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Classification and staging

TL;DR — Retinoblastoma uses several non-interchangeable systems. ICRB/IIRC groups A–E describe intraocular eye burden and historically predict globe salvage; AJCC eighth-edition cTNMH describes patient-level anatomic extent and heritability; IRSS stages disease after enucleation and through extraocular/metastatic spread. A group D eye is not an IRSS stage D patient. Every outcome must name the system, version, unit of analysis and initial treatment.

Decision-relevant evidence

  • In 565 eyes treated with systemic chemotherapy plus focal therapy, cT1 salvage was 95% (139/147), cT2 56% (230/410) and cT3 0%; ICRB group salvage was 98%, 93%, 76% and 44% for A, B, C and D. Odds of treatment failure rose 13.6-fold from cT1 to cT2 and 50.1-fold from group A to group D (Yousef 2021, PMID 33769386).

  • Diffuse seeds had 42% salvage versus 62% for focal seeds in the same cohort (P < 0.0001), which is why the authors argue cT2b should be subdivided by seed morphology in the next edition (PMID 33769386).

  • All three intraocular schemes predict pathology and metastasis-free survival about equally, so the choice matters mainly for comparability. Across 1,362 primarily enucleated patients from 16 centres in 11 countries, 751 (55.1%) had at least one high-risk feature; the positive predictive value of group D for high-risk pathology was 42.0% (ICRB Philadelphia), 35.1% (ICRB Los Angeles) and 43.2% (COG), and of group E 58.5%, 59.0% and 59.5%. Inter-scheme agreement was 0.8–0.9 and AJCC cT stratified more finely, from above 55% at cT3a to 72.3% at cT3e (Kurian 2025, PMID 39922380).

  • The group-D/E boundary moves eyes between categories. Reclassifying 332 advanced eyes from IIRC to ICRB upstaged 57 of 150 group D eyes (17%) to group E; upstaged eyes underwent primary enucleation in 30% versus 11% of those not upstaged (P = 0.003), and 12-month Kaplan-Meier ocular survival was 79%, 59%, 49% and 1% for ICRB D, E1, E2 and E3 (Singh 2024, PMID 38830602; see also Sedaghat 2024, PMID 38688458).

  • Centres do not even agree which version they are using. In a survey of 39 retinoblastoma centres covering 1,807 group D eyes, 27% used the Children's Hospital of Los Angeles version, 33% the Children's Oncology Group version, 23% the Philadelphia version and 17% were unsure. Primary enucleation rates for the same nominal group ranged from 0% to 100% (mean 29%), and varied by version — Philadelphia 8%, COG 34%, CHLA 37% — and by region — Latin America 57%, Asia 40%, Europe 36%, Africa 10%, United States 8%, Middle East 8% (Scelfo 2017, PMID 28730089).

  • Clinical stage tracks the presenting sign. Among 4,578 treatment-naive children from 259 centres in 121 countries, the proportion presenting with curable IRSS stage 0/I/II disease was 94.8% for strabismus, 90.1% for leukocoria, 89.7% for iris changes, 84.2% for hyphema, 82.1% for red eye, 66.7% for orbital cellulitis and 33.7% for orbital mass; leukocoria was the most common sign at every national income level (Yanagihara 2025, PMID 40334716).

  • The global study used cTNMH and found cT4 in 0.8% of high-income versus 42.9% of low-income children (PMID 35839812).

  • Pathological stage carries the survival information after enucleation. In 700 consecutive primarily enucleated Chinese patients, five-year overall survival was 95.5% and disease-specific survival 95.7%, but pathological stage split it sharply: pT1 99.5%, pT2a 95.5%, pT3a 100%, pT3b 93.0%, pT3c/d 92.3% and pT4 40.9%. Enucleation within 26 days of diagnosis gave 96.1% versus 86.9% when delayed (P = 0.017), and cT3c eyes — raised intraocular pressure with neovascularisation or buphthalmos — did worse (87.1%) than other cT2b/cT3 categories (Zhao 2021, PMID 34944860).

  • One clinicopathological variant sits outside the usual staging logic. Diffuse infiltrating retinoblastoma accounted for 132 of 2,854 eyes (4.6%, 95% CI 3.9–5.5) in an international registry series; median age was 24 months, none were bilateral, and staging clustered at cT3 (95.5%) with no cT1 or cT4. Five-year survival for cT3 diffuse infiltrating disease was 82% (78–86) versus 94% (93–95) for cT3 non-diffuse (P < 0.001), with a hazard ratio for metastatic death of 3.3 (1.8–5.9) and more high-risk pathology (41% versus 28%, P = 0.004) (Tomar 2025, PMID 40738737).

  • Anterior-chamber seeding has its own morphological classification with pathological correlates: in 25 primarily enucleated group E eyes, type 1 seeds appeared in 36%, type 2 in 32% and type 3 in 32%; seeding involved the anterior chamber in 100% and the posterior chamber in 72%, intraocular tissue infiltration was present in 92%, and type 3 seeds were more often associated with ciliary-body infiltration (88% versus 41%, P = 0.04) (Jakati 2022, PMID 34958963; review Kaliki 2021, PMID 34185374).

  • Stage III IRSS describes regional/orbital disease and requires multimodal therapy; a 54-child randomized comparison reported four-year survival 63% (95% CI 0.41–0.79) with VEC versus 25% (0.08–0.46) with an alternating five-drug regimen (P = 0.05 for the trend), with CNS relapse the dominant cause of death in both arms (Chawla 2016, PMID 27449712).

  • Staging investigations can be stage-directed rather than universal: among 259 patients who had both bone-marrow biopsy and lumbar puncture at diagnosis, 18 (7%) were positive, and no stage 0 or stage I patient was positive even in the presence of high-risk histopathological features — so the authors conclude marrow and cerebrospinal-fluid evaluation is not required at stages 0 and I but is required at stages III and IV (Bakhshi 2011, PMID 21364467).

Clinical and research frame

Domain Operational meaning Evidence boundary
ICRB/IIRC A–E Eye Intraocular burden and seeds; globe-salvage comparison
cTNMH 8th edition Child plus eye/heredity Common cancer-staging language
pTNM Enucleated eye Histopathologic extension
IRSS 0–IV Child after treatment/staging Extraocular and metastatic treatment strata
Laterality/heritable status Child/family Must be recorded alongside stage

Interpretation rules

  • Keep the child-level endpoints of survival and metastasis separate from the eye-level endpoint of globe salvage.

  • Report initial stage, laterality, heritability, prior treatment and follow-up; otherwise comparisons are not transportable.

  • A retrospective eye series estimates performance in selected eyes; it does not establish superiority over another route.

  • Absence of metastasis in a small series is a safety observation, not proof that risk is zero.

  • Treatment-era effects matter because external-beam radiotherapy, systemic chemotherapy, IAC and intravitreal therapy create different late-risk profiles.

  • Income stratum and access are effect modifiers, not background descriptors (Global Retinoblastoma Study Group 2022, PMID 35839812).

Evidence register

The following records were each retrieved live from PubMed E-utilities on 2026-09-01 and re-fetched live during the independent audit on the same date. Every identifier below resolved, and its author, year, journal and title matched the citation as written. Inclusion records the evidence base for this page; a register entry asserts that the record exists and is on topic, not that it supports a specific effect estimate.

PMID Year Study or review Role in this page
33769386 2021 The Predictive Value of the Eighth Edition of the Clinical TNM Staging System for the Likelihood of Eye Salvage for Intraocular Retinoblastoma by Systemic Chemotherapy and Focal Therapy. Topic-resolved source (Yousef 2021, PMID 33769386)
35839812 2022 The Global Retinoblastoma Outcome Study: a prospective, cluster-based analysis of 4064 patients from 149 countries. Topic-resolved source (Global 2022, PMID 35839812)
27449712 2016 Multimodal Therapy for Stage III Retinoblastoma (International Retinoblastoma Staging System): A Prospective Comparative Study. Topic-resolved source (Chawla 2016, PMID 27449712)
33120616 2020 Modern treatment of retinoblastoma: A 2020 review. Topic-resolved source (Ancona-Lezama 2020, PMID 33120616)
26023180 2016 Retinoblastoma. Topic-resolved source (Ortiz 2016, PMID 26023180)
39922380 2025 High-Risk Retinoblastoma Based on International Classification Systems: Analysis of 1362 Eyes. Topic-resolved source (Kurian 2025, PMID 39922380)
28730089 2017 An international survey of classification and treatment choices for group D retinoblastoma. Topic-resolved source (Scelfo 2017, PMID 28730089)
38830602 2024 Evolving criteria for group E retinoblastoma: impact on outcomes. Topic-resolved source (Singh 2024, PMID 38830602)
39955086 2025 Effect of intra-arterial chemotherapy drug regimens on globe salvage outcomes of retinoblastoma patients. Topic-resolved source (He 2025, PMID 39955086)
40993900 2025 Intra-arterial Chemotherapy for Retinoblastoma: Real-world Experience. Topic-resolved source (Das 2025, PMID 40993900)
39388193 2024 Survival and Health Care Burden of Children With Retinoblastoma in Europe. Topic-resolved source (Virgili 2024, PMID 39388193)
38492167 2024 Epidemiology, Diagnosis and Genetics of Retinoblastoma: ICMR Consensus Guidelines. Topic-resolved source (Singh 2024, PMID 38492167)
34958963 2022 Aqueous Seeding in Retinoblastoma: Classification and Clinicopathologic Correlation. Topic-resolved source (Jakati 2022, PMID 34958963)
38688458 2024 Advanced intraocular retinoblastoma: evolving criteria for group E disease. Topic-resolved source (Sedaghat 2024, PMID 38688458)
39735524 2024 Retinoblastoma in Ethiopian Children: Imaging Findings and Staging. Topic-resolved source (Woldeyohannes 2024, PMID 39735524)
27981923 2016 Tumor Regression Patterns in Retinoblastoma. Topic-resolved source (Zafar 2016, PMID 27981923)
28069617 2017 Ocular oncology: advances in retinoblastoma, uveal melanoma and conjunctival melanoma. Topic-resolved source (Vasalaki 2017, PMID 28069617)
22421935 2012 Retinoblastoma: an overview. Topic-resolved source (Ray 2012, PMID 22421935)
39267557 2024 [Metachronous bilateral retinoblastoma: a case report]. Topic-resolved source (Mengjiang 2024, PMID 39267557)
42486661 2026 Retinoblastoma presenting as congenital glaucoma. Topic-resolved source (AlShimali 2026, PMID 42486661)
33817429 2021 Globe salvage treatment in group D and group E retinoblastoma. Topic-resolved source (Hussain 2021, PMID 33817429)
30009948 2018 Strabismus in retinoblastoma survivors with long-term follow-up. Topic-resolved source (Fabian 2018, PMID 30009948)
35848346 2023 Retinoblastoma and uveal melanoma in Jordan: incidence, demographics, and survival (2011-2020). Topic-resolved source (Yousef 2023, PMID 35848346)
34185374 2021 Aqueous seeding in intraocular retinoblastoma: A review. Topic-resolved source (Kaliki 2021, PMID 34185374)
38615905 2024 Recent progress in retinoblastoma: Pathogenesis, presentation, diagnosis and management. Topic-resolved source (Zhou 2024, PMID 38615905)
29737052 2018 Retinoblastoma for Pediatric Ophthalmologists. Topic-resolved source (AlAli 2018, PMID 29737052)
29915461 2018 Classification and staging of retinoblastoma. Topic-resolved source (Fabian 2018, PMID 29915461)
25940424 2015 Retinoblastoma: diagnosis and management--the UK perspective. Topic-resolved source (Jenkinson 2015, PMID 25940424)
29043448 2017 [Retinoblastoma and retinocytoma (retinoma)]. Topic-resolved source (Metz 2017, PMID 29043448)
40738737 2025 Diffuse infiltrating retinoblastoma: a multicentre, international, data-sharing study. Topic-resolved source (Tomar 2025, PMID 40738737)
3323180 1987 Intraocular and extraocular retinoblastoma. Topic-resolved source (Grabowski 1987, PMID 3323180)
9166573 1997 MR imaging in retinoblastoma. Topic-resolved source (Barkhof 1997, PMID 9166573)
16632438 2006 Survival in extra-orbital metastatic retinoblastoma:treatment results. Topic-resolved source (Leal-Leal 2006, PMID 16632438)
34944860 2021 Retinoblastoma Survival Following Primary Enucleation by AJCC Staging. Topic-resolved source (Zhao 2021, PMID 34944860)
28399338 2017 Genetics and Molecular Diagnostics in Retinoblastoma--An Update. Topic-resolved source (Soliman 2017, PMID 28399338)
21364467 2011 Bone marrow aspirations and lumbar punctures in retinoblastoma at diagnosis: correlation with IRSS staging. Topic-resolved source (Bakhshi 2011, PMID 21364467)
29337595 2017 Outcome of extraocular retinoblastoma in a resource limited center from low middle income country. Topic-resolved source (Pant 2017, PMID 29337595)
40334716 2025 Clinical Stage of Retinoblastoma Based on Presenting Signs of 4578 Patients from 121 Countries. Topic-resolved source (Yanagihara 2025, PMID 40334716)
22463820 2012 Outcome, pathologic findings, and compliance in orbital retinoblastoma (International Retinoblastoma Staging System stage III) treated with neoadjuvant chemotherapy: a prospective study. Topic-resolved source (Radhakrishnan 2012, PMID 22463820)

Source chronology

Era marker PMID What the record contributes
1987 3323180 Intraocular and extraocular retinoblastoma. (Grabowski 1987, PMID 3323180)
1997 9166573 MR imaging in retinoblastoma. (Barkhof 1997, PMID 9166573)
2006 16632438 Survival in extra-orbital metastatic retinoblastoma:treatment results. (Leal-Leal 2006, PMID 16632438)
2011 21364467 Bone marrow aspirations and lumbar punctures in retinoblastoma at diagnosis: correlation with IRSS staging. (Bakhshi 2011, PMID 21364467)
2012 22421935 Retinoblastoma: an overview. (Ray 2012, PMID 22421935)
2012 22463820 Outcome, pathologic findings, and compliance in orbital retinoblastoma (International Retinoblastoma Staging System stage III) treated with neoadjuvant chemotherapy: a prospective study. (Radhakrishnan 2012, PMID 22463820)
2015 25940424 Retinoblastoma: diagnosis and management--the UK perspective. (Jenkinson 2015, PMID 25940424)
2016 26023180 Retinoblastoma. (Ortiz 2016, PMID 26023180)
2016 27449712 Multimodal Therapy for Stage III Retinoblastoma (International Retinoblastoma Staging System): A Prospective Comparative Study. (Chawla 2016, PMID 27449712)
2016 27981923 Tumor Regression Patterns in Retinoblastoma. (Zafar 2016, PMID 27981923)
2017 28069617 Ocular oncology: advances in retinoblastoma, uveal melanoma and conjunctival melanoma. (Vasalaki 2017, PMID 28069617)
2017 28399338 Genetics and Molecular Diagnostics in Retinoblastoma--An Update. (Soliman 2017, PMID 28399338)
2017 28730089 An international survey of classification and treatment choices for group D retinoblastoma. (Scelfo 2017, PMID 28730089)
2017 29043448 [Retinoblastoma and retinocytoma (retinoma)]. (Metz 2017, PMID 29043448)
2017 29337595 Outcome of extraocular retinoblastoma in a resource limited center from low middle income country. (Pant 2017, PMID 29337595)

Evidence limitations

  • Most intraocular treatment evidence is observational, single-centre and reported per eye; bilateral eyes within one child are statistically correlated.

  • Classification and treatment changed over time, producing stage migration and confounding by indication.

  • Rare metastatic and late-effect outcomes require multinational cohorts and decades of follow-up.

  • Verification is abstract-level. Every claim on this page was checked against the abstract of the record it cites during the independent audit on 2026-09-01; where an abstract could not support a claim, the claim was removed or restated as an explicit limit. Claims requiring full text beyond the abstract are not made here.

Open questions

  • Can heterogeneous cT2b disease be subdivided reproducibly? The current evidence register defines the design space but does not close the question.

  • Which classification best predicts vision, not only globe salvage? The current evidence register defines the design space but does not close the question.

  • How much apparent treatment effect reflects classification migration? The current evidence register defines the design space but does not close the question.

References

  1. Yousef YA, et al. The Predictive Value of the Eighth Edition of the Clinical TNM Staging System for the Likelihood of Eye Salvage for Intraocular Retinoblastoma by Systemic Chemotherapy and Focal Therapy. Journal of pediatric hematology/oncology. 2021;43:e841-e847. PMID 33769386
  2. Global Retinoblastoma Study Group. The Global Retinoblastoma Outcome Study: a prospective, cluster-based analysis of 4064 patients from 149 countries. The Lancet. Global health. 2022;10:e1128-e1140. PMID 35839812
  3. Chawla B, et al. Multimodal Therapy for Stage III Retinoblastoma (International Retinoblastoma Staging System): A Prospective Comparative Study. Ophthalmology. 2016;123:1933-9. PMID 27449712
  4. Ancona-Lezama D, et al. Modern treatment of retinoblastoma: A 2020 review. Indian journal of ophthalmology. 2020;68:2356-2365. PMID 33120616
  5. Ortiz MV, et al. Retinoblastoma. Journal of child neurology. 2016;31:227-36. PMID 26023180
  6. Kurian DE, et al. High-Risk Retinoblastoma Based on International Classification Systems: Analysis of 1362 Eyes. Ophthalmology. Retina. 2025;9:787-797. PMID 39922380
  7. Scelfo C, et al. An international survey of classification and treatment choices for group D retinoblastoma. International journal of ophthalmology. 2017;10:961-967. PMID 28730089
  8. Singh A, et al. Evolving criteria for group E retinoblastoma: impact on outcomes. Canadian journal of ophthalmology. Journal canadien d'ophtalmologie. 2024;59:e534-e541. PMID 38830602
  9. He X, et al. Effect of intra-arterial chemotherapy drug regimens on globe salvage outcomes of retinoblastoma patients. The British journal of ophthalmology. 2025;109:888-893. PMID 39955086
  10. Das A, et al. Intra-arterial Chemotherapy for Retinoblastoma: Real-world Experience. International ophthalmology clinics. 2025;65:60-67. PMID 40993900
  11. Virgili G, et al. Survival and Health Care Burden of Children With Retinoblastoma in Europe. JAMA ophthalmology. 2024;142:1062-70. PMID 39388193
  12. Singh L, et al. Epidemiology, Diagnosis and Genetics of Retinoblastoma: ICMR Consensus Guidelines. Indian journal of pediatrics. 2024;91:1147-1156. PMID 38492167
  13. Jakati S, et al. Aqueous Seeding in Retinoblastoma: Classification and Clinicopathologic Correlation. Ophthalmology. Retina. 2022;6:421-428. PMID 34958963
  14. Sedaghat A, et al. Advanced intraocular retinoblastoma: evolving criteria for group E disease. Canadian journal of ophthalmology. Journal canadien d'ophtalmologie. 2024;59:e635-e641. PMID 38688458
  15. Woldeyohannes AM, et al. Retinoblastoma in Ethiopian Children: Imaging Findings and Staging. Ethiopian journal of health sciences. 2024;34:39-46. PMID 39735524
  16. Zafar SN, et al. Tumor Regression Patterns in Retinoblastoma. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2016;26:896-899. PMID 27981923
  17. Vasalaki M, et al. Ocular oncology: advances in retinoblastoma, uveal melanoma and conjunctival melanoma. British medical bulletin. 2017;121:107-119. PMID 28069617
  18. Ray A, et al. Retinoblastoma: an overview. Indian journal of pediatrics. 2012;79:916-21. PMID 22421935
  19. Mengjiang R, et al. [Metachronous bilateral retinoblastoma: a case report]. [Zhonghua yan ke za zhi] Chinese journal of ophthalmology. 2024;60:776-778. PMID 39267557
  20. AlShimali R, et al. Retinoblastoma presenting as congenital glaucoma. BMJ case reports. 2026;19. PMID 42486661
  21. Hussain AK, et al. Globe salvage treatment in group D and group E retinoblastoma. Romanian journal of ophthalmology. 2021;65:20-24. PMID 33817429
  22. Fabian ID, et al. Strabismus in retinoblastoma survivors with long-term follow-up. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus. 2018;22:276.e1-276.e7. PMID 30009948
  23. Yousef YA, et al. Retinoblastoma and uveal melanoma in Jordan: incidence, demographics, and survival (2011-2020). Ophthalmic genetics. 2023;44:119-126. PMID 35848346
  24. Kaliki S. Aqueous seeding in intraocular retinoblastoma: A review. Clinical & experimental ophthalmology. 2021;49:606-614. PMID 34185374
  25. Zhou M, et al. Recent progress in retinoblastoma: Pathogenesis, presentation, diagnosis and management. Asia-Pacific journal of ophthalmology (Philadelphia, Pa.). 2024;13:100058. PMID 38615905
  26. AlAli A, et al. Retinoblastoma for Pediatric Ophthalmologists. Asia-Pacific journal of ophthalmology (Philadelphia, Pa.). 2018;7:160-168. PMID 29737052
  27. Fabian ID, et al. Classification and staging of retinoblastoma. Community eye health. 2018;31:11-13. PMID 29915461
  28. Jenkinson H. Retinoblastoma: diagnosis and management--the UK perspective. Archives of disease in childhood. 2015;100:1070-5. PMID 25940424
  29. Metz KA, et al. [Retinoblastoma and retinocytoma (retinoma)]. Der Pathologe. 2017;38:507-514. PMID 29043448
  30. Tomar AS, et al. Diffuse infiltrating retinoblastoma: a multicentre, international, data-sharing study. The British journal of ophthalmology. 2025;109:1409-1416. PMID 40738737
  31. Grabowski EF, et al. Intraocular and extraocular retinoblastoma. Hematology/oncology clinics of North America. 1987;1:721-35. PMID 3323180
  32. Barkhof F, et al. MR imaging in retinoblastoma. European radiology. 1997;7:726-31. PMID 9166573
  33. Leal-Leal CA, et al. Survival in extra-orbital metastatic retinoblastoma:treatment results. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2006;8:39-44. PMID 16632438
  34. Zhao J, et al. Retinoblastoma Survival Following Primary Enucleation by AJCC Staging. Cancers. 2021;13. PMID 34944860
  35. Soliman SE, et al. Genetics and Molecular Diagnostics in Retinoblastoma--An Update. Asia-Pacific journal of ophthalmology (Philadelphia, Pa.). 2017;6:197-207. PMID 28399338
  36. Bakhshi S, et al. Bone marrow aspirations and lumbar punctures in retinoblastoma at diagnosis: correlation with IRSS staging. Journal of pediatric hematology/oncology. 2011;33:e182-5. PMID 21364467
  37. Pant G, et al. Outcome of extraocular retinoblastoma in a resource limited center from low middle income country. Pediatric hematology and oncology. 2017;34:419-424. PMID 29337595
  38. Yanagihara RT, et al. Clinical Stage of Retinoblastoma Based on Presenting Signs of 4578 Patients from 121 Countries. Ophthalmology. 2025;132:1045-1053. PMID 40334716
  39. Radhakrishnan V, et al. Outcome, pathologic findings, and compliance in orbital retinoblastoma (International Retinoblastoma Staging System stage III) treated with neoadjuvant chemotherapy: a prospective study. Ophthalmology. 2012;119:1470-7. PMID 22463820