Chapter 14

Multidisciplinary Management

of Retinoblastoma: Diagnosis, Treatment,

and Future Direction

Maurizio L. Ghisoli, Peter E. Zage, Cindy Herzog, Patty Chevez-Barrios, Murali Chintagumpala, Richard L. Hurwitz, Anita Mahajan,

and Dan S. Gombos

Abstract Retinoblastoma is a relatively uncommon tumor of childhood that arises from the retina and accounts for about 3% of the cancers occurring in children younger than 15 years. The treatment of retinoblastoma is complex and requires a multidisciplinary team that includes pediatric oncologists, ophthalmologists, ocular pathologists, geneticists, and radiation oncologists, all of whom have expertise in retinoblastoma management. This chapter includes a brief discussion of the presentation, classification, and pathologic features of the disease. Available treatment options are also discussed, including enucleation, chemoreduction, systemic or local chemotherapy, focal therapy with cryotherapy, laser photocoagulation, or plaque brachytherapy, and external-beam radiation therapy.

14.1 Historical Perspective

Retinoblastoma is a relatively uncommon tumor of childhood that arises from the retina and accounts for about 3% of the cancers occurring in children younger than 15 years. The estimated annual incidence in the United States is approximately 10–14 cases per 1 million children between birth and 4 years. Although retinoblastoma may occur at any age, it most often occurs in young children, usually before 2 years, and 95% of cases are diagnosed before 5 years. Retinoblastoma occurs in heritable (40%) and nonheritable (60%) forms. It is usually confined to the eye and, as a result, has a cure rate in the United States approaching 98–99%. The present challenge for those who treat retinoblastoma is to help the patient avoid loss of an eye, blindness, and other late effects of treatment, including secondary nonocular tumors.

The treatment of retinoblastoma is complex and requires a multidisciplinary team that includes pediatric oncologists, geneticists, ocular pathologist, ophthalmologists,

M.L. Ghisoli (B)

Department of Hematology and Oncology, Medical City Children’s Hospital, Texas Oncology, Dallas, TX, USA

e-mail: maurizio.ghisoli@usoncology.com

Oncology Series 6, DOI 10.1007/978-1-4419-0374-7_14,

C Springer Science+Business Media, LLC 2011

The majority of retinoblastoma foci harbor calcium, which can be easily confirmed on ultrasonography and/or computed tomography. Increasingly, however, many specialty centers prefer magnetic resonance imaging over computed tomography because of magnetic resonance imaging’s superiority in visualizing the orbital portion of the optic nerve and pineal region. Ret Cam (Clarity Medical Systems, Pleasanton, CA) imaging allows digital photographs to be taken of the ocular fundus and has become the standard of care in baseline and follow-up intraocular tumor imaging. Historically, lumbar puncture and bone marrow biopsies were performed routinely in all patients. Today, this is limited to those at increased risk for developing extraocular disease.

14.3 Classification

Since the 1960s, the most common classification system used to describe intraocular retinoblastoma has been the Reese–Ellsworth (R–E) system, developed by Algernon Reese and Robert Ellsworth [1]. This system was initially designed to predict prognosis in patients treated with EBRT and, therefore, is a classification (or grouping) system rather than a true staging system. The R–E system has been used consistently to compare outcomes of different treatment modalities and classifies eye tumors into five groups (Table 14.1).

Because current treatment strategies more commonly consist of primary chemotherapy combined with focal treatment, a new classification system was developed by Dr. Linn Murphree [2]. The international classification for intraocular retinoblastoma (also called the ABC system) [2] incorporates the natural history of the disease and better predicts outcomes of current treatments, including systemic

chemotherapy [3]. It consists of five groups (A–E), with specific criteria for determination of tumor volume and dissemination to the subretinal and vitreous portions of the globe (Table 14.2). It is the preferred classification for ongoing Children’s Oncology Group (COG) trials (see Section 14.8).

Table 14.2 International classification for intraocular retinoblastoma, ABC system

14.4 Genetics

Retinoblastoma tumors are characterized as having biallelic inactivation of the retinoblastoma gene on chromosome 13q14 [4]. The protein encoded by the retinoblastoma gene (pRB) prevents activation of the genes necessary for DNA replication and cell division [5]. Absent or deficient pRB allows cells to replicate continuously. In about 40% of patients, the mutation that occurs in the first allele is a germline mutation; 30% of these cases are de novo, and 10% are inherited from a parent. In the remaining 60% of patients, the mutation in the first allele occurs in a retinal precursor cell. The second allele then also mutates in the retina [4, 6]. The presence of multiple tumors in both eyes of young patients (less than 1 year old) who have the germline mutation contrasts with single retinal tumors observed in older patients, which can be explained by this “two-hit” theory [4–7].

Patients with hereditary retinoblastoma are at increased risk for second nonocular tumors [8, 9]. Thus, detection of the retinoblastoma gene mutation in both the leukocytes and tumor cells of a patient with unilateral retinoblastoma confirms the presence of a germline mutation. This information is especially useful in those patients with unilateral retinoblastoma who have no family history of the disease but are at risk for developing additional retinoblastoma foci and need frequent follow-up eye examinations, enabling early diagnosis of new tumors; this