Gastrointestinal Stromal Tumors (GISTs)

Dr ganesh

GISTs
Originally classified as other tumors: leiomyoma,
leiomyoblastoma, leiomyosarcoma or schwannomas

1998- the discovery of gain-of-function mutations in

the c-KIT proto-oncogene in GISTs that allowed GISTs to be distinguished reliably from these other histopathological subtypes of GI tumors

GISTs
The most common mesenchymal neoplasm of the GI tract. 1%-3% of GI malignant tumors Recently described as a distinct clinical and histopathological entity: Type of sarcoma, a tumor of mesenchymal (connective tissue) origin

Epidemiology
4000-6000 new cases in the USA each year with annual incidence of 11-14 per 106 Occur mostly in patients with a median age of 60 years (40-80) No predilection for either gender Familial GISTs- autosomal dominant Type I neurofibromatosis (7% mostly in the small intestine without KIT mutations) Carney triad (GISTs + paraganglioma +pulmonary chondroma)

The KIT revolution

c-KIT (CD117), a type III receptor tyrosine kinase (RTK) that is involved in the development and maintenance of RBC, mast cells, melanocytes, germ cells and interstitial cells of Cajal (ICC). Loss of function KIT mutations result in anemia, loss of mast cells, white coat spotting due to failure of migration of dermal melanocytes, sterility due to a block in gametogenesis and gastrointestinal abnormalities due to loss of ICC.

GIST: Involved Sites

Occurs anywhere in GI tract/abdomen

Site
Gastric

Incidence %
60-70

Small intestine
Colon Other (omentum, mesentery, esophagus)

20-30
<5 <5

Clinical Presentation
Often asymptomatic, especially early in tumor
development, discovered incidentally by CT or endoscopy

Symptomatic:

Signs/symptoms related to location of tumor

Vague GI pain or discomfort

GI hemorrhage
Anorexia, weight loss, nausea, anemia, and
additional GI complaints

Diagnostic studies
CT for initial evaluation and surveillance for recurrence
EUS determines size and extent of the tumor FDG-PET reveals small metastases and establish baseline metabolic activity and assess therapy response Routine use of PET for surveillance after resection is not yet recommended

Histopathology of GIST: Biological Markers Used in Diagnosis of GIST

GISTs positive for

CD117 (c-Kit receptor tyrosine kinase)

Positive in >95%

CD34 (mesenchymal/haematopoietic precursor cell marker)

Positive in 60% to 70%

Vimentin and smooth muscle actin

Positive in 15% to 60% DOG1

Desmin S-100 (rare- in small intestine 10%) Keratin (rare 10%)

CD117 (c-Kit)positive staining GIST

The need for a biopsy is debatable

FNA- cytologic morphology immunohistochemistry PCR analysis for KIT mutations FNA- not consistently diagnostic FNA- controversial due to risk of rupture and dissemination Resectable lesion in the absence of metastatic diseasea preoperative diagnosis may be unnecessary If diagnosis would impact the extent of resection or if unresectable or metastatic disease is present , biopsy is warrant Biopsy should be open or by endoscopy and not percutaneous

GIST
GIST The cellular morphology of GISTs ranges from 1.) Spindle cell type 70 percent 2.) Epithelioid type 20 percent 3.) Mixed type 10 percent

Staging
Tx -can not be assessed T0 no evidence of primary tumor T1 2 cm T2 >2 cm but 5cm T3 >5 cm but 10cm T4 >10 cm

Regional node
Nx- can not be assessed N0 - no nodal mets N1 regional node mets

metastasis
M0 no metastasis M1 distant metastasis

Traditional Treatment Options Pre-Imatinib Mesylate (Glivec)

Surgery is primary treatment modality for GISTs 5-year survival 50% to 65% Recurrence have been reported up to 20 years after
surgery

If incomplete resection/metastatic at presentation Median survival <1 year 5-year survival <35%

Treatment
Surgery remain primary Rx of GIST of any location Simple wedge resection is favoured For tumors of lesser curvature segmental resection to prevent luminal narrowing A resection margin of 1-2 cms sufficient Routine lymphedenectomy not recomended

Conclusions
Surgery in M1 patients still an individual decision. No data from randomized or prospectively controlled yet available Residual tumor resection is safe Resection of progressive tumor is less rewarding Multifocal resection is not recommended without considering the patients personal situation Our experience with systemic therapy is: it more often avoids emergency surgery

 Therapy revolutionised by develoment of TK1 inhibitors like imatinib & sunitinib. Neoadjuant chemo : decrease extent of resection required, diminish the vascularity of tumor, R0 resection feassible <5% develop progressive ds during neoadjuant therapy

Resistance to Imatinib
Primary resistance : no achievement of stable disease or

progressing disease within 6 months of an initial clinical response (KIT exon 9 mutation or no detectable kinase mutation wild-type tumors)
Secondary resistance: disease progression after more than 6

months clinical response (new acquired kinase mutation in KIT or PDGF-R that interfere with Imatinib activity) Dose escalation of imatinib is the first step Use of other kinase inhibitors (Sunitinib) Surgery, radiofrequency ablation or hepatic artery chemoembolisation

SUTENT (Sunitinib Malate) Capsules

Thank you