Tumors

Choroidal and Retinal Pigment Epithelial Lesions

A pigmented fundus lesion in a child is usually benign. Flat choroidal nevi are common and are not a cause for concern. Malignant melanoma of the choroid is extremely rare in children. Choroidal osteoma is a benign bony tumor of the uveal tract that may occur in childhood, usually presenting with decreased vision. Diffuse hemangioma of the choroid associated with Sturge-Weber syndrome is discussed in Chapter 28. Patients with neurofibromatosis 1 often have flat, tan-colored spots in the choroid (see Chapter 28).

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a sharply demarcated, flat, hyperpigmented lesion that may be isolated or multifocal (Fig 25-17). Such lesions are sometimes grouped, in which case they are also known as bear tracks.

Figure 25-17 Congenital hypertrophy of the retinal pigment epithelium (CHRPE). Examples of varying clinical appearances. A, Small CHRPE. B, Medium-sized CHRPE; note the homogeneous black color and well-defined margins of this nummular lesion. C, Color fundus photograph. D, Corresponding fluorescein angiogram of a large CHRPE. Note the loss of retinal pigment epithelium architecture and highlighted choroidal vasculature. (Parts A, C, and D courtesy of Timothy G. Murray, MD.)

Pigmented lesions similar to CHRPE have been associated with Gardner syndrome. Gardner syndrome is autosomal dominant and is caused by a mutation in the APC gene located on 5q21. Patients with Gardner syndrome have many polyps of the colon and are at very high risk for adenocarcinoma of the colon in early adulthood. They may also have skeletal hamartomas and various other soft-tissue tumors. The pigmented retinal lesions associated with Gardner syndrome are different from CHRPE in that they have a surrounding halo and tail of depigmentation that is oriented

radially and directed toward the optic nerve. The presence of 4 or more pigmented retinal lesions not restricted to 1 sector of the fundus or bilateral involvement should raise suspicion of Gardner syndrome.

Combined hamartoma of the retina and retinal pigment epithelium is an ill-defined, elevated, variably pigmented tumor that may be juxtapapillary or located in the retinal periphery. The tumor is often minimally elevated and has retinal traction and tortuous retinal vessels. In peripheral tumors, dragging of the retinal vessels is a prominent feature. The tumors have a variable composition of glial tissue and RPE. This condition can be associated with neurofibromatosis types 1 and 2, incontinentia pigmenti, X-linked retinoschisis, and facial hemangiomas.

Retinoblastoma

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. Retinoblastoma is typically diagnosed during the first year of life in familial and bilateral cases and between ages 1 and 3 years in sporadic unilateral cases. Approximately 90% of cases are diagnosed before 3 years of age; onset later than age 5 is rare but can occur. The most common initial sign is leukocoria (white pupil), which is usually first noticed by the family and described as a glow, glint, or cat’s-eye appearance (Fig 25-18). The differential diagnosis of leukocoria is shown in Table 25-6. 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.

Figure 25-18 Leukocoria of the right eye, which is visible in this family photograph of a 1-year-old girl with retinoblastoma.

(Courtesy of A. Linn Murphree, MD.)

Table 25-6

Diagnosis

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 25-19). 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 25-20. 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.

Figure 25-19 Wide-angle fundus photograph showing multiple endophytic retinoblastoma lesions, left eye. (Courtesy of A. Linn

Murphree, MD.)

Figure 25-20 Endophytic retinoblastoma with vitreous seeding.

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 25-21). 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.

Figure 25-21 Exophytic retinoblastoma with overlying detached retina.

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.

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 neurocutaneous syndromes (see Chapter 28).

Evaluation of a patient with presumed retinoblastoma requires imaging of the head and orbits, which can confirm the diagnosis and evaluate for extraocular extension and intracranial disease. In the past, computed tomography (CT) was used to facilitate the diagnosis by demonstrating intraocular calcification. However, CT is no longer recommended by the European Retinoblastoma Imaging Collaboration because of the increased risk of secondary tumors in many patients being evaluated for retinoblastoma. Magnetic resonance imaging and ultrasonography, which avoid the use of radiation, are recommended. Other, 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.

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.

Genetics 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 one 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 25-7). 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).

Table 25-7

Genetic testing for retinoblastoma is important to aid in 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 detection of 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 successfully used to select embryos that are free from the germinal RB1 mutation.

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.

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 Reese-Ellsworth classification (Table 25-8) was originally developed to predict globe salvage after external-beam radiation. Although it is still useful for comparing contemporary treatment modalities with older ones, the International Classification of Retinoblastoma (Table 25-9) is more useful for predicting the response to chemotherapy. 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

Table 25-9

Treatment

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 recommended 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 25-22) and is often used in cases of bilateral retinoblastoma. Most studies of chemoreduction for retinoblastoma have employed 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.

Figure 25-22 A, Left eye of 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 of chemotherapy have been used as an adjuvant to other treatments.

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