Editing GIST (section)

== '''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

{| class="wikitable"
|'''Type'''
|'''CD117'''
|'''DOG-1'''
|'''PKC-theta'''
|'''CD34'''
|'''SMA*'''
|'''S100 protein'''
|'''Desmin'''
|-
|GISTs
|<nowiki>+</nowiki>

(>95%)
|<nowiki>+</nowiki>

(97%)
|<nowiki>+</nowiki>

(72%)
|<nowiki>+</nowiki>

(60 to 70%)
|<nowiki>+/–</nowiki>

(30 to 40%)
|–

(5% +)
|Very rare
|-
|Leiomyoma
|–
|–
|
|<nowiki>+</nowiki>

(10 to 15%)
|<nowiki>+</nowiki>
|–
|<nowiki>+</nowiki>
|-
|Leiomyosarcoma
|–
|–
|<nowiki>+</nowiki>

(10%)
|–
|<nowiki>+</nowiki>
|–
|<nowiki>+</nowiki>
|-
|Schwannoma
|–
|–
|<nowiki>+</nowiki>

(10%)
|–
|–
|<nowiki>+</nowiki>
|–
|}

* 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 5mm<sup>2</sup>, 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