Retinoblastoma pathophysiology: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
m (Bot: Removing from Primary care)
 
(165 intermediate revisions by 10 users not shown)
Line 1: Line 1:
{{CMG}}
__NOTOC__
{{Retinoblastoma}}
{{Retinoblastoma}}
{{CMG}}; {{AE}} {{Sahar}} {{Simrat}}
==Overview==
==Overview==
'''Retinoblastoma''' is a [[cancer]] of the [[retina]]. Development of this tumor is initiated by [[mutation]]s<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>
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.


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>
== 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==
*[[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>
*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>
*Two [[Mutation|mutational]] events are needed for the [[development]] of retinoblastoma.
*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]].
*In the acquired form, both [[mutations]] occur during [[somatic]] divisions.
*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>
**This [[13q deletion syndrome|syndrome]] is the result of the [[deletion]] of the long arm of [[chromosome 13]].
**[[Symptoms]] may vary according to the size of the [[deletion]], but it may lead to [[developmental delay]] as well.
**[[Child|Children]] with [[chromosome]] 13q14 [[Deletion (genetics)|deletions]] may develop retinoblastoma at a later age and they develop a unilateral [[tumor]].
*[[Mosaicism]], presence of [[RB1]] [[gene mutation]] in some [[cells]] of the affected person, may occur in retinoblastoma.
**[[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]]


==Function of retinoblastoma proteins==
==Gross Pathology==
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.<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>. 
*[[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 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>
**[[Endophyte|Endophytic]]
**Exophytic
**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: 400px;" | {{fontcolor|#FFF|Features}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
:Endophytic
| style="padding: 5px 5px; background: #F5F5F5;" |
*Growth occurs inwards into the [[vitreous]]
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Exophytic
| style="padding: 5px 5px; background: #F5F5F5;" |
*Growth occurs outwards towards [[choroid]]
*Associated with non-rhegmatogenous [[retinal detachment]]
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Mixed
| style="padding: 5px 5px; background: #F5F5F5;" |
*Most common type
*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]]


'''So, when there is a deletion of RB gene, the RB proteins no more present which leads to unhindered cell proliferation leading to tumors.'''
* 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>


==Genetics==
*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.
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.
**These [[Cell (biology)|cells]] resemble the [[photoreceptors]] and are arranged similar to [[Flower|flowers]].
===Knudson's two hit hypothesis and retinoblastoma:===
*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]].
 
* Retinoblastoma may be [[Classification|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==
*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==
<references/>
{{Reflist|2}}
 
​
==See also==
*[[Eye cancer]]
*[[Eye examination]]


{{Nervous tissue tumors}}
[[Category:Medicine]]
 
[[Category:Ophthalmology]]
[[Category:Types of cancer]]
[[Category:hereditary cancers]]
[[Category:Oncology]]
[[Category:Oncology]]
[[Category:Oncology stub]]
[[Category:Up-To-Date]]
 
[[Category:Surgery]]
{{WikiDoc Help Menu}}
{{WikiDoc Sources}}

Latest revision as of 23:59, 29 July 2020

Retinoblastoma Microchapters

Home

Patient Information

Overview

Historical perspective

Classification

Pathophysiology

Causes

Differentiating Retinoblastoma from other Diseases

Epidemiology & Demographics

Risk Factors

Screening

Natural history, Complications, and Prognosis

Diagnosis

Diagnostic Study of Choice

History & Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

Echocardiography and Ultrasound

CT scan

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Retinoblastoma pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Retinoblastoma pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Retinoblastoma pathophysiology

CDC on Retinoblastoma pathophysiology

Retinoblastoma pathophysiology in the news

Blogs on Retinoblastoma pathophysiology

Directions to Hospitals Treating Retinoblastoma

Risk calculators and risk factors for Retinoblastoma pathophysiology

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

  1. ↑ Dunn JM, Phillips RA, Becker AJ, Gallie BL (September 1988). "Identification of germline and somatic mutations affecting the retinoblastoma gene". Science. 241 (4874): 1797–800. PMID 3175621.
  2. ↑ Dunn JM, Phillips RA, Zhu X, Becker A, Gallie BL (November 1989). "Mutations in the RB1 gene and their effects on transcription". Mol. Cell. Biol. 9 (11): 4596–604. PMC 363605. PMID 2601691.
  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.
  6. ↑ 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.
  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.
  10. ↑ Das D, Bhattacharjee K, Barthakur SS, Tahiliani PS, Deka P, Bhattacharjee H, Deka A, Paul R (May 2014). "A new rosette in retinoblastoma". Indian J Ophthalmol. 62 (5): 638–41. doi:10.4103/0301-4738.129786. PMC 4065523. PMID 24881618.
  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.
  15. ↑ Zhang Z, Shi JT, Wang NL, Ma JM (2012). "Retinoblastoma in a young adult mimicking Coats' disease". Int J Ophthalmol. 5 (5): 625–9. doi:10.3980/j.issn.2222-3959.2012.05.16. PMC 3484701. PMID 23166876.
  16. ↑ Yousef YA, Istetieh J, Nawaiseh I, Al-Hussaini M, Alrawashdeh K, Jaradat I, Sultan I, Mehyar M (September 2014). "Resistant retinoblastoma in a 23-year-old patient". Oman J Ophthalmol. 7 (3): 138–40. doi:10.4103/0974-620X.142597. PMC 4220401. PMID 25378879.
  17. ↑ Takahashi T, Tamura S, Inoue M, Isayama Y, Sashikata T (February 1983). "Retinoblastoma in a 26-year-old adult". Ophthalmology. 90 (2): 179–83. PMID 6856254.

​

Retrieved from "https://www.wikidoc.org/index.php?title=Retinoblastoma_pathophysiology&oldid=1642861"