1886
Most common ocular tumor of childhood.
Occurs in approximately six of 100,000 live births.
Accounts for 2 to 4% of pediatric malignancies globally.
Its incidence ranges from one in 20,000 to one in 15,000 children.
There are 250 to 300 new cases per year in the US and approximately 8000 worldwide.
Most common intraocular tumor of childhood and represents approximately 35% of pediatric cancers.
India has the most new patients with retinoblastoma, followed by China.
Mortality rates in low income countries range from 40 to 70% in contrast with the 3 to 5% mortality in high income countries.
A malignant tumor of the embryonic neural retina.
60% of patients have unilateral disease.
Almost 40% have a germline mutation.
Only 10% will have a positive family history.
Approximately 40% of children with retinoblastoma carry a germline or constitutional mutation of the RB1 gene.
Essentially all patients with bilateral disease and approximately 15% of children with unilateral disease have the RB1 mutation.
Patients have biallelic inactivation of the RB gene on chromosome 13q14.
Patients with a germline RB1 mutation are predisposed to the development of other malignancies.
The risk of transmitting the germline RB1 mutation to offspring is 50%.
Mutation of the first allele is a germ line one in 40%, with 10% being inherited from a parent and 30% newly arising.
The first allele becomes mutant in retinal precursor cells in 60% of patients, and the second allele mutation occurs in the retina causing a double hit phenomenon resulting in multiple retinoblastomas arising in both eyes occurring at an early age.
Most common mechanisms to inactivate the second copy are loss of the whole chromosome, large deletions and gene conversion resulting in loss of heterozygosity for markers near the RBI locus.
Arises from inactivation of both allelic copies of the retinoblastoma tumor suppressor gene (RB1) within the developing retina.
Most cases are initiated by biallelic inactivation of the retina blastoma gene (RB1).
Germline mutation is inherited as an autosomal dominant pattern.
Germline RB1 variants confirm predisposition to one or more retinoblastomas in at least 95% of carriers, they confer predisposition to other neoplasms, especially bone and soft tissue sarcoma, melanoma, glioma, and small cell lung, bladder, and triple negative breast cancers with an absolute excess risk of approximately 0.6 to 1% per year of life.
Approximately 1.4% of retinoblastomas is caused by MYCN amplification and wild type RB1.
These tumors originate in long and medium wavelength cone precursors-responsible for red and green color vision.
Long and medium wave cones are present across the entire retina, concentrated in the central macular region and especially in the fovea..
Average age at diagnosis is two years in unilateral cases and one year in bilateral cases.
Retinoblastoma is routinely cured when detected early, however, more advanced and genomically altered retinoblastomas are at risk for recurrence, metastasis and death.
Common presenting signs include leukocoria, strabismus, and decreased vision.
Unilateral, unifocal retinoblastoma usually arises due to sequential somatic mutations of the retinoblastoma tumor suppressor gene within the developing retina.
Bilateral, multifocal cases develop with either inherited or acquired germline mutations in one copy of RB1, and the risk of passing the autosomal dominant trait to their offspring.
Early detection and aggressive treatment has essentially eliminated dissemination of disease and mortality.
In both the sporadic and inherited forms of retinoblastoma the tumor demonstrates loss of RBI function.
When an initial mutation occurs in the retina, single lesions develop in a single eye and occurs often at a later age.
Patients with bilateral disease present at an earlier age than patients with unilateral disease.
Essentially all children with bilateral disease carry a constitutional mutation yet only 10-20% of these children have a family history of the disease.
80% of children with bilateral disease have a de novo mutation of the RB1 gene during gametogenesis, primarily during spermatogenesis.
The retinoblastoma protein is a transcriptional cofactor and adaptor protein that regulates gene expression.
The retinoblastoma protein is expressed in almost every cell type and serves as a regulator of cellular proliferation, death and differentiation.
All patients should undergo genetic evaluation.
The most common cause of leukocoria in a child is retinoblastoma.
Diagnosis is based on funduscopic examination, ocular ultrasound, and MRI imaging of the orbit and brain.
Ultrasound shows intralesional calcification typical of retinoblastoma.
Neuroimaging allows for the detection of extra ocular retinoblastoma in the optic nerve, the orbit, and involvement of the pineal gland, trilateral disease.
Most cases in the U.S. vast majority of patients have intraocular disease and have a 90% chance of cure.
High-risk features of spread includes involvement of the optic nerve posterior to the lamina cribosa or Choroidal invasion.
With the above findings additional systemic treatment to surgery is indicated.
Disease confined to the eye can be cured by enucleation and additional therapy is usually not necessary.
Following enucleation the eye is studied for evidence of tumor invasion outside the eye.
Treatment includes enucleation, radioactive plaque therapy, cryotherapy, laser therapy, external beam radiation, and intra-arterial chemotherapy.
The ultimate choice of therapy depends on tumor size, tumor location, presence or absence of vitreous seeds and additional patient factors.
Survival rates 90-98% in the US and 23% in some developing countries.
Patients with unfavorable pathology treatment with adjuvant chemotherapy or active surveillance to identify extra ocular lesion that still may be curable.
Highly lethal when metastatic disease is present.
Metastases or where in the developed world, where early diagnosis and achieves cure for most children.
Cure of the disease outside the eye is rare.
In children with bilateral disease and treated with external beam radiation, there is a 30% cumulative risk of mortality by age 40 from a second cancer.
Intraocular retinoblastoma groups A-D International Intraocular Retinoblastoma Classification can respond to chemotherapy.
Advanced disease in group IIRC E which exhibits clinical signs associated with higher risk for extra ocular disease is treated with chemotherapy.
In a retrospective study of 100 enucleated IIRC groups D and E eyes treated with or without primary chemotherapy: chemotherapy before enucleation in the group E eyes downstaged pathological evidence of extra ocular extension, and increased the risk of metastatic death from reduced surveillance and inappropriate management of high-risk disease, if the nucleation was performed longer than three months after diagnosis (Zhao J et al).
In the above study pre-enucleation chemotherapy masked unfavorable pathology that would warrant further treatment or surveillance, and as a result extraocular disease progressed to death.
Long-term morbidity related, especially to external beam radiation, such as chronic dry eye, retinopathy, optic nerve neuropathy, cataract, midfacial dysmorphism secondary to poor orbital development.
Chemotherapy with local treatment is effective in patients with group I to III retinoblastoma, permitting the avoidance of external beam radiotherapy in the majority of young children.
The current standard practice is to administer six cycles of CEV (carbon platinum,etopside,and vincristine): a 3 cycle regimen with unilateral pathological high risk retinoblastoma was not inferior to six cycles of CEV chemotherapy.
Survival only above study at five years was about 90%.
Metastatic disease is treated with systemic and intrathecal/intraventricular chemotherapy, stem cell transplantation and in some cases radiation.
Superselective ophthalmic artery infusions of chemotherapy can deliver agents directly to the eye, minimize systemic exposure and can destroy tumors and preserve or even restore vision in some cases (Abramson D et al.
In high risk patients adjuvant chemotherapy with carboplatinum, etoposide, and vincristine has demonstrated efficacy.