Cholangiocarcinoma pathophysiology: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
No edit summary
 
(37 intermediate revisions by 4 users not shown)
Line 1: Line 1:
__NOTOC__
__NOTOC__
{{Cholangiocarcinoma}}
{{Cholangiocarcinoma}}
{{CMG}};{{AE}}{{SM}}{{PSK}}
 
{{CMG}}; {{AE}} {{F.K}}, {{Anmol}}
==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, cholangiocarcinomas are sclerotic masses without hemorrhage or macroscopic [[necrosis]]. Cholangicarcinomas 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, cholangiocarcinomas may vary from [[cellular differentiation|undifferentiated to well-differentiated]]. They are often surrounded by a brisk [[fibrosis|fibrotic]] or [[desmoplastic]] tissue.
The [[epithelial cell]] lining the [[bile ducts]] are called [[cholangiocytes]]. The malignant transformsation of cholangiocytes leads to cholangiocarcinoma. [[Malignant]] [[transformation]] of cholangiocytes into cholangiocarcinoma include [[hyperplasia]], [[metaplasia]] and dysplasia. Biliary intraepithelial [[neoplasia]] is believed to be the initial lesion of cholangiocarcinoma, particularly in patients with [[hepatolithiasis]] in [[bile ducts]]. Gross pathologic features characteristic to intrahepatic cholangiocarcinoma are divided in three subtypes and include mass forming type, periductal infiltrating type, and intraductal growth type. On microscopic pathology, characteristic findings of cholangiocarcinoma include [[Cuboidal epithelia|cuboidal]] or columnar [[mucin]] producing cells and dense fibrous (desmoplastic) [[stroma]].


==Pathophysiology==
==Pathophysiology==
*Cholangiocarcinoma is originated by a malignant transformation of cholangiocytes, the epithelial cells lining the 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>
*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>
*In specimens of bile ducts from patients with hepatolithiasis, biliary intraepithelial neoplasia is common finding and is considered to be a precursor lesion of cholangiocarcinoma.<ref name=radio>Cholangiocarcinoma. Radiopaedia. http://radiopaedia.org/articles/cholangiocarcinoma</ref>
*[[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>
===Molecular pathogenesis===
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>


*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.
===Pathogenesis===
*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.
*The [[epithelial cell]] lining the bile ducts are called [[cholangiocytes]]. The malignant transformsation of [[cholangiocytes]] leads to cholangiocarcinoma.<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>
*COX-2 can be activated by members of the [[EGFR]] (epidermal growth factor receptor) family, in particular the tyrosine kinase ERBB2 (HER-2/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 ERBB2 expression has also been associated with increased invasiveness, proliferation, and mobility of cholangiocarcinoma cells.
*Malignant transformation of [[cholangiocytes]] into cholangiocarcinoma include following stages:<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>
*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.
*#[[Hyperplasia]]
*Furthermore, it should be noted that the membrane receptor TGR5, which responds to bile acids, is overexpressed in cholangiocarcinomas and confers resistance to apoptosis.
*#[[Metaplasia]]
*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.
*#[[Dysplasia]]
*The expression of the [[VEGF|vascular endothelial growth factor-C]] (VEGF-C), an important lymphangiogenetic factor, has been found elevated in approximately 50% of cholangiocarcinomas 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.
*#Frank carcinoma
*Progression of [[malignancy]] is believed to be due to:<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>
**[[Inflammation]]
**[[Obstruction]] of [[bile ducts]]
**[[Biliary]] intraepithelia [[neoplasia]]
*[[Biliary]] intraepithelial neoplasia is believed to be the initial lesion of cholangiocarcinoma, particularly in patients with [[hepatolithiasis]] in bile ducts.


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, which reduces senescence in malignized cholangiocytes.
==Genetics==
<div style="text-align: center">'''Algorithm showing molecular mechanism of cholangiocarcinoma'''<ref name="pmid21691113">{{cite journal |vauthors=Wadsworth CA, Dixon PH, Wong JH, Chapman MH, McKay SC, Sharif A, Spalding DR, Pereira SP, Thomas HC, Taylor-Robinson SD, Whittaker J, Williamson C, Khan SA |title=Genetic factors in the pathogenesis of cholangiocarcinoma |journal=Dig Dis |volume=29 |issue=1 |pages=93–7 |year=2011 |pmid=21691113 |pmc=3696362 |doi=10.1159/000324688 |url=}}</ref><ref name="pmid25332972">{{cite journal |vauthors=Maroni L, Pierantonelli I, Banales JM, Benedetti A, Marzioni M |title=The significance of genetics for cholangiocarcinoma development |journal=Ann Transl Med |volume=1 |issue=3 |pages=28 |year=2013 |pmid=25332972 |pmc=4200671 |doi=10.3978/j.issn.2305-5839.2012.10.04 |url=}}</ref><ref name="pmid25966424">{{cite journal |vauthors=Kongpetch S, Jusakul A, Ong CK, Lim WK, Rozen SG, Tan P, Teh BT |title=Pathogenesis of cholangiocarcinoma: From genetics to signalling pathways |journal=Best Pract Res Clin Gastroenterol |volume=29 |issue=2 |pages=233–44 |year=2015 |pmid=25966424 |doi=10.1016/j.bpg.2015.02.002 |url=}}</ref></div>
<br>
{{Family tree/start}}
{{Family tree| | | | | | | | A01 | | | | | | A01=Cholangiocytes}}
{{Family tree| | | | | | | | |!| | | | | | | }}
{{Family tree| | | | | | | | B01 | | | | | | B01=Proinflammatory cytokines ([[TNF-α]] and [[IL-6]])}}
{{Family tree| | | | | | | | |!| | | | | | | }}
{{Family tree| | | | C01 | | C02 | | C03 | | C01=Several cytokines )|C02=Stimulates the expression of inducible nitric oxide synthase (iNOS) and enhancing NO production|C03=Reactive oxygen species}}
{{Family tree| | | | | |`|v|'| |`|v|'| | | | }}
{{Family tree| | D01 | | |!| | | D02 | | | | D01=[[EGFR]] (epidermal growth factor receptor) family, specifically the tyrosine kinase ErbB-2 ([[HER2/neu]]|D02=Inhibit DNA repair mechanism}}
{{Family tree| |!|!| | | |!| | | |!| | | | | }}
{{Family tree| |!|!|,|-|-|(| | | |!| | | | | }}
{{Family tree| |!| E02 | | E01 | |!| | | | | E01=Nitrosylation of caspase|E02=Stimulation of [[Cyclooxygenase|cyclooxygenase 2]] (COX-2)}}
{{Family tree| |!| |!| | | |!| | |!| | | | | }}
{{Family tree| E03 |!| | | |!| | |!| | | | | E03=Increased invasiveness, proliferation, and mobility of cholangiocytes}}
{{Family tree| | | |!| | | |!| | |!| | | | | }}
{{Family tree| | | F01 | | |!| | |!| | | | | F01=Prostaglandin E2 production(Rate limitimg step)}}
{{Family tree| | | |`|-|v|-|'| | |!| | | | | }}
{{Family tree| | | | | |!| | | | |!| | | | | }}
{{Family tree| | | |,|-|^|-|.| | |!| | | | | }}
{{Family tree| | | G01 | | G02 | | G03 | | | | G01=Activate cell cycle of cholangiocytes|G02=Inhibit apoptosis of cholangiocytes|G03=Promotes mutagenesis}}
{{Family tree/end}}


==Gross Pathology==
==Gross Pathology==
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>
Gross pathologic features characteristic to intrahepatic cholangiocarcinoma are divided in three subtypes and include:<ref name="pmid21191517">{{cite journal |vauthors=Nakanuma Y, Sato Y, Harada K, Sasaki M, Xu J, Ikeda H |title=Pathological classification of intrahepatic cholangiocarcinoma based on a new concept |journal=World J Hepatol |volume=2 |issue=12 |pages=419–27 |year=2010 |pmid=21191517 |pmc=3010511 |doi=10.4254/wjh.v2.i12.419 |url=}}</ref><ref name="pmid21808282">{{cite journal |vauthors=Blechacz B, Komuta M, Roskams T, Gores GJ |title=Clinical diagnosis and staging of cholangiocarcinoma |journal=Nat Rev Gastroenterol Hepatol |volume=8 |issue=9 |pages=512–22 |year=2011 |pmid=21808282 |pmc=3331791 |doi=10.1038/nrgastro.2011.131 |url=}}</ref><ref name="pmid28261592">{{cite journal |vauthors=Vijgen S, Terris B, Rubbia-Brandt L |title=Pathology of intrahepatic cholangiocarcinoma |journal=Hepatobiliary Surg Nutr |volume=6 |issue=1 |pages=22–34 |year=2017 |pmid=28261592 |pmc=5332210 |doi=10.21037/hbsn.2016.11.04 |url=}}</ref>
*'''Mass-forming type'''
**Nodular lesion or mass in the hepatic [[parenchyma]]
**Gray to gray-white, firm and solid carcinoma
*'''Periductal infiltrating type'''
**Spreading of the [[carcinoma]] along the portal tracts with [[stricture]] of the affected [[bile ducts]] 
**Dilatation of the peripheral [[bile ducts]]
*'''Intraductal growth type'''
**Polypoid or papillary tumor within the variably dilated bile duct lumen
**[[Malignant]] progression of an intraductal papillary [[neoplasm]] of the [[bile duct]]


'''Mass-forming''':
{|
Intrahepatic exophytic nodular (peripheral) tumors are most commonly of the mass-forming subtype. They demonstrate variable amounts of central fibrosis.
|
 
[[File:Cholangiocarcinoma.png|thumb|400px|left|Intrahepatic cholangiocarcinoma [https://commons.wikimedia.org/wiki/File:Cholangiocarcinoma.png Source: By Banchob Sripa, via Wikimedia Commons]<ref name="urlFile:Cholangiocarcinoma.png - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/wiki/File:Cholangiocarcinoma.png |title=File:Cholangiocarcinoma.png - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]
'''Periductal infiltrating''':
|
Periductal infiltrating intrahepatic tumors are most common at the hilum, where they are known as Klatskin tumor. It can be present in combination with mass forming tumors within the liver. Growth along the walls of the duct may narrow or dilate the duct.
[[File:CCA Cholangiocarcinoma.jpg|thumb|400px|left|Cholangiocarcinoma [https://commons.wikimedia.org/wiki/File:CCA_Cholangiocarcinoma.jpg Source: By Sripa B, Kaewkes S, Sithithaworn P, Mairiang E, Laha T, et al, via Wikimedia Commons]<ref name="urlFile:CCA Cholangiocarcinoma.jpg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/wiki/File:CCA_Cholangiocarcinoma.jpg |title=File:CCA Cholangiocarcinoma.jpg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]
 
|}
'''Intraductal''':
<br style="clear:left" />
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.


==Microscopic Pathology==
==Microscopic Pathology==
*[[Histology|Histologically]], cholangiocarcinomas may vary from [[cellular differentiation|undifferentiated to well-differentiated]].
On microscopic pathology, characteristic findings of cholangiocarcinoma include:
*They are often surrounded by a brisk [[fibrosis|fibrotic]] or [[desmoplastic]] tissue.
*[[Cuboidal]] or columnar [[mucin]] producing cells
*In the presence of extensive fibrosis, it can be difficult to distinguish well-differentiated cholangiocarcinoma from normal reactive [[epithelium]].
*Dense fibrous (desmoplastic) [[stroma]]
*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.
Shown below is a micrograph of an intrahepatic cholangiocarcinoma (right of image) adjacent to benign hepatocytes (left of image). H&E stain.


[[Image:800px-Cholangiocarcinoma_-_very_high_mag.jpg‎|200px|Micrograph of an intrahepatic cholangiocarcinoma (right of image) adjacent to benign hepatocytes (left of image)]]
[[File:Cholangiocarcinoma - histopathology.png|thumb|800px|left|Cholangiocarcinoma histopathology [https://commons.wikimedia.org/wiki/File:Cholangiocarcinoma_-_high_mag.jpg Source: By Nephron (Own work), via Wikimedia Commons]<ref name="urlFile:Cholangiocarcinoma - high mag.jpg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/wiki/File:Cholangiocarcinoma_-_high_mag.jpg |title=File:Cholangiocarcinoma - high mag.jpg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]


==Immunohistochemistry==
<br style="clear:left" />
*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>
 
===Video===
{{#ev:youtube|ov5ULXfuJs0}}


==References==
==References==
{{reflist|2}}
{{Reflist|2}}
 
[[Category:Disease]]
[[Category:Rare cancers]]
[[Category:Rare diseases]]
[[Category:Types of cancer]]
[[Category:Hepatology]]
[[Category:Gastroenterology]]


{{WH}}
{{WH}}
{{WS}}
{{WS}}
[[Category: (name of the system)]]

Latest revision as of 20:18, 6 February 2018

Cholangiocarcinoma Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Cholangiocarcinoma from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

CT

MRI

Echocardiography or Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Cholangiocarcinoma pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Cholangiocarcinoma pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Cholangiocarcinoma pathophysiology

CDC on Cholangiocarcinoma pathophysiology

Cholangiocarcinoma pathophysiology in the news

Blogs on Cholangiocarcinoma pathophysiology

Directions to Hospitals Treating Cholangiocarcinoma

Risk calculators and risk factors for Cholangiocarcinoma pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2], Anmol Pitliya, M.B.B.S. M.D.[3]

Overview

The epithelial cell lining the bile ducts are called cholangiocytes. The malignant transformsation of cholangiocytes leads to cholangiocarcinoma. Malignant transformation of cholangiocytes into cholangiocarcinoma include hyperplasia, metaplasia and dysplasia. Biliary intraepithelial neoplasia is believed to be the initial lesion of cholangiocarcinoma, particularly in patients with hepatolithiasis in bile ducts. Gross pathologic features characteristic to intrahepatic cholangiocarcinoma are divided in three subtypes and include mass forming type, periductal infiltrating type, and intraductal growth type. On microscopic pathology, characteristic findings of cholangiocarcinoma include cuboidal or columnar mucin producing cells and dense fibrous (desmoplastic) stroma.

Pathophysiology

Pathogenesis

Genetics

Algorithm showing molecular mechanism of cholangiocarcinoma[5][6][7]


 
 
 
 
 
 
 
Cholangiocytes
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Proinflammatory cytokines (TNF-α and IL-6)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Several cytokines )
 
Stimulates the expression of inducible nitric oxide synthase (iNOS) and enhancing NO production
 
Reactive oxygen species
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EGFR (epidermal growth factor receptor) family, specifically the tyrosine kinase ErbB-2 (HER2/neu
 
 
 
 
 
 
Inhibit DNA repair mechanism
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stimulation of cyclooxygenase 2 (COX-2)
 
Nitrosylation of caspase
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Increased invasiveness, proliferation, and mobility of cholangiocytes
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prostaglandin E2 production(Rate limitimg step)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Activate cell cycle of cholangiocytes
 
Inhibit apoptosis of cholangiocytes
 
Promotes mutagenesis
 
 
 

Gross Pathology

Gross pathologic features characteristic to intrahepatic cholangiocarcinoma are divided in three subtypes and include:[8][9][10]

  • Mass-forming type
    • Nodular lesion or mass in the hepatic parenchyma
    • Gray to gray-white, firm and solid carcinoma
  • Periductal infiltrating type
  • Intraductal growth type
    • Polypoid or papillary tumor within the variably dilated bile duct lumen
    • Malignant progression of an intraductal papillary neoplasm of the bile duct
Intrahepatic cholangiocarcinoma Source: By Banchob Sripa, via Wikimedia Commons[11]
Cholangiocarcinoma Source: By Sripa B, Kaewkes S, Sithithaworn P, Mairiang E, Laha T, et al, via Wikimedia Commons[12]


Microscopic Pathology

On microscopic pathology, characteristic findings of cholangiocarcinoma include:

Cholangiocarcinoma histopathology Source: By Nephron (Own work), via Wikimedia Commons[13]


References

  1. ↑ Fava, G.; Lorenzini, I. (2012). "Molecular Pathogenesis of Cholangiocarcinoma". International Journal of Hepatology. 2012: 1–7. doi:10.1155/2012/630543. ISSN 2090-3448.
  2. ↑ 2.0 2.1 Sirica A (2005). "Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy". Hepatology. 41 (1): 5–15. PMID 15690474.
  3. ↑ Holzinger F, Z'graggen K, Büchler M. "Mechanisms of biliary carcinogenesis: a pathogenetic multi-stage cascade towards cholangiocarcinoma". Ann Oncol. 10 Suppl 4: 122–6. PMID 10436802.
  4. ↑ Gores G (2003). "Cholangiocarcinoma: current concepts and insights". Hepatology. 37 (5): 961–9. PMID 12717374.
  5. ↑ Wadsworth CA, Dixon PH, Wong JH, Chapman MH, McKay SC, Sharif A, Spalding DR, Pereira SP, Thomas HC, Taylor-Robinson SD, Whittaker J, Williamson C, Khan SA (2011). "Genetic factors in the pathogenesis of cholangiocarcinoma". Dig Dis. 29 (1): 93–7. doi:10.1159/000324688. PMC 3696362. PMID 21691113.
  6. ↑ Maroni L, Pierantonelli I, Banales JM, Benedetti A, Marzioni M (2013). "The significance of genetics for cholangiocarcinoma development". Ann Transl Med. 1 (3): 28. doi:10.3978/j.issn.2305-5839.2012.10.04. PMC 4200671. PMID 25332972.
  7. ↑ Kongpetch S, Jusakul A, Ong CK, Lim WK, Rozen SG, Tan P, Teh BT (2015). "Pathogenesis of cholangiocarcinoma: From genetics to signalling pathways". Best Pract Res Clin Gastroenterol. 29 (2): 233–44. doi:10.1016/j.bpg.2015.02.002. PMID 25966424.
  8. ↑ Nakanuma Y, Sato Y, Harada K, Sasaki M, Xu J, Ikeda H (2010). "Pathological classification of intrahepatic cholangiocarcinoma based on a new concept". World J Hepatol. 2 (12): 419–27. doi:10.4254/wjh.v2.i12.419. PMC 3010511. PMID 21191517.
  9. ↑ Blechacz B, Komuta M, Roskams T, Gores GJ (2011). "Clinical diagnosis and staging of cholangiocarcinoma". Nat Rev Gastroenterol Hepatol. 8 (9): 512–22. doi:10.1038/nrgastro.2011.131. PMC 3331791. PMID 21808282.
  10. ↑ Vijgen S, Terris B, Rubbia-Brandt L (2017). "Pathology of intrahepatic cholangiocarcinoma". Hepatobiliary Surg Nutr. 6 (1): 22–34. doi:10.21037/hbsn.2016.11.04. PMC 5332210. PMID 28261592.
  11. ↑ "File:Cholangiocarcinoma.png - Wikimedia Commons". External link in |title= (help)
  12. ↑ "File:CCA Cholangiocarcinoma.jpg - Wikimedia Commons".
  13. ↑ "File:Cholangiocarcinoma - high mag.jpg - Wikimedia Commons".

Template:WH Template:WS

Retrieved from "https://www.wikidoc.org/index.php?title=Cholangiocarcinoma_pathophysiology&oldid=1440261"