March 15, 2023

GIST
Epidemiology.................................................................................................................................................................................................... 1
Prognostic Factors.......................................................................................................................................................................... 1
Pathology............................................................................................................................................................................................................ 3
Classification..................................................................................................................................................................................... 3
Molecular pathogenesis................................................................................................................................................................ 3
Staging................................................................................................................................................................................................................. 5
GIST TNM Staging AJCC 8th Edition........................................................................................................................................... 5
Treatment for Local Disease....................................................................................................................................................................... 6
Surgery................................................................................................................................................................................................ 6
Neoadjuvant Treatment................................................................................................................................................................ 6
Adjuvant Treatment....................................................................................................................................................................... 8
Treatment for Advanced GIST.................................................................................................................................................................... 9
First-line Treatment: Imatinib................................................................................................................................................... 9
Subsequent Management of Imatinib-refractory Disease............................................................................................ 11

EPIDEMIOLOGY
 7 to 15 cases per million population per year
 Autopsy shows higher frequency

Sites by frequency
 Stomach (60%)
 Small intestine (30%)
 Duodenum (5%)
 Rectum (2%)
 Colon (1-2%)
 Esophagus (<1%)

Familial / genetic cause

 Appears as multiple lesions
 Neurofibromatosis type 1 (NF-1): small bowel GIST
 Carney triad: gastric GIST (SDH-deficient), paraganglioma, pulmonary chondroma
o These may occur at different ages
 Carney–Stratakis syndrome: mutation in one of SDH subunits
 Familial GIST (rare)

Prognostic Factors
Imaging characteristics
 Most measure at 5cm at diagnosis
 Local invasion: mesenteric fat infiltration, exophytic growth pattern
 LN involvement

Tumor site, size and mitotic rate

 High mitotic rate defined as >5 mitoses per 50 high power field (=5mm2)
 GIST can be anywhere in the GI tract (but more common in gastric > small bowel > colorectal)
 o Among all sarcoma in small bowel, GIST is the most common (others: leiomyo(sarco)ma)
Better prognosis:
 Size ≤5cm (regardless of mitotic rate) has relatively low metastatic potential
 Low mitotic rate (with size more than 10cm) has 10% metastatic rate
Worse prognosis
 Small bowel tumors >10cm (even with low mitotic rate) (>50% risk)
 Small bowel tumors <5cm, but high mitotic rate (50% risk)
 Colorectal GIST is rare, but seemingly slightly worse than small bowel GIST

LN involvement
 Nodal involvement is rare
 Routine nodal dissection is not necessary
 Exception = SDH-mutant or SDH-epimutant GIST

Tumor rupture
 Tumor rupture (either spontaneously or at surgery) is an independent risk factor

Driver mutations
 Good prognosis: KIT exon 11 mutations
 Poor prognosis: KIT exon 9, KIT WT
 10% patients are primary resistance to imatinib

Prognostic models
 TNM staging
 MSKCC GIST nomogram

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PATHOLOGY
Classification
Cellular origin of GIST
 Intestinal cells of Cajal – gastrointestinal pacemaker cells
 Virtually all GISTs have a potential for malignant behaviour

Histopathology
Cellular morphology
 Spindle cell type – 70%
 Epithelioid type – 10% (more commonly in stomach and omentum)
 Mixed type – 10-15%
Immunohistochemistry
 95% of GISTs have c-KIT (CD117) expression
o Weak staining of <10% of tumour extension is also considered to be KIT negative GIST
o IHC CD117 positive is independent from the mutation status of KIT and PDGFRA
o DOG-1 (90%) is pathognomonic à must check if c-kit negative (35% of time, DOG-1 positive)
 PKC-theta (70%) and CD34+ (70%)
 Differential diagnosis by IHC
Type CD117 DOG-1 CD34 SMA S100 Desmin
GIST 95+ 97%+ 70%+ 30% + 10% 2-4%
Leiomyoma - - 15% + + - +
Leiomyosarcoma - - - + - +
Schwannoma - - - - + -
Other ddx = malignant nerve sheath tumour, solitary fibrous tumour

Molecular pathogenesis
 GIST is commonly caused by active mutation in KIT (80%) or PDGFRA (10%) – mutually exclusive
o For those lack KIT mutation, 40% has activating mutation in PDGFRA gene
 For KIT/PDGFRA WT GIST (10%), IHC for SDHB protein may be done

KIT as a major driver mutation

 KIT is a type III tyrosine kinase receptor (TKR)
 Exon 11 mutation (70%) (encoding the juxtamembrane domain)
o à relieve its autoinhibitory function à constitutive, ligand-independent activation
o Mutation patterns = interstitial deletions > point mutation
 Exon 9 mutation (10-20%)
o à spontaneous dimerization
o Mainly associated with small bowel GIST with greater malignant potential
o Recommend the upfront use of 800mg Glivec

PDGFRA mutations
 5-10% of GIST
 Associated with localized gastric GIST and epithelioid morphology
 D842V mutation is the most frequent

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Secondary mutation after use of Imatinib
 Examples: exons 13/14 (for ATP-binding); exon 17/18 for activation loop
 They favour the active conformation of the kinase, leading to impaired binding of imatinib,

GIST wild type

 Up to 15% of adult GIST (and 90% paediatric GIST) lack KIT and PDGFRA mutations
 Other mutations = SDH gene mutation (30%) and BRAF (7%)
SDH-deficient GIST
 Involved in 30% GIST WT
 Restricted to stomach GIST, typically occur in children and young adults
 Mostly slow progression
 50% of the cases have germline mutation (tumour suppressor gene model)

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STAGING
GIST TNM Staging AJCC 8th Edition
T N M Mitotic rate
T1: Size ≤2cm N1: Regional LN+ M1: Distant Low: ≤5 mitoses per 5mm2
metastasis
T2: Size 2-5cm High: ≤5 mitoses per 5mm2
T3: Size 5-10cm
T4: Size >10cm

Prognostic group
Gastric GIST
T N M Mitotic rate Stage PD%
T1 or T2 Low IA 0-2%
T3 Low IB 3-4%
T1 or T2 High II 16%
N0 M0
T4 Low II 12%
T3 High IIIA 55%
T4 High IIIB 85%
Any T N1 Any rate IV
Any T Any N M1 Any rate IV

Small intestinal, Colorectal GIST

T N M Mitotic rate Stage PD%
T1 or Low I 0-4%
T2
T3 Low II 25%
N0 M0
T1 High IIIA 50%
T4 Low IIIA 50%
T2-4 High IIIB 75-90%
Any T N1 Any rate IV
Any T Any N M1 Any rate IV

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TREATMENT FOR LOCAL DISEASE
Surgery
Biopsy and Diagnosis
 EUS-guided fine needle aspiration biopsy
 CT imaging for any dumbbell shape lesion

Principles for Primary Resection for GIST

 All GIST ≥2cm should be resected
o For GIST <2cm, monitoring is an option if no suspicious EUS features
o Suspicious features: irregularity, cystic spaces, ulceration, echogenic foci, and heterogeneity.
 Surgical resection is the mainstay of treatment for potentially resectable disease
o For borderline disease/ extensive surgery needed, consider neoadjuvant imatinib
 Unresectability criteria
o Infiltration of celiac trunk/ SMA/ mesenteric artery-to-portal vein
 Aim for a complete resection (R0) with an intact pseudocapsule
o Goal of achieving negative resection margin
o Avoid rupture – that may increase risk of disease recurrence
o R1 resection (without rupture) has same RFS compared with R0; but R1 is a/w rupture
 Laparoscopic approach is discouraged in patients with large tumours ‘.’ Chance of rupture
 Extensive surgery to remove unaffected tissue is unnecessary.
 Routine lymphadenectomy is NOT needed

Neoadjuvant Treatment
Patient selection
 [NCCN] Marginally resectable disease; or those with risk of significant morbidity
o Commonly for large GIST in distal rectum, esophagus etc.

Prior mutational analysis is recommended (UK)
o To identify less sensitive/ resistant tumors
Regimen and Duration
 Imatinib 400mg daily
o 800mg daily for KIT exon 9 mutation [NICE]
 Early tumor response assessment needed by PETCT (prefer at 6weeks)
o Not to delay surgery in non-responding disease
 Best response seen at 28 weeks and plateau at 34 weeks - can be reviewed by CT +/- PETCT
o Up to 12 months ‘.’ Longer treatment may be detrimental / increase recurrence after surgery
 Imatinib can safely be stopped a few days before surgery; and resumed after
 Postoperative treatment = to complete a total of three year of imatinib

Evidence
 For >5cm, or resectable recurrent disease, imatinib for 8-12 weeks 1: ORR 7%, 5-yr OS 77%
 For >10cm gastric GIST, given imatinib for 6-9 months 2: ORR 60%, R0 rate 91%, 2-yr OS 98%

1
RTOG 0132/ACRIN 6665 trial. J Surg Oncol. 2009;99(1):42.
2
Asian trial. Br J Cancer. 2017;117(1):25
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Adjuvant Treatment
Regimen
 Use of imatinib for three years
 Dose = 400mg daily
o (may propose 800mg KIT exon 9 mutants – not approved by NICE)

Risk stratification
AFIP prognostic model (Miettinen)
Progression free during long-term follow-up by primary site
Tumor size (cm) Gastric Jejunum/ileum Duodenum Rectum
Mitotic rate (HPF) ≤5/50
≤2 100% 100% 100% 100%
2 to 5 98% 95% 91% 91%
5 to 10 96% 76% (moderate) 66%* 43%*
>10 88% (moderate) 48%
Mitotic rate (HPF) >5/50
2 100%^ 50%^ (high) - 46% (high)
2 to 5 84% (moderate) 27% (high) 50% (high) 48% (high)
5 to 10 45% 15% (high) 14%* (high) 29%* (high)
>10 14% 10% (high)
Mitotic rate is counted in an area of 5 mm2 on the glass slide section. For older microscopes with traditional
field size optics, 50 HPF is equivalent to 5 mm2. For modern microscopes with wider 40× lenses/fields, 20
HPF is equivalent to 5 mm2

* Data are combined for tumors >5 cm.

^ Small number of cases.

Indication for Imatinib

 (NICE) Any patients with high risk should be given Imatinib
 Tumor rupture – count as occult peritoneal disease (=high risk)
 NOT recommended for D842V PDGFAR or NF-1 ‘.’ Insensitive
 Controversial for SDH-negative / wild type GIST

Evidence
 (ACOSOG Z90013) Completely resected GIST (size >3cm, KIT+), Imatinib (1yr) vs. placebo
o Stopped early when planned interim analysis showed positive result
o At median FU of 20months, RFS (primary endpoint) = 8% vs. 20%; 1yr RFS (98% vs. 83%)
o Subgroup = relapse rate in high risk (47% vs. 19%); and in moderate-risk (14% vs. 5%)
 (EORTC 620244) Intermediate or high-risk patients, given two years of Imatinib vs. placebo
o Five-year imatinib failure-free survival (87% vs. 84%, NS), 3-yr RFS (84% vs. 66%)
o Even in high-risk group, the 5-yr IFFS shows positive trend only
 (SSG XVIII5) high-risk GIST given 36 vs. 12 months of imatinib
o High risk = size >10cm, mitotic rate >10, tumor rupture, or tumor size >5cm & mitotic rate >5.
3
ACOSOG Z9001 Lancet. 2009;373(9669):1097.
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EORTC 62024 J Clin Oncol. 2015;33(36):4276.
5
SSG XVIII. JAMA. 2012 Mar;307(12):1265-72.
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 o 5-yr RFS (66% vs. 48%) with 5-yr OS benefit (92% vs. 86%) or 10-yr OS (79% vs. 65%)
o Common side effects = periorbital edema (75%), diarrhea (60%)
o No benefits in non-KIT mutation GIST

Points to note for imatinib: cure or just delay recurrence?

 Pre-clinical data suggest imatinib is NOT curative, but inducing cellular quiescence
 Evidence: higher rate of recurrence within 6-12 months of discontinuation of imatinib
 Phase 2 trial (PERSIST-5) for 5-yr imatinib: 5-yr RFS 90%, OS 95%, but 50% discontinue ‘.’ intolerance
 Ongoing phase 3 trial by SSG: NCT02413736 (3 vs. 5-year use of adjuvant imatinib)

TREATMENT FOR ADVANCED GIST

First-line Treatment: Imatinib
Regimen
 Imatinib 400mg daily
 NO significant difference for dosage above 400mg, except for KIT exon 9 mutation [ESMO]
 [NICE] does NOT approve 600/800mg Imatinib

Evidence
Efficacy
 (Blanke et al. 20086) Phase II trial with longest FU: median OS 5 years
 (EORTC trial 20047) 2-year PFS 50%, CR in 5%
 (Intergroup trial 20088) ORR 75%, PFS 18-20months.
Dosage
 (MetaGIST9) Small but significant PFS advantage in 400mg BD dose, but no OS benefits
o For KIT exon 9, 400mg BD is associated with improved PFS and ORR (47% vs. 21%)
o Note: only KIT exon 9 is predictive of response to higher dose.

Assess response to therapy

 CT imaging
o GIST may enlarge at early treatment ‘.’ intratumoral hemorrhage or myxoid degeneration
o A decrease in tumour density is an early clinical marker of antitumour activity
o Late responses are often seen in patient with initially stable disease
o .’. Response = absence of progression 2 months after therapy
o A typical progression pattern is the ‘nodule within the mass’
 PET imaging – identify response at an earlier time than CT
o Standard practice in daily setting; and more useful in neoadjuvant setting
o Note: A small proportion of GIST has no FDG uptake

RECIST vs. Choi criteria

 RECIST may fail to capture the response of GIST
 Choi criteria
6
J Clin Oncol. 2008;26(4):620.
7
Lancet. 2004 Sep 25-Oct 1;364(9440):1127-34.
8
J Clin Oncol. 2008 Feb 1;26(4):626-32.
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J Clin Oncol. 2010;28(7):1247.
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 Response RECIST Modified Choi
CR Disappearance of all target lesions Disappearance of all target lesions
PR At least a 30% decrease in the sum of the Decrease in tumor size ≥10% and
greatest unidimensional diameters of decrease in tumor density ≥15% on CT
target lesions
SD Any cases that do not qualify for either Does not meet the criteria for CR, PR or
partial response or progressive disease PD
PD An increase of at least 20% in the sum of Increase in tumor size ≥10% and does
the diameters of target lesions not meet PR criteria by tumor density

Role of molecular analysis

 KIT mutation
o All KIT mutations seem to have response to imatinib
o Exon 9 mutation may warrant higher dose (800mg daily) [NICE]
 PDGFAR mutation
o PDGFRA mutations in exons 12, 14, 18 occur in 10-20% of patients
o D842V mutation in exon 18 is primary resistant to imatinib
o Other non-D842V mutation seems responsive to imatinib

Side effects of Imatinib and their management

 Fluid retention / peripheral oedema: periorbital oedema and ascites; mostly in morning
o May not response to diuretics
o Improve with salt restriction
 Muscle cramps
o No definite treatment
 Nausea and vomiting, dyspepsia
o Generally, not a problem when it is taken with food
 Rash
o Maculopapular and mild
o Treatment: short course of high-dose glucocorticoids; desensitization
Special cases
PDGFRA D842V mutant tumours
 [NICE] Avapritinib 300mg daily is the first line treatment
 High response rate of 90%
 Side effects: CNS toxicities (dizziness; hallucinations; and intracranial hemorrhage)
 Second line treatment: Ripretinib

SDH-deficient tumours and NF-related GIST

 High rate of primary resistance (no response in first 6 months) to imatinib
 NO good TKI; poor response to Sunitinib, Regorafenib

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Subsequent Management of Imatinib-refractory Disease
Dose escalation to Imatinib 800mg daily
 Dose escalation from 400mg daily to 400mg BD may have response
 ~30% patients have ORR10 or stable disease after dose escalation, with PFS ~5 months
 Side effects: higher chance of anaemia
 *Increasing dose is unlikely to benefit patients who progress rapidly (within 2mo starting therapy)

2L = Sunitinib
 Sunitinib 50mg daily (4 weeks on/2 weeks off) = PFS 27wk vs. 6wk in placebo 11
 Side effects = fatigue, diarrhoea, skin discolouration, and nausea

3L = regorafenib
 (GRID12) Regorafenib 160 mg daily (3 weeks on/1 week off)
 Targeting secondary mutations in exon 17 after imatinib

10
Europe: Lancet. 2004;364(9440):1127. American: J Clin Oncol. 2008;26(4):626.
11
Lancet. 2006 Oct 14;368(9544):1329-38.
12
Lancet. 2013;381(9863):295–302
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