GISTs and Neuroendocrine Tumors Notes

GISTs and Neuroendocrine Tumors

What is GIST?

• Gastrointestinal stromal tumor, most common type of sarcoma.

• A tumor of the interstitial cells of Cajal (ICC).

• Can occur anywhere in the digestive organs:

  • Most commonly in the stomach.

  • Small intestine.

  • Large intestine.

  • Rectum.

Main Features

• Arises from or shares a common phenotype with the interstitial cells of Cajal within the myenteric plexus of the muscularis propria.

• Most common site is the stomach (60%), followed by the ileum and jejunum (30%).

• Micro/mini/subclinical GIST: minute growths (1-10mm) of interstitial cells of Cajal/GIST-like cells.

• M:F = 1.1 (no clear sex predilection).

• Mean age at diagnosis is 60-65 years old.

Pathogenesis

• Mutations of gene encoding tyrosine kinase C-KIT, the receptor for stem cell factor (75-80%).

• Mutations that activate a related tyrosine kinase, platelet-derived growth factor receptor A (PDGFRA); activating mutations in tyrosine kinase (5%).

• GISTs appear to arise from, or share a common stem cell with, the interstitial cells of Cajal.

• Interstitial cells of Cajal express c-KIT and are located in the muscularis propria; they serve as pacemaker cells for gut peristalsis.

Diagnosis

• Most common presentation: gastrointestinal bleeding or abdominal pain.

• May be an incidental finding during radiologic or endoscopic workup for other clinical issues.

• CT usually shows a solid, heterogeneous mass.

• Endoscopy shows a subepithelial lesion.

• Endoscopic ultrasound reveals a hypoechoic solid mass.

• Definitive diagnosis: only through histologic examination and immunohistochemistry.

Microscopic Picture

• GISTs originate from the interstitial cells of Cajal.

• They may show differentiation towards smooth muscle cells, neural cells, mixed (smooth muscle and neural), or neither cell types.

• Most specific marker: DOG1.

• Most useful marker: c-KIT (CD117) {targeted therapy}.

Treatment

• Most GISTs are treated with surgical resection.

• Imatinib mesylate (Gleevec): tyrosine kinase inhibitor of KIT and PDGFR$\alpha$

• Gleevec is a Tyrosine Kinase (TK) inhibitor.

• Small molecule targets Receptor tyrosine kinase (RTK); high affinity cell surface receptors for many growth factors, cytokines, and hormones.

• New mutations allow resistance to drug.

Prognosis

• GIST can have a clinically malignant behavior.

• Prognosis depends upon:

  • Tumor size.

  • Mitotic rate.

  • Site of origin.

• Intraoperative tumor rupture is associated with poorer prognosis.

• Complete surgical resection improves local recurrence rate and overall survival.

• Incomplete resection is associated with a higher risk of recurrence.

Neuroendocrine Tumors (NETs)

• Heterogeneous group derived from neuroendocrine cells in many organs:

  • Gastrointestinal tract.

  • Lung.

  • Adrenals (phaeochromocytoma).

  • Thyroid (medullary carcinoma).

• Most NETs occur sporadically, but some are associated with genetic cancer syndromes:

  • Von Hippel–Lindau (VHL) syndrome.

  • Multiple endocrine tumor (MEN 1).

  • Tuberous sclerosis.

  • Neurofibromatosis type 1.

• Can present with diarrhea and GI symptoms.

• Also present with symptoms specific to each NET.

• Commonly occur in the GI tract.

MEN Syndromes

• MEN-1

  • Pancreatic tumors (Insulinoma, gastrinoma, vipoma).

  • Pituitary adenoma.

  • Parathyroid hyperplasia (Yes).

• MEN-2A

  • Parathyroid hyperplasia (Yes, 50%).

  • Medullary thyroid carcinoma (100%).

  • Pheochromocytoma (50%).

• MEN-2B

  • Medullary thyroid carcinoma (100%).

  • Pheochromocytoma (80%).

  • Marfanoid body habitus.

  • Multiple mucosal neuromata.

• FMTC

  • Medullary thyroid carcinoma (>95%).

NETs - Functioning vs Non-Functioning

• NETs can be clinically symptomatic (functioning) or silent (nonfunctioning).

• Both types frequently synthesize more than one peptide, although often these are not associated with specific syndromes.

• Non-functioning tumors may be an incidental finding or present with symptoms related to tumor bulk: obstruction, jaundice, bleeding, or abdominal mass.

• Non-functioning pancreatic NETs often contain peptide hormone on immunostaining, but this remains functionally inactive.

Histopathology

• Histopathology includes features such as positive staining for chromogranin A and specific hormones like gastrin, pro-insulin, and glucagon.

• May be benign or malignant.

• Should be removed surgically whenever possible.

Investigations

• Biochemical investigations.

• Specific Imaging: ultrasound, CT, MRI, PET-scanning and/or radio-labelled somatostatin analogue.

• Endoscopy and biopsy.

Neuroendocrine Tumors Causing Chronic Diarrhea & Their Markers

NET Secretion Products

Management

• Surgical resection of the primary lesion is the optimal management of pancreatic endocrine tumors.

• Multidisciplinary approach.

• Depends on the presence or absence of metastases.

• Debulking of the tumor, including liver metastases, is frequently carried out to facilitate systemic treatment.

• Somatostatin analogues, such as octreotide and lanreotide, are used to control hormonal-related symptoms and also have a tumor-modulating effect.

• Chemotherapeutic agents.

Gut Hormone Panel

• VERY unstable.

• Patient should fast overnight.

• Patient should stop PPIs for 2 weeks and H2 antagonist for 72hrs.

• Sample must be sent to the lab immediately on ice.

• MUST be separated within 30 mins of collection.

• Transported to referral lab by courier on dry ice.

Case 1: Gastrinoma (Zollinger-Ellison syndrome)

• Symptoms:

  • Peptic ulcer disease: Multiple ulcers refractory to standard therapy, Giant ulcers, Recurrent ulcers, Ulcers with unexplained diarrhea, Duodenal ulcer not related to Helicobacter pylori infection or NSAID use.

  • GERD, diarrhea, and weight loss.

• Diagnosis:

  • Fasting hypergastrinemia (Patient must be off H2 receptor blockers or proton pump inhibitors).

• Treatment:

  • Proton pump inhibitors (e.g., omeprazole, lansoprazole).

  • H2 receptor blockers.

  • Surgical Care.

Case 2: Carcinoid Syndrome

• Symptoms:

  • Recurrent abdominal pain.

  • Cutaneous flushing.

  • Diarrhea.

  • Cardiac manifestations: Valvular heart lesions.

  • Wheezing or asthma-like syndrome due to bronchial constriction.

• Diagnosis:

  • Tumors secrete serotonin that is metabolized to 5-hydroxyindole acetic acid (5HIAA).

  • 24-hour urine collection in ACIDIFIED bottle to measure 5-HIAA.

Case 3: Carcinoid Tumor

• Symptoms:

  • abdominal tenderness

  • diarrhea

  • PR bleeding

• Diagnosis:

  • Urine 5HIAA output 100 umol/24h (0-42) (elevated)

  • Octreotide scan confirms carcinoid

• Post treatment

  • Urine 5HIAA output 40 umol/24h (0-42) (normal)

Case 4: Insulinoma

• Symptoms:

  • increased hunger

  • confusion

  • fainting

  • symptoms episodic in nature, worsened by fasting and exercise, relieved by food intake

• Diagnosis:

  • Supervised prolonged fasting

    • Monitoring of symptoms of hypoglycaemia development

    • Measurement of Blood glucose

    • Measurement of insulin and C-peptide

    • Samples should be taken to confirm hypoglycaemia and for later

    • Hypoglycaemia is then corrected with oral or intravenous glucose and Whipple’s triad completed by confirmation of the resolution of symptoms.

• Whipple’s triad confirmed

  • Patient had symptoms of hypoglycemia.

  • Low blood glucose measured at the time of symptoms.

  • Symptoms resolved on correction of hypoglycemia.

Case 5: Glucagonoma

• Symptoms:

  • persistent subacute eczema affecting her lower extremities

  • long-standing type 2 diabetes mellitus

  • recurrent episodes of deep-vein thrombosis in her right leg

  • weight loss

  • anorexia

  • weakness

  • glossitis

  • angular stomatitis

  • itching cutaneous eruptions of erythematous polycyclic migratory lesions with scaling advancing borders and central resolution.

• Diagnosis:

  • Ultrasonography: hypoechoic tumor in her distal pancreas

  • CT scan: 5 to 7 cm hypervascularized tumor in the tail of her pancreas without evidence of metastatic disease

  • Histological findings were compatible with the diagnosis of migratory necrotizing erythema.

  • Serum glucagon :2340 pg/mL (normal range, 55-177 pg/mL (elevated)

• 4D syndrome consists of diabetes, dermatitis, DVT, and depression.

• The cutaneous lesions in this phase of the disease can easily be confused with nonspecific dermatitis, which occurs more often in patients with diabetes mellitus.

• Diagnosis: Determining the level of glucagonemia Correctly performing a biopsy of the skin during an advanced phase of the disease allows for a diagnosis of necrolytic migratory erythema.

Case 6: VIPoma

• Symptoms:

  • one year history of watery diarrhea despite fasting

  • 5-6 motions per day without pathological products in stool.

  • The diarrhea is accompanied by weakness, anorexia and weight loss

  • progressive muscle cramps which was aggravated in the last 24 hours where she presented with muscular weakness with inability to walk

• Diagnosis:

  • Abdominal ultrasound showed a pancreatic head tumor of 3.2 cm and a hepatic nodule of 1.3 cm in the VII hepatic segment suggestive of metastasis

  • Hormonal determination revealed markedly elevated VIP levels (119.4 pmol/L, normal 0-30)

• Radioimmunoassay :Plasma vasoactive intestinal peptide (VIP) levels.

Somatostatinoma

• Pentad of:

  • Diabetes mellitus

  • Cholelithiasis

  • Weight loss

  • Steatorrhea and diarrhea

  • Hypochlorhydria /achlorhydria

• Fasting serum somatostatin level.