Retinoblastoma is the most common malignant intraocular tumor of childhood and one of the most common pediatric solid tumors, with an incidence of 1:14,000–1:20,000 live births. It is equally common in both sexes and has no racial predilection. Retinoblastoma is a neuroblastic tumor and is therefore biologically similar to neuroblastoma and medulloblastoma. The tumor can be unilateral or bilateral; 30%–40% of cases are bilateral. In familial and bilateral cases, retinoblastoma is typically diagnosed during the first year of life; in sporadic unilateral cases, between 1 and 3 years of age. Approximately 90% of cases are diagnosed before 3 years of age; onset later than age 5 years is rare but can occur.
The most common initial sign is leukocoria (white pupillary reflex), which is usually first noticed by the family and described as a glow, glint, or cat’s-eye appearance (Fig 25-24). The differential diagnosis of leukocoria is presented in Table 25-7. Approximately 25% of cases present with strabismus (esotropia or exotropia). Less common presentations include vitreous hemorrhage, hyphema, ocular or periocular inflammation, glaucoma, proptosis, and pseudohypopyon.
Diagnosis of retinoblastoma is usually based on its ophthalmoscopic appearance. Intraocular retinoblastoma can exhibit a variety of growth patterns. With endophytic growth, it appears as a white to cream-colored mass that breaks through the internal limiting membrane (Fig 25-25). Endophytic retinoblastoma is sometimes associated with vitreous seeding, in which individual cells or fragments of tumor tissue become separated from the main mass, as shown in Figure 25-26. Vitreous seeds may be few and localized or so extensive that the clinical picture resembles endophthalmitis. Occasionally, malignant cells enter the anterior chamber and form a pseudohypopyon.
Exophytic tumors are usually yellow-white and occur in the subretinal space; the overlying retinal vessels are commonly larger in caliber and more tortuous (Fig 25-27). Exophytic retinoblastoma growth is often associated with subretinal fluid accumulation, which can obscure the tumor and closely mimic the appearance of an exudative retinal detachment suggestive of advanced Coats disease. Retinoblastoma cells have the potential to implant on previously uninvolved retinal tissue and grow, thereby creating an impression of multicentricity in an eye with only a single primary tumor.
Large tumors often show signs of both endophytic and exophytic growth. Small retinoblastoma lesions appear as a grayish mass and are frequently confined between the internal and external limiting membranes. A third pattern, diffuse infiltrative retinoblastoma, is usually unilateral and nonhereditary. It is found in children older than 5 years. The tumor presents with conjunctival injection, anterior chamber seeds, pseudohypopyon, large clumps of vitreous cells, and retinal infiltration of tumor. Because no distinct tumor mass is present, diagnostic confusion with inflammatory conditions is common.
Figure 25-25 Fundus photograph showing multiple endophytic retinoblastoma lesions, left eye.
(Courtesy of A. Linn Murphree, MD.)
Figure 25-26 Endophytic retinoblastoma with vitreous seeding.
Figure 25-27 Exophytic retinoblastoma with overlying detached retina.
Spontaneous regression of retinoblastoma is possible. It can be asymptomatic, resulting in the development of a benign retinocytoma, or it can be associated with inflammation and, ultimately, phthisis bulbi. In either case, the genetic implications are the same as for an individual with an active retinoblastoma.
The most common retinal lesion simulating retinoblastoma is seen in Coats disease. The presence of crystalline material, extensive subretinal fluid, and peripheral vascular abnormalities—combined with the absence of calcium—suggests Coats disease. Astrocytic hamartomas and hemangioblastomas are benign retinal tumors that may simulate the appearance of small retinoblastomas. Both are usually associated with neuro-oculocutaneous syndromes (see Chapter 28).
Evaluation of a patient with presumed retinoblastoma requires imaging of the head and orbits, which can confirm the diagnosis and assess for extraocular extension and intracranial disease. Computed tomography is discouraged because of the possible increased risk of secondary tumors due to radiation exposure. Magnetic resonance imaging and ultrasonography are recommended. More invasive tests are reserved for atypical cases. Aspiration of ocular fluids for diagnostic testing should be performed only under the most unusual circumstances because such procedures can disseminate malignant cells. Recently, however, it was demonstrated that cell-free tumor-derived DNA may be obtained from aqueous humor.
The characteristic histologic features of retinoblastoma include Flexner-Wintersteiner rosettes, which are usually present, and fleurettes, which are less common. Both represent limited degrees of retinal cellular differentiation. Homer Wright rosettes are also frequently present but are less specific for retinoblastoma because they are common in other neuroblastic tumors. Calcification of varying extent is usually present.
Berry JL, Xu L, Murphree AL, et al. Potential of aqueous humor as a surrogate tumor biopsy for retinoblastoma. JAMA Ophthalmol. 2017;135(11):1221–1230.
de Graaf P, Göricke S, Rodjan F, et al; European Retinoblastoma Imaging Collaboration. Guidelines for imaging retinoblastoma: imaging principles and MRI standardization. Pediatr Radiol. 2012;42(1):2–14.
The retinoblastoma gene (RB1) maps to a locus within the q14 band of chromosome 13 and codes for a protein, pRB, that suppresses tumor formation. For retinoblastoma to occur, both RB1 genes must have a mutation. Approximately 60% of retinoblastoma cases arise from somatic nonhereditary mutations of both alleles of RB1 in a retinal cell. These mutations generally result in unifocal and unilateral tumors. In the other 40% of patients, a germline mutation in 1 of the 2 alleles of RB1 either is inherited from an affected parent (10% of all retinoblastoma cases) or occurs spontaneously in 1 of the gametes. A second somatic mutation in a retinal cell is all that is necessary for retinoblastoma to develop; such cases are often multicentric and bilateral.
Genetic counseling for families of retinoblastoma patients is complex (Table 25-8). Both parents and all siblings should be examined. In approximately 1% of cases, a parent may be found to have an unsuspected fundus lesion that represents a spontaneously regressed retinoblastoma (retinocytoma).
Genetic testing for retinoblastoma is important for determining the risk of subsequent cancers (both retinoblastoma and other primary neoplasms) in the affected child and the risk of retinoblastoma in other family members. The probability of detecting the RB1 gene depends on many factors, including the capabilities of the molecular diagnostic laboratory, the presence of tumor tissue, and the ability to test other affected family members.
Preimplantation genetic testing can be performed, and in vitro fertilization techniques have been used successfully to select embryos that are free from the germinal RB1 mutation.
Dhar SU, Chintagumpala M, Noll C, Chévez-Barrios P, Paysse EA, Plon SE. Outcomes of integrating genetics in management of patients with retinoblastoma. Arch Ophthalmol. 2011;129(11):1428–1434.
Classification of retinoblastoma
The International Classification of Retinoblastoma (ICRB; Table 25-9) is useful for predicting the success of chemoreduction and has superseded the Reese-Ellsworth classification, which was originally developed to predict globe salvage after external-beam radiotherapy. The American Joint Committee on Cancer (AJCC) also has a staging system for retinoblastoma that addresses both intraocular and extraocular disease (see BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors).
Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113(12):2276–2280.
Table 25-8 Genetic Counseling for Retinoblastoma
Table 25-9 International Classification of Retinoblastoma
The management of retinoblastoma has changed dramatically over the past decade and continues to evolve. Many specialists may be involved, including ocular oncologists, pediatric ophthalmologists, geneticists, genetic counselors, pediatric oncologists, and radiation oncologists. External-beam radiation is seldom used to treat intraocular retinoblastoma because of its high association with development of craniofacial deformity and secondary tumors in the field of radiation. When the likelihood of salvaging vision is low, primary enucleation of eyes with advanced unilateral retinoblastoma is often performed to avoid the adverse effects of systemic chemotherapy. To prevent extraocular spread of the tumor, the surgeon should minimize manipulation of the globe and obtain a long segment of optic nerve. Small retinoblastoma tumors can often be treated with either laser photocoagulation or cryotherapy.
Primary systemic chemotherapy (chemoreduction) followed by local therapy (consolidation) has been used to spare vision for larger tumors (Fig 25-28) and is often used in cases of bilateral retinoblastoma. Most studies of chemoreduction for retinoblastoma have used vincristine, carboplatin, and an epipodophyllotoxin. Others have added cyclosporine. Chemotherapy is rarely successful when used alone and often requires local therapy (cryotherapy, laser photocoagulation, thermotherapy, or plaque radiotherapy) as well. Adverse effects of chemoreduction treatment include low blood count, hair loss, hearing loss, renal toxicity, neurologic and cardiac disturbances, and possible increased risk for acute myelogenous leukemia.
A, Left eye of an infant with bilateral retinoblastoma; 2 tumors straddle the optic nerve. B, After chemoreduction and laser consolidation, the tumors are nonviable. The child’s visual acuity was 20/25 at age 5 years.
Intra-arterial chemotherapy has recently been reported as an alternative to systemic chemoreduction for unilateral retinoblastoma in group B, C, D, or E eyes. Chemotherapy is delivered via cannulation of the ophthalmic artery in single or multiple sessions. Many chemotherapy agents have been used; melphalan is the most common. Overall, the results show higher rates of globe salvage in eyes treated initially and in those that did not respond to prior treatments. Systemic complications include neutropenia and metastasis. Ocular complications include vascular occlusion, blepharoptosis, cilia loss, temporary dysmotility, and periocular edema in the distribution of the supratrochlear artery. There is concern about the radiation that is delivered during the procedure, especially for patients with germline RB1 gene mutations, who are at higher risk for malignant tumors.
Intravitreal chemotherapy has been used for refractory and recurrent vitreous seeding from retinoblastoma. Periocular injections have been used for adjuvant chemotherapy.
Treated retinoblastoma sometimes disappears altogether, but more often it persists as a calcified mass (type 1, or “cottage cheese,” pattern) or a noncalcified, translucent grayish lesion (type 2, or “fish flesh,” pattern), which may be difficult to distinguish from untreated tumor. Type 3 regression has elements of both types 1 and 2, and type 4 regression is a flat, atrophic scar. A child with treated retinoblastoma must be observed closely for new or recurrent tumor formation, with frequent examinations under anesthesia if necessary.
Extraocular retinoblastoma, though uncommon in the United States, is still problematic in developing countries, primarily because of delay in diagnosis. The 4 major types are optic nerve involvement, orbital invasion, central nervous system (CNS) involvement, and distant metastasis. Treatment of extraocular retinoblastoma includes intensive multimodality chemotherapy, autologous hematopoietic stem cell rescue, and external-beam radiotherapy. Long-term disease-free survival is possible if the CNS is not involved; otherwise, the prognosis is usually poor.
Patients with trilateral retinoblastoma have a primitive neuroectodermal tumor (PNET) of the pineal gland or parasellar region in addition to retinoblastoma. In patients with unilateral retinoblastoma, the risk of trilateral retinoblastoma has been less than 0.5%; in those with bilateral retinoblastoma, less than 5%–15%. However, the rate of trilateral retinoblastoma appears to be lower in patients treated with chemoreduction. Treatment usually involves a multimodal approach, and the prognosis is poor.
Abramson DH, Dunkel IJ, Brodie SE, Marr B, Gobin YP. Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology. 2010;117(8):1623–1629.
Shields CL, Alset AE, Say EA, Caywood E, Jabbour P, Shields JA. Retinoblastoma control with primary intra-arterial chemotherapy: outcomes before and during the intravitreal chemotherapy era. J Pediatr Ophthalmol Strabismus. 2016;53(5):275–284.
Identification of RB1 mutations is very useful in determining how frequently to monitor patients. Patients with unilateral tumors who have somatic mutations are not at risk for development of additional tumors (ocular or systemic). Patients who undergo globe salvage require frequent examinations to monitor for tumor recurrence. In these patients, examinations under anesthesia are typically performed every 4–8 weeks until age 3 years. Recurrence of retinoblastoma is common and can occur years after treatment.
In patients with germline mutations, periodic MRI of the brain is performed to screen for CNS metastases and PNET, which have poor prognoses. Results of genetic testing can also help determine whether siblings need to be monitored. If genetic testing is not available, siblings should be monitored routinely during the first 2 years of life.
Because of their risk of developing secondary malignancies, patients with germline mutations require long-term follow-up by oncologists and ophthalmologists. Nonocular tumors are common in these patients; the estimated incidence rate is 1% per year of life (eg, 10% prevalence by age 10 years, 30% by age 30 years). The incidence is higher among patients treated with external-beam radiation before 1 year of age. The most common secondary tumors (and the mean age at diagnosis) are PNET (2.7 years), sarcoma (13 years), melanoma (27 years), and carcinomas (29 years). For patients with second nonocular tumors, the risk of additional malignant tumors is even greater.
Correa ZM, Berry JL. Review of retinoblastoma. Pediatric Ophthalmology Education Center. April 28, 2016. Available at https://www.aao.org/disease-review/review-of-retinoblastoma.
Woo KI, Harbour JW. Review of 676 second primary tumors in patients with retinoblastoma: association between age at onset and tumor type. Arch Ophthalmol. 2010;128(7):865–870.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.