A I II 1 2 H1 H0 20/20 0.2 logMAR B F+F C D Figure 1. (A) Pedigree of a family with a unilaterally affected father discovered to be mosaic (H1) for a high penetrance RB1 mutation when his second child was found to have bilateral retinoblastoma (H1).11 The child had late diagnosis requiring intensive therapy, with sub-optimal visual prognosis. (B) DePICTRB visualization3,5 demonstrating the child’s follow-up and treatment timeline. (C) At presentation, the right eye was staged TNMH29 cT2b and IIRC25 Group D and the left eye TNMH29 cT1b and IIRC25 Group B. (D) Following extensive treatments, there was tumor regression with inactive scars bilaterally. Visual acuity was fixates and follows in the right eye and 0.2 logMAR by Cardiff in the left eye.

Figure 2. Media campaigns play a role in increasing public awareness of retinoblastoma. This illustrates a newspaper article from Finland highlighting the diagnostic importance of photoleukocoria.

A B C D Figure 3. Presentation and staging of eyes with retinoblastoma. (A) Fundus photograph of a clinically invisible solitary tumor (TNMH29 cT1a, IIRC25 group A) detected by OCT at 15 days of age. The child was H1 with RB1 mutation diagnosed in utero. (B) As the tumor grows, it gains blood supply and assumes a lobulated shape. This fundus photo demonstrates a large central perifoveal tumor with multiple smaller tumors. Yellow luteal pigment is seen at the inferior edge of the central tumor, corresponding to the fovea. There was less than 5 mm of associated subretinal fluid and no evidence of seeding (TNMH29 cT1b, IIRC25 group B). Tumor may then extend beyond the inner limiting membrane giving rise to vitreous seeding (C, D) and into the subretinal space with seeding (TNMH29 cT2b, IIRC25 group D) (D). (E) Fundus photograph of a total exudative retinal detachment overlying a large inferior tumor. (F) Ultrasound biomicroscopy demonstrating an anteriorly situated tumor adjacent to the ciliary body. Histopathology following enucleation confirmed invasion into the ciliary muscle. (G) Advanced Coats’ disease may mimic unilateral retinoblastoma, particularly in the presence of retinal detachment. While this child was initially diagnosed with Coats’ disease based on total exudative retinal detachment without calcification, both vitreous and subretinal seeding was evident during EUA and retinoblastoma diagnosis was confirmed following enucleation.43 E F G

A B C Figure 4. High risk histopathological features predictive of increased metastatic risk. (A) Low magnification histopathological section of a TNMH29 cT2b (IIRC25 group D) eye demonstrating massive choroidal invasion, trans-scleral and extra-scleral invasion, with tumor extending beyond the confines of the lamina cribrosa. Clinically, the tumor was multilobulated with overlying exudative retinal detachment and extensive subretinal seeding. The optic nerve and fovea were not visualized at presentation. (B) Histopathological section under high magnification demonstrating full thickness tumor invasion of the sclera, with invasion of the adjacent episclera and adipose tissue (TNMH29 pT4). (C) Histopathological section under high magnification showing post-lamina cribrosa invasion. The tumor did not extend to the resection margin of the optic nerve.

PPV with endoresection 2018 Therapies for Intraocular Retinoblastoma Chemotherapy Systemic Intra-arterial Intravitreal Focal Therapy Laser Cryotherapy Radiotherapy Brachytherapy EBRT Stereotactic/ Proton beam Surgery Enucleation PPV with endoresection Figure 5. The multimodal therapeutic options for intraocular retinoblastoma in 2018 include chemotherapy combined with focal therapies, and surgical approaches. The relative “weighting” of value of each therapy for the eye and whole patient is provided. Therapies highlighted in grey are rarely used today, only as salvage therapy for tumors refractory to the other available modalities.

A B Figure 6. Chemotherapy reduces tumor volume so that focal therapy, such as laser photocoagulation, can be used to physically eradicate any remaining live tumor cells. (A) Tumor regression following systemic chemotherapy and laser treatment to obtain long term regression and inactive scar (TNMH29 cT1b and IIRC25 group B). (B) Tumor regression after intra-arterial chemotherapy (IAC) and laser treatment in unilateral retinoblastoma (TNMH29 cT1b and IIRC25 group B) to obtain long term regression and inactive scar. (C) Note the peripheral choroidal pigmentary disturbance characteristic of treatment with IAC, which is not seen in the untreated normal right eye. In contrast, this choroidal pigmentary change is not evident post treatment with systemic chemotherapy. C