Retinoblastoma in Pediatric Age

Introduction

Retinoblastoma is the most common primary intraocular malignancy in children, representing approximately 4% of all pediatric cancers. This rare but significant tumor arises from primitive neuroectodermal cells of the developing retina, specifically the cone precursor cells. Early diagnosis and intervention are crucial for both vision preservation and survival.

Key Points:

• Most common primary intraocular tumor in children, with excellent survival rates when detected early
• First cancer to demonstrate a genetic origin, caused by mutations in the RB1 tumor suppressor gene on chromosome 13
• Presents in both hereditary (40%) and non-hereditary (60%) forms, with different implications for management and surveillance
• Demonstrates a unique "two-hit" hypothesis in cancer genetics, requiring mutation of both RB1 alleles for tumor development
• Serves as a model for understanding cancer genetics and developing targeted therapies in pediatric oncology

Epidemiology

Retinoblastoma affects approximately 1 in 15,000 to 20,000 live births worldwide, with about 8,000 new cases annually. The incidence varies geographically, with higher rates in developing countries due to delayed diagnosis.

• Distribution patterns:
  • 60% unilateral cases: typically non-hereditary, median age of diagnosis 24 months
  • 40% bilateral cases: always hereditary, median age of diagnosis 12 months
  • 15% unilateral cases are hereditary despite single eye involvement
• Risk factors:
  • Family history of retinoblastoma (5% of cases)
  • Presence of 13q deletion syndrome
  • Young parental age at conception
  • No significant gender or racial predilection
• Geographic variations:
  • Higher mortality in developing countries due to delayed presentation
  • Better outcomes in countries with established screening programs
  • Varying access to specialized treatment centers globally

Pathophysiology

Retinoblastoma develops through a complex molecular pathway involving the RB1 tumor suppressor gene, which plays a crucial role in cell cycle regulation and development.

• Genetic mechanisms:
  • Hereditary form: Germline mutation present in all cells, second mutation occurs somatically
  • Non-hereditary form: Both mutations occur somatically in retinal cells
  • Loss of heterozygosity often occurs through mitotic recombination or non-disjunction
• Molecular pathways:
  • RB1 protein regulates G1/S cell cycle checkpoint
  • Loss of RB1 leads to dysregulation of E2F transcription factors
  • Additional genetic changes involve MYCN amplification
  • Epigenetic modifications play a role in tumor progression
• Tumor progression:
  • Initial intraretinal growth patterns: endophytic, exophytic, or mixed
  • Potential for vitreous seeding in advanced cases
  • Risk of extraocular spread through optic nerve or choroid

Clinical Presentation

Retinoblastoma presents with various signs and symptoms, often detected by parents or during routine pediatric examinations. Early recognition is crucial for optimal outcomes.

• Primary presenting signs:
  • Leukocoria (white pupillary reflex) - present in 60% of cases
  • Strabismus (eye misalignment) - present in 20% of cases
  • Vision loss or poor visual tracking
  • Heterochromia (different colored irises)
• Advanced disease manifestations:
  • Buphthalmos (enlarged eye)
  • Orbital cellulitis-like presentation
  • Secondary glaucoma with eye pain
  • Proptosis (forward displacement of eye)
• Associated findings:
  • Anterior chamber inflammation
  • Hyphema (blood in anterior chamber)
  • Vitreous hemorrhage
  • Retinal detachment

Diagnosis

Diagnosis requires a systematic approach combining clinical examination, imaging studies, and genetic testing. Early detection is crucial for optimal outcomes.

• Clinical examination:
  • Comprehensive ophthalmologic examination under anesthesia
  • Wide-field RetCam imaging for documentation
  • Detailed fundus mapping and tumor measurements
• Imaging studies:
  • B-scan ultrasonography: calcifications and tumor dimensions
  • MRI with contrast: extraocular extension and CNS involvement
  • CT scan: calcifications (limited use due to radiation)
  • Optical coherence tomography for small tumors
• Classification systems:
  • International Classification of Retinoblastoma (ICRB):
    • Group A: Small tumors away from fovea/disc
    • Group B: Larger tumors or macular/peripapillary location
    • Group C: Localized seeding
    • Group D: Diffuse seeding
    • Group E: Extensive involvement/neovascular glaucoma
• Genetic evaluation:
  • RB1 mutation analysis
  • Genetic counseling for families
  • Screening protocols for siblings and offspring

Microscopic View

Treatment

Treatment of retinoblastoma requires a multidisciplinary approach, with strategies tailored to tumor characteristics, laterality, and staging. The primary goals are survival, globe salvage, and vision preservation.

• Primary treatment modalities:
  • Systemic chemotherapy:
    • VEC protocol (vincristine, etoposide, carboplatin)
    • Chemoreduction followed by consolidation
    • High-dose chemotherapy for metastatic disease
  • Local therapy options:
    • Intra-arterial chemotherapy (melphalan, topotecan)
    • Intravitreal chemotherapy for vitreous seeding
    • Transpupillary thermotherapy
    • Cryotherapy for peripheral tumors
    • Laser photocoagulation
  • Radiation therapy:
    • External beam radiotherapy (reserved for specific cases)
    • Plaque brachytherapy for localized tumors
• Surgical interventions:
  • Enucleation for advanced unilateral disease
  • Secondary implants and prosthetic fitting
  • Management of orbital recurrence
• Treatment selection factors:
  • Tumor size and location
  • Presence of vitreous or subretinal seeding
  • Uni- vs. bilateral involvement
  • Age of patient
  • Family preferences and access to care

Prognosis

The prognosis for retinoblastoma has improved dramatically with modern treatment approaches, though outcomes vary significantly based on multiple factors.

• Survival rates:
  • Over 95% survival in developed countries
  • 70-80% survival in developing countries
  • Nearly 100% survival for intraocular disease
• Prognostic factors:
  • Stage at diagnosis
  • Genetic status (hereditary vs. non-hereditary)
  • Presence of high-risk histopathological features
  • Access to specialized treatment centers
• Long-term considerations:
  • Secondary malignancies:
    • 50% lifetime risk in hereditary cases
    • Common types: osteosarcoma, soft tissue sarcomas
    • Increased risk with radiation exposure
  • Quality of life:
    • Visual outcomes and adaptation
    • Psychosocial adjustment
    • Academic and professional achievement
• Follow-up requirements:
  • Regular ophthalmologic examinations
  • Screening for second primary tumors
  • Genetic counseling for family planning
  • Psychosocial support and rehabilitation