Definition of GIST
- Rare mesenchymal tumors of gastrointestinal tract arising from interstitial cells of Cajal
- It represents 1-2% of all neoplasm of the gastrointestinal tract
Distribution of GIST
- Stomach (50%)
- Small bowel (25%)
- Colorectum (10% )
- Esophagus (< 5%),
- Omentum (< 5%),
- Retroperitoneum
- Less frequently affect non-tubular portions (Extra GISTs): Mesentery, Omentum
GISTs tend to be sporadic but may also be part of syndromes such as Carney’s triad (GIST, extra-adrenal paraganglioma and pulmo- nary chondroma) and neurofibromatosis.
Presentation of GIST patient
Asymptomatic : Incidental finding during endoscopy or laparotomy (one third).
Symptoms : Enlarging abdominal mass & fullness.
- Loss of appetite, Loss of weight.
- Bleeding, Hematemesis, Melena, Anemia.
- Obstruction, Perforation, Intussusception, Dysphagia.
- Vague abdominal pain (by tumor itself or from hemorrhage into the tumor).
- Consumptive hypothyroidism – In treatment-naïve patients with GIST, excessive degradation of thyroid hormone caused by overexpression of the thyroid hormone inactivating enzyme type 3 iodothyronine deiodinase (D3) within large GISTs. Typically require high levels of thyroid hormone supplementation.
Metastatic Symptoms
- Peritoneum and liver (50-60%), lungs & bones (10%).
- Regional LN metastasis are rare (5%).
Investigation for GIST
- Endoscopy/ Colonoscopy
- EUS/Rectal EUS
- CE-EUS ( Heterogenous enhancement due to avascular areas of necrosis on perfusion images.)
- CECT Scan :
- Imaging method of choice. Oral as well as intravenous contrast should be administered to define the bowel margins.
- GIST enhance with IV contrast, other mesenchymal tumor do not enhance. Appear as solid, smoothly contoured mass, large tumors (>15 cm) may appear more complex due to necrosis, hemorrhage, or degenerating components.
- To assess distant metastases
- MRI: Preferred for preoperative evaluation of primary rectal GISTs, and for hepatic studies. Small GISTs on MRI appear round and symmetric, larger GISTs are asymmetric and lobulated.
Morphological (HPE) diagnosis
Histological Subtypes:
- Spindle cell – 70% (cells with pale eosinophilic fibrillary cytoplasm, ovoid uniform nuclei and ill-defined cell borders)
- Differential diagnosis of spindle cell GIST includes:
1) smooth muscle tumours (leiomyoma or leiomyosarcoma)
2) schwannoma
3) hemangioma
4) plexiform fibromyxoma
5) intra-abdominal desmoid-type fibromatosis
6) inflammatory myofibroblastic tumour
7) solitary fibrous tumour
8) sarcomatoid carcinoma.
- Differential diagnosis of spindle cell GIST includes:
- Epithelioid – 20% (rounded cells with eosinophilic to clear cytoplasm arranged in sheets and nests)
- Differential diagnosis of epithelioid GIST includes:
1) Metastatic melanoma
2) Clear cell sarcoma
3) Epithelioid variants of Leiomyosarcoma
4) Epithelioid Hemangio-endothelioma
- Differential diagnosis of epithelioid GIST includes:
- Mixed – 10% (spindle and epithelioid cells)
Immunohistochemical assessment ( IHC) for GIST
- Required to further confirm the diagnosis, and help to distinguish GISTs from other subepithelial tumors.
- 5% of GISTs are CD117 immunonegative, 5% of GISTs are DOG1 immunonegative and 1% of GISTs are immunonegative for both.
Mutational analysis, Molecular genetics for GIST
- Has predictive value for sensitivity to molecular-targeted therapy, and also prognostic value.
- If initial treatment is with imatinib, mutational analysis is particularly critical, since some GISTs are insensitive to the drug (e.g. those with D842V mutation in exon 18 of PDGFRA).
- GIST is associated with mutation in either KIT or PDGFRα (platelet derived growth factor receptor alpha) gene.
KIT Protooncogene Mutation in GIST
KIT protooncogene (4q12) mutation (60–70% of cases) - Result in cell proliferation and inhibition of apoptosis:
- KIT exon 11 mutations are more sensitive to imatinib than exon 9 mutations
- GIST with mutations in KIT exon 11 mainly originate in the stomach and show comparatively indolent clinical behaviour.
- GIST with mutations in KIT exon 9 are mainly located in the small or large intestine
When exon 17 mutation is a primary mutation, activated KIT is generally imatinib resistant and has shown to confer secondary resistance to imatinib in vitro.
PDGFR α-tyrosine kinase receptor mutation in GIST
- PDGFR α-tyrosine kinase receptor mutation (10–15%).
- Most PDGFRα-mutated GIST are located in the stomach (15–18%) followed by the small intestine (5–7%), follow a comparatively indolent clinical course.
- Mutations in exon 12, exon 14, or indels in exon 18 result in imatinib-sensitive PDGFRA mutants.
- Mutations in PDGFRa exon 18 D842V missense are well documented to be resistant to imatinib and other TKIs.
PDGRFa D842V Mutation: Neoadjuvant Avapritinib
Wild Type GIST
15% of GIST having no mutations in either KIT or PDGFRα are called “Wild-Type” GIST but they can have other genetic alterations and need to be tested for:
1) Succinate dehydrogenase (SDH) mutation (10% patient).
- SDH-deficient GIST mainly arise in the stomach of children and adolescent and young adults <30 years of age who characteristically have multinodular gastric masses, disease course is often, but not always, clinically indolent.
- GIST with SDH deficiency are considered to be resistant imatinib, partly sensitive to VEGFR2 inhibitors, such as regorafenib and sunitinib.
2) NF1 - if positive may indicate occult neurofibromatosis.
3) BRAF ( can use BRAF inhibitor: Dabrafenib)
Wild types lacking mutations also in BRAF and NF1 dubbed “quadruple wild-type”
neurotrophic tyrosine receptor kinase (NTRK)
- ( NTRK rearrangement: NTRK inhibitor: Entrectinib)
Risk Stratification of GIST
Risk factors that influence prognosis in patients with GIST are mainly based on the characteristics of the primary tumor.
- Intestinal GIST high risk - >5 cm or >5 mitoses per 50 HPF (currently used 5 mm square which is equivalent to 5/50 HPF)
- Gastric GIST high risk - >10 cm or have >5 mitoses per 50 HPFs (currently used 5 mm square which is equivalent to 5/50 HPF)
- GIST arising from the stomach are associated with more favorable survival outcomes compared with those arising from the small intestine, colon, rectum, or mesentery.
- Tumor rupture (either spontaneously or at surgery) is an independent risk factor that negatively impacts disease-free survival.
- Other negative prognostic factors include: Young age (more likely wild type), Incomplete resection, Infiltration to neighboring structures, Epithelioid type.
- Wild type: Tumor stain positive for KIT but no detectable mutation in KIT. Poor response to Imatinib
- High Ki-67 counts, high S phase fraction, DNA aneuploidy.
- C kit negative
Classification for GIST
The first classification introduced in 2002 (NIH) using tumor size and mitotic rate
• In 2006, Armed Forced Institute of Pathology (AFIP) classification added tumor location to the NIH classification
• AFIP was the first to define total area for mitotic counting (5mm2) or equivalence to 50 HPF (older microscope)
and 20 HPF (newer wide-lens microscope)
• Latest classification in 2008, add tumor perforation as part of prognostic index (Modified NIH)
Principle of Surgery for GIST
For resectable GIST, complete surgical resection with negative microscopic margin is the gold standard
• Organ and function preservation surgery is oncologically allowed if able to achieve negative margin
• Routine lymph node dissection is unnecessary due to extremely rare LN metastasis
- Aim : R0 resection with intact pseudo capsule.
- At time of surgery, peritoneal and hepatic surfaces should be explored to look for evidence of peritoneal dissemination or liver involvement.
- Tumour should be carefully dissected to avoid rupture because of risk of dissemination.
- Tumor & pseudo capsule should be resected with a 5cm margin
- Lymph node dissection not advocated unless preoperative macroscopic evidence of lymph node involvement, because node involvement is very rare
Management of GIST
Can be divided into:
- Surgery
- Neoadjuvant
- Adjuvant therapy
Overview of Localized GIST management
Overview of Advanced or Metastatic GIST
PD: Progressive disease
PR: Partial response
SD: stable disease
Neoadjuvant for GIST
Aims of neoadjuvant therapy (NAT) are to facilitate organ or function preserving surgery, avoid tumor rupture and reduce post-operative complication
* Tumor shrinkage by imatinib make more conservative R0 resection possible especially when GIST involving oesophagus, duodenum and rectum
* Several studies have shown NAT with imatinib leads to higher OS, DFS and PFS and R0 resection (low level
evidence, mostly level II/III)
Only imatinib is evaluated in these studies with imatinib dosage 400-600mg daily
The optimal duration of treatment also not clear with 3-6 months duration is recommended based on median response time to imatinib is 3 months and the effect reach plateau at 6 months. ESMO recommend 6-12 months
* The best modality to assess response to TKI also unclear. CECT and PET-CT have both been used.
* Reduce tumor density without change in size can be consider good response to imatinib, a criterion which can be underestimate when using RECIST (Response Evaluation Criteria in Solid Tumours) criteria.
* Choi criteria is a better option since its use tumor density to classify the response.
What is limitation of neoadjuvant in GIST?
Another unresolved issue is the need of tissue biopsy and testing for c-KIT and PDGFRA mutation before neoadjuvant therapy to ensure best response to TKI therapy
• Other risk of NAT include disease progression in unresponsive tumor and pre-operative complication
(hemorrhage, necrosis, perforation) will cause the patient to undergo surgery under non-ideal condition
Surgery for GIST
- Aim : R0 resection with intact pseudo capsule.
- At time of surgery, peritoneal and hepatic surfaces should be explored to look for evidence of peritoneal dissemination or liver involvement.
- Tumour should be carefully dissected to avoid rupture because of risk of dissemination.
- Tumor & pseudo capsule should be resected with a 5cm margin
- Lymph node dissection not advocated unless preoperative macroscopic evidence of lymph node involvement, because node involvement is very rare
Esophageal GIST:
- Esophagectomy with complete resection of involved surrounding tissue
- Esophageal sparing wide local excision (less morbidity) for lesions <2cm
Duodenal GIST:
- Commonly at 2nd or 3rd part
- Partial duodenal resection or pancreaticoduodenectomy (more common)
Gastric GIST:
- Local resection
- Gastrectomy - lesions involving pylorus or gastroesophageal junction
Adjuvant Therapy for GIST
Aim to reduce risk of recurrence which mainly occur in high-risk group within the first 5 years post operation
• No standard regime for follow up but ESMO recommend CT scan every 3-6 months for 1st 3 years (on adjuvant) then 3-monthly for 2 years, 6-monthly for subsequent 3 years followed by annual follow up for another 5 years
• Low risk tumor can be followed up less frequently with imaging surveillance every 6-12 months for 5 years
• 3 agents approved for treatment of GIST:
- Imatinib (Gleevec)
- Sunitinib (Sutent)
- Ponatinib
• Patient selection using risk stratification is far from perfect and should also consider mutation subtype
• Patients with KIT exon 9, PDGFRA exon 18 mutation and wild type tumor has inferior response to Imatinib
• High dose Imatinib (800mg OD) can be considered in case of KIT exon 9 mutation
• Sunitinib is preferred in exon 9, 13, 14 and wild type with Ponatinib can be effective in exon 17 mutation
• NCCN and ESMO recommend against adjuvant therapy in case of PDGFRA D842V mutation (poor response)
Factors affecting recurrences in GIST
• 5 factors associated with recurrence:
- high mitotic count
- non-gastric location
- large size
- tumor rupture and short
- duration adjuvant imatinib (<12 months)
• NCCN and ESMO recommend adjuvant therapy with Imatinib for 3 years in patients with high risk of recurrence
• This recommendation is based on several prospective phase II and III trial which showed higher RFS in patient treated with adjuvant therapy (Imatinib 400mg OD)
Adjuvant Therapy for KIT exon 17 mutation GIST
Ponatinib can be effective in exon 17 mutation
High dose imatinib ( 800mg OD) can be considered in which cases?
High dose Imatinib (800mg OD) can be considered in case of KIT exon 9 mutation
Sunitinib is preferred in which type of GIST subtypes?
• Sunitinib is preferred in exon 9, 13, 14 and wild type
