Clinical Oncology and therapeutics.

1. Gastrointestinal Stromal
Tumors
April 21st 2017
Presenter:
Dr. Sarthak Moharir
PGY1,Dept. Of Radiotherapy

2. Brief
 Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms of the
gastrointestinal tract
 Normal counterpart is the interstitial cell of Cajal. (pacemaker cells)
 In the 2000s, they became targetable by new tyrosine-kinase inhibitors (TKI), given the
role played by KIT and platelet-derived growth factor receptor alpha (PDGFRA) in their
pathogenesis.
 From the clinical point of view, surgery is the mainstay treatment when GISTs are
localized.
 adjuvant therapy is used depending on their risk of relapse.
 GISTs can occur at any age, with a median occurrence at 60 years to 65 years. A small
minority of GISTs affect children and adolescents: most of them are WT for KIT and
PDGFRA and may take place within selected syndromes.

3. Genetics Of GISTs
 Pathogenesis: KIT- and PDGFRA-mutations (>80%): gain of
function.
 A little more than 5-10% are Wild Type GISTs (Non-mutated
KIT/PDGFRA)
 Gain-of-function mutations of the oncogenes located on
chromosome 4 (4q12) coding for the type III receptor tyrosine
kinases KIT and PDGFRA.

4.  They are mutually exclusive and result in the constitutive activation of either
KIT or PDGFRA, Which are normally autoinhibited.
 predisposing conditions for WT GISTs, which include the Carney triad
(marked by GIST, pulmonary chondromas, and extra-adrenal
paragangliomas), the hereditary Carney-Stratakis syndrome (marked by
GIST and familial paragangliomas), and type 1 neurofibromatosis (NF-1).
 Hereditary syndromes driven by germ-line mutations to KIT or PDGFRA are
very rare but well recognized.
Genetics Of GISTs

5. Clinical Behaviour and Natural History
 >50% of GIST cases arise from the stomach, 25% from the small
bowel, 5% from the rectum, A small minority from the esophagus.
 Some GISTs have been labeled as extragastrointestinal, apparently
arising from the mesentery, omentum, and retroperitoneum ( It is
Unclear whether these are metastasis or true extra-intestinal primaries)
 Main sites of spread is the peritoneum. Regional Lymph node extension
is rare.

6.  Tumors larger than 2 cm have a higher risk of recurrence and
metastasis. This risk increases significantly for tumors larger than
3 cm to 5 cm.
 GISTs with five or more mitoses per 50 high-powered field (HPF)
have a worse prognosis, whereas mitotic rates higher than 10 per
50 HPF predicts high recurrence and metastatic rates regardless
of tumor size or location, with 5-year survival rates ~25%.
 The tumor site also plays an important role in prognosis, with
jejunal and ileal GISTs displaying more malignant behavior
compared to duodenal, rectal, or gastric GISTs.
Clinical Behaviour and Natural History

7. Pathology
 GISTs can be made up of spindle cells (in more than two-
thirds of cases), epithelioid cells, or both.
 Aside from the PDGFRA mutated epitheloid cell GISTs,
there is no clinical implication of the histopthology.
 There are no pathologic features to make a distinction
between malignant GISTs and clinically benign lesions.
 Currently, all GISTs are considered to be malignant, with a
HIGHLY variable risk of distant relapse.

8. Clinical Features
 GISTs tend to grow outward into the GI wall.
 They are diagnosed late because of the lack of
obstructive symptoms. Diagnosis is made after as
major abdominal masses or as causes of
gastrointestinal bleeding, hemoperitoneum,
perforations, etc.
 one-fourth of GISTs are diagnosed in a clinical
emergency, often leading to surgical explorations
resulting in the unexpected finding of the disease.
 One-fourth of GISTs are discovered incidentally during
diagnostic assessments (Endoscopy, USG, or CT
scan) done for other reasons.
 remaining are diagnosed because of symptoms of
compression from an abdominal mass, or chronic
anemia, fatigue, etc.

9. Diagnosis
 GISTs must be included in the differential of any abdominal mass.
 When the pertinence of the tumor to the GI wall is made clear, the possibility of
a GIST is obvious.
 Differential diagnosis for the same may include: Epithelial tumors, small bowel
endocrine tumors, lymphomas, paragangliomas, etc. retroperitoneal sarcomas
and desmoid-type fibromatosis, germ cell tumors, and lymphomas are the main
alternatives.
 A diagnostic core needle biopsy can be done, allowing pathologic diagnosis
and, in the case of GIST, a mutational analysis, prior to any surgical
exploration. The risk of perforation(especially for gastric lesions), leading to
tumor spillage must be factored in.
 Biopsy may be Endoscopic USG guided, or CT guided.

10. Diagnostic Work Up
 The natural history of advanced GISTs is marked by their potential extension to
the peritoneum and/or the liver. Thus, a CT Abdomen is the staging procedure
of choice to rule out metastatic disease to the peritoneum/liver.
 Metastasis to lungs, bone etc. occur in very advanced cases and investigations
for the same are not routinely required. Assessed via CT Thorax and Bone
scan.
 Lymph node regional metastases are not typical of GISTs, as for mesenchymal
tumors in general, with the exception of WT GISTs occurring in children and/or
within syndromes.
 All syndromic GISTs are to be considered as multifocal and multicentric.

11. Staging
 Conventional staging is seldom used in clinical practice and management.
 On a working basis, Localised disease must be differentiated from metastatic
disease, and the risk of recurrance/relapse must be quantified.

12.  Current risk classification systems are based on the combination of mitotic
count, tumor size, and site of origin. The combination of these three factors
allows one to forecast a risk of relapse
 Mitotic count is the main prognostic factor, proportionally correlating to the
risk of relapse.
 Tumor size is the next prognostic factor. On one side, it singles out very small
gastric lesions (<2 cm), which may undergo watchful surveillance if incidentally
discovered endoscopically. On the other, it highlights lesions in excess of 5 to
10 cm, which have a worse prognosis.
 With regard to the Primary Site, gastric lesions have a better prognosis than
small bowel and rectal GISTs.
Staging

13. TNM STAGING
TX Primary cannot be assesed.
T0 No evidence of primary tumor
T1 Tumor <2cm
T2 Tumor >2cm but <5cm
T3 Tumor >5 cm but <10 cm
T4 Tumor >10cm in greatest
dimension
N0 No regional lymph
node metastasis
N1 Regional lymph node
metastasis
M0 No distant metastasis
M1 Distant metastasis

14. Management
 Localized GISTs with no evidence of distant metastases are treated with
surgery, followed by adjuvant medical therapy if the risk of relapse is
significant.
 All GISTs ≥2 cm in size should be resected when possible, because none of
them can be considered benign.
 When surgery is unfeasible or could be made easier through downsizing,
medical therapy is used if the genotype is sensitive to Imatinib(KIT/PDGFRA
mutation ++) followed by surgery and the completion of a medical adjuvant
treatment.
 When the disease is metastatic, medical therapy with TKIs is standard
treatment and should be maintained indefinitely.

15. Management
 TUMORS <2CMS: Both observation and resection for GISTs 1 to 2 cm can be
considered, after discussion with the patient. The endoscopic resection of
small gastric GISTs could be an option in these presentations (with a risk of
perforation).
 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.
 When the disease is metastatic or locally advanced, medical therapy is the
best choice and is currently based on imatinib continued indefinitely.

16. Principles of surgical management
 When the disease is metastatic, medical therapy with TKIs is standard treatment and
should be maintained indefinitely.
 Surgery 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.
 The goal of surgery is R0 excision. R0 or R1 resections are associated with better
prognosis than an R2 excision.
 local relapse after R0 surgery is very unlikely in GISTs.
 Tumor rupture or violation of the tumor capsule during surgery are associated with a
very high risk of recurrence, and therefore should be avoided.
 Lymphadenectomy is not routinely required, because lymph nodes are rarely involved
(in adult patients) and are thus resected only when they are clinically suspect.

17.  Adjuvant medical therapy with imatinib
was demonstrated to substantially
improve relapse-free intervals, although
with a trend to lose the benefit in a time
span of 1 to 3 years from the end of
therapy.
 Adjuvant therapy with TKIs can delay, but
probably not avoid, a relapse, if this is due
to occur.
 Extensive resection can be avoided if
Imatinib therapy is used pre-operatively
for the downstaging of the tumor.
Adjuvant Therapy

18.  Preoperative imatinib can shrink gastric, periampullary,
or rectal GISTs to such an extent as to allow more
limited excisions (wedge gastrectomy, excision of
periampullary lesions, transanal/perineal resection of
rectal GISTs, respectively), and imatinib can then be
continued postoperatively to complete the adjuvant
treatment.
 Duration of pre-operative medical therapy is generally
6 to 12 months, which corresponds to the time interval
when the maximum degree of tumor shrinkage was
shown to occur in studies on advanced GISTs

19. Secondary Resistance and 2nd / 3rd line
therapeautics
 Standard second-line therapy is sunitinib, which is a TKI inhibiting KIT and
PDGFRA but also displaying antiangiogenic activity by the inhibition of vascular
endothelial growth factor receptor (VEGFR)1, 2, and 3.
 Effective at increasing progression-free survival by 5 months in a randomized
trial versus placebo in patients failing (or intolerant) to imatinib.
 For third line therapy, agents with a mechanism of action other than imatinib,
sunitinib, and regorafenib try to address the limiting factor of the
heterogeneous nature of secondary resistance.

20. Assessment of Tumor Response
After starting an effective TKI, a symptomatic patient may
well feel a clear degree of subjective mprovement, in just a
matter of days.
 IMAGING: Positron-emission tomography (PET) scans are
useful in assessment, because they can demonstrate
tumor responsiveness in a matter of weeks.
 A positive PET scan may turn negative in a few days.
 This does not correspond to the disappearance of the
tumor lesion, but rather be the consequence of the
metabolic switch off that the tumor undergoes when an
effective TKI targets its cells
 when a PET scan has become negative, the tumor lesion
will not be visible to functional imaging, so that a CT scan,
MRI, or ultrasounds need to be used in order to evaluate
the evolution of tumor lesions.

22. Thank you