Renal cell carcinoma pathophysiology: Difference between revisions

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{{Kidney cancer}}
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{{CMG}} {{AE}} {{F.K}}
{{Renal cell carcinoma}}


==Overview==
==Overview==
'''Renal cell carcinoma''' is the most common form of '''kidney cancer''' arising from the [[renal tubule]]. It is the most common type of [[kidney]] [[cancer]] in adults. Initial treatment is [[surgery]]. It is notoriously resistant to [[radiation therapy]] and [[chemotherapy]], although some cases respond to [[immunotherapy]]. The advent of targeted cancer therapies such as [[sunitinib]] has vastly improved the outlook for treatment of RCC.
The [[pathophysiology]] of renal cell carcinomas plays an important role in differentiating between the types of renal cell carcinomas and in choosing appropriate targeted medical therapies. Sporadic forms of clear cell renal carcinomas, the most common form of renal cell carcinomas, have similar pathophysiological mechanisms to those of [[Von Hippel-Lindau Disease|von Hippel-Lindau]] (VHL) disease. On the other hand, ''MET'' [[proto-oncogene]] seems to play a role in the disease [[pathogenesis]] of papillary forms of renal cell carcinoma. Uniquely also, [[Oncocytoma|oncocytomas]] are [[benign tumors]] that arise from type A intercalated cells, whereas [[chromophobe]] renal cell carcinoma arises from type B intercalated cells.
 
==Pathophysiology==
===Sporadic Forms of Clear Cell Renal Carcinoma===
 
* Although [[Von Hippel-Lindau Disease|Von Hippel-Lindau]] (VHL), an [[autosomal dominant]] disorder, is characterized by the mutation of the [[Von Hippel-Lindau tumor suppressor|''VHL'' gene]] - a [[tumor suppressor gene]] -  and the consequential development of renal clear cell carcinomas following the silencing of the remaining normal ''[[Von Hippel–Lindau tumor suppressor|VHL]]'' [[gene]], the [[gene]] itself has been identified to be similarly responsible of the development of sporadic forms of renal clear cell carcinomas.<ref name="pmid16339096">{{cite journal| author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref>


==Classification and pathophysiology==
* [[VHL|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.<ref name="pmid7585187">{{cite journal| author=Iliopoulos O, Kibel A, Gray S, Kaelin WG| title=Tumour suppression by the human von Hippel-Lindau gene product. | journal=Nat Med | year= 1995 | volume= 1 | issue= 8 | pages= 822-6 | pmid=7585187 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7585187  }} </ref><ref name="pmid7585510">{{cite journal| author=Chen F, Kishida T, Duh FM, Renbaum P, Orcutt ML, Schmidt L et al.| title=Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. | journal=Cancer Res | year= 1995 | volume= 55 | issue= 21 | pages= 4804-7 | pmid=7585510 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7585510  }} </ref><ref name="pmid8855223">{{cite journal| author=Iliopoulos O, Levy AP, Jiang C, Kaelin WG, Goldberg MA| title=Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. | journal=Proc Natl Acad Sci U S A | year= 1996 | volume= 93 | issue= 20 | pages= 10595-9 | pmid=8855223 | doi= | pmc=PMC38198 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8855223  }} </ref><ref name="pmid10823831">{{cite journal| author=Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC et al.| title=Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. | journal=J Biol Chem | year= 2000 | volume= 275 | issue= 33 | pages= 25733-41 | pmid=10823831 | doi=10.1074/jbc.M002740200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10823831  }} </ref><ref name="pmid10878807">{{cite journal| author=Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE et al.| title=Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. | journal=Nat Cell Biol | year= 2000 | volume= 2 | issue= 7 | pages= 423-7 | pmid=10878807 | doi=10.1038/35017054 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10878807  }} </ref><ref name="pmid10944113">{{cite journal| author=Tanimoto K, Makino Y, Pereira T, Poellinger L| title=Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. | journal=EMBO J | year= 2000 | volume= 19 | issue= 16 | pages= 4298-309 | pmid=10944113 | doi=10.1093/emboj/19.16.4298 | pmc=PMC302039 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10944113  }} </ref>
* Normally, inhibition of HIF by [[Von Hippel–Lindau tumor suppressor|VHL]] prevents the encoding of proteins that promote [[angiogenesis]], such as [[vascular endothelial growth factor]] ([[Vascular endothelial growth factor|VEGF]]), [[transforming growth factor alpha]] ([[Transforming growth factor alpha|TGF-alpha]]), glucose receptors such as [[GLUT1|GLUT-1 glucose transporter]], and [[CA9|carbonic anhydrase IX]] ([[CA9]]) which ensures acid-base balance.<ref name="pmid7585187">{{cite journal| author=Iliopoulos O, Kibel A, Gray S, Kaelin WG| title=Tumour suppression by the human von Hippel-Lindau gene product. |journal=Nat Med | year= 1995 | volume= 1 | issue= 8 | pages= 822-6 | pmid=7585187 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7585187  }} </ref><ref name="pmid7585510">{{cite journal| author=Chen F, Kishida T, Duh FM, Renbaum P, Orcutt ML, Schmidt L et al.| title=Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. | journal=Cancer Res | year= 1995 | volume= 55 | issue= 21 | pages= 4804-7 |pmid=7585510 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7585510  }} </ref> Inhibition of VHL induces the overexpression of these proteins, mimicking [[hypoxemia]], and facilitates the development of clear cell carcinoma.<ref name="pmid16339096">{{cite journal| author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref> 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]]<ref name="pmid9651579">{{cite journal| author=Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN et al.| title=The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. | journal=Mol Cell | year= 1998 | volume= 1 | issue= 7 | pages= 959-68 | pmid=9651579 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9651579  }} </ref>, chaperonin TRiC/CCT<ref name="pmid14636579">{{cite journal| author=Feldman DE, Spiess C, Howard DE, Frydman J| title=Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding. | journal=Mol Cell | year= 2003 | volume= 12 | issue= 5 | pages= 1213-24 | pmid=14636579 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14636579  }} </ref>, [[microtubules]]<ref name="pmid12510195">{{cite journal| author=Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W| title=Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. | journal=Nat Cell Biol | year= 2003 | volume= 5 | issue= 1 | pages= 64-70 | pmid=12510195 | doi=10.1038/ncb899 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12510195  }} </ref>, and transcription factor Jade-1<ref name="pmid12169691">{{cite journal| author=Zhou MI, Wang H, Ross JJ, Kuzmin I, Xu C, Cohen HT| title=The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1. | journal=J Biol Chem | year= 2002 | volume= 277 | issue= 42 | pages= 39887-98 | pmid=12169691 | doi=10.1074/jbc.M205040200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12169691  }} </ref><ref name="pmid14973063">{{cite journal| author=Zhou MI, Wang H, Foy RL, Ross JJ, Cohen HT| title=Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent. | journal=Cancer Res | year= 2004 | volume= 64 | issue= 4 | pages= 1278-86 | pmid=14973063 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14973063  }} </ref><ref name="pmid16046545">{{cite journal| author=Zhou MI, Foy RL, Chitalia VC, Zhao J, Panchenko MV, Wang H et al.| title=Jade-1, a candidate renal tumor suppressor that promotes apoptosis. | journal=Proc Natl Acad Sci U S A | year= 2005 | volume= 102 | issue= 31 | pages= 11035-40 | pmid=16046545 | doi=10.1073/pnas.0500757102 | pmc=PMC1182408 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16046545  }} </ref>.


Recent genetic studies have altered the approaches used in classifying renal cell carcinoma. The following system can be used to classify these tumors:<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>
===Familial Forms of Clear Cell Renal Carcinoma===


* [[Clear cell carcinoma]] ([[Von Hippel-Lindau tumor suppressor|VHL]] and others on [[chromosome 3]])
* The [[Translocations|translocation]] and loss of [[Chromosome 3 (human)|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 gene]].<ref name="pmid470981">{{cite journal| author=Cohen AJ, Li FP, Berg S, Marchetto DJ, Tsai S, Jacobs SC et al.| title=Hereditary renal-cell carcinoma associated with a chromosomal translocation. | journal=N Engl J Med | year= 1979 | volume= 301 | issue= 11 | pages= 592-5 | pmid=470981 | doi=10.1056/NEJM197909133011107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=470981  }} </ref>
* [[Papillary]] carcinoma ([[C-Met|MET]], [[PRCC (gene)|PRCC]])
* [[Chromophobe]] renal carcinoma
* [[Collecting duct]] carcinoma


Other associated genes include TRC8, OGG1, [[HNF1A]], [[HNF1B]], [[TFE3]], RCCP3, and RCC17.
===Papillary Renal Cell Carcinoma===


{{CMG}}
* It is believed that chromosomal aberrations, including the duplication of [[chromosome 7]] encoding ''MET'' proto-oncogene, a [[tyrosine kinase]] activated by [[hepatocyte growth factor]], may contribute to sporadic cases of papillary renal cell carcinoma in a small percentage of cases.<ref name="pmid9195569">{{cite journal| author=Delahunt B, Eble JN| title=Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. | journal=Mod Pathol | year= 1997 | volume= 10 | issue= 6 | pages= 537-44 | pmid=9195569 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9195569  }} </ref><ref name="pmid14559804">{{cite journal| author=Gunawan B, von Heydebreck A, Fritsch T, Huber W, Ringert RH, Jakse G et al.| title=Cytogenetic and morphologic typing of 58 papillary renal cell carcinomas: evidence for a cytogenetic evolution of type 2 from type 1 tumors. | journal=Cancer Res | year= 2003 | volume= 63 | issue= 19 | pages= 6200-5 | pmid=14559804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14559804  }} </ref><ref name="pmid10433944">{{cite journal| author=Lubensky IA, Schmidt L, Zhuang Z, Weirich G, Pack S, Zambrano N et al.| title=Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. | journal=Am J Pathol | year= 1999 | volume= 155 | issue= 2 | pages= 517-26 | pmid=10433944 | doi=10.1016/S0002-9440(10)65147-4 | pmc=PMC1866853 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10433944  }} </ref><ref name="pmid9140397">{{cite journal| author=Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P et al.| title=Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. | journal=Nat Genet | year= 1997 | volume= 16 | issue= 1 | pages= 68-73 | pmid=9140397 | doi=10.1038/ng0597-68 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9140397  }} </ref>
{{Renal cell carcinoma}}
* On the other hand, hereditary forms of papillary cell carcinoma have a different [[pathophysiology]]. Hereditary forms have an [[autosomal dominant]] pattern.<ref name="pmid7853572">{{cite journal| author=Zbar B, Glenn G, Lubensky I, Choyke P, Walther MM, Magnusson G et al.| title=Hereditary papillary renal cell carcinoma: clinical studies in 10 families. | journal=J Urol | year= 1995 | volume= 153 | issue= 3 Pt 2 | pages= 907-12 | pmid=7853572 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7853572  }} </ref> In hereditary forms, pathological cellular transformation is facilitated by MET auto-activation due to the duplication of [[chromosome 7]].<ref name="pmid9731534">{{cite journal| author=Zhuang Z, Park WS, Pack S, Schmidt L, Vortmeyer AO, Pak E et al.| title=Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. | journal=Nat Genet | year= 1998 | volume= 20 | issue= 1 | pages= 66-9 | pmid=9731534 | doi=10.1038/1727 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9731534  }} </ref><ref name="pmid9715275">{{cite journal| author=Fischer J, Palmedo G, von Knobloch R, Bugert P, Prayer-Galetti T, Pagano F et al.| title=Duplication and overexpression of the mutant allele of the MET proto-oncogene in multiple hereditary papillary renal cell tumours. | journal=Oncogene | year= 1998 | volume= 17 | issue= 6 | pages= 733-9 | pmid=9715275 | doi=10.1038/sj.onc.1201983 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9715275  }} </ref>


==Overview==
Papillary renal cell carcinoma has 2 histologic types:
Other images of kidney cancer can be seen through simple instruments such as [[microscopes]].
{| style="border-collapse:collapse; text-align:left;" cellpadding="5" border="1" align="center"
|+ '''''Types of Papillary Renal Cell Carcinoma<ref name="pmid16339096">{{cite journal| author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref>'''''


===Pathology===
| style="background:#4479BA; color: #FFFFFF;" align="center" + |'''Type''' || style="background:#4479BA; color: #FFFFFF;" align="center" + |'''Cell Size''' || style="background:#4479BA; color: #FFFFFF;" align="center" + |'''Cytoplasm''' || style="background:#4479BA; color: #FFFFFF;" align="center" + |'''Nucleus'''|| style="background:#4479BA; color: #FFFFFF;" align="center" + |'''Nucleolus'''
|-
| bgcolor="#DCDCDC" |'''Type I''' || Small || Pale || Small and oval || Indistinct
|-
| bgcolor="#DCDCDC" |'''Type II''' || Large || Abundant eosinophilic || Large and spherical || Distinct
|}
<sup><center>Adapted from Cohen HT, McGovern FJ. Renal-cell carcinoma. ''N Engl J Med''. 2005 Dec 8;353(23):2477-90</center></sup>


Gross examination shows a hypervascular lesion in the renal cortex, which is frequently multilobulated, yellow (because of the lipid accumulation) and calcified.
===Oncocytoma and Chromophobe Renal Cell Carcinoma===


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>
* Oncocytomas are [[benign tumors]] that arise from type A [[intercalated cells]], whereas [[chromophobe]] renal cell carcinoma arises from type B [[intercalated cells]].<ref name="pmid16339096">{{cite journal|author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 |volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref>
* Occasionally, oncocytomas and [[chromophobe]] renal cell carcinoma are associated with [[Birt-Hogg-Dubé syndrome|Birt-Hogg-Dube (BHD) syndrome]]. The [[BHD|''BHD'' gene]] encodes [[folliculin]], a [[Tumor suppressor|tumor suppressor protein]].<ref name="pmid12204536">{{cite journal| author=Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML et al.| title=Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. | journal=Cancer Cell | year= 2002 | volume= 2 | issue= 2 | pages= 157-64 | pmid=12204536 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12204536  }} </ref><ref name="pmid12907635">{{cite journal| author=Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K et al.| title=Inactivation of BHD in sporadic renal tumors. | journal=Cancer Res | year= 2003 | volume= 63 | issue= 15 | pages= 4583-7 | pmid=12907635 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12907635  }} </ref><ref name="pmid14627671">{{cite journal| author=da Silva NF, Gentle D, Hesson LB, Morton DG, Latif F, Maher ER| title=Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer. | journal=J Med Genet | year= 2003 | volume= 40 | issue= 11 | pages= 820-4 | pmid=14627671 | doi= | pmc=PMC1735328 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14627671  }} </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).
===Collecting Duct Renal Cell Carcinoma===


[[Image:Renal cell ca.jpg|thumb|left|350px|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.]]
* Collecting duct renal cell carcinomas are aggressive [[malignant]] tumors. It resembles transitional cell carcinomas. [[Medullary carcinoma]], a variant of collecting duct renal cell carcinoma, is associated with [[sickle cell disease]] and [[Category: (name of the system)]] trait.<ref name="pmid16339096">{{cite journal|author=Cohen HT, McGovern FJ| title=Renal-cell carcinoma. | journal=N Engl J Med | year= 2005 |volume= 353 | issue= 23 | pages= 2477-90 | pmid=16339096 | doi=10.1056/NEJMra043172 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339096  }} </ref>
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==References==
==References==
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==References==
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Overview

The pathophysiology of renal cell carcinomas plays an important role in differentiating between the types of renal cell carcinomas and in choosing appropriate targeted medical therapies. Sporadic forms of clear cell renal carcinomas, the most common form of renal cell carcinomas, have similar pathophysiological mechanisms to those of von Hippel-Lindau (VHL) disease. On the other hand, MET proto-oncogene seems to play a role in the disease pathogenesis of papillary forms of renal cell carcinoma. Uniquely also, oncocytomas are benign tumors that arise from type A intercalated cells, whereas chromophobe renal cell carcinoma arises from type B intercalated cells.

Pathophysiology

Sporadic Forms of 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.[1]

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 gene.[14]

Papillary Renal Cell Carcinoma

Papillary renal cell carcinoma has 2 histologic types:

Types of Papillary Renal Cell Carcinoma[1]
Type Cell Size Cytoplasm Nucleus Nucleolus
Type I Small Pale Small and oval Indistinct
Type II Large Abundant eosinophilic Large and spherical Distinct
Adapted from Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005 Dec 8;353(23):2477-90

Oncocytoma and Chromophobe Renal Cell Carcinoma

Collecting Duct Renal Cell Carcinoma

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Cohen HT, McGovern FJ (2005). "Renal-cell carcinoma". N Engl J Med. 353 (23): 2477–90. doi:10.1056/NEJMra043172. PMID 16339096.
  2. ↑ 2.0 2.1 Iliopoulos O, Kibel A, Gray S, Kaelin WG (1995). "Tumour suppression by the human von Hippel-Lindau gene product". Nat Med. 1 (8): 822–6. PMID 7585187.
  3. ↑ 3.0 3.1 Chen F, Kishida T, Duh FM, Renbaum P, Orcutt ML, Schmidt L; et al. (1995). "Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene". Cancer Res. 55 (21): 4804–7. PMID 7585510.
  4. ↑ Iliopoulos O, Levy AP, Jiang C, Kaelin WG, Goldberg MA (1996). "Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein". Proc Natl Acad Sci U S A. 93 (20): 10595–9. PMC 38198. PMID 8855223.
  5. ↑ Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC; et al. (2000). "Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein". J Biol Chem. 275 (33): 25733–41. doi:10.1074/jbc.M002740200. PMID 10823831.
  6. ↑ Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE; et al. (2000). "Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein". Nat Cell Biol. 2 (7): 423–7. doi:10.1038/35017054. PMID 10878807.
  7. ↑ Tanimoto K, Makino Y, Pereira T, Poellinger L (2000). "Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein". EMBO J. 19 (16): 4298–309. doi:10.1093/emboj/19.16.4298. PMC 302039. PMID 10944113.
  8. ↑ Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN; et al. (1998). "The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix". Mol Cell. 1 (7): 959–68. PMID 9651579.
  9. ↑ Feldman DE, Spiess C, Howard DE, Frydman J (2003). "Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding". Mol Cell. 12 (5): 1213–24. PMID 14636579.
  10. ↑ Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W (2003). "Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL". Nat Cell Biol. 5 (1): 64–70. doi:10.1038/ncb899. PMID 12510195.
  11. ↑ Zhou MI, Wang H, Ross JJ, Kuzmin I, Xu C, Cohen HT (2002). "The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1". J Biol Chem. 277 (42): 39887–98. doi:10.1074/jbc.M205040200. PMID 12169691.
  12. ↑ Zhou MI, Wang H, Foy RL, Ross JJ, Cohen HT (2004). "Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent". Cancer Res. 64 (4): 1278–86. PMID 14973063.
  13. ↑ Zhou MI, Foy RL, Chitalia VC, Zhao J, Panchenko MV, Wang H; et al. (2005). "Jade-1, a candidate renal tumor suppressor that promotes apoptosis". Proc Natl Acad Sci U S A. 102 (31): 11035–40. doi:10.1073/pnas.0500757102. PMC 1182408. PMID 16046545.
  14. ↑ Cohen AJ, Li FP, Berg S, Marchetto DJ, Tsai S, Jacobs SC; et al. (1979). "Hereditary renal-cell carcinoma associated with a chromosomal translocation". N Engl J Med. 301 (11): 592–5. doi:10.1056/NEJM197909133011107. PMID 470981.
  15. ↑ Delahunt B, Eble JN (1997). "Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors". Mod Pathol. 10 (6): 537–44. PMID 9195569.
  16. ↑ Gunawan B, von Heydebreck A, Fritsch T, Huber W, Ringert RH, Jakse G; et al. (2003). "Cytogenetic and morphologic typing of 58 papillary renal cell carcinomas: evidence for a cytogenetic evolution of type 2 from type 1 tumors". Cancer Res. 63 (19): 6200–5. PMID 14559804.
  17. ↑ Lubensky IA, Schmidt L, Zhuang Z, Weirich G, Pack S, Zambrano N; et al. (1999). "Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype". Am J Pathol. 155 (2): 517–26. doi:10.1016/S0002-9440(10)65147-4. PMC 1866853. PMID 10433944.
  18. ↑ Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P; et al. (1997). "Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas". Nat Genet. 16 (1): 68–73. doi:10.1038/ng0597-68. PMID 9140397.
  19. ↑ Zbar B, Glenn G, Lubensky I, Choyke P, Walther MM, Magnusson G; et al. (1995). "Hereditary papillary renal cell carcinoma: clinical studies in 10 families". J Urol. 153 (3 Pt 2): 907–12. PMID 7853572.
  20. ↑ Zhuang Z, Park WS, Pack S, Schmidt L, Vortmeyer AO, Pak E; et al. (1998). "Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas". Nat Genet. 20 (1): 66–9. doi:10.1038/1727. PMID 9731534.
  21. ↑ Fischer J, Palmedo G, von Knobloch R, Bugert P, Prayer-Galetti T, Pagano F; et al. (1998). "Duplication and overexpression of the mutant allele of the MET proto-oncogene in multiple hereditary papillary renal cell tumours". Oncogene. 17 (6): 733–9. doi:10.1038/sj.onc.1201983. PMID 9715275.
  22. ↑ Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML; et al. (2002). "Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome". Cancer Cell. 2 (2): 157–64. PMID 12204536.
  23. ↑ Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K; et al. (2003). "Inactivation of BHD in sporadic renal tumors". Cancer Res. 63 (15): 4583–7. PMID 12907635.
  24. ↑ da Silva NF, Gentle D, Hesson LB, Morton DG, Latif F, Maher ER (2003). "Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer". J Med Genet. 40 (11): 820–4. PMC 1735328. PMID 14627671.

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