AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Angiography
• Intervention
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Angiography
• Intervention
• References

Background

Retinoblastoma (RB) is a malignant tumor of the developing retina that occurs in children, usually before age 5 years, and may be unilateral or bilateral. About 60% of patients have unilateral RB, with a mean age at diagnosis of 24 months, and about 40% have bilateral RB, with a mean age at diagnosis of 15 months. Mutations in the RB gene (chromosomal location 13q14) predispose individuals to the disease, as well as to an increased risk of developing pineal tumors, extracranial sarcomas, and melanoma. When a patient with RB develops a pineal tumor, the term trilateral RB (TRB) is used.

RB may occur sporadically (60%), or it may be inherited (40%). Historically, the RB trait seemed to be transmitted in an autosomal dominant pattern. Occasionally, however, the trait skips a generation in families, indicating genetic carriers.

Pathophysiology

The tumor arises from the retina, extends into the vitreous cavity, and spreads extraocularly via infiltration into the optic nerve, with direct extension through the subarachnoid space. Once RB fills the orbit, it can also spread to the choroid plexus, where it can metastasize hematogenously to the brain, bone, liver, kidney, lung, testes, and lymph nodes. If radiation therapy is used, the patient is at risk for osteosarcoma 10 years later.

In 1980, Bader et al coined the term TRB to define patients with bilateral RB plus an intracranial midline tumor, because the pineal is considered to be a sensitive organ (third eye) in some animal species. Midline tumors have been reported to occur in 3% of patients with bilateral RB, and those who develop TRB are diagnosed with bilateral RB at an early age, often with a familial history of RB. On average, 3 years after successful treatment of RB, a pineal tumor is discovered when signs or symptoms of increased intracranial pressure develop.

RB also tends to spread to the leptomeninges; leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with primary central nervous system (CNS) tumors. Thus, cytologic examination of lumbar cerebrospinal fluid (CSF) is routinely used to detect LMD.

Frequency

United States

The prevalence of RB is consistently reported at 11 cases per million children younger than 5 years (Devesa, 1975). Approximately 250-350 new cases are diagnosed each year in the United States, with more than 90% of patients presenting before age 5 years (Tamboli et al, 1990).

International

Worldwide, the incidence of RB has increased over the past 60 years and is estimated to be 1 case in 15,000-20,000 live births.

Mortality/Morbidity

The age at diagnosis varies considerably, as does the distribution of the disease stage; hence, mortality rates also vary in different parts of the world. In the United States, 89% of cases are diagnosed before age 3 years; in Pakistan, 60% of cases are diagnosed after age 5 years. Late diagnosis significantly affects the stage of the disease and, hence, the prognosis. RB causes 5% of childhood blindness and 1% of childhood cancer-related deaths.

• The mortality rate associated with optic nerve invasion up to the lamina cribrosa is 15%; beyond the lamina cribrosa, the rate is 44%; and to the line of resection, the rate is 65%.
• Before this century, RB was a uniformly fatal disease. With early diagnosis and treatment, survival in the United States is greater than 90%; however, patients with a germline RB mutation have a substantial risk of presenting with a second high-grade malignancy.
• Other tumors, notably osteosarcomas, are also common in survivors.

Race

RB does not have a racial predisposition.

Sex

RB does not have a predisposition by sex.

Age

Children with bilateral RB usually present during their first year of life. The peak age for the diagnosis of unilateral RB is between 24 and 30 months.

Anatomy

Two classic patterns of macroscopic growth have been described: (1) endophytic, in which the tumor grows toward the center of the eye, breaking through the inner layers of the retina into the vitreous cavity, and (2) exophytic, in which the tumor grows predominantly from the outer layers of the retina, away from the center of the eye and toward the subretinal space. Large tumors with an exophytic growth pattern may cause detachment of the retina from the choroid, with subsequent accumulation of fluid in the subretinal space. Both endophytic and exophytic growth patterns may be present in the same eye, and neither pattern is significant in terms of the prognosis.

A third type of growth pattern, diffuse infiltrating RB, is also recognized. This pattern is found in 1-2% of enucleated eyes and usually occurs in older patients.

Histopathologically, the Flexner-Wintersteiner rosette is the characteristic morphologic form of differentiation found in RB, and it appears to represent an attempt by the tumor cells to differentiate into photoreceptor cells.

In RB, the globulin content of the aqueous humor increases; therefore, the albumin-globulin (A/G) ratio decreases, which is contrary to what occurs in non-neoplastic and/or inflammatory conditions, and makes this a useful adjunct for the diagnosis of RB.

Clinical Details

Patients with RB can present in a variety of ways. Most patients will present with leukocoria (also called white pupillary reflex or cat's-eye reflex) instead of a normal healthy black pupil or red reflex (similar to "red eye" in photographs). However, other eye diseases can also cause leukocoria, such as congenital cataract (which may be hereditary or secondary to conditions, such congenital rubella or galactosemia, as well as retrolental fibroplasia), intraocular infections, persistent primary hyperplastic vitreous, retrolental fibroplasia (retinopathy of prematurity), and Coats disease (exudative retinopathy). An ophthalmologist may need to be consulted to determine the correct diagnosis.

A crossed eye, or strabismus, is the second most common feature in the presentation of RB. The child's eye may turn out (toward the ear, termed exotropia) or turn in (toward the nose, termed esotropia).

Patients with RB may also present with a red and painful eye, poor vision, inflammation of the tissue surrounding the eye, an enlarged or dilated pupil, differently colored irides (heterochromia), failure to thrive (trouble eating or drinking), extra fingers or toes, malformed ears, or mental retardation. The globes in patients with RB are generally of normal size.

A recent study (Hadjistilianou et al, 2006) reported 2 patients with bilateral RB who had unusual presentations: phthisis bulbi and buphthalmos. The authors speculated that delayed diagnosis led to the very rare combination of these 2 signs in different eyes of the same patient. No viable tumor cells in the phthisic eyes were demonstrated with histopathology, and the tumor was active in both buphthalmic eyes, infiltrating the choroid and optic nerve.

Preferred Examination

Detailed ophthalmologic examination includes indirect ophthalmoscopy, examination under anesthesia, visual field charting, and visual acuity testing. Routine systemic evaluations are performed, such as complete blood cell counts, liver function studies, and kidney function studies.

Fine-needle aspiration (FNA) biopsy can be used as a diagnostic modality in select intraocular tumors and similar conditions. In advanced cases, a metastatic workup must be performed, including a bone marrow biopsy, CSF cytologic tests for malignant cells, and bone scanning.

The volume of the intraocular tumor is estimated by means of orbital A and B scanning and/or a computed tomography (CT) scanning. On rare occasions, RB is discovered during a well-baby examination. Most often, a parent first detects the symptoms of RB.

Limitations of Techniques

Although FNA biopsy is associated with few complications (Shields et al, 1993), this technique should be used selectively for cases in which less-invasive diagnostic measures have not established the definitive diagnosis of RB.

DIFFERENTIALS

Section 3 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Angiography
• Intervention
• References

Other Problems to be Considered

Persistent hyperplastic primary vitreous
Coats disease
Retrolental fibrosis
Melanoma
Drusen
Retinal detachment
Toxocara canis infection
Retinopathy of prematurity
Orbital cellulitis
Pseudohypopyon
Hyphema
Vitreal hemorrhage
Uveitis

RADIOGRAPH

Section 4 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Angiography
• Intervention
• References

Findings

Radiographic examinations do not help in the definitive diagnosis of this intracranial tumor.

CT SCAN

Section 5 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Angiography
• Intervention
• References

Findings

On CT scans, RB is seen as a mass that is predominantly located in the posterior ocular pole. The mass may have distinct contours and an inhomogeneous structure, and it may contain calcifications in 70.5% of cases.

Degree of Confidence

CT scanning has high sensitivity in the detection of intraocular tumors, and it has a specificity of 91% for RB. This modality has allowed the staging of intraocular tumors, the detection of extrabulbar growth, and the determination of further treatment approaches. CT scanning can be used to follow up tumors to determine the effect of treatment and to establish a timely diagnosis of malignant tumor relapses.

False Positives/Negatives

An epibulbar osseous choristoma can simulate extraocular extension of RB in an eye with an intraocular malignancy; however, the intraocular contents display features typical of RB without extraocular extension.

MRI

Section 6 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Angiography
• Intervention
• References

Findings

Magnetic resonance imaging (MRI) is not as specific for diagnosing RB as CT scanning because of MRI's insensitivity for detecting calcium. When calcium is detected, it may be seen as an area of low signal intensity on all pulse sequences.

RB is usually visualized as a mass that is slightly hyperintense relative to the vitreous on T1-weighted images and that is hypointense on T2-weighted images. T1 hyperintensity may be due to the presence of melanin. Mild-to-marked enhancement is seen on gadolinium (Gd)–enhanced T1-weighted images.

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving

orstraightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape.

Like CT scanning, MRI has a role in the detection of extraocular tumor spread, especially extension into the optic canal. It can also depict intracranial tumors associated with TRB.

Retinal detachment is well depicted on MRI.

ULTRASOUND

Section 7 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Angiography
• Intervention
• References

Findings

Three-dimensional (3-D) ultrasonography

Three-dimensional ultrasonography can be used to perform retinal and tumor mapping, which is useful in planning localized or plaque radiation. Subsequently, 3-D ultrasonography can also help confirm the proper positioning of such plaques. In addition, calcification and retinal detachment can be diagnosed with this modality; however, 3-D ultrasonography is not useful for depicting the extraocular spread of tumors. General anesthesia must be a part of this examination, because the eye should be still during the scan.

Color Doppler imaging

Color Doppler imaging reveals slightly vascularized tumor areas and can depict blood flow inside the tumor.

ANGIOGRAPHY

Section 8 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Angiography
• Intervention
• References

Findings

Retinal fluorescein angiography helps to confirm the diagnosis of RB.

Degree of Confidence

Fluorescein angiography can be used to diagnose RB but is not usually performed for this disease because of the availability of noninvasive cross-sectional imaging methods.

False Positives/Negatives

False-positive results can occur in cases involving other similar pathologies (see Differentials).

INTERVENTION

Section 9 of 10  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Angiography
• Intervention
• References

External-beam irradiation

External-beam irradiation is not used as often as some other therapies because of long-term radiation complications—the most important of which is the development of radiation-induced tumors—and because of greater success with other modalities (Shields et al, 2004). Patients with RB have a higher-than-normal incidence of secondary tumors, which is further increased by radiation. Radiation also arrests bone growth, resulting in an asymmetrical face. This treatment is, however, useful in patients who have progressive disease despite chemotherapy or who have marked vitreous spread.

Plaque radiation therapy

Plaque radiation therapy delivers radiation in a more localized manner than external-beam radiation, which, theoretically, should minimize development of radiation-induced tumors. Plaque radiation therapy is more effective for larger tumors than cryotherapy and photocoagulation. However, plaque radiotherapy has a higher incidence of localized radiation complications involving the optic nerve and retina. Commonly used plaques are cobalt-60 (⁶⁰Co) and ruthenium-106 (¹⁰⁶Ru).

Cobalt-60 ophthalmic plaques

Cobalt-60 eye plaques were the first type of plaque therapy used for intraocular tumors and act as a high-energy source. ⁶⁰Co rings are encased in a platinum shell that does not block the radiation; therefore, ⁶⁰Co eye plaques send out radiation in all directions. On a standard radiograph, a ⁶⁰Co eye plaque demonstrates a spherical distribution of radiation.

Ruthenium-106 ophthalmic plaques

Ruthenium-106 ophthalmic plaques emit beta particles, which typically travel 4-5 mm into the eye. High-energy bremsstrahlung photons are also emitted, although they are minor components of the radiation dose.

Low-energy plaques

Low-energy plaques have largely replaced ⁶⁰Co and ¹⁰⁶Ru sources for plaque radiation therapy.

Treatment of metastasis

Postenucleation adjuvant therapy is safe and effective in that it significantly reduces the occurrence of metastasis in patients with RB that has high-risk histopathologic characteristics.

Research

Clinical trials addressing the advanced stages of RB are ongoing in many parts of the world. RB research has uncovered an alteration in the way a cancer cell communicates internally; this alteration is now believed to be found in all cancer cells. Consequently, studying this rare cancer may yield clues for the earlier detection of common cancers. However, although such advances may be made through targeted research, more often, they spring from nontargeted fundamental, translational, or applied research.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Angiography
• Intervention
• References

• Abramson DH, Du TT, Beaverson KL. (Neonatal) retinoblastoma in the first month of life. Arch Ophthalmol. Jun 2002;120(6):738-42.
• Albert DM. Historic review of retinoblastoma. Ophthalmology. Jun 1987;94(6):654-62. [Medline].
• Bader JL, Miller RW, Meadows AT, et al. Trilateral retinoblastoma. Lancet. Sep 13 1980;2(8194):582-3.
• Bishop JO, Madson EC. Retinoblastoma. Review of the current status. Surv Ophthalmol. May-Jun 1975;19(6):342-66. [Medline].
• Devesa SS. The incidence of retinoblastoma. Am J Ophthalmol. Aug 1975;80(2):263-5. [Medline].
• Finger PT, Romero JM, Rosen RB, et al. Three-dimensional ultrasonography of choroidal melanoma: localization of radioactive eye plaques. Arch Ophthalmol. Mar 1998;116(3):305-12. [Medline].
• Gajjar A, Fouladi M, Walter AW, et al. Comparison of lumbar and shunt cerebrospinal fluid specimens for cytologic detection of leptomeningeal disease in pediatric patients with brain tumors. J Clin Oncol. Jun 1999;17(6):1825-8. [Full Text].
• Hadjistilianou T, De Francesco S, Marconcini S, et al. Phthisis bulbi and buphthalmos as presenting signs of retinoblastoma: a report of two cases and literature review. Eur J Ophthalmol. May-Jun 2006;16(3):465-9.
• Honavar SG, Singh AD, Shields CL, et al. Postenucleation adjuvant therapy in high-risk retinoblastoma. Arch Ophthalmol. Jul 2002;120(7):923-31.
• Marback EF, Stout TJ, Rao NA. Osseous choristoma of the conjunctiva simulating extraocular extension of retinoblastoma. Am J Ophthalmol. Jun 2002;133(6):825-7.
• McCaffery S, Simon EM, Fischbein NJ, et al. Three-dimensional high-resolution magnetic resonance imaging of ocular and orbital malignancies. Arch Ophthalmol. Jun 2002;120(6):747-54.
• McCormick B, Ellsworth R, Abramson D, et al. Radiation therapy for retinoblastoma: comparison of results with lens-sparing versus lateral beam techniques. Int J Radiat Oncol Biol Phys. Sep 1988;15(3):567-74.
• Romero JM, Finger PT, Iezzi R, et al. Three-dimensional ultrasonography of choroidal melanoma: extrascleral extension. Am J Ophthalmol. Dec 1998;126(6):842-4.
• Shields CL, Mashayekhi A, Demirci H, et al. Practical approach to management of retinoblastoma. Arch Ophthalmol. May 2004;122(5):729-35.
• Shields JA, Shields CL, Ehya H, et al. Fine-needle aspiration biopsy of suspected intraocular tumors. The 1992 Urwick Lecture. Ophthalmology. Nov 1993;100(11):1677-84.
• Tamboli A, Podgor MJ, Horm JW. The incidence of retinoblastoma in the United States: 1974 through 1985. Arch Ophthalmol. Jan 1990;108(1):128-32.

Article Last Updated: Feb 2, 2007