Gastrointestinal stromal tumor pathophysiology: Difference between revisions
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==Genetics== | ==Genetics== | ||
Gene(s) involved in the pathogenesis of gastrointestinal stromal tumors include mutations in c-Kit gene and PDGFRA gene.<ref name="pmid14645423">{{cite journal |vauthors=Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA |title=Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor |journal=J. Clin. Oncol. |volume=21 |issue=23 |pages=4342–9 |year=2003 |pmid=14645423 |doi=10.1200/JCO.2003.04.190 |url=}}</ref><ref name="pmid9438854">{{cite journal |vauthors=Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y |title=Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors |journal=Science |volume=279 |issue=5350 |pages=577–80 |year=1998 |pmid=9438854 |doi= |url=}}</ref> | Gene(s) involved in the pathogenesis of gastrointestinal stromal tumors include mutations in c-Kit gene and PDGFRA gene.<ref name="pmid14645423">{{cite journal |vauthors=Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA |title=Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor |journal=J. Clin. Oncol. |volume=21 |issue=23 |pages=4342–9 |year=2003 |pmid=14645423 |doi=10.1200/JCO.2003.04.190 |url=}}</ref><ref name="pmid9438854">{{cite journal |vauthors=Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y |title=Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors |journal=Science |volume=279 |issue=5350 |pages=577–80 |year=1998 |pmid=9438854 |doi= |url=}}</ref><ref name="DuensingMedeiros2004">{{cite journal|last1=Duensing|first1=Anette|last2=Medeiros|first2=Fabiola|last3=McConarty|first3=Bryna|last4=Joseph|first4=Nora E|last5=Panigrahy|first5=Dipak|last6=Singer|first6=Samuel|last7=Fletcher|first7=Christopher DM|last8=Demetri|first8=George D|last9=Fletcher|first9=Jonathan A|title=Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs)|journal=Oncogene|volume=23|issue=22|year=2004|pages=3999–4006|issn=0950-9232|doi=10.1038/sj.onc.1207525}}</ref><ref name="LuxRubin2000">{{cite journal|last1=Lux|first1=Marcia L.|last2=Rubin|first2=Brian P.|last3=Biase|first3=Tara L.|last4=Chen|first4=Chang-Jie|last5=Maclure|first5=Timothy|last6=Demetri|first6=George|last7=Xiao|first7=Sheng|last8=Singer|first8=Samuel|last9=Fletcher|first9=Christopher D.M.|last10=Fletcher|first10=Jonathan A.|title=KIT Extracellular and Kinase Domain Mutations in Gastrointestinal Stromal Tumors|journal=The American Journal of Pathology|volume=156|issue=3|year=2000|pages=791–795|issn=00029440|doi=10.1016/S0002-9440(10)64946-2}}</ref> | ||
*The c-kit gene is a proto-oncogene and located on chromosome 4q11-12 (long (q) arm of chromosome 4 at position 12). | *The c-kit gene is a proto-oncogene and located on chromosome 4q11-12 (long (q) arm of chromosome 4 at position 12). | ||
**The c-kit gene encodes for KIT protein which is a transmembrane tyrosine kinase. | **The c-kit gene encodes for KIT protein which is a transmembrane tyrosine kinase. | ||
| Line 94: | Line 96: | ||
***The signaling pathways stimulated by the PDGFRA gene control many important cellular processes such as cell growth and proliferation. | ***The signaling pathways stimulated by the PDGFRA gene control many important cellular processes such as cell growth and proliferation. | ||
**As a result of mutation, the PDGFRA gene gets activated on its own and leads to inhibition of apoptosis and uncontrolled cell proliferation. | **As a result of mutation, the PDGFRA gene gets activated on its own and leads to inhibition of apoptosis and uncontrolled cell proliferation. | ||
*In some rare cases where the patient do not exhibit the typical c-Kit and PDGFRA mutation, reports of mutation in ''BRAF'' mutations and protein kinase C have been observed. | *In some rare cases where the patient do not exhibit the typical c-Kit and PDGFRA mutation, reports of mutation in ''BRAF'' mutations and protein kinase C have been observed. | ||
==Associated Conditions== | ==Associated Conditions== | ||
Revision as of 20:54, 1 December 2017
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Gastrointestinal stromal tumor Microchapters |
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Differentiating Gastrointestinal stromal tumor from other Diseases |
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Risk calculators and risk factors for Gastrointestinal stromal tumor pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]
Overview
On microscopic histopathological analysis, spindle cells or plump epithelioid cells are characteristic findings of gastrointestinal stromal tumor.
Pathophysiology
- GIST are tumors involving the connective tissue of the GI tract.
Recent studies have shown that approximately one third of GIST lesions have smooth muscle lineages, another third were neurogenic in origin, and the final third lacked any detectable lineage-specific markers by immunohistochemical analysis.
- GIST can occur in any part of the gastrointestinal tract but the most common location is stomach, with the second most common location as small intestine. Less frequent sites of occurrence include the colon, rectum and esophagus. Rare sites include pancreas, omentum, or mesentery.
- GIST can arises from the submucosal layer or the smooth muscle cells of the GI tract.
- GIST tumors can either be benign or malignant. They can be any size. GIST can grow as an endophytic or exophytic lesions.
- Endophytic lesions are linear lesions that grow along the lumen of the affected organ.
- Exophytic lesions can present as a protruding outgrowth outside the lumen of GI tract.
- GISTs are thought to arise from interstitial cells of Cajal (ICC), that are normally part of the autonomic nervous system of the intestine. They serve a pacemaker function in controlling motility.[1]
- GISTs are believed to arise from the interstitial cells of Cajal, with 95% staining positive for CD117 (c-KIT) and 70% for CD34. The former is a tyrosine kinase growth factor receptor and the target of ST-571 (Imatinib; Glivec).
- Macroscopically these tumours are rounded with frequent hemorrhagic change. Larger tumours also may demonstrate necrosis and cystic change. Size is variable ranging form 1 to 30cm.
- Histology demonstrates a relatively cellular tumor comprised of spindle cells (70-80%) and or plump epithelioid cells (20-30%). They appear to arise from the muscularis propria layer.[2]
Overview
The exact pathogenesis of [disease name] is not fully understood.
OR
It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
OR
[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
OR
Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
OR
[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
OR
The progression to [disease name] usually involves the [molecular pathway].
OR
The pathophysiology of [disease/malignancy] depends on the histological subtype.
Pathophysiology
Pathogenesis
- The exact pathogenesis of [disease name] is not fully understood.
OR
- It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
- [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
- Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
- [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
- The progression to [disease name] usually involves the [molecular pathway].
- The pathophysiology of [disease/malignancy] depends on the histological subtype.
Genetics
Gene(s) involved in the pathogenesis of gastrointestinal stromal tumors include mutations in c-Kit gene and PDGFRA gene.[3][4][5][6]
- The c-kit gene is a proto-oncogene and located on chromosome 4q11-12 (long (q) arm of chromosome 4 at position 12).
- The c-kit gene encodes for KIT protein which is a transmembrane tyrosine kinase.
- The KIT protein is located on the cell membrane of certain cell types.
- Stem cell factor is the ligand that binds to KIT protein, which in turn leads to activation of KIT protein.
- Upon activation, the KIT protein leads to activation of other intracellular proteins by a process known as phosphorylation (which involves adding oxygen and phosphorus at specific positions).
- The activation of these intracellular proteins such as (MAP kinase and RAS) plays a vital role in multiple signaling pathways.
- The signaling pathways stimulated by the KIT protein control many important cellular processes such as cell growth and proliferation.
- In addition, KIT protein signaling also has a role in the development of gastrointestinal tract cells known as interstitial cells of Cajal.
- The most commonly observed mutation site in c-Kit gene involves exon 11 leading to a gain-of-function mutation.
- Gain of function mutation leads to overexpression and autophosphorylation of c-Kit that leads to inhibition of apoptosis and uncontrolled cell proliferation.
- Almost 90-95% of patients with GIST have mutated c-Kit gene.
- About 10% cases of GIST are associated with PDGFRA gene.
- The PDGFRA gene is located on chromosome 4q11-12 (long (q) arm of chromosome 4 at position 12).
- The PDGFRA gene encodes for the protein; platelet-derived growth factor receptor alpha (PDGFRA), which belongs to a family of proteins known as receptor tyrosine kinases.
- The platelet-derived growth factor is the ligand that binds to PDGFRA ,which in turn activates the PDGFRA.
- Upon activation, the PDGFRA leads to activation of other intracellular proteins by a process known as phosphorylation.
- The activation of these intracellular proteins such as (MAP kinase and RAS) plays a vital role in multiple signaling pathways.
- The signaling pathways stimulated by the PDGFRA gene control many important cellular processes such as cell growth and proliferation.
- As a result of mutation, the PDGFRA gene gets activated on its own and leads to inhibition of apoptosis and uncontrolled cell proliferation.
- In some rare cases where the patient do not exhibit the typical c-Kit and PDGFRA mutation, reports of mutation in BRAF mutations and protein kinase C have been observed.
Associated Conditions
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ Miettinen M, Lasota J (2006). "Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis". Arch Pathol Lab Med. 130 (10): 1466–78. PMID 17090188.
- ↑ "Gastrointestinal stromal tumour".
- ↑ Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA (2003). "Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor". J. Clin. Oncol. 21 (23): 4342–9. doi:10.1200/JCO.2003.04.190. PMID 14645423.
- ↑ Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y (1998). "Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors". Science. 279 (5350): 577–80. PMID 9438854.
- ↑ Duensing, Anette; Medeiros, Fabiola; McConarty, Bryna; Joseph, Nora E; Panigrahy, Dipak; Singer, Samuel; Fletcher, Christopher DM; Demetri, George D; Fletcher, Jonathan A (2004). "Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs)". Oncogene. 23 (22): 3999–4006. doi:10.1038/sj.onc.1207525. ISSN 0950-9232.
- ↑ Lux, Marcia L.; Rubin, Brian P.; Biase, Tara L.; Chen, Chang-Jie; Maclure, Timothy; Demetri, George; Xiao, Sheng; Singer, Samuel; Fletcher, Christopher D.M.; Fletcher, Jonathan A. (2000). "KIT Extracellular and Kinase Domain Mutations in Gastrointestinal Stromal Tumors". The American Journal of Pathology. 156 (3): 791–795. doi:10.1016/S0002-9440(10)64946-2. ISSN 0002-9440.