Retinoblastoma pathophysiology: Difference between revisions
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*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 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 [[familial]] form (48% of the cases), the first [[mutation]] occurs during [[germ cell]] division and the second one 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. | *In the sporadic form, both [[mutations]] occur during the lifetime of the individual. | ||
*([[Rb]]) gene product limits the 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 [[Rb]] protein binds to [[E2F]], a [[transcription factor]]. Loss of this active, functional [[protein]] ([[Rb]]) causes cell cycle dysregulation. | |||
==Genetics== | ==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> | *[[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> | ||
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*In the acquired form, both [[mutations]] occur during [[somatic]] divisions. | *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> | *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> | *[[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]]. | **This [[13q deletion syndrome|syndrome]] is the result of the [[deletion]] of the long arm of [[chromosome 13]]. | ||
Revision as of 13:45, 14 May 2019
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]: Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Sahar Memar Montazerin, M.D.[3]
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Retinoblastoma Microchapters |
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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.[1]
Pathogenesis
- Retinoblastoma is a neoplasm which is caused by the inactivation of RB1 gene, a tumor suppressor gene.[2]
- 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.[3]
- 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.[4]
- In the sporadic form, both mutations occur during the lifetime of the individual.
- (Rb) gene product limits the cell progression from the G1 phase to the S phase of the cell cycle.[5]
- Active Rb protein binds to E2F, a transcription factor. Loss of this active, functional protein (Rb) causes cell cycle dysregulation.
Genetics
- Retinoblastoma occurs due to mutational inactivation of RB1 gene located on the chromosome 13.[6]
- The RB1 gene acts as tumor suppressor gene.[7]
- Two 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.[8]
- Retinoblastoma may also occur as part of 13q deletion syndrome.[9]
- This 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.
- Children with chromosome 13q14 deletions may develop retinoblastoma at a later age and they develop a unilateral tumor.
- Mosaicism, presence of RB1 gene mutation in some not all the cells of the affected person, may occur in retinoblastoma.
- Patients with mosaic mutation often have unilateral retinoblastoma, later onset of the tumor and no family history of the disease.
Gross Pathology
- Macroscopic appearance of the tumor varies according to the staging of the tumor.[10]
- 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 tumor can be classified into five sub-group according to its growth pattern. These patterns are recognizable grossly.[11]
- Endophytic
- Exophytic
- Mixed
- Diffuse infiltrative
- Necrotic variant
These growth pattern are described in the below table:
| Growth patterns | Features |
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Microscopic Pathology
Microscopically, retinoblastoma is a neoplasm consists of:[12]
- Small hyperchromatic cells with a high nuclear to cytoplasmic ratio
- Large areas of necrosis
- Multifocal area of calcifications
Retinoblastoma may be classified according to the degree of differentiation to well/poor-differentiated.
- Well-differentiated tumor is known as >50% Homer-Wright (HW) rosettes.
- Poor-differentiated tumor is known as <50% Flexner-Wintersteiner (FW) rosettes.
Also, the tumor is graded according to the presence and degree of necrosis as follows:[13]
- None (<25%)
- Mild (25%-50%)
- Extensive (>50%)
Microscopically, both undifferentiated and differentiated elements may be present.[14]
- Undifferentiated elements appear as collections of small, round cells with hyperchromatic nuclei
- Differentiated elements include:
- Flexner-Wintersteiner rosettes
- Homer-Wright rosettes
- Fluerettes from photoreceptor differentiation
Immunohistochemistry
- There is no specific immunohistochemical marker for the diagnosis of retinoblastoma.[15][16]
- The most commonly applied marker is neuron specific enolase (NSE)
- Other useful markers are such as:
- Although there is no specific biomarker for the diagnosis of retinoblastoma, it may be needed for the diagnosis of undifferentiated form of the tumor.[17][18]
- IHC may be useful for the identification of photoreceptors and glial cells in the retinoblastoma.
- IHC may also be useful in identifying the level of differentiation of the tumor by detecting red and green cones found in rosettes and fleurettes and blue cones which do not form rosettes and fleurettes.
References
- ↑ Schefler AC, Abramson DH (2008). "Retinoblastoma: what is new in 2007-2008". Curr Opin Ophthalmol. 19 (6): 526–34. doi:10.1097/ICU.0b013e328312975b. PMID 18854698.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Fabian ID, Rosser E, Sagoo MS (2018). "Epidemiological and genetic considerations in retinoblastoma". Community Eye Health. 31 (101): 29–30. PMC 5998388. PMID 29915469.
- ↑ Clark, Robin D.; Avishay, Stefanie G. (2015). "Retinoblastoma: Genetic Counseling and Testing": 77–88. doi:10.1007/978-3-662-43451-2_8.
- ↑ 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.
- ↑ Singh, Arun (2015). Clinical ophthalmic oncology : retinoblastoma. Heidelberg: Springer. ISBN 978-3-662-43451-2.
- ↑ 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.
- ↑ Singh L, Pushker N, Sen S, Singh MK, Chauhan FA, Kashyap S (August 2015). "Prognostic significance of polo-like kinases in retinoblastoma: correlation with patient outcome, clinical and histopathological parameters". Clin. Experiment. Ophthalmol. 43 (6): 550–7. doi:10.1111/ceo.12517. PMID 25754767.
- ↑ Retinoblastoma. Wikipedia(2015) https://en.wikipedia.org/wiki/Retinoblastoma Accessed on October 10 2015
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.