Gastrointestinal stromal tumor pathophysiology
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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
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 vary considerably in their presentation and clinical course, ranging from
- 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, peritoneum, omentum, or mesentery.[1]
- GIST are the most common mesenchymal tumors.[2]
- Earlier GIST previously thought to arise from the submucosal or smooth muscle cells of the GI tract but recent data has proved that GIST are derived from the interstitial cells of Cajal (intestinal pacemaker cell).
- GIST tumors can either be benign or malignant. They can be any size ranging from small benign tumors to massive malignant lesions with wide metastases.
- 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 the GI tract.
- GIST have a variable malignant potential.[3]
- 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.[6][7]
- 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.[8]
| S.No | |||
|---|---|---|---|
| Benign (no tumor-related mortality) | |||
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
Genes involved in the pathogenesis of gastrointestinal stromal tumors include mutations in c-Kit gene and PDGFRA (platelet derived growth factor receptor-alpha) gene. In some rare cases where the patient do not exhibit the typical c-Kit and PDGFRA mutation, reports of mutation in BRAF kinase, succinate dehydrogenase (SDH) and protein kinase C have been observed. The majority of GISTs are sporadic in origin. [9][10][11][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 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.
- The most commonly observed mutation site in PDGFRA gene involves exon 18.
- As a result of mutation, the PDGFRA gene gets activated on its own and leads to inhibition of apoptosis and uncontrolled cell proliferation.
Associated Conditions
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, GISTs can be divided into:
- Spindle cell (60%-70%): Spindle cells are compact, highly cellular, arranged in fascicular or whorled pattern with minimal amount of stroma and contain eosinophilic, basophilic or amphophilic cytoplasm.
- Epithelioid (30%-40%): Epithelioid tumors have abundant cytoplasm which is amphophilic to clear and cellular borders are clearly defined.
- Spindle cell or epithelioid (10%).
References
- ↑ Reith JD, Goldblum JR, Lyles RH, Weiss SW (2000). "Extragastrointestinal (soft tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome". Mod. Pathol. 13 (5): 577–85. doi:10.1038/modpathol.3880099. PMID 10824931.
- ↑ Miettinen M, Lasota J (2001). "Gastrointestinal stromal tumors--definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis". Virchows Arch. 438 (1): 1–12. PMID 11213830.
- ↑ Joensuu H, Vehtari A, Riihimäki J, Nishida T, Steigen SE, Brabec P, Plank L, Nilsson B, Cirilli C, Braconi C, Bordoni A, Magnusson MK, Linke Z, Sufliarsky J, Federico M, Jonasson JG, Dei Tos AP, Rutkowski P (2012). "Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts". Lancet Oncol. 13 (3): 265–74. doi:10.1016/S1470-2045(11)70299-6. PMID 22153892.
- ↑ Woodall CE, Brock GN, Fan J, Byam JA, Scoggins CR, McMasters KM, Martin RC (2009). "An evaluation of 2537 gastrointestinal stromal tumors for a proposed clinical staging system". Arch Surg. 144 (7): 670–8. doi:10.1001/archsurg.2009.108. PMID 19620548.
- ↑ Emile JF, Brahimi S, Coindre JM, Bringuier PP, Monges G, Samb P, Doucet L, Hostein I, Landi B, Buisine MP, Neuville A, Bouché O, Cervera P, Pretet JL, Tisserand J, Gauthier A, Le Cesne A, Sabourin JC, Scoazec JY, Bonvalot S, Corless CL, Heinrich MC, Blay JY, Aegerter P (2012). "Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population-based study differ from those of advanced GISTs". Med. Oncol. 29 (3): 1765–72. doi:10.1007/s12032-011-0074-y. PMID 21953054.
- ↑ 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.
- ↑ Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM (1998). "Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal". Am. J. Pathol. 152 (5): 1259–69. PMC 1858579. PMID 9588894.
- ↑ "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.