Retinoblastoma: Current Concepts
Retinoblastoma : Current Concepts in Diagnosis and Management
Retinoblastoma is the most common intraocular malignancy of childhood. It is responsible for 1% of all deaths from cancer in age group under 15 years. Retinoblastoma was described as early as 1597 by Petrus Pawius in Amsterdam but the exact nature of tumor was poorly understood during the next two hundred years. Retinoblastoma is derived from retinal cells of the immature neural epithelium. Reported incidence of retinoblastima is 11 cases per million children under 5 years or 1/18000 live births. In 90% of cases, the tumor arises before two years of age and is diagnosed before 4 years. Retinoblastoma can be inherited as familial in 8% or sporadic in 94%. In 1962, Stellard proposed that there is deletion of a portion of long arm of chromosome 13 which is termed as 13q 14 locus in retinoblastoma. Usually there is a mutation or deletion of RBI gene. Retinoblastoma can be of endophytic type which grows towards vitreous cavity and usually there is positive family history. Exophytic retinoblastoma grows towards choroid. Usually there is associated retinal detachment and glaucoma. Diffuse infilterative type usually occurs in older children associated with relatively flat infilteration of retina by tumor cells and hence diagnosis is usually delayed.
Leukocoria is the commonest presentation occurring in 50% children followed by strabismus (20%), exotropia (11%), esotropia (9%), red, painful eye with glaucoma (7%), poor vision (5%) and orbital cellulitis like condition (3%). Atypical presentation of RB can have hyphema (1%), not eating, failure to thrive (0.5%), white spots on iris (0.5%), strange expressions (0.5%), heterochromia iridis (1%), unilateral mydriasis (2%), pseudo-hypopyon, vitreous haemorrhage, uveitis, indolent endophthalmitis, calcified intraocular abscess, prolonged fever, proptosis, nystagmus, serous RD and corneal involvement as keratitis or ulcer.
Diagnostic work-up should include clinical examination comprising of external ocular examination, Slit lamp biomicroscopy, Indirect Ophthalmoscopy of both eyes. Fundus fluorescein angiography usually shows dilated feeding vessels in the arterial phase, hyper vascularity in the venous phase and late staining of mass. Ultrasonography is very useful in telling whether tumour is solid or cystic. It detects tumour as small as 2mm. It is the best modality to detect calcification and helps in following changes in tumour size. CT Scan helps in following changes in tumour size, defining extent of RB and in detecting tumour calcification. RB appears as hypointense in T2 weighted MRI and hyperintense on T1 and proton weighted MRI. It demonstrates spread along optic nerve, sub-arachnoid seedling and involvement of brain. For fine needle biopsy, limbal transiris approach is used in cases with metastasis to uvea with no evidence of primary non-ocular tumour. Immuno-histochemical studies like Aqueous Neuron Specific Enloase (NSE), both alpha and gamma show increased levels. Aqueous LDH leves are increased and show elevated ratio of serum LDH5 to LDH1 levels. Aqueous Cytology shows a positive angiogenesis assay. CEA, Alpha feto protein, Lymphocyte toxicity testing,32 P uptake also help in diagnosis but have become obsolete now. Bone marrow aspiration and biopsy, examination of CSF, bone films, bone scan, whole body CT, MRI, should be done to rule out metastasis. COX-2, a prostaglandin synthase (causes angiogenesis and tumorogenesis) is overexpressed (96%) in retinoblastoma specimens examined by labelled-streptavidinbiotin method (Karim MM et al, AJO, 2000) as observed in colorectal cancers. Some well differentiated retinoblastoma express rhodopsin and S-antigen, proteins that participate in phototransduction of vision.
Management of retinoblastoma has gradually changed over the past few decades. There is a trend away from enucleation and external beam radiotherapy towards focal conservative treatments. This is primarily because of earlier detection of the disease and more focused treatment modalities. The goals of treatment are, most importantly, to save the child’s life and, secondly, to salvage the eye or vision if possible.
Enucleation is a common method for managing retinoblastoma. Enucleation with long stump of optic nerve should be done if advanced disease with no hope for salvageable vision, or if invasion of the tumor into ON, choroid or orbit is possible. Eyes with secondary glaucoma, pars plana seeding or anterior chamber invasion are generally best managed with enucleation. External beam radio-therapy is very useful because of radio-sensitive nature of retinoblastoma. It is done for treating advanced retinoblastoma with massive vitreous seeding. This can be employed by irradiating whole eye or by lens sparing technique. Tumor recurrence after radiotherapy is usually within 1 to 4 years. The incidence of second cancer after radiotherapy increases to 35% from 6% without radiotherapy. Cryo therapy is useful for size less than 3.5 mm and 2.0mm in thickness with no evidence of vitreous seeds. It is done by triple freeze thaw technique.
Laser photocoagulation is done for small posterior RB less than 4.5 mm in size and 2.5 mm in thickness without vitreous seeding. Argon, Diode or Xenon-arc laser can be used with 70% tumor control rate and 30% recurrence rate. Radio-active plaque (Brachy therapy) with Cobalt 60, Iridium 192, Iodine 125, Isotopes, 35 and 40gy is delivered to all visible disease. It is done for tumor less than 15mm in area and 12mm from optic disc or fovea and when there is vitreous seeding or tumor is too large to be treated by cryo-therapy. Thermotherapy is a method of delivering heat to the eye using ultrasound, microwave or infrared radiation. The goal is to deliver a temperature of 42oC to 60oC to spare the retinal vessels from photo-coagulation. Heat has synergistic effect with both chemotherapy and radiation therapy for treating retinoblastoma. This therapy is helpful for smaller tumors less than 3mm. Chemotherapy is suited for small tumors adjacent to the fovea and ON where radiation or laser photocoagulation will cause more profound visual loss.
Intravenous chemoreduction is a method of reducing tumor volume to allow for more focused, less damaging, therapeutic measures. The chemotherapy used is carboplatin, etoposide and vincristine. This regimen of six cycles has ocular salvage rate of 70%. After chemoreduction, regressed tumor scar needs consolidation with focal measures for complete control usually at 2nd or 3rd cycle. Subconjunctival chemoreduction specially carboplatin, which penetrates sclera, has shown encouraging results in animals and human trials but it needs consolidation with focal therapy also. Systemic chemotherapy is needed for metastasis to ON, choroid, orbit and distal organs. The drugs used are cyclophosphamide, vincristine, etoposide and carboplatin for 6-18 months depending upon circumstances. Orbital exenteration is used for orbital recurrence after child has received a maximum acceptable dose of radiation and chemotherapy.
Photo-dynamic therapy works by transferring energy from specific wavelength of light causing the creation of highly reactive singlet oxygen species. These agents (Benzo porphyrin) destroy membrane of cells that contain photo-sensitive dye. Patients should be followed every 4 months until 2 years of age, every 6 months from 2-5 years and every year after age of 5 years. All siblings and parents of retinoblastoma patients should undergo examinations with dilated pupils, to allow earlier examination and treatment of children at presymptomatic disease stage.
The prognosis for life and vision in patients with retinoblastoma has vastly improved over the past century primarily because of earlier detection of the disease as well as improved treatments. One hundred years ago, retinoblastoma was nearly always fatal. Gradually the prognosis improved and approximately 30% of affected patients survived in 1930s, 80% in 1960s and nearly 95% in the 1990s. Bad prognostic signs are delay in diagnosis, recurrent disease, tumor invasion in optic nerve, vitreous, seeding, increased volume of choroid and involvement of sub-arachnoid space.
S.K. Arya1,
Prof. Sunandan Sood2
1Reader,
2Head, Department of Ophthalmology,
Govt. Medical College,
Sector 32, Chandigarh.
