Retinoblastoma

Retinoblastoma, which is the most common intraocular pediatric tumor, typically affects children younger than 4 years. Even though retinoblastoma is considered a congenital type of malignant tumor, it is rarely recognized neonatally. Two forms of retinoblastoma—hereditary and sporadic—are described. These forms differ in their clinical presentation and prognosis.

Hereditary retinoblastoma is usually bilateral and multifocal and clinically presents at an earlier age (mean, 6 months). It is associated with a germline mutation in the tumor suppression RB1 gene, located on chromosome 13q14. In a small percentage of patients with heritable retinoblastoma (3% to 7%), intracranial neuroectodermal pineal or suprasellar tumors, termed trilateral retinoblastoma, will develop. Trilateral tumors usually present months after the initial discovery of the ocular lesions and have an associated dismal prognosis. Patients with hereditary RB1 mutations have increased risk (progressive throughout their lifetime) of the development of other malignancies; such malignancies especially develop in patients who have undergone radiation therapy. Secondary tumors that develop most often include osteogenic and other soft tissue sarcomas, leukemia, and malignant melanoma. Secondary nonocular tumors are the leading cause of death in these patients, rather than the primary retinoblastoma itself.

Sporadic retinoblastoma is usually solitary and unilateral and is associated with spontaneous somatic mutations of the RB1 gene. The average age at presentation varies from 13 to 18 months. Patients with sporadic noninvasive intraocular tumors have an excellent prognosis, with a survival rate approaching 90%.

Approximately two thirds of all retinoblastoma cases are unilateral, and one third are bilateral. Several classification systems have been developed for intraocular retinoblastoma, all of which are based on expected results of therapy and predicted salvage of the globe. The rapid evolution of newer retinoblastoma treatment has resulted in the replacement of the previously widely accepted Reese-Ellsworth classification, which is based on intraocular tumor staging and is used in tumor management after external beam radiation. A new International Classification of Retinoblastoma is based mainly on the natural history of retinoblastoma (early disease [group A] to late disease [group E]) and upon the extent of tumor seeding within the vitreous and subretinal space (Box 7-1). This classification is more applicable for patients treated with chemotherapy.

For purposes of disease prognostication, it is important to assess tumor growth pattern, which is described according to the retinal spread of tumor. Endophytic tumors grow anteriorly into the vitreous, whereas exophytic tumors grow into subretinal space and tend to have earlier choroidal involvement and increased risk of metastatic spread. Optic nerve involvement is a marker for aggressive and advanced tumors and is associated with a high risk of metastatic disease and consequent increased mortality rates. The most uncommon pattern of spread is that of diffuse infiltrative tumor growth within the retina, which is not characterized by the presence of a nodular mass or by intralesional calcifications. This type of retinoblastoma presents at a later age, with the clinical symptoms sometimes mimicking an inflammatory process.

Leukocoria (or white pupillary reflex) is the most common presenting sign of retinoblastoma. For tumors located in the posterior globe, leukocoria may indicate advanced disease because a lesion in the posterior retina must be sufficiently large to produce leukocoria. Strabismus is the second major presenting sign of retinoblastoma. In contrast to leukocoria, tumors presenting with strabismus as their initial sign are associated with a higher survival rate and a higher chance of salvage of the globe. Patients with exophytic tumor growth may present with retinal detachment surrounding the tumor, indicating tumor extension into the subretinal space.

Leukocoria in a young child that is confirmed by an ophthalmoscopic examination requires further evaluation. Imaging may reliably distinguish retinoblastoma from a host of other conditions that also may present with leukocoria (e.g., persistent hyperplastic primary vitreous, Toxascaris infection, Coats disease, and medulloepithelioma). In many retinoblastoma centers, eye ultrasonography has replaced orbital CT for initial disease assessment. Three-dimensional high-frequency ultrasound is sufficient for assessment of tumor and calcifications but is less suitable for the evaluation of extraocular spread. Retinoblastoma is readily visible on ultrasound as an echogenic irregular retinal mass with focal acoustic shadows. CT is an excellent tool for depicting ocular calcifications (Fig. 7-1, A), but its use in retinoblastoma evaluation has markedly decreased because of the associated radiation risks. MRI has become a relatively quick and convenient modality for the evaluation of retinoblastoma. A variety of tailored MR sequences are beneficial in illustrating the different features of these masses. Specifically, intraocular hemorrhages and calcifications are depicted best on gradient sequences, whereas the malignant, markedly cellular nature of these tumors (composed of immature retinoblasts) is confirmed on T2-weighted and DWI sequences (Fig. 7-1, B and C). Contrast-enhanced sequences provide important information that may affect prognosis and treatment options with respect to tumor spread into the optic nerve (Fig. 7-1, D), anterior chamber, or other adjacent orbital structures. In addition, MRI serves as a surveillance examination of the brain when monitoring for possible leptomeningeal spread of tumor or for the presence of retinoblastoma in more remote locations.

Standard treatment for retinoblastoma has evolved in the past several decades from prior methods of surgical enucleation or external radiation. Most retinoblastoma referral centers are now using alternative therapies that are aimed at eye salvage and avoiding the risks inherent with radiation. These methods include systemic chemotherapy (chemoreduction) along with focal treatments (eye-sparing radiotherapy [local plaque radiation], laser photocoagulation, and cryotherapy) as the primary treatment modality, especially when tumors are small. Orbital imaging is therefore an essential step in deciding the appropriate treatment.

Medulloepithelioma

A medulloepithelioma is another pediatric malignant intraocular tumor that may present with leukocoria. This tumor is a rare embryonal type of neoplasm arising from the nonpigmented epithelial lining of the ciliary body. Patients usually are diagnosed in the first decade of life (at a mean age of 6 years); only rarely is medulloepithelioma seen in adults. Many imaging features of medulloepithelioma may closely resemble those of a retinoblastoma, such as presentation with a nodular enhancing intraocular mass, which occasionally will have calcifications (Fig. 7-2). A medulloepithelioma differs from a retinoblastoma mainly by its anterior location, but it may appear identical to a retinoblastoma when it is located in the vicinity of the optic nerve. Medulloepitheliomas have been divided into two types, teratoid and nonteratoid (diktyoma), based on their histologies. More complex teratoid medulloepitheliomas are composed of heteroplastic elements, including cartilage, which may have associated calcifications, whereas the nonteratoid diktyoma presents as a well-defined, noncalcified mass with associated diffuse contrast enhancement.

Hereditary Orbital Hamartomatosis

Many neurocutaneous disorders (phakomatoses) may have typical ocular masses that may or may not be visible with modern imaging techniques. These lesions represent hereditary hamartomas, which are composed of tissues with limited capacity for proliferation. Examples of these entities may be seen in the settings of tuberous sclerosis, neurofibromatosis (NF), and von Hippel-Lindau disease.

Ocular manifestations of tuberous sclerosis include astrocytic hamartomas of the retina and optic disk. These lesions have a typical appearance on ophthalmologic examination; however, they may calcify as the patient ages and may in fact resemble drusen when located on the optic disk. On thin-section high-resolution T2-weighted imaging, hamartomas of tuberous sclerosis are visible as small hypointense nodules within the posterior globe (e-Fig. 7-3).

Ocular stigmata of NF may present as neuronal hamartomas of the iris, called Lisch nodules, which only occur with NF type 1. Lisch nodules can only rarely be visualized with imaging.

Persons with Sturge-Weber syndrome and von Hippel-Lindau disease may have ocular vascular lesions. Choroidal vascular lesions in persons with Sturge-Weber syndrome may be diffuse or localized and can simulate melanoma on ophthalmoscopic examination, but they may be differentiated from one another on MRI examination. Choroidal vascular lesions demonstrate a typical hyperintense signal on T1-weighted and T2-weighted sequences, which is opposite to the signal characteristics expected with melanoma (a bright T1-weighted signal and a hypointense T2-weighted signal). Ocular manifestations of von Hippel-Lindau disease consist of retinal angiomatosis, which may cause severe complications, including retinal detachment and ocular destruction, and usually present later in childhood or in early adulthood (in the second and third decades of life).

Drusen

Disc drusen are nonhamartomatous subretinal lesions without astrocytic hyperplasia that are associated with the presence of intrapapillary, partially calcified hyaline bodies that form concretions of unknown nature. Drusen likely are the most common etiology for congenital bilateral elevation of the optic nerve discs. Drusen may be detected on funduscopic evaluation or may be seen as an incidental finding on imaging. In both scenarios, it is important to establish the benign nature of disk elevation so as not to confuse drusen (which cause pseudopapilledema) with true papilledema. Equivocal results of ophthalmoscopic examination may lead to orbital imaging, which will either confirm the presence of disc drusen or detect the source of the increased intracranial pressure. Drusen may be diagnosed with use of ultrasound, appearing as foci of increased echogenicity, or drusen can be seen on noncontrast CT most often as bilateral punctuate calcifications within the optic nerve heads (e-Fig. 7-4). MRI demonstrates isolated mild protrusion of the optic discs into the vitreous without perioptic cerebrospinal fluid space enlargement or other imaging features of papilledema. Clinically, drusen are usually asymptomatic and only rarely may be associated with slowly progressive visual loss.