CLINICAL:
Retinoblastoma (RB) is most common intraocular malignancy of childhood; average age at diagnosis 18 mos; congenital retinoblastoma about 1 in 15-30K; 25-33% bilateral, autosomal dominant inheritance; congenital bilateral retinoblastoma has predilection to develop 2nd radiation-induced malignancy (sarcoma) within 10 years of treatment; trilateral retinoblastoma has pineal PNET; overall causes 1% of childhood mortality; 5% childhood blindness; 90% present with leukokoria, strabismus, glaucoma, vision loss; 10% mimic orbital cellulitis and other inflammatory conditions; 50% of all cases of childhood leukokoria caused by retinoblastoma.

PATHOLOGY:
The tumor begins in the nuclear layer of retina; it is a PNET (Primitive Neuro Ectodermal Tumor) with small round or ovoid cells; the cells arrange themselves into Flexner-Wintersteiner rosettes; RB has characteristic calcifications; necrosis; it may be multi-centric in origin; capable of rapid growth; can invade adjacent tissues; spread through globe, through subarachnoid space into brain, through intraorbital vasculature to bone and viscera.

CT: Shows a soft tissue mass with calcifications involving the retina, and often extending into the vitreous. Look for tumor infiltrating through the sclera, into the nerve and/or the intraconal fat.

MR: sl/mod hyperintense on T1; moderate/marked hypointensity on T2; Ca++ areas may be hypointense on both T1 & T2. Staging - look for violation of sclera and invasion into vitreous.

The retinoblastoma gene (RB1) is on the long arm of chromosome 13, location 13q14.2. This gene regulates Brn-2 expression in retinoblastoma. - - LINK -

Germline RB1 mutations in 77 out of 85 bilateral RB patients (91%), 7 out of 10 familial unilateral (70%), and 6 out of 85 unilateral patients with no family history of RB (7%), were identified. - - LINK -

In Knudson's classic article ( PNAS 68 (1971):820-823 [PubMed] he postulated two mutations were needed to cause retinoblastoma; and, that the frequency of multiple tumors followed a Poisson distribution.

He explained that the point rate of mutation was high enough, and the number of retinal ganglion cells large enough, that penetrance should be close to 75% for a second genetic event to cause the cancer.

One of these mutations may be inherited as a germ-line mutation. There are 2,000,000 retinal ganglion cells in each eye - that may undergo a second somatic mutation. He calculated a mutation rate of approximately 2/10,000,000 per year would explain the empirical observations of inherited and heritable retinoblastoma. Thus, the rate of the second mutation is high enough to explain the observed penetrance of retinoblastoma at 0.7 -0.9, since each eye presents 2,000,000 cells for mutation at a rate of 2 mutations/10,000,000 cells/year. He also observed that the majority of patients with multiple lesions had a germ-line mutation; and, that unilateral cases without a germ-line mutation are 55-65%.