Retinoblastoma is the most common intraocular malignancy in children. In 1964, Francois1 reported an incidence varying from 1 in 34,000 to 1 in 14,000 births and noted a steady increase in the frequency of occurrence of the tumor between 1927 and 1960. A number of studies support this finding and indicate a worldwide incidence of 1 in 3500 to 1 in 25,000, with no significant difference between the sexes or races.2-9 An apparent mortality rate for blacks 2.5 times greater than that for whites has been reported, but seems to be attributable to delays in diagnosis rather than a higher disease incidence.10 In general, there seems to be little correlation of disease incidence with geographic location. However, in some populations (e.g., Jamaicans, Nigerians, Haitians), 11 apparently higher incidence rates have been observed for what appears to be the unilateral sporadic form of retinoblastoma; this may suggest an environmental modification of the probability of tumor formation.12
Presenting Signs and Symptoms
In the majority of cases, the first sign at presentation is the characteristic cat's-eye reflex, which is usually noted by the child's parents or pediatrician. This white, pink-white, or yellow-white pupillary reflex, termed leukokoria, results from replacement of the vitreous by the tumor or by a tumor growing in the macula13,14 (Fig. 36-1). Another common symptom, strabismus (exotropia or esotropia), can occur alone when small macular tumors interfere with vision, or can be associated with leukokoria. It is not uncommon to find after an accurate patient history is taken that strabismus occurred some months before leukokoria.
Presenting signs of retinoblastoma. A, Leukokoria: exophytic retinoblastoma, overlying retinal detachment, clear lens, and visible retinal blood vessels. B, Multifocal retinoblastoma. (Courtesy of R. Frezzotti, MD, Director of the Institute of Ophthalmological Sciences, University of Siena, Italy.)
Less frequent presenting signs for retinoblastoma are red, painful eye with secondary glaucoma, low-vision orbital cellulitis, unilateral mydriasis, and heterochromia.15 Sometimes the tumor can be difficult to differentiate from a variety of simulating lesions, such as persistent hyperplastic primary vitreous, retrolental fibroplasia, Coats disease, toxocara canis infection, retinal dysplasia, and chronic retinal detachment.16,17 In 265 patients with pseudoretinoblastoma, persistent hyperplastic primary vitreous, followed by retrolental fibroplasia and posterior cataract, was the most common simulating condition.18 Of 136 children with suspected retinoblastoma reported to the Ocular Oncology Service of the Wills Eye Hospital in Philadelphia between 1974 and 1978, 60 had retinoblastoma and 76 had simulating lesions, the most frequent being ocular toxocariasis (26 percent), persistent hyperplastic primary vitreous (20 percent), and Coats disease (16 percent). Despite these complications, most simulating lesions can be distinguished through modern diagnostic methods (described later in this chapter) or after a careful history of the family and the affected child.16,17,19
A complete workup for such a patient includes an ophthalmologic examination; a systemic, pediatric, and radiographic evaluation; and, more recently, genetic studies (Table 36-1).17,19,20 At fundus examination, the disease can be unifocal or multifocal; in bilateral cases, usually one eye is in a more advanced stage, while the contralateral eye has one or more tumor foci (Fig. 36-1 B). Furthermore, fundus examination of the first-degree relatives may also document the presence of a retinoma or a regressed retinoblastoma and indicate a potential hereditary basis for the tumor.
Table 36-1: Clinical and Laboratory Assessment for Retinoblastoma Patients |Favorite Table|Download (.pdf) Table 36-1: Clinical and Laboratory Assessment for Retinoblastoma Patients
|Ophthalmologic examination |
|Binocular indirect ophthalmoscopy with scleral indentation (child, parents, siblings, relatives) |
|Site and dimensions of the tumor(s) |
|Necrosis, calcification |
|Degree of vascularization, hemorrhage |
|Vitreous "seeding" |
|Retinal detachment |
|Fundus photography and drawing of the lesion(s) |
|Slit-lamp examination |
|Pseudohypopion, hyphema |
|Corneal and lens transparency |
|Rubeosis iris |
|Corneal diameter (buphthalmos) |
|Pupil, anisocoria |
|Ecography (calcification, biometry) |
|Aqueous and vitreous cytology and enzymology-fine-needle aspiration biopsy |
|Systemic examination |
|Radiographic examination |
|Skull x-ray |
|Computed tomography (orbits and brain with and without contrast enhancement) |
|Magnetic resonance imaging (orbits and brain) |
|Pediatric examination |
|Bone marrow biopsy |
|Lumbar puncture (cerebrospinal fluid examination) |
|Serologic tests (toxocara) |
|Neurologic evaluation |
|Genetic studies |
|Esterase D |
|High-resolution chromosome analysis-karyotyping |
|DNA analysis of blood and tumor tissues |
The average age at diagnosis is 12 months for bilateral retinoblastoma and 18 months for unilateral cases, with 90 percent of the patients diagnosed before age 3. Several factors may influence the time of diagnosis and therapy, 21,22 including (a) ignorance of the revealing signs, (b) difficulty in ophthalmoscopic examination (age of the patient, level of transparency of the media, full mydriasis, and scleral indentation), (c) socioeconomic situation, (d) unusual clinical manifestations, and (e) multiple consultants.
Unusual Clinical Manifestations
It is an exceptional instance when retinoblastoma presents after the age of 7, and the older the child, the more unusual the first signs of the disease. These unusual manifestations include orbital cellulitis and edema of the lids; hypopyon, hyphema, iris heterochromia, and keratitis (anterior segment); and vitreous opacification, retinal cysts, vitreous hemorrhage, and endophthalmitis (posterior segment).23 Atypical uveitis in an older child, particularly if associated with secondary glaucoma and a poor response to corticosteroids, may be the first manifestation of a late retinoblastoma24 (Fig. 36-2 A). Repetitive diagnostic anterior chamber paracentesis may yield negative results.23 Among 618 cases of retinoblastoma in older children, 41 (6.6 percent) were misdiagnosed as primary ocular inflammations.25
Unusual manifestations of retinoblastoma. A, Pseudouveitis in retinoblastoma. B, Nodules at the pupillary margin and pseudohypopyon caused by a retinoblastoma. (Courtesy of R. Frezzotti, MD, Director of the Institute of Ophthalmological Sciences, University of Siena, Italy.)
Sometimes retinoblastoma can resemble a panophthalmitis, which is frequently seen as a reaction to a necrotic uveal melanoma.26 Pseudohypopyon as a result of retinoblastoma cells settled in the anterior chamber is another rare sign of the disease (Fig. 36-2 B). A diffuse, infiltrating retinoblastoma can present with hypopyon or a severe anterior uveitis.27,28 The term diffuse infiltrated retinoblastoma has been used to describe a form of the tumor in which no well-defined exophytic or endophytic mass is evident. This retinoblastoma pattern frequently produces aqueous and vitreous seeding, particularly in older children, 27,29-32 and seems to have a low potential for malignancy, although there is still controversy on this point.27,28 Furthermore, cystic retinoblastoma, presumably a variant of the diffuse infiltrating type, tends to simulate uveitis and presents with clinically visible cysts.33,34
Associated Clinical Abnormalities
The 13q-deletion syndrome includes sporadic retinoblastoma in association with moderate growth and mental retardation, a broad, prominent, nasal bridge, a short nose, ear abnormalities, and muscular hypotonia.35,36 Niebuhr and Ottosen also reported seven cases of retinoblastoma associated with systemic abnormalities (mental retardation, microcephaly, genital malformations, and ear abnormalities) in a review of 13q deletions and 13 ring chromosomes.37 Such a karyotypic analysis prompted by the presentation of dysmorphic features can facilitate early detection of a deletion in the long arm of chromosome 13. Subsequent ophthalmoscopic examination can identify the retinoblastoma at an earlier stage.38
The term retinoma has been used to denote a benign tumor of retinocytic origin. Although the origins of this entity are obscure, it has been proposed that it arises from a mutation in the retinoblastoma susceptibility gene in a well-differentiated retinocyte and leads to a hyperplastic nodule of differentiated cells.39 Retinomas are composed of apparently benign cells that show photoreceptor differentiation with no evidence of necrosis or mitotic activity, but with numerous rosettes.40 Characteristically, retinomas have at least two of the following characteristics: irregular translucent retinal mass, calcification, and pigment epithelium migration and proliferation (Fig. 36-3 A). Histopathologic and immunohistochemical studies suggest that retinomas are primary benign tumors, not regressed retinoblastomas. Malignant transformation of retinomas is quite rare, although some cases have been reported, notably a 7-year-old girl who developed an undifferentiated retinoblastoma 3 years after the diagnosis of a retinoma.41,42
Abnormalities associated with retinoblastoma. A, Retinoma: translucent retinal mass and pigment epithelium migration and proliferation. B, Spontaneously regressed retinoblastoma. (Courtesy of R. Frezzotti, MD, Director of the Institute of Ophthalmological Sciences, University of Siena, Italy.)
Various physiological conditions (including reduced blood supply and necrosis, calcium [as an inhibitor of tumor growth], and host immune defense mechanisms) could be implicated in the spontaneous regression of retinoblastoma (Fig. 36-3 B). Often, bulbi with intraocular calcification are the final physical embodiment of a spontaneously regressed retinoblastoma.43 These phthisis bulbi can be attributed to tumor necrosis after ocular ischemia but cannot explain the retinoma, because the vascular supply in these lesions is intact.44 On the basis of the available data, it appears that the term regressed retinoblastoma should be reserved to describe shrunken, calcified, phthisical eyes, whereas retinoma should be used to refer to nonprogressive retinal lesions that are highly associated with retinoblastoma but lack a malignant pattern.45
Bader and coauthors46 coined the term trilateral retinoblastoma to describe the association between bilateral retinoblastoma and midline brain tumors, usually in the pineal region. Similar observations had been reported by Jensen and Miller10 and Jakobiec et al., 47 and had suggested that involvement of the pineal gland (third eye) represents a further point of origin for multicentric retinoblastoma rather than a second primary tumor.48 In patients with hereditary retinoblastoma, both the pineal and the retina may contain susceptible cells. Because these pineal tumors may be indistinguishable from well-differentiated retinoblastomas, they are also called ectopic retinoblastomas.46 It is possible that pineal tumors have been misinterpreted as intracranial spread of retinoblastoma, 49 whereas the advent of CT scanning and MRI has facilitated more accurate diagnoses. This is clinically important, because an ectopic intracranial retinoblastoma requires adequate therapy to the whole neuraxis, as well as high-dose equivalent radiotherapy to the primary tumor. Intrathecal therapy with methotrexate should also be considered.50
The term second site primary malignant tumor refers to nonmetastatic tumors arising in disease-free patients successfully treated for the initial disease. Some of the tumors found in association with retinoblastoma include osteosarcoma, fibrosarcoma, chondrosarcoma, epithelial malignant tumors, Ewing sarcoma, leukemia, lymphoma, melanoma, brain tumors, and pinealoblastoma. These second tumors have been classified into five groups:51 (a) tumors appearing in the irradiated area; (b) tumors appearing outside and remote from the irradiated area; (c) tumors in patients not receiving radiotherapy; (d) tumors that cannot be characterized as primary or metastases; and (e) tumors appearing in members of retinoblastoma families who are free of retinal tumors.
Reese, Merriam, and Martin52 reported the first two cases of second tumors in 55 retinoblastoma patients treated with external radiation and surgery. These patients presented with a maxillary sinus sarcoma and a rhabdomyosarcoma of the temporal muscle. A similar case of mixed-cell fibrosarcoma has been reported by Frezzotti and Guerra.53 A causal relationship between radiation therapy and secondary tumors has been suggested.54-56 However, from the reported series of cases, two important observations have emerged: (a) The great majority of children in whom second neoplasms developed had suffered bilateral retinoblastoma, and (b) the incidence of second neoplasms in this group of children was similar whether or not they received radiation. These conclusions have been supported by studies that have reported the incidence of second nonocular tumors and analyzed the effect of radiation therapy. Osteogenic sarcomas have been the most common second-site neoplasms in all the published series. Derkinderen, 57 Lueder, 58 Draper, 59 and their colleagues found low rates of development of second tumors and are in agreement that the incidence increases with radiation therapy. Abramson et al. reported the incidence of second tumors in patients with hereditary retinoblastoma and found a frequency of 20 percent at 10 years, 50 percent at 20 years, and 90 percent at 30 years after diagnosis.60 Somewhat lower rates have been recorded by other authors. For example, in a series of 215 bilateral retinoblastomas, second tumors developed in 4.4 percent of the patients during the first 10 years of follow-up, in 18.3 percent after 20 years, and in 26.1 percent after 30 years.61
Retinoblastoma occurs either as an intraocular mass between the choroid and the retina (exophytic) or as a bulge from the retina toward vitreous (endophytic). However, most of the advanced tumors examined showed both patterns of growth. Retinoblastoma rarely spreads superficially (1 percent), forming no mass and invading the whole retina (diffuse infiltrating retinoblastoma).
The tumor is histologically characterized by the presence of rosettes and fleurettes, which are believed to represent maturation and differentiation of the neoplastic cells. Rosettes are spherical structures (circular in section) constituted by uniform cuboidal or short columnar cells arranged in an orderly fashion around a small round lumen (Flexner-Wintersteiner rosette) or without any lumen (Homer-Right rosette). The latter type can often be found in other neuroectodermal tumors, such as medulloblastomas. Fleurettes are arranged in the opposite way, with short and thin stromal axes surrounded by fairly differentiated neoplastic cells with the apical part facing the externum, resembling the shape of a flower (Fig. 36-4 A). Often the tumor appears highly necrotic, with the surviving cells positioned around blood vessels, creating structures called pseudorosettes. Calcified foci can be found in areas of necrosis, as can debris from nucleic acids, giving rise to basophilic vessel walls.62,63
Histopathology of retinoblastoma. A, A well-differentiated retinoblastoma showing rosettes and fleurettes (hematoxylin-eosin, 100). B, Low-differentiated retinoblastoma infiltrating the choroid and sclera (hematoxylin-eosin, 100). (Courtesy of P. Toti, MD, Institute of Anatomic Pathology, University of Siena, Italy.)
A retinoblastoma tumor is capable of spreading outside the bulb through the eye coats, invading the choroid and the sclera. It is the invasion of this highly vascularized choroid that represents an effective vehicle for distant metastasis (Fig. 36-4 B), and such choroid invasion is directly correlated with a poor prognosis. Invasion also can involve the optic nerve and meningeal space, providing access to the central nervous system. Growth patterns and other histologic parameters (such as pseudorosettes, necrosis, and calcification), although necessary for the identification of the tumor itself, do not seem to offer much information in regard to the prognosis. The degree of differentiation and the number of mitoses show a weak correlation with the prognosis; however, stronger relationships exist with invasion of the choroid and sclera. In particular, progressive invasion of the eye coats, even in the horizontal plane, is highly informative in determining the prognosis.64,65
Because many of the symptoms described above are clearly not specific to retinoblastoma and because early surgical or conservative treatment is of primary importance in the survival of these patients, it is imperative to confirm these impressions by examination. There are a variety of diagnostic tools available for this, including CT, MRI, ultrasonography, and FNAB. The application and advantages of each procedure are briefly discussed below.
Computed Tomography and Magnetic Resonance Imaging.
CT is a valuable adjunct in the differential diagnosis, staging, and treatment of retinoblastoma.66,67 Intraocular calcification in children under 3 years of age is highly suggestive of a retinoblastoma. Some studies have reported that the degree of calcification appeared to depend on tumor size, with the smallest tumor showing calcification 8 mm in diameter and 4 mm in thickness68,69 (Fig. 36-5 A). However, in children more than 3 years of age confusion may arise from some simulating lesions, including retinal astrocytoma, retrolental fibroplasia, toxocariasis, and optic-nerve-head drusen, which can also produce calcifications.68-70 Thus, CT is often coupled with MRI to better detect subtle scleral invasion, infiltrative spread along the optic nerve, subarachnoid seeding, or involvement of the central nervous system through direct tumor extension or by metastasis.71 Furthermore, MRI appears to be more sensitive in the differential diagnosis of lesions simulating retinoblastoma70,72,73 and in the evaluation of the degree of tumor differentiation.74
Diagnostic tools for retinoblastoma. A, CT scan: retinoblastoma filling the whole vitreous cavity with typical calcifications (Courtesy of C. Venturi, MD, Department of Neuroradiology, University of Siena, Italy). B, B scan technique. The echogram shows a lesion with an irregular oval shape and dense acoustic tissue. High attenuation of ultrasound is occurring, with the shadowing of the echoes coming from the orbital tissue. The tumor has developed in the vitreous and occupies it almost entirely. (Courtesy of E. Motolese, MD, Institute of Ophthalmological Sciences, University of Siena, Italy.)
The role of both CT and MRI in staging and therapy is of great importance in accurately determining extraocular disease such as intracranial metastasis, retrobulbar spread, orbital recurrence, and secondary tumors, and it is often on the basis of these diagnostic results that further treatment (radiotherapy and/or chemotherapy) is planned. Still, subtle optic nerve involvement cannot be predicted reliably.68 By using CT as a diagnostic tool, Danziger and Price75 proposed the division of retinoblastoma cases into three groups: grade I tumors are high-density masses with calcification in any part of the eyeball; grade II tumors are high-density masses involving the optic nerve and orbital soft tissue but with rare calcifications; and grade III tumors are intracranial or extraorbital high-density masses showing marked contrast enhancement. These classifications further aid in the determination of appropriate therapeutic measures.
Ultrasonography is another diagnostic technique that can distinguish the type of growth for retinoblastoma and related tumor types. Endophytic and exophytic growths show variations in the ultrasonographic context of both A and B scanning techniques.
In the case of an endophytic growth, the retinoblastoma appears as a single or, more often, a multiple lesion on the retinal plane. The tumors are monolobate or multilobate and have a roundish or irregular oval shape, with dense acoustics and variable homogeneity (Fig. 36-5 B). A discrete attenuation of the ultrasound occurs, with the shadowing of the echoes coming from the orbital tissue. The attenuation is considerable if, as is often the case, areas of calcification are found inside the tumor mass.76 The tumor itself may develop within the vitreous chamber and occupy it almost entirely, and, at times, areas of pseudocysts may be found in front of and/or in the context of the neoplastic mass, thus making it difficult to recognize the lesion.77 Nevertheless, the attenuation of the ultrasound is considerable.
With the exophytic growth, the diagnosis is harder to establish, especially if the tumor is analyzed during the initial stage. It is easily confused with the high echogenic portion of the sclera, while no significant evidence of it appears on the retinal plane. The only significant noticeable sign is a certain attenuation of the ultrasound coming from the orbital tissue, with a display on the echogram that simulates the acoustic shadow of the optic nerve, but does not resemble it in topography and size.77
In the case of an endophytic tumor growth, a standardized A scan tracing shows an opening peak that appears at high or medium reflectivity but is never maximal. This is the case because the internal retinal surface is considerably compromised and heterogeneous, thus attenuating the contrast that exists at the vitreous-retinal interface level. The opening peak can be maximal, however, if the tumor has an exophytic growth as long as the layer of the limiting internal membrane and the nerve fibers are not disintegrated by the growth of the tumor.77,78
In the opposite case, a peak at high reflectivity found during a subsequent checkup may reveal a peritumorous satellite area, even if small and confined, rather than an opening peak of the tumor. The internal structure of the tumor usually appears quite regular at medium-high reflectivity and at medium reflectivity in the case of a retinoblastoma with no calcifications.77 Vitreous activity with the absence of seeding is minor in retinoblastoma before photocoagulation, while afterward it is possible to find juxtalesional vitreous echoes at medium reflectivity and, sometimes, areas of peritumorous retinal fissions.79
Invasion of the sclera entails the loss of its homogeneity as an acoustic interface and causes a decrease in the reflectivity of the closing scleral peak that may be mistaken for the retinal echoes of the same tumor. This represents an important ultrasonographic sign, which can determine the margins and posterior borders of the lesion. In the A and B scanning methods, the calcifications are characteristically evident even when the amplitude appears reduced. Furthermore, suspicion of invasion of the optic nerve is indicated by the presence in the nervous tissue of an ultrasonographic tracing that reproduces the features of a retinoblastoma in an A scan.
Fine-Needle Aspiration Biopsy.
The cytologic approach to the study of retinoblastoma has become particularly relevant as the techniques for obtaining tumor material have improved. Specimens from the posterior chamber can be obtained by using vitrectomy techniques in addition to anterior chamber paracentesis for cytologic and enzymologic evaluation of the aqueous. Aqueous and vitreous aspiration for cytologic studies may be useful in differentiating retinoblastoma from the previously described simulating conditions.
The use of fine-needle biopsy in ophthalmology, originally introduced by Schyberg for the diagnosis of orbital tumors, was utilized in the diagnosis of intraocular neoplasms by Jakobiec et al.80 and extended to the diagnosis of intraocular and extraocular retinoblastoma by Char and Miller.81 This approach is not recommended as a routine procedure for retinoblastoma and generally is reserved for children who present with unusual manifestations or for differentiating an orbital recurrence of retinoblastoma from a second malignant neoplasm.81 A limbal approach is used for anterior segment tumors, whereas a via pars plana approach after opening of the conjunctiva, scleral diathermy, and 1.5-mm sclerotomy is used for posterior tumors.82,83 Complications that may occur with the use of fine-needle biopsy include intraocular hemorrhage, retinal detachment, and recurrence in the orbit or along the intraocular needle tract. Although tumoral-cell seedings within the scleral needle tracks after biopsy are controversial, 84,85 this possibility suggests that fine-needle biopsy be limited to patients who present diagnostic uncertainties. These patients include older children with suspected retinoblastoma and rather atypical findings and children with orbital masses who previously have been treated for retinoblastoma.86-88
If a retinoblastoma or a related ocular tumor is discovered at an early stage and diagnostic tools have appropriately classified the type, there are several current and effective methods for treatment, including enucleation, external-beam irradiation, episcleral plaques, xenon arc and argon laser photocoagulation, cryotherapy, and chemotherapy. The choice of treatment depends on factors such as (a) multifocal or unifocal disease, (b) site and size of the tumor, (c) diffuse or focal vitreous seeding, (d) age of the child, and (e) histopathologic findings. Therefore, an appropriate therapeutic approach greatly depends on accurate staging of the disease.
Staging and Classification.
The most widely used staging system for retinoblastoma, which was proposed by Reese and Ellsworth, 89 is based on the ophthalmoscopic evaluation of the tumor extension and generally is limited to patients with intraocular retinoblastoma. Pratt extended this system to include intraocular and extraocular extension of the disease.90 Another system is based on an accurate evaluation of the histopathologic findings.91 Most recently, a pretreatment TNM classification has been introduced that also addresses the importance of visual acuity in addition to patient survival and ocular extension.92 Table 36-2 presents the different criteria for these classification systems.
Enucleation is the standard treatment in unilateral cases and for the more severely affected eye in bilateral ones. An attempt to save the eye is worthwhile only when there is hope for useful vision and no risk of a systemic prognosis.93 Generally there are several major indications that call for the nonconservative removal of the diseased eye. These tumor characteristics include (a) a large mass involving more than 50 percent of the retina associated with retinal detachment, (b) a buphthalmic painful eye, (c) a phthisical eye (in bilateral cases), and (d) unsuccessful conservative treatment (radiotherapy with or without chemotherapy and photocoagulation). Regardless of which of the various enucleation techniques is used, the procedure should be performed with the least trauma possible for the patient while avoiding scleral perforation, and at least 10 mm of the optic nerve should be resected.94 After enucleation, the use of an implant is recommended for both cosmetic reasons and to stimulate orbital growth. Usually a conformer is used for 2 to 3 days directly after surgery, followed by a temporary insert prosthesis (about 1 week after enucleation) after complete healing of the surgical incision.13
Retinoblastoma is a highly radiosensitive tumor, and the first attempt at its treatment with x-rays occurred in 1903.95 External-beam irradiation, utilizing gamma rays from a linear accelerator, is now the most commonly used treatment for intraocular and orbital disease. This technique is indicated when (a) in unilateral retinoblastoma cases there is a large tumor not involving the macula and optic nerve, (b) in bilateral retinoblastoma cases there are advanced tumors in both eyes, or in the remaining eye when multiple tumors or diffuse vitreous seeding is present, and (c) in orbital tissue, where histopathologic studies of the enucleated eye and optic nerve document an invasion of the optic nerve, scleral invasion, or orbital recurrence.13
The goal of external irradiation in retinoblastoma is to sterilize the entire retina and vitreous of malignant cells with the best possible visual prognosis. A dose generally considered to be optimally therapeutic is 4000 rad fractionated into about 20 doses over a 3- to 4-week period. At the Utrecht Retinoblastoma Center, a highly accurate irradiation method has been developed, 96 based on the temporal approach, which ensures precise delivery of a uniform radiation dose to the whole retina or vitreous with maximal sparing of the lens. Accurate positioning of the collimated field is obtained by magnetic fixation of the eye to the beam-defining collimator by a low-vacuum contact lens. Because the eye is fixed in the isocenter of the accelerator, rotation of the gantry directs the beam. Other centers have adopted this technique and have confirmed the extreme precision and sharp-beam profile that can be obtained.97,98
Four regression patterns after radiation for retinoblastoma have been described by Reese and Ellsworth99 and by Buys et al.101 These patterns are described as follows: type I—characterized by calcification, marked alterations of the retinal pigment epithelium, and the cottage cheese aspect; type II—the tumor is shrunken in size and adopts a gray, translucent appearance (fish flesh); type III—a combination of the patterns seen for types I and II; and type IV—represented by the typical pattern after cobalt-plaque treatment, with complete destruction of the tumor and choroid; the white scar represents the sclera underlying the tumor.
Buys et al. found that the most common type of regression at the first evaluation was type III (43.8 percent). However, after a minimum of 7 years, a decrease in this pattern was found (from 43.8 to 36 percent). It was also reported that the type II patterns can turn into any one of the other types over a number of years. Furthermore, a correlation seems to exist between the size of the tumor and the regression pattern.101
As with most procedures, complications can arise after external irradiation. They are divided into immediate, usually reversible complications and late, usually irreversible complications. The most severe complications are growth retardation of the orbital region, dry-eye syndrome caused by the reduced or absent lacrimal secretion, radiation cataract, iris atrophy, vascular changes, and retinal exudates (radiation retinopathy).102
The use of radon seed brachytherapy for the conservative treatment of retinoblastoma was introduced in 1929. In 1948, Stallard developed radioactive applicators using radium, and these applications were later modified to use60 Co. Later techniques expanded to include125 Ie, 192 Ir, and 106 Ru eye plaques, which are now all used routinely in the focal treatment of the disease.103 Many treatment centers have a preference for125 I plaques because orbital tissues can be shielded with a gold-plaque carrier, ridge plaques can limit the spread of radiation to the nerve and foveal region, and there is less radiation exposure for the patient and the assisting staff.104 Regardless of the type used, the episcleral plaque technique is highly advantageous compared with other forms of therapy because the procedure time is short while the dose of irradiation is delivered directly to the tumor, minimizing radiation effects to the extraocular structures.
The use of radioactive scleral plaques as a primary treatment is particularly successful for medium-size tumors no greater than 12 mm in diameter and more than 3 mm from the optic disk or macula.105 Scleral plaques are also useful as a secondary treatment for recurrent or new tumors which are impossible to control using photo- or cryocoagulation. The regression patterns seen after plaque treatment appear to be identical to those described for external-beam irradiation (types I, II, and III). However, a type IV radiation regression pattern characterized by complete destruction of the tumor choroid and all vessels, leaving a white scleral patch, has been observed only after cobalt plaque treatment.100
In 1955, Meyer-Schwickerath developed a photocoagulation technique using a xenon arc in which retinoblastomas are surrounded by a ring of coagulation placed in the normal retina before the tumor tissue itself is treated.106 The experience of others104,107-110 suggests that the success of photocoagulation is due to the destruction of the retinal blood supply, not to its effect on the tumor itself or on the underlying choroid. The best results have occurred with tumors up to 4 to 5 disk diameters in size, with an elevation of 4 diopters, 111,112 although tumors up to 6 or more disk diameters have also been treated successfully in this way.107,108 Indications, contraindications, and results of photocoagulation appear to be disparate. There are different opinions regarding the size, elevation, site, and clinical conditions in which retinoblastoma should be treated with photocoagulation.109 Photocoagulation has been suggested as a primary approach for small and moderate retinoblastomas posterior to the equator and for the treatment of recurrent or new tumors after external radiotherapy or radioactive plaques.108 Photocoagulation is not appropriate when tumors lie directly on the optic nerve or when there is vitreous seeding.
Complications arising from the use of photocoagulation may include occasional retinal hemorrhage; retinal traction; retinal folds; macular distortion; iris damage; corneal edema; and/or cataract (caused by inadvertent iris heating or energy absorption by preexisting opacities). The regression patterns observed after photocoagulation treatment depend on the size and elevation of the tumor (Fig. 36-6). Furthermore, it appears that vascularization of the tumor can influence sensitivity to xenon photocoagulation.107 After photocoagulation, small tumors appear as a flat avascular pigmented scar. Larger tumors may present marked coarctation, reduced vascularization, and a translucent gray appearance similar to that described as fish flesh. However, both of these regression patterns closely resemble those of types I and II after radiotherapy.
Regression patterns for retinoblastoma after photocoagulation. A, A small retinoblastoma. B, After indirect xenon-arc photocoagulation. C, After direct xenon-arc photocoagulation. (Courtesy of R. Frezzotti, MD, Director of the Institute of Ophthalmological Sciences, University of Siena, Italy.)
Cryotherapy113 for retinoblastoma can be used as a primary or supplementary treatment after other conservative therapeutic attempts and can be effective in clinical situations involving new or recurrent tumors after irradiation therapy or in tumors anterior to the equator in eyes that have not been treated.114 Cryotherapy can be successful on tumors up to 3.5 mm in diameter and 2.0 mm in thickness, but more than one treatment may be necessary.115
Vitreous base tumors are very rarely cured with cryocoagulation alone.116 Localization of the tumor is obtained by indentation with a cryoprobe under indirect ophthalmoscopy. Tumors are frozen with applications of −80°C for 30 to 60 s, and the treatment is typically repeated three times.117 Cryotherapy destroys the tumor by direct intracellular and intravascular formation of microcrystals. The most frequent complications after cryotherapy are conjunctival and lid edema.
To date, chemotherapy has played only a secondary role in the treatment of retinoblastoma, because good control can be achieved with more local treatment. There is also a relative paucity of randomized studies on the efficacy of chemotherapy compared with other therapeutic procedures, and this is further complicated by a lack of suitable markers for the detection of minimal residual disease.57,59,60,118 The first to use a chemotherapeutic agent in retinoblastoma treatment was Kupfer, who obtained partial regression of a retinal tumor mass by using nitrogen mustard.119 After this preliminary experience, other antitumor drugs, especially vincristine and cyclophosphamide, were used alone or in combination in several situations, such as in association with radiotherapy for advanced disease120,121 to reduce the mortality caused by micrometastatic disease120-127 and with locally advanced disease or distant metastasis.128-130 Especially in the last group of patients, sequential chemotherapy protocols or courses of intensive chemotherapy followed by autologous bone marrow transplantation have given encouraging results. Despite these achievements, the role of antiblastic chemotherapy in the treatment of retinoblastoma remains controversial, and the only generally accepted indications for it are orbital or metastatic disease, trilateral retinoblastoma, and salvage therapy for relapses in the residual eye. More controversial indications include shrinkage of the neoplastic mass, optic nerve infiltration beyond the lamina cribrosa, and choroidal infiltration (whole thickness and/or ciliary body invasion) with or without optic nerve involvement up to the lamina cribrosa. This mode of therapy still awaits homogeneous staging and therapeutic criteria to evaluate its general efficacy.131,132