Retinoblastoma

Retinoblastoma: Excerpt from The 5-Minute Pediatric Consult

Kelly C. Goldsmith, MD

Retinoblastoma - BASICS

Retinoblastoma - description

• The most common primary intraocular tumor of childhood
• Malignant tumor of the embryonic neural retina

Retinoblastoma - epidemiology

• 1:16,000–25,000 live births
• The most common primary intraocular tumor of childhood (ocular leukemia most common overall)
• Represents 3% of all pediatric malignancies
• No sex, race, geographic, or socioeconomic predilection
• 90% diagnosed <4 years of age
• Median age at diagnosis for unilateral disease is 24 months and 12 months for bilateral disease (see “Genetics”)

Retinoblastoma - risk factors

Retinoblastoma - genetics

Tumor development depends on loss of function of both copies of the RB1 gene (located on chromosome 13) in a retinoblast. Hereditary and nonhereditary (sporadic) forms exist.

• Hereditary retinoblastoma (RB):
  • 45% of all RB
  • 1 RB1 gene is dysfunctional in all cells (germline mutation); mutation in remaining RB1 gene in any retinal cell will lead to development of a tumor.
  • 90% probability of 2nd mutation occurring in at least 1 (but usually more) retinal cells leading to tumor development (high penetrance)
  • Therefore, multiple tumors are common (bilateral and/or multifocal).
  • Mean age at diagnosis: 12 months
  • Only 8% have positive familial history; remainder are new germline mutations.
  • ~40–45% of offspring will develop RB (autosomal-dominant transmission, 90% penetrance).
  • RB1 gene mutation in all cells predisposes to 2nd (non-RB) malignancies as well.
• Nonhereditary RB:
  • 55% of all RB
  • No germline RB1 mutation; 2 acquired (somatic) RB1 mutations must occur in a single retinal cell (a rare event).
  • Always unilateral
  • Rarely diagnosed before 6 months (mean, 24 months)
  • No increased risk of RB in offspring
  • No increased risk of 2nd malignancy

Retinoblastoma - pathophysiology

• Originates in retinal cell precursor (retinoblast)
• Histology: Small round blue cells with large hyperchromatic nuclei and scant cytoplasm
• Growth of tumor may be endophytic (from inner surface of retina to vitreous) or exophytic (from outer layer of retina into subretinal space); may cause retinal detachment.
• Spread is via optic nerve (common) with potential to invade CNS, direct extension beyond the eye, and lymphatic or hematogenous spread (uncommon).
• Tumor cells may break off from primary mass and grow independently within the eye (called “vitreous seeding”); single tumor with seeding may be confused with multifocal disease.

Retinoblastoma - DIAGNOSIS

Retinoblastoma - signs & symptoms

Retinoblastoma - history

• Familial history of retinoblastoma or any eye tumors: Hereditary retinoblastoma; siblings may require eye exam
• Leukocoria (white pupil, “cat’s eye reflex”): Often noted in photographs of children with advanced intraocular RB (60%)
• Strabismus, either eso- or exotropic (20%): Esotropia is more common in the general population, so exotropia is more suspicious.
• Eye complaints: RB is rarely painful (unless secondary glaucoma or inflammation is present); vision problems are rare complaints because tumor is usually unilateral.
• Inflammation, heterochromia, and glaucoma: Rare presentations (<10%)
• Neurologic signs, orbital/ periorbital masses, bone pain, anorexia, signs of cytopenias: May represent metastatic disease
• Associated conditions: 13q deletion syndrome has RB, dysmorphism, mental retardation, and genitourinary (GU) or other anomalies.

Retinoblastoma - physical exam

• Only 3% discovered with routine funduscopic examination. Leukocoria more common as presenting sign.
• Proptosis and orbital/periorbital masses: Late sequelae of mass effect
• Check for red reflex in darkened room: Screen for RB in office.
• Evaluate for anisocoria.
• Cover test to assess for strabismus (20%)
• Test vision of each eye independently to identify unilateral RB.

Retinoblastoma - tests

Retinoblastoma - lab

• Ophthalmologic examination: Confirmation of diagnosis based on ophthalmologic examination by a specialist in pediatric ocular tumors via direct and indirect ophthalmoscopy (and examination under anesthesia [EUA]) and by imaging modalities (MRI or CT). Parents and siblings should also undergo ophthalmologic screening in many cases.
• Biopsy: Biopsy confirmation is rarely necessary (risk for tumor seeding).
• CBC: Assess for bone marrow involvement.
• CSF cytology: Evaluate for leptomeningeal spread (only necessary if tumor has spread beyond the globe).
• Chromosome analysis: Should be performed, but even in hereditary cases only 5% have mutations detectable by this means.

Retinoblastoma - imaging

CT or MRI: Evaluate primary tumor (80% have calcification) and optic nerve extension, leptomeningeal spread, pineal blastoma (in 4% of hereditary RB, patients will have bilateral RB and pineal tumor noted on MRI = “trilateral RB”).

Retinoblastoma - diag proced-surgery

• Intraocular and extraocular staging systems exist.
• Most RB in the US is intraocular without metastatic disease.
• Patients with tumor extension outside the globe should have a lumbar puncture to assess for tumor cells in CSF and bone marrow evaluation for complete staging.

Retinoblastoma - differencial diagnosis

• Coats disease: Acquired anomaly, males, retinal telangiectasias
• Persistent hyperplastic primary vitreous (PHPV)
• Inflammatory conditions: Hypopyon, uveitis, iritis, endophthalmitis
• Toxoplasmosis, Toxocara canis, other ocular infections
• Retinopathy of prematurity (ROP)

Retinoblastoma - TREATMENT

Retinoblastoma - general measures

• Primary goals:
  • Eradicate tumor
  • Prevent metastasis
• Secondary goals:
  • Salvage the eye and retain useful vision.
  • Cosmetic considerations
• Treatment must be individualized, depending on bilateral or unilateral disease, potential for salvageable vision, and evidence of local extension or metastatic disease. Referral to a center with oncologic and ophthalmologic specialists is essential.
• Minimal (nonbulky) intraocular disease:
  • Plaque radiotherapy (radioactive seeds sewn to episcleral surface above RB lesion): This provides local radiation to tumor in selected solitary RBs, up to 16 mm in diameter with or without vitreous seeds
  • Photocoagulation (laser directed at tumor blood vessels): For selected small RBs, usually <3 mm.
  • Transpupillary thermotherapy (TTT; laser aimed directly at tumor with lower temp vs. photocoagulation): Treatment of peripapillary tumors for which photocoagulation cannot be used.
  • Cryotherapy (topical freeze technique): For selected RBs <3–4 mm in diameter without vitreous seeding, which are located anteriorly in the eye
  • Locally delivered chemotherapy: Subtenon/subconjunctival chemotherapy (usually carboplatin) delivered by direct intraocular injection
• Bulky intraocular disease:
  • Current trend is toward eye salvage therapy: Initial systemic chemotherapy for tumor reduction followed by local definitive therapy (as for nonbulky disease)
  • Tumor resection without enucleation is not possible because of risk of tumor spillage; enucleation of involved eye (with long segment of optic nerve removal to ensure tumor-free margins) may be required for large tumors refractory to chemoreduction or when vision is not salvageable.
  • External beam radiation therapy (EBRT): RB is extremely radiosensitive; however, increases risk of 2nd malignancy (especially in hereditary RB). Other effects: Dry eye, cataract, retinopathy, and cosmetic deformity from bone maldevelopment. EBRT is still an important modality but is avoided whenever effective alternative therapies are available.
• Metastatic disease:
  • Multiagent chemotherapy with or without autologous bone marrow transplantation; poor results to date
  • Effective treatment requires multidisciplinary collaboration between ophthalmologists, oncologists, and radiation oncologists.

Retinoblastoma - FOLLOW UP

• Frequent ophthalmologic examinations (including EUA) are mandatory to evaluate response to therapy and to screen for disease progression, particularly in hereditary RB.
• Therapy must include genetic counseling regarding the risk of 2nd malignancies (with or without adjuvant XRT), risk to siblings, as well as the risk to future children of affected patients with hereditary RB.
• Primary care physicians must be aware of the risks of 2nd malignancies (see “Prognosis”) and maintain an appropriately high index of suspicion for their development.
• Primary care physicians should be aware of the genetics of RB and screen siblings appropriately.
• Pitfalls:
  • Missed or delayed diagnosis: Ophthalmologic examination by a specialist in pediatric ocular tumors required to establish diagnosis and follow regression or recurrence in treated eyes, follow for development of new tumors in hereditary cases
  • Failure to recognize the possibility that a child with RB has a genetic predisposition, especially in the frequent setting where there is no familial history of RB
  • Failure to refer for appropriate genetic counseling

Retinoblastoma - prognosis

• Mortality from retinoblastoma is 8% (U).
• Survival depends on extent (stage) of disease.
• Metastatic disease is uncommon in the US but can occur up to 5 years after diagnosis and has a poor outcome (same for hereditary and nonhereditary).
• Prognosis for vision depends on size and location of tumor(s).
• 2nd malignancy is most common cause of death in hereditary RB:
  • These include osteosarcoma (most frequent), pineal blastoma, melanoma, fibrosarcoma, and others.
  • Rates of 2nd malignancy in hereditary RB are 10% at 10 years and as high as 40% at 30 years in patients who received EBRT (70% of 2nd tumors occur in the field of radiation, 30% elsewhere).

Retinoblastoma - complications

• Metastatic spread: Local spread within orbit, through the optic nerve to brain, or to distant sites (uncommon)
• Loss of eye: Surgical enucleation in advanced cases
• Blindness: In advanced, bilateral disease; bilateral enucleation rarely required
• Cosmetic deformity: From enucleation, ocular prosthesis lacks normal eye movements; potential orbital bone hypoplasia secondary to EBRT
• 2nd malignancy: Patients with hereditary RB have a predisposition to cancer; this risk is greatly increased by exposure to radiotherapy.

Retinoblastoma - bibliography

1. Abramson DH, Frank CM, Susman M, et al. Presenting signs of retinoblastoma. J Pediatr. 1998;132(3 pt 1):505–508.
2. Abramson DH, Schefler AC. Update on retinoblastoma. Retina. 2004;24(6):828–848.
Donaldson SS, Eghert PR, Newsham I, et al. Retinoblastoma. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology, 3rd ed. Philadelphia/New York: Lippincott-Raven; 1997:699–715.
3. Gallie BL, Dunn JM, Chan HS, et al. The genetics of retinoblastoma: Relevance to the patient. Pediatr Clin North Am. 1991;38:299–315.
4. Magramm I. Amblyopia: Etiology, detection, and treatment. Pediatr Rev. 1992;13(1):7–14.
5. Nahum MP, Gdal-On M, Kuten A, et al. Longterm follow-up of children with retinoblastoma. Pediatr Hematol Oncol. 2001;18(3):173–179.
6. Shields JA, Shields CL. Clinicopathologic factors related to metastasis in retinoblastoma. Mayo Clin Proc. 1994;69:50–56.

Retinoblastoma - CODES

Retinoblastoma - icd9

190.5 Malignant neoplasm of eye, retina

Retinoblastoma - PATIENT TEACHING-MED

Siblings and children of patients with RB should undergo ophthalmologic examinations under anesthesia to detect the presence of RB early.

Retinoblastoma - FAQ

• Q: What is the risk that a child with RB will become blind?
• A: Vision is salvageable in 100% of eyes with low-stage involvement, and in 81% overall. In <10% of patients are both eyes affected severely enough to threaten vision (bilateral disease only occurs in hereditary RB).
• Q: What is the chance that a child with RB in 1 eye will get it in the other?
• A: Bilateral disease is seen with hereditary RB. A child with unilateral disease has a 15% chance of having hereditary RB, which would put the contralateral eye at risk; this risk is much higher if the child has multifocal involvement or is <1 year of age.
• Q: What happens to the eye socket after an enucleation?
• A: Prostheses can be made to fit the socket of the enucleated eye to give excellent cosmetic results.
• Q: Is there a test to identify hereditary cases?
• A: Routine chromosome analysis does not reveal a defect related to the RB gene in the majority (95%) of hereditary cases. Specialized molecular tests may be used in research labs, but because there are many possible mutations, this is costly and time-consuming. In general, hereditary cases are determined clinically because of young presentation, family history, and/or bilateral or multifocal unilateral disease.

Book Source Details

• Book Title: The 5-Minute Pediatric Consult
• Author(s): M. William Schwartz MD; et al.
• Year of Publication: 2008
• Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.

More About Retinoblastoma

• Back to disease: Retinoblastoma: Introduction
• Next Book Extract About Retinoblastoma: Surveys relating to Retinoblastoma
• More Book Extracts: All Online Books for Retinoblastoma

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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.

More About This Book: Title: The 5-Minute Pediatric Consult Authors: M. William Schwartz MD; et al. Publisher: Lippincott Williams & Wilkins Copyright: 2008 ISBN: 0-7817-7577-9

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