Renal cell carcinoma pathophysiology: Difference between revisions

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Revision as of 19:26, 28 December 2013

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Pathophysiology

Sporadic Clear Cell Renal Carcinoma

Although Von Hippel-Lindau (VHL), an autosomal dominant disorder, is characterized by the mutation of the VHL gene - a tumor suppressor gene - and the consequential development of renal clear cell carcinomas following the silencing of the remaining normal VHL gene, the gene itself has been identified to be similarly responsible of the development of sporadic forms of renal clear cell carcinomas.

VHL protein is an oxygen sensing regulator of hypoxic responses. It has a major role in binding and inhibiting transciptional activators hypoxia-induced factor (HIF) 1-alpha and 2-alpha via ubiquination and destruction using elongin proteins C and B that bind to cul2 protein of the ubiquitin ligase protein (cullin) family.(12,13,11,9,10,15,16,17,14) Normally, inhibition of HIF by VHL prevents the encoding of proteins that promote angiogenesis, such as vascular endothelial growth factor (VEGF), transforming growth factor alpha (TGF-alpha), glucose receptors such as GLUT-1 glucose transporter, and carbonic anhydrase IX (CA9) which ensures acid-base balance.(9,10,0) Inhibition of VHL induces the overexpression of these proteins, mimicking hypoxemia, and facilitates the development of clear cell carcinoma.(0) The disease process is not believed to be due to the simple interaction between VHL protein and HIF. Other proteins are also thought to be involved in the process, including fibronectin(27), chaperonin TRiC/CCT(28), microtubules(29), and transcription factor Jade-1(30-32).

Familial Forms of Clear Cell Renal Carcinoma

The translocation and loss of chromosome 3p at the site 3p14 is hypothesized to be responsible for the development of renal clear cell carcinomas in other familial forms not related to VHL disease.(33)

References

@@ Line 5: / Line 5: @@
 ==Pathophysiology==
-===Genetics===
+===Sporadic Clear Cell Renal Carcinoma===
-Recent genetic studies have altered the approaches of understanding renal cell carcinoma. <ref name="pmid10768592">{{cite journal |author=Reuter VE, Presti JC |title=Contemporary approach to the classification of renal epithelial tumors |journal=Semin. Oncol. |volume=27 |issue=2 |pages=124–37 |year=2000 |month=April |pmid=10768592 |doi= |url=}}</ref><ref name="pmid12351585">{{cite journal |author=Bodmer D, van den Hurk W, van Groningen JJ, ''et al'' |title=Understanding familial and non-familial renal cell cancer |journal=Hum. Mol. Genet. |volume=11 |issue=20 |pages=2489–98 |year=2002 |month=October |pmid=12351585 |doi= |url=http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12351585}}</ref><ref name="isbn0-7216-0187-1">{{cite book |author=Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. |title=Robbins and Cotran pathologic basis of disease |publisher=Elsevier Saunders |location=St. Louis, Mo |year=2005 |pages=1016 |isbn=0-7216-0187-1 |oclc= |doi= |accessdate=}}</ref>
+Although Von Hippel-Lindau (VHL), an autosomal dominant disorder, is characterized by the mutation of the ''VHL'' gene - a tumor suppressor gene -  and the consequential development of renal clear cell carcinomas following the silencing of the remaining normal ''VHL'' gene, the gene itself has been identified to be similarly responsible of the development of sporadic forms of renal clear cell carcinomas.
-* [[Von Hippel-Lindau tumor suppressor|VHL]] and others on [[chromosome 3]] - [[Clear cell carcinoma]]
+VHL protein is an oxygen sensing regulator of hypoxic responses. It has a major role in binding and inhibiting transciptional activators hypoxia-induced factor (HIF) 1-alpha and 2-alpha via ubiquination and destruction using elongin proteins C and B that bind to cul2 protein of the ubiquitin ligase protein (cullin) family.(12,13,11,9,10,15,16,17,14) Normally, inhibition of HIF by VHL prevents the encoding of proteins that promote angiogenesis, such as vascular endothelial growth factor (VEGF), transforming growth factor alpha (TGF-alpha), glucose receptors such as GLUT-1 glucose transporter, and carbonic anhydrase IX (CA9) which ensures acid-base balance.(9,10,0) Inhibition of VHL induces the overexpression of these proteins, mimicking hypoxemia, and facilitates the development of clear cell carcinoma.(0) The disease process is not believed to be due to the simple interaction between VHL protein and HIF. Other proteins are also thought to be involved in the process, including fibronectin(27), chaperonin TRiC/CCT(28), microtubules(29), and transcription factor Jade-1(30-32).
-* [[C-Met|MET]], [[PRCC (gene)|PRCC]] - [[Papillary]] carcinoma
-* Other associated genes include TRC8, OGG1, [[HNF1A]], [[HNF1B]], [[TFE3]], RCCP3, and RCC17.
-=== Gross Pathology ===
+===Familial Forms of Clear Cell Renal Carcinoma===
+The translocation and loss of chromosome 3p at the site 3p14 is hypothesized to be responsible for the development of renal clear cell carcinomas in other familial forms not related to VHL disease.(33)
-Gross examination shows a hypervascular lesion in the renal cortex, which is frequently multilobulated, yellow (because of the lipid accumulation) and calcified.
-[[Image:Renal cell ca.jpg|thumb|center|300px|Renal cell carcinoma: This 8-centimeter carcinoma of the lower pole of the kidney shows extension beyond the cortical surface, but it does not infiltrate the perinephric adipose tissue. Microscopically, it is of the clear cell type.]]
-=== Light Microscopy ===
-Light microscopy shows tumor cells forming cords, papillae, tubules or nests, and are atypical, polygonal and large. Because these cells accumulate [[glycogen]] and [[lipid]]s, their cytoplasm appear "clear", lipid-laden, the nuclei remain in the middle of the cells, and the cellular membrane is evident. Some cells may be smaller, with eosinophilic cytoplasm, resembling normal tubular cells. The stroma is reduced, but well vascularized. The tumor grows in large front, compressing the surrounding parenchyma, producing a pseudocapsule.<ref>http://www.pathologyatlas.ro/Renal%20Clear%20Cell%20Carcinoma.html</ref>
-Secretion of vasoactive substances (e.g. [[renin]]) may cause [[arterial hypertension]], and release of [[erythropoietin]] may cause [[polycythemia]] (increased production of [[red blood cell]]s).
 ==References==