Editing GIST


== '''Epidemiology''' ==

* Most common mesenchymal     neoplasm of the GIT
* 1% of all GIT neoplasms but     most common sarcoma subtype

== '''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


== '''Risk factors''' ==

* Typically seen in patients     >50yo
* More common in men
* 5% are associated with an     underlying heritable mutation
** Familial GIST syndrome -      mutation in KIT or PDGFRA
** Neurofibromatosis 1
** Carney-Stratakis syndrome      (GIST and paraganglioma, with or without pulmonary chondroma)

== '''Presentation''' ==

* Often asymptomatic and found     incidentally
* Symptoms dependent on area of     origin
** Stomach - early satiety,      bloating, vague epigastric pain, melaena, haematemesis (uncommon)
** Small bowel - abdominal      pain, fullness, bowel obstruction, or bleeding
** Incidental/bleeding/palpable      mass/pressure symptoms/obstruction
** Bleeding occurs when they      outgrow their blood supply and ulcerate
* Tumours can rarely rupture     intra-abdominally, generally requiring emergent surgery

== '''Workup''' ==

* Endoscopy
** Smooth-appearing, round,      submucosal tumour, '''occasionally with an area of central ulceration'''
** Conventional endoscopic      biopsy has a low diagnostic yield
** EUS-directed FNA is      preferred - sensitivity of 82% and specificity of 100%
** Sabiston suggests that      histologic confirmation is not essential for resection, given that most      submucosal GI tumours require resection regardless of histology; but this      does not seem like practical advice. Diagnosing a GIST pre-op means that      no lymphadenectomy will be required.
* CT abdo/pelvis with PO/IV     contrast for staging
** Centred in submucosal space,      as it rises from intramuscular layer
** Well-marginated, rarely see      lymphadenopathy
** Often heterogenous
* MRI can help evaluate for     periampullary or rectal tumours, and in patients who cannot have IV     contrast
* FDG-PET - good uptake

== '''Staging''' ==

* See prognostic table based on     stage under 'prognosis'

{| class="wikitable"
|'''Primary tumor (T)'''
|
|
|
|
|-
|'''T category'''
|'''T criteria'''
|
|
|
|-
|TX
|Primary tumor  cannot be assessed
|
|
|
|-
|T0
|No evidence of  primary tumor
|
|
|
|-
|T1
|Tumor 2 cm or less
|
|
|
|-
|T2
|Tumor more than 2  cm but not more than 5 cm
|
|
|
|-
|T3
|Tumor more than 5  cm but not more than 10 cm
|
|
|
|-
|T4
|Tumor more than 10  cm in greatest dimension
|
|
|
|-
|'''Regional lymph nodes (N)'''
|
|
|
|
|-
|'''N category'''
|'''N criteria'''
|
|
|
|-
|N0
|No regional lymph  node metastasis or unknown lymph node status
|
|
|
|-
|N1
|Regional lymph  node metastasis
|
|
|
|-
|'''Distant metastasis (M)'''
|
|
|
|
|-
|'''M category'''
|'''M criteria'''
|
|
|
|-
|M0
|No distant  metastasis
|
|
|
|-
|M1
|Distant metastasis
|
|
|
|-
|'''Mitotic rate ('grade') in Sabiston'''
|
|
|
|
|-
|'''Mitotic rate'''
|'''Definition'''
|
|
|
|-
|Low
|Five or fewer mitoses per 5 mm2
|
|
|
|-
|High
|Over five mitoses per 5 mm2
|
|
|
|-
|'''Prognostic stage groups'''
|
|
|
|
|-
|'''Gastric and omental GIST'''
|
|
|
|
|-
|'''When T is...'''
|'''And N is...'''
|'''And M is...'''
|'''And mitotic rate is...'''
|'''Then the stage group is...'''
|-
|T1 or T2
|N0
|M0
|Low
|IA
|-
|T3
|N0
|M0
|Low
|IB
|-
|T1
|N0
|M0
|High
|II
|-
|T2
|N0
|M0
|High
|II
|-
|T4
|N0
|M0
|Low
|II
|-
|T3
|N0
|M0
|High
|IIIA
|-
|T4
|N0
|M0
|High
|IIIB
|-
|Any T
|N1
|M0
|Any rate
|IV
|-
|Any T
|Any N
|M1
|Any rate
|IV
|-
|'''Small intestinal, esophageal, colorectal,  mesenteric, and peritoneal GIST'''
|
|
|
|
|-
|'''When T is...'''
|'''And N is...'''
|'''And M is...'''
|'''And mitotic rate is...'''
|'''Then the stage group is...'''
|-
|T1 or T2
|N0
|M0
|Low
|I
|-
|T3
|N0
|M0
|Low
|II
|-
|T1
|N0
|M0
|High
|IIIA
|-
|T4
|N0
|M0
|Low
|IIIA
|-
|T2
|N0
|M0
|High
|IIIB
|-
|T3
|N0
|M0
|High
|IIIB
|-
|T4
|N0
|M0
|High
|IIIB
|-
|Any T
|N1
|M0
|Any rate
|IV
|-
|Any T
|Any N
|M1
|Any rate
|IV
|}

== '''Management''' ==

* Low-risk tumours can be     observed (below)
* Most tumours should have R0     resection
* Non-resectable, metastatic or     recurrent disease is largely treated with chemotherapy, but certain     interventions may still be possible

== '''Observation''' ==

* Requirements:
** <2cm
** No high-risk endoscopy      features (irregular borders, ulceration, echogenic foci, heterogeneity)
** Not symptomatic
* Protocol:
** Endoscopy and EUS every 6-12      months

== '''Primary surgery''' ==

* Indications:
** Anything resectable and not      meeting criteria for close observation
** Absence of prohibitive      comorbidities and with a life expectancy of more than a few years
* Unresectable if infiltration     of the coeliac trunk, SMA or portal vein
* R0 local resection, intact     capsule, negative microscopic margin. No role for lymphadenectomy. No     specific margin required, just R0.
* Be careful not to spill     tumour - will result in peritoneal seeding and recurrence in 100% of     patients
* Also tumours are very     vascular - can bleed a lot
* 70% of patients with tumours     >3cm were cured by surgery alone
* GISTs <2cm found     incidentally in surgical specimens do not require further treatment
* Choice of surgery
** Wide local excision
** Enucleation
** Sleeve gastrectomy
** Total gastrectomy
** With or without en bloc      resection of adjacent organs

== '''Surgery for metastases''' ==

* Consider in patients that had     a good response to neoadjuvant imatinib - predicts good response to     metastectomy
* Timing typically 6-9 months     after initiation of imatinib
* Consider RFA or hepatic     artery embolization for isolated liver metastases

== '''Chemotherapy''' ==

* Neoadjuvant
** Indications:
*** Locally advanced tumours       such that multi-visceral resection would be required
*** Non-metastatic but       borderline resectable disease
*** Limited metastatic disease       which might be resectable, to assess response
** Can be continued up until      the time of surgery
* Adjuvant
** Indications:
*** High-risk pathological       features on resection (see below)
*** Tumour spillage during       resection
** Approach:
*** Risk-stratify with AFIP
*** Consider molecular       genotyping to better characterise response to imatinib
**** Worse response in KIT exon        9 mutation, PDGFRA exon 18 mutation, and KIT/PDGFRA wild type)
*** Intermediate or high-risk:       imatinib three years
*** No, very low or low-risk       GIST: surveillance
** Imatinib (Gleevec) 400-800mg      PO daily (tyrosine kinase inhibitor that blocks the unregulated c-kit      tyrosine kinase)
*** Works best if a mutation in       KIT is present, but some patients with wild type KIT are still       sensitive, due to the similarities between KIT and PDGFR-alpha
*** 400mg normally, 400mg BD if       Exon 9 mutation is present
** Second-line - sunitinib or      regorafenib
** 3 years is the current      standard of care
** 3 years vs 5 years currently      being investigated, trial completion date 2028
* Palliative


== Prognosis ==

* Prognosticating calculators:
** AFIP model - most      commonly-used. Classify as no, low, intermediate or high risk.
** NIH/Fletcher critera -      incorporates tumour rupture
* Median survival >5 years     even in metastatic disease



'''AFIP prognostic model: Recurrence risk for gastrointestinal stromal tumors (GISTs) of the stomach, small intestine, and rectum by mitotic rate and tumor size'''
{| class="wikitable"
|'''Tumor size (cm)'''
|'''Risk of disease progression during long-term  follow-up by primary site'''
|
|
|
|-
|
|'''Gastric'''
|'''Jejunum/ileum*'''
|'''Duodenum'''
|'''Rectum'''
|-
|'''Mitotic rate¶ (HPF): ≤5/50'''
|
|
|
|
|-
|≤2
|No risk
|No risk
|No risk
|No risk
|-
|2 to 5
|Very low
|Low
|Low
|Low
|-
|5 to 10
|Low
|Intermediate
|Limited data
|Limited data
|-
|>10
|Intermediate
|High
|High
|High
|-
|'''Mitotic rate¶ (HPF): >5/50'''
|
|
|
|
|-
|≤2
|No riskΔ
|HighΔ
|Limited data
|High
|-
|2 to 5
|Intermediate
|High
|High
|High
|-
|>5
|High
|High
|High◊
|High◊
|}


'''AFIP prognostic model: progression-free survival for gastrointestinal stromal tumors (GISTs) of the stomach, small intestine, and rectum by mitotic rate and tumor size*'''
{| class="wikitable"
|'''Tumor size'''

'''(cm)'''
|'''Percent of patients progression free during  long-term follow-up by primary site'''
|
|
|
|-
|
|'''Gastric'''
|'''Jejunum/ileum'''
|'''Duodenum'''
|'''Rectum'''
|-
|'''Mitotic rate¶ (HPF): ≤5/50'''
|
|
|
|
|-
|≤2
|100
|100
|100
|100
|-
|2 to 5
|98.1
|95.7
|91.7
|91.5
|-
|5 to 10
|96.4
|76
|66*
|43*
|-
|>10
|88
|48
|
|
|-
|'''Mitotic rate¶ (HPF): >5/50'''
|
|
|
|
|-
|≤2
|100Δ
|50Δ
|–
|46
|-
|2 to 5
|84
|27
|50
|48
|-
|5 to 10
|45
|15
|14*
|29*
|-
|>10
|14
|10
|
|
|}


'''Modified NIH risk stratification criteria for GIST with rupture included'''
{| class="wikitable"
|'''Risk category'''
|'''Tumor size (cm)'''
|'''Mitotic index (per 50 HPFs)'''
|'''Primary tumor site'''
|-
|Very low risk
|<2.0
|≤5
|Any
|-
|Low risk
|2.1 to 5.0
|≤5
|Any
|-
|Intermediate risk
|2.1 to 5.0
|>5
|Gastric
|-
|
|<5.0
|6 to 10
|Any
|-
|
|5.1 to 10.0
|≤5
|Gastric
|-
|High risk
|Any
|Any
|Tumor rupture
|-
|
|>10 cm
|Any
|Any
|-
|
|Any
|>10
|Any
|-
|
|>5.0
|>5
|Any
|-
|
|2.1 to 5.0
|>5
|Nongastric
|-
|
|5.1 to 10.0
|≤5
|Nongastric
|}
[[Category:UGIS]]