Gastrointestinal Stromal Tumor (GIST) : A Comprehensive Review

Introduction:

• Is a tumor of mesenchymal origin (previously thought to be of smooth muscle origin)
• Most common mesenchymal neoplasm of GI tract
• Arise from interstitial cells of Cajal
• Incidence: 7-15 cases per million per year
• 95% overexpress KIT (CD117), 80% express BCL-2 and 70% express CD34
• KIT negative GIST will express PDGFRA
• Sites: stomach (40-60%), SI (20-40%), colon/rectum (5-15%)

Surgical Anatomy of Stomach

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Other facts:

• Gastric GIST arise most commonly after 50 years
• 5% of all GIST are associated with an underlying heritable mutation such as familial GIST syndrome (mutation in KIT and PDGFRA), NF-1, Carney-Stratakis syndrome (GIST+paraganglioma+/-pulmonary chondroma)
• 2 pathological variants: spindle cell (70%)> epithelioid (30%)

Clinical features:

• Non-specific symptoms: early satiety, bloating and vague abdominal pain
• Bleeding: Malena or frank hematemesis
• Tumor rupture with intra-abdominal hemorrhage is uncommon, but when it occurs, it requires urgent surgical intervention.

Diagnosis:

• CECT with IV and oral contrast is the IOC: helps in diagnosis as well as staging of disease and is non-invasive
• MRI is indicated only when there is contraindication of CT and for rectal GIST.
• Staging of the disease is important especially when the patient is considered for neoadjuvant imatinib therapy.
• PET-CT is the gold standard investigation for recurrent GIST.

Role of biopsy/tissue diagnosis in GIST (current consensus):

• Is not recommended as it is a submucosal tumor (go for direct upfront surgery if there is high suspicion of GIST in imaging and the disease is operable)
• If there is diagnostic dilemma then go for biopsy
• EUS guided FNA is superior to UGI endoscopy guided biopsy as the tumor is submucosal.
• Sensitivity and specificity of EUS guided FNA: 82% and 100% respectively

Treatment:

• Mainstay of treatment: complete surgical excision
• Indication of surgery: size >2 cm and symptoms
• For tumors <2 cm:
  • If high risk features are present on endoscopy or EUS go for surgery
  • If not can be observed with 6-12 monthly EUS/endoscopy follow up

High risk features:

• Irregular borders
• Ulceration
• Echogenic foci
• Heterogeneity 

Choices of surgery:

• Depending on tumor size and sites surgeries can vary from wide local excision, enucleation, sleeve gastrectomy, or total gastrectomy.

Aim of surgery:

• R0 resection 
• Lymph node dissection is not required as lymphatic metastasis is very rare 
• Tumor should be handled carefully intraoperatively to avoid rupture or spillage.

Prognostication: 

• 2 main prognostic factors:
  • Tumor size 
  • Mitotic rate

• Based on long term follow up study of 1700 patients with Gastric GIST, malignant potential based on combination of these 2 factors have been established as shown below:

Malignant potential	Comments	Mortality
Benign	Size: up to 2 cmMitosis: up to 5/50 hpf	No tumor related mortality
Probably benign	Size: 2-5 cmMitosis: same as above	<3%
Uncertain/ low malignant potential	Size: up to 2 cmMitosis: >5/50 hpf	–
Low to moderate	Size: >10 cm Mitosis: same as benignORSize: 2-5 cmMitosis: >5/50 hpf	12-15%
High	Size: 5-10 cm Mitosis: >5/50 hpfORSize: >10 cmMitosis: >5/50 hpf	49-86%

Role of adjuvant therapy:

• Drug of choice: imatinib (tyrosine kinase inhibitor)
• Indication: metastatic disease, resectable but moderate to high-risk malignant potential
• Can be used as neoadjuvant therapy if the disease is non-metastatic but unresectable.

Landmark trials in GIST:

• ACOSOG Z9001 trial:
  • C-KIT positive tumors 3 cm or larger who underwent complete resection found that patients treated with imatinib for 1 year had significantly improved 1 year recurrence free survival (98% VS 83%).

• Scandinavian Sarcoma group trial:
  • Compared adjuvant course of imatinib (36 months VS 12 months) after resection of high-risk GIST
  • Result: extended course (36 months) had higher 5-year RFS and OS.
  • This trial has established a 3-year course as the standard of care after resection of high-risk GIST.

Algorithm for management of GIST:

Reference: Sabiston textbook of surgery 21^st edition