Gastrointestinal Stromal Tumors: Review on Morphology, Molecular Pathology, Prognosis, and Differential Diagnosis

2006 ◽  
Vol 130 (10) ◽  
pp. 1466-1478 ◽  
Author(s):  
Markku Miettinen ◽  
Jerzy Lasota
Keyword(s):  
Smooth Muscle ◽  
Gastrointestinal Tract ◽  
Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Intestinal Tumors ◽  
Secondary Resistance ◽  
Prognostic Features ◽  
Stromal Tumors ◽  
Small Intestinal ◽  
Domain Exon

Abstract Context.—Gastrointestinal stromal tumors (GISTs) are specific, generally Kit (CD117)-positive, mesenchymal tumors of the gastrointestinal tract encompassing a majority of tumors previously considered gastrointestinal smooth muscle tumors. They are believed to originate from interstitial cells of Cajal or related stem cells. Objective.—To review current clinicopathologically relevant information on GIST. Data Sources.—Literature in Medline and authors' own experience. Conclusions.—GISTs usually occur in older adults (median age 55–60 years) and rarely in children in the second decade (<1%) throughout the gastrointestinal tract: 60% in stomach, 35% in small intestine, and less than 5% in rectum, esophagus, omentum, and mesentery; most GISTs in the latter 2 sites are metastatic. Five percent of GISTs occur in patients with neurofibromatosis type 1 syndrome (multiple small intestinal tumors) and in Carney triad (gastric epithelioid GISTs in young females). Familial GISTs occur in patients with inheritable germline Kit or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Histologically GISTs vary from spindle cell tumors to epithelioid and pleomorphic tumors. Most GISTs (95%) express Kit (CD117), CD34 (70%), and heavy caldesmon (80%), whereas 25% are positive for smooth muscle actin and less than 5% for desmin. Tumor size and mitotic activity are best predictive prognostic features; small intestinal tumors behave more aggressively than gastric tumors with similar parameters. Mutually exclusive gain-of-function Kit or PDGFRA mutations occur in a majority of GISTs representing in-frame deletions, point mutations, duplications and insertions. Mutations in Kit juxtamembrane domain (exon 11) are the most common in GISTs of all sites, whereas rare Kit extracellular domain (exon 9) Ala502-Tyr503 duplication is specific for intestinal GISTs. Mutations in PDGFRA have been identified in juxtamembrane (exon 12) and tyrosine kinase domains (exons 14 and 18), nearly exclusively in gastric GISTs, mostly in epithelioid variants. Some Kit and PDGFRA mutations have a prognostic value. Kit/PDGFRA tyrosine kinase inhibitor imatinib has been successfully used in the treatment of metastatic GISTs for more than 5 years. However, primary and acquired secondary resistance linked to certain types of Kit and PDGFRA mutations is limiting long-term success necessitating the use of alternative treatments.

Cellular Origin of Gastrointestinal Stromal Tumors

2000 ◽  
Vol 124 (10) ◽  
pp. 1471-1475 ◽  
Author(s):  
Lina Wang ◽  
Hernan Vargas ◽  
Samuel W. French
Keyword(s):  
Stem Cells ◽  
Smooth Muscle ◽  
Gastrointestinal Tract ◽  
Gastrointestinal Stromal Tumors ◽  
Benign Tumors ◽  
Cell Phenotype ◽  
Stromal Tumors ◽  
Cellular Origin ◽  
Benign Leiomyoma ◽  
Malignant Gists

Abstract Context.—Interstitial cells of Cajal (ICCs), also known as pacemaker cells, are cells in the gastrointestinal tract that play a role in the control of gut motility. The ICCs express the c-kit proto-oncogene encoding a type III tyrosine kinase (KIT) receptor, a ligand that is known as stem cell factor (SCF). The maturation of ICCs is dependent on SCF-KIT interaction. The cellular origin, differentiation, nomenclature, and prognosis of gastrointestinal stromal tumors (GISTs) are controversial. Objective.—To test the hypothesis that GISTs originate from CD34-positive stem cells and differentiate toward an ICC phenotype. Materials and Methods.—We studied 27 cases of smooth muscle differentiated GISTs collected for 14 years (1985–1999), including 8 benign (leiomyoma), 15 malignant primary (leiomyosarcoma), and 4 metastatic to the liver. Immunohistochemical studies of selected lineage-directed monoclonal antibodies of c-kit (CD117), CD34, vimentin, desmin, α-actin, S100, and MIB-1 were performed on both normal and tumor tissues. Results.—Immunoperoxidase stains of normal gastrointestinal tract showed both c-kit and CD34-positive cells surrounding the Auerbach ganglia plexus in the gastrointestinal tract. Twenty-seven of 27 tumors strongly expressed c-kit. Fourteen of 27 tumors were positive for CD34. Of the malignant GISTs, 14 of 19 were positive for CD34; of the benign tumors, 0 of 8 were positive for CD34. Thus, CD34 was the best indicator of malignant phenotype. Conclusion.—This is the first description of benign smooth muscle GISTs negative for CD34. The results of this study suggest that GISTs originate from CD34-positive stem cells and differentiate toward pacemaker cell phenotype. The lack of expression of CD34 in the benign GIST may indicate that benign GISTs are composed of more mature ICCs, whereas malignant GISTs are composed of dedifferentiated ICCs that express CD34-positive stem cells.

scholarly journals Small Intestinal and Mesenteric Multiple Gastrointestinal Stromal Tumors Causing Occult Bleeding

2016 ◽  
Vol 2016 ◽  
pp. 1-4
Author(s):  
Tolga Dinc ◽  
Selami Ilgaz Kayilioglu ◽  
Ahmet Erdogan ◽  
Erdinc Cetinkaya ◽  
Ozgur Akgul ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Male Patient ◽  
Gastrointestinal Stromal Tumors ◽  
Genetic Basis ◽  
Therapeutic Modality ◽  
Case Presentation ◽  
Stromal Tumors ◽  
Factor Receptor Alpha ◽  
Occult Bleeding ◽  
Small Intestinal

Gastrointestinal stromal tumors are the meseancymal neoplasms which may involve any part of gastrointestinal tract. C-Kit and platelet derived factor receptor alpha polypeptide are believed to be responsible for the genetic basis. This case presentation aimed to discuss the diagnostic and therapeutic modality of multiple small intestinal, omental, and mesenteric GISTs with different sizes which caused occult bleeding in a 43-year-old male patient.

scholarly journals Gastrointestinal Stromal Tumors (GISTs) and Extragastrointestinal Stromal Tumors (E-GISTs) - A Review

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Sunil Vitthalrao Jagtap
Keyword(s):  
Smooth Muscle ◽  
Gastrointestinal Tract ◽  
Gastrointestinal Stromal Tumors ◽  
Multidisciplinary Approach ◽  
Malignant Tumors ◽  
Tumor Type ◽  
Stromal Tumors ◽  
Long Term Follow Up

GISTs (Gastrointestinal Stromal Tumors) are the most frequently encountered mesenchymal tumor of the gastrointestinal tract. Gastrointestinal stromal tumors have been recognized as a biologically distinctive tumor type, different from smooth muscle and neural tumors of the gastrointestinal tract (GIT). GISTs present 0.1%-3.0% of gastrointestinal malignant tumors. The goals in treating patients with GIST are to maximize the chance of cure, minimize recurrence. A multidisciplinary approach to patients with GISTs is necessary to optimize the timing of medical and surgical therapy as they have unpredictable behavior. Also long term follow up is essential for all patients, independent of their benign or malignant characteristics. This review highlight on clinical, diagnostic imaging, histopatholpgical, immunohistochemical ,new markers and management modalities for Gastrointestinal Stromal Tumors (GISTs) and Extragastrointestinal stromal tumors (E-GISTs).

scholarly journals Gastrointestinal stromal tumors (GIST) of the stomach as a cause of upper gastrointestinal bleeding

2007 ◽  
Vol 54 (1) ◽  
pp. 115-118 ◽  
Author(s):  
K. Ebrahimi ◽  
D. Velickovic ◽  
B. Spica ◽  
P. Sabljak ◽  
M. Bjelovic ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Gastrointestinal Tract ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitor ◽  
Mass Effect ◽  
Mesenchymal Tumor ◽  
Intestinal Cell ◽  
Gastric Gist ◽  
Stromal Tumors ◽  
Significant Difference

Gastrointestinal stromal tumors (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. GIST is currently defined as a gastrointestinal tract mesenchymal tumor containing spindle cells (less commonly epitheloid cells or rarely both) and showing CD 117 (c-kit protein) positivity in more than 95% of cases. Although they may arise throughout the gut, the commonest site are stomach (60-70%), small intestine (20-30%), colorectum (5%) and esophagus (up to 5%). Rarely, GISTs develop in the retroperitoneum, omentum or mesentery. GIST originates from the intestinal cell of Cajal (ICC). ICCs are located in and around the myenteric plexus and are thought to function as intestinal pacemaker cells. Historically, GIST were often misclassified as leiomyomas or leiomyosarcomas. Subsequently, it has been determined that GISTs have distinct ultrastructural features and immunophenotypical markers compared with smooth muscle and smooth muscle tumors. GIST predominantly occur in middle aged and older patients, with no significant difference in the sex incidence. Data from the recent population study suggest an incidence of about 10-22 cases per million persons per year. Clinical presentation of GIST varies widely, and depends on tumor size and location. GISTs that caused symptoms tended to be larger with an average size of 6cm versus 2cm for asymptomatic GISTs. Symptoms are most commonly related to mass effect or bleeding. GISTs can grow very large before producing symptoms. Commonest symptom of gastric GIST is manifest or occult bleeding. Abundant, life-threatening bleeding that require urgent surgery is rare. For patient with primary, localized, nonmetastatic GIST, complete surgical resection represents the only chance for cure. Lymhadenectomy is not necessary, because lymph node metastasis is very rare. The 5 year survival rate in patients with resected primary GISTs ranges from 48-65%. Conventional che- Br. 1 GIST zeluca kao uzrok krvarenja iz gornjih partija 117 digestivnog trakta motherapy and radiation therapy is ineffective in the treatment of GIST. Imatinib mesilate (a tyrosine kinase inhibitor) was confirmed to be effective against metastatic or unresectable GISTs.

scholarly journals Mechanisms of the resistance of gastrointestinal stromal tumors to imatinib

2018 ◽  
Vol 99 (6) ◽  
pp. 959-965
Author(s):  
A R Galembikova ◽  
S V Boichuk
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Gastrointestinal Stromal Tumors ◽  
Target Therapy ◽  
Acquired Resistance ◽  
Mesenchymal Tumors ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Mutational Status

The review describes the modern concepts of the primary and secondary (acquired) resistance of gastrointestinal stromal tumors to the targeted drug imatinib. Gastrointestinal stromal tumors are the mesenchymal tumors of gastrointestinal tract that originate from interstitial cells of Cajal or their stem cell precursors. Up to 85 % of gastrointestinal stromal tumors have the mutations of KIT gene that lead to ligand-independent activation of this tyrosine kinase. Imatinib is an inhibitor of KIT tyrosine kinase which is hyperexpressed in 70-85 % of cases on the cell membrane of gastrointestinal stromal tumors. Despite the high effectiveness of imatinib in gastrointestinal stromal tumors, up to 15 % of patients do not respond to this therapy, and over 50 % of patients acquire the resistance to this drug 2 years after initiation of target therapy with imatinib. The mechanisms of primary resistance include basically the mutational status of KIT, PDGFRA and, rarely, mutations of SDH, NF1, BRAF, PI3K3CA, CBL, and KRAS. The mechanisms of secondary resistance of tumor cells to imatinib are not restricted to the secondary mutations of KIT and PDGFRA, but also might be due to the loss of KIT expression associated by overexpression of the alternative receptor- and non-receptor tyrosine kinases, such as MET, AXL, FGFR2α, FAK, etc. Alternative mechanisms of acquired resistance might be due to the mutations of BRAF gene.

scholarly journals Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

2021 ◽  
Vol 22 (2) ◽  
pp. 493
Author(s):  
Christos Vallilas ◽  
Panagiotis Sarantis ◽  
Anastasios Kyriazoglou ◽  
Evangelos Koustas ◽  
Stamatios Theocharis ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Cancer Therapeutics ◽  
Gastrointestinal Neoplasms ◽  
Mesenchymal Tumors ◽  
Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

Molecular Correlates of Imatinib Resistance in Gastrointestinal Stromal Tumors

2006 ◽  
Vol 24 (29) ◽  
pp. 4764-4774 ◽  
Author(s):  
Michael C. Heinrich ◽  
Christopher L. Corless ◽  
Charles D. Blanke ◽  
George D. Demetri ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Molecular Mechanisms ◽  
Clonal Evolution ◽  
Clinical Problem ◽  
Primary Resistance ◽  
Imatinib Resistance ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Rnai Technology ◽  
Imatinib Resistant

Purpose Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem. Patients and Methods One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity. Results Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P = .002). Evidence for clonal evolution and/or polyclonal secondary kinase mutations was seen in three (18.8%) of 16 patients. Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical KIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways. Conclusion Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. These findings have implications for future approaches to the growing problem of imatinib resistance in patients with advanced GISTs.

PLX9486 shows anti-tumor efficacy in patient-derived, tyrosine kinase inhibitor-resistant KIT-mutant xenograft models of gastrointestinal stromal tumors

2018 ◽  
Vol 19 (2) ◽  
pp. 201-210 ◽  
Author(s):  
Yemarshet K. Gebreyohannes ◽  
Elizabeth A. Burton ◽  
Agnieszka Wozniak ◽  
Bernice Matusow ◽  
Gaston Habets ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitor ◽  
Stromal Tumors ◽  
Xenograft Models

scholarly journals Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST)

Oncotarget ◽  
2014 ◽  
Vol 6 (4) ◽  
pp. 1954-1966 ◽  
Author(s):  
Daruka Mahadevan ◽  
Noah Theiss ◽  
Carla Morales ◽  
Amy E. Stejskal ◽  
Laurence S. Cooke ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Combination Therapies ◽  
Stromal Tumors ◽  
Imatinib Resistant

scholarly journals The importance of molecular biology in development, prognosis, treatment and resistance to targeted therapy in gastrointestinal stromal tumors

2011 ◽  
pp. 69-79
Author(s):  
Alessandro Comandone ◽  
Elisa Berno ◽  
Simona Chiadò Cutin ◽  
Antonella Boglione
Keyword(s):  
Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Neoplastic Transformation ◽  
Response To Therapy ◽  
Mesenchymal Tumors ◽  
Kit Mutation ◽  
Stromal Tumors ◽  
Receive Treatment

Gastrointestinal stromal tumors (GISTs) are the commonest mesenchymal tumors of the gastroenteric tract, and are generally believed to originate from the neoplastic transformation of the interstitial cells of Cajal, the pacemaker structures of the stomach and intestine. Exon and genetic mutations (point/deletions) are fundamental for the development of GISTs: the constitutional characteristic of this neoplasm is the presence of the cell surface Kit receptor. Kit is the product of the proto-oncogene cKit, situated in chromosome 4. Ninety-eight percent of GISTs express mutated isoforms of Kit or of PDGFRA (Platelet growth factor receptor a). Kit mutation is the basic condition for autophosphorylation of tyrosine kinase residues in proteins. Autophosphorylation initiates pathogenetic processes in Cajal cells, toward a neoplastic transformation. Imatinib mesilate and, more recently, sunitinib are tyrosine kinase inhibitors, specific antagonists for Kit and PDGFRA, with good activity against GISTs. Most molecular and clinical data currently available concern imatinib. Exon mutations are strategic as prognostic and as predictive factors. In recent years, much evidence suggests that survival, response to therapy and resistance to imatinib are related to different mutations. In the near future, GIST patients will receive treatment differentiated by expressed Kit and PDGFRA mutations, thus truly individualized therapy.

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