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A rare eye tumor disease representing the most common intraocular malignancy in children. It is a life threatening neoplasia but is potentially curable and it can be hereditary or non hereditary, unilateral or bilateral.
ORPHA:790Classification level: Disorder
Retonoblastoma (RB) has an incidence of approximately 1/15-20,000 in Europe.
RB manifests most often in young children (90% of cases <3 years old). Early clinical signs are leukocoria and strabismus. RB is most often painless and children rarely complain of visual impairment despite its rapid progression towards loss of vision in the affected eye. Other rare signs include hypopyon, vitreous hemorrhage, non rhegmatogenous retinal detachment, neovascular glaucoma and orbital cellulitis. In later stages, rarely seen in high income countries (HIC), intracranial dissemination and hematagenous metastasis, mainly to bones and bone marrow, are observed and are life-threatening. Most retinoblastomas (60%) are unilateral. Hereditary RB refers to those that arise due to a genetic predisposition (irrespective of family history); most of these patients have a bilateral disease and they are at increased risk to develop secondary tumors, mainly sarcoma but also pineoblastoma/supra-sellar tumor (both named ''trilateral retinoblastoma''), glial tumor, melanoma and carcinoma.
RB is caused by inactivating mutations of both alleles of RB1 (13q14) with a high (90%) penetrance (RB risk) in most mutations. Some mutations have a low penetrance (asymptomatic carriers or unilateral RB). Some rare unilateral retinoblastoma cases may arise without RB1 gene mutation but with somatic NMYC amplification. Monosomy 13q14 also causes RB.
Diagnosis is mainly clinical: Indirect ophthalmoscopy supported by fundal photography. Orbital ultrasound delineates intraocular tumor and usually shows calcification. MRI imaging is used to evaluate intra/extraocular and intracranial extension. Tumor staging (i.e. bone marrow examination, lumbar puncture and/or radionuclide bone scan) should be performed only in patients at risk of extra-ocular metastases.
Differential diagnoses, particularly in unilateral cases, include anterior chamber or lens abnormalities especially PHPV (persistence of hyperplastic vitreous), toxocariasis, X-linked retinoschisis, uveitis, medulloepithelioma, von Hippel disease, Norrie disease, retinopathy of prematurity and Coats disease (the most difficult differential diagnosis).
Prenatal and preimplantation genetic diagnoses are available in specialized centers in most HIC.
Patients with hereditary RB inherit RB1 mutation from a parent and thus the predisposition to RB is transmitted in an autosomal dominant manner. However, more than 75% of predisposed patients do not inherit the mutated RB1 from an affected parent, but might have had a de novo mutation in a parental gamete or post-zygotically. Genetic testing needs to be proposed to all patients and their families, even when retinoblastoma is unilateral.
Management and treatment
Treatment requires a multidisciplinary highly specialized approach. In HIC, conservative treatments for at least one eye are possible in most bilateral cases and increasingly used in unilateral cases. Laser treatment alone or combined with systemic chemotherapy, cryotherapy and brachytherapy are very efficient tools as well as the more recently developped local chemotherapy using intra-arterial and/or intravitreous delivery. Enucleation is still frequently used in large unilateral RB as well as in bilateral with large unilateral tumor. External beam radiotherapy is now avoided (risk of late effects, including second cancers in irradiated field).
Vital prognosis is excellent in HIC. Visual prognosis is dictated by tumor location and size at diagnosis (macular involvement has a poor visual prognosis). Eye preservation is possible with early diagnosis. After conservative treatment, visual prognosis depends on macular involvement. If not treated promptly, RB may rapidly metastasize and be fatal, which is still frequent in low income countries.