GIST

Epidemiology

• Most common mesenchymal neoplasm of the GIT
• 1% of all GIT neoplasms but most common sarcoma subtype

Pathophysiology

• Derived from the interstitial cells of Cajal (pacemaker of smooth muscle)
  • Therefore grows from muscularis propria layer
  • This means it has a mesenchymal origin and is a type of sarcoma (malignant mesenchymal neoplasm)
  • Can have either a spindle cell or epithelioid appearance
  • 80% have a mutation in KIT leading to overexpression
• Relevant markers:
  • KIT (CD117) - a gene which codes for a receptor tyrosine kinase (c-kit), which 95% of GISTs overexpress, and is the target for imatinib (tyrosine kinase inhibitor).
    • There is a KIT mutation in about 80% of GISTs
    • This is a proto-oncogene that is a transmembrane receptor for the stem cell growth factor. Its binding causes tyrosine kinase receptor homodimerization, autophosphorylation and activation of multiple pathways, including RAS, RAF, MAPK, AKT and STAT3.
    • Certain mutations of the c-kit receptor confer constitutive activation, which ultimately results in cellular proliferation.
    • Specific KIT mutations
      • The specific KIT exon which contains the GIST mutation affects the molecular and clinical phenotype
      • Primary mutations:
        • Exon 9 mutations, generally seen in small bowel or colon GIST, are less sensitive to imatinib
        • Exon 11 (most common - 70%)
        • Exon 12
        • Exon 17
      • Secondary mutations (rare - commonly secondary acquired resistance to imatinib):
        • Exon 13 mutation confers high sensitivity to imatinib
        • Exon 14
        • Exon 17
        • Exon 18
  • PDGFRA (platelet-derived growth factor receptor alpha) - most GISTs that lack a KIT mutation will have a PDGFRA mutation. This bears striking similarity to c-kit. Overall 7% of GISTs have a mutation.
    • Commonly arise in stomach, with more indolent disease
    • Exon 18 is most common
  • KIT and PDGFRA wild type cancers
    • 10-15% of all GISTs
    • Usually seen with SDH mutations (Carney) or NF1
    • Often indolent and in stomach
  • CD34 is also used to confirm diagnosis - human progenitor cell antigen - expressed by 70-90% of GISTs
  • DOG1 is a calcium-activated chloride channel which is also found in both GIST and Cajal cells
  • Stain positive for anoctamin-1 in 98%, actin in 20-30%, S100 in 2-4% and desmin in 2-4%
• Almost all KIT (CD117) positive, while 2/3 CD34 positive
  • This differentiates GIST from leiomyoma
  • Below table relates to staining, not mutations

Type	CD117	DOG-1	PKC-theta	CD34	SMA*	S100 protein	Desmin
GISTs	+ (>95%)	+ (97%)	+ (72%)	+ (60 to 70%)	+/– (30 to 40%)	– (5% +)	Very rare
Leiomyoma	–	–		+ (10 to 15%)	+	–	+
Leiomyosarcoma	–	–	+ (10%)	–	+	–	+
Schwannoma	–	–	+ (10%)	–	–	+	–

• Can appear anywhere in GIT - closer to mouth has better prognosis
  • Stomach 40-60% - best prognosis
  • Small intestine 20-40% - worst prognosis
  • Colon/rectum 5-15%
• Most often metastasises to liver or peritoneum or direct local extension, only rarely to lymph nodes
• Malignant GISTs are larger than 5cm at time of diagnosis in 80% of patients. The other useful indicators are mitotic index and evidence of tumour invasion into lamina propria.
  • Mitotic rate defined as total count of mitoses per 5mm², reported in the most proliferative area of the tumour
  • Melanoma, paraganglioma, NETs, and nerve sheath tumours can mimic GIST microscopically
• Risk stratification
  • Tumour size
  • Mitotic rate
  • Primary tumour site
  • Tumour rupture
  • Biomarkers - some suggestion KIT mutations carry a worse prognosis
• Gross appearance - firm, grey-white lesions with a whorled appearance on cut surface
• Microscopy - well-differentiated smooth muscle cells

Risk factors

• Typically seen in patients >50yo
• More common in men
• 5% are associated with an underlying heritable mutation
  • Familial GIST syndrome - mutation in KIT or PDGFRA
  • Neurofibromatosis 1
  • Carney-Stratakis syndrome (GIST and paraganglioma, with or without pulmonary chondroma)

Presentation

• Often asymptomatic and found incidentally
• Symptoms dependent on area of origin
  • Stomach - early satiety, bloating, vague epigastric pain, melaena, haematemesis (uncommon)
  • Small bowel - abdominal pain, fullness, bowel obstruction, or bleeding
  • Incidental/bleeding/palpable mass/pressure symptoms/obstruction
  • Bleeding occurs when they outgrow their blood supply and ulcerate
• Tumours can rarely rupture intra-abdominally, generally requiring emergent surgery

Workup

• Endoscopy
  • Smooth-appearing, round, submucosal tumour, occasionally with an area of central ulceration
  • Conventional endoscopic biopsy has a low diagnostic yield
  • EUS-directed FNA is preferred - sensitivity of 82% and specificity of 100%
  • Sabiston suggests that histologic confirmation is not essential for resection, given that most submucosal GI tumours require resection regardless of histology; but this does not seem like practical advice. Diagnosing a GIST pre-op means that no lymphadenectomy will be required.
• CT abdo/pelvis with PO/IV contrast for staging
  • Centred in submucosal space, as it rises from intramuscular layer
  • Well-marginated, rarely see lymphadenopathy
  • Often heterogenous
• MRI can help evaluate for periampullary or rectal tumours, and in patients who cannot have IV contrast
• FDG-PET - good uptake

Staging

• See prognostic table based on stage under 'prognosis'

Primary tumor (T)
T category	T criteria
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Tumor 2 cm or less
T2	Tumor more than 2 cm but not more than 5 cm
T3	Tumor more than 5 cm but not more than 10 cm
T4	Tumor more than 10 cm in greatest dimension
Regional lymph nodes (N)
N category	N criteria
N0	No regional lymph node metastasis or unknown lymph node status
N1	Regional lymph node metastasis
Distant metastasis (M)
M category	M criteria
M0	No distant metastasis
M1	Distant metastasis
Mitotic rate ('grade') in Sabiston
Mitotic rate	Definition
Low	Five or fewer mitoses per 5 mm2
High	Over five mitoses per 5 mm2
Prognostic stage groups
Gastric and omental GIST
When T is...	And N is...	And M is...	And mitotic rate is...	Then the stage group is...
T1 or T2	N0	M0	Low	IA
T3	N0	M0	Low	IB
T1	N0	M0	High	II
T2	N0	M0	High	II
T4	N0	M0	Low	II
T3	N0	M0	High	IIIA
T4	N0	M0	High	IIIB
Any T	N1	M0	Any rate	IV
Any T	Any N	M1	Any rate	IV
Small intestinal, esophageal, colorectal, mesenteric, and peritoneal GIST
When T is...	And N is...	And M is...	And mitotic rate is...	Then the stage group is...
T1 or T2	N0	M0	Low	I
T3	N0	M0	Low	II
T1	N0	M0	High	IIIA
T4	N0	M0	Low	IIIA
T2	N0	M0	High	IIIB
T3	N0	M0	High	IIIB
T4	N0	M0	High	IIIB
Any T	N1	M0	Any rate	IV
Any T	Any N	M1	Any rate	IV

Management

• Low-risk tumours can be observed (below)
• Most tumours should have R0 resection
• Non-resectable, metastatic or recurrent disease is largely treated with chemotherapy, but certain interventions may still be possible

Observation

• Requirements:
  • <2cm
  • No high-risk endoscopy features (irregular borders, ulceration, echogenic foci, heterogeneity)
  • Not symptomatic
• Protocol:
  • Endoscopy and EUS every 6-12 months

Primary surgery

• Indications:
  • Anything resectable and not meeting criteria for close observation
  • Absence of prohibitive comorbidities and with a life expectancy of more than a few years
• Unresectable if infiltration of the coeliac trunk, SMA or portal vein
• R0 local resection, intact capsule, negative microscopic margin. No role for lymphadenectomy. No specific margin required, just R0.
• Be careful not to spill tumour - will result in peritoneal seeding and recurrence in 100% of patients
• Also tumours are very vascular - can bleed a lot
• 70% of patients with tumours >3cm were cured by surgery alone
• GISTs <2cm found incidentally in surgical specimens do not require further treatment
• Choice of surgery
  • Wide local excision
  • Enucleation
  • Sleeve gastrectomy
  • Total gastrectomy
  • With or without en bloc resection of adjacent organs

Surgery for metastases

• Consider in patients that had a good response to neoadjuvant imatinib - predicts good response to metastectomy
• Timing typically 6-9 months after initiation of imatinib
• Consider RFA or hepatic artery embolization for isolated liver metastases

Chemotherapy

• Neoadjuvant
  • Indications:
    • Locally advanced tumours such that multi-visceral resection would be required
    • Non-metastatic but borderline resectable disease
    • Limited metastatic disease which might be resectable, to assess response
  • Can be continued up until the time of surgery
• Adjuvant
  • Indications:
    • High-risk pathological features on resection (see below)
    • Tumour spillage during resection
  • Approach:
    • Risk-stratify with AFIP
    • Consider molecular genotyping to better characterise response to imatinib
      • Worse response in KIT exon 9 mutation, PDGFRA exon 18 mutation, and KIT/PDGFRA wild type)
    • Intermediate or high-risk: imatinib three years
    • No, very low or low-risk GIST: surveillance
  • Imatinib (Gleevec) 400-800mg PO daily (tyrosine kinase inhibitor that blocks the unregulated c-kit tyrosine kinase)
    • Works best if a mutation in KIT is present, but some patients with wild type KIT are still sensitive, due to the similarities between KIT and PDGFR-alpha
    • 400mg normally, 400mg BD if Exon 9 mutation is present
  • Second-line - sunitinib or regorafenib
  • 3 years is the current standard of care
  • 3 years vs 5 years currently being investigated, trial completion date 2028
• Palliative

Prognosis

• Prognosticating calculators:
  • AFIP model - most commonly-used. Classify as no, low, intermediate or high risk.
  • NIH/Fletcher critera - incorporates tumour rupture
• Median survival >5 years even in metastatic disease

AFIP prognostic model: Recurrence risk for gastrointestinal stromal tumors (GISTs) of the stomach, small intestine, and rectum by mitotic rate and tumor size

Tumor size (cm)	Risk of disease progression during long-term follow-up by primary site
	Gastric	Jejunum/ileum*	Duodenum	Rectum
Mitotic rate¶ (HPF): ≤5/50
≤2	No risk	No risk	No risk	No risk
2 to 5	Very low	Low	Low	Low
5 to 10	Low	Intermediate	Limited data	Limited data
>10	Intermediate	High	High	High
Mitotic rate¶ (HPF): >5/50
≤2	No riskΔ	HighΔ	Limited data	High
2 to 5	Intermediate	High	High	High
>5	High	High	High◊	High◊

AFIP prognostic model: progression-free survival for gastrointestinal stromal tumors (GISTs) of the stomach, small intestine, and rectum by mitotic rate and tumor size*

Tumor size (cm)	Percent of patients progression free during long-term follow-up by primary site
	Gastric	Jejunum/ileum	Duodenum	Rectum
Mitotic rate¶ (HPF): ≤5/50
≤2	100	100	100	100
2 to 5	98.1	95.7	91.7	91.5
5 to 10	96.4	76	66*	43*
>10	88	48
Mitotic rate¶ (HPF): >5/50
≤2	100Δ	50Δ	–	46
2 to 5	84	27	50	48
5 to 10	45	15	14*	29*
>10	14	10

Modified NIH risk stratification criteria for GIST with rupture included

Risk category	Tumor size (cm)	Mitotic index (per 50 HPFs)	Primary tumor site
Very low risk	<2.0	≤5	Any
Low risk	2.1 to 5.0	≤5	Any
Intermediate risk	2.1 to 5.0	>5	Gastric
	<5.0	6 to 10	Any
	5.1 to 10.0	≤5	Gastric
High risk	Any	Any	Tumor rupture
	>10 cm	Any	Any
	Any	>10	Any
	>5.0	>5	Any
	2.1 to 5.0	>5	Nongastric
	5.1 to 10.0	≤5	Nongastric