Gastrointestinal stromal tumor pathophysiology: Difference between revisions

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{{Gastrointestinal stromal tumor}}
{{Gastrointestinal stromal tumor}}
{{CMG}}
{{CMG}}{{AE}}{{Akshun}}
 
==Overview==
 
Gastrointestinal stromal tumors (GISTs) are rare but the most common [[mesenchymal]] (nonepithelial) [[tumors]] of the [[gastrointestinal tract]]. GISTs are derived from the [[interstitial cells of Cajal]] or undifferen2tiated [[precursor]] cells that finally develop into [[interstitial cells of Cajal]]. GIST [[Tumor|tumors]] can either be [[benign]] [[Tumor|tumors]] or massive [[malignant]] [[Tumor|tumors]] with widespread [[metastasis]]. They can occur in any part of the [[gastrointestinal tract]] with the most common location as [[stomach]]. GIST ([[tumors]]) can grow as an endophytic or exophytic [[Lesion|lesions]]. [[Genes]] involved in the [[pathogenesis]] of gastrointestinal stromal tumors include [[mutations]] in c-Kit [[gene]] and PDGFRA ([[platelet]] derived [[growth factor]] receptor-alpha) [[gene]]. Both Kit [[gene]] and PDGFRA are [[tyrosine kinase]] [[Receptor (biochemistry)|receptors]] and control [[cell proliferation]]. [[Mutation]] in c-Kit [[gene]] and PDGFRA leads to [[inhibition]] of [[apoptosis]] and uncontrolled [[cell proliferation]]. In some rare cases where the [[patient]] do not [[Exhibitionism|exhibit]] the typical [[mutation]] in c-Kit and PDGFRA, [[mutation|mutations]] in [[succinate dehydrogenase]] ([[SDH]]) have been reported. Conditions associated with GIST include [[urticaria pigmentosa]], [[neurofibromatosis type 1]], and Carney-Stratakis [[syndrome]]. On [[gross pathology]], GISTs have a rounded appearance with areas of [[hemorrhage]]. On [[microscopic]] [[histopathological]] [[analysis]], GISTs are [[cellular]] [[tumor|tumors]] arising from [[muscularis]] propria and composed of [[spindle cells]] (70%), [[Epithelioid cell|epithelioid cells]] (20%) or either one of them.
==Pathophysiology==
* Gastrointestinal stromal tumors (GISTs) are rare but the most common [[mesenchymal]] (nonepithelial) [[tumors]] of the [[gastrointestinal tract]].<ref name="pmid11213830">{{cite journal |vauthors=Miettinen M, Lasota J |title=Gastrointestinal stromal tumors--definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis |journal=Virchows Arch. |volume=438 |issue=1 |pages=1–12 |year=2001 |pmid=11213830 |doi= |url=}}</ref>
* GIST tumors can either be [[benign]] [[Tumor|tumors]] or massive [[malignant]] [[Tumor|tumors]] with widespread [[metastasis]].
* Earlier GIST were thought to arise from the [[submucosal]] or [[smooth muscle cells]] of the [[Gastrointestinal tract|GI tract]]. However recent research have proved that GISTs are derived from the [[Interstitial cells of Cajal|interstitial cells of Caja]]<nowiki/>l or undifferentiated [[Precursors|precursor]] cells that finally develop into [[interstitial cells of Cajal]].<ref name="miettinen">{{cite journal |author=Miettinen M, Lasota J |title=Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis |journal=Arch Pathol Lab Med |volume=130 |issue=10 |pages=1466-78 |year=2006 |id=PMID 17090188}}</ref><ref name="pmid9588894">{{cite journal |vauthors=Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM |title=Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal |journal=Am. J. Pathol. |volume=152 |issue=5 |pages=1259–69 |year=1998 |pmid=9588894 |pmc=1858579 |doi= |url=}}</ref>
** [[Interstitial cells of Cajal]] (ICC) are a normal part of [[myenteric plexus]] and the [[autonomic nervous system]] of the [[intestine]]. 
** [[Interstitial cells of Cajal]] serve as a [[pacemaker]] of [[intestine]] and controls [[intestinal]] motility.
** [[Molecular]] [[analysis]] has shown that GISTs arising from the [[interstitial cells of Cajal]], stain positive for [[CD117]] (c-KIT) in 90% cases and [[CD34]] in 70% of cases. Around 5% of the cases are positive for PDGFRA. The rest of the cases are defined as wild type (negative for both [[CD117]] and PDGFRA).
*** [[CD117]] is encoded by the ''KIT ''[[gene]]. Other names for [[CD117]] include [[Proto-oncogene protein C-kit|proto-oncogene c-Kit]] and [[tyrosine kinase]] [[Receptor (biochemistry)|receptor]] Kit. 
*** [[CD34]] is the [[myeloid]] [[progenitor cell]] [[antigen]] and also known as [[Hematopoiesis|hematopoietic]] [[progenitor]] [[Cell (biology)|cell]] [[antigen]] [[CD34]]. 
*** PDGFRA is [[platelet]] derived [[growth factor]] [[Receptor (biochemistry)|receptor]]-alpha and is a [[tyrosine kinase]] [[Receptor (biochemistry)|receptor]].
* GIST can occur in any part of the [[Gastrointestinal tract|gastrointestinal tract.]] Thus, GIST vary considerably in their presentation and [[clinical]] course, ranging from being [[asymptomatic]] to presenting with severe signs and [[Symptom|symptoms]] of [[bleeding]], [[abdominal pain]] and [[perforation]].<ref name="pmid10824931">{{cite journal |vauthors=Reith JD, Goldblum JR, Lyles RH, Weiss SW |title=Extragastrointestinal (soft tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome |journal=Mod. Pathol. |volume=13 |issue=5 |pages=577–85 |year=2000 |pmid=10824931 |doi=10.1038/modpathol.3880099 |url=}}</ref>
** The most common location for GIST is the [[stomach]] with the second most common location as the [[small intestine]].
** Less frequent sites of occurrence include the [[colon]], [[rectum]] and [[esophagus]]. 
** Rare sites include [[pancreas]], [[peritoneum]], [[omentum]], or [[mesentery]].
*GIST ([[Tumor|tumors]]) can grow as an endophytic or exophytic [[Lesion|lesions]].
**Endophytic [[Lesion|lesions]] are [[benign]] linear [[Lesion|lesions]] that grow along the [[lumen]] of the affected [[Organ (anatomy)|organ]].
**Exophytic [[Lesion|lesions]] can present as a protruding outgrowth outside the [[lumen]] of the [[Gastrointestinal tract|GI tract]].
*GIST have a variable [[malignant]] potential.<ref name="pmid22153892">{{cite journal |vauthors=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 |title=Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts |journal=Lancet Oncol. |volume=13 |issue=3 |pages=265–74 |year=2012 |pmid=22153892 |doi=10.1016/S1470-2045(11)70299-6 |url=}}</ref>
**About 40% of GISTs that are localized at initial [[diagnosis]] give rise to [[metastasis]].
**Of all GIST, 10%-20% present with distant [[metastasis]] with the liver being the most frequent site of [[metastasis]].<ref name="pmid19620548">{{cite journal |vauthors=Woodall CE, Brock GN, Fan J, Byam JA, Scoggins CR, McMasters KM, Martin RC |title=An evaluation of 2537 gastrointestinal stromal tumors for a proposed clinical staging system |journal=Arch Surg |volume=144 |issue=7 |pages=670–8 |year=2009 |pmid=19620548 |doi=10.1001/archsurg.2009.108 |url=}}</ref><ref name="pmid21953054">{{cite journal |vauthors=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 |title=Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population-based study differ from those of advanced GISTs |journal=Med. Oncol. |volume=29 |issue=3 |pages=1765–72 |year=2012 |pmid=21953054 |doi=10.1007/s12032-011-0074-y |url=}}</ref>
**Other common sites of [[metastasis]] include the [[bone]], [[peritoneum]], [[retroperitoneum]], [[lung]], and [[pleura]].
 
==Genetics==
[[Genes]] involved in the [[pathogenesis]] of gastrointestinal stromal tumors include [[mutations]] in c-Kit [[gene]] and PDGFRA ([[platelet]] derived growth factor [[Receptor (biochemistry)|receptor]]-alpha) [[gene]]. In some rare cases where the [[patient]] do not [[Exhibitionism|exhibit]] the typical c-Kit and PDGFRA [[mutation]], mutation in [[succinate dehydrogenase]] (SDH) have been reported. Rare [[genes]] involved include ''[[BRAF]]'' kinase, and [[protein kinase C]]. The majority of GISTs are sporadic in origin. <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]] 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]]. Less common sites include [[Exon|exons]] 9 and 13.
**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.
**C-Kit (a [[tyrosine kinase]] growth factor [[receptor]]) is also the target of medical therapy in GIST; ST-571 ([[Imatinib]]; Glivec).
*About 10% cases of GIST are associated with PDGFRA gene.
**The PDGFRA gene is located on [[Chromosome 4|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]] (same as c-Kit explained above). 
***The activation of these [[intracellular]] [[proteins]] such as ([[MAP kinase]] and RAS) plays a vital role in multiple signaling pathways.
***The multiple signaling pathways stimulated by 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]]. 
 
 
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{{familytree | | | | | | C01 | | | | | | C02 | | | | | C03 |C01=KIT gene mutation|C02=PDGFRA mutation|C03=Wild type (absence of KIT/PDGFRA mutation)}}
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{{familytree | | D01 | | | | | | D02 | | D03 | | | | | D04 |D01=Exon 9,13 & 17|D02=Exon 11|D03= Exon 18|D04=Mutant succinate dehydrogenase}}
{{familytree | | |!| | | | | | | |!| | | |!| | | | | | |!| |}}
{{familytree | | E01 | | | | | | E02 | | E03 | | | | | E04 |E01=Uncontrolled KIT signalling|E02=KIT receptor mutation & uncontrolled activation|E03=Uncontrolled activation|E04=Dysfunction of electron transport mitochondria}}
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{{familytree | | | | | | | | | | | | | | | | | | | | | F01 |F01=Defective oxidative phosphorylation}}
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{{familytree | | | | | | | | | | | | | | | | | | | | | G01 |G01=Abnormal stabilization of HIF transcription factor<br>(Hypoxia-inducible factor-1)}}
{{familytree/end}}
 
==Associated Conditions==
*[[Urticaria pigmentosa]]
*[[Neurofibromatosis type 1]]
*Carney-Stratakis syndrome
 
==Gross Pathology==
On gross pathology, GISTs have the following findings:
*Rounded [[appearance]] with areas of [[hemorrhage]].
*Large [[tumors]] may have [[necrosis]] or cystic change.
*Variable size (ranging from 1 to 30cms).
[[image:Gist.jpg|thumb|center|Gross pathology: Gastrointestinal stromal tumor of stomach. Source:Courtesy of Ed Uthman, MD]]
 
==Microscopic Pathology==
On [[microscopic]] [[histopathological]] analysis, GISTs are cellular [[tumor|tumors]] arising from muscularis propria and composed of:<ref>{{Cite web | title = Gastrointestinal stromal tumour| url = http://radiopaedia.org/articles/gastrointestinal-stromal-tumour-1}}</ref>
*[[Spindle cells]] (60%-80%): [[Spindle cells]] have a fascicular or whorled like appearance and are made of multiple compact cells with minimal stroma and eosinophilic, basophilic or amphophilic cytoplasm. The [[CD117]] expression in spindle cells are generally diffuse and strong. 
*[[Epithelioid cell|Epithelioid cells]] (20%-30%): Epithelioid tumors are clearly defined with an abundant [[cytoplasm]] which is amphophilic to clear. The [[CD117]] expression in epithelioid cells is generally focal and weakly positive. 
*[[Spindle cells]] or ep[[Epithelioid cell|ithelioid cells]] (10%).
[[File:Gastric GIST High Mag(1).jpg|left|frame|350x350px|Histology of GIST on high magnification. Source: [GFDL (<nowiki>http://www.gnu.org/copyleft/fdl.html</nowiki>) or CC-BY-SA-3.0 (<nowiki>http://creativecommons.org/licenses/by-sa/3.0/</nowiki>)], via Wikimedia Commons<ref>By No machine-readable author provided. KGH assumed (based on copyright claims). [GFDL (<nowiki>http://www.gnu.org/copyleft/fdl.html</nowiki>) or CC-BY-SA-3.0 (<nowiki>http://creativecommons.org/licenses/by-sa/3.0/</nowiki>)], via Wikimedia Commons</ref>
]]
[[File:Gastric GIST Low mag.jpg|none|frame|341x341px|Histology of GIST on low magnification. Source: [GFDL (<nowiki>http://www.gnu.org/copyleft/fdl.html</nowiki>) or CC-BY-SA-3.0 (<nowiki>http://creativecommons.org/licenses/by-sa/3.0/</nowiki>)], via Wikimedia Commons<ref>By No machine-readable author provided. KGH assumed (based on copyright claims). [GFDL (<nowiki>http://www.gnu.org/copyleft/fdl.html</nowiki>) or CC-BY-SA-3.0 (<nowiki>http://creativecommons.org/licenses/by-sa/3.0/</nowiki>)], via Wikimedia Commons</ref>]]
<br clear="left" />


==Histopathology==
[[Image:gist.jpg|thumb|left|Gastrointestinal stromal tumor of stomach. Courtesy of Ed Uthman, MD.]]
<br clear="left"/>
==References==
==References==
{{reflist|2}}
{{reflist|2}}
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Latest revision as of 19:06, 22 February 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

Overview

Gastrointestinal stromal tumors (GISTs) are rare but the most common mesenchymal (nonepithelial) tumors of the gastrointestinal tract. GISTs are derived from the interstitial cells of Cajal or undifferen2tiated precursor cells that finally develop into interstitial cells of Cajal. GIST tumors can either be benign tumors or massive malignant tumors with widespread metastasis. They can occur in any part of the gastrointestinal tract with the most common location as stomach. GIST (tumors) can grow as an endophytic or exophytic lesions. Genes involved in the pathogenesis of gastrointestinal stromal tumors include mutations in c-Kit gene and PDGFRA (platelet derived growth factor receptor-alpha) gene. Both Kit gene and PDGFRA are tyrosine kinase receptors and control cell proliferation. Mutation in c-Kit gene and PDGFRA leads to inhibition of apoptosis and uncontrolled cell proliferation. In some rare cases where the patient do not exhibit the typical mutation in c-Kit and PDGFRA, mutations in succinate dehydrogenase (SDH) have been reported. Conditions associated with GIST include urticaria pigmentosa, neurofibromatosis type 1, and Carney-Stratakis syndrome. On gross pathology, GISTs have a rounded appearance with areas of hemorrhage. On microscopic histopathological analysis, GISTs are cellular tumors arising from muscularis propria and composed of spindle cells (70%), epithelioid cells (20%) or either one of them.

Pathophysiology

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, mutation in succinate dehydrogenase (SDH) have been reported. Rare genes involved include BRAF kinase, and protein kinase C. The majority of GISTs are sporadic in origin. [8][9][10][11]



 
 
 
 
 
 
 
 
 
 
 
 
 
Gastrointestinal stromal tumors
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uncontrolled cell proliferation can be from
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KIT gene mutation
 
 
 
 
 
PDGFRA mutation
 
 
 
 
Wild type (absence of KIT/PDGFRA mutation)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exon 9,13 & 17
 
 
 
 
 
Exon 11
 
Exon 18
 
 
 
 
Mutant succinate dehydrogenase
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uncontrolled KIT signalling
 
 
 
 
 
KIT receptor mutation & uncontrolled activation
 
Uncontrolled activation
 
 
 
 
Dysfunction of electron transport mitochondria
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Defective oxidative phosphorylation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal stabilization of HIF transcription factor
(Hypoxia-inducible factor-1)

Associated Conditions

Gross Pathology

On gross pathology, GISTs have the following findings:

Gross pathology: Gastrointestinal stromal tumor of stomach. Source:Courtesy of Ed Uthman, MD

Microscopic Pathology

On microscopic histopathological analysis, GISTs are cellular tumors arising from muscularis propria and composed of:[12]

  • Spindle cells (60%-80%): Spindle cells have a fascicular or whorled like appearance and are made of multiple compact cells with minimal stroma and eosinophilic, basophilic or amphophilic cytoplasm. The CD117 expression in spindle cells are generally diffuse and strong.
  • Epithelioid cells (20%-30%): Epithelioid tumors are clearly defined with an abundant cytoplasm which is amphophilic to clear. The CD117 expression in epithelioid cells is generally focal and weakly positive.
  • Spindle cells or epithelioid cells (10%).
Histology of GIST on high magnification. Source: [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons[13]
Histology of GIST on low magnification. Source: [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons[14]


References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ "Gastrointestinal stromal tumour".
  13. ↑ By No machine-readable author provided. KGH assumed (based on copyright claims). [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons
  14. ↑ By No machine-readable author provided. KGH assumed (based on copyright claims). [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons


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