Retinoblastoma

• Small round blue cell. Most common intraocular malignancy. White reflex.
• Retinal mass, variable calcification.

Description

Retinoblastoma (RB) is a rare, malignant tumour of the retina, originating from the nuclear layers of the retina, specifically the retinoblasts (immature cells of the retina). It is the most common intraocular tumour in children.

Pathogenesis

Retinoblastoma is primarily associated with mutations in the RB1 gene on chromosome 13, a tumour suppressor gene. This disease can present as either a hereditary (40% of cases, usually bilateral) or sporadic (60% of cases, usually unilateral) form. The hereditary form is autosomal dominant and affected individuals carry a germline mutation in one allele of the RB1 gene, with the second hit occurring somatically.

Subtype

• Sporadic (60%) – Usually unilateral eye involvement
• Hereditary (40%) – Usually bilateral eye involvement.

Epidemiology, Risk Factors & Associations

Retinoblastoma is the most prevalent primary intraocular malignancy in children, accounting for approximately 3% of all malignancies occurring in children under 15 years of age. The incidence of retinoblastoma is fairly consistent globally, at around 1 case per 15,000-20,000 live births. It is usually diagnosed before the age of 5, with a peak incidence at 1-2 years. There is no predilection for sex or race.

• Risk Factors: The major risk factor is a familial history of retinoblastoma due to the presence of a germline mutation in the RB1 gene. This is associated with a 45% chance of developing retinoblastoma.
• Associations: A distinct variant of hereditary retinoblastoma includes trilateral retinoblastoma, characterised by bilateral retinoblastomas with a concurrent midline intracranial primitive neuroectodermal tumour (PNET), typically a pineoblastoma, occurring in 5-15% of hereditary retinoblastoma. Quadrilateral retinoblastoma adds suprasellar or parasellar PNET to the triad.

In terms of genetic syndromes, retinoblastoma is associated with:

• Retinoma/Retinocytoma: A benign, spontaneously regressed variant of retinoblastoma, typically seen in patients with germline RB1 mutations.
• 13q Deletion Syndrome: A syndrome characterised by various malformations, with retinoblastoma occurring in a proportion of cases due to deletion of the region of chromosome 13 where the RB1 gene is located.
• Li-Fraumeni Syndrome
• Beckwith-Wiedemann syndrome

The non-hereditary form of retinoblastoma is caused by somatic mutations in the RB1 gene in retinal cells, with no increased risk to siblings or offspring. The hereditary form, meanwhile, confers an increased risk to siblings and offspring due to the presence of a germline RB1 mutation. In hereditary retinoblastoma, second cancers can develop later in life, such as osteosarcoma, melanoma, and soft tissue sarcomas, particularly in patients who received radiotherapy.

Clinical Features

Classic clinical features of retinoblastoma include:

• Leukocoria (white pupillary reflex): Also known as loss of red reflex, this is the most common presenting symptom, occurring in approximately 60% of cases.
• Strabismus (crossed or misaligned eyes): The second most common symptom, occurring in approximately 20% of cases.
• Decreased vision, eye redness, and inflammation may also be present.

Complications

Potential complications include:

• Blindness in the affected eye
• Glaucoma secondary to tumour seeding in the anterior chamber
• Extraocular extension of the tumour leading to orbital cellulitis-like symptoms or CNS involvement (very rare, particularly in cases of delayed diagnosis or treatment).
• Secondary cancers later in life, particularly in individuals with germline RB1 mutations.

Subtypes

Based on histopathology, retinoblastoma can be classified into:

• Endophytic: Growing into the vitreous from the retina
• Exophytic: Growing outwards into the subretinal space
• Diffuse infiltrating: A rare subtype, showing diffuse growth within the retina

Pathological Features

Histopathology

Microscopic evaluation of retinoblastoma shows small, round, blue cells forming rosettes (Flexner-Wintersteiner rosettes). There may be areas of necrosis and calcification within the tumour.

Serology and Genetics

In inherited cases, germline mutations in the RB1 gene can be detected in blood or saliva samples. In sporadic cases, somatic mutations are confined to the tumour cells.

Radiological Features

General Features

• Intraocular solid mass located within the retina (often with associated retinal detachment)
• They may be endophytic (growing into the vitreous) or exophytic (growing into the subretinal space).
• Calcification within the mass (in up to 95% of cases). Increases with therapeutic response.
• Potential optic nerve invasion.
• Severe disease features include neovascularisation of the iris, hyphaema, vitreous seeding, anterior chamber invasion, and extraocular extension.
• Ultrasound is the preferred initial modality for retinoblastoma
• MRI is superior in detecting optic nerve and extraocular extension and differentiating retinoblastoma from other conditions.

Ultrasound

• Solid mass with medium to high internal reflectivity mass due to calcifications
• Calcifications as high spike echoes with shadowing
• Absence of choroidal excavation beneath the tumour

CT

• Hyperdense mass with characteristic calcification (over 95% of cases)
• Vitreous may be abnormally dense from debris, haemorrhage or increased globulin content
• Possible extension into the optic nerve or brain

MRI

• T1: Iso- to hyperintense compared to vitreous; calcifications are hypointense
• T2: Hypointense compared to vitreous; calcifications are hypointense. May demonstrate retinal detachment with associated haemorrhage, resulting in fluid-fluid level
• T1 C+ (Gd): Strong contrast enhancement in tumour
• DWI: Demonstrates restricted diffusion.

Nuclear Medicine

Although not common, FDG-PET can detect distant metastases in advanced cases.

Angiography

Fluorescein angiography helps in visualising intra-tumoral vasculature, but its use is currently rare.

Grading and Staging

The International Retinoblastoma Staging System (IRSS) is used to stage retinoblastoma:

• Stage 0: No eye enucleation. Complete remission after six cycles of chemotherapy.
• Stage 1: Eye enucleation. Histopathology shows no high-risk features.
• Stage 2: Eye enucleation. Histopathology shows high-risk features such as choroidal invasion, anterior chamber involvement, or retrolaminar optic nerve invasion.
• Stage 3: Regional lymph node involvement or local residual tumour.
  • Stage 3a: Microscopic residual tumour.
  • Stage 3b: Pre-chemotherapy orbital disease, regional nodal disease.
• Stage 4: Distant metastasis.
  • Stage 4a: Haematogenous metastasis to one site.
  • Stage 4b: Haematogenous metastasis to multiple sites or central nervous system (CNS) involvement.

This staging is important in determining the treatment and predicting prognosis. The higher the stage, the more advanced the disease and the worse the prognosis. For example, patients with Stage 0 or 1 typically have a survival rate above 95%, whereas those with Stage 4b have a survival rate below 50%. The presence of high-risk histopathological features may necessitate adjuvant therapy, such as chemotherapy or radiotherapy.

Prognosis

The overall survival rate is over 95% in developed countries but can be lower in developing countries due to late diagnosis. The survival rate decreases with extraocular extension and metastatic disease.

Diagnosis

The diagnosis of retinoblastoma typically involves a thorough ocular examination, imaging studies (ultrasound, CT, MRI), and in some cases, genetic testing for RB1 mutations. In general, tumour biopsy is avoided due to the risk of tumour seeding.

Differential Diagnosis

Clinically-based

Differentials for white reflex include:

• Persistent Hyperplastic Primary Vitreous (PHPV): A congenital anomaly resulting in a fibrovascular, retrolental mass, typically unilateral. Differentiating features include the absence of calcifications and tumour seeds. It’s also associated with microphthalmia and cataract.
• Coats’ Disease: Characterised by retinal telangiectasia and exudative retinopathy, primarily affecting males. There is absence of a mass lesion and lack of calcifications, along with the characteristic light-bulb appearance on fluorescein angiography.
• Toxocariasis: This is a parasitic infection of the eye presenting as a unilateral focal mass with vitreous inflammation. There are no calcifications as seen in retinoblastoma. Epidemiological clues can help differentiate, as it is commonly seen in rural areas or in children with a history of eating soil or uncooked meats.
• Retinopathy of Prematurity (ROP): A disease of premature babies that have been exposed to high oxygen levels. Unlike retinoblastoma, ROP is more peripherally located and often bilateral. There’s no mass or calcification. The history of prematurity is suggestive.
• Retinal Haemangioblastoma: Seen in Von Hippel-Lindau disease, these are vascular tumours, often with an associated lipid exudate. On imaging, it may present as a round or oval vascular mass with an aneurysmal dilatation of feeding retinal arteriole and draining venule. Unlike retinoblastoma, they lack calcifications.

Management

Treatment usually involves a multidisciplinary team, including ophthalmologists, oncologists, and radiation oncologists. Therapeutic approaches may include systemic chemotherapy, local therapy (cryotherapy, laser photocoagulation, thermotherapy), radiotherapy, and enucleation for advanced disease. Genetic counselling is important in hereditary cases.