Cholangiocarcinoma pathophysiology: Difference between revisions
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'''Intraductal''': | '''Intraductal''': | ||
Intraductal tumors make up 8-18% of resected cholangiocarcinomas and a much smaller number of all cholangiocarcinomas (as most are inoperable). They are | 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== | ||
Revision as of 19:08, 12 November 2015
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Shivali Marketkar, M.B.B.S. [2]Suveenkrishna Pothuru, M.B,B.S. [3]
Overview
Cholangiocarcinoma is originated by a malignant transformation of cholangiocytes, the epithelial cells lining the biliary ducts.[1] 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.[2] 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.[3] On microscopic histopathological analysis, cholangiocarcinomas may vary from undifferentiated to well-differentiated. They are often surrounded by a brisk fibrotic or desmoplastic tissue.
Pathophysiology
- Cholangiocarcinoma is originated by a malignant transformation of cholangiocytes, the epithelial cells lining the biliary ducts.[1]
- 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.[4]
- 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.[3]
- Chronic inflammation, obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in the progression of cancer.[4][5][6]
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.[2]
- 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.
- In addition, NO and several cytokines can inhibit cholangiocyte apoptosis, both directly, by the nitrosylation of caspase, and indirectly, through the stimulation of 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.
- 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.
- 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.
- Furthermore, it should be noted that the membrane receptor TGR5, which responds to bile acids, is overexpressed in cholangiocarcinomas and confers resistance to apoptosis.
- 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.
- The expression of the 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.
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 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.
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. 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:[3]
Mass-forming: Intrahepatic exophytic nodular (peripheral) tumors are most commonly of the mass-forming subtype. They demonstrate variable amounts of central fibrosis.
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.
Intraductal: 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
- Histologically, cholangiocarcinomas may vary from undifferentiated to well-differentiated.
- They are often surrounded by a brisk fibrotic or desmoplastic tissue.
- In the presence of extensive fibrosis, it can be difficult to distinguish well-differentiated cholangiocarcinoma from normal reactive epithelium.
- 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.
Immunohistochemistry
- There is no entirely specific immunohistochemical stain that can distinguish malignant from benign biliary ductal tissue, although staining for cytokeratin, carcinoembryonic antigen, and mucin may aid in diagnosis.[7] Most tumors (>90%) are adenocarcinomas.[8]
Video
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References
- ↑ 1.0 1.1 Fava, G.; Lorenzini, I. (2012). "Molecular Pathogenesis of Cholangiocarcinoma". International Journal of Hepatology. 2012: 1–7. doi:10.1155/2012/630543. ISSN 2090-3448.
- ↑ 2.0 2.1 Macias, Rocio I. R. (2014). "Cholangiocarcinoma: Biology, Clinical Management, and Pharmacological Perspectives". ISRN Hepatology. 2014: 1–13. doi:10.1155/2014/828074. ISSN 2314-4041.
- ↑ 3.0 3.1 3.2 Cholangiocarcinoma. Radiopaedia. http://radiopaedia.org/articles/cholangiocarcinoma
- ↑ 4.0 4.1 Sirica A (2005). "Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy". Hepatology. 41 (1): 5–15. PMID 15690474.
- ↑ 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.
- ↑ Gores G (2003). "Cholangiocarcinoma: current concepts and insights". Hepatology. 37 (5): 961–9. PMID 12717374.
- ↑ de Groen P, Gores G, LaRusso N, Gunderson L, Nagorney D (1999). "Biliary tract cancers". N Engl J Med. 341 (18): 1368–78. PMID 10536130.
- ↑ Henson D, Albores-Saavedra J, Corle D (1992). "Carcinoma of the extrahepatic bile ducts. Histologic types, stage of disease, grade, and survival rates". Cancer. 70 (6): 1498–501. PMID 1516001.