Retinoblastoma pathophysiology: Difference between revisions
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'''[[Flexner-Wintersteiner rosettes]]''':It is named after [[Simon Flexner]](1863-1946), a pathologist and [[Hugo Wintersteiner]](1865-1946), a Austrian ophthalmologist. The tumor cells that form this rosette circumscribe a central lumen that contain small cytoplasmic extensions of the surrounding cells and lack neurophil. | '''[[Flexner-Wintersteiner rosettes]]''':It is named after [[Simon Flexner]](1863-1946), a pathologist and [[Hugo Wintersteiner]](1865-1946), a Austrian ophthalmologist. The tumor cells that form this rosette circumscribe a central lumen that contain small cytoplasmic extensions of the surrounding cells and lack neurophil. | ||
'''[[Homer-Wright rosettes]]''': It is named after [[James Homer Wright]](1869-1928) who was the first director of the Massachusetts General Hospital pathology laboratory and the developer of Wright stain.<ref name="pmid11756774">{{cite journal |author=Lee RE, Young RH, Castleman B |title=James Homer Wright: a biography of the enigmatic creator of the Wright stain on the occasion of its centennial |journal=[[The American Journal of Surgical Pathology]] |volume=26 |issue=1 |pages=88–96 |year=2002 |month=January |pmid=11756774 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0147-5185&volume=26&issue=1&spage=88 |accessdate=2012-05-14}}</ref>In this type of rosette, the differentiated tumor cells surround the central lumen composed of [[neurophil]] which contains primitive neuronal processes or neurites. These are considered pseudo since they differ from | '''[[Homer-Wright rosettes]]''': It is named after [[James Homer Wright]](1869-1928) who was the first director of the Massachusetts General Hospital pathology laboratory and the developer of Wright stain.<ref name="pmid11756774">{{cite journal |author=Lee RE, Young RH, Castleman B |title=James Homer Wright: a biography of the enigmatic creator of the Wright stain on the occasion of its centennial |journal=[[The American Journal of Surgical Pathology]] |volume=26 |issue=1 |pages=88–96 |year=2002 |month=January |pmid=11756774 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0147-5185&volume=26&issue=1&spage=88 |accessdate=2012-05-14}}</ref>In this type of rosette, the differentiated tumor cells surround the central lumen composed of [[neurophil]] which contains primitive neuronal processes or neurites. These are considered pseudo since they differ from true rosettes which have a empty lumen. | ||
'''[[Fleurette]]''': The term fleurette is applied to an elaborate form of photoreceptor differentiation of retinoblastoma cells. Some research workers like Tso et al. think that the presence of fleurettes implies a better prognosis. However, another study claimed that single photoreceptor cells or fleurettes were of no prognostic significance.<ref name="pmid4421038">{{cite journal |author=Sevel D, Röhm GF, Sealy R |title=Clinical significance of the fleurette in retinoblastoma |journal=[[The British Journal of Ophthalmology]] |volume=58 |issue=7 |pages=687–93 |year=1974 |month=July |pmid=4421038 |pmc=1214987 |doi= |url=http://bjo.bmj.com/cgi/pmidlookup?view=long&pmid=4421038 |accessdate=2012-05-14}}</ref> | '''[[Fleurette]]''': The term fleurette is applied to an elaborate form of photoreceptor differentiation of retinoblastoma cells. Some research workers like Tso et al. think that the presence of fleurettes implies a better prognosis. However, another study claimed that single photoreceptor cells or fleurettes were of no prognostic significance.<ref name="pmid4421038">{{cite journal |author=Sevel D, Röhm GF, Sealy R |title=Clinical significance of the fleurette in retinoblastoma |journal=[[The British Journal of Ophthalmology]] |volume=58 |issue=7 |pages=687–93 |year=1974 |month=July |pmid=4421038 |pmc=1214987 |doi= |url=http://bjo.bmj.com/cgi/pmidlookup?view=long&pmid=4421038 |accessdate=2012-05-14}}</ref> | ||
Revision as of 17:07, 14 May 2012
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
Retinoblastoma is a cancer of the retina. Development of this tumor is initiated by mutations[1] that inactivate both copies of the RB1 gene, which codes for the retinoblastoma protein.[2]. The Retinoblastoma gene acts as a tumor suppressor gene. The RB1 gene is composed of 27 exons which encodes for a 110kd nuclear phosphoprotein.[3] The cDNA fragment detects atleast 70 kilobases(kb) in human chromosome band 13q14 of which a part of it or complete 70 kilobases in that band are frequently deleted in retinoblastomas and osteosarcomas.[4]
In addition to the RB1 gene deletion, a number of studies also indicated other molecular events are necessary for genesis of tumor.[5][6]
Molecular Pathogenesis
The proteins derived from RB gene play a key role in regulating advancement of cell cycle from G1 to S phases. These proteins negatively regulate two important positive regulators of cell cycle entry, E2F transcription factors and Cyclin dependent kinases. RB proteins repress the transcriptional activity of E2Fs in growth arrested cells. Positive growth factor signaling leads to activation of cyclin dependent kinases which inturn phosporylte the RB proteins inactivating them which will lead to E2F activation and additional cyclin dependent activity. The end result is the cell cycle is propelled forward irreversibly leading to DNA synthesis.[7].
So, when there is a deletion of RB gene, the RB proteins are no more present which leads to unhindered cell proliferation leading to tumors.
Genetics
Retinoblastoma is inherited in autosomal dominant fashion. Each child of a parent with familial bilateral retinoblastoma has a 50% risk of inheriting the retinoblastoma gene. The penetrance of retinoblastoma is usually 90%. Genetic modifiers and partial inactivation of RB gene may sometimes lead to lower penetrance.
Knudson's two hit hypothesis and retinoblastoma:
In 1971, Alfred Knudson proposed his "two-hit" theory based upon empiric observations of the clinical genetics of retinoblastoma, revealing the role of tumor-suppressor genes in human cancer. Knudson proposed that
In the dominant inherited form of Rb, one mutation is inherited via germ line and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells.[8]
The Knudson hypothesis was validated later with the cloning of RB1, the first tumor-suppressor gene to be identified.
Histopathology
Retinoblastoma is a primitive neuroepithelial neoplasm. Retnal photoreceptor cells are developed from immature neural epithelium from which retinoblastoma is thought to arise from.[9]
It is composed of uniformly small round or polygonal mitotically active cells. The tumor cells are primitive undifferentiated cells with scant cytoplasm and round to oval nuclei, showing finely granular chromatin and absence of nucleoli. This morphologic appearance is very similar to other undifferentiated neuroectodermal tumors such as medulloblastoma.
The charesteristic features are:
Flexner-Wintersteiner rosettes:It is named after Simon Flexner(1863-1946), a pathologist and Hugo Wintersteiner(1865-1946), a Austrian ophthalmologist. The tumor cells that form this rosette circumscribe a central lumen that contain small cytoplasmic extensions of the surrounding cells and lack neurophil.
Homer-Wright rosettes: It is named after James Homer Wright(1869-1928) who was the first director of the Massachusetts General Hospital pathology laboratory and the developer of Wright stain.[10]In this type of rosette, the differentiated tumor cells surround the central lumen composed of neurophil which contains primitive neuronal processes or neurites. These are considered pseudo since they differ from true rosettes which have a empty lumen.
Fleurette: The term fleurette is applied to an elaborate form of photoreceptor differentiation of retinoblastoma cells. Some research workers like Tso et al. think that the presence of fleurettes implies a better prognosis. However, another study claimed that single photoreceptor cells or fleurettes were of no prognostic significance.[11]
These rosettes signify a specific form of tumor differentiation.
References
- ↑ Knudson A (1971). "Mutation and cancer: statistical study of retinoblastoma". Proc Natl Acad Sci U S A. 68 (4): 820–3. PMID 5279gadgqetqer523 Check
|pmid=value (help). - ↑ Friend S, Bernards R, Rogelj S, Weinberg R, Rapaport J, Albert D, Dryja T. "A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma". Nature. 323 (6089): 643–6. PMID 2877398.
- ↑ Aerts I, Lumbroso-Le Rouic L, Gauthier-Villars M, Brisse H, Doz F, Desjardins L (2006). "Retinoblastoma". Orphanet Journal of Rare Diseases. 1: 31. doi:10.1186/1750-1172-1-31. PMC 1586012. PMID 16934146. Retrieved 2012-05-03.
- ↑ Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP (1986). "A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma". Nature. 323 (6089): 643–6. doi:10.1038/323643a0. PMID 2877398. Retrieved 2012-05-03.
- ↑ Zielinski B, Gratias S, Toedt G, Mendrzyk F, Stange DE, Radlwimmer B, Lohmann DR, Lichter P (2005). "Detection of chromosomal imbalances in retinoblastoma by matrix-based comparative genomic hybridization". Genes, Chromosomes & Cancer. 43 (3): 294–301. doi:10.1002/gcc.20186. PMID 15834944. Retrieved 2012-05-03. Unknown parameter
|month=ignored (help) - ↑ Mairal A, Pinglier E, Gilbert E, Peter M, Validire P, Desjardins L, Doz F, Aurias A, Couturier J (2000). <370::AID-GCC2>3.0.CO;2-8 "Detection of chromosome imbalances in retinoblastoma by parallel karyotype and CGH analyses". Genes, Chromosomes & Cancer. 28 (4): 370–9. PMID 10862045. Retrieved 2012-05-03. Unknown parameter
|month=ignored (help) - ↑ Henley SA, Dick FA (2012). "The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle". Cell Division. 7 (1): 10. doi:10.1186/1747-1028-7-10. PMC 3325851. PMID 22417103. Retrieved 2012-05-03.
- ↑ Sábado Alvarez C (2008). "Molecular biology of retinoblastoma". Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 10 (7): 389–94. PMID 18628066. Unknown parameter
|month=ignored (help);|access-date=requires|url=(help) - ↑ Smirniotopoulos JG, Bargallo N, Mafee MF (1994). "Differential diagnosis of leukokoria: radiologic-pathologic correlation". Radiographics : a Review Publication of the Radiological Society of North America, Inc. 14 (5): 1059–79, quiz 1081–2. PMID 7991814. Retrieved 2012-05-07. Unknown parameter
|month=ignored (help) - ↑ Lee RE, Young RH, Castleman B (2002). "James Homer Wright: a biography of the enigmatic creator of the Wright stain on the occasion of its centennial". The American Journal of Surgical Pathology. 26 (1): 88–96. PMID 11756774. Retrieved 2012-05-14. Unknown parameter
|month=ignored (help) - ↑ Sevel D, Röhm GF, Sealy R (1974). "Clinical significance of the fleurette in retinoblastoma". The British Journal of Ophthalmology. 58 (7): 687–93. PMC 1214987. PMID 4421038. Retrieved 2012-05-14. Unknown parameter
|month=ignored (help)