Retinoblastoma pathophysiology: Difference between revisions

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{{CMG}}{{AE}}{{Simrat}}
__NOTOC__
{{Retinoblastoma}}
{{Retinoblastoma}}
{{CMG}}; {{AE}} {{Sahar}} {{Simrat}}
==Overview==
==Overview==
On gross pathology, viable tumor [[cells]] near [[blood vessels]] and zones of [[necrosis]] in [[avascular]] areas are characteristic findings of retinoblastoma. On [[microscopic]] [[histopathological]] analysis, small, round-cell tumor of neuroepithelial origin, Flexner-Wintersteiner rosettes, and Homer-Wright rosettes are characteristic findings of retinoblastoma. Retinoblastoma can be bilateral or unilateral, spontaneous or familial. In 30% to 40% of cases, retinoblastoma is accompanied by a germinal [[mutation]] in the ''RB1'' [[gene]].<ref name="pmid18854698">{{cite journal| author=Schefler AC, Abramson DH| title=Retinoblastoma: what is new in 2007-2008. | journal=Curr Opin Ophthalmol | year= 2008 | volume= 19 | issue= 6 | pages= 526-34 | pmid=18854698 | doi=10.1097/ICU.0b013e328312975b | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18854698  }} </ref>
Retinoblastoma is a [[neoplasm]] which is caused by the inactivation of [[RB1]] [[gene]], a [[tumor suppressor gene]], located on the long arm of the [[chromosome 13]]. [[Mutation]] in both [[alleles]] of the [[RB1]] [[gene]] is necessary for the inactivation of the [[gene]]. This [[disorder]] may occur in the [[familial]] or sporadic form. ([[Rb]]) [[gene]] product limits the [[cell]] progression from the [[G1 phase]] to the [[S phase]] of the [[cell cycle]]. Loss of this active, functional [[protein]] ([[Rb]]) causes [[cell cycle]] [[dysregulation]] and subsequent overgrowth and [[tumor]] formation.
 
==Pathogenesis==
*Retinoblastoma is a neoplasm which is caused by the inactivation of RB1 gene, a tumor suppressor gene.<ref name="pmid3175621">{{cite journal |vauthors=Dunn JM, Phillips RA, Becker AJ, Gallie BL |title=Identification of germline and somatic mutations affecting the retinoblastoma gene |journal=Science |volume=241 |issue=4874 |pages=1797–800 |date=September 1988 |pmid=3175621 |doi= |url=}}</ref>
*Normally, RB1 gene is necessary for the normal differentiation and growth of retinal stem cells and its mutation results in unregulated growth of these cells and development of the tumor.
*Mutation in both alleles of the RB1 gene is necessary for the inactivation of the gene.<ref name="pmid2601691">{{cite journal |vauthors=Dunn JM, Phillips RA, Zhu X, Becker A, Gallie BL |title=Mutations in the RB1 gene and their effects on transcription |journal=Mol. Cell. Biol. |volume=9 |issue=11 |pages=4596–604 |date=November 1989 |pmid=2601691 |pmc=363605 |doi= |url=}}</ref>
*This disorder may occur in the familial or sporadic form.  
*In the familial form (48% of the cases), the first mutation occurs during germ cell division and the second one later during the division of somatic cells.<ref name="pmid15637391">{{cite journal |vauthors=Garber JE, Offit K |title=Hereditary cancer predisposition syndromes |journal=J. Clin. Oncol. |volume=23 |issue=2 |pages=276–92 |date=January 2005 |pmid=15637391 |doi=10.1200/JCO.2005.10.042 |url=}}</ref>
*In the sporadic form, both mutations occur during the lifetime of the individual.


== Pathophysiology ==
===Pathogenesis===
*Retinoblastoma is a [[neoplasm]] which is caused by the inactivation of [[RB1]] [[gene]], a [[tumor suppressor gene]].<ref name="pmid3175621">{{cite journal |vauthors=Dunn JM, Phillips RA, Becker AJ, Gallie BL |title=Identification of germline and somatic mutations affecting the retinoblastoma gene |journal=Science |volume=241 |issue=4874 |pages=1797–800 |date=September 1988 |pmid=3175621 |doi= |url=}}</ref>
*Normally, [[RB1]] [[gene]] is necessary for the normal [[differentiation]] and growth of [[retinal]] [[stem cells]] and its [[mutation]] results in unregulated growth of these [[cells]] and [[development]] of the [[tumor]].
*[[Mutation]] in both [[alleles]] of the [[RB1]] [[gene]] is necessary for the inactivation of the [[gene]].<ref name="pmid2601691">{{cite journal |vauthors=Dunn JM, Phillips RA, Zhu X, Becker A, Gallie BL |title=Mutations in the RB1 gene and their effects on transcription |journal=Mol. Cell. Biol. |volume=9 |issue=11 |pages=4596–604 |date=November 1989 |pmid=2601691 |pmc=363605 |doi= |url=}}</ref>
*This [[disorder]] may occur in the [[familial]] or sporadic form.
*In the [[familial]] form (48% of the cases), the first [[mutation]] occurs during [[germ cell]] division and the second [[mutation]] occurs later during the division of [[Somatic cell|somatic cells]].<ref name="pmid15637391">{{cite journal |vauthors=Garber JE, Offit K |title=Hereditary cancer predisposition syndromes |journal=J. Clin. Oncol. |volume=23 |issue=2 |pages=276–92 |date=January 2005 |pmid=15637391 |doi=10.1200/JCO.2005.10.042 |url=}}</ref>
*In the sporadic form, both [[mutations]] occur during the lifetime of the individual.
*([[Rb]]) [[gene]] product limits the [[Cell (biology)|cell]] progression from the [[G1 phase]] to the [[S phase]] of the [[cell cycle]].<ref name="GoodrichWang1991">{{cite journal|last1=Goodrich|first1=David W.|last2=Wang|first2=Nan Ping|last3=Qian|first3=Yue-Wei|last4=Lee|first4=Eva Y.-H.P.|last5=Lee|first5=Wen-Hwa|title=The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle|journal=Cell|volume=67|issue=2|year=1991|pages=293–302|issn=00928674|doi=10.1016/0092-8674(91)90181-W}}</ref>
*Active form of [[RB]] [[protein]] prevent the interaction of [[E2F]], a [[transcription factor]]. Loss of this active, functional [[protein]] ([[Rb]]) causes [[Transcription (genetics)|transcribing]] the [[gene]] and subsequent [[cell cycle]] dysregulation, overgrowth and [[tumor]] formation.
==Genetics==
==Genetics==
*Retinoblastoma occurs due to mutational inactivation of RB1 gene located on the chromosome 13.<ref name="pmid5279523">{{cite journal |vauthors=Knudson AG |title=Mutation and cancer: statistical study of retinoblastoma |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=68 |issue=4 |pages=820–3 |date=April 1971 |pmid=5279523 |pmc=389051 |doi= |url=}}</ref>
*[[Retinoblastoma]] occurs due to [[Mutation|mutational]] inactivation of [[RB1]] [[gene]] located on the [[chromosome 13]].<ref name="pmid5279523">{{cite journal |vauthors=Knudson AG |title=Mutation and cancer: statistical study of retinoblastoma |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=68 |issue=4 |pages=820–3 |date=April 1971 |pmid=5279523 |pmc=389051 |doi= |url=}}</ref>
*Two mutational events are needed for the development of retinoblastoma.  
*The [[RB1]] [[gene]] acts as [[tumor suppressor gene]].<ref name="pmid2877398">{{cite journal |vauthors=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 |date=1986 |pmid=2877398 |doi=10.1038/323643a0 |url=}}</ref>
*In familial form, with autosomal dominant inheritance, one mutation occurs in the germline and the second one during the somatic division of the retinal cells.
*Two [[Mutation|mutational]] events are needed for the [[development]] of retinoblastoma.  
*In the acquired form, both mutations occur during somatic divisions.
*In [[familial]] form, with [[autosomal dominant]] [[inheritance]], one [[mutation]] occurs in the [[germline]] and the second one during the [[somatic]] division of the [[retinal]] [[cells]].
*Another gene which has been associated with the pathogenesis of retinoblastoma is MYCN gene.<ref name="pmid29915469">{{cite journal |vauthors=Fabian ID, Rosser E, Sagoo MS |title=Epidemiological and genetic considerations in retinoblastoma |journal=Community Eye Health |volume=31 |issue=101 |pages=29–30 |date=2018 |pmid=29915469 |pmc=5998388 |doi= |url=}}</ref>
*In the acquired form, both [[mutations]] occur during [[somatic]] divisions.
**Somatic amplification of MYCN oncogene is responsible for <3% of the non-heritable form of the retinoblastoma cases.
*Another [[gene]] which has been associated with the [[pathogenesis]] of retinoblastoma is MYCN [[gene]].<ref name="pmid29915469">{{cite journal |vauthors=Fabian ID, Rosser E, Sagoo MS |title=Epidemiological and genetic considerations in retinoblastoma |journal=Community Eye Health |volume=31 |issue=101 |pages=29–30 |date=2018 |pmid=29915469 |pmc=5998388 |doi= |url=}}</ref>
 
*Retinoblastoma may also occur as part of [[13q deletion syndrome]].<ref name="ClarkAvishay2015">{{cite journal|last1=Clark|first1=Robin D.|last2=Avishay|first2=Stefanie G.|title=Retinoblastoma: Genetic Counseling and Testing|year=2015|pages=77–88|doi=10.1007/978-3-662-43451-2_8}}</ref>
Usually retinoblastoma is caused by mutational inactivation of both [[alleles]] of the retinoblastoma (''RB1'') [[gene]].<ref name="FingerHarbour2002">{{cite journal|last1=Finger|first1=Paul T|last2=Harbour|first2=J.William|last3=Karcioglu|first3=Zeynel A|title=Risk Factors for Metastasis in Retinoblastoma|journal=Survey of Ophthalmology|volume=47|issue=1|year=2002|pages=1–16|issn=00396257|doi=10.1016/S0039-6257(01)00279-X}}</ref> The ''RB1'' gene maps to chromosome 13q14 and encodes a [[nuclear protein]] ([[Rb]]) that acts as a [[tumor suppressor]].<ref name="FriendBernards1986">{{cite journal|last1=Friend|first1=Stephen H.|last2=Bernards|first2=Rene|last3=Rogelj|first3=Snezna|last4=Weinberg|first4=Robert A.|last5=Rapaport|first5=Joyce M.|last6=Albert|first6=Daniel M.|last7=Dryja|first7=Thaddeus P.|title=A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma|journal=Nature|volume=323|issue=6089|year=1986|pages=643–646|issn=0028-0836|doi=10.1038/323643a0}}</ref><ref name="FungMurphree1987">{{cite journal|last1=Fung|first1=Y.|last2=Murphree|first2=A.|last3=T'Ang|first3=A|last4=Qian|first4=J|last5=Hinrichs|first5=S.|last6=Benedict|first6=W.|title=Structural evidence for the authenticity of the human retinoblastoma gene|journal=Science|volume=236|issue=4809|year=1987|pages=1657–1661|issn=0036-8075|doi=10.1126/science.2885916}}</ref><ref name="LeeBookstein1987">{{cite journal|last1=Lee|first1=W.|last2=Bookstein|first2=R.|last3=Hong|first3=F.|last4=Young|first4=L.|last5=Shew|first5=J.|last6=Lee|first6=E.|title=Human retinoblastoma susceptibility gene: cloning, identification, and sequence|journal=Science|volume=235|issue=4794|year=1987|pages=1394–1399|issn=0036-8075|doi=10.1126/science.3823889}}</ref> This protein ([[Rb]]) restricts the cell's ability to progress from the [[G1 phase]] to the [[S phase]] of the cell cycle.<ref name="GoodrichWang1991">{{cite journal|last1=Goodrich|first1=David W.|last2=Wang|first2=Nan Ping|last3=Qian|first3=Yue-Wei|last4=Lee|first4=Eva Y.-H.P.|last5=Lee|first5=Wen-Hwa|title=The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle|journal=Cell|volume=67|issue=2|year=1991|pages=293–302|issn=00928674|doi=10.1016/0092-8674(91)90181-W}}</ref>  [[Rb]] binds to [[E2F]], a [[transcription factor]], when active. Loss of this active, functional [[protein]] ([[Rb]]) causes cell cycle dysregulation.
**This [[13q deletion syndrome|syndrome]] is the result of the [[deletion]] of the long arm of [[chromosome 13]].
The inherited form of retinoblastoma is due to a germline mutation that can be either [[familial]] or sporadic.<ref name="LeidermanKiss2007">{{cite journal|last1=Leiderman|first1=Yannek I.|last2=Kiss|first2=Szilárd|last3=Mukai|first3=Shizuo|title=Molecular Genetics ofRB1——The Retinoblastoma Gene|journal=Seminars in Ophthalmology|volume=22|issue=4|year=2007|pages=247–254|issn=0882-0538|doi=10.1080/08820530701745165}}</ref> Retinoblastoma may be unilateral or bilateral.
**[[Symptoms]] may vary according to the size of the [[deletion]], but it may lead to [[developmental delay]] as well.
*Bilateral tumors (30-40% of cases) essentially always have a germline mutation. In 10 percent of bilateral patients, a positive history of retinoblastoma is seen, which suggests that the majority of bilateral cases arise from a new germline mutation.
**[[Child|Children]] with [[chromosome]] 13q14 [[Deletion (genetics)|deletions]] may develop retinoblastoma at a later age and they develop a unilateral [[tumor]].
*Unilateral tumors (60-70% of cases) are caused by a germline mutation in approximately 15% of cases, whereas 85% are sporadic.  Patients with unilateral disease can also have the heritable form of the disease; these are often multifocal and account for 12 to 15 percent of retinoblastoma cases. The remaining children with retinoblastoma have the unilateral, non-germline, and non-heritable form of the disease.
*[[Mosaicism]], presence of [[RB1]] [[gene mutation]] in some [[cells]] of the affected person, may occur in retinoblastoma.
*Thus, approximately 30% to 40% of cases are due to a germline [[mutation]]. This mutation is inherited in an [[autosomal dominant]] fashion with approximately 90% penetrance (i.e the child of a retinoblastoma survivor who has a germline mutation has a 50% chance of inheriting a mutation, and if they do so a 90% chance of developing retinoblastoma. Thus there is an overall chance of 45% of having retinoblastoma (50% x 90%).<ref name="radio">  Retinoblastoma. Radiopedia(2015) http://radiopaedia.org/articles/retinoblastoma Accessed on October 10, 2015</ref>
**[[Patient|Patients]] with [[Mosaicism|mosaic mutation]] often have unilateral retinoblastoma, later onset of the [[tumor]], and no [[family history]] of the [[disease]].
==Associated Conditions==
*Heritable form of this [[disorder]] is associated with the development of non-ocular [[malignancies]] including:<ref name="TseBrennan2015">{{cite journal|last1=Tse|first1=Brian C.|last2=Brennan|first2=Rachel C.|last3=Rodriguez-Galindo|first3=Carlos|last4=Wilson|first4=Matthew W.|title=Non-ocular Tumors|year=2015|pages=201–208|doi=10.1007/978-3-662-43451-2_19}}</ref>
**Different types of [[Sarcoma]]
**[[Small cell lung cancer]]
**[[Bladder cancer]]
**[[Breast cancer]]
**[[Glioblastoma]]


==Gross Pathology==
==Gross Pathology==
*Macroscopic appearance of the tumor varies according to the staging of the tumor.<ref name="pmid24881618">{{cite journal |vauthors=Das D, Bhattacharjee K, Barthakur SS, Tahiliani PS, Deka P, Bhattacharjee H, Deka A, Paul R |title=A new rosette in retinoblastoma |journal=Indian J Ophthalmol |volume=62 |issue=5 |pages=638–41 |date=May 2014 |pmid=24881618 |pmc=4065523 |doi=10.4103/0301-4738.129786 |url=}}</ref>
*[[Macroscopic]] appearance of the [[tumor]] varies according to the [[Cancer staging|staging]] of the [[tumor]].<ref name="pmid24881618">{{cite journal |vauthors=Das D, Bhattacharjee K, Barthakur SS, Tahiliani PS, Deka P, Bhattacharjee H, Deka A, Paul R |title=A new rosette in retinoblastoma |journal=Indian J Ophthalmol |volume=62 |issue=5 |pages=638–41 |date=May 2014 |pmid=24881618 |pmc=4065523 |doi=10.4103/0301-4738.129786 |url=}}</ref>
*The tumor is white and has areas of calcification and necrosis.
*The [[tumor]] is white and has areas of [[calcification]] and [[necrosis]].
*The presence of calcium is more noticeable when the tumor was treated via prior chemotherapy or radiotherapy.
*The presence of [[calcium]] is more noticeable when the [[tumor]] is treated via prior [[chemotherapy]] or [[radiotherapy]].
 
*The [[tumor]] can be [[Classification|classified]] into five sub-groups according to its growth pattern:<ref name="SinghMurphree2015">{{cite book | last = Singh | first = Arun | title = Clinical ophthalmic oncology : retinoblastoma | publisher = Springer | location = Heidelberg | year = 2015 | isbn = 978-3-662-43451-2 }}</ref>
Macroscopically, viable tumor cells are found near [[blood vessels]], while zones of [[necrosis]] are found in relatively avascular areas. Macroscopic examination reveals a white elevated mass with fine surface vessels. Early retinoblastoma presents as a solitary or multifocal, well-circumscribed translucent mass. The tumor becomes more pink in color, with dilated feeding [[blood vessels]] as the disease advances. The tumor may exhibit three patterns of growth, which is tabulated below:
**[[Endophyte|Endophytic]]
{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align=center
**Exophytic
|valign=top|
**Mixed
**Diffuse infiltrative
**[[Necrotic]] variant
These [[growth]] patterns are described in the table below:
{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align="center"
| valign="top" |
|+
|+
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Growth patterns}}
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Growth patterns}}
Line 41: Line 56:
:Endophytic
:Endophytic
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*Growth occurs inwards into the vitreous
*Growth occurs inwards into the [[vitreous]]
*Cell clusters may detach and float in the vitreous (vitreous seeding)
*Tumor cells can enter the anterior chamber and layer behind the cornea, causing a pseudo-hypopyon
*Spontaneous necrosis of the tumor can lead to a severe intraocular inflammatory response, presenting as pseudo-endophthalmitis
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Exophytic
:Exophytic
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*Growth occurs outwards toward choroid  
*Growth occurs outwards towards [[choroid]]
*Associated with non-rhegmatogeneous retinal detachment
*Associated with non-rhegmatogenous [[retinal detachment]]
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Combined endophytic and exophytic
:Mixed
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*Most common type
*Mixed components of endophytic and exophytic are seen
*Mixed components of endophytic and exophytic are seen
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Diffuse Infiltrative
| style="padding: 5px 5px; background: #F5F5F5;" |
*More commonly seen among older [[Child|children]]
*Diffuse growth of the [[tumor]] without an obvious [[retinal]] [[mass]]
*Frequently involves [[anterior chamber]] and causes pseudohypopyon of [[Tumor cell|tumor cells]]
*Clinically can be mistaken for an [[inflammatory process]]
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Necrotic
| style="padding: 5px 5px; background: #F5F5F5;" |
*May present as an [[inflammatory process]] and can be mistaken for [[orbital cellulitis]] with [[chemosis]] and [[proptosis]]
*Associated with increased risk of [[metastasis]]
|-
|-
|}
|}
{|
|[[image:Retinoblastoma gross pathology.jpeg|thumb|400px|Gross pathology of retinoblastoma, Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 9461]]
<br style="clear:left" />
|-
|}
==Microscopic Pathology==
* [[Microscopic|Microscopically]], retinoblastoma is characterized by:<ref name="pmid22288967">{{cite journal |vauthors=Kashyap S, Sethi S, Meel R, Pushker N, Sen S, Bajaj MS, Chandra M, Ghose S |title=A histopathologic analysis of eyes primarily enucleated for advanced intraocular retinoblastoma from a developing country |journal=Arch. Pathol. Lab. Med. |volume=136 |issue=2 |pages=190–3 |date=February 2012 |pmid=22288967 |doi=10.5858/arpa.2010-0759-OA |url=}}</ref>
**Small [[Hyperchromicity|hyperchromatic]] [[cells]] with a high [[nuclear]] to [[cytoplasmic]] ratio
**Large areas of [[necrosis]]
**Multifocal area of [[Calcification|calcifications]]
* Retinoblastoma [[histopathology]] is a combination of undifferentiated [[Cell (biology)|cells]] and areas of [[tumor]] [[differentiation]] shown as rosettes and fleurettes.<ref name="Chévez-BarriosEagle2015">{{cite journal|last1=Chévez-Barrios|first1=Patricia|last2=Eagle|first2=Ralph C.|last3=Marback|first3=Eduardo F.|title=Histopathologic Features and Prognostic Factors|year=2015|pages=167–183|doi=10.1007/978-3-662-43451-2_16}}</ref>


[[File:Retinoblastoma gross pathology.jpeg|thumb|none|200px|Retinoblastoma gross pathology<ref name="radio1">Image courtesy of Dr. Frank Gaillard [http://www.radiopaedia.org Radiopaedia] (original file [http://radiopaedia.org/cases/retinoblastoma-gross-pathology]).[http://radiopaedia.org/licence Creative Commons BY-SA-NC</ref>]]
*The most differentiated part is formed from a bouquet-like aggregates of [[Cell (biology)|cells]] called fleurettes, where [[Mitosis|mitoses]] or [[necrosis]] are not present.
**These [[Cell (biology)|cells]] resemble the [[photoreceptors]] and are arranged similar to [[Flower|flowers]].
*The rosettes are composed of [[Cell (biology)|cells]] with varying degrees of differentiation.
*There are two types of rosettes:
**Flexner–Wintersteiner rosette: Composed of a ring of [[cells]] surrounding a clear center resembling the [[Retina|subretinal]] space.
**Homer Wright rosette: Comprises of a rim of [[cells]] with a [[lumen]] filled by [[cytoplasmic]] prolongations of the [[tumor]] [[cells]].


==Microscopic Pathology==
* Retinoblastoma may be [[Classification|classified]] according to the degree of [[differentiation]] to well/poor-differentiated.
Microscopically, both undifferentiated and differentiated elements may be present.<ref name="wiki">  Retinoblastoma. Wikipedia(2015) https://en.wikipedia.org/wiki/Retinoblastoma Accessed on October 10 2015</ref>
**Well-differentiated [[tumor]] is > 50% Homer-Wright (HW) rosettes.
*Undifferentiated elements appear as collections of small, round cells with hyperchromatic nuclei
**Poor-differentiated [[tumor]] is < 50%  Flexner-Wintersteiner (FW) rosettes.
*Differentiated elements include:
**Flexner-Wintersteiner rosettes
**Homer-Wright rosettes
**Fluerettes from [[photoreceptor]] differentiation
<gallery>
Image:Retinoblastoma Pathology (2).jpg|Retinoblastoma 400 X magnification<ref name=microscope>Images of microscopic appearance of retinoblastoma. Wikipedia 2015. https://en.wikipedia.org/wiki/Retinoblastoma</ref>
Image:Flexner- Wintersteiner Rosettes in Retinoblastoma.jpg|Flexner- Wintersteiner Rosettes in retinoblastoma<ref name=microscope>Images of microscopic appearance of retinoblastoma. Wikipedia 2015. https://en.wikipedia.org/wiki/Retinoblastoma</ref>
</gallery>


==Immunohistochemistry==
*There is no specific [[immunohistochemical]] [[marker]] for the [[diagnosis]] of retinoblastoma.<ref name="pmid16049534">{{cite journal |vauthors=Odashiro AN, Pereira PR, de Souza Filho JP, Cruess SR, Burnier MN |title=Retinoblastoma in an adult: case report and literature review |journal=Can. J. Ophthalmol. |volume=40 |issue=2 |pages=188–91 |date=April 2005 |pmid=16049534 |doi=10.1016/S0008-4182(05)80032-8 |url=}}</ref><ref name="pmid23166876">{{cite journal |vauthors=Zhang Z, Shi JT, Wang NL, Ma JM |title=Retinoblastoma in a young adult mimicking Coats' disease |journal=Int J Ophthalmol |volume=5 |issue=5 |pages=625–9 |date=2012 |pmid=23166876 |pmc=3484701 |doi=10.3980/j.issn.2222-3959.2012.05.16 |url=}}</ref>
*The most commonly applied [[marker]] is neuron specific enolase (NSE).
*Other useful [[Marker|markers]] are:
**[[Synaptophysin]]
**[[CD56]]
**[[Glial fibrillary acidic protein]] ([[GFAP]])
*Although there is no specific [[biomarker]] for the [[diagnosis]] of retinoblastoma, it may be needed for the [[diagnosis]] of undifferentiated form of the [[tumor]].<ref name="pmid25378879">{{cite journal |vauthors=Yousef YA, Istetieh J, Nawaiseh I, Al-Hussaini M, Alrawashdeh K, Jaradat I, Sultan I, Mehyar M |title=Resistant retinoblastoma in a 23-year-old patient |journal=Oman J Ophthalmol |volume=7 |issue=3 |pages=138–40 |date=September 2014 |pmid=25378879 |pmc=4220401 |doi=10.4103/0974-620X.142597 |url=}}</ref><ref name="pmid6856254">{{cite journal |vauthors=Takahashi T, Tamura S, Inoue M, Isayama Y, Sashikata T |title=Retinoblastoma in a 26-year-old adult |journal=Ophthalmology |volume=90 |issue=2 |pages=179–83 |date=February 1983 |pmid=6856254 |doi= |url=}}</ref>
*[[Immunocytochemistry|IHC]] may be useful for the identification of [[photoreceptors]] and [[glial cells]] in the retinoblastoma.
*[[Immunocytochemistry|IHC]] may also be useful in identifying the level of differentiation of the [[tumor]] by detecting red and green [[cones]] found in the rosettes and fleurettes and blue [[cones]] which do not form rosettes and fleurettes.
==References==
==References==
{{Reflist|2}}
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2] Simrat Sarai, M.D. [3]

Overview

Retinoblastoma is a neoplasm which is caused by the inactivation of RB1 gene, a tumor suppressor gene, located on the long arm of the chromosome 13. Mutation in both alleles of the RB1 gene is necessary for the inactivation of the gene. This disorder may occur in the familial or sporadic form. (Rb) gene product limits the cell progression from the G1 phase to the S phase of the cell cycle. Loss of this active, functional protein (Rb) causes cell cycle dysregulation and subsequent overgrowth and tumor formation.

Pathophysiology

Pathogenesis

Genetics

Associated Conditions

Gross Pathology

These growth patterns are described in the table below:

Growth patterns Features
Endophytic
Exophytic
Mixed
  • Most common type
  • Mixed components of endophytic and exophytic are seen
Diffuse Infiltrative
Necrotic
Gross pathology of retinoblastoma, Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 9461


Microscopic Pathology

  • The most differentiated part is formed from a bouquet-like aggregates of cells called fleurettes, where mitoses or necrosis are not present.
  • The rosettes are composed of cells with varying degrees of differentiation.
  • There are two types of rosettes:
    • Flexner–Wintersteiner rosette: Composed of a ring of cells surrounding a clear center resembling the subretinal space.
    • Homer Wright rosette: Comprises of a rim of cells with a lumen filled by cytoplasmic prolongations of the tumor cells.
  • Retinoblastoma may be classified according to the degree of differentiation to well/poor-differentiated.
    • Well-differentiated tumor is > 50% Homer-Wright (HW) rosettes.
    • Poor-differentiated tumor is < 50% Flexner-Wintersteiner (FW) rosettes.

Immunohistochemistry

References

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  3. Garber JE, Offit K (January 2005). "Hereditary cancer predisposition syndromes". J. Clin. Oncol. 23 (2): 276–92. doi:10.1200/JCO.2005.10.042. PMID 15637391.
  4. Goodrich, David W.; Wang, Nan Ping; Qian, Yue-Wei; Lee, Eva Y.-H.P.; Lee, Wen-Hwa (1991). "The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle". Cell. 67 (2): 293–302. doi:10.1016/0092-8674(91)90181-W. ISSN 0092-8674.
  5. Knudson AG (April 1971). "Mutation and cancer: statistical study of retinoblastoma". Proc. Natl. Acad. Sci. U.S.A. 68 (4): 820–3. PMC 389051. PMID 5279523.
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  7. Fabian ID, Rosser E, Sagoo MS (2018). "Epidemiological and genetic considerations in retinoblastoma". Community Eye Health. 31 (101): 29–30. PMC 5998388. PMID 29915469.
  8. Clark, Robin D.; Avishay, Stefanie G. (2015). "Retinoblastoma: Genetic Counseling and Testing": 77–88. doi:10.1007/978-3-662-43451-2_8.
  9. Tse, Brian C.; Brennan, Rachel C.; Rodriguez-Galindo, Carlos; Wilson, Matthew W. (2015). "Non-ocular Tumors": 201–208. doi:10.1007/978-3-662-43451-2_19.
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  11. Singh, Arun (2015). Clinical ophthalmic oncology : retinoblastoma. Heidelberg: Springer. ISBN 978-3-662-43451-2.
  12. Kashyap S, Sethi S, Meel R, Pushker N, Sen S, Bajaj MS, Chandra M, Ghose S (February 2012). "A histopathologic analysis of eyes primarily enucleated for advanced intraocular retinoblastoma from a developing country". Arch. Pathol. Lab. Med. 136 (2): 190–3. doi:10.5858/arpa.2010-0759-OA. PMID 22288967.
  13. Chévez-Barrios, Patricia; Eagle, Ralph C.; Marback, Eduardo F. (2015). "Histopathologic Features and Prognostic Factors": 167–183. doi:10.1007/978-3-662-43451-2_16.
  14. Odashiro AN, Pereira PR, de Souza Filho JP, Cruess SR, Burnier MN (April 2005). "Retinoblastoma in an adult: case report and literature review". Can. J. Ophthalmol. 40 (2): 188–91. doi:10.1016/S0008-4182(05)80032-8. PMID 16049534.
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