GIST can develop anywhere along the GI tract, from the esophagus to the rectum; however, Gastric (50%), small-intestine (25%), and colorectal (10%) GIST are most common. Only 15% of GIST are found in the esophagus, mesentery, or omentum. Depending on the tumor site, over 30% of GIST exhibit high-risk (malignant) behavior, such as metastasis and infiltration. The majority of esophageal and colon GIST are malignant, while only 25% of gastric GIST are overtly malignant. The metastatic pattern is predominantly intra-abdominal, with spread throughout the peritoneal cavity and to the liver. Lymph nodal invasion is uncommon. True smooth muscle tumors—leiomyomas—also occur throughout the GI tract but are now thought to be rare in comparison with GIST, except in the esophagus, where they are more common. Emory TS, Sobin LH, Lukes L, Lee DH, O’Leary TJ. Prognosis of gastrointestinal smooth muscle (stromal) tumors: dependence on anatomic site . Am J Surg Pathol . 1999;23:82-87. Hatch KF, Blanchard DK, Hatch GF, et al. Tumors of the rectum and anal canal. World J Surg. 2000;24:437-443. Pidhorecky I, Cheney RT, Kraybill WG, Gibbs JF. Gastrointestinal stromal tumors: current diagnosis, biologic behavior, and management. Ann Surg Oncol . 2000;7:705-712. Kindblom LG, Meis-Kindblom J, B ümming P, et al . Incidence, prevalence, phenotype and biologic spectrum of gastrointestinal stromal cell tumors (GIST) – a population-based study of 600 cases. Ann Oncol. 2002;13:157. Abstract 5770.
An alarming 72% of GI tumors now verified as GIST originally had been classified as other tumors. 34% were classified as leiomyoma. 18% were classified as leiomyosarcoma. 13% were classified as leiomyoblastoma. 7% were classified as other tumors. Clearly, the incidence of GIST is much higher than previously believed. Variable disease criteria and confusing nomenclature often led to misclassification and underdiagnosis of GIST. Kindblom LG, Meis-Kindblom J, B ü mming P, et al. Incidence, prevalence, phenotype and biologic spectrum of gastrointestinal stromal cell tumors (GIST) – a population-based study of 600 cases. Ann Oncol. 2002;13:157. Abstract 577O. Kindblom LG . New tests reveal GIST more common, more aggressive than earlier thought. Available at: www.peerviewpress.com/asco2003c. Accessed March 9, 2004.
GIST cannot always be distinguished from smooth muscle tumors using basic histologic methods—light microscopy and hematoxylin-eosin (H-E) staining. Advances in modern immunohistochemistry (IHC) and other techniques now allow GIST to be distinguished from other histopathologic subtypes of GI sarcomas and mesenchymal cell proliferations. Miettinen M, Lasota J. Gastrointestinal stromal tumors (GISTs): definition, occurrence, pathology, differential diagnosis and molecular genetics. Pol J Pathol . 2003;54:3-24.
Over 80% of GIST have KIT gene mutations. Exon 11: Mutations in the intracellular juxtamembrane region occur in mast cell tumors and GIST. Comprise ~70% of all mutations in GIST Are generally point mutations (missense), in-frame deletions, or duplications Are associated with constitutive ligand-independent receptor dimerization and activation of the kinase domain (gain-of-function mutations) Occur more frequently in high-risk GIST than in intermediate-risk GIST (and are rarely or never found in leiomyomas or leiomyosarcomas) Predict a poor prognosis: 49% 5-year patient survival rate vs 86% 5-year survival rate of patients with non – exon 11 mutations Exon 9: Mutations in the extracellular juxtamembrane region involve a similar activation mechanism. Exon 13: Mutations in the split tyrosine kinase domain also occur in GIST. Other KIT mutations have been identified in other diseases. Exon 17: Mutations in the phosphotransferase domain occur in mast cell and germ cell tumors and result in tyrosine kinase activation that requires no dimerization. Exon 17 mutations render these tumors resistant to imatinib mesylate. Exon 2: A mutation in the proximal extracellular domain has been identified in 2 hematologic disorders: myelofibrosis and chronic myeloid leukemia (CML). Seven percent of GIST have PDGFRA gain-of-function intragenic mutations. Taniguchi M, Nishida T, Hirota S, et al. Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. Cancer Res. 1999;59:4297-4300. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577-580. Lasota J, Jasinski M, Sarlomo-Rikala M, Miettinen M. Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am J Pathol. 1999;154:53-60. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol. 2002;33:484-495. Corless CL, Heinrich MC, Duensing A, et al. PDGFRA and KIT gain-of-function mutations are alternative oncogenic mechanisms in gastrointestinal stromal tumors (GIST). Proc Am Assoc Cancer Res. 2003;44. Abstract R4447.
The major histologic patterns of GIST are spindle cell and epithelioid. GIST with a spindle cell morphology often will appear syncytial while clear cell borders are common in epithelioid GIST. Gastric GIST are often of spindle cell morphology, with the epithelioid GIST often historically misclassified as myoblastomas. GIST of the small intestine are primarily of spindle cell morphology. A salient feature of small intestine GIST, especially those of lower risk, is the presence of aggregates of collagen fibers known as skeinoid fibers. In contrast, epithelioid GIST of the small intestine are generally of high risk. Spindle cell morphologies dominate GIST at other sites. Miettinen M, Lasota J. Gastrointestinal stromal tumors (GISTs): definition, occurrence, pathology, differential diagnosis and molecular genetics. Pol J Pathol . 2003;54:3-24.
GIST are often defined as KIT - positive mesenchymal tumors of the GI tract. Over 90% of reported cases (but not all GIST) express KIT. KIT is a type III transmembrane receptor tyrosine kinase, the protein product of the KIT proto-oncogene. KIT is the single most common tumor marker for GIST. CD34 is a mesenchymal and hematopoietic precursor cell marker that is positive in many tumors of mesenchymal origin. It is expressed in 60% to 70% of GIST, making it a modestly sensitive and specific diagnostic GIST marker. Vimentin and smooth-muscle actin are variably expressed by GIST. Desmin is rarely present in GIST. In contrast, true smooth-muscle tumors often express high levels of desmin and smooth-muscle actin. S-100 is used to distinguish tumors of neural crest origin, such as schwannomas and melanomas, and it is particularly useful for differentiating GIST with neural phenotype (formerly GANT) from primary schwannomas. Miettinen M, Lasota J. Gastrointestinal stromal tumors—definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch . 2001;438:1-12. Miettinen M, Sobin LH, Sarlomo-Rikala M. Immunohistochemical spectrum of GIST at different sites and their differential diagnosis with a reference to CD117 (KIT). Mod Pathol. 2000;13:1134-1142. Sarlomo-Rikala M, Kovatich AJ, Barusevicius A, Miettinen M. CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol . 1998;11:728-734. Wang L, Vargas H, French SW. Cellular origin of gastrointestinal stromal tumors: a study of 27 cases. Arch Pathol Lab Med. 2000;124:1471-1475.
Gist For Internist
GIST FOR INTERNISTS Dr. Napa Parinyanitikul Medical Oncology unit Department of Medicine Faculty of Medicine King Chulalongkorn Memorial Hospital
Introduction <ul><li>Gastrointestinal-Stromal tumor (GIST) is a most common mesenchymal neoplasm of gastrointestinal organ. </li></ul><ul><li>Not difference in sex. </li></ul><ul><li>75% found in patients older than 50 years. </li></ul><ul><li>These tumors can arise anywhere in the GI tract. </li></ul>
Clinical Manifestation <ul><li>GIST may occur anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum. </li></ul>Emory et al. Am J Surg Pathol . 1999;23:82. 50% Stomach 25% Small intestine 10% 15% Colon Other ( rectum, esophagus, mesentery, retroperitoneum )
Clinical Manifestation <ul><li>Clinical feature </li></ul><ul><ul><li>: non-specific symptoms </li></ul></ul><ul><ul><li>: asymptomatic </li></ul></ul><ul><ul><li>: UGIB, abdominal mass, vague abdominal pain and discomfort </li></ul></ul><ul><ul><li>: Anemia, Anorexia, weight loss, nausea, fatigue </li></ul></ul><ul><ul><li>: Acute intraperitoneal bleeding or perforation </li></ul></ul><ul><li>Small, insignificant lesions may be found incidentally at endoscopy or at the time of surgery for other cancers as gastric cancer . </li></ul>
Clinical Manifestation <ul><li>Average duration of presenting symptoms is 4-6 months. </li></ul><ul><li>Most GISTs arise from the bowel wall grow into the mucosa and cause ulceration or protrude towards the serosal side -> submucosal lesion </li></ul><ul><li>LN metastasis is rare presentation. </li></ul><ul><li>But in advance GISTs may found lung or bone metastasis. </li></ul>
Historical Classification as Other Soft-Tissue Sarcomas <ul><li>A retrospective Swedish study determined that 72% of GI tumors now identified as GIST had been originally classified as other tumors </li></ul>Kindblom et al. Ann Oncol. 2002;13:157. Abstract 577O. Kindblom . At: www.peerviewpress.com/asco2003c . 7% 13% 18% 34% 28% N=600 GIST Leiomyoma Leiomyosarcoma Leiomyoblastoma Other
Pathology : Morphologic Similarity To Smooth Muscle Tumors Low-Grade GIST High-Grade GIST Courtesy of Dr. C. Corless. Leiomyoma Leiomyosarcoma
Pathogenesis <ul><li>Originally arised from interstitial cell of Cajal . (ICC) </li></ul><ul><li>KIT-positive fibroblast-like cells </li></ul><ul><li>Pacemaker cells of the gut </li></ul><ul><ul><li>Intercalated between intramural neurons and smooth muscle cells </li></ul></ul><ul><ul><li>Generate electrical slow waves </li></ul></ul><ul><li>Loss of ICC function has been implicated in diabetic gastroenteropathy, gastroenteric arrhythmia, and Hirschsprung’s disease </li></ul>
Pathogenesis <ul><li>GIST and ICC may arise from a common mesenchymal stem cell associated with enteric neural plexus. </li></ul><ul><li>GIST shares several characteristics with ICC. </li></ul><ul><li>ICC hyperplasia is evidence in GI tracts of pateints with familial GIST. </li></ul>Takayama et al. Arch Histol cytol 2002, 65 :1-26 Wang et al. Arch Pathol Lab Med 2000, 124:1471-1475
KIT and PDGFRA Mutations in GIST Heinrich et al. Hum Pathol. 2002;33:484. Corless et al. Proc Am Assoc Cancer Res. 2003;44. Abstract R4447. Membrane Cytoplasm Exon 11 (67.5%) Exon 9 (11%) Exon 13 (0.9%) Exon 17 (0.5%) Exon 12 (0.9%) Exon 18 (6.3%) KIT (70-75%) PDGFRA 7% Overall mutation frequency: 87.4% Wild type 10-15% Exon 14 (0.3%)
GIST : Diagnosis <ul><li>Depend on </li></ul><ul><ul><li>Hx+PE </li></ul></ul><ul><ul><li>Radiology (CT scan , MRI whole abdomen, PET/CT) </li></ul></ul><ul><ul><li>Pathology (FNA or Biopsy) </li></ul></ul>
GIST : Staging <ul><li>Evaluate symptoms or extend of mass </li></ul><ul><li>Detect metastasis </li></ul><ul><li>Assess tumor resectability </li></ul>
GIST : Biopsy <ul><li>Preoperative biopsy in a resectable mass is commonly performed but may not be necessary and is associated with risks. </li></ul><ul><li>GISTs may be soft and fragile. </li></ul><ul><li>Biopsy may cause hemorrhage ad increase the risk of tumor dissemination. </li></ul>
GIST: Major Morphologic Patterns Spindle Cell (70%) Epithelioid (9%) Courtesy of Dr. C. Corless. Other-> mixed 21%
Immunohistochemistry <ul><li>~ 95% of reported cases of GIST are positive for KIT (CD117) </li></ul><ul><li>Other markers often positive in GIST </li></ul><ul><ul><li>CD34 (mesenchymal/hematopoietic precursor cell marker) </li></ul></ul><ul><ul><ul><li>Positive in 60%-70% </li></ul></ul></ul><ul><ul><li>Smooth-muscle actin </li></ul></ul><ul><ul><ul><li>Positive in 15%-60% </li></ul></ul></ul><ul><ul><li>S-100 </li></ul></ul><ul><ul><ul><li>Positive in 10% </li></ul></ul></ul><ul><li>GIST rarely express desmin. </li></ul>Different KIT staining patterns in GIST Courtesy of Dr. C. Corless. Miettinen and Lasota. Virchows Arch . 2001;438:1.
GIST : Management <ul><li>Primary GIST </li></ul><ul><ul><li>Resectable GIST -> surgery (only curative Rx) </li></ul></ul><ul><li>Locally advanced or Advanced GIST </li></ul><ul><ul><li>Neoadjuvant imatinib then surgery </li></ul></ul><ul><ul><li>Palliative imatinib </li></ul></ul>