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{{Retinoblastoma}}
{{Retinoblastoma}}
{{CMG}}; {{AE}} {{Sahar}} {{Simrat}}
{{CMG}}; {{AE}} {{Sahar}} {{Simrat}}
==Overview
==Overview==
There are several classification system available for retinoblastoma. As the treatment of the tumor has evolved, a new classification system has been introduced. For intraocular diseases the available grouping systems include the IIRC, ICRB and cTNMH systems. For extraocular diseases, the IRSS and cTNMH schemes can be used.
There are several [[classification]] systems available for retinoblastoma. As the treatment of the [[tumor]] has evolved, a new [[classification]] system has been introduced. For [[Ocular|intraocular]] [[diseases|disease]], the available grouping systems include International Intraocular Retinoblastoma [[Classification]] (IIRC), Intraocular [[Classification]] of Retinoblastoma (ICRB), and [[TNM|cTNMH systems]]. For [[Ocular|extraocular]] [[disease]], the International Retinoblastoma [[Cancer staging|Staging]] System (IRSS) and [[TNM Staging System|cTNMH]] schemes can be used.
==Classification==
==Classification==
Retinoblastoma has been classified according to different classification system for variable purpuses.<ref name="pmid23787805">{{cite journal |vauthors=Chantada GL, Sampor C, Bosaleh A, Solernou V, Fandiño A, de Dávila MT |title=Comparison of staging systems for extraocular retinoblastoma: analysis of 533 patients |journal=JAMA Ophthalmol |volume=131 |issue=9 |pages=1127–34 |date=September 2013 |pmid=23787805 |doi=10.1001/jamaophthalmol.2013.260 |url=}}</ref><br>
* Retinoblastoma has been [[Classification|classified]] according to different [[classification]] systems for variable purposes.<ref name="pmid23787805">{{cite journal |vauthors=Chantada GL, Sampor C, Bosaleh A, Solernou V, Fandiño A, de Dávila MT |title=Comparison of staging systems for extraocular retinoblastoma: analysis of 533 patients |journal=JAMA Ophthalmol |volume=131 |issue=9 |pages=1127–34 |date=September 2013 |pmid=23787805 |doi=10.1001/jamaophthalmol.2013.260 |url=}}</ref>
Each classification system has been developed depending on the change in the management of tumor.<br>
* Each [[classification]] system has been developed depending on the change in the management of the [[tumor]].
For treatment purposes, retinoblastoma is classified to:
* For treatment purposes, retinoblastoma is [[Classification|classified]] into:
*'''Intra-ocular retinoblastoma''' classification system includes:
**International Intraocular Retinoblastoma Classification (IIRC)<ref name="pmid16996605">{{cite journal |vauthors=Shields CL, Mashayekhi A, Au AK, Czyz C, Leahey A, Meadows AT, Shields JA |title=The International Classification of Retinoblastoma predicts chemoreduction success |journal=Ophthalmology |volume=113 |issue=12 |pages=2276–80 |date=December 2006 |pmid=16996605 |doi=10.1016/j.ophtha.2006.06.018 |url=}}</ref><ref name="pmid17729249">{{cite journal |vauthors=Zage PE, Reitman AJ, Seshadri R, Weinstein JL, Mets MB, Zeid JL, Greenwald MJ, Strauss LC, Goldman S |title=Outcomes of a two-drug chemotherapy regimen for intraocular retinoblastoma |journal=Pediatr Blood Cancer |volume=50 |issue=3 |pages=567–72 |date=March 2008 |pmid=17729249 |doi=10.1002/pbc.21301 |url=}}</ref><ref name="pmid19172510">{{cite journal |vauthors=Novetsky DE, Abramson DH, Kim JW, Dunkel IJ |title=Published international classification of retinoblastoma (ICRB) definitions contain inconsistencies--an analysis of impact |journal=Ophthalmic Genet. |volume=30 |issue=1 |pages=40–4 |date=March 2009 |pmid=19172510 |doi=10.1080/13816810802452168 |url=}}</ref>
**Intraocular Classification of Retinoblastoma (ICRB)
**The cTNMH system of American Joint Committee on Cancer (AJCC)
Reese-Ellsworth Classification for Intraocular Tumors is another staging system for retinoblastoma.<ref name="pmid15763190">{{cite journal |vauthors=Linn Murphree A |title=Intraocular retinoblastoma: the case for a new group classification |journal=Ophthalmol Clin North Am |volume=18 |issue=1 |pages=41–53, viii |date=March 2005 |pmid=15763190 |doi=10.1016/j.ohc.2004.11.003 |url=}}</ref>
*This classification system was first introduced in 1960 and used to predict the chance of eye salvage after external beam radiotherapy. However, following the introduction of chemotherapy for retinoblastoma treatment, it lost its significance.


=== '''Intraocular Retinoblastoma''' [[Classification]] System ===
**This [[classification]] system incudes the following:
***International Intraocular Retinoblastoma [[Classification]] (IIRC)<ref name="pmid16996605">{{cite journal |vauthors=Shields CL, Mashayekhi A, Au AK, Czyz C, Leahey A, Meadows AT, Shields JA |title=The International Classification of Retinoblastoma predicts chemoreduction success |journal=Ophthalmology |volume=113 |issue=12 |pages=2276–80 |date=December 2006 |pmid=16996605 |doi=10.1016/j.ophtha.2006.06.018 |url=}}</ref><ref name="pmid17729249">{{cite journal |vauthors=Zage PE, Reitman AJ, Seshadri R, Weinstein JL, Mets MB, Zeid JL, Greenwald MJ, Strauss LC, Goldman S |title=Outcomes of a two-drug chemotherapy regimen for intraocular retinoblastoma |journal=Pediatr Blood Cancer |volume=50 |issue=3 |pages=567–72 |date=March 2008 |pmid=17729249 |doi=10.1002/pbc.21301 |url=}}</ref><ref name="pmid19172510">{{cite journal |vauthors=Novetsky DE, Abramson DH, Kim JW, Dunkel IJ |title=Published international classification of retinoblastoma (ICRB) definitions contain inconsistencies--an analysis of impact |journal=Ophthalmic Genet. |volume=30 |issue=1 |pages=40–4 |date=March 2009 |pmid=19172510 |doi=10.1080/13816810802452168 |url=}}</ref>
***Intraocular Classification of Retinoblastoma (ICRB)
***The [[TNM classification|cTNMH]] system of American Joint Committee on [[Cancer]] (AJCC)
==== Intraocular [[Classification|Classifications]] of Retinoblastoma and their [[Features (pattern recognition)|Features]] ====
{| border="3"
{| border="3"
|+ Intraocular classifications of retinoblastoma and their features
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF}} !! style="background: #4479BA; width: 600px;" | {{fontcolor|#FFF|International Intraocular Retinoblastoma Classification (IIRC)}} !! style="background: #4479BA; width: 600px;" | {{fontcolor|#FFF|Intraocular Classification of Retinoblastoma (ICRB)}}
!! International Intraocular Retinoblastoma Classification (IIRC) !! Intraocular Classification of Retinoblastoma (ICRB)
|-
|-
! Group A
! style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |Group A
(very low
(very low
risk)
risk)
|Small intraretinal tumors away from foveola and optic nerve<br>3mm or smaller in the greatest dimension, confined to the retina<br>Located further than 3 mm from the foveola and 1.5 mm from the optic disc
|style="padding: 5px 5px; background: #F5F5F5; |
| Tumors ≤ 3 mm (in basal dimension or thickness)
* Small [[Retina|intraretinal]] [[tumors]] away from foveola and [[optic nerve]]
* 3mm or smaller in the greatest dimension, confined to the [[retina]]
* Located > 3 mm from the [[Foveola suprameatica|foveola]] and 1.5 mm from the [[optic disc]]
|style="padding: 5px 5px; background: #F5F5F5; |
* [[Tumors]] ≤ 3 mm (in basal dimension or thickness)
|-
|-
!Group B
!style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |Group B
(low risk)
(low risk)
|Tumors confined to the retina<br>Not in the group A<br>Tumor-associated subretinal fluid less than 3 mm from the tumor with no subretinal seeding.
|style="padding: 5px 5px; background: #F5F5F5; |
|Tumors > 3 mm (in basal dimension or thickness) or<br>Macular location (≤ 3 mm to foveola)<br>Juxtapapillary location (≤ 1.5 mm to disc)<br>Additional subretinal fluid (≤3 mm from margin)
* [[Tumors]] confined to the [[retina]]
* Not in group A
* [[Tumor]]-associated [[Retina|subretinal]] fluid less than 3 mm from the [[tumor]] with no [[Retina|subretinal]] seeding
|style="padding: 5px 5px; background: #F5F5F5; |
* [[Tumors]] > 3 mm (in basal dimension or thickness) or
* [[Macular]] location (≤ 3 mm to [[Foveola suprameatica|foveola]])
* Juxtapapillary location (≤ 1.5 mm to [[Optic disc|disc]])
* Additional [[Retina|subretinal]] fluid (≤3 mm from margin)
|-
|-
! Group C
! style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |Group C
(moderate
(moderate
risk)
risk)
|Local disease with minimal subretinal or vitreous seeding with following characteristics:<br>Discrete<br>Subretinal fluid, present or past, without seeding involving up to one-fourth of the retina<br>Local fine vitreous seeding may be present close to the discrete tumor<br>Local subretinal seeding less than 3 mm (2 DD) from the tumor
|style="padding: 5px 5px; background: #F5F5F5; |
|Tumor with:<br>Subretinal seeds ≤ 3 mm from tumor<br>Vitreous seeds ≤ 3 mm from tumor<br>Both subretinal and vitreous seeds ≤ 3 mm from retinoblastoma
* Local [[disease]] with minimal [[Retina|subretinal]] or [[vitreous]] seeding with the following characteristics:
** Discrete
** [[Retina|Subretinal]] fluid, present or past, without seeding involving up to one-fourth of the [[retina]]
** Local fine [[vitreous]] seeding may be present close to the discrete [[tumor]]
** Local [[Retina|subretinal]] seeding less than 3 mm (2 DD) from the [[tumor]]
|style="padding: 5px 5px; background: #F5F5F5; |
* [[Tumor]] with:
** [[Retina|Subretinal]] seeds ≤ 3 mm from [[tumor]]
** [[Vitreous]] seeds ≤ 3 mm from [[tumor]]
** Both [[Retina|subretinal]] and [[vitreous]] seeds ≤ 3 mm from the [[tumor]]
|-
|-
!Group D
!style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |Group D
(high risk)
(high risk)
|Diffuse tumor with significant vitreous or subretinal seeding<br>Maybe massive or diffuse<br>Subretinal fluid present or past without seeding, involving up to total retinal detachment<br>The diffuse or massive vitreous disease may include “greasy” seeds or avascular tumor masses<br>Diffuse subretinal seeding may include subretinal plaques or tumor nodules
|style="padding: 5px 5px; background: #F5F5F5; |
|Tumor with:<br>Subretinal seeds > 3 mm from tumor<br>Vitreous seeds > 3 mm from tumor<br>Both subretinal and vitreous seeds > 3 mm from retinoblastoma
* Diffuse [[tumor]] with significant [[vitreous]] or [[Retina|subretinal]] seeding
* Maybe massive or diffuse
* [[Retina|Subretinal]] fluid present or past without seeding, involving up to total [[retinal detachment]]
* The diffuse or massive [[vitreous]] [[disease]] may include “greasy” seeds or [[avascular]] [[tumor]] [[Mass|masses]]
* Diffuse [[Retina|subretinal]] seeding may include [[Retina|subretinal]] plaques or [[tumor]] [[Nodule (medicine)|nodules]]
|style="padding: 5px 5px; background: #F5F5F5; |
* [[Tumor]] with:
** [[Retina|Subretinal]] seeds > 3 mm from [[tumor]]
** [[Vitreous]] seeds > 3 mm from [[tumor]]
** Both [[Retina|subretinal]] and [[vitreous]] seeds > 3 mm from retinoblastoma
|-
|-
!Group E
!style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align="center" |Group E
(very high
(very high
risk)
risk)
|Presence of any one or more of the following poor prognosis features<br>Tumor touching the lens<br>Tumor anterior to anterior vitreous face involving the ciliary body or anterior segment<br>Diffuse infiltrating retinoblastoma<br>Neovascular glaucoma<br>Opaque media from hemorrhage<br>Tumor necrosis with aseptic orbital cellulitis<br>Phthisis bulbi
|style="padding: 5px 5px; background: #F5F5F5; |
|Extensive tumor filling >50% globe or with<br>Neovascular glaucoma<br>Opaque media from hemorrhage in the anterior chamber, vitreous or subretinal space<br>Invasion of the post-laminar optic nerve<br>choroid (>2 mm), sclera, orbit, anterior chamber
* Presence of any one or more of the following poor [[prognosis|prognostic]] [[Features (pattern recognition)|features]]:
** [[Tumor]] touching the [[lens]]
** [[Tumor]] [[Anatomical terms of location|anterior]] to [[Anatomical terms of location|anterior]] [[vitreous]] face involving the [[ciliary body]] or [[Anatomical terms of location|anterior]] segment
** Diffuse infiltrating retinoblastoma
** [[Neovascular glaucoma]]
** Opaque media from [[hemorrhage]]
** [[Tumor]] [[necrosis]] with [[aseptic]] [[orbital cellulitis]]
** [[Phthisis bulbi]]
|style="padding: 5px 5px; background: #F5F5F5; |
* Extensive [[tumor]] filling >50% globe or with<br>[[neovascular glaucoma]]
* Opaque media from [[hemorrhage]] in the [[anterior chamber]], [[vitreous]], or [[Retina|subretinal]] space
* Invasion of the post-laminar [[optic nerve]]<br>[[choroid]] (>2 mm), [[sclera]], [[orbit]], and [[anterior chamber]]
|}
 
=== Reese-Ellsworth [[Classification]] for Intraocular [[Tumors]]<ref name="pmid15763190">{{cite journal |vauthors=Linn Murphree A |title=Intraocular retinoblastoma: the case for a new group classification |journal=Ophthalmol Clin North Am |volume=18 |issue=1 |pages=41–53, viii |date=March 2005 |pmid=15763190 |doi=10.1016/j.ohc.2004.11.003 |url=}}</ref> ===
*This [[classification]] system was first introduced in 1960 and used to predict the chance of salvaging the [[eye]] after [[external beam radiotherapy]].
*However, following the introduction of [[chemotherapy]] for retinoblastoma treatment, it lost its significance.
{| style="border: 0px; font-size: 90%; margin: 3px; width: 800px;" align="center"
| valign="top" |
|}
 
==== Reese-Ellsworth [[Classification]]<ref name="MurphreeChantada2015">{{cite journal|last1=Murphree|first1=A. Linn|last2=Chantada|first2=Guillermo L.|title=Retinoblastoma: Staging and Grouping|year=2015|pages=29–37|doi=10.1007/978-3-662-43451-2_3}}</ref> ====
{| style="border: 0px; font-size: 90%; margin: 3px; width: 800px;" align="center"
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Stage}}
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Sub-stage}}
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Features}}
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Prognosis}}
|-
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Group I
| style="padding: 5px 5px; background: #F5F5F5;" |
*a
| style="padding: 5px 5px; background: #F5F5F5;" |
*Solitory [[tumor]] < 6 mm at or behind the equator
| style="padding: 5px 5px; background: #F5F5F5;" |
*Very favorable
|-
| style="padding: 5px 5px; background: #F5F5F5;" |
* b
| style="padding: 5px 5px; background: #F5F5F5;" |
* Multiple [[Tumor|tumors]], none > 6 mm, all are at or behind the equator
| style="padding: 5px 5px; background: #F5F5F5;" |
* Very favorable
|-
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Group II
| style="padding: 5px 5px; background: #F5F5F5;" |
* a
| style="padding: 5px 5px; background: #F5F5F5;" |
* Solitary [[tumor]], 6 to 15 mm, all at or behind the equator
| style="padding: 5px 5px; background: #F5F5F5;" |
* Favorable
|-
| style="padding: 5px 5px; background: #F5F5F5;" |
* b
| style="padding: 5px 5px; background: #F5F5F5;" |
* Multiple [[Tumor|tumors]], 6 to 15 mm, behind the equator
| style="padding: 5px 5px; background: #F5F5F5;" |
* Favorable
|-
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Group III
| style="padding: 5px 5px; background: #F5F5F5;" |
* a
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Lesion]] [[Anatomical terms of location|anterior]] to the equator
| style="padding: 5px 5px; background: #F5F5F5;" |
* Undetermind
|-
| style="padding: 5px 5px; background: #F5F5F5;" |
* b
| style="padding: 5px 5px; background: #F5F5F5;" |
* Solitary [[tumor]] larger than 15 mm, behind the equator
| style="padding: 5px 5px; background: #F5F5F5;" |
* Undetermined
|-
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Group IV
| style="padding: 5px 5px; background: #F5F5F5;" |
* a
| style="padding: 5px 5px; background: #F5F5F5;" |
* Multiple [[Tumor|tumors]], some larger than 15 mm
| style="padding: 5px 5px; background: #F5F5F5;" |
* Unfavorable
|-
| style="padding: 5px 5px; background: #F5F5F5;" |
* b
| style="padding: 5px 5px; background: #F5F5F5;" |
* Any [[Lesion|lesions]] extending to the [[ora serrata]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Unfavorable
|-
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |Group V
| style="padding: 5px 5px; background: #F5F5F5;" |
* a
| style="padding: 5px 5px; background: #F5F5F5;" |
* Massive [[tumor]] occupying over half the [[retina]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Very unfavorable
|-
| style="padding: 5px 5px; background: #F5F5F5;" |
* b
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Vitreous]] seeding
| style="padding: 5px 5px; background: #F5F5F5;" |
* Very unfavorable
|}
|}
*'''Extra-ocular retinoblastoma''' classification system are such as:
 
**International retinoblastoma staging system
=== '''Extra-ocular Retinoblastoma''' Classification System ===
**cTNMH system of American Joint Committee on Cancer (AJCC)
**This classification system includes the following:
the cTNMH system has been developed by the American Joint Committee on Cancer (AJCC).<ref name="pmid29915471">{{cite journal |vauthors= |title=TNM8: The updated TNM classification for retinoblastoma |journal=Community Eye Health |volume=31 |issue=101 |pages=34 |date=2018 |pmid=29915471 |pmc=5998398 |doi= |url=}}</ref>
***International retinoblastoma staging system
*The tumor classified according to the size of the primary tumor (T), lymph node involvement (N) and presence of systemic metastasis (M).
***[[TNM|cTNMH]] system of American Joint Committee on Cancer (AJCC)<ref name="pmid29915471">{{cite journal |vauthors= |title=TNM8: The updated TNM classification for retinoblastoma |journal=Community Eye Health |volume=31 |issue=101 |pages=34 |date=2018 |pmid=29915471 |pmc=5998398 |doi= |url=}}</ref>
*The recently edited guideline added H for retinoblastoma as the hereditary component for Rb gene.
 
*This category also includes a pathological subgroup (pTNM) which is frequently used by the ophthalmic pathologist.
*To see the full [[Cancer staging|staging]] system [[Retinoblastoma staging|click here]].
*To see the full staging system [[Retinoblastoma staging|click here]].
 
==References==
==References==
{{reflist|2}}
{{reflist|2}}
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Latest revision as of 15:26, 17 January 2021

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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

There are several classification systems available for retinoblastoma. As the treatment of the tumor has evolved, a new classification system has been introduced. For intraocular disease, the available grouping systems include International Intraocular Retinoblastoma Classification (IIRC), Intraocular Classification of Retinoblastoma (ICRB), and cTNMH systems. For extraocular disease, the International Retinoblastoma Staging System (IRSS) and cTNMH schemes can be used.

Classification

Intraocular Retinoblastoma Classification System

Intraocular Classifications of Retinoblastoma and their Features

International Intraocular Retinoblastoma Classification (IIRC) Intraocular Classification of Retinoblastoma (ICRB)
Group A

(very low risk)

  • Tumors ≤ 3 mm (in basal dimension or thickness)
Group B

(low risk)

  • Tumors > 3 mm (in basal dimension or thickness) or
  • Macular location (≤ 3 mm to foveola)
  • Juxtapapillary location (≤ 1.5 mm to disc)
  • Additional subretinal fluid (≤3 mm from margin)
Group C

(moderate risk)

Group D

(high risk)

Group E

(very high risk)

Reese-Ellsworth Classification for Intraocular Tumors[5]

Reese-Ellsworth Classification[6]

Stage Sub-stage Features Prognosis
Group I
  • a
  • Solitory tumor < 6 mm at or behind the equator
  • Very favorable
  • b
  • Multiple tumors, none > 6 mm, all are at or behind the equator
  • Very favorable
Group II
  • a
  • Solitary tumor, 6 to 15 mm, all at or behind the equator
  • Favorable
  • b
  • Multiple tumors, 6 to 15 mm, behind the equator
  • Favorable
Group III
  • a
  • Undetermind
  • b
  • Solitary tumor larger than 15 mm, behind the equator
  • Undetermined
Group IV
  • a
  • Multiple tumors, some larger than 15 mm
  • Unfavorable
  • b
  • Unfavorable
Group V
  • a
  • Very unfavorable
  • b
  • Very unfavorable

Extra-ocular Retinoblastoma Classification System

    • This classification system includes the following:
      • International retinoblastoma staging system
      • cTNMH system of American Joint Committee on Cancer (AJCC)[7]

References

  1. Chantada GL, Sampor C, Bosaleh A, Solernou V, Fandiño A, de Dávila MT (September 2013). "Comparison of staging systems for extraocular retinoblastoma: analysis of 533 patients". JAMA Ophthalmol. 131 (9): 1127–34. doi:10.1001/jamaophthalmol.2013.260. PMID 23787805.
  2. Shields CL, Mashayekhi A, Au AK, Czyz C, Leahey A, Meadows AT, Shields JA (December 2006). "The International Classification of Retinoblastoma predicts chemoreduction success". Ophthalmology. 113 (12): 2276–80. doi:10.1016/j.ophtha.2006.06.018. PMID 16996605.
  3. Zage PE, Reitman AJ, Seshadri R, Weinstein JL, Mets MB, Zeid JL, Greenwald MJ, Strauss LC, Goldman S (March 2008). "Outcomes of a two-drug chemotherapy regimen for intraocular retinoblastoma". Pediatr Blood Cancer. 50 (3): 567–72. doi:10.1002/pbc.21301. PMID 17729249.
  4. Novetsky DE, Abramson DH, Kim JW, Dunkel IJ (March 2009). "Published international classification of retinoblastoma (ICRB) definitions contain inconsistencies--an analysis of impact". Ophthalmic Genet. 30 (1): 40–4. doi:10.1080/13816810802452168. PMID 19172510.
  5. Linn Murphree A (March 2005). "Intraocular retinoblastoma: the case for a new group classification". Ophthalmol Clin North Am. 18 (1): 41–53, viii. doi:10.1016/j.ohc.2004.11.003. PMID 15763190.
  6. Murphree, A. Linn; Chantada, Guillermo L. (2015). "Retinoblastoma: Staging and Grouping": 29–37. doi:10.1007/978-3-662-43451-2_3.
  7. "TNM8: The updated TNM classification for retinoblastoma". Community Eye Health. 31 (101): 34. 2018. PMC 5998398. PMID 29915471.

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