GIST of stomach, infiltration into the diaphragm is not uncommon. Haematogenous spread can occur into lungs and bone.
• Rarely lymphatic spread can occur.

Gastrointestinal Stromal Tumour Prognosis:

It depends upon three factors:

• Size more than 5 cm
• High mitotic index
• Tumour invasion into lamina propria

Gastrointestinal Stromal Tumour Diagnosis:

• Diagnosis is by endoscopy and biopsy. If ulcer is present, it is easy to take a biopsy. If ulcer is not present, a biopsy on a biopsy should be taken. It is difficult in cases of GIST of small intestines.
• CECT scan can define the growth and infiltration with or without lymph nodes.

Tumour Markers:

• They express CD117/CD34 antigen. CD117 is known as C-kit receptor.

Gastrointestinal Stromal Tumour Treatment;

• Treatment is in the form of resection. Diagnosis of malignancy is by mitotic figures: <10 mitoses/high power field (HPF) suggests a low grade malignancy. >10 mitoses/HPF suggests high grade malignancy.
• Increased incidence of C-kit has also been found in patients with neurofibroma.
• The drug of choice for GIST is Imatinib Mesylate.

Imatinib Mesylate:

• It is a tyrosinekinase inhibitor.
• It is the first drug of choice in high-risk patients.
• Given as 400 mg/day for 3 years as adjuvant treatment.
• Not given for low-risk patients of R-O resection.
• It should be given, if tumour ruptures on table.
• It is the drug of choice for unresectable and metastatic tumours. Long-term side effects include abdominal cramp, bleeding wounds, gums, swelling of face and feet, etc.
• Imatinib with doxorubicin has shown some benefit in high grade tumours.

Neuroendocrine Tumours (NET)

• Its original name is karzinoide—means features resembling carcinoma.
• Today these carcinoid tumours are called NeuroEndocrine Tumours (NET).
• It arises from argentaffin/chromaffin cells which are present in the crypts of the villi of intestine. These cells are called Kulchitsky cells. These cells stain with ammonical silver salt solution to black colour. Hence, they are called argentaffinoma or chromaffinoma.
• They secrete 5-HT (serotonin or 5-hydroxytryptamine).
• They can be single or multiple and can be associated with adenocarcinoma.
• Median age of presentation is 63 years.
• NET are classified as:
  • Low grade: Grade 1, G1
  • Intermediate: Grade 2, G2
  • High grade: Grade 3, G3
• Symptoms occurring due to hormone secretion from these tumours together constitute carcinoid syndrome.
• Midgut NET occurs within last 2 feet of ileum and secretes important hormones such as serotonin (5-HT) and substance-P.
• Location, pattern of growth, depth of invasion decide malignancy.
• The tumour appears as a small firm submucosal nodule with large mesenteric lymph nodal mass.
• Tumour produces desmoplastic reaction resulting in fibrosis, intestinal kinking and intestinal obstruction.
• Intermittent recurrent colicky abdominal pain, diarrhoea and weight loss are the features.

Comparison of NET at various sites:

Neuroendocrine Tumours Sites:

• Appendix: 65%. It is the most common site. It occurs more commonly in females. When the tumour occurs in the appendix, it is usually benign, hard and occurs in distal one-third of appendix.
• Terminal ileum: 30%. Most of them are malignant. When the tumour occurs in the ileum it is usually malignant and produces multiple bulky secondaries in the liver, even when primary is very small. Fibrosis of the mesentery results in kinking of bowel causing periodic abdominal pain.
• The hormones produced by the tumour 5-HT (serotonin) are not metabolised because of the secondaries. So, they are absorbed into the circulation and produce various symptoms. This is called carcinoid syndrome.

Carcinoid Syndrome:

• Usually malignant NET from ileum produces classical symptoms of vasomotor, cardiac and gastrointestinal.
• Invariably it is associated with massive hepatomegaly due to metastasis.
• Hormones responsible for symptoms are serotonin, 5-HTP, histamine, dopamine, prostaglandins, etc.

Signs and Symptoms:

• Vasomotor: These are the most common findings seen in about 80% of cases. These can be erythromatous red flushing attacks, either involving entire body or limited to areas such as face, neck and upper chest.
• Gastrointestinal: Episodic watery diarrhoea is seen in about 70–75% of patients. It is caused by hormone serotonin. It responds to methysergide which is a serotonin antagonist.
• Cardiac: Pulmonary stenosis is the most common cardiac lesion followed by tricuspid insufficiency and tricuspid stenosis.

Neuroendocrine Tumours Diagnosis:

1. 5-hydroxyindole acetic acid (5-HIAA), a serotonin metabolite is elevateIt is measured in 24-hour urine sample.
2. Chromogranin-A (CgA) has a specificity around 95%.
3. Thus a combination of 5-HIAA with CgA measurements is recommended.
4. CT scan: It can identify as NET—it appears to be solid, with spiculated borders and radiating strands. CT scan helps to locate NET and to define lymph nodal mass.
5. MRI is not used for diagnosis but can detect liver metastasis.
6. Scintigraphy is useful in detecting extra-abdominal disease. It can detect somatostatin receptor sites. Octreotide is used for scintigraphy.
7. 18FDG-PET (18F-fluorodeoxyglucose positron emission tomography) is useful only in high grade NET which has high Ki-67 expression.

Neuroendocrine Tumours Surgery:

• Excision/resection of the NET with intestinal segment for small primary tumours less than 1 cm in size.
• Larger tumours: Resection of tumour, intestine and mesentery.
• Terminal ileal NET: Right hemicolectomy.
• Disseminated disease: Surgical debulking.

Pharmacotherapy:

• Octreotide (somatostatin analogues) is the drug of choice in treating patients with symptoms. Mainly used in carcinoid syndrome to treat flushing and diarrhoe
• Metastatic tumours are treated by debulking (if possible) with combination chemotherapy using Inj streptozotocin, 5-fluorouracil (5-FU) and cyclophosphamide.
• Bromocriptine 2.5 mg twice a day can be given to reduce the symptoms. Other agents which can be used are methysergide and diphenoxylate hydrochloride.
• Secondaries in the liver are treated by intra-arterial (hepatic artery) streptozocin. Localised liver metastasis can be treated with resection.
• Therapeutic embolisation of hepatic artery by using gel foam, etwill reduce the size of the liver, thereby decreasing discomfort to the patient.
• Injection octreotide 100 mg IV is the drug of choice in cases of carcinoid crisis (severe bronchospasm).

Octreotide in Carcinoid Syndrome:

1. It is used to suppress the tumour growth.
2. Control symptoms—flushing, wheezing, diarrhoea.
3. It controls the release of GI hormones.
4. Dose is 100 µg subcutaneously three times a day in patients with mild/moderate, non-life-threatening carcinoid syndrome.

Malignant Lymphoma:

Primary: Arising from lymphoid tissue.

Secondary: Part of systemic lymphomIleum is the most common site of lymphoma

Precipitating Factors:

1. Crohn’s disease
2. Celiac disease
3. Immunosuppression—AIDS—usually it is a nonHodgkin’s lymphoma of ‘B’ cell origin.