Overview

Question 1

What is the incidence and median age for presentation of RB?

Answer 1

1 in 15,000 live births (250–300 cases/yr); Median age: 1 yo for bilat Dz, and 2 yo for unilat; 95% <5 yo

Question 2

What is the most common eye tumor in infants?

Answer 2

Metastatic leukemia (1,000 cases/yr). RB is the #1 primary tumor.

Question 3

What are the 3 most common ocular tumors (considering all age groups)?

Answer 3

Metastatic carcinoma, melanoma, and RB

Question 4

What % of multifocal RB is heritable vs. from somatic mutations?

Answer 4

40% are heritable, and 60% are from somatic mutations in the RB1 gene. Heritable RB is associated with germline mutations which can be de novo; appx 25% of heritable RB has a positive family Hx.

Question 5

What % of RBs are bilat/multifocal vs. unilat at presentation?

Answer 5

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

Question 6

To what other malignancy are RB pts particularly prone?

Answer 6

RB pts are prone to osteosarcoma.

Question 7

What gene is mutated in RB?

Answer 7

The RB1 tumor suppressor gene is mutated in RB.

Question 8

On what chromosome is the RB tumor suppressor gene located?

Answer 8

The RB tumor suppressor gene is located on chromosome 13.

Question 9

What cell cycle checkpoint does RB1 affect?

Answer 9

RB1 affects the G1/S checkpoint.

Question 10

What is the cell of origin for RB?

Answer 10

RB arises from neuroepithelial cells (from the nucleated photoreceptor layer of the inner retina).

Question 11

What is Knudson 2-hit hypothesis for heritable RB?

Answer 11

1st hit: germline RB1 mutation

2nd hit: somatic loss of heterozygosity d/t mitotic recombination error, or allelic loss. p53 suppression with MDM2 amplification may also be involved as a 3rd hit.

Question 12

What is the unique histologic feature/pattern associated with RB?

Answer 12

Flexner–Wintersteiner rosettes (also small round blue cells, +Ca2+, necrosis)

Question 13

What are the 5 patterns of spread for RB?

Answer 13

Patterns of spread for RB:

1. Local extension
2. Optic nerve to brain
3. CSF to leptomeninges/subarachnoid
4. Heme mets
5. Lymphatic dissemination via conjunctiva, ciliary body, extraocular tissues

Question 14

What are the most common sites of hematogenous spread in RB? What % of pts present with DMs?

Answer 14

Bone, liver, and spleen. 10%–15% of pts present with DMs.

Question 15

What are 2 tumor-related factors that correlate with an increased risk for mets?

Answer 15

Thickness (relates to invasion of optic nerve, uvea, orbit, choroid) and size of lesion

Question 16

What is trilat RB? How common is it? What is the prognosis?

Answer 16

Trilat RB is bilat RB + intracranial PNET (pineal or suprasellar), representing 3%–9% of hereditary RB (rare). It is almost uniformly fatal.

Question 17

How do pts present with RB in the United States vs. in developing countries?

Answer 17

In the United States: 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)

Question 18

What are the 3 main morphologic growth patterns of RB?

Answer 18

Endophytic mass (projects into vitreous), exophytic (associated with exudative retinal detachment), and diffuse infiltrating RB (least common)

Question 19

What are the major negative prognostic factors in RB?

Answer 19

Delay in Dx of >6 mos, Hx of intraocular Sg leading to seeding, cataracts, thick tumors, Hx of RT (b/c of high risk for secondary cancers), extraocular extension

Question 20

How many cases of retinoblastoma occur in the United States each year?

What is the most common presentation of this intraocular tumor?

Answer 20

Retinoblastoma is the most common intraocular pediatric tumor, with approximately 300 new cases per year. It most commonly presents with leukocoria, which is an abnormal white reflection from the retina. The majority of patients present under 2 years of age. Children with bilateral tumors present at a younger age.

Question 21

What are some of the key genetic differences between bilateral versus unilateral retinoblastoma?

Answer 21

Bilateral retinoblastoma is always heritable. Bilateral tumors occur more commonly in younger children. Unilateral, multifocal disease is generally heritable. In general, 65% to 80% of cases are unilateral. The heritable form of retinoblastoma with a germline mutation can be either familial or sporadic.

Question 22

What is the most common secondary tumor associated with retinoblastoma?

Answer 22

Osteogenic sarcoma is the most common secondary tumor associated with retinoblastoma, accounting for 44% of secondary tumors. The 50-year cumulative incidence of second malignancy is 51% for hereditary and 5% for nonhereditary cases.

Question 23

What is the pathogenesis of retinoblastoma?

Answer 23

Both alleles of the Rb gene located on chromosome 13q14 are inactivated, leading to tumorigenesis. The gene acts as a tumor suppressor when it functions normally. The Knudson hypothesis suggests that children with sporadic retinoblastoma are genetically normal at conception and during embryonic development two somatic mutations (“two hits”) occur in the cell line leading to the retinal photoreceptors. However, in familial retinoblastoma, the fertilized egg already carries one copy of the mutated allele. In this case, if any cell sustains a second hit, retinoblastoma develops.

Question 24

What is the estimated 50-year cumulative incidence of second cancers for hereditary and nonhereditary retinoblastoma?

Answer 24

The estimated 50-year cumulative incidence of second cancers is 51% for hereditary and 5% for nonhereditary cases. While the most common secondary malignancy is osteogenic sarcoma, other radiation-induced second malignant neoplasms include fibrosarcoma and other spindle-cell neoplasms.