Orbito—Ocular Tumors: Rhabdomyosarcoma and Retinoblastoma

• Retinoblastoma is the most common primary intraocular malignancy of childhood, accounting for about 3% of all childhood cancers, occurring in up to 1:18000 live births.
• After uveal melanoma, it is the second most common malignant intraocular tumor.
• Survival rates are over 95% in specialized centers, with preservation of vision in the majority of eyes, but are much lower in the developing world.

Growth Pattern

• Retinoblastoma can be endophytic (into the vitreous) with seeding of tumor cells throughout the eye.
• Exophytic (into the subretinal space) leading to retinal detachment, or mixed, or the retina may be diffusely infiltrated.
• Optic nerve invasion may occur, with the spread of tumor along the subarachnoid space to the brain.
• Metastatic spread is to regional nodes, lung, brain, and bone.
• It can also be heritable and non-heritable.

Genetics

• The tumor suppressor gene in which mutations predisposing to retinoblastoma occur is RB1; over 900 different mutations have been reported to date.
• The size of a gene deletion tends to correlate with aggressive retinoblastoma behavior. Mutations in RB1 or associated genes in a common pathway are also disrupted in many sporadic tumors.

Heritable (Hereditary, Germline) Retinoblastoma

• Accounts for 40%.
• In heritable retinoblastoma, one of the pairs of alleles of RB1 is mutated in all the cells in the body. When a further mutagenic event ('second hit' according to the 'two-hit' hypothesis proposed by Knudson) affects the second allele, the cell may then undergo malignant transformation.
• Because of the presence of the mutation in all cells, a large majority of these children develop bilateral and multifocal tumors.
• Heritable retinoblastoma patients also have a predisposition to non-ocular cancers such as pinealoblastoma ('trilateral retinoblastoma,' which occurs in up to 10%, usually before the age of 5), osteosarcoma, soft tissue sarcoma, and melanoma; each of these tends to occur in a particular age group.
• The risk of a second malignancy is about 6%, but this increases five-fold if external beam irradiation has been used to treat the original tumor, the second tumor tending to arise within the irradiated field.

• Non-heritable (non-hereditary, somatic) retinoblastoma. The tumor is unilateral, not transmissible, and does not predispose the patient to second non-ocular cancers.
• If a patient has a solitary retinoblastoma and no positive family history, this is almost certainly (but not conclusively) non-heritable so that the risk in each sibling and the patient’s offspring is about 1%. Ninety per cent of children with unilateral retinoblastoma will have the non-hereditary form.
• There is somatic mutation which occurs after fertilization and this is not passed down from the parents to the offspring.

Screening of at-risk family members:

• Germline mutations are autosomal dominant and so transmitted to 50%, but because of incomplete penetrance only 40% of offspring will be affected. Detection of mutations in RB1 has approached 95% in recent years.
• Once identified in a particular child, the same mutation can be sought in siblings, its presence confirming their high-risk status.
• Siblings at risk of retinoblastoma should be screened by prenatal ultrasonography, by ophthalmoscopy soon after birth and then regularly until the age of 4 or 5 years.
• Early diagnosis correlates with a higher chance of preserving vision, salvaging the eye, and preserving life.
• If a child has heritable retinoblastoma, the risk to siblings is 2% if the parents are healthy and 40% if a parent is affected.

• Presentation is within the first year of life in bilateral cases and around 2 years of age if the tumor is unilateral. Careful inquiry about a family history of ocular tumors is critical.
• Leukocoria (white pupillary reflex) is the commonest presentation (60%) and may first be noticed in family photographs.
• Strabismus is the second most common (20%). Fundus examination is therefore mandatory in all cases of childhood squint.
• Painful red eye with secondary glaucoma, which may be associated with pseudoinflammation.
• Poor vision.
• Inflammation or pseudoinflammation.
• Routine examination of a patient known to be at risk.
• Orbital inflammation mimicking orbital or preseptal cellulitis may occur with necrotic tumors.
• Orbital invasion or visible extraocular growth may occur in neglected cases.
• Metastatic disease involving regional lymph nodes and the brain before the detection of ocular involvement is rare.

Signs

• An intraretinal tumor is a homogeneous, dome-shaped white lesion that becomes irregular, often with white flecks of calcification.
• An endophytic tumor projects into the vitreous as a white mass that may 'seed' into the gel.
• An exophytic tumor forms multilobular subretinal white masses and causes overlying retinal detachment.

• Red reflex testing with a direct ophthalmoscope is a simple screening test for leukocoria that is easily employed in the community.
• Ultrasound is used mainly to assess tumor size. It also detects calcification within the tumor and is helpful in the exclusion of simulating lesions such as Coats disease.

• General examination for congenital abnormalities of the face and hands.
• Tonometry.
• Measurement of the corneal diameter.
• Anterior chamber examination with a hand-held slit lamp.
• Ophthalmoscopy, documenting all findings with color drawings or photography.
• CT also detects calcification but entails a significant dose of radiation so is avoided by many practitioners.
• Plain X-rays may be used to detect calcification in resource-poor regions.
• MRI does not detect calcification but is useful for optic nerve evaluation, detection of extraocular extension and pinealoblastoma and to aid differentiation from simulating conditions.

Systemic Assessment

• Systemic assessment includes physical examination and MRI scans of the orbit and skull as a minimum in high-risk cases.
• If these indicate the presence of metastatic disease then bone scans, bone marrow aspiration and lumbar puncture are also performed.
• Genetic studies on tumor tissue and blood samples from the patient and relatives.

Histology

• Tumors are composed of small basophilic cells (retinoblasts) with large hyperchromatic nuclei and scanty cytoplasm.
• Many retinoblastomas are undifferentiated but varying degrees of differentiation are characterized by the formation of structures known as rosettes (Flexner–Wintersteiner, Homer–Wright, and fleurettes).

• A collaborative approach is required involving the ophthalmologist, pediatric oncologist, ocular pathologist, geneticist, allied health professionals, and parents.
• Treatment is highly individualized. The prognosis has improved significantly in recent years.
• Chemotherapy is the mainstay of treatment in most cases and may be used in conjunction with local treatments.
• Chemo-reduction may be followed by focal treatment with cryotherapy or TTT to consolidate tumor control.
• Intravenous treatment: carboplatin, etoposide, and vincristine (CEV) are given in three–six cycles according to the grade of retinoblastoma. Single- (carboplatin alone) or dual-agent therapy has also given favorable results in some circumstances, such as bridging therapy to allow deferral of more aggressive measures.
• Selective ophthalmic artery infusion: this is a promising new therapeutic option with high rates of globe salvage. The treatment offers significantly better results than intravenous treatment.
• Melphalan or topotecan is then injected over about 30 minutes and is carried into the branches of the arteries that supply blood to the uvea and retina. The overall safety profile is better than IV multi-drug chemotherapy.
• Intravitreal melphalan seems to be effective for vitreous seeding, though it carries a small risk of extraocular dissemination.
• TTT achieves focal consolidation following chemotherapy or is sometimes used as an isolated treatment. Focal techniques such as TTT and cryotherapy exert both a direct effect and probably increase susceptibility to the effects of chemotherapy.
• Cryotherapy using a triple freeze–thaw technique is useful for pre-equatorial tumors without either deep invasion or vitreous seeding.
• Brachytherapy using a radioactive plaque can be utilized for an anterior tumor if there is no vitreous seeding and in other circumstances such as resistance to chemotherapy.
• External beam radiotherapy should be avoided if possible, particularly in patients with heritable retinoblastoma because of the risk of inducing a second malignancy. At present, this option is used only for eyes with residual or relapsed retinoblastoma following previous intravenous or ophthalmic artery infusion.
• Enucleation is generally indicated if there is neovascular glaucoma, anterior chamber infiltration, optic nerve invasion or if a tumor occupies more than half the vitreous volume (group E).
• It is also considered if chemo-reduction fails, is useful for diffuse retinoblastoma because of a poor visual prognosis and a high risk of recurrence with other modalities.
• Enucleation should be performed with minimal manipulation and it is imperative to excise a section of the optic nerve to at least 10 mm.

Extra-ocular Extension

• Adjuvant chemotherapy consisting of a 6-month course of CEV is given subsequent to enucleation at some centers if there is retrolaminar or massive choroidal spread.
• External beam radiotherapy is indicated when there is tumor extension to the cut end of the optic nerve at enucleation, or extension through the sclera.
• Systemic spread, especially CNS involvement, involves aggressive treatment with high dose chemotherapy.

Follow Up

• Careful review at frequent intervals is generally required following treatment, in order to detect recurrence or the development of a new tumor, particularly in heritable disease.
• External beam radiotherapy should be avoided if possible in children with heritable retinoblastoma, because of the risk of inducing a late second malignancy in the radiation field.

• Persistent anterior fetal vasculature
• Persistent posterior fetal vasculature
• Retinopathy of prematurity
• Coat’s disease
• Toxocariasis
• Retinoma
• Retinal astrocytoma
• Vitreoretinal dysplasia