Trilateral Retinoblastoma
The term trilateral retinoblastoma is reserved for cases of bilateral retinoblastoma associated with ectopic intracranial retinoblastoma. The ectopic focus is usually located in the pineal gland or the parasellar region and historically has been termed a pinealoblastoma. This tumor affects up to 5% of children with a germline RB1 mutation. Rarely, a child may present with ectopic intracranial retinoblastoma prior to ocular involvement. More commonly, this independent malignancy presents months to years after treatment of the intraocular retinoblastoma.
Several different observations support the concept of primary intracranial pinealoblastoma. CT helped to establish that intracranial tumors in some patients dying from retinoblastoma are anatomically separate from the primary tumors in the orbit. These intracranial tumors are not associated with metastatic disease elsewhere in the body, and, unlike metastatic retinoblastoma, they often demonstrate features of differentiation such as Flexner-Wintersteiner rosettes (see Chapter 11, Fig 11-41). Embryologic, immunologic, and phylogenic evidence of photoreceptor differentiation in the pineal gland offers further support for the concept of trilateral retinoblastoma.
All patients with retinoblastoma should undergo baseline neuroimaging studies to exclude intracranial involvement. Patients with germline RB1 gene mutations (ie, bilateral retinoblastoma, unilateral multifocal retinoblastoma, or unilateral retinoblastoma with a positive family history) should undergo serial imaging of the central nervous system (CNS). Studies suggest that serial MRI with and without contrast is most sensitive for CNS involvement and does not expose the child to radiation. Median survival of patients with retinoblastoma with CNS involvement is approximately 8 months. Recent studies report a decrease in the incidence of trilateral retinoblastoma in patients treated with systemic chemotherapy, suggesting a possible prophylactic effect.
Jubran RF, Erdreich-Epstein A, Butturini A, Murphree AL, Villablanca JG. Approaches to treatment for extraocular retinoblastoma: Children’s Hospital Los Angeles experience. J Pediatr Hematol Oncol. 2004;26(1):31–34.
Shields CL, Meadows AT, Shields JA, Carvalho C, Smith AF. Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch Ophthalmol. 2001;119(9):1269–1272.
Treatment
When retinoblastoma is being treated, it is first and foremost important to understand that it is a malignancy. When the disease is contained within the eye, survival rates exceed 95% in the Western world. However, with extraocular spread, survival rates decrease to under 50%. Therefore, when a treatment strategy is being decided, the first goal must be preservation of life, then preservation of the eye, and, finally, preservation of vision. The modern management of intraocular retinoblastoma currently incorporates a combination of different treatment modalities, including enucleation, chemotherapy, photocoagulation, cryotherapy, external-beam radiation therapy, and plaque brachytherapy. Metastatic disease is managed using intensive chemotherapy, radiation, and bone marrow transplantation. The treatment of children with retinoblastoma requires a team approach, including an ocular oncologist, pediatric ophthalmologist, pediatric oncologist, and radiation oncologist.
Enucleation
Enucleation remains the definitive treatment for retinoblastoma, providing, in most cases, a complete surgical resection of the disease. Typically, enucleation is considered an appropriate intervention when
the tumor involves more than 50% of the globe orbital or optic nerve involvement is suspected anterior segment involvement is present neovascular glaucoma is present
there is limited visual potential in the affected eye
Enucleation techniques are aimed at minimizing the potential for inadvertent globe penetration while obtaining the greatest length of resected optic nerve that is feasible, typically longer than 10 mm. Porous integrated implants, such as hydroxyapatite or porous polyethylene, are currently used by most surgeons.
Attempts at globe-conserving therapy should be undertaken only by ophthalmologists well versed in the management of this rare childhood tumor and in conjunction with similarly experienced pediatric oncologists. Failed attempts at eye salvage may place a child at risk of metastatic disease.
Chemotherapy
A significant advance in the management of bilateral intraocular retinoblastoma in the past 2 decades has been the use of primary systemic chemotherapy. Systemic administration of chemotherapy reduces tumor volume, allowing for subsequent application of consolidative focal therapy with laser, cryotherapy, or radiotherapy (Fig 19-13). These changes have come about as a result of improvements in the treatment of both brain tumors and metastatic retinoblastoma. Current regimens incorporate varying combinations of carboplatin, vincristine, etoposide, and cyclosporine. Children receive drugs intravenously every 3–4 weeks for 4–9 cycles of chemotherapy. Meanwhile, serial EUAs are performed, during which tumor response is observed and focal therapies are administered. Drug regimens, routes of administration, and dose schedules should be determined by a pediatric oncologist experienced in the treatment of children with retinoblastoma.
Figure 19-13 Retinoblastoma. A, Before chemotherapy. B, Reduced tumor volume after 2 cycles of chemotherapy alone.
Local chemotherapy
Subconjunctival carboplatin with and without systemic chemotherapy has been used in the treatment of retinoblastoma. It has been abandoned by many centers because of complications such as orbital myositis, periocular fibrosis, and optic neuropathy. Local chemotherapeutic delivery to the eye with
agents such as melphalan by intravitreal injection and/or selective canalization of the ophthalmic artery has been used in its place with increased success, particularly in eyes with vitreous disease.
Photocoagulation and Hyperthermia
Xenon arc and argon laser (532 nm) have traditionally been used to treat retinoblastomas smaller than 3 mm in apical height with basal dimensions less than 10 mm. Two to 3 rows of encircling retinal photocoagulation destroy the tumor’s blood supply, with ensuing regression. Newer lasers allow for direct confluent treatment of the tumor surface. The diode laser (810 nm) is used to provide hyperthermia. Direct application to the surface increases the tumor’s temperature to the 45°–60° Celsius range and has a direct cytotoxic effect, which can be augmented by both chemotherapy and radiation (Fig 19-14).
Figure 19-14 Retinoblastoma. A, Before treatment. B, Same eye 6 months later, after treatment with chemoreduction and
laser therapy. (Courtesy of Timothy G. Murray, MD.)
Cryotherapy
Also effective for tumors in the size range of less than 10 mm in basal dimension and 3 mm in apical thickness, cryotherapy is applied under direct visualization with a triple freeze–thaw technique. Typically, laser photoablation is chosen for posteriorly located tumors and cryoablation for more anteriorly located tumors. Repetitive tumor treatments are often required for both techniques, along with close follow-up for tumor growth or treatment complications.
External-Beam Radiation Therapy
Retinoblastoma tumors are responsive to radiation. Current techniques use focused megavoltage radiation treatments, often employing lens-sparing techniques, to deliver 4000–4500 cGy over a 4–6- week treatment interval. Typically, those treated are children with bilateral disease not amenable to laser or cryotherapy. Globe salvage rates are excellent, with up to 85% of eyes being retained. Visual function is often excellent and limited only by tumor location or secondary complications.
Two major concerns have limited the application of external-beam radiotherapy using standard techniques:
1. the association of germline mutations of the RB1 gene with a lifelong increase in the risk of