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Edit Comment Close Premium member Presentation Transcript Gastrointestinal Stromal Tumours(GIST) : Gastrointestinal Stromal Tumours(GIST) Dr. Rakesh kumar .A M.D.,(D.M) INTRODUCTION : INTRODUCTION Stromal or mesenchymal tumors of the GI tract are divided into two group 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 : EPIDEMIOLOGY Most common non epithelial benign neoplasm of the GI tract . GIST represents a form of sarcoma that comprises appr 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 : MOLECULAR PATHOBIOLOGY 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 : 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 Receptor Tyrosine Kinase Families : Receptor Tyrosine Kinase Families - The total number of PTKs does not exceed 1000 (human genome project). - Of the 91 protein tyrosine kinases identified thus far, 59 are receptor PTK and 32 are non-receptor PTK GIST and c-kit : 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) : 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 Approx 80 % of GISTs have KIT protooncogene mutations 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 Slide 9: 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? : 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 : LOCATION Stomach – 50 percent Small bowel – 25 percent Colon/ Rectum– 10 percent Omentum/mesentery 7 – percent Esophagus – 5 percent CELLULAR MORPHOLOGY : 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 : 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) Slide 14: H&E stain C-kit(CD117) Slide 15: ‘Spindle-cell’ tumor with High mitotic rate Slide 16: Epitheloid type Determinants of Malignant Behavior : Determinants of Malignant 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 Caveat: Even very small lesions (< 2 cm) with a low mitotic rate occasionally metastasize Metastasis : 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 : 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 : 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 : CT scan Endoscopy : Endoscopy Slide 25: PET scan and CT scans in a patient with a GIST metastatic to the liver, before (left) and after treatment with imatinib mesylate Management : 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 (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 Slide 28: 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 : 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 ADV. GIST MANAGEMENT OF UNRESECTABLE GIST : MANAGEMENT OF UNRESECTABLE GIST MANAGEMENT OF METASTATIC GIST : MANAGEMENT OF METASTATIC GIST The incidental (asymptomatic) UGI subepithelial mass : 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 Slide 34: 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 Adapted from: Hwang JH, Kimmey MB. Gastroenterology. 2004 Jan;126(1):301-7. Slide 35: Thank Q You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.
GIST rocky3415 Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: (To copy code, click on the text box) Embed: URL: Thumbnail: WordPress Embed Customize Embed The presentation is successfully added In Your Favorites. Views: 2774 Category: Science & Tech.. License: All Rights Reserved Like it (10) Dislike it (0) Added: October 29, 2009 This Presentation is Public Favorites: 0 Presentation Description No description available. Comments Posting comment... By: sachkasamna (15 month(s) ago) i need to download this presentation ..plz help Saving..... Post Reply Close Saving..... Edit Comment Close By: mkarichery (15 month(s) ago) nice ppt. is it poosible to download this one Saving..... Post Reply Close Saving..... Edit Comment Close Premium member Presentation Transcript Gastrointestinal Stromal Tumours(GIST) : Gastrointestinal Stromal Tumours(GIST) Dr. Rakesh kumar .A M.D.,(D.M) INTRODUCTION : INTRODUCTION Stromal or mesenchymal tumors of the GI tract are divided into two group 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 : EPIDEMIOLOGY Most common non epithelial benign neoplasm of the GI tract . GIST represents a form of sarcoma that comprises appr 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 : MOLECULAR PATHOBIOLOGY 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 : 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 Receptor Tyrosine Kinase Families : Receptor Tyrosine Kinase Families - The total number of PTKs does not exceed 1000 (human genome project). - Of the 91 protein tyrosine kinases identified thus far, 59 are receptor PTK and 32 are non-receptor PTK GIST and c-kit : 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) : 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 Approx 80 % of GISTs have KIT protooncogene mutations 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 Slide 9: 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? : 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 : LOCATION Stomach – 50 percent Small bowel – 25 percent Colon/ Rectum– 10 percent Omentum/mesentery 7 – percent Esophagus – 5 percent CELLULAR MORPHOLOGY : 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 : 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) Slide 14: H&E stain C-kit(CD117) Slide 15: ‘Spindle-cell’ tumor with High mitotic rate Slide 16: Epitheloid type Determinants of Malignant Behavior : Determinants of Malignant 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 Caveat: Even very small lesions (< 2 cm) with a low mitotic rate occasionally metastasize Metastasis : 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 : 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 : 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 : CT scan Endoscopy : Endoscopy Slide 25: PET scan and CT scans in a patient with a GIST metastatic to the liver, before (left) and after treatment with imatinib mesylate Management : 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 (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 Slide 28: 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 : 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 ADV. GIST MANAGEMENT OF UNRESECTABLE GIST : MANAGEMENT OF UNRESECTABLE GIST MANAGEMENT OF METASTATIC GIST : MANAGEMENT OF METASTATIC GIST The incidental (asymptomatic) UGI subepithelial mass : 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 Slide 34: 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 Adapted from: Hwang JH, Kimmey MB. Gastroenterology. 2004 Jan;126(1):301-7. Slide 35: Thank Q