Langue

Français
TSGI

MOLECULAR DIAGNOSIS OF GIST

1. What are GISTS?

  • Gastro-intestinal stromal tumors account for no more than 1% of all tumors of the GI tract
  • GIST belong to a sub-group of tumors of the GI tract known as mesenchymal tumors or mesenchymal gut neoplasms
  • Most GISTs are classified as smooth muscle tumors. However, some show evidence of autonomic neural differentiation (these GISTs are also sometimes called Gastrointestinal Autonomic Nerve Tumors or GANTs or plexosarcomas). Both of these sub-types of GIST are CD-117 positive on immunohistochemistry (IHC)
  • The primary tumor of GISTs are most often found in the stomach (60-70% of cases) and in the small intestine (30% of cases), with the remainder found in the oesophagus, colon or rectum. Metastasis can be found mostly in the peritoneal/abdominal cavity and liver.
  • GISTs should be differentiated from leiomyomas and leiomyosarcomas, which are a distinct group of tumors that usually do not stain positive for CD-117

2. How are GISTs diagnosed?

  • GIST most commonly display a spindle cell histology, but an epithelioid or mixed cell-type pattern have also been described
  • GIST diagnosis confirmation is usually possible using IHC for CD-117 which stains in cases of over-expression associated with activating KIT mutations
  • However, different patterns of expression of CD-117 are possible due to :
  1. IHC technical variations
  2. Aberrant expressions in some tumors
  3. Specimen available for analysis
  • Therefore, a more complete IHC pattern is usually necessary to differentiate GIST from different sarcomas (vimentine, S-100, etc)

3. Why is it important to get a molecular diagnosis?

  • From a diagnostic point of view :
  1. The majority of GISTs have activating KIT mutations, associated with CD-117 over-expression demonstrated by IHC. However, some GISTs have platelet derived growth factor receptor alpha (PDGFRA) mutations that do not cause over-expression CD-117
  2. IHC for CD-117 can be negative even in cases of KIT mutations, because this technique is not always reliable and varies due to the heterogeneity of the tumor and quality of the specimen. Molecular diagnosis is therefore a reliable method to evaluate and confirm a presumed diagnosis of GIST on histo-pathology.
  3. CD-117 testing has not been thoroughly evaluated and validated in a large setting. Much like HER2 testing, the IHC technique should usually be completed by a confirmatory test. Since more than 90% of GIST present molecular anomalies of KIT or PDGFRA, this is an excellent complement of histopathology. Since CD-117 staining is not fully standardized, when the histopathology is suggestive of GIST and IHC for CD-117 is negative or equivocal, further testing for molecular anomalies is necessary.
  • From a clinical point of view :
  1. The type and location of the KIT or PDGFRA mutation can be predictive of response to imatinib therapy
  2. Progression of GIST patients treated with imatinib is often due to the growth of tumors with different/additional mutations that are less responsive or are responsible for resistance to imatinib therapy

4. Which patients should you consider for a molecular diagnosis?

  • De novo patients in whom you suspect a GIST on histopathology or IHC for CD-117
  • Patients who had a diagnosis of sarcoma, but who may have GIST based on clinical characteristics
  • GIST patients who may be developing resistance to imatinib therapy

5. Why has the "Centre Hospitalier de l'Universite de Montreal" (CHUM) established a centre for molecular diagnosis of GISTS?

  • The CHUM has established Canada's first centre with the capability to test for mutations in KIT and PDGFRA
  • Thanks to a grant from Novartis Pharma Canada, CHUM is able to offer molecular diagnosis of GIST free of charge to centres across Canada

6. How should you order the test?

  • The test should be ordered using the attached form and sending the pathology report
  • Paraffin-embedded or 10 slides of 10 microns specimen are preferable. Frozen specimen are also adequate for analysis, however, expedition conditions have to be discussed prior to shipping. Cytology blocks are not considered adequate. If no other specimen is available, it is preferable to discuss about it with the reference center before sending the specimen.
  • The sample should be sent by courier to the address indicated on the form.

7. How soon will you get the results and how are these sent to you?

  • The results of the test will be sent to you within 5 weeks of reception by fax and regular mail
  • The report will include an interpretation of the results by a specialist in molecular diagnostics.

For technical information contact Louise Robin, medical technologist, at 514-890-8000 ext 27210 or by writing an email at louise.robin.chum@ssss.gouv.qc.ca.