Gastrointestinal Stromal Tumours(GIST)

INTRODUCTION :

• Stromal or mesenchymal tumors of the GI tract are divided into two groups:– 1. Those identical to tumors of the soft tissue arising in the

rest of the body (Lipomas, Schwannomas, Hemangiomas, Usual Leiomyomas, etc.)

– 2. Stromal tumors arising from the smooth muscle of the alimentary tract: GIST

• The term “GIST” was applied by Mazur and Clark in 1983 to define intra-abdominal tumors that were not carcinomas .

EPIDEMIOLOGY

• Most common non epithelial benign neoplasm of the GI tract .

• GIST represents a form of sarcoma that comprises approx. 1% to 3% of all malignant GI tumors.

• GIST occurs predominantly in adults .

• The incidence has been slightly higher in men than women.

• Small asymptomatic GISTs are found at autopsy in more than 50 % of individuals over the age of 50

• GIST treatment trials estimate an annual incidence of 4,500 – 6,000 new cases

MOLECULAR PATHOBIOLOGY GIST

• GIST represents a form of sarcoma.

• GISTs originally thought to derive from smooth muscle, but only rarely showed clear-cut features of complete muscle differentiation.

• Work in the 1990s: Some tumors classified as GIST were truly myogenic, some neural, others bidirectional and some had the ‘null’ phenotype

• Up to two-thirds were CD34 positive

• Unfortunately, Schwannomas and a proportion of true smooth muscle tumors were also CD 34 positive

ENTER :Membrane (Receptor) Tyrosine Kinase

• PTKs are involved in cellular signaling pathways and regulate key cell functions such as proliferation, differentiation, anti-apoptotic signaling and neurite outgrowth.

• Unregulated activation of these enzymes can lead to various forms of cancer as well as benign proliferative conditions.

•Nishida T, Hirota S, Taniguchi M, et al: Familial gastrointestinal stromal tumours with germline mutation of the KIT gene

GIST and C-kit

• The c-kit receptor is one of many membrane tyrosine kinase receptors involved in cellular signaling pathways.

• CD117 molecule (or antigen) is part of the c-kit receptor, a membrane tyrosine kinase.

• The c-kit receptor is a product of the c-kit or KIT protooncogene.

• The CD117 antigen is expressed by almost all GISTs in contrast to other spindle-cell tumors of the GI tract

UNCONTROLLED KINASE ACTIVATION (THE MOLECULAR

ETIOLOGY)

• In normal cells activation of the of the c-kit tyrosine kinase requires the presence of an endogenous ligand (KIT ligand, c-kit ligand, or stem cell factor)

• Approx 80 % of GISTs have KIT protooncogene mutations that lead to activation of the c-kit receptor resulting in spontaneous receptor activation not requiring a ligand

• Observed both in sporadic and hereditary cases • A subset of GISTs lacking c-kit mutations have activating

mutations in the PGFRa gene (platelet derived growth factor receptor alpha), another tyrosine kinase

GISTs are identified by:

• either c-kit immunoreactivity (detection of the CD117 antigen) or

• the presence of activating mutations in KIT or PDGFRa

Are GISTs derived from ICCs?

• Interstitial cells of Cajal (ICC) form the interface between the autonomic innervation of the bowel wall and the smooth muscle itself.

• The KIT RTK plays essential roles in the development and maintenance of normal ICCs .

• Ultrastructural and immunophenotypic features of both neuronal and smooth muscle differentiation (just like GISTs)

• It is postulated that GISTs originate from CD34 positive stem cells within the wall of the gut and differentiate toward the pacemaker cell phenotype (ICC)

• Malignant GISTs may represent dedifferentiated ICCs that maintain a CD34-positive stem cell phenotype

• Attractive hypothesis but still open to question

LOCATION : 

• Stomach – 50 percent

• Small bowel – 25 percent

• Colon/ Rectum– 10 percent

• Omentum/mesentery 7 – percent

• Esophagus – 5 percent

CELLULAR MORPHOLOGY

• Three relatively distinctive types– Spindle cell type – 70 percent – Epithelioid type – 20 percent, more commonly c-

kit negative and found in omentum and mesentery – Mixed type – 10 percent Histologic type may be

of prognostic significance, worse with epitheloid

HISTOPATHOLOGY

• Differential Diagnosis – H&E stain: Melanoma, leiomyoma/sarcoma, peripheral

nerve sheath tumor, desmoid – Histology difficult

– Immunophenotyping crucial • 95 % are positive for C-kit (CD117) • 60-70 % positive for CD34 • Negative for alpha-smooth muscle actin (SMA) (leiomyoma) • Negative for S100 protein (Schwannoma) • Negative for Desmin (desmoids)

H&E stain C-kit(CD 117)

Determinants of Malignant Determinants of Malignant Behavior Behavior

• Size: More than 3 cm in diameter(most malignant GISTs are larger than 10 cm at

diagnosis)

• Mitotic rate: > 25 mitoses per 50 high power fields

• Warning: Even very small lesions (< 2 cm) with a low mitotic rate occasionally metastasize

Approach for defining Risk of Aggressive Behavior in Gastrointestinal

Stromal Tumors

Metastasis

• GISTs behave differently than other soft tissue sarcomas: – GISTs frequently metastasize to the liver and

rarely to regional lymph nodes – GISTs virtually never metastasize to lungs whereas

this is the most common site of metastasis for leiomyosarcomas

CLINICAL MANIFESTATIONS

• Mesenchymal tumors of the GI tract are often asymptomatic and discovered incidentally during endoscopic or barium studies.

• Overt GI bleeding — 40 percent • Abdominal mass — 40 percent • Abdominal pain — 20 percent

– The vast majority of GIST metastases at presentation are intra-abdominal, either with metastases to the liver, omentum, or peritoneal cavity .

Diagnosis : 

• CT scan – Leiomyomas: solid hypodense lesions – GISTs: typically enhance with IV contrast

• Endoscopy • Smoothly contoured submucosal mass, possible

central umbilication

• EUS • Hypoechoic mass arising from muscularis propria

CT scan

Endoscopy

• PET scan and CT scans in a patient with a GIST metastatic to the liver, before (left) and after treatment with imatinib mesylate

Management :

• European Consensus Conference Recommendations (Meeting in Lugano Mar 2004) pub in Ann Oncol. 2005 Apr;16(4):566-78.

• NCCN Sarcoma Guideline (GIST chapter) updated in 2005

Imatinib (Gleevec) a Tyrosine Kinase Inhibitor

• Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase.

• Imatinib is also an inhibitor PDGF and c-kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in (GIST) cells, which express an activating c-kit mutation

Imatinib (Gleevec) a Tyrosine Kinase Inhibitor

• Imatinib (Gleevec) is very effective for CD114 positive GISTs

• It also has antitumor effficacy in tumors that lack KIT mutations but have alterations in the PDGF pathway

• Some PDGFRa mutations are imatinib-sensitive, others not therefore, patients with advanced tumors that are histologically c/w GIST should not be denied a trial of imatinib if they are c-kit negative.

Management

PRIMARY, LOCALIZED DISEASE (EARLY-STAGE GIST)

• Surgery remains the mainstay of treatment for patients with primary localized GIST

• GIST lesions are highly vascularized and often exhibit a fragile pseudocapsule; therefore, surgeons should be careful to minimize the risk of tumor rupture.

• GIST rarely involves the locoregional lymph nodes. • Adjuvant Therapy :At present, it is unclear whether the

administration of imatinib in the postresection adjuvant setting would confer significant clinical benefits on patients.

MANAGEMENT OF ADV. GIST

MANAGEMENT OF UNRESECTABLE GIST :

MANAGEMENT OF METASTATIC GIST : 

The incidental (asymptomatic) UGI subepithelial mass

• No firm clinical guidelines or consensus • Surface Endoscopy can establish a lipomatous nature of the

mass • If mass is > 1 cm referral for EUS, if < 1 cm repeat EGD in

one year, if stable probably no follow-up • If mass arises from muscle layer (4th EUS layer mass) and is

> 3 cm referral for surgery (likely GIST) • Clinical conundrum: The 1 - 3 cm mass • 4th layer mass should undergo EUS-FNA and c-kit staining • If a GIST is found discuss management strategies, esp.

surgery

• If results are indeterminate or patient does not wish (or is not a candidate for) resection, endoscopic follow up

• Recommendations depend on the age of the patient, index of suspicion, etc.

• One reasonable strategy: EUS follow-up a year later and if lesion is stable for two consecutive follow-up periods, lengthening of the follow-up period.