Gastrointestinal Stromal Tumor (GIST)

Marc Tubay, MD

(T) Primary Tumor	Adapted from 7th edition AJCC Staging Forms.
TNM	Definitions
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Tumor ≤ 2 cm
T2	Tumor > 2 cm but ≤ 5 cm
T3	Tumor > 5 cm but ≤ 10 cm
T4	Tumor > 10 cm
(N) Regional Lymph Nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis
(M) Distant Metastasis
M0	No distant metastasis
M1	Distant metastasis
(G) Histologic Grade
GX	Histologic grade cannot be assessed
G1	Low grade (mitotic rate ≤ 5 per 50 high-power fields)
G2	High grade (mitotic rate > 5 per 50 high-power fields)
Size of tumor is measured in the greatest dimension.

AJCC Stages/Prognostic Groups for Gastric GIST				Adapted from 7th edition AJCC Staging Forms.
Stage	T	N	M	G
IA	T1	N0	M0	G1
	T2	N0	M0	G1
IB	T3	N0	M0	G1
II	T1	N0	M0	G2
	T2	N0	M0	G2
	T4	N0	M0	G1
IIIA	T3	N0	M0	G2
IIIB	T4	N0	M0	G2
IV	Any T	N1	M0	Any G
	Any T	Any N	M1	Any G
The AJCC stage grouping schema are slightly different for gastric and small bowel GISTs, owing to slightly different biological activities. The staging for gastric GIST should also be used for omentum.

AJCC Stages/Prognostic Groups for Small Intestinal GIST				Adapted from 7th edition AJCC Staging Forms.
Stage	T	N	M	G
I	T1 or T2	N0	M0	G1
II	T3	N0	M0	G1
IIIA	T1	N0	M0	G2
	T4	N0	M0	G1
IIIB	T2	N0	M0	G2
	T3	N0	M0	G2
	T4	N0	M0	G2
IV	Any T	N1	M0	Any G
	Any T	Any N	M1	Any G
The small bowel GIST staging grouping may be applied to esophageal, duodenal, colorectal, and peritoneal GISTs. As there is only minimal data regarding extragastrointestinal GISTs, precise grouping of these rare tumors can be problematic. In cases of extragastrointestinal GISTs and other less common varieties, the staging grouping for small bowel tumors may be used. The T, N, and M criteria reflect imaging findings, whereas tumor grading (G) is based on histologic criteria.

Gastrointestinal Stromal Tumor Prognostic Grouping
Malignancy Risk	Size Criteria	Histologic Criteria
Very low risk	< 2 cm	≤ 5 per 50 HPF
Low risk	2-5 cm	≤ 5 per 50 HPF
Intermediate risk	< 5 cm	6-10 per 50 HPF
	5-10 cm	≤ 5 per 50 HPF
High risk	> 5 cm	> 5 per 50 HPF
	> 10 cm	Any mitotic rate
	Any size	> 10 per 50 HPF
From Levy AD et al: Gastrointestinal stromal tumors: radiologic features with pathologic correlation. Radiographics. 23(2):283-304, 2003. This system for stratification of aggressive potential in tumors without known metastatic disease was widely used prior to the advent of AJCC TNM staging system and has now been replaced. Size is measured in the greatest dimension. Histologic criteria reflects the number of mitotic figures per 50 high-power fields (HPF).

Low magnification of H&E section from the wall of stomach shows gastrointestinal stromal tumor (GIST)

. The tumor measures 2.5 cm in largest dimension. Note the overlying stretched gastric mucosa

. (Original magnification 10×.)

Higher magnification shows a portion of gastric mucosal epithelium in the upper aspect of the photomicrograph

. The lower aspect of the photomicrograph shows a tumor composed of bundles of spindle cells characteristic of GIST. (Original magnification 400×.)

Immunohistochemical stain with antibody against C-kit (CD117) demonstrates positive (brown) staining in the spindle cells. The GIST tumor originates from gastrointestinal pacemaker cells (intercalated cells of Cajal). (Original magnification 100×.)

Immunohistochemical stain with antibody for smooth muscle actin (SMA) stains smooth muscle cells brown. The tumor

is negative for SMA, differentiating GIST from other smooth muscle tumors. Note the positive internal control staining in the smooth muscle cells in the stomach wall

. (Original magnification 100×.)

Coronal graphic shows a gastric GIST

. Precise staging is based on tumor size and grade in the absence of nodal or metastatic disease.

Axial graphic shows a gastric GIST with solid hepatic metastases, representing stage IV.

Coronal graphic shows a gastric GIST with peritoneal metastases. This is a stage IV lesion.

Coronal graphic shows a small bowel GIST with hepatic metastases. This is a stage IV lesion.

Coronal graphic shows a small bowel GIST with hepatic and peritoneal metastases. This is a stage IV lesion.

Coronal graphic shows the decrease in size and more cystic nature of primary small bowel GIST after therapy, as well as hepatic and peritoneal metastases.

Axial graphic shows mid-esophageal GIST. The small bowel stage grouping should be used in this case. Precise staging is based on lesion size and grade.

Axial graphic demonstrates a primary retroperitoneal GIST. The small bowel stage grouping should be used in this case. Precise staging is based on lesion size and grade.

Sagittal graphic shows a rectal GIST. The small bowel stage grouping would be used in this case. Precise staging is based on lesion size and grade.

Sagittal graphic shows the decrease in size and more cystic appearance of a rectal GIST after therapy.

	METASTASES, ORGAN FREQUENCY
	Liver	46-65%
	Peritoneum	21-41%
	Retroperitoneum	4%
	Lungs	2-6%
	Bone	2-6%
	Subcutaneous/scar tissue	2%
	Pleura	2%
	Rare nodal involvement	< 1-6%

OVERVIEW

General Comments

Most common mesenchymal malignancy of GI tract
- Represents about 5-6% of all sarcomas
- 80% of gastrointestinal sarcomas are GISTs
- Accounts for < 1% of all GI malignancies
Historically misdiagnosed smooth muscle tumors
- Diagnosed as leiomyomas, leiomyoblastomas, or leiomyosarcomas
- Improved immunohistological and electron microscopy techniques allowed for accurate characterization of GISTs after 1983
AJCC TNM staging criteria
- Recently established; took effect January 1, 2010
- Previously, there was no formal TNM staging system, and risk stratification for metastatic potential was based on tumor size and mitotic rate
Minority (20-30%) of GISTs demonstrate malignant behavior
- Smaller, more homogeneous tumors tend to be benign and have lower histologic grade
- Tumors < 2 cm rarely demonstrate high histologic grade

Classification

Soft tissue sarcoma, distinct from leiomyoma/leiomyosarcoma and nerve sheath tumors

PATHOLOGY

Routes of Spread

Local spread
- Transperitoneal spread
  - Common pattern of spread, may occur early
- Invasion of surrounding structures
  - Less common than peritoneal seeding
Nodal metastasis
- Very rare in GIST
- More likely to occur in women and patients < 40 years old
- More common in gastric epithelioid/mixed-type ulcerated endoluminal GIST
Distant metastasis
- Most commonly metastasizes to liver
- Uncommon to spread to lung or other soft tissue sites

General Features

Comments
- Solid, vascular intramural/submucosal mass
- Exophytic growth pattern (not usually infiltrative)
  - Can demonstrate intra- or extraluminal growth
- Tumor may be heterogeneous with variable amount of necrosis/hemorrhage
- Can occur anywhere along GI tract
  - Stomach (50-70%)
  - Duodenum and small intestine (20-25%)
  - Colon and rectum (5-10%)
  - Esophagus (2-5%)
- In up to 10% of cases, can occur outside gut (extragastrointestinal GIST)
  - Retroperitoneum
  - Mesentery
  - Omentum
- Majority (70-80%) of GISTs are benign
  - Risk of malignancy can be difficult to estimate
  - Potential for metastatic spread can be predicted by tumor size and histologic grading
Genetics
- c-KIT
  - Tyrosine kinase oncogene
  - Encodes for transmembrane growth factor receptor, CD117
  - More than 90% of patients with GIST have c-KIT mutations
  - Mutation results in upregulation of tyrosine kinase activity and altered cell growth
- PDGFRA
  - Tyrosine kinase oncogene
  - Less than 10% of patients with GIST harbor a PDGFRA mutation
  - Involved with intracellular signaling pathways similar to c-KIT
Etiology
- Believed to arise from interstitial cells of Cajal
  - “Pacemaker” cells of GI tract
  - Thought to regulate peristalsis
- Result of tyrosine kinase oncogene mutation (c-KIT, PDGFRA)
  - Results in unregulated cellular growth
- No described environmental risk factors
Epidemiology & cancer incidence
- 4,500-6,000 new cases each year in USA
- Equal sex predilection
- Wide age range at presentation (typically 40-70 years but can occur earlier)
  - 75% of cases in patients > 50 years of age
  - Median age at presentation: 58-63 years
Associated diseases, abnormalities
- Vast majority of GISTs are sporadic and isolated
- Carney triad
  - Association between GIST, pulmonary chondroma, and extraadrenal paraganglioma
  - Likely sporadic; no known genetic abnormality
  - Typically epithelioid variant of GIST
  - Strong female predilection (up to 85%)
  - Usually occur in stomach and may be multifocal
  - Minority of patients will have all 3 tumor types at presentation
  - GIST is often 1st tumor to present
- Increased risk of GIST in patients with neurofibromatosis type 1 (NF1)
  - 5-25% of patients with NF1 will develop a GIST
  - Often multifocal
  - Predominate in small bowel (as opposed to stomach in sporadic GIST)
  - < 20% of lesions in NF1 patients with GIST will have typical c-KIT or PDGFRA mutations
  - Tumor may show S100 positivity (cell marker associated with neural differentiation)
  - Tend to be of low histologic grade and rarely metastatic
- Familial GIST syndromes
  - Rare; due to inherited germline mutation of c-KIT or PDGFRA
  - Autosomal dominant mode of inheritance
  - GISTs tend to occur at younger age compared to nonfamilial GISTs
  - Often associated with dermatological abnormalities

Gross Pathology & Surgical Features

Friable, well-circumscribed mass
Unencapsulated but may have pseudocapsule
Larger tumors may demonstrate central necrosis, cystic degeneration, or hemorrhagic components
Measure between 2-30 cm at presentation

Microscopic Pathology

H&E
- Spindle cell variant (70%)
- Epithelioid variant (20%)
- Mixed cell type (10%)
Special stains
- Immunophenotyping essential to differentiate from other mesenchymal tumors
  - CD117 (c-KIT) positive in nearly 100% of tumors
  - CD34 positive in 70-80% of tumors

IMAGING FINDINGS

Detection

CECT of abdomen and pelvis
- Primary imaging modality for tumor detection
- Triple-phase examination may be helpful to evaluate tumor vascularity, but single portal venous phase acquisition with oral contrast is usually adequate for diagnosis
- Mass arising from gut wall
  - Intramural growth pattern for small lesions, transmural appearance in larger masses
  - May also demonstrate intra- or extraluminal predominant growth pattern
  - Smaller tumors are often well defined
  - Larger tumors and those of higher grade often have more irregular margins
  - Invasion of adjacent structures not common and may suggest higher grade lesion
  - Larger lesion with extraluminal growth may appear as a nonspecific abdominal mass with originating loop of bowel draped along periphery
- “Embedded organ” sign
  - Helpful in identifying organ of origin when large mass is found
    - Compressed hollow organ adjacent to mass → organ is not site of origin
    - When part of hollow organ appears embedded within mass → organ is likely site of origin
- Avid contrast enhancement
  - Small tumors show homogeneous enhancement
  - Central necrosis and cystic changes are common in larger tumors (> 3 cm)
  - More heterogeneous enhancement may suggest higher grade tumor
- Extragastrointestinal GISTs appear as nonspecific soft tissue density enhancing masses
  - Wide DDx necessitates biopsy
  - May be difficult to differentiate from metastatic disease; entire gut must be examined closely to exclude a small primary tumor
Upper GI fluoroscopic examination
- Smooth submucosal/mural mass lesion
- May have irregular contour if necrotic or ulcerated
- Necrotic components may communicate with gut lumen
- Larger masses may displace adjacent bowel loops
- Findings may be suggestive, but cross-sectional imaging necessary for complete characterization and evaluation for metastatic disease
Endoscopy
- Often an incidental finding
- Mural/submucosal mass
- Cross-sectional imaging necessary to evaluate extraluminal extent and presence of metastatic disease
Ultrasound typically not helpful for characterization of primary tumor
- Well-marginated masses closely associated with bowel
  - Often with preservation of typical gut wall signature
- Smaller masses are typically homogeneously hypoechoic
- May show internal heterogeneity with central anechoic components, representing hemorrhage/necrosis
- Association between larger more heterogeneous tumors and higher malignant potential
- Hepatic or peritoneal metastatic disease may be identified, though nonspecific in appearance
- Hepatic metastatic disease may demonstrate a simple cystic appearance after therapy
MR
- Variable appearance based on degree of necrosis/hemorrhage
- Solid portions of tumor will typically demonstrate ↓ T1 and ↑ T2 signal
- Necrotic/hemorrhagic components will have variable signal intensity
- Viable tumor enhances avidly
- Hepatic and peritoneal/serosal metastatic disease may be appreciated

Staging

Local staging (T)
- T staging depends solely on maximum tumor size
  - T1: Tumor size ≤ 2 cm
  - T2: Tumor size > 2 cm but ≤ 5 cm
  - T3: Tumor size > 5 cm but ≤ 10 cm
  - T4: Tumor size > 10 cm
- Diameter may be necessarily estimated in case of ruptured tumor
- Depth of gut wall invasion not useful metric as most GISTs are transmural
- Invasion of adjacent organs should be described, though does not influence tumor staging
Nodal staging (N)
- Lymph node involvement is rare
- Nodal dissection usually not indicated at time of surgical resection unless suspicious nodes are seen at imaging
Metastatic staging (M)
- Intraabdominal spread (liver or peritoneum/serosa) most common
- Adherence of primary mass to liver does not constitute hepatic metastatic disease
- Multiple primary GISTs (in setting of familial GIST or NF1) may be difficult to distinguish from metastases
- Single omental, peritoneal, or retroperitoneal mass may represent primary GIST vs. metastatic spread from unknown primary
  - Extragastrointestinal GIST should be diagnosis of exclusion, and great care should be taken to evaluate for gut primary
- Liver metastasis
  - Metastases are frequently hypervascular and may be missed if imaging is performed only during portal venous phase
Histologic grading (G)
- Based on number of mitotic figures per 50 highpower fields (HPF)
  - ≤ 5 per 50 HPF = low grade (G1)
  - > 5 per 50 HPF = high grade (G2)
Imaging modalities
- CECT of abdomen and pelvis for staging
  - Single portal venous phase examination with oral and IV contrast is adequate
  - Baseline density measurements of mass (in Hounsfield units) should be noted, avoiding overtly necrotic components
  - Identification of hepatic metastatic disease critical
  - Careful attention should be paid to mesentery and peritoneum to evaluate for soft tissue nodular implants
  - While nodal involvement is rare, suspicious lymph nodes should be described
- CECT of chest often not necessary as GIST rarely demonstrates extraabdominal spread
- PET
  - Evaluate baseline SUV(max)
  - Evaluate for additional foci of uptake suggestive of metastatic disease
- Contrast-enhanced MR
  - Most helpful in evaluation of known/suspected rectal GIST
  - Pelvic sidewall and adjacent organ involvement should be noted
  - Early peritoneal or hepatic metastatic disease may be detected