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| {{Cholangiocarcinoma}} | | {{Cholangiocarcinoma}} |
| {{CMG}};{{AE}}{{SM}}{{PSK}} | | |
| | {{CMG}}; {{AE}} {{F.K}} |
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| ==Overview== | | ==Overview== |
| Cholangiocarcinoma is originated by a malignant transformation of [[cholangiocytes]], the epithelial cells lining the [[Bile ducts|biliary ducts]].<ref name="FavaLorenzini2012">{{cite journal|last1=Fava|first1=G.|last2=Lorenzini|first2=I.|title=Molecular Pathogenesis of Cholangiocarcinoma|journal=International Journal of Hepatology|volume=2012|year=2012|pages=1–7|issn=2090-3448|doi=10.1155/2012/630543}}</ref> Many genetic mutations altering pathways that govern cell proliferation and survival have been discovered in cholangiocarcinoma. It has been suggested that chronic cholestasis and [[inflammation]] may enhance cell proliferation, which would increase the risk of somatic [[mutations]].<ref name="Macias2014">{{cite journal|last1=Macias|first1=Rocio I. R.|title=Cholangiocarcinoma: Biology, Clinical Management, and Pharmacological Perspectives|journal=ISRN Hepatology|volume=2014|year=2014|pages=1–13|issn=2314-4041|doi=10.1155/2014/828074}}</ref> On gross pathology, cholangiocarcinoma is a sclerotic mass without hemorrhage or macroscopic [[necrosis]]. Cholangicarcinoma may be classified according to macroscopic growth pattern into three subtypes include mass-forming, periductal infiltrating, and intraductal cholangiocarcinomas.<ref name=radio>Cholangiocarcinoma. Radiopaedia. http://radiopaedia.org/articles/cholangiocarcinoma</ref> On microscopic histopathological analysis, cholangiocarcinoma may vary from [[cellular differentiation|undifferentiated to well-differentiated]]. They are often surrounded by a brisk [[fibrosis|fibrotic]] or [[desmoplastic]] tissue.
| | The exact pathogenesis of [disease name] is not fully understood. |
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| | 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]. |
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| | [Pathogen name] is usually transmitted via the [transmission route] route to the human host. |
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| | Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell. |
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| ==Pathophysiology==
| | [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells]. |
| *Cholangiocarcinoma is originated by a malignant transformation of [[cholangiocytes]], the [[epithelial cells]] lining the [[Bile duct|biliary ducts]].<ref name="FavaLorenzini2012">{{cite journal|last1=Fava|first1=G.|last2=Lorenzini|first2=I.|title=Molecular Pathogenesis of Cholangiocarcinoma|journal=International Journal of Hepatology|volume=2012|year=2012|pages=1–7|issn=2090-3448|doi=10.1155/2012/630543}}</ref>
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| *Cholangiocarcinoma is thought to develop through a series of stages from early [[hyperplasia]], [[metaplasia]], [[dysplasia]], to the development of frank [[carcinoma]] in a process similar to that observed in the development of [[colon cancer]].<ref name="targeting">{{cite journal |author=Sirica A |title=Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy |journal=Hepatology |volume=41 |issue=1 |pages=5–15 |year=2005 |id=PMID 15690474}}</ref>
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| *In specimens of bile ducts from patients with hepatolithiasis, biliary intraepithelial neoplasia is a common finding and is considered to be a precursor lesion of cholangiocarcinoma.<ref name=radio>Cholangiocarcinoma. Radiopaedia. http://radiopaedia.org/articles/cholangiocarcinoma</ref>
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| *[[inflammation|Chronic inflammation]], obstruction of the bile ducts, and the resulting impaired bile flow are thought to play a role in the progression of cancer.<ref name="targeting"/><ref>{{cite journal |author=Holzinger F, Z'graggen K, Büchler M |title=Mechanisms of biliary carcinogenesis: a pathogenetic multi-stage cascade towards cholangiocarcinoma |journal=Ann Oncol |volume=10 Suppl 4 |issue= |pages=122-6 |year= |id=PMID 10436802}}</ref><ref>{{cite journal |author=Gores G |title=Cholangiocarcinoma: current concepts and insights |journal=Hepatology |volume=37 |issue=5 |pages=961-9 |year=2003 |id=PMID 12717374}}</ref>
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| ===Molecular pathogenesis===
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| The molecular mechanisms underlying the development of cholangiocarcinoma are largely unknown. Many genetic [[mutations]] altering pathways that govern cell proliferation and survival have been discovered in cholangiocarcinoma. It has been suggested that chronic cholestasis and inflammation may enhance cell proliferation, which would increase the risk of the accumulation of somatic mutations.<ref name="Macias2014">{{cite journal|last1=Macias|first1=Rocio I. R.|title=Cholangiocarcinoma: Biology, Clinical Management, and Pharmacological Perspectives|journal=ISRN Hepatology|volume=2014|year=2014|pages=1–13|issn=2314-4041|doi=10.1155/2014/828074}}</ref>
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| *In cholangiolar cells, proinflammatory [[cytokines]] such as [[TNF-α]] and [[IL-6]], stimulate the expression of inducible nitric oxide synthase (iNOS), enhancing NO production. Reactive oxygen species, together with NO interact with DNA and inhibit DNA repair mechanisms. The result is the promotion of mutagenesis.
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| *In addition, NO and several cytokines can inhibit cholangiocyte [[apoptosis]], both directly, by the nitrosylation of caspase, and indirectly, through the stimulation of [[Cyclooxygenase|cyclooxygenase 2]] (COX-2), the rate-limiting enzyme in [[prostaglandin]] biosynthesis. Via prostaglandin E2 production, this enzyme is able to inhibit [[apoptosis]] and activate the cell cycle.
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| *COX-2 can be activated by members of the [[EGFR]] (epidermal growth factor receptor) family, in particular the tyrosine kinase ErbB-2 ([[HER2/neu]]). This is overexpressed in a moderate proportion of cholangiocarcinomas, mostly of the extrahepatic cholangiocarcinoma type, as well as in animal models of cholangiocarcinogenesis. Moreover, a high [[ErbB-2]] expression has also been associated with increased invasiveness, proliferation, and mobility of cholangiocarcinoma cells.
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| *Previous ‘‘in vitro’’ studies have suggested an indirect mutagenic ability of most hydrophobic bile acids, such as deoxycholic acid, which may favor cholangiocarcinogenesis. It has been reported that this effect could be due to EGFR pathway-dependent upregulation of COX-2. However, some studies have shown that bile acids do not induce direct damage in [[DNA]] but act as promoters, stimulating cholangiolar cells proliferation, probably via the activation of growth factors, such as EGFR.
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| *Furthermore, it should be noted that the membrane receptor TGR5, which responds to bile acids, is overexpressed in cholangiocarcinoma and confers resistance to apoptosis.
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| *In contrast, the nuclear receptor FXR, which also behaves as a bile acid sensor, seems to play a role in the protection against the development of cholangiocarcinoma.
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| *The expression of the [[VEGF|vascular endothelial growth factor-C]] (VEGF-C), an important lymphangiogenetic factor, has been found elevated in approximately 50% of cholangiocarcinoma analysed. Interestingly, VEGF-C upregulation was associated with a worse prognosis in patients with intrahepatic cholangiocarcinoma. The activation of VEGF receptor (VEGFR) stimulates the proliferation and migration of [[endothelial cells]], and these effects are enhanced by estrogens, through the induction of the expression of VEGFR.
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| In experimental models of chemically induced cholangiocarcinoma in rats a significant increase in the expression of [[IL-6]] has been found in tumor cells. Moreover, IL-6 has also been found to be elevated in the serum of patients with cholangiocarcinoma. This cytokine is known to play a key role in cholangiocyte malignization. First, IL-6 favors the ability of these cells to elude apoptosis by upregulation of the antiapoptotic protein Mcl-1 (myeloid cell leukemia-1) through the [[STAT|STAT3]] and [[AKT]] signaling pathways. Second, IL-6 activates mitogen-activated protein kinase p38, which promotes cell proliferation and stimulates telomerase activity. It reduces senescence in malignized cholangiocytes.
| | The progression to [disease name] usually involves the [molecular pathway]. |
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| ==Gross Pathology==
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| On gross pathology, cholangiocarcinomas are sclerotic masses without hemorrhage or macroscopic necrosis. The peripheral mass appears as a large white-grey lesion characterized by fibrosis (fibrotic core) and associated with capsular retraction. [[Calcification|Calcifications]] are rare. Sometimes there is concomitant dilatation of adjacent bile ducts and atrophy of corresponding liver segments. Cholangicarcinomas may be classified according to macroscopic growth pattern into three subtypes:<ref name=radio>Cholangiocarcinoma. Radiopaedia. http://radiopaedia.org/articles/cholangiocarcinoma</ref>
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| '''Mass-forming''':
| | The pathophysiology of [disease/malignancy] depends on the histological subtype. |
| Intrahepatic exophytic nodular (peripheral) tumors are most commonly of the mass-forming subtype. They demonstrate variable amounts of central fibrosis.
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| '''Periductal infiltrating''':
| | ==Pathophysiology== |
| Periductal infiltrating intrahepatic tumors are most common at the hilum, where they are known as Klatskin tumor. Periductal infiltrating cholangiocarcinoma can be present in combination with mass forming tumor within the liver. Growth along the walls of the duct may narrow or dilate the duct.
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| '''Intraductal''':
| | ===Pathogenesis=== |
| Intraductal tumors make up 8-18% of resected cholangiocarcinomas and a much smaller number of all cholangiocarcinomas (as most are inoperable). They are characterized by alterations in duct caliber, usually duct ectasia with or without a visible mass. If a mass is visible it may be mural or polypoid in shape. The duct dilatation is thought to be due to abundant mucin production.
| | *The exact pathogenesis of [disease name] is not fully understood. |
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| | *It is understood 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. |
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| ==Microscopic Pathology== | | ==Genetics== |
| *[[Histology|Histologically]], cholangiocarcinomas may vary from [[cellular differentiation|undifferentiated to well-differentiated]]. | | *[Disease name] is transmitted in [mode of genetic transmission] pattern. |
| *They are often surrounded by a brisk [[fibrosis|fibrotic]] or [[desmoplastic]] tissue. | | *Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3]. |
| *In the presence of extensive fibrosis, it can be difficult to distinguish well-differentiated cholangiocarcinoma from normal reactive [[epithelium]]. | | *The development of [disease name] is the result of multiple genetic mutations. |
| *In general, the active tumor is at the periphery, with the central portions having been replaced by fibrosis, accounting for the capsular retraction which may be seen in intrahepatic tumors.
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| Shown below is a micrograph of an intrahepatic cholangiocarcinoma (right of image) adjacent to benign hepatocytes (left of image). H&E stain.
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| [[Image:800px-Cholangiocarcinoma_-_very_high_mag.jpg|200px|Micrograph of an intrahepatic cholangiocarcinoma (right of image) adjacent to benign hepatocytes (left of image)]]
| | ==Associated Conditions== |
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| ==Immunohistochemistry== | | ==Gross Pathology== |
| *There is no entirely specific [[immunohistochemistry|immunohistochemical]] stain that can distinguish [[malignant]] from [[benign]] biliary ductal tissue, although staining for [[cytokeratin]], [[carcinoembryonic antigen]], and [[mucin]] may aid in diagnosis.<ref name="nejm">{{cite journal |author=de Groen P, Gores G, LaRusso N, Gunderson L, Nagorney D |title=Biliary tract cancers |journal=N Engl J Med |volume=341 |issue=18 |pages=1368–78 |year=1999 |id=PMID 10536130}}</ref> Most tumors (>90%) are [[adenocarcinoma]]s.<ref>{{cite journal |author=Henson D, Albores-Saavedra J, Corle D |title=Carcinoma of the extrahepatic bile ducts. Histologic types, stage of disease, grade, and survival rates |journal=Cancer |volume=70 |issue=6 |pages=1498-501 |year=1992 |id=PMID 1516001}}</ref> | | *On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. |
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| ===Video=== | | ==Microscopic Pathology== |
| {{#ev:youtube|ov5ULXfuJs0}}
| | *On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. |
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| ==References== | | ==References== |
| {{reflist|2}} | | {{Reflist|2}} |
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| [[Category:Disease]]
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| [[Category:Rare cancers]]
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| [[Category:Rare diseases]]
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| [[Category:Types of cancer]]
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| [[Category:Hepatology]]
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| [[Category:Gastroenterology]]
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| {{WH}} | | {{WH}} |
| {{WS}} | | {{WS}} |
| [[Category:Up-To-Date]]
| | [[Category: (name of the system)]] |
| [[Category:Oncology]]
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| [[Category:Medicine]]
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| [[Category:Gastroenterology]]
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| [[Category:Surgery]]
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [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 understood 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
- [Disease name] is transmitted in [mode of genetic transmission] pattern.
- Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
- The development of [disease name] is the result of multiple genetic mutations.
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
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