1. The International Classification for Retinoblastoma

2. Guillermo Chantada (1), Fran  ois Doz (2), Celia Antoneli (3), Richard Grundy (4), Clare Stannard (5), Ira J Dunkel (6), Eric Grabowski (7), Carlos Leal-Leal (8), Carlos Rodríguez- Galindo (9), Enrique Schvartzman (1), Maja Beck Popovic (10), Bernhard Kremens (11), Anna T. Meadows (12), Jean-Michel Zucker(2) (1)Hospital JP Garrahan, Hematology-Oncology, Buenos Aires, Argentina; (2)Institut Curie, Pediatric Oncology, Paris, France; (3)Hospital AC Camargo, Pediatric Oncology, Sao Paulo, Brazil; (4) Birmingham Children´s Hospital, Pediatric Oncology, Birmingham, United Kingdom; (5) Groote Schuur Hospital and University of Cape Town, Radiation Oncology, Cape Town, South Africa, (6) Memorial Sloan Kettering Cancer Center, Pediatrics, New York, United States; (7) Massachussetts General Hospital-Harvard Medical School, Boston, Massachusetts, United States, (8) Instituto Nacional de Pediatría, Oncology, Mexico, Mexico; (9) St Jude Children´s Research Hospital, Hematology-Oncology, Memphis, United States; (10)’CHUV, Pediatric Hemato-Oncology Unit, Lausanne, Switzerland; (11)University of Essen, Pediatric Oncology, Essen, Germany; (12) Childrens Hospital of Philadelphia, Division of Oncology, Philadelphia, United States

4. Publications from Latin America (1995-2005) Argentina: Two prospective studies. Grabowski-Abramson classification Brazil: Two prospective studies. CCG classification Mexico: Retrospective study on 500 patients. St Jude’s Classification

5. Publications from developed countries Latest prospective study: Howarth et al, 1980. St Jude’s classifcation France: Khelfaoui et al, 1996. No staging info USA: Honnovar et al, 2002; Uusitalo et al 2001. No staging info Several countries: Autologous stem cell transplantation: No staging info

6. Objectives To develop a new classification to discriminate subgroups with different survival To allow for comparison of different centers To help discriminate between subgroups of potential different outcome

7. There is no widely used staging system for extraocular retinoblastoma Why?

8. Retinoblastoma classifications Grabowski-Abramson (Hematol Oncol Clin North Am. 1:721-735,1987) updated by Abramson Classification 2002 St Jude´s (Cancer 1980, 45-851-858, updated 1997) TNM (UICC, latest version 2002) CCSG (Wolff et al, 1978) Cape Town. (Br J Ophthalmol 1979, 63,560- 570) updated 2002

9. Many include ophthalmological data unfamiliar to the oncologist Included in St Jude’s classification Included in TNM classification Included in the Cape Town classification

10. Some do not consider all prognostic factors CCG: No mention of postlaminar optic nerve or choroidal invasion St Jude: No definition of choroidal invasion, does not mention postlaminar invasion Grabowski-Abramson: Does not discriminate degrees of choroidal invasion TNM & Cape Town: No definition of choroidal invasion

11. The International Classification for Retinoblastoma Stage 0: Not enucleated patients Stage 1: Enucleated patients with complete resected tumors Stage 2: Enucleated patients with microscopical residual Stage 3: Regional disease Stage 4: Metastatic Disease (a) not CNS involvement (b) CNS disease

12. Major features of this classification Separates conservatively treated patients from enucleated and metastatic ones Proposes microstaging for putative risk factors of enucleated eyes Extent of extraocular disease by imaging studies and pathology (e.g. CSF and BM)

13. Stage 0 and 1 Stage 2 and 3 Stage 4 Risk stratification according to stage CurabilityCurability Potential for cure

14. Information needed for treatment decisions Post laminar optic nerve extension Choroid invasion Scleral invasion Other ocular coats involvement (anterior segment) Combination of these features

15. Optic Nerve microstaging N0. No tumor in optic nerve N1. Anterior lamina cribrosa N2. Posterior lamina cribrosa N3. Cut section and/or subarachnoid invasion NX. Unknown

16. Choroid microstaging C0. No choroidal invasion C1. Superficial choroid invasion C2. Deep choroid invasion

17. Scleral Microstaging S0. No scleral involvement S1. Microscopical extension into sclera S2. Microscopical extension through sclera into the orbit

18. What will be this classification used for? Having a standard for eye pathology and extent of disease evaluation Comparing among different groups Assessing incidence and disease extension by international registries Defining the need for adjuvant therapy in special subgroups

19. Challenges To define minimum standards for pathological processing of enucleated eyes To prospectively validate the classification in a larger cohort To disseminate it to groups and centers with high patient burden

20. Future steps Interest eye pathologists Set up definitions Set up a registry Provide a facility for centralized review for developing countries e-teaching support Analyze data to validate results