|
|
| Line 2: |
Line 2: |
| {{Retinoblastoma}} | | {{Retinoblastoma}} |
| ==Overview== | | ==Overview== |
| Retinoblastoma is a cancer of the retina. Development of this tumor is initiated by mutations<ref>{{cite journal |author=Knudson A |title=Mutation and cancer: statistical study of retinoblastoma |journal=Proc Natl Acad Sci U S A |volume=68 |issue=4 |pages=820-3 |year=1971 |pmid=5279gadgqetqer523}}</ref> that inactivate both copies of the [[RB1]] gene, which codes for the [[retinoblastoma protein]]<ref>{{cite journal |author=Friend S, Bernards R, Rogelj S, Weinberg R, Rapaport J, Albert D, Dryja T |title=A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma |journal=Nature |volume=323 |issue=6089 |pages=643-6 |year= |pmid=2877398}}</ref>. The Retinoblastoma gene acts as a [[tumor suppressor]] gene. The RB1 gene is composed of 27 exons which encodes for a 110kd nuclear phosphoprotein.<ref name="pmid16934146">{{cite journal |author=Aerts I, Lumbroso-Le Rouic L, Gauthier-Villars M, Brisse H, Doz F, Desjardins L |title=Retinoblastoma |journal=[[Orphanet Journal of Rare Diseases]] |volume=1 |issue= |pages=31 |year=2006 |pmid=16934146 |pmc=1586012 |doi=10.1186/1750-1172-1-31 |url=http://www.ojrd.com/content/1//31 |accessdate=2012-05-03}}</ref> 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.<ref name="pmid2877398">{{cite journal |author=Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP |title=A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma |journal=[[Nature]] |volume=323 |issue=6089 |pages=643–6 |year=1986 |pmid=2877398 |doi=10.1038/323643a0 |url=http://dx.doi.org/10.1038/323643a0 |accessdate=2012-05-03}}</ref> In addition to the RB1 gene deletion, a number of studies also indicated other molecular events are necessary for genesis of tumor.<ref name="pmid15834944">{{cite journal |author=Zielinski B, Gratias S, Toedt G, Mendrzyk F, Stange DE, Radlwimmer B, Lohmann DR, Lichter P |title=Detection of chromosomal imbalances in retinoblastoma by matrix-based comparative genomic hybridization |journal=[[Genes, Chromosomes & Cancer]] |volume=43 |issue=3 |pages=294–301 |year=2005 |month=July |pmid=15834944 |doi=10.1002/gcc.20186 |url=http://dx.doi.org/10.1002/gcc.20186 |accessdate=2012-05-03}}</ref><ref name="pmid10862045">{{cite journal |author=Mairal A, Pinglier E, Gilbert E, Peter M, Validire P, Desjardins L, Doz F, Aurias A, Couturier J |title=Detection of chromosome imbalances in retinoblastoma by parallel karyotype and CGH analyses |journal=[[Genes, Chromosomes & Cancer]] |volume=28 |issue=4 |pages=370–9 |year=2000 |month=August |pmid=10862045 |doi= |url=http://dx.doi.org/10.1002/1098-2264(200008)28:4<370::AID-GCC2>3.0.CO;2-8 |accessdate=2012-05-03}}</ref>
| |
|
| |
|
| ==Molecular Pathogenesis== | | ===Morphology=== |
| 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 in turn phosporylate 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.<ref name="pmid22417103">{{cite journal |author=Henley SA, Dick FA |title=The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle |journal=[[Cell Division]] |volume=7 |issue=1 |pages=10 |year=2012 |pmid=22417103 |pmc=3325851 |doi=10.1186/1747-1028-7-10 |url=http://www.celldiv.com/content/7/1/10 |accessdate=2012-05-03}}</ref>. 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.
| | Gross and microscopic appearances of retinoblastoma are identical in both hereditary and sporadic types. Macroscopically, viable tumor cells are found near blood vessels, while zones of necrosis are found in relatively avascular areas. Microscopically, both undifferentiated and differentiated elements may be present. Undifferentiated elements appear as collections of small, round cells with hyperchromatic nuclei; differentiated elements include [[Flexner-Wintersteiner rosette]]s, [[Homer-Wright rosette]]s,<ref>{{cite book|last=Lee,|first=K. Weng Sehu,... William R.|title=Ophthalmic pathology : an illustrated guide for clinicans|year=2005|publisher=Blackwell publ.|location=Malden|isbn=978-0-7279-1779-9|pages=262|url=http://books.google.com/?id=kwYeEqWd4dUC&pg=PA262&dq=retinoblastoma+homer#v=onepage&q=retinoblastoma%20homer&f=false}}</ref> and fluerettes from photoreceptor differentiation.<ref>Kumar V, Abbas AK, Fausto N. Robbins and Cotran Pathologic Basis of Disease. Seventh Edition. Philadelphia: Elsevier Saunders, 2005, p. 1442.</ref> |
|
| |
|
| ==Genetics==
| | <gallery> |
| 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. | | Image:Wardrop retinoblastoma.jpg|Drawing of a large retinoblastoma |
| | Image:Trilateral retinoblastoma.jpg|Aspect of trilateral retinoblastoma on MRI |
| | Image:Retinoblastoma ultrasound.jpg|An ocular ultrasound of a large retinoblastoma tumor within the eye of a three-year-old boy |
| | Image:Retinoblastooma.jpg|Funduscopic finding of a retinoblastoma |
| | Image:Fundus retinoblastoma.jpg|Ocular fundus aspect of retinoblastoma |
| | Image:Retinoblastoma_in_enucleated_eyeball.jpg|Gross pathology of retinoblastoma tumor in enucleated eye of three-year-old female |
| | Image:Retinoblastoma .jpg|Large exophytic white tumor with foci of calcification producing total exudative retinal detachment |
| | Image:Retinoblastoma rosette.jpg|Flexner-Wintersteiner rosettes in Retinoblatoma |
| | Image:Rtbl400.GIF|Retinoblastoma, 400 X magnification |
| | Image:RB1.JPG|Crystal structure of the Retinoblastoma tumour suppressor protein bound to E2F peptide Polymer. |
| | </gallery> |
|
| |
|
| ===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.<ref name="pmid18628066">{{cite journal |author=Sábado Alvarez C |title=Molecular biology of retinoblastoma |journal=[[Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico]] |volume=10 |issue=7 |pages=389–94 |year=2008 |month=July |pmid=18628066 |doi= |url= |accessdate=2012-05-03}}</ref> The Knudson hypothesis was validated later with the cloning of RB1, the first tumor-suppressor gene to be identified.
| |
|
| |
| ==Laterality, Unifocal versus Multifocal and Sporadic versus Inherited retinoblastoma==
| |
| Bilateral Disease is always heritable. Unilateral, unifocal disease is not heritable. Most of the times, multifocal, unilateral disease is heritable and should prompt investigation for a germline mutation.
| |
| The inherited form of retinoblastoma requires a germline mutation that can be either familial (inherited from one of the parents) or sporadic ( the result of new germline mutation). In familial retinoblastoma, the fertilized egg carries one defective copy of the RB1 gene, and all retinal cells in this offspring carry only a single functional RB1 [gene copy. If this surviving copy is eliminated in a retinal cell by a somatic mutation (the second hit of the Knudson two-hit hypothesis), the cell will lack RB1 gene function and will proliferate into a tumor. In sporadic retinoblastoma, the fertilized egg is genetically wild type at the RB1 locus. In the retina of this offspring, retinoblastoma development requires two successive somatic mutations striking both copies of the RB1 gene in the retinal precursor cells. Because only a single somatic mutation is needed to eliminate RB1 function in familial cases, multiple cells in both eyes are affected. In contrast, the two somatic mutations required in sporadic disease are unlikely to affect a single cell lineage, yielding at most one tumor. Therefore familial retinoblastoma usually result in multifocal, bilateral disease and sporadic cases usually result in unifocal, unilateral tumor. Most of the children with the nonheritable form of the disease have new germline mutations and lack a family history.
| |
|
| |
| ==Histopathology==
| |
| Retinoblastoma is a primitive neuroepithelial neoplasm. Retnal photoreceptor cells are developed from immature neural epithelium from which retinoblastoma is thought to arise from.<ref name="pmid7991814">{{cite journal |author=Smirniotopoulos JG, Bargallo N, Mafee MF |title=Differential diagnosis of leukokoria: radiologic-pathologic correlation |journal=[[Radiographics : a Review Publication of the Radiological Society of North America, Inc]] |volume=14 |issue=5 |pages=1059–79; quiz 1081–2 |year=1994 |month=September |pmid=7991814 |doi= |url=http://radiographics.rsnajnls.org/cgi/pmidlookup?view=long&pmid=7991814 |accessdate=2012-05-07}}</ref>
| |
|
| |
| It is composed of uniformly small round or polygonal basophilic (blue) 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 characteristic findings are:
| |
|
| |
| [[Necrosis]]: Similar to many tumors, the retinoblastoma cells are very rapidly growing and that is why more viable (basophilic) cells are closer to the central core of the blood vessels and as they outgrow the blood supply they become necrotic which can be appreciated histologically as eosinophilic(pink) ill-defined structures away from the blood vessels. This peri-vascular pattern of growth of tumor cells is considered the most prominent feature of retinoblastoma. Extensive ocular tissue and tumor necrosis is associated with histologic high-risk prognostic factors for tumor metastasis and mortality.<ref name="pmid17076529">{{cite journal |author=Chong EM, Coffee RE, Chintagumpala M, Hurwitz RL, Hurwitz MY, Chévez-Barrios P |title=Extensively necrotic retinoblastoma is associated with high-risk prognostic factors |journal=[[Archives of Pathology & Laboratory Medicine]] |volume=130 |issue=11 |pages=1669–72 |year=2006 |month=November |pmid=17076529|doi=10.1043/1543-2165(2006)130[1669:ENRIAW]2.0.CO;2|url=http://www.archivesofpathology.org/doi/full/10.1043/1543-2165(2006)130[1669:ENRIAW]2.0.CO;2 |accessdate=2012-05-19}}</ref>
| |
|
| |
| 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 neutrophil. When looked under electron microscope, the tumor cells have the features of primitive photoreceptor cells.
| |
|
| |
| * 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.
| |
|
| |
| Flexner-Wintersteiner rosettes and Homer-Wright rosettes both signify a specific form of tumor differentiation.
| |
|
| |
| * Fleurette: The term fleurette is applied to an elaborate form of photoreceptor differentiation of retinoblastoma cells. These structres are small bouquet like structures of benign-appearing tumor cells that show variable degree of photoreceptor differentiation. 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>
| |
| * Calcification, Hemorrhage.
| |
|
| |
| ==Associated Conditions==
| |
|
| |
| ===Trilateral Retinoblastoma===
| |
| *Trilateral retinoblastoma is the term that refers to bilateral retinoblastoma associated with an intracranial [[primitive neuroectodermal tumor]] in the [[pineal]] or [[suprasellar region]]. It has a poor [[prognosis]] especially when there is [[leptomeningeal]] involvement and when the tumor spreads in to [[subarachnoid space]]. For dissemination of tumor cells into the sub-arachnoid space, [[Optic nerve]] involvement is an important portal.<ref name="pmid7900586">{{cite journal |author=Provenzale JM, Weber AL, Klintworth GK, McLendon RE |title=Radiologic-pathologic correlation. Bilateral retinoblastoma with coexistent pinealoblastoma (trilateral retinoblastoma) |journal=[[AJNR. American Journal of Neuroradiology]] |volume=16 |issue=1 |pages=157–65 |year=1995 |month=January |pmid=7900586 |doi= |url=http://www.ajnr.org/cgi/pmidlookup?view=long&pmid=7900586 |accessdate=2012-05-02}}</ref>
| |
| *The mean length of survival is 9.7 months in patients who undergo treatment and 1.3 months in those who do not after a pineal or sellar mass is detected.<ref name="pmid1985763">{{cite journal |author=Holladay DA, Holladay A, Montebello JF, Redmond KP |title=Clinical presentation, treatment, and outcome of trilateral retinoblastoma |journal=[[Cancer]] |volume=67 |issue=3 |pages=710–5 |year=1991 |month=February |pmid=1985763 |doi= |url= |accessdate=2012-05-02}}</ref>
| |
|
| |
|
| ==See also== | | ==See also== |
