Gastrointestinal Stromal Tumour (GIST)

 

Epidemiology:

    • Adults (50s – 60s)
    • Familial GISTs:
      • Middle-aged patients most commonly
      • As young as 18 years
    • Children (rare)

 

Common sites:

    • stomach (66%)
    • small bowel (25%)
    • colorectal (10%)

 

Gross features:

    • solitary or multiple
    • submucosal to subserosal
      • subserosal may be attached by a pedicle – “omental GIST”
    • tan
    • rounded or ovoid
    • circumscribed
    • not usually whorled pattern of leiomyoma
    • slightly firm to soft
    • hemorrhagic areas commonly
    • may have necrosis or cystic changes in large tumour
    • may have myxoid change
    • can’t tell benign from malignant easily on gross

 

Histologic features:

    • cellular
    • mitotic activity variable
    • spindle cell type (70%):
      • relatively uniform spindle cells in short fascicles, whorls, storiform, or palisaded
      • pale eosinophilic cytoplasm
      • uniform ovoid nuclei with vesicular chromatin
      • sclerosing type
      • palisaded-vacuolated subtype
    • epithelioid type (20%):
      • rounded cells
      • variably eosinophilic or clear cytoplasm
        • may see eosinophilic ring around nucleus in clear cells
        • may have paranuclear vacuoles
      • nuclei regular and round to ovoid with vesicular chromatin
        • more tapered ends than smooth muscle tumours
      • rarely signet-ring (glycogen)
      • sometimes fibrous septa may create an organoid pattern
      • nuclear pleomorphism occurs more often in epithelilid tumours
        • sarcomatoid features sometimes with significant nuclear atypia and mitotic activity
      • sclerosing maybe
      • discohesive maybe
      • hypercellular maybe
      • pseudopapillary pattern maybe
    • mixed type (10%):
    • stromal skenoid steroid fibres
      • hyaline or fibrillary dense eosinophilic globules/structures (PAS-positive)
    • hyalinization around vessels
    • may have myxoid  or hyalinized stroma (5%)
    • may have lymphoplasmacytic inflammatory infiltrate
      • “sprinkling of lymphocytes” is typical
    • Dedifferentiated GIST (rare):
      • Transition from a morphologically recognizeable low-grade tumour to an anaplastic or pleomorphic morphology is appreciated
      • Kit IHC negative within the anaplastic cells
      • De novo, or after treatment with imatinib
    • familial cases:
      • hyperplasia of interstitial cells of Cajal (look between layers of MP)
    • gastrointestinal autonomic nerve tumours (GANTs):

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

c-KIT (CD117)*

95%

Negative in PDGFRA mutated

Not good 

CD34

70%

Gastric less likely

Most spindle cell GISTs

Less likely in epithelioid

 

SMA

30-40%

 

S100

5%

 

CAM5.2

25% (weak, scattered)

 

CK8

37% (weak, scattered)

 

Caldesmon

“frequently”

 

DOG-1

(ANO1)

95%

Regardless of KIT or PDGFRA mutation status

Small subset of mesenchymal tumours including leiomyomas and synovial sarcomas

SDHB

Succinate dehydrogenase subunit B

Granular cytoplasmic staining is lost in SDH-deficient GIST

 
    • *Positive c-kit staining requires cytoplasmic plus membrane accentuation
    • other tumours that are c-kit +
      • mastocytosis
      • germ cell tumours
      • melanoma
      • angiosarcoma

 

 

Molecular features:

    • similar for familial and sporadic cases
    • c-KIT (receptor for stem cell factor) mutations (85%)
      • exon 11 usually, juxtamembrane domain, 3’ end or 5’ end
        • best response to imatinib
      • in-frame deletions (worse prognosis than single-nucleotide substitions)
        • codons 557 and 558 usually
      • single-nucleotide substitutions
        • V559D, V559A, V560D, W557R, L576P are most common
      • Duplications (1-18 codons) (more favourable prognosis usually, indolent course)
        • Internal tandem duplications
        • 3’ portion of exon 11 typically
        • Exons 13 and 17 rarely
        • K642E, N822K, among others
      • insertions
      • complex mutations combining the above
      • exon 9 mutations (~10% of GISTs) (more clinically aggressive)
        • distal extracellular domain
        • small bowel involvement commonly
        • may benefit from higher dose of imatinib
      • tyrosine kinase domain mutations (< 5%)
        • exon 13 mutations
        • exon 17 mutations
        • spindle cell morphology typically
        • small bowel frequently
      • most are sensitive to imatinib
      • homozygous (actually hemizygous) are often more aggressive than heterozygous mutants
      • secondary mutation that confers tumour resistance to imatinib (acquired during treatment) (50% of GIST patients being treated with imatinib)
        • KIT V654A
          1. Sensitive to sunitinib
        • KIT T670I
          1. Sensitive to sunitinib
    • platelet-derived growth factor receptor-alpha (PDGFRA) mutations (up to 10%)
      • epithelioid morphology (typically)
      • stomach and omentum (almost always)
      • exon 18 substitution D842V most common (less likely to have favorable or sustained response to imatinib)
        • notably resistant to imatinib
      • exon 12 deletion rarely
      • exon 14 substitutions rarely (favorable clinical course)
    • BRAF V600E mutation (small subset)
      • Mutually exclusivce to PDGFRA and KIT mutations
    • Familial GISTs arise from germline mutations in exons 8, 11, and 13 of KIT and exon 12 of PDGFRA, identical to the mutations identified in sporadic GISTs
      • GISTs in almost all patients
      • Stomach and small bowel typically
      • Middle-aged patients most commonly
        • As young as 18 years
    • GISTs in children or associated with NF1 do not contain KIT or PDGFRA mutations
    • Deletions / monosomy of chromosomes 14 and 22
    • Succinate dehydrogenase subunits B, C, and D, germline mutations
      • Autosomal dominant
      • Carney-Stratakis syndrome
      • Approximately 50% of pediatric GIST
        • Nodal metastases often
        • Imatinib resitance
        • Overall indolent course
      • Lack KIT and PDGFRA mutations

 

Other features:

    • you can never call a GIST definitely benign
    • approximately 25% of gastric GISTs are clinically malignant
    • prognostic indicators:
      • size
        • >10cm is high risk regardless of other features
      • mitotic count
        • <5/50 HPF benign
        • >10/50HPF is high risk regardless of other features
      • location
        • small intestine – most are malignant
      • symptomatic have worse prognosis
      • tumour necrosis has been reported as a poor prognostic factor
      • mucosal invasion has been reported as a poor prognostic factor
      • ulceration has been reported as a poor prognostic factor
      • tumour ruptureincreases the risk of recurrence with intraabdominal seeding
        • intraoperative tumour rupture associated with shortened survival
    • most malignant GISTs run a slow course over years
    • cell of origin: interstitial cells of Cajal
    • Tumour syndromes:
      • SDH-deficient GIST (germline mutations in SDH complex family)
        • Carney’s triad – epithelioid gastric GIST, paraganglioma, pulmonary chondroma
          • KIT positive by IHC typically
          • Lacking KIT and PDGFRA mutations
        • Carney-Stratakis syndrome – GIST, paraganglioma
        • Pediatric GIST
          • 50% have SDH complex subunit gene mutation
          • Girls predominantly
          • Metastasize to lymph nodes often
          • Lack mutations in KIT and PDGFRA often
        • “pediatric-type” GISTs in adults
          • Histomorphology identical to pediatric GIST
          • Nodal metastases
          • Imatinib resistance
          • Overall indolent course
        • Stomach
        • Multiondular or plexiform growth
        • Lobules of tumour separated by bands of smooth muscle
        • Hypercellular
        • Epithelioid cytomorphology
        • Metastasize to lymph nodes
        • Insensitive to imatinib
        • Despite recurrences and distant metastases, they typically follow a more indolent clinical courese
      • Familial GIST syndrome (germline KIT mutations)
        • Mastocytosis maybe (urticarial pigmentosa)
        • Hyperpigmented macules on the skin of the perineum, axilla, hands, face maybe
        • Diffuse ICC hyperplasia in the bowel wall
      • Neurofibromatosis type 1 (NF1)
        • Most common GI tumour in NF1
        • Small bowel mostly
        • Multifocal mostly
          • Distinction from metastatic deposits is of major clinical significance
          • Multiple small GISTs should raise index of suspicion particularly in the small bowel
        • Relatively small
        • Mitotically inactive
        • Indolent course
        • Diffuse ICC hyperplasia often adjacent in myenteric plexus
        • Very low frequency of KIT or PDGFRA mutations
    • STI571 (imatinib/Gleevec) (a tyrosine kinase inhibitor) is indicated in treatment of unresectable or metastatic GIST
      • Mutation testing is not required; CD117 (c-kit) IHC is enough)
        • Even c-kit negative tumours may respond therefore they are also eligible (should be DOG-1+)
      • Clinical response in 80% of metastatic or unresectable GIST (improved PFS and OS)
        • Less likely favorable or sustained response for tumours without a KIT mutation
        • Most patients eventually progress
    • Sunitinib approved for patients who do not tolerate imatinib, or have progression on imatinib therapy
      • Again, no need for molecular testing (CCO 2015)
      • Inhibits phosphorylation of multiple TKIs including c-kit, platelet derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR)
    • Regorafenib FDA approved as third-line therapy for progression on sunitinib

 

References:

    • Robbins 2005
    • Sternberg 2004
    • Gastrointestinal and Liver Pathology 2005
    • Bosman FT, Carneiro F, Hruban RH, Theise ND.  WHO Classification of Tumours of the Digestive System (2010)
    • Odze & Goldblum.  Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas, 3rd ed.  (2015)
    • Sarcoma Disease Site Group. Imatinib mesylate (Gleevec™) for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumours. Verma S, Agbassi C, reviewers. Toronto (ON): Cancer Care Ontario; 2015 May 21 Program in Evidence-based Care Evidence-Based Series No.: 11-7 Version 3.
    • Members of the Sarcoma Disease Site Group. Sunitinib malate for gastrointestinal stromal tumour (GIST) in imatinib mesylate resistant patients. Razak A, Poon R, reviewers. Toronto (ON): Cancer Care Ontario; 2009 Jun 9 [Endorsed 2014 Jan 15; Ed & Info 2015 Oct]. Program in Evidence-based Care Evidence-Based Series No.: 11-8 Version 2 Education and Information 2015.