Boris Hristov and Benjamin D. Smith
What is the incidence and median age for presentation of retinoblastoma (RB)?
250–300 cases/yr of RB; 95% <5 yo (1 yo for familial, 2 yo for sporadic)
What is the most common eye tumor in infants?
Metastatic leukemia (1,000 cases/yr). RB is the #1 primary tumor.
What are the 3 most common ocular tumors (considering all age groups)?
Metastatic carcinoma, melanoma, and RB
What % of multifocal RB is inherited vs. from de novo germline mutations?
40% are heritable (only 10% have a positive family Hx [“familial”]), and 60% are from new germline mutations; 93% have a negative family Hx.
What % of RBs are bilat/multifocal vs. unilat?
20%–30% bilat/multifocal vs. 70%–80% unilat. Bilat tumors are typically multifocal (~5 tumors on avg).
To what other malignancy are RB pts particularly prone?
RB pts are prone to osteosarcoma.
What gene is mutated in RB?
The RB1 tumor suppressor gene (del 13q14, germline deletion) is mutated in RB.
What cell cycle checkpoint does RB1 affect?
RB1 affects the G1/S checkpoint.
What is the cell of origin for RB?
RB arises from neuroepithelial cells (from the nucleated photoreceptor layer of the inner retina).
How do the 1st hit vs. the 2nd hit differ in terms of mechanisms?
1. 1st hit: germline deletion
2. 2nd hit: somatic mitotic recombination error
What pathway is involved in the 3rd hit that leads to tumor formation?
1. 3rd hit: p53 suppression with MDM2 amplification (two thirds of tumors)
On what chromosome is the RB tumor suppressor gene located?
The RB tumor suppressor gene is located on chromosome 13.
Are there mutational hot spots on the RB gene?
No. Various mutations are seen in each of the 20 exons involved, but there are no mutational hot spots on the RB gene.
What is the unique histologic feature/pattern associated with RB?
Flexner-Wintersteiner rosettes (also small round blue cells, +Ca2+, necrosis)
What are the 5 patterns of spread for RB?
Patterns of spread for RB:
1. Local extension
2. Optic nerve to brain
3. CSF to leptomeninges/subarachnoid
4. Heme mets
5. LN from conjunctiva, ciliary body, iris
What are the most common sites of hematogeneous spread in RB? What % of pts present with DMs?
Bone, liver, and spleen. 10%–15% of pts present with DMs.
What are 2 tumor-related factors that correlate with an increased risk for mets?
Thickness (relates to invasion of optic nerve, uvea, orbit, choroid) and size of lesion
What is trilat RB? How common is it? What is the prognosis?
Trilat RB is bilat RB + CNS midline PNET (pineal or suprasellar), representing 3%–9% of hereditary RB (rare). It is uniformly fatal.
How does RB present grossly?
Endophytic mass (projects into vitreous) and less frequently exophytic
What % of cases are bilat at presentation?
10%–15% of RB cases are bilat.
How do pts present with RB in the U.S. vs. in developing countries?
1. In the U.S.: leukocoria > strabismus > painful glaucoma, and irritability. Leukocoria refers to an abnl white reflection from the retina.
2. In developing countries: proptosis, orbital mass, and mets (more advanced)
What are the major negative prognostic factors in RB?
Delay in Dx >6 mos of age, Hx of intraocular surgery leading to seeding, cataracts, thick tumors, and Hx of RT (because such pts are fairly advanced)
What is the DDx for pts who present with leukocoria?
Hyperlastic primary vitreous, retrolental fibrodysplasia, Coat Dz, congenital cataracts, toxocariasis, and toxoplasmosis
Is Bx done for RB?
Generally not. Because of the fear of seeding, the Dx is established clinically.
What is the typical workup for pts with an intraocular mass?
Intraocular mass workup: H&P (EUA, max dilated pupil, scleral indentation), labs, US/CT/MRI
When are bone scan, BM Bx, and LP indicated?
If the tumor is not confined to the globe (with deep invasion), BM Bx, LP, and bone scan are indicated.
What % of RBs are calcified?
90% of RBs are calcified.
What is the most commonly used staging system for RB? For what does this system predict?
Reese-Ellsworth grouping system; used to predict for visual preservation after EBRT (does not predict for survival)
What staging system is used in ongoing COG protocols?
The International Classification for Intraocular Retinoblastoma is used for staging in ongoing COG protocols.
Summarize the International Classification for Intraocular Retinoblastoma.
1. Group A: all tumors ≤3 mm, confined to retina, and <3 mm from foveola and <1.5 mm from optic disc
2. Group B: all tumors confined to retina, clear subretinal fluid <3 mm from tumor with no subretinal seeding
3. Group C: discrete tumors, subretinal fluid without seeding involving up to one fourth of retina, local fine vitreous seeding close to discrete tumor, local subretinal seeding <3 mm from tumor
4. Group D: massive or diffuse tumors; subretinal fluid or diffuse vitreous seeding; retinal detachment; diffuse or massive Dz including greasy seeds or avascular tumor masses; subretinal seeding may include subretinal plaques or tumor nodules
5. Group E: presence of any of the following features: tumor touching lens, tumor ant to ant vitreous surface involving ciliary body or ant segment, diffuse infiltrating RB, neovascular glaucoma, opaque media from hemorrhage, tumor necrosis with aseptic orbital cellulites, phthisis bulbi (shrunken, nonfunctional eye)
What is the Tx paradigm for unilat intraocular RB?
Unilat intraocular RB Tx paradigm: preserve eye with chemoreduction × 6 cycles (vincristine/carboplatin/etoposide [VCE]) → focal therapy (if needed)
What are some focal therapies used for RB?
Enucleation, EBRT or brachytherapy (plaque), cryotherapy, photocoagulation (laser), thermochemo (thermal + carboplatin), sub-Tenon injection of carboplatin (preferred approach at the Johns Hopkins Hospital)
To what does “sub-Tenon” injection refer?
Injection of agents into eye through the capsule of Tenon (thin outer membrane enveloping the eye)
When can cryotherapy/laser be used in RB?
Small lesions, at least 4 disc diameters from the fovea/optic disc
What is the generally accepted Tx breakdown based on the international RB groupings?
UCSF (Lin P et al., Am J Ophthalmol 2009):
1. Group A: focal therapy only (laser, cryotherapy, hyperthermia, brachytherapy)
2. Group B: vincristine + carboplatin × 6 cycles; focal therapy after 2–6 cycles
3. Group C: VCE × 6 cycles; focal therapy
4. Group D: same as group C; EBRT
5. Group E: enucleation; 3-agent chemo
When is EBRT typically used in the management of RB without enucleation?
Dz persistence or progression with chemo; extraocular extension, small intraocular tumor in the macula, diffuse vitreous seeding, or subretinal implants; used only if visual preservation is possible
What evidence supports the addition of consolidative local therapy after chemoreduction in RB pts with seeding at Dx?
Per Shields et al. (retrospective): chemo vs. chemo + local Tx: in eyes with seeding before Tx, the addition of local Tx to chemo × 6 cycles decreased the vitreous and subretinal seeding recurrences from 75% to 0% (p = 0.04) and 67% to 0% (p = 0.003), respectively. (Ophthalmology 1997)
What are commonly used EBRT doses?
36–40 Gy with progressive Dz and 26 Gy for persistent Dz (e.g., after sub-Tenon chemo—lower RT dose because of increased retinopathy rates with chemo)
How is bilat RB managed?
Individualize the Tx for each eye (bilat eye preservation, if possible).
How is extraocular Dz managed?
Orbital EBRT, chemo +/− RT for palliation; intrathecal chemo, high-dose chemo with stem cell transplant
What is the eye preservation rate in most RB series?
60%–90% (65%–100% for Reese-Ellsworth groups 1–3)
How is EBRT given, and what are the volumes irradiated?
4–6 MV IMRT/3D to entire globe + 5–8 mm of optic nerve (spare lens and iris for lower stages), 0.5 cm bolus if needed
What RT fields/setups are used for unilat vs. bilat RB?
1. Unilateral: 4 ant oblique fields
2. Bilateral: Opposed lat + ant oblique fields
What chemo agents are employed in RB?
Vincristine and carboplatin. If there is advanced Dz, add topoisomerase inhibitors.
What are the indications for enucleation? How much optic nerve needs to be removed?
Large tumors filling vitreous, tumors in ant chamber, and those with neovascular glaucoma; need to remove 10–15 mm of optic nerve with globe
When is CRT indicated after enucleation for RB?
Adj CRT is indicated for RB whenever there is a +margin or + LN post enucleation
What are the indications for episcleral brachytherapy? What is the dose used?
Solitary lesion 6–15 mm base diameter, ≤10 mm thick, >3 mm from disc/fovea; 40 Gy to apex, 100–120 Gy to base
What isotopes and plaque sizes are used in episcleral brachytherapy for RB?
I-125 or Ru-106 (more uniform loading), diameter of tumor + 4 mm (2-mm margin around the tumor)
What are the main advantages of proton RT in the Tx of RB?
Better orbital bone sparing (Lee CT et al., IJROBP 2005) and better lens sparing (Krengli M et al., IJROBP 2005)
What is the 2nd malignancy rate in familial cases of RB treated with RT vs. no RT?
1. With RT: 4% at 10 yrs, 18% at 35 yrs, 50% at 50 yrs
2. Without RT: 15%–35% rate at 50 yrs, mainly sarcomas (soft tissue and osteosarcoma) and melanomas
Is the risk of 2nd malignancy also increased in sporadic forms treated with RT?
Yes, but minimally—5% at 50 yrs (Wong FL, JAMA 1997)
What are some complications from RT?
Midfacial/orbital hypoplasia, 2nd malignancy (sarcoma), and cataracts
What are the complications from episcleral plaque therapy?
Retinopathy, maculopathy, glaucoma, and papillopathy
In what manner and how often should pts with bilat RB be screened for trilat RB?
With biannual MRIs of the brain for at least 5 yrs