Retinoblastoma

Updated by Vinita Takiar

BACKGROUND

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 at presentation?

25% bilat/multifocal vs. 70%–80% unilat. Bilat tumors are typically multifocal (∼5 tumors on avg) and present younger (∼15 mos).

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 is mutated in RB.

On what chromosome is the RB tumor suppressor gene located?

The RB tumor suppressor gene is located on chromosome 13.

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 1^st hit vs. the 2^nd hit differ in terms of mechanisms?

1^st hit: germline deletion

2^nd hit: somatic loss of heterozygosity due to mitotic recombination error, allelic loss, or loss of ch13

What pathway is involved in the 3^rd hit that leads to tumor formation?

3^rd hit: p53 suppression with MDM2 amplification (two-thirds of tumors)

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 hematogenous 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 almost uniformly fatal.

How does RB present grossly?

Endophytic mass (projects into vitreous) and less frequently exophytic

How do pts present with RB in the U.S. vs. in developing countries?

In the U.S.: leukocoria > strabismus > painful glaucoma, and irritability. Leukocoria refers to an abnl white reflection from the retina.

In developing countries: proptosis, orbital mass, and mets (more advanced)

What are the major negative prognostic factors in RB?

Delay in Dx of >6 mos, Hx of intraocular surgery leading to seeding, cataracts, thick tumors, and Hx of RT (because of high risk for secondary cancers), extraocular extension

WORKUP/STAGING

What is the DDx for pts who present with leukocoria?

Toxocariasis, hyperplastic primary vitreous, Coat’s Dz, retrolental fibrodysplasia, congenital cataracts, 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, ocular US), labs, US/CT, MRI (most sensitive to evaluate extraocular extension)

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.

Group A: all tumors ≤3 mm in thickness, confined to retina, and ≥3 mm from foveola and ≥1.5 mm from optic disc

Group B: all tumors confined to retina, clear subretinal fluid ≤3 mm from tumor with no subretinal seeding

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

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

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)

TREATMENT/PROGNOSIS

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

What are some focal therapies used for RB?

Enucleation, EBRT or brachytherapy (plaque), cryotherapy, photocoagulation (laser), thermochemo (thermal + carboplatin), sub-Tenon injection of carboplatin, intra-arterial chemotherapy.

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):

Group A: focal therapy only (laser, cryotherapy, hyperthermia, brachytherapy)

Group B: vincristine + carboplatin × 6 cycles; focal therapy after 2–6 cycles

Group C: VCE × 6 cycles; focal therapy

Group D: same as group C; EBRT

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?

36–45 Gy with progressive Dz

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% (95% for Reese-Ellsworth groups I–III)

How is EBRT given, and what are the volumes irradiated?

4–6 MV IMRT/3D, proton therapy, electron therapy if available 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?

Old standard for unilateral Dz is 4 ant oblique fields and for bilateral Dz opposed lat + ant oblique fields. Currently, with advanced techniques, there are no specific beam arrangement, but do tend to be anterior or anterior obliques.

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?

Group E tumors, occupying >50% of the globe, no vision, painful eyes, extension to optic nerve; 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; 40–45 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, lower energy [beta] and less dose to anterior ocular structures), 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 when the whole eye does not need to be treated (Krengli M et al., IJROBP 2005)