This document provides information on gastrointestinal stromal tumors (GISTs) including their definition, epidemiology, etiology, molecular pathogenesis, genetic classification, anatomy, pathology, screening, diagnosis, staging, prognostic factors, risk stratification, management of localized, advanced, inoperable, and metastatic disease, treatment with tyrosine kinase inhibitors, response evaluation, and follow up. GISTs are rare mesenchymal tumors of the GI tract that are driven by mutations in KIT or PDGFRA genes. Surgery is the main treatment for localized disease while advanced disease is treated with tyrosine kinase inhibitors.

2. • Definition
• Epidemiology
• Etiology
• Molecular Pathogenesis
• Genetic Classification
• Anatomy
• Pathology
• Screening
• Diagnosis
• Staging
• Prognostic Factors
• Risk Stratification
• Localised Disease
• Advanced/inoperable
• Metastatic
• TKI resistance
• Response Evaluation
• Follow Up

3. • Gastrointestinal stromal tumors (GIST) are mesenchymal
neoplasms of the gastrointestinal tract .
• The tumor cell’s normal counterpart
is the interstitial cell of Cajal.
• This serves as a pace-maker of
gastrointestinal motility,
providing an interface between
autonomic nerve stimulation and
the muscle layer of the gastro-
intestinal wall .

4. EPIDEMIOLOGY
• GISTs are rare cancers.
• Crude incidence -- approximately 1.5 out of 100,000 per year .
• Males > females.
• Median Age : 60 to 65 years.

5. ETIOLOGY
• Majority are sporadic
• No specific causes are known, although KIT- and PDGFRA-
mutations are seen in majority GISTs .
GIST
Sporadi
c
Familial
Pediatri
c

7. FAMILIAL GIST
• 5% of all cases
• Primary familial GIST syndrome
• Neurofibromatosis type 1 (NF1)
• Carney-stratakis syndrome/ Carney Stratakis dyad

9. PEDIATRIC GIST
• GISTs are rare in children or young adults,
• They have distinct clinical as well as molecular and pathologic
features in this patient population.
• M> F
• MC symptom : Chronic gastrointestinal bleeding
• MC Histology : Epitheloid
• Mostly tend to arise within defined syndromes, including the
Carney triad and Carney-Stratakis syndrome
• 85% of pediatric GISTs lack mutations in KIT or PDGFRA .

10. Most pediatric GISTs have loss of function of SDH family enzyme (SDHA,
SDHB, SDHC, or SDHD) due to a mutation in one of the SDH gene
subunits, and are hence often described as "SDH-deficient

11. MOLECULAR PATHOGENESIS
• GIST are a relatively heterogeneous and complex group of
lesions.
• KIT and PDGFRA they are the drivers of the disease .
• KIT and PDGFRA reside on chromosome 4q12 with both
genes encoding homologous transmembrane glycoproteins
• Gain-of-function mutations of these oncogenes can be found in
approximately 80% of GISTs.

12. • They are mutually exclusive and result in the constitutive
activation of either KIT or PDGFRA, which normally are
autoinhibited, being activated by the binding of their
respective ligands (i.e., stem-cell factor [Steel factor] and
platelet-derived growth factor A)
• The activation of the receptor binds two molecules of KIT or
PDGFRA (dimerization), giving rise to downstream oncogenic
signaling, which for both KIT and PDGFRA involves the
RAS/MAPK and the PI3K/AKT/mammalian target of
rapamycin (mTOR) pathways.

15. KIT

16. • Mutations can be deletions, insertions, and missense mutations.

17. EXON 11
• Most common KIT mutation
• Internal tandem duplication -- gastric GISTs that follow an
indolent course
• Deletions - aggressive clinical course with a higher risk of
recurrence and shorter survival.
• Exon 11 deletion involving codon 557 & 558 have poor disease
survival compared to other mutations.

18. Exon 9 :
• MC – duplications .
• small bowel involvement and a more clinically
aggressive neoplasm
Exon 13 & 17 :
• affect the tyrosine kinase domain
• less than 5% of sporadic GISTS .
• spindle cell morphology
• small bowel > stomach

19. PDGFRA
• 7% of GISTs harbor a mutation in PDGFRA
• MC – Stomach
• Epitheloid morphology
• MC - exon 18 affecting the TK2 domain
• PDGFRA JM domain (exon 12)– rare, can be point mutations,
deletions, or deletion insertions.
• PDGFRA exon 14 mutations are also typically missense mutations
that have been associated with a favorable clinical course

20. GENETIC CLASSIFICATION

21. GIST - Wildtype
• 10% to 15%
• They make up a family of tumor subsets with different
pathogenetic backgrounds and, to some extent, different
natural histories .
• Their classification :
• (1) SDH-deficient GISTs - young females.
(2) neurofibromatosis (NF)-1–related GISTs
(3) BRAF V600E mutation , etc

22. SDH DEFICIENT
• Half of WT GISTs are marked by alterations involving the
SDH complex, which is crucial for the Krebs cycle and
mitochondrial respiratory cell function.
• Immunohistochemically, these GIST are negative to SDHB
staining.

24. • GISTs + pulmonary chondromas + paragangliomas.
• These GIST arise in children and young adults of the female
sex.
• Location : gastric and multifocal
• They metastasize to lymph nodes, have a rather indolent
evolution.
• Given the absence of mutations to the SDH complex, a
posttranscriptional defect leading to dysfunctions of the SDH
complex may be in place.
CARNEY TRIAD

25. Carney-Stratakis syndrome
/Carney-Stratakis dyad
• GIST + paragangliomas
• The median age of these patients is somewhat higher and the
female to male predominance is lower, but the course of
disease is indolent as well.
• Autosomal dominant disorder with incomplete penetrance
• Germline mutations in one of the subunits of the SDH gene,
causing loss of function of one of the SDH enzymes (typically
SDHB, SDHC, or SDHD

26. Neurofibromatosis (NF)-1–related
GISTs
• WT SDHB-positive GISTs can occur in the context of NF-1
• Pathogenesis : the absence of neurofibromin (i.e., the product
of the NF-1 gene), which is mutated leading to increased
activity of the RAS pathway.
• GISTs related to NF-1 are typically multicentric as well, and
have a rather indolent course, but arise from the small bowel.
• Of course, NF-1 may coexist with a non–NF-1-related GISTs.

27. Others…
• V600E mutation of BRAF or
• More Rare : HRAS, NRAS, and PIK3 mutations.
• All this makes the so-called WT GISTs a variegated family of
tumors, which can now be identified not only through a
negative definition (i.e., by the lack of KIT and PDGFRA
mutations), but through immunohistochemical or cytogenetic
markers, pointing to specific subsets with different natural
histories.

28. ANATOMY :
• GIST – Location :
Stomach > 50%,
small bowel – 25%,
Rectum – 5%,
& small minority from the esophagus.
• Some are extragastrointestinal, arising from the mesentery,
omentum, and retroperitoneum.

29. PATHOLOGY
• GISTs can be made up of spindle cells (in more than two-thirds of
cases), epithelioid cells, or both .
• Epithelioid-cell GISTs are more common in the stomach and
include those that are PDGFRA mutated.

30. • There are no major clinical implications in the microscopic
aspect of lesions.
• No pathologic distinction between benign and malignant GIST
• All GISTs are currently considered malignant neoplasms,
although with a highly variable risk of distant relapse, which is
negligible in a significant proportion of them.
• Risk classification systems are used to prognosticate based
today on a pathologic factor (i.e., the mitotic count) and two
clinical variables (tumor size and tumor site)

31. IMMUNOHISTOCHEMISTRY
• Hallmark - positive for KIT (CD117) and DOG-1
• Some are CD117 negative, which is typical of PDGFRA-mutated
GISTs, but immunohistochemical status does not reflect the
mutational status with regard to KIT and PDGFRA, per se, so that it
has no concrete predictive value for sensitivity to TKIs.

33. • Given their morphology, GISTs must be differentiated from
other soft tissue tumors of the gastrointestinal wall, including
those of smooth muscle and neural origin and desmoid-type
fibromatosis, endocrine tumors, melanocytic tumors,
lymphomas, etc.
• Desmin is rarely positive, as opposed to vimentin and CD34.
• A negative stain for SDHB identifies the subgroup of SDH-
deficient WT GISTs

35. • Genotyping is important as it has obvious predictive value, which is
crucial for all patients who are candidates for medical therapy
• It also has prognostic implications, at least given the peculiar natural
history of WT GISTs.
• Genotyping also confirms the pathologic diagnosis in
KIT/PDGFRA-mutated GIST, or leads to further pathologic and
molecular assessments in WT GISTs.
• Thus, although there are subsets of GISTs with such a low risk of
relapse as not to make them candidates for any medical therapy, a
mutational analysis is currently a part of any pathologic diagnosis
of GISTs

36. SCREENING
• GISTs are rare cancers.
• Therefore, population-based screening policies cant be made
• The clinical aim should be a timely diagnosis in the individual
patient with symptoms and/or signs of disease.

37. DIAGNOSIS
• Many are diagnosed late due to the outward growth of many
GISTs within the gastrointestinal wall
• They present either as major abdominal masses or as causes of
gastrointestinal bleeding, hemoperitoneum, perforations .
Thus diagnosed as :
• 25% - clinical emergency – bleeding,perforation
• 25% - incidental diagnosis
• 25% - symptoms of compression from an abdominal mass, or
chronic anemia, fatigue, and the like
Therefore, GISTs should be included in the differential
diagnosis of abdominal masses.

38. IMAGING
• CT > MRI (except in rectal GIST)
• CT appearance : solid, smoothly contoured mass that enhances
brightly with intravenous contrast.
• Very large tumors (>15 cm) may appear more complex due to
necrosis, hemorrhage, or degenerating components .

39. UGIE & EUS
• Central ulceration is occasionally seen.
• Endoscopic ultrasonography (EUS) helps to identify the layer
of origin and for guided biopsy.
• Endosonographically - GISTs are typically hypoechoic,
homogeneous lesions with well-defined margins, although
they can rarely have irregular margins and ulcerations.
• UGIE -- GIST appears as submucosal mass
with smooth margins, with a normal
overlying mucosa, and bulging into the
gastric lumen .

40. PREOPERATIVE BIOPSY
• Generally not done –
 Tumor seedling
 Bleeding
• Endoscopic biopsy :
 Less bleeding
 Metastatic disease
 If neoadjuvant imatinib planned.

41. PET CT
• The reported sensitivity of PET for GIST (including
metastatic lesions) is 86 to 100 percent.
• FDG-PET helps to detect early response to a tyrosine
kinase inhibitor, which may be important when
treatment is administered in the neoadjuvant setting.

42. Differential Diagnosis

43. STAGING
• Conventional stage classification is seldom used .
• Clinicians mainly distinguish localized from metastatic disease
and, if the disease is localized and amenable to complete
surgery, quantify the risk of relapse .
• If localised , risk stratification helps to plan further treatment
• Current risk classification systems are based on the
combination of mitotic count, tumor size, and site of origin.

44. • Advanced GISTs usually initially extends to the peritoneum
and/or the liver.
• Lung metastases are rare, except in rectal GISTs.
• CT chest and abdomen is done as routine staging procedure in
advanced GIST
• Bone metastases are possible, but they are usually confined to the
very advanced stages of disease, so that the skeleton is not
routinely assessed in the lack of symptoms.
• Lymph node regional metastases are not typical of GISTs, except
in WT GISTs occurring in children and/or within syndromes.

45. PROGNOSTIC FACTORS
• Large tumor size
• High mitotic counts
• Non-gastric location
• Presence of rupture
• Male sex

46. Mitotic count :
• Main prognostic factor, proportionally correlating to the risk of
relapse.
• Problem : less reproducible
Tumor size :
• Very small gastric lesions (<2 cm) - watchful surveillance if
incidentally discovered endoscopically
• Lesions > 5 to 10 cm -- worse prognosis.
Site Of Origin :
• Gastric lesions have a better prognosis than small bowel and
rectal GISTs.
RISK STRATIFICATION

48. • Armed Forces Institute of Pathology (AFIP) risk classification
• The Memorial Sloan Kettering Cancer Center (MSKCC)
nomogram
• The contour maps.
• NIH
RISK STRATIFICATION TOOLS

49. Modified NIH Criteria

50. MANAGEMENT

51. Localized
Localized ,
Inoperable
Metastatic
Surgery +/- Adj Rx
Medical Rx Surgery 
Adj Rx
Medical Therapy With
TKI

52. SURGERY
• If disease is localized, surgery is the treatment mainstay.
• All GISTs ≥2 cm in size should be resected.
• 1-2cm, either observation or resection.
• Regardless of their size, any small GIST that is symptomatic
(e.g., bleeding from erosions through the mucosa) or increases
in size on serial follow-up should be resected

53. NCCN – Gastric GIST
• Complete surgical resection is recommended for small gastric
GIST <2 cm at high risk of recurrence based upon EUS
appearance such as :
 Irregular borders
 Cystic spaces
 Ulceration
 Echogenic foci
 Heterogeneity in appearance

54. PRINCIPLES OF SURGERY
• Goal : Complete gross resection with an intact pseudocapsule
• Surgery usually is a wedge or segmental resection of the
involved gastric or intestinal tract
• On laparotomy/laparoscopy, the abdomen should be
thoroughly explored to identify and remove any previously
undetected peritoneal metastatic deposits.
• A lymphadenectomy is not routinely required.

55. • Extensive resection may be required as in total gastrectomy for a large
proximal gastric GIST, pancreaticoduodenectomy for a periampullary
GIST, or abdominoperineal resection for a low rectal GIST
• Tumor rupture or violation of the tumor capsule during surgery are
associated with a very high risk of recurrence, and therefore should be
avoided.
Syndromic GIST :
• Tumors are often multifocal
• The extent of surgery should be decided on a case-by-case basis,
taking into account the risk of recurrence, the lack of benefit from
currently available TKIs, and the actual behavior of the underlying
disease

56. MEDICAL MANAGEMENT
• Small molecule tyrosine kinase inhibitors (tkis)
• Prototype : imatinib.
• These agents block signaling
via KIT and PDGFRA by
binding to the adenosine
triphosphate-binding pocket
required for phosphorylation
and activation of the receptor.
The end result is inhibition of
tumor proliferation.

58. NEO ADJUVANT IMATINIB
• Preoperative imatinib can shrink gastric, periampullary, or
rectal GISTs to such an extent as to allow more limited
excisions.
• Imatinib can then be continued postoperatively to complete the
adjuvant treatment
• Thus, if extensive surgery is required for complete tumor
removal, preoperative imatinib should be considered

59. • It is not given in patients with platelet-derived growth factor
receptor-alpha (PDGFRA) D842V mutation, or a succinate
dehydrogenase (SDH)-deficient or neurofibromatosis (NF)-
related GIST, and instead proceed directly to surgery.
• Usual dose - imatinib is 400 mg daily.
• Exon 9 KIT mutation - 800 mg per day
• Optimal duration -- "maximal response," usually not
exceeding 10 to 12 months

61. ADJUVANT IMATINIB
• It depends on the risk of recurrence.
• Adjuvant imatinib for those patients who meet criteria for "high-
risk" and who have an estimated risk of recurrence that is >30 to
50 %

63. • The primary endpoint was RFS.

65. • Optimal Duration ???
• Patient Subsets – Who will get maximum benefit ???
• Patients with GIST of more than 3 cm are a highly
heterogeneous population
• The risk of relapse is just not dependent on size alone, but also
by mitotic index, location of the primary site, and molecular
factors.
Imatinib was given accelerated approval in the
United States in 2008 for adjuvant treatment of
completely resected GISTs ≥3 cm in size

66. EORTC 62024

67. • 908 patients with intermediate- or high-risk GIST.
• The primary endpoint was originally overall survival, but the
protocol was modified in 2009 to change the primary endpoint
to imatinib failure-free survival (IFFS, the time to death or
starting a TKI other than imatinib)
• At a median follow-up of 4.7 years :
IMATINIB CONTROL
5 yr IFFS 87% 84%
3 yr RFS 84% 66%
5 yr OS 100% 99%

68. Imatinib Duration ??
• SSG XVIII trial — The Scandinavian Sarcoma Group (SSG)
XVIII trial
• compared 36 versus 12 months of adjuvant imatinib (400 mg
daily) in 400 patients with high-risk resected GIST [23]. High-
risk was defined according to the modified consensus criteria
[24] as having at least one of the following: tumor size >10
cm, mitotic count >10 per 50 high-power fields (HPF), tumor
size >5 cm with mitotic rate >5/HPF, or tumor rupture.

70. • At a median follow-up of 54 months :
• Prolonged treatment was associated with a significant
improvement in RFS
3 yr IMATINIB 1 yr IMATINIB
5 yr RFS 66% 48%
5 yr OS 92% 82%
90months RFS 71% 52%
90months OS 92% 85%
Side Effects :
Periorbital edema
Diarrhea
Muscle cramps
74%
54%
49%
59%
44%
31%
• However, most were grade 1 or 2; the number of grade 3 or 4
events was similar in both groups.

71. • However, within 6 to 12 months of discontinuing adjuvant
imatinib, rates of disease recurrence were similarly increased
A multivariate analysis of data from the SSG XVIII trial : four
factors predictive of disease recurrence :
• Non-gastric location
• High mitotic count
• Tumor rupture
• Large size
Standard : 36
months of Imatinib
in high risk GIST

72. IMPACT OF MOLECULAR
SUBTYPES – SSG XVIII
• Patients with KIT exon 11 deletion or insertion-deletion mutations
had better RFS when allocated to three years of therapy (five-year
RFS 71 versus 41 percent),
• KIT exon 11 deletion mutations, deletions that involved codons 557
and/or 558 , and deletions that led to pTrp557_Lys558del were
associated with poor RFS in the one-year group but not in the three-
year group.
• In addition, in the subset with KIT exon 11 deletion mutations,
tumors with mitotic counts that were higher than the median had
unfavorable RFS with one year of therapy but not in the three-year
group

73. • Molecular analysis on all tumors should be done
• Recommended dose of imatinib is- 400 mg daily
• Exon 9 mutations – 800mg can be given.
• Adjuvant imatinib is not indicated in patients with succinate
dehydrogenase (SDH)-deficient GIST, neurofibromatosis (NF)-
related GIST, and PDGFRA D842V GIST.
• Duration : 36 months or longer is preferred over shorter
treatment durations.
• For all patients undergoing neoadjuvant imatinib, imatinib
should be continued postoperatively to complete a total of at
least three years of imatinib therapy (combined preoperative and
postoperative)

74. • Rates of disease recurrence is high within 6 to 12 months of
discontinuing adjuvant imatinib for up to three years.
• Thus it is possible that imatinib is maintaining tumor
dormancy rather than eradicating microdeposits.
• So further continuation of imatinib beyond 3yrs is being
studied.

75. METASTATIC GIST
• While TKIs control tumor growth in over 80 percent of
patients, complete responses are only rarely achieved, and
surgical resection remains the only potentially curative therapy
for GIST.
• Most patients who initially respond to upfront imatinib
eventually acquire resistance via additional mutations in the
KIT gene.
• The median time to progression is approximately two years

76. Based on retrospective studies :
• Resection benefits responding patients (ie, those who have a
partial response, stable disease, or focal progression)
• Resection, even if complete, does not eliminate the need for
continued treatment with a TKI therapy.
• Progression-free survival is significantly shorter in patients
who discontinue imatinib as compared with those who
continue the drug after resection

77. Surgery – Metastatic Disease
• Surgery of metastatic residual responding disease can be used
when reasonably feasible, but its added value prognostically is
unproven.
• When imatinib fails and/ or is ineffective, other available TKIs
and judicious use of surgery of limited progression are resorted
to .
• This treatment strategy has substantially improved the
prognosis of advanced GIST patients by increasing median
survival in terms of years.

78. IMATINIB
• It is the first line standard
• GISTs with exon 11 KIT mutations have shown the best imatinib
response rates.
• In exon 9 mutations : 800mg dose is recommended
• In the metastatic setting, treatment with imatinib should be
continued indefinitely, since treatment interruption is generally
followed by relatively rapid tumour progression, even when lesions
have been previously surgically excised

83. PRIMARY RESISTANCE
• No response to therapy or early progression within 6 months
of therapy.
• Tumours with no KIT mutation or those with a PDGFRA
D842V mutation were less likely to have a favorable or a
sustained response to imatinib.
• The D842V mutation is insensitivite to available TKIs, along
with a few other rare exon 18 mutations, whereas the deletion
of codons 842 to 845 is sensitive.

84. SECONDARY RESISTANCE
• Secondary resistance is the limiting factor of imatinib, with a
median time to the event averaging 2 years in the frontline
advanced setting.
• It is due to :
 Occurrence of new mutations to the same primarily mutated
oncogene, or, less frequently, oncogene amplifications or
alterations of alternative pathways
 Changes of the pharmacokinetics of the drug.

85. • Secondary mutations in KIT-mutated GISTs are relatively
limited in number, affecting exons 13 and 14, which encode
the ATP-binding pocket, or exons 17 and 18, which encode the
activation loop.

86. SUNITINIB
• Inhibits - KIT and PDGFRA but also displays antiangiogenic
activity by the inhibition of vascular endothelial growth factor
receptor (VEGFR)1, 2, and 3.
• It was effective at increasing progression-free survival by 5
months in a randomized trial versus placebo in patients failing
(or intolerant) to imatinib.
• Its molecular profile is such as to include activity on exon 9
KIT mutations as well as on secondary mutations of regions
coding for the ATP- binding pocket, thus potentially covering
mutations which are, respectively, less affected or not affected
by imatinib

87. REGORAFENIB
• Regorafenib,is another TKI with activity on KIT and PDGFRA
as well as VEGFR1, 2, and 3, and thus with antiangiogenic
properties, is standard third-line therapy for advanced GIST
patients.
• It is effective as a third-line therapy in patients failing both
imatinib and sunitinib, by providing a median advantage of 4
months of progression-free survival over placebo in a
randomized clinical trial

91. RESPONSE EVALUATION

92. CT & MRI
• There is decrease in density of responding lesions, with
decreased contrast enhancement
• CT scans and MRI detect actual changes in the tumor tissue,
which correspond to pathologic signs of tumor response. These
were found to take shape in terms of a myxoid degeneration
widely affecting responding tumor lesions, with signs of
apoptosis
• MRI – MRI, it entails an hypointense signaling on T1-
weighted images and hyperintense on T2-weighted images,
and decreased contrast enhancement.

93. FOLLOW UP
• The maximum risk interval averages 2 to 3 years after surgery
or, if an adjuvant therapy was done, after its completion.
• Local relapses are infrequent and tend to develop outwards
from the gastrointestinal wall: therefore, an endoscopy is
generally not used as a routine follow-up procedure.
• A CT scan is the most sensitive exam to pick up peritoneal and
liver metastases and is recommended.
• It can be replaced by magnetic resonance imaging (MRI),
while ultrasound is much less sensitive on the peritoneum.

94. FOLLOW UP - NCCN
For a completely resected GIST :
• History and physical examination every three to six months for
five years, then annually.
• A computed tomography (CT) scan is recommended every
three to six months for three to five years, then annually.
• More locally advanced or metastatic disease who are receiving
imatinib, history and physical examination, laboratory studies ,
as well as abdominopelvic ct scan are recommended every
three to six months.

95. ESMO – Adjuvant Follow up
• High Risk : cross-sectional imaging every six months during
adjuvant imatinib, every three to four months during the two
years that follow treatment discontinuation, where the risk of
disease recurrence is highest, then at 6 to 12 month intervals to
complete 10 years of follow-up.
• For very low-risk cases, every-other-year scanning seems
reasonable.