Retinoblastoma
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?
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?
1st hit: germline deletion
2nd hit: somatic mitotic recombination error
What pathway is involved in the 3rd hit that leads to tumor formation?
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:
Local extension
Optic nerve to brain
CSF to leptomeninges/subarachnoid
Heme mets
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?
In the U.S.: leukocoria > strabismus > painful glaucoma, and irritability. Leukocoria refers to an abnl white reflection from the retina.
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