Retinoblastoma: Symptoms, Types, Causes and Treatment

Retinoblastoma is a rare but serious eye cancer that primarily affects young children. As the most common intraocular malignancy in childhood, understanding its symptoms, types, causes, and treatment options is crucial for early detection, effective management, and optimal outcomes. This comprehensive guide synthesizes current scientific evidence to provide an up-to-date resource for families, patients, and healthcare professionals.

Symptoms of Retinoblastoma

Retinoblastoma often presents with noticeable and sometimes subtle signs in infants and young children. Recognizing these early symptoms not only increases the chance of saving vision but can also be life-saving. Because retinoblastoma can be visible to the naked eye, parents and caregivers are often the first to notice something unusual, prompting evaluation by an eye specialist.

Symptom	Description	Frequency/Significance	Source
Leukocoria	White pupillary reflex (‘cat’s eye reflex’)	Most common presenting symptom	1 2 3 4
Strabismus	Misalignment of the eyes (crossed eyes)	Second most common symptom	2 4
Pain/Red Eye	Ocular discomfort and redness	Usually in advanced stages	1 3
Proptosis	Bulging of the eye	Sign of advanced disease	3
Visual Loss	Diminished vision or blindness	May occur, especially if tumor is large	2 4
Inflammation	Edema, orbital cellulitis, hypopyon, hyphema	Less common, late presentation	2 3

Table 1: Key Symptoms

Understanding the Symptoms

Leukocoria (White Pupillary Reflex)

Leukocoria is the hallmark symptom of retinoblastoma. It often appears as a white, yellow, or cream-colored reflection in the pupil when light shines into the eye—commonly noticed in flash photographs or by caregivers. This abnormal reflex is caused by the tumor reflecting light back through the pupil, replacing the normal "red-eye" reflex seen in healthy eyes. Early detection of leukocoria is crucial, as it can be the first and only sign of disease in its early stages 1 2 4.

Strabismus (Misaligned Eyes)

Strabismus, or crossed eyes, is the second most frequent symptom. It happens when the tumor interferes with the normal function of the retina, affecting vision and eye alignment. Parents may notice their child’s eyes are not looking in the same direction 2 4.

Advanced and Less Common Symptoms

In advanced cases, retinoblastoma can cause pain, redness, and proptosis (bulging eye), symptoms that indicate the tumor may have spread outside the eyeball (extraocular extension). Other late signs include swelling, inflammation, and even symptoms mimicking infection, such as orbital cellulitis 1 3. Visual loss can also occur, particularly if the tumor is large or centrally located 2.

Importance of Early Recognition

Because some symptoms, like leukocoria and strabismus, are relatively specific to intraocular disease in children, their appearance should prompt urgent ophthalmic evaluation. Early diagnosis can make the difference between saving vision, the eye, and the child’s life.

Types of Retinoblastoma

Retinoblastoma is not a uniform disease. It manifests in several forms, each with unique implications for genetics, treatment, and prognosis. Understanding the different types helps guide clinical decisions and genetic counseling.

Type	Description	Key Features	Source
Unilateral	One eye affected	Most cases; usually non-heritable	2 7 11
Bilateral	Both eyes affected	All heritable cases; early onset	2 7 11
Trilateral	Both eyes + intracranial tumor	Rare; associated with heritable cases	6 7
Subtype 1	Cone-differentiated, heritable	Early onset, fewer mutations	5 11
Subtype 2	Cone-dedifferentiated, aggressive	More mutations, higher metastasis risk	5 12

Table 2: Types and Subtypes of Retinoblastoma

Clinical Types

Unilateral Retinoblastoma

• One eye involved
• Most common presentation (about 60%)
• Typically diagnosed around age 2
• Usually non-heritable (sporadic), but 15% can still carry a germline mutation 2 7 11

Bilateral Retinoblastoma

• Both eyes involved
• Accounts for 40% of cases
• Presents earlier, often before age 1
• Always heritable, due to germline RB1 mutation 2 7 11

Trilateral Retinoblastoma

• Retinal tumors plus a midline intracranial tumor (often pinealoblastoma)
• Rare, but strongly linked to heritable (germline) RB1 mutations
• Requires specific surveillance and management 6 7

Molecular Subtypes

Subtype 1: Cone Differentiated

• Associated with heritable, early-onset disease
• Tumors maintain differentiated cone photoreceptor characteristics
• Fewer additional genetic mutations beyond RB1 loss
• Generally less aggressive 5 11

Subtype 2: Cone Dedifferentiated

• Characterized by dedifferentiation with stemness features
• More genetic alterations, including MYCN amplification
• Higher risk of metastasis and more aggressive clinical course 5 12
• Shows neuronal/ganglion cell gene expression

Why the Distinction Matters

• Genetic counseling: Bilateral and trilateral cases imply heritable risk, affecting family planning and screening.
• Prognosis and treatment: Subtype 2 tumors are more aggressive and may require intensive therapy 5 12.
• Surveillance: Heritable cases must be monitored for second primary tumors.

Causes of Retinoblastoma

Retinoblastoma provides a classic model for understanding how genetics and mutations drive cancer formation. Both hereditary and non-hereditary mechanisms are involved, with implications for risk to siblings and future offspring.

Cause	Mechanism	Genetic Risk/Implications	Source
RB1 Gene Mutation	Loss of tumor suppressor function	High in heritable cases	1 7 8 9 10 11
Germline Mutation	Inherited (every cell in body)	All bilateral, some unilateral	2 7 9 11
Somatic Mutation	Acquired (only retinal cells)	Most unilateral, non-heritable	8 9 11
MYCN Amplification	Oncogene activation (rare, non-RB1)	Aggressive, rare, non-heritable	11
Other Gene Alterations	BCOR, CNVs, other predispositions	Potential for other cancers	12

Table 3: Causes and Genetic Mechanisms

The Role of the RB1 Gene

The Two-Hit Hypothesis

• Retinoblastoma is caused by the inactivation of both copies of the RB1 tumor suppressor gene in a retinal cell.
• In heritable cases, one RB1 mutation is present in all cells (germline); a second mutation occurs in a retinal cell (“two hits”).
• In non-heritable cases, both mutations arise independently in a single retinal cell (somatic) 1 7 8 9 11.

Heritable (Germline) vs. Non-Heritable (Somatic)

• Heritable: All bilateral, multifocal, and some unilateral cases. These children carry a germline mutation and have a high risk (>90%) of developing retinoblastoma and increased risk of second cancers 2 7 9 11.
• Non-heritable: Most unilateral cases; both mutations are somatic and confined to the retinal tumor 8 11.

Other Genetic Factors

• MYCN amplification: Rare, non-RB1 mutant retinoblastoma, associated with aggressive disease 11.
• Other alterations: Additional somatic changes (e.g., BCOR mutations, CNVs) may influence tumor behavior, metastasis risk, and predisposition to other cancers 12.

Cell of Origin

• Recent research suggests that the cancer originates from maturing cone precursor cells in the developing retina 5 10.

Implications for Families

• Genetic testing is critical for family counseling, as heritable retinoblastoma carries a risk for siblings and future generations.
• Identification of RB1 mutations informs surveillance for secondary tumors and guides long-term care 7 9 11 12.

Treatment of Retinoblastoma

Treatment for retinoblastoma has evolved dramatically, shifting from eye removal as the standard of care to eye- and vision-preserving therapies. The choice of treatment depends on tumor stage, laterality, genetics, and available resources.

Treatment	Approach/Technique	Main Indication/Benefit	Source
Enucleation	Surgical removal of the eye	Advanced, unilateral, no vision	1 2 4 13 17
Systemic Chemotherapy	IV drugs for chemoreduction	Globe salvage, reduce tumor size	13 15 16 17
Intra-arterial Chemo	Direct ophthalmic artery infusion	Targeted, for resistant/recurrent	13 14 15 16
Focal Therapy	Laser, cryotherapy, thermotherapy, brachytherapy	Small tumors, consolidation	2 4 15 16
Intravitreal Chemo	Direct injection into vitreous	Vitreous seeding control	14 16
Radiotherapy	External beam or plaque brachytherapy	Rare, salvage, large tumors	2 4 15
Genetic Counseling	Family risk assessment	All heritable and some unilateral	7 9 11 12

Table 4: Treatment Approaches

Treatment Modalities Explained

Enucleation

• Historically the mainstay, now reserved for advanced unilateral cases with no potential for vision or when life is threatened.
• Modern prosthetics offer excellent cosmetic results 1 2 4 13 17.

Chemotherapy

• Systemic (IV) chemoreduction: Shrinks tumors, making them amenable to focal therapy. Used for medium to large tumors and in bilateral disease 13 15 16 17.
• Intra-arterial chemotherapy: Delivers drugs directly to the eye via the ophthalmic artery, minimizing systemic toxicity. Increasingly used as primary or salvage therapy 13 14 15 16.
• Intravitreal chemotherapy: For vitreous seeding (tumor cells in the gel of the eye) 14 16.

Focal (Local) Therapies

• Laser photocoagulation and thermotherapy: Used for small tumors.
• Cryotherapy: Freezes and destroys peripheral tumors.
• Plaque brachytherapy: Radioactive disc applied to the eye, suitable for selected cases 2 4 15 16.

Radiotherapy

• External beam: Rarely used now due to risk of secondary cancers, but still an option for large, refractory tumors 2 4 15.
• Plaque: Limited, targeted radiation to minimize side effects.

Genetic Counseling and Surveillance

• Essential for families with heritable disease to assess risk and guide screening for second tumors 7 9 11 12.

Recent Advances and Future Directions

• Minimally invasive diagnostic techniques: Such as analysis of cell-free tumor DNA from aqueous humor, enabling diagnosis and mutation analysis without removing the eye 9.
• Molecularly targeted therapies: Emerging, particularly for aggressive subtypes 10 16.
• Multidisciplinary care: Long-term follow-up is critical for survivors, especially those with heritable disease, due to risk of new cancers 2 12.

Conclusion

Retinoblastoma, while rare, is a life- and vision-threatening pediatric cancer that exemplifies the importance of early detection, genetic understanding, and multidisciplinary care. Advances in diagnosis and therapy have dramatically improved survival and quality of life, especially in resource-rich settings.

Key Takeaways:

• Early symptoms like leukocoria and strabismus are critical for prompt diagnosis and better outcomes.
• Types include unilateral (often non-heritable), bilateral and trilateral (heritable), plus molecular subtypes influencing prognosis.
• Causes center on RB1 gene mutations, with both hereditary and sporadic forms, and rare involvement of other genes like MYCN and BCOR.
• Treatment has shifted from enucleation to eye-preserving chemotherapy and focal therapies, with personalized approaches guided by genetic findings.

By understanding the complexity and nuances of retinoblastoma, families and clinicians can work together toward the best possible outcomes for affected children.