Chapter 146 – Retinoblastoma
JAMES J. AUGSBURGER
MICHAEL E. GIBLIN
• Primary malignant neoplasm of the retina that arises from immature retinal cells.
• Affects infants and children.
• Leukokoria in one or both eyes.
• White retinal tumor fed and drained by dilated, tortuous retinal blood vessels.
• Well-established tendency to invade optic nerve and choroid, extend extrasclerally, invade the brain, and metastasize.
• Unilateral (60–70%) or bilateral (30–40%) ocular involvement; most unilateral cases are unifocal, and most bilateral cases are multifocal in both eyes.
• Germinal (heritable, 40%) and somatic (nonheritable, 60%) forms.
• Autosomal dominant inheritance pattern in germinal cases.
• Attributable to loss or inactivation of both alleles of retinoblastoma gene, a tumor suppressor gene on the long arm of chromosome 13.
• Seeding of viable tumor cells into vitreous or subretinal space.
• Neovascular glaucoma in infancy or childhood.
• Nonrhegmatogenous retinal detachment.
• Intralesional calcification detectable by ultrasonography and computed tomography in most cases.
• Second (nonretinoblastoma) malignancy in substantial proportion of survivors of germinal disease.
Retinoblastoma is a primary malignant intraocular neoplasm that arises from immature retinoblasts within the developing retina. It is the most common primary intraocular malignancy of childhood in all racial groups. The neoplasm has strong tendencies to invade the brain via the optic nerve and to metastasize widely. Untreated children typically die of their disease within 2–4 years of the onset of symptoms.
EPIDEMIOLOGY AND PATHOGENESIS
Retinoblastoma has a cumulative lifetime incidence of approximately 1 in 15,000 individuals. Its annual incidence is highest in the first few months of life; thereafter, the yearly incidence decreases steadily and is extremely low by 6 years of age. In spite of its early onset in most children, retinoblastoma is rarely diagnosed congenitally or even within the first 3 months of life, except in familial cases. The median age at the time of diagnosis is approximately 12 months in children who have bilateral retinoblastoma and 24 months in those who suffer unilateral disease ( Fig. 146-1 ). Retinoblastoma affects boys and girls with equal frequency and has no known racial predilection.
Figure 146-1 Cumulative frequency of retinoblastoma diagnosis. Frequency is shown as a function of age at diagnosis in subgroups of unilateral versus bilateral disease. The data from which these curves are derived come from the private practice of James J. Augsburger, M.D.
Approximately 60–70% of retinoblastoma cases are unilateral, and the remaining 30–40% are bilateral. In unilateral cases, only a single tumor is usually present in the affected eye. In bilateral cases, multifocal tumors in both eyes are the rule. Retinoblastoma is generally a sporadic condition (i.e., no previously affected family members exist). Most children who have the sporadic form of retinoblastoma are affected unilaterally. A small number of patients have a prior family history of retinoblastoma, in which case one of the parents is probably a survivor of the disease. In hereditary cases, the affected child usually, but not always, has multiple tumors in both eyes. Transmission of the disease in such families follows genetic rules of autosomal dominant inheritance. 
Retinoblastoma appears to result from loss or inactivation of both normal alleles of the retinoblastoma gene, a DNA sequence localized to a small segment of the long arm (the q14 region) of chromosome 13 (see Chapter 1 ). The timing of the loss or inactivation of the two normal alleles determines whether the disease is germinal (i.e., can be inherited by the offspring of an affected person) or somatic (i.e., cannot be inherited by the offspring of an affected person). In germinal retinoblastoma, at least one normal allele must be lost or inactivated prior to the first mitotic division of embryogenesis. This circumstance arises if the sperm or the egg contains defective DNA from an affected or carrier parent or develops that defect by means of spontaneous mutation prior to fertilization. In somatic retinoblastoma, both alleles are present and active beyond the stage of the fertilized egg, but one or more subsequent spontaneous mutations occur to delete or inactivate both alleles in at least one immature retinal cell (retinoblast).
Figure 146-2 Hereditary probabilities in retinoblastoma.
The majority of cases of retinoblastoma are sporadic (i.e., diagnosed in patients who have no family history of retinoblastoma and no affected family members on comprehensive familial ophthalmic examination). The hereditary probabilities in a newly diagnosed child who has retinoblastoma are shown in Fig. 146-2 .
The most common presenting manifestation of retinoblastoma is a white glow in the pupil (leukokoria) ( Fig. 146-3 ). This appearance is caused by reflection of light from the white intraocular tumor. Depending on the intraocular extent of the tumor and its laterality, one or both eyes may exhibit this appearance. The second most common presenting manifestation is strabismus, which may be either esotropia or exotropia. Because of the association between retinoblastoma and strabismus, every child who has strabismus must undergo a complete ophthalmic examination to rule out retinoblastoma (as well as other potentially treatable ocular diseases). Presenting manifestations of retinoblastoma encountered less frequently include a red eye, excessive tearing, globe expansion (buphthalmos) and corneal clouding that result from elevated intraocular pressure, discoloration of the iris in the involved eye (usually caused by neovascularization of the iris), loss of the fundus reflection in the affected eye due to intraocular bleeding from the tumor, clumping or layering of white tumor cells on the iris or in the aqueous humor, spontaneous hyphema, and orbital cellulitis.
Although slit-lamp biomicroscopy of young children is frequently quite difficult, every effort should be made to perform this examination in the office at the time of initial patient assessment. This examination allows one to assess the anterior chamber and iris for evidence of tumor cells and iris neovascularization and to evaluate the clarity of the lens and retrolental vitreous. In almost all children with retinoblastoma, even those who have advanced intraocular tumor that fills most of the globe, the lens is completely clear. Slit-lamp biomicroscopy may also disclose finely dispersed cells or tumor cell clumps (seeds) in the vitreous.
Using indirect ophthalmoscopy, the extent of the intraocular tumor, the presence and extent of retinal detachment, and the presence and extent of intravitreal or subretinal tumor seeds can be determined. In eyes that have less advanced disease, well-defined individual tumors may be identified, often in association with dilated, tortuous retinal blood vessels ( Fig. 146-4 ).
Figure 146-3 Bilateral leukokoria as a result of retinoblastoma. Note the white pupillary reflection in each eye.
Figure 146-4 Typical appearance of intraretinal retinoblastoma. Opaque, yellow-white macular tumor fed and drained by dilated, tortuous retinal blood vessels.
Small tumors along the ora serrata and finely dispersed vitreous cells may also be detected during such an examination. In infants and cooperative older children, indirect ophthalmoscopy with scleral depression can be performed in the office; however, in toddlers and uncooperative older children, this examination almost always requires anesthesia.
Discrete intraretinal tumors appear as white, round to oval, dome-shaped retinal masses (see Fig. 146-4 ). Even relatively small tumors tend to attract retinal blood vessels, which ramify prominently on the surface of the lesion. Very small tumors sometimes appear as translucent, insubstantial thickenings of the retina. Examination of the fundus using a green filter (red-free light) often accentuates such subtle lesions. Larger tumors are frequently associated with a nonrhegmatogenous retinal detachment, which may become bullous and involve the entire retina. This tends to occur with tumors that grow from the retina toward the retinal pigment epithelium and choroid (exophytic growth pattern). In other cases, finely dispersed tumor cells or cell clumps accumulate in the gelatinous vitreous that overlies tumors growing from the retina toward the vitreous (endophytic growth pattern). Many tumors exhibit elements of both endophytic and exophytic growth. A small proportion of eyes with retinoblastoma exhibit generalized thickening of the retina by the tumor, a growth pattern referred to as diffuse infiltrating retinoblastoma. This form of retinoblastoma is commonly associated with diffuse vitreous seeding and is sometimes associated with extension of tumor cells into the anterior chamber aqueous.
Occasionally, a retinoblastoma stops growing spontaneously and loses its malignant character. Such a tumor is called a retinoma. Tumors of this type tend to appear virtually identical to regressed retinoblastoma lesions following successful radiation
Figure 146-5 Retinoma (spontaneously arrested retinoblastoma).
therapy ( Fig. 146-5 ). In other cases, massive intraocular retinoblastomas occasionally undergo spontaneous necrosis, which results in phthisis bulbi.
DIAGNOSIS AND ANCILLARY TESTING
Ultrasonography frequently provides helpful differential diagnostic information in cases of suspected retinoblastoma. Most relatively large tumors (>10–15?mm in diameter) contain multiple foci of intralesional calcification. B-scan ultrasonography of such a tumor shows the lesion to be strongly sonoreflective because of the intralesional calcification ( Fig. 146-6 ). In addition, the calcific mass shadows the sclera and orbital soft tissues posteriorly. When the examiner reduces the gain of the instrument, the reflections from the calcific particles within the tumor persist. Standardized A-scan ultrasonography typically shows multiple highly reflective intralesional foci.
Computed tomography (CT) helps confirm the diagnosis, especially in cases of tumor-filled eyes in which there is uncertainty whether the leukokoria results from retinoblastoma or a simulating disorder such as Coats’ disease.  Because retinoblastoma tumors are characteristically calcified, they usually show up brightly on CT images ( Fig. 146-7 ). However, intralesional calcification is not always present in retinoblastoma. Particularly important in this category are children who suffer diffuse infiltrating retinoblastoma.  Children with this clinical form of retinoblastoma characteristically develop tumors multicentrically within the retina and exhibit extensive seeding into the vitreous but no associated intratumoral calcification.
Magnetic resonance imaging (MRI) is the most useful and informative tool for evaluating the sellar and parasellar regions of the brain (to rule out ectopic intracranial retinoblastoma) and for studying the orbital optic nerve. At the same time, however, MRI appears to be less valuable than CT in assessing the intraocular tumor because it does not show the intralesional calcification characteristic of this malignancy.
Fluorescein angiography is usually not performed as a diagnostic aid in suspected retinoblastoma. If this technique is performed on a discrete intraretinal retinoblastoma, the angiogram shows rapid filling of the feeder artery, prompt filling of the intralesional vasculature, and rapid draining via the efferent vein. The intralesional capillaries tend to leak fluorescein, so the tumor characteristically stains brightly in the late frames.
The differential diagnosis of retinoblastoma is given in Box 146-1 . Coats’ disease is the disorder most frequently mistaken for retinoblastoma.
Figure 146-6 B-scan ultrasonography of retinoblastoma. Solid, posterior intraocular mass contains strong particulate reflections attributable to intralesional calcification.
Figure 146-7 Computed tomography of bilateral intraocular retinoblastoma. Intraocular masses appear bright because of intralesional calcification.
Differential Diagnosis of Retinoblastoma
DIFFERENTIAL DIAGNOSIS OF LEUKOKORIA
Persistent hyperplastic primary vitreous
Cicatricial retinopathy of prematurity
Familial exudative vitreoretinopathy
Incontinentia pigmenti retinopathy
DIFFERENTIAL DIAGNOSIS OF VITREOUS SEEDS
Pars planitis (intermediate uveitis)
Microbial endophthalmitis or retinitis
DIFFERENTIAL DIAGNOSIS OF DISCRETE RETINAL TUMORS
Astrocytoma of retina
Retinal capillary hemangioma
Focal patches of myelinated retinal nerve fibers
Children who have germinal retinoblastoma have a strong tendency to develop nonretinoblastoma malignancies.     Around the time of diagnosis of the intraocular disease, a primary nonretinoblastoma intracranial malignancy (which is usually categorized histopathologically as either a pineoblastoma or an ectopic intracranial retinoblastoma) is the most common neoplasm encountered. Presenting features of such a tumor include somnolence, headache, and other neurological symptoms. Central nervous system imaging studies show a solid tumor that involves the suprasellar or parasellar regions of the brain. Ophthalmoscopy frequently reveals papilledema. Because this type of tumor usually occurs in children who have germinal retinoblastoma and bilateral disease, this association is commonly referred to as trilateral retinoblastoma.  The intracranial malignancy has a strong tendency to seed the cerebrospinal fluid and thereby spawn implantation tumors along the spinal cord. This malignancy is usually fatal.  Later in life, various sarcomas of bone and soft tissues represent the most frequent nonretinoblastoma malignancies in these patients.  Oculo-orbital external beam radiation therapy for retinoblastoma prior to the age of 1 year appears to substantially increase the likelihood that such tumors will occur in the field of treatment later in life,  but they may also occur in tissues far removed from and unrelated to the radiation.
Some children who develop retinoblastoma have a syndrome of multiple congenital anomalies attributed to a major deletion in the long arm of chromosome 13 (13q deletion syndrome). In such cases, the deletion is usually demonstrable by karyotype analysis. All infants who have 13q deletion syndrome should be screened ophthalmoscopically for retinoblastoma.
Baseline Systemic Evaluation
The standard baseline clinical evaluation of children who have newly diagnosed retinoblastoma includes all the studies shown in Box 146-2 . However, most children who have newly diagnosed retinoblastoma evaluated in the United States and other economically advanced countries have no clinical evidence of extraocular or metastatic disease at baseline examination. In such children, the yield of positive findings from bone marrow aspiration or biopsy, lumbar puncture, and bone scan is low. Consequently, these ancillary studies are generally not recommended, except for children who have advanced intraocular disease or clinical evidence of extraocular tumor extension at baseline.
Genetic testing should be considered for all children who have bilateral or familial retinoblastoma. Modern molecular biology techniques enable investigators to determine the precise genetic defect in a given individual or family and to assess the risk that a particular individual may transmit the disease to offspring. Children with germinal retinoblastoma and unaffected carriers of the disease must be advised of their potential to transmit the disease when they reach reproductive age.
Baseline Systemic Evaluation in Retinoblastoma
Complete pediatric history and physical examination
Blood for complete blood count (CBC)
MRI or CT of brain, especially in bilateral or familial cases to look for ectopic intracranial retinoblastoma
Lumbar puncture for cerebrospinal fluid analysis**
Bone marrow aspiration or biopsy**
*Currently advocated only for children with advanced intraocular disease or clinically extraocular disease at baseline.
Retinoblastoma is characterized histopathologically by malignant neuroepithelial cells (retinoblasts) that arise within the immature retina. The retinoblasts typically appear to have a large basophilic nucleus and scanty cytoplasm. Cellular necrosis and intralesional calcification are frequent associations, especially in larger tumors. In some cases, tissue differentiation occurs, often producing Flexner-Wintersteiner rosettes ( Fig. 146-8 , A) or Homer Wright rosettes ( Fig. 146-8 , B). In occasional cases, photoreceptor differentiation of individual retinoblasts (fleurettes) may also be observed ( Fig. 146-8 , C). Retinoblastoma has a strong tendency to invade the optic nerve and choroid and extend out of the globe via either the optic nerve or the scleral emissary canals.
Histopathological studies of eyes that contain clinical retinomas show such tumors to be composed entirely of benign-appearing neuronal cells with photoreceptor differentiation, most notably in the form of fleurettes. Necrosis and mitotic activity
Figure 146-8 Histopathology of retinoblastoma. A, Flexner-Wintersteiner rosettes. B, Homer Wright rosettes. C, Fleurettes.
are absent, but limited amounts of calcification are present in some of these lesions. The histopathological term applied to such tumors is retinocytoma.
Currently employed treatment options for retinoblastoma are listed in Box 146-3 . Factors that influence the management recommendations for children who have retinoblastoma include the size of the tumor or tumors, the location of the tumors, the laterality of the disease, the vision or visual potential in the affected eye, and the vision or visual potential in the unaffected eye (assuming the disease is unilateral). Any associated ocular problems such as retinal detachment, vitreous hemorrhage, neovascularization of the iris, and secondary glaucoma are also taken into account. Finally, the age and general health of the child must be considered, as well as personal preferences of the child’s parents or legal guardians.
Chemotherapy is currently the primary therapeutic option in children with bilateral retinoblastoma.  It is also employed as initial treatment in some children with unilateral disease when the affected eye is believed to be salvageable. The most common chemotherapeutic regimen in use around the world today consists of a combination of carboplatin, etoposide or a related drug, and vincristine. In some centers, cyclosporine is added to this regimen to reduce the multidrug resistance that occurs in many retinoblastomas. Chemotherapy must be supervised by a pediatric oncologist who is familiar with the side effects and complications of the drugs and can monitor the child closely during treatment. If chemotherapy is employed, it is given as a cyclic treatment every 3 to 4 weeks for six or more cycles. Most intraocular retinoblastoma lesions (including vitreous seeds) regress substantially within the first two cycles ( Fig. 146-9 ). Partially regressed tumors that are still viable following the second cycle of chemotherapy and any new tumors that develop during the course of chemotherapy must be treated by local therapies such as cryotherapy, laser therapy, and episcleral plaque radiation therapy    (see later for details). Residual or recurrent vitreous seeds following chemotherapy usually require external beam radiation therapy  if the eye is to be salvaged.
Chemotherapy is also used to treat children with extraocular tumor extension at presentation or detected on histopathological study of an enucleated eye, orbital tumor recurrence after enucleation, intracranial invasion by tumor, and metastatic disease. Unfortunately, most children who develop metastatic or intracranial retinoblastoma ultimately die of this disease. 
In spite of the current popularity of chemotherapy as the primary treatment for retinoblastoma, enucleation remains an important therapeutic option for this disease. This treatment is particularly
Treatment Options for Intraocular Retinoblastoma
• External beam radiation therapy
• Plaque radiotherapy
Photocoagulation and laser therapy
Observation (for spontaneously arrested retinoblastoma, retinoma)
applicable to children who have unilateral advanced intraocular disease. Enucleation is sometimes recommended for both eyes in children who have bilateral far-advanced disease not amenable to any eye-preserving therapy and for the more severely affected eye in markedly asymmetrical bilateral cases. If enucleation is performed, the ophthalmic surgeon must attempt to obtain a long section of optic nerve during surgery. The principal route of exit of tumor cells from the eye is along the optic nerve. Prior pathological studies have shown that enucleation is usually curative in retinoblastoma if an optic nerve section longer than 5?mm is obtained with the globe. If possible, the ophthalmic surgeon should attempt to obtain an optic nerve section 10–15?mm long in every case.
Contrary to some popular recommendations, insertion of an orbital implant at the time of enucleation appears to be appropriate except when there is a strong likelihood of residual tumor in the orbit. The cosmetic results of enucleation are generally quite satisfactory as long as the child does not also undergo orbital radiation therapy.
External Beam Radiation Therapy
Prior to the development of effective chemotherapy for retinoblastoma, the most commonly employed regional eye-preserving therapy for this disease was external beam radiation therapy. This treatment is usually performed using a linear accelerator in
Figure 146-9 Chemotherapy for retinoblastoma. A, Pretreatment appearance of macular retinoblastoma. B, Same lesion after two cycles of chemotherapy using vincristine, etoposide, and carboplatin.
Figure 146-10 External beam radiation therapy for retinoblastoma. A, Pretreatment appearance of macular retinoblastoma. B, Regressed lesion 2 months after external beam radiation therapy.
a hospital radiation therapy department. Various radiotherapeutic setups for treatment of the whole eye have been devised, but the pros and cons of the different techniques are beyond the scope of this chapter. Standard target doses of radiation to the eye and orbit are in the range of 40–50?Gy given in multiple fractions of 150–200?cGy over 4–5 weeks.
External beam radiation therapy results in highly effective regression of vascularized retinal tumors ( Fig. 146-10 ). Even very large, cohesive retinoblastomas commonly show pronounced clinical regression within several weeks after treatment. Two main patterns of postirradiation tumor regression have been identified. In the first pattern (type I), the tumor regresses to an almost exclusively calcific, avascular residual mound. In the second pattern (type II), the tumor regresses without prominent calcification but with a gray-tan fish-flesh appearance. The dilated retinal vessels usually become markedly attenuated with both regression patterns. In type III regression, a combination of both regression patterns occurs ( Fig. 146-10 , B).
External beam radiation therapy is applicable to eyes containing one or more tumors that involve the optic disc, eyes that show diffuse vitreous seeding, and eyes for which prior chemotherapy or local treatments, such as photocoagulation, laser therapy, cryotherapy, or plaque radiotherapy, failed. Vitreous seeds generally do not respond well to radiation therapy, presumably because of their relatively hypoxic status. As also might be expected, the larger the intraocular tumor, the less predictable the successful local response to treatment.
If the whole eye is treated by external beam radiation therapy, a radiation-related cataract is likely to result. Such a cataract typically begins as posterior subcapsular clouding. In some children, the cataract remains limited and stable in extent after development. In other children, it becomes progressively more pronounced and gradually obscures details of the fundus and worsens vision. In such situations, cataract extraction is usually required.  Fortunately, the cataract usually does not form for at least 6 months after radiation therapy and is often delayed for as much as 1–1.5 years after treatment. At the radiation levels mentioned earlier, other significant intraocular complications such as radiation retinopathy and neovascular glaucoma are extremely uncommon. External beam radiation therapy also causes orbital bone growth arrest, which results in a cosmetic facial deformity in many children who have retinoblastoma. This complication is most pronounced in children who undergo treatment prior to the age of 1 year. Fortunately, the resultant deformities associated with current radiation doses and instrumentation are generally not as severe as those associated with higher doses of radiation therapy and electron beam therapy used in the past. External beam radiation therapy also increases the risk of nonretinoblastoma malignancies in the field of treatment in survivors of germinal retinoblastoma  (see Course and Outcome section later). This effect also appears most pronounced in children irradiated before the age of 1 year. Because of this, most ocular oncologists currently recommend delaying external beam radiation therapy until the child is 1 year old if possible.
Plaque Radiation Therapy
In some children who have relatively large but localized retinoblastomas, even in the presence of limited localized vitreous seeding, plaque radiation therapy may be employed successfully. The principal isotopes used in radioactive eye plaques at present are iodine-125 and ruthenium-106. When such plaques are used to treat retinoblastoma, a target dose of 40–45?Gy to the tumor apex is generally employed. As a result of the physical dose-distribution considerations of the plaques, the base of the tumor always receives a substantially higher dose than the apex. In contrast, the orbital tissues receive only a small fraction of the radiation dose because a metallic layer on the outer surface of the plaque effectively shields the emissions in that direction. Plaque radiation therapy typically produces prompt regression of treated tumors ( Fig. 146-11 ). This form of therapy seems particularly applicable to eyes that contain a solitary medium to large tumor that does not involve the optic disc or macula and is associated with no more than a limited amount of adjacent vitreous seeding. It may also be used in eyes for which prior local therapy, such as photocoagulation, laser therapy, or cryotherapy, failed, as well as in some eyes that failed prior external beam radiation therapy locally.
Photocoagulation has been used for a number of years to treat eyes that contain one or a few small tumors, clear optical media, and no vitreous seeds. Such treatments are generally not advocated for tumors that involve the optic disc or macula. Tumors most amenable to this form of therapy are quite small, usually less than 7?mm in basal diameter and 2–3?mm thick, and posterior to the ocular equator. Until recently, xenon arc photocoagulation was the modality employed in almost all retinoblastoma management. The technique consisted of the creation of intense burns that overlapped in a complete circle around the base of the tumor. These burns were intended to block the tumor’s retinal vascular supply. The treatment had to be repeated every 3–4 weeks until all that remained was an atrophic chorioretinal lesion. Unless the entire tumor was so small that it could be totally encompassed in a single photocoagulation burn, treatment was usually not directed at the tumor itself, in case the internal limiting membrane ruptured and released viable tumor cells
Figure 146-11 Plaque radiation therapy for retinoblastoma. A, Pretreatment appearance of macular retinoblastoma. B, Regressed lesion 6 weeks following iodine-125 notched plaque radiotherapy.
into the overlying vitreous. Photocoagulation can also be performed using various lasers (see the next section).
Since the advent of laser systems that can deliver the treatment beam via an indirect ophthalmoscope or operating microscope, many small to medium retinoblastoma tumors that would have been difficult or impossible to treat effectively using xenon arc photocoagulator can now be treated using laser therapy. Initially, laser therapy was performed using a technique similar to that described for the xenon arc photocoagulator. Later, some clinicians found that they could create an effective, intense confluent burn (as opposed to the overlapping burns of xenon arc photocoagulation) two to three spot diameters wide around the tumor base by using continuous or long-duration exposures. More recently, low-power, long-duration, long-wavelength laser therapy (commonly referred to as transpupillary thermotherapy) has gained popularity as a treatment for selected retinoblastomas. In this therapy, a diode laser (wavelength in the infrared range) is focused on the tumor using a slit lamp, operating microscope, or indirect ophthalmoscope. Large spot sizes (generally 2–3?mm in diameter) are used if the pupil can be dilated widely. Individual exposures of at least 60 seconds are employed at sufficiently low power settings to produce a dull white discoloration of the tumor during treatment. The entire lesion is treated with a series of overlapping spots. The effectiveness of laser therapy is usually checked within 2–4 weeks, and treatment is repeated if necessary until the entire tumor is gone.
Trans-scleral cryotherapy under indirect ophthalmoscopic visualization may be used to treat one to a few equatorial or pre-equatorial retinoblastoma tumors of small to medium size, but it should not be used to treat eyes that have vitreous seeding. A double or triple freeze-thaw technique is usually employed, and the ice ball is allowed to encompass the entire tumor and overlying vitreous during each freezing cycle. As with photocoagulation and laser therapy, this form of treatment is generally repeated every 2–4 weeks until the entire tumor is gone.
Most children with bilateral retinoblastoma, multifocal retinoblastoma, or both, and occasional children with unilateral retinoblastoma, are currently managed by multimodality therapy. If a child has small intraretinal tumors without vitreous seeding and the macula and optic disc are not involved by tumor, he or she is typically treated by a combination of laser therapy and cryotherapy (laser for the more posterior tumors, and cryotherapy for the more peripheral tumors). If the child has larger tumors or ones that involve the central macula or optic disc, he or she is frequently treated initially by chemotherapy in an effort to shrink the tumors. Once partial regression of the tumors has been achieved, sequential locally destructive therapies (laser therapy, cryotherapy, plaque radiotherapy) are used to destroy the residual lesions. In some instances, laser therapy or cryotherapy is performed shortly after intravenous administration of chemotherapy. Such treatments are frequently referred to as photochemotherapy, chemothermotherapy, and chemocryotherapy. Accumulated laboratory and clinical experience indicates that these combination therapies produce greater local destructive effects than the same therapies applied sequentially on separate dates.
In view of the recognized natural history of retinoblastoma, observation with no therapeutic intervention is usually not advocated. However, a number of circumstances exist in which such an approach is almost certainly warranted. The most important circumstance is that of a spontaneously arrested retinoblastoma. As mentioned earlier (see Ocular Manifestations ), a spontaneously arrested retinoblastoma (retinoma) appears similar to a regressed retinoblastoma after irradiation (see Fig. 146-5 ); however, such tumors are detected in eyes that have received no prior radiation therapy or other treatment. Although retinomas have the same implications for inheritance of retinoblastoma as do viable lesions, such tumors usually remain dormant clinically and appear to have limited malignant potential. Consequently, they should simply be monitored on a regular basis, with no intervention unless they show evidence of renewed clinical activity. A second circumstance in which continued observation may be appropriate is that of true spontaneous regression of retinoblastoma.  Spontaneous regression is characterized by phthisis bulbi of the involved eye.
COURSE AND OUTCOME
As many as 45% of eyes treated initially by some form of eye-preserving therapy eventually require subsequent therapy by the same or another modality because of the development of new or recurrent intraocular tumors. In spite of the need for secondary sequential treatments, the great majority of eyes that have small to medium-sized tumors and no vitreous seeding are salvaged with useful vision.
Following local obliterative treatment of retinoblastoma, children must be re-examined within 2–4 weeks to assess treatment efficacy. Supplemental local treatment is performed at those evaluations if the prior therapy appears inadequate. Once
treatment appears to have totally eradicated all intraocular tumors, children are monitored every 3 months for at least 2 years. Thereafter, children should be followed at 6-month intervals until they are at least 6 years old, after which they should be followed at yearly intervals.
Some children have substantial orbital extension of tumor at the time of their initial diagnosis and treatment, and others develop orbital recurrence after enucleation. Although such cases were almost invariably fatal in the past, current evidence suggests that at least some of these children can now be saved by an aggressive regimen of tumor debulking, supplemental orbital irradiation, and systemic multidrug chemotherapy.   Unfortunately, the prognosis for children who have intracranial extension or widespread metastasis remains dismal.
Untreated, children who have retinoblastoma almost always die of intracranial extension or widely disseminated disease within approximately 2 years of tumor detection. Recognized adverse clinical prognostic factors for retinoblastoma-related death include larger size of the intraocular tumor, older age of the child at detection and diagnosis, and, most important, evidence of retrobulbar optic nerve expansion by tumor or trans-scleral extraocular tumor extension on CT or other imaging studies. The survival rate for both unilaterally and bilaterally affected children who have retinoblastoma in developed countries is currently about 90–95% ( Fig. 146-12 ). Most retinoblastoma-related deaths occur within 2–3 years of the initiation of treatment; few deaths attributable directly to retinoblastoma occur thereafter.
As mentioned previously, children with germinal retinoblastoma who survive their intraocular retinoblastoma have a substantially increased risk of death from one or more nonretinoblastoma malignancies over the course of their lifetimes. The exact probability of such an event is somewhat controversial, but the best available evidence suggests that at least 20% of survivors of germinal retinoblastoma develop such malignancies within 25 years of their retinoblastoma treatment.  During the period from just before diagnosis of the intraocular cancer to about 2 years after, the most common nonretinoblastoma malignancies that arise are pineoblastoma and ectopic intracranial retinoblastoma involving the suprasellar or parasellar tissues (trilateral retinoblastoma). Such lesions can cause obstructive hydrocephalus as well as seeding into the cerebrospinal fluid and implantation metastasis along the spinal cord. Unfortunately, most cases of ectopic intracranial retinoblastoma are fatal in spite
Figure 146-12 Survival of children with retinoblastoma. Separate curves are plotted for children with unilateral and bilateral disease. These curves are based on deaths from retinoblastoma only. Other causes of death, including deaths due to second malignancies, are not considered in the computation of these curves. The data from which these curves are derived come from the private practice of James J. Augsburger, M.D.
of aggressive treatment. After this period, the most common nonretinoblastoma malignancies are bony and soft tissue sarcomas.    The osteogenic sarcomas arise most frequently in the long bones, such as the femur and tibia, but the soft tissue sarcomas are much more common in the orbit or face, particularly in patients who undergo oculo-orbital irradiation for retinoblastoma in childhood. The orbital and facial nonretinoblastoma malignancies in most of these individuals appear to be radiation induced. As with ectopic intracranial retinoblastomas and pineoblastomas, the sarcomas and other nonretinoblastoma malignancies that develop in survivors of germinal retinoblastoma are frequently fatal unless detected promptly and treated aggressively.
The principal pathological prognostic factors for tumor-related mortality in retinoblastoma appear to be the presence of optic nerve invasion, massive choroidal invasion, and trans-scleral tumor extension into the orbit. The severity of anaplasia does not appear to have much impact on survival prognosis. In recent years, the most commonly employed staging system for survival in retinoblastoma is one that categorizes affected children as those who have tumor confined to the eyes (stage 1), those who have local extraocular extension into the optic nerve or orbit (stage 2), and those who have metastatic disease (stage 3). The tumor-node-metastasis (TNM) system is also used in some centers to group children according to survival prognosis.
The prognosis for preservation of the eye with at least some useful vision can be assessed with some degree of success using classifications such as the Reese-Ellsworth system and the Essen prognosis classification. The principal prognostic factors for ocular mortality (failure to preserve the eye) and visual mortality (failure to retain useful vision) include the size of intraocular tumors, the presence and extent of vitreous seeds, the presence and extent of retinal detachment, and the locations of the tumors within the eye.
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