Gastrointestinal Stromal Tumors

Gastrointestinal Stromal Tumors Aruna Kommareddy, M.D. Fellow, Hematology/Oncology Washington University School of Medicine Case Presentation: History • 58 year old male with H/O DM, HTN • Symptoms of fatigue, SOB with activity and dysphagia more to solids in Oct 2000. Was found to be anemic. • Referred to GI • Endoscopy on 11/11 00 revealed an esophageal ulcer Pathology • • • • Biopsy revealed GIST Strong positive for C-kit and CD 34 No mitotic activity Ulceration could imply malignant behavior, but limited specimen Radiology • CT chest and abdomen 11/11/00 :Thickening distal third of esophagus and small nodes in peri-esophageal space • PET scan 11/16/00: Moderately increased uptake in distal esophagus, otherwise normal Pathology • Esophagectomy in Dec 2000 • Gross: Mass 6.5x5.5x3.5 cm mass at the GE junction with an ulcer 1.3 cm on the mucosal surface • Microscopy: Spindle cell tumor, mitosis 5-25 per 10 HPF • Tumor involved esophagus and stomach • Negative nodes-4/4 • Based on size, mitotic count and mucosal invasion-malignant GIST History • • • • • Did well until June 02 Experienced weight loss EGD/biopsy – Gastric polyps, No GIST CT scan 8/02: Chest: Extensive mediastinal mass from the level of the aortic arch to lower chest, displacing trachea, bronchi and compressing left atrium, pericardial effusion • Abdomen: Diffuse intraabdominal metastases, lymphadenopathy, LUQ mass 12.7x6.0 cm, liver mass 3x4cm History • Early Sept 02: Orthostatic admitted to ICU for monitoring and R/O tamponade • Echo: moderate pericardial effusion, no tamponade • Esophagoscopy, broncoscopy and biopsyAtypical cells.?Mucinous neoplasm. No evidence of GIST • Biopsy of liver mass 9/02 : GIST • Was seen in ICU by Medical oncology…. GIST • Gastro Intestinal Stromal Tumors • Around 5,000 to 6,000 new cases each year • Tends to occur in middle aged persons with a slight male predilection • Occur throughout the GI tract Distribution • • • • • Stomach 50-60% Small bowel 20-30% Large bowel 10% Esophagus 5% Else where in abdomen 5% Symptoms • Symptoms depend on the site and size of the tumor • Include: – Abdominal pain – Dysphagia – Gastrointestinal bleeding – Symptoms of bowel obstruction – Small tumors may be asymptomatic Diagnosis • Light microscopy in conjunction with Immuno-histochemistry Light microscopy Spindle Epitheliod Mixed Human pathology, Vol 33, May 2002 Immunohistochemistry • Positive staining for CD117, a cell surface antigen on the extracellular domain of the KIT receptor • Positivity alone without a typical morphological appearance may be a false positive • < 2% of tumors are negative for CD 117 • Such tumors are labeled “Stromal cell neoplasm most consistent with GIST” • 60-70% of tumors are also positive for CD 34 Benign Vs Malignant • Features favoring benign lesions in general like: – – – – – Size less than 5 cm Low number of mitosis per HPF No mucosal invasion Low cellularity Low markers of cell proliferation • The above have shown to be associated with malignant behavior in some but not in other studies. • With prolonged follow up any GIST has the potential to behave in a malignant fashion. • 50% of primary localized tumors that are resected relapse after 5 years of follow up. Malignant Versus Benign Size Very Low risk Low risk Intermediate risk High risk <2 cm 2-5 cm <5 cm 5-10 cm  >5 cm >10 cm Any size Mitotic count <5/50 HPF <5/50 HPF 6-10/50 HPF <5/50 HPF >5/50 HPF  Any count >10/50 HPF Human pathology, Vol 33, May 2002 Disease specific survival and tumor size Ann Surg 231:51-57, 2000 Prognosis • The 5-year survival for malignant GIST varies widely and has been reported to be from 28 to 80%. • Median survival of patients in whom complete surgical resection is not possible is 10–23 months. • The median survival from the time of diagnosis of metastatic or recurrent disease has been reported from 12 to 19 months. History of GIST? • Until the late1960’s stromal tumors arising in the GI tract were referred to as smooth muscle neoplasms of the gastrointestinal tract. • Immuno-histochemistry in the 1980’s demonstrated that some of these tumors lacked features of smooth muscle differentiation, some had markers of neuronal differentiation and some had neither of the above markers. • This led to Mazur and clark to coin the general term “Gastrointestinal stromal tumors” to collectively refer a group of mesenchymal tumors of neurogenic or myogenic differentiation. History of GIST • In the 1990’s it was shown that a significant proportion (60-70%)of tumors showed CD 34 immunopositivity • But schwann cell and true smooth muscle cell neoplasms were also positive • Lots of confusion prevailed until late 1990,s… Discovery of Kit • In 1986 a new acute transforming feline retrovirus, the Hardy-Zuckerman 4 feline sarcoma virus (HZ4-FeSV) was isolated from a feline fibrosarcoma. • The viral genome of HZ4-FeSV contained a new oncogene that was designated v-kit • C-kit is the cellular homologue of the oncogene v-kit • It encodes a transmembrane tyrosine kinase receptor called kit. Nature 1988 Sep 1;335(6185):88-9 What is Kit? • Kit is a 145-KD glycoprotein • The kit receptor can be detected by immunohistochemical staining for CD117 • CD117 is an epitope on the extra-cellular domain of the Kit receptor • Steel factor (SLF), also known as stem-cell factor, is the ligand for Kit • Binding of SLF to Kit results in receptor homodimerization, activation of KIT tyrosine kinase activity, and resultant phosphorylation of a variety of substrates that serve as effectors of intracellular signal transduction. Kit Human pathology, Vol 33, May 2002 Kit and relationship to GIST • SCF-KIT interaction has been shown to be essential for development of melanocytes, erythrocytes, germ cells, mast cells and ICCs • Mice with mutations involving kit have cellular defects in hematopoiesis, melanogenesis and gametogenesis and also lack the network of interstitial cells of Cajal. • In 1995 it was shown that the interstitial cells of Cajal express the Kit receptor • Nature 1995 Jan 26;373(6512):347-9 Kit and relationship to GIST • Hirota et al investigated the mutational status of c-kit in mesenchymal tumors of the GI tract. • They examined 49 mesenchymal tumors that were diagnosed as gastrointestinal stromal tumors • 94% (46/49) of these expressed KIT. • 82% (40/49) were CD34-positive • 78% (38/49) were positive for both KIT and CD34 • Also demonstrated that ICC were positive for kit and CD 34. • They also demonstrated that mutations of c-kit resulted in gain of function of the enzymatic activity of the KIT tyrosine kinase Kit and GIST • Mutations of several different exons of the c-kit gene (exon 11 and rarely, exons 9 and 13 )can cause constitutive activation of the tyrosine kinase function of c-kit. • These mutations result in: – – – – Auto-phosphorylation of c-kit Ligand-independent tyrosine kinase activity Uncontrolled cell proliferation Stimulation of downstream signaling pathways Mutations Human pathology, Vol 33, May 2002 Are KIT mutations seen in benign and malignant tumors? • In a study evaluating KIT expression and activation • 48 GISTs : 10 benign • 10 borderline • 28 malignant • Immunohistochemical KIT expression was demonstrated in each case. • KIT mutations were found in 44 tumors (92%) • KIT mutations were identified in each of 10 histologically benign GISTs. • Cancer Research 61, 8118-8121, November 15, 2001 Gist and KIT and Imatinib • Since activation of Kit played a crucial role in the pathogenesis of GIST, inhibition of Kit would be therapeutic. • Imatinib was found to be an inhibitor not specific for ABL or the kinase domain of the BCR-ABL fusion protein. Preclinical experiments • A C-kit expressing human myeloid leukemia cell line, M-07e,was treated with STI 571 before stimulation with Steel factor (SLF) and STI 571 inhibited c-kit autophosphorylation. • The activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which had an activated mutant form of C-kit was tested. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. • Heinrich Blood, Vol. 96 No. 3 (August 1), 2000: pp. 925-932 Preclinical experiments • A human GIST cell line, (GIST882) which expressed an activating KIT mutation (K642E) leading to constitutive tyrosine phosphorylation was tested • Tyrosine phosphorylation was rapidly and completely abolished after incubating the cells with Imatinib. • GIST882 cells evidenced decreased proliferation and the onset of apoptotic cell death after prolonged incubation with Imatinib • Oncogene 2001;20:5054-5058 First patient to be treated with Imatinib • 54 year old female with metastatic GIST diagnosed in 1996 • Liver metastases and multiple small intra-abdominal metastases were excised in February 1998 and in September 1998 • Seven cycles of chemotherapy with doxorubicin, ifosfamide, and dacarbazine with no response • In March 1999 had bowel obstruction and on laparotomy had diffuse intraabdominal mets. • Received thalidomide and interferon with no response • Treatment with 400 mg Imatinib once daily was started in March 2000. • N. Engl. J. Med., 344: 1052-1056, 2001 PET scan 4 weeks later Phase II trial • A multicenter phase II trial of STI571 was initiated in July 2000 . • Patients with un-resectable or metastatic GIST were randomized to receive 400 or 600 mg of STI571 per day. • 147 patients were enrolled • Side effects: mild-to-moderate edema, diarrhea, and fatigue were common. • Gastrointestinal or intraabdominal hemorrhage occurred in approximately 5 percent of patients. There were no significant differences in toxic effects or response between the two doses. • 88 percent were alive one year after the initiation of treatment with Imatinib • NEJM Volume 347:472-480 August 15, 2002 Phase II trial cont • 86% of tumor specimens analyzed (72 patients) had activating mutations of KIT – 71% exon 11 – 14% exon 9 – 1% exon 17 • Patients whose tumor had no detectable KIT mutation were eight times more likely to have primary progression in response to STI571 (44%) compared with patients whose tumor expressed an exon 11 activating KIT mutation Questions • What is the right dosage? • Will neoadjuvant therapy improve outcome? • Will adjuvant therapy improve outcome? • What are the mechanisms of Imatinib resistance? • What are the treatment options for patients who progressed on Imatinib? Ongoing trials • North American Sarcoma intergroup study S0033 • Testing if 400 bid is better than 400 qd • Has closed after accruing 600 patients Ongoing Phase II Neo-adjuvant/ adjuvant trials • Patients with primary or recurrent potentially resectable malignant GIST • Treatment continues for 8 weeks in the absence of disease progression. • Patients with disease progression are considered for immediate surgical resection. • Otherwise, after 8 weeks, patients undergo surgical resection to debulk all gross tumor. • Two to four weeks after surgery, patients receive oral Imatinib once daily for 2 years. High Risk patients after surgical resection • Patients With Completely Resected High-Risk GIST • High-risk is defined as any of the following: – – – – – Tumor at least 10 cm in greatest dimension Presence of tumor rupture before or during surgery Intraperitoneal hemorrhage Multifocal intraperitoneal tumors Positive microscopic margins • Patients receive Imatinib daily beginning within 84 days of surgical resection. Treatment continues for 1 year in the absence of disease recurrence or unacceptable toxicity Phase III adjuvant therapy trials • Randomized phase III trial of patients who have primary GIST that has been completely removed by surgery. – Arm I: Patients receive imatinib once daily for 1 year. – If disease recurs during the year of initial treatment, dose of imatinib is increased. – Patients who develop a recurrence after the year of initial treatment restart imatinib and continue taking the drug for an additional year. – Arm II: Patients receive oral placebo once daily for 1 year. – Patients who develop a recurrence at any time discontinue placebo and crossover to arm I. Genetic predictors of response • Study of predictors of response to Imatinib mesylate in patients with metastatic or unresectable GIST – Identify KIT sequence alterations – Tumor cytogenetic abnormalities, responsible for case-to-case differences in therapeutic response to imatinib mesylate in patients with metastatic GIST Treatment options prior to Imatinib • Surgical resection of the primary tumor, followed by observation • Adjuvant therapy in high risk tumors was not beneficial • Radiation -limited by its potential toxicity to the surrounding tissues • Was used for positive margins in gastric or rectal GIST Chemotherapy HUMAN PATHOLOGY Volume 33, (May 2002) Peritoneal and Liver Mets • Removal of gross tumor followed by intraperitonial chemotherapy with cisplatin and doxorubicin or mitoxantrone. • In 27 patients with disease isolated to the peritoneum the median time to recurrence was increased from 8 months to 21 months with the addition of intraperitoneal mitoxantrone. • Intraperitoneal chemo for recurrent GIST is being tested in imatinib resistant tumors. • Hepatic artery embolization can be done for liver metastases Imatinib Resistance • Patients with resistant tumors are treated in the traditional way as mentioned previously What happened to our patient? • • • • • • • Started on imatinib on 9/20/02 Remarkable improvement of symptoms. With in 15 days did not require pain meds. Constipation resolved Energy level improved. Gained 30 pounds (Partly secondary to imatinib) Last seen on 3/10/03. Doing well clinically and radiologically • CT scan -11/02 :Fluid collections at sites of previous tumor representing liquefaction necrosis • CT 1/03: Decrease in size of the cystic fluid collections. CT chest before and after Structure of Imatinib (4-[(4-methyl-1-piperazinyl)methyl]-N-[4methyl-3-[{4-(3-pyridinyl)-2pyrimidinyl}amino] phenyl] benzamide methanesulfonate.