Definition
- Most common Mesenchymal tumours of the GI tract
- 1-3% of all primary GI malignancy
- Arises from the Interstitial Cells of Cajal
- Submucosal in origin and distrubted through the smooth muscle and nervous plexi
- Pacemaker cells of the Myenteric Plexus
- Locations
- 60% Stomach
- 30% Jejunum and Ileum
- 5% Duodenum
- 4% Colorectal
- < 1% Oesophagus
- Male = Female
- Average age 60
- All are on a spectrum of malignant potential
- Predictors of this are
- Size
- Location
- Mitotic rate
Aetiology
- Similar to Leiomyoma (benign) or Leiomyosarcoma (malignant)
- Predominantly sporadic (95%)
- Can be associated with familial conditions:
- Neurofibromatosis Type 1
- Von-Hippel-Lindau disease
- Carney triad (subtype of MEN), syndrome of
- GIST
- Pulmonary Chondroma
- Extra-adrenal Paraganglioma
- Familial KIT and PDGFR genes
Pathology
- Macro and Micro
- Submucosal mass on gastroscopy
- +/- Central ulceration
- Necrosis from outgrowth of blood supply
- +/- Central ulceration
- Firm grey-white with whorled appearance on cut surface
- DDx Leiomyoma, Leiomyosarcoma
- These are c-KIT negative
- DDx Leiomyoma, Leiomyosarcoma
- Submucosal mass on gastroscopy
- Morphology
- 70% = Spindle cell
- Usually, minimal atypia
- Shows smooth muscle & neural differentiation
- 20% = Epithelioid
- 10% = Mixed
- Metastases very late in disease progression
- Haematogenous and trans-peritoneal most common
- Liver, peritoneum common
- Lung very rare
- Lymphatic spread negligible
- Haematogenous and trans-peritoneal most common
- 70% = Spindle cell
Immunohistochemistry and Genetics
-
95% stain positive for KIT mutation (CD117)
- Causes autonomous activity of tyrosine kinase receptor
- DOG-1 also highly sensitive
- NB: Leiomyoma, Leiomyosarcoma are KIT negative
-
Main genetic defects leading to GIST are
- C-Kit proto-oncogene (85%)
- PDGF-α mutation (3-5%)
- Commonest KIT mutation on exons 11 and 9
-
15% are Wild Type and have different behaviour
- i.e. No mutation in C-Kit or PDGFR
- Seen in NF-1
-
GISTS: Negative for Desmin
- Distinguishes it from smooth muscle cell tumours (Leiomyoma)
-
cKIT mutation GIST - occur because a gain of function mutation in the gene cKIT results in a mutant receptor tyrosine kinase (this protein is called KIT/CD117)
-
PDGRFA mutation GIST - his accounts for 5-10% of GISTS. They are often resistant to imatinib.
-
Wild-type GIST - 5%. Negative for cKIT and PDGFRA mutations. More likely to be a hereditary GIST such as NF1 and Carney triad.
Clinical Presentation
- 1/3 are incidental findings on gastroscopy/ imaging
- 80% are symptomatic
- GI bleeding (most common, central ulceration)
- Occult
- Overt
- GI bleeding (most common, central ulceration)
- Abdo pain
- Dysphagia
- Palpable mass
- Peritonitis (due to perforation)
Investigations
- Endoscopy and biopsy
- If resectable lesion, no biopsy is required
- If unresectable or planning neoadjuvant or multiple lesions or evidence of metastatic disease – tissue diagnosis required and biopsies should be done
- EUS +/- FNA
- CT-scan
- Aim to identify site of origin
- CT-PET
- NB: If typical endoscopy/EUS/CT PET characteristics, may not need tissue diagnosis prior to surgery
Endoscopy
- Can get suspicion from clinical appearance
- Submucosal lesion
- But lots of DDx
- Leiomyoma
- Neuroendocrine Tumour
- Heterotropic pancreas
- But lots of DDx
- May have central ulceration
- Submucosal lesion
- If doing biopsies
- Multiple biopsies from the same side (bite-on-bite) tunnelled biopsies
- Remember submucosal
- Often difficult/non-diagnostic
- -ve biopsy does not exclude GIST
- Multiple biopsies from the same side (bite-on-bite) tunnelled biopsies
- No role for endoscopic removal
- Submucosal lesion so EMR/ESD not appropriate
- Submucosal lesion so EMR/ESD not appropriate
EUS
- Anatomical location
- Most GISTs arise from Muscularis Propria
- Size
- Sonographic Characteristics
- Low risk
- Homogenous, regular border
- High risk
- Heterogenous, irregular border
- Low risk
- EUS guided FNA cytology gives tissue diagnosis
CT scan
- Most commonly an intestinal-based mass with bulk of tumour extrinsic to bowel
- May have
- Central necrosis
- Heterogeneous enhancement
- Good for attempting to determine resectability with regards to nearby structures
- Used for staging/surveillance
- PET would be more ideal but not funded
- NB: ? Limited utility in surveillance chest scans due to very low rates of metastasis to lungs
CT-PET
- Most GISTs are FDG-avid
- Good for staging
- Good for metastatic disease missed on CT
- Indications:
- Very large lesions
- Recurrence
- Metastatic Disease
- Assess treatment response
- Distinguish between bleeding and tumour progression
- Also used to see response to neoadjuvant/ adjuvant therapy
- Limited funding for on-going surveillance
MRI Scan
- No added benefit over CT-scan
- Offers soft tissue resolution if assessing site of origin
- Rectal lesions
Staging
- Main prognostic factors are
- Size
- Site
- Mitotic rate
- Reflected in the staging system
T Staging Based on size of lesion
- 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 Staging Rare to have nodal metastasis
- N0: No regional lymph node metastasis or unknown lymph node status
- N1: Regional lymph node metastasis
M Staging
- M0: No distant metastasis
- M1: Distant metastasis
Mitotic Rate
- Low: 5 or fewer mitoses per 5 mm2
- High: More than 5 mitoses per 5 mm2
Stage Grouping Gastric and omental GIST
| Stage IA: | T1 - 2 | N0 | M0 | Low mitotic rate |
| Stage IB: | T3 | N0 | M0 | Low mitotic rate |
| Stage II: | T1 - 2 | N0 | M0 | High mitotic rate |
| T4 | N0 | M0 | Low mitotic rate | |
| Stage IIIA: | T3 | N0 | M0 | High mitotic rate |
| Stage IIIB: | T4 | N0 | M0 | High mitotic rate |
| Stage IVA: | Any T | N1 | M0 | Any mitotic rate |
| Any T | Any N | M1 | Any mitotic rate |
Esophageal, small intestinal, colorectal, mesenteric and peritoneal GIST
| Stage I: | T1 - 2 | N0 | M0 | Low mitotic rate |
| Stage II: | T3 | N0 | M0 | Low mitotic rate |
| Stage IIIA: | T4 | N0 | M0 | Low mitotic rate |
| T1 | N0 | M0 | High mitotic rate | |
| Stage IIIB: | T2 - 4 | N0 | M0 | High mitotic rate |
| Stage IVA: | Any T | N1 | M0 | Any mitotic rate |
| Any T | Any N | M1 | Any mitotic rate |
Management
- Principles of management
- MDM discussion
- Risk stratification
- Patient factors and wishes vs tumour factors
- Surgery
- Targeted Therapy
Risk Stratification
- Consider surveillance strategy for small gastric GISTs
- Very low risk of spread
Surgery
- Indication for surgery
-
2cm
- If <2cm can surviell with CT in 6 months and surgery if growth >.5cm
- Irregular borders
- Heterogenous density on CT, echogenicity on USS or avidity on PET
- Cystic spaces on EUS
- Any GIST not in the stomach (higher malignant potential)
-
- Usually, main mode of curative management
- If no metastatic disease
- Aim for R0 resection (1-2cm margins)
- Wide margins not required
- Lap vs open depending on lesion location and surgeon experience
- Similar outcomes, less pain, faster to discharge with laparoscopic
- Wedge or segmental excision often sufficient
- Aim for no-handling technique
- Do not want to rupture lesion
- Aim to preserve function, as patients may live for long time so want to reduce morbidity
- Aim for no-handling technique
- If tumour close to GOJ, can use Merendino Procedure
- Interposition of jejunal pedicle conduit between distal oesophagus and stomach remnant
- Location of tumour may determine extent of resection
- If large, proximal gastric tumour may require formal gastrectomy
- Lesser curve, posterior wall, and cardiac lesions more difficult to access
- Oesophageal GIST:
- Needs to be distinguished from Leiomyoma
- GIST = Oesophagectomy but Leiomyoma can be enucleated
- Lymphadenectomy not required, unless clear LN lesion
- Surgery with clear margins is considered curative treatment
Targeted Therapy
- Tyrosine Kinase Inhibitors
- Consider mutational profile
- Will direct which tyrosine kinase inhibitor to use
- Imatinib/Gleevec (400mg/day) first line
- Selective Type 3 Tyrosine Kinase Inhibitor
- Blocks Tyrosine Kinase receptor
- Usually well tolerated
- Side effects – Periorbital oedema, myalgia, skin rash, acute tumoral bleed, cardiotoxicity
- 80% of pts will respond including KIT and PDGFRA mutation pts
- 50% response rate even in Wild Type Mutation
- 20% will have initial or late resistance to treatment
- If resistant, first increase dose from 400mg Daily to 800mg
- If continues to have poor response, consider 2nd line therapy – Sunitinib or Regorafenib
Indications for TKIs
- Neoadjuvant to downstage borderline resectable disease
- Operate as soon as gets resectable, as GISTs develop resistance to TKIs over time
- Need to confirm mutational status prior to imatinib use – need biopsies
- Treatment duration 6-12 months
- Use CT-PET as well as conventional CT to assess response
- Adjuvant therapy if tumour has high risk features
- Size
- Mitotic rate > 5
- Location (not stomach)
- Perforated disease
- Trial imatinib vs placebo stopped early
- Prolonged RFS and recurrence rates C.F placebo
- Can use calculator
- Memorial Sloan Kettering Cancer Center
- https://www.mskcc.org/nomograms/gastrointestinal/stromal_tumor
- Size
- Mitotic rate
-
5 or <5
-
- Location
- Rectum, Colon, Stomach or SB
- Treatment duration: 3 years – shown to have improved DFS and OS
- Metastatic disease
- Patients who do not want surgery
Prognosis
- If completely resected
- 5yr survival – 50%
-
10cm, 5yr survival – 20%
- High risk of recurrence
- Risk lowest with stomach
- Most common in liver or peritoneal cavity
- Resection for recurrence has limited role
- Metastatic disease – median survival 20 months
- Most important predictors of malignant potential = Size & Mitotic Rate
Follow-up
- Annual CT for up to 5 years
- If high-risk of recurrence
- 6 monthly CT
- Most recurrence within 2 years