Retinablastoma:The current concepts
Santosh G Honavar, MD, FACS
Introduction
Retinoblastoma is the most common intraocular malignancy in children, with a reported incidence ranging from 1 in 15,000 to 1 in 18,000 live births.1 It is second only to uveal melanoma in the frequency of occurrence of malignant intraocular tumors. There is no racial or gender predisposition in the incidence of retinoblastoma. Retinoblastoma is bilateral in about 25 to 35% of cases. 2 The average age at diagnosis is 18 months, unilateral cases being diagnosed at around 24 months and bilat eral cases before 12 months. 2
Pawius described retinoblastoma as early as in 1597.3 In 1809, Wardrop re ferred to the tumor as fungus haematodes and suggested enucleation as the primary mode of management.3 The discovery of ophthalmoloscope in 1851 facilitated recognition of specific clini cal features of retinoblastoma. Initially thought to be derived from the glial cells, it was called a glioma of the ret ina by Virchow (1864)3.Flexner (1891) and Wintersteiner (1897) believed it to be a neuroepithelioma because of the presence of rosettes.3Later, there was a consensus that the tumor originated from the retinoblasts and the Ameri can Ophthalmological Society officially accepted the term retinoblastoma in 1926.4
Retinoblastoma was associated with near certain death just over a century ago. Early tumor recognition aided by indirect ophthalmoscopy and refined enucleation technique contributed to an improved survival from 5% in 1896 to 81% in 1967. 2 Advances in external beam radiotherapy in the 1960s and 1970s and further progress in planning and delivery provided an excellent alternative to enucleation and resulted in substantial eye salvage.2 Focal therapeutic measures such as cryotherapy, photocoagulation and plaque brachy therapy allowed targeted treatment of smaller tumors entailing vision salvage. Parallel advancements in ophthalmic diagnostics and introduction of ultra sonography, computed tomography, and magnetic resonance imaging con tributed to improved diagnostic accu racy and early detection of extraocular retinoblastoma.
Despite all the advances that took place between 1960 and 1990, the overall management of retinoblastoma stood at cross roads in the 1990s. The outstanding issues related related to identif cation of a child at risk of developing retinoblastoma by genetic testing, op timization of vision salvage by minimi zation of the size of the tumor regres sion scar, reduction in the incidence of second malignant neoplasm following external beam radiotherapy by explor ing for alternative therapeutic modalities, reduction in the incidence of sys temic metastasis following enucleation, and improvement in the prognosis of orbital retinoblastoma and metastatic retinoblastoma.
The recent advances such as identific tion of genetic mutations,5,6 replace ment of external beam radiotherapy by chemoreduction as the primary man agement modality, use of chemoreduc tion to minimize the size of regression scar with consequent optimization of visual potential,7-11 identification of histopathologic high-risk factors follow ing enucleation 12 and provision of adjuvant therapy to reduce the incidence of systemic metastasis,13 protocol-based management of retinoblastoma with accidental perforation or intraocular surgery14-16 and aggressive multimodal therapy in the management of orbital retinoblastoma17,18 have contributed to improved outcome in terms of better survival, improved eye salvage and potential for optimal visual recovery.
Genetics of Retinoblastoma
Out of the newly diagnosed cases of retinoblastoma only 6% are familial while 94% are sporadic.2,19 Bilateral retinoblastomas involve germinal mutations in all cases. Approximately 15% of unilateral sporadic retinoblastoma is caused by germinal mutations affecting only one eye while the 85% are sporadic.2
In 1971, Knudson proposed the two hit hypothesis. He stated that for retino blastoma to develop, two chromosom al mutations are needed.20 In hereditary retinoblastoma, the initial hit is a germi nal mutation, which is inherited and is found in all the cells. The second hit de velops in the somatic retinal cells lead ing to the development of retinoblastoma. Therefore, hereditary cases are predisposed to the development of no nocular tumors such as osteosarcoma.
In unilateral sporadic retinoblastoma, both the hits occur during the devel opment of the retina and are somatic mutations. Therefore there is no risk of second nonocular tumors.
Genetic counseling is an important aspect in the management of retinoblastoma. In patients with a positive family history, 40% of the siblings would be at risk of developing retinoblastoma and 40% of the offspring of the affected patient may develop retinoblas toma. In patients with no family history of retinoblastoma, if the affected child has unilateral retinoblastoma, 1% of the siblings are at risk and 8% of the offspring may develop retinoblas toma. In cases of bilateral retinoblastoma with no positive family history, 6% of the siblings and 40% of the offspring have a chance of developing retinoblastoma.2
Apart from empiric genetic counseling as described above, the current trend is to identify the mutation and compute specifc antenatal risk.We screened twenty-one probands, twelve with bilateral retinoblastoma and 9 with unilateral retinoblastoma, for mutations in the RB1 gene using genomic DNA from peripheral blood leukocytes as well as tumors. Amplifcation of individual exons and fanking regions of the RB1 gene were carried out, followed by direct sequencing of the amplifed products. Sequences of affected individuals were compared with those of controls. Mutations were identifed in seven patients, fve with bilateral and two with unilateral retinoblastoma. Analysis of the peripheral blood of seven patients with unilateral disease showed no mutations. 5
Subsequently, we carried out mutational screening of the exons and promoter of the RB1 gene in Indian patients with retinoblastoma in order to determine the range of mutations giving rise to the disease. Eight novel mutations were identified, including 4 single base changes, 2 small deletions and 1 duplication. These were g.64365T>G (Tyr325Ter), g.78131G>A (Trp515Ter), g.150061G>T (Glu 587Ter), g.170383C>G (S834X), g.41924A>C (IVS3-2A>C),g.150064ins4, g.160792del22, and g.76940del14 (IVS15 del +20-33). All mutations pro duced nonsense codons or frameshifts. Detectable mutations in exons were found in 46% of patients tested.6Knowledge of the full range of muta tions can aid in the design of screening tests for individuals at risk.6
Histopathology of Retinoblastoma
On low magnification, basophilic areas of tumor are seen along with eosinophilic areas of necrosis and more basophilic areas of calcification within the tumor. Poorly differentiated tumors consist of small to medium sized round cells with large hyperchromatic nuclei and scanty cytoplasm with mitotic figures.Well-dif ferentiated tumors show the presence of rosettes and fleurettes.These can be of various types. Flexner-Wintersteiner rosettes consist of columnar cells ar ranged around a central lumen. This is highly characteristic of retinoblastoma and is also seen in medulloepithelioma. Homer Wright rosettes consist of cells arranged around a central neuromuscular tangle. This is also found in neu roblastomas, medulloblastomas and medulloepitheliomas. Pseudorosette refers to the arrangement of tumor cells around blood vessels. They are not signs of good differentiation. Fleurettes are eosinophilic structures composed of tumor cells with pear shaped eosinophilic processes projecting through a fenestrated membrane. Rosettes and fleurettes indicate that the tumor cells show photoreceptor differentiation. In addition basophilic deposits (precipitated DNA released after tumor necrosis) can be found in the walls of the lumen of blood vessels.2
Clinical Manifestations of Retinoblastoma
Leucocoria is the most common presenting feature of retinoblastoma, fol lowed by strabismus, painful blind eye and loss of vision. Table 1 lists the common presenting signs and symptoms of retinoblastoma 21.The clinical presentation of retinoblas toma depends on the stage of the disease 10.Early lesions are likely to be missed, unless an indirect ophthalmos copy is performed. The tumor appears as a translucent or white fluffy retinal mass (Figure 1). The child may present with strabismus if the tumor involves the macula or with reduced visual acu ity. 10 Moderately advanced lesions usually present with leucocoria due to the re flection of light by the white mass in the fundus (Figure 2).
Figure 1. Early manifestation of retinoblastoma with a localized tumor
Figure 2. Lecocoria is the most common clinical presentation of retinoblastoma
As the tumor grows further, three patterns are usually seen:
| Leucocoria | 56% |
| Strabismus | 20% |
| Red painful eye | 7% |
| Poor vision | 5% |
| Asymptomatic | 3% |
| Orbital Cellulitis | 3% |
| Unilateral Mydriasis | 2% |
| Heterochromia Iridis | 1% |
| Hyphema | 1% |
• Endophytic, in which the tumor grows into the vitreous cavity (Figure 3). A yellow white mass progressively fills the entire vitreous cavity and vitreous seeds occur. The retinal vessels are not seen on the tumor surface.
• Exophytic, in which the tumor grows towards the subretinal space (Figure 4). Retinal detachment usually occurs and retinal vessels are seen over the tumor.
• Diffuse infiltrating tumor, in which the tumor diffusely involves the retina causing just a placoid thickness of the retina and not a mass. This is gener ally seen in older children and usually there is a delay in the diagnosis (Figure 5).
Advanced tumors manifest with prop tosis secondary to optic nerve extension or orbital extension (Figure 6) and systemic metastasis.10 Retinoblastoma can spread through the optic nerve with relative ease especially once the lamina cribrosa is breached. Orbital extension may present with proptosis and is most likely to occur at the site of the scleral emissary veins. Systemic metastasis oc curs to the brain, skull, distant bones and the lymph nodes.
Figure 3. Endophytic tumor with vitreous seeds
Figure 4. Exophytic retinal tumor with exuda tive retinal detachment
Figure 5. Diffuse infiltrative retinoblastoma with placoid retinal thickening seen on gross examination of the enucleated eye in a 7-yearold child
Some of the atypical manifestations of retinoblastoma include pseudohypopy on (Figure 7), spontaneous hyphema (Figure 8), vitreous hemorrhage (Figure 9), phthisis bulbi (Figure 10) and preseptal or orbital cellulites (Figure 11).
- Figure 6. Retinoblastoma with orbital exten sion in a 3-year-old child
- Figure 7. A 5-year-old child with retinoblasto ma with anterior segment seeding manifesting with tumor hypopyon
- Figure 8. A 4-year-old with spontaneous hy phema in the left eye. Ultrasonography con firmed the diagnosis of retinoblastoma
- Figure 9. Spontaneous vitreous hemorrhage as the presenting feature of retinoblastoma in a 4-year-old child
- Figure 10. An 18-month-old child with bilateral retinoblastoma. The right eye has secondary glaucoma and enlarged cornea while the left eye is phthisical.
- Figure 11. A 3-year-old child with retinoblas toma presenting with orbital cellulites
