Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Retinal Disease_Wright, Spiegel, Thompson_2006
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FIGURE 9-8A,B. Extraocular retinoblastoma in the United States is rare. However, in Third World countries it may be the most common presenting sign of the disease. (A) 3.5-year-old child from Mexico presented with extraocular disease in the right eye and intraocular disease in the left. On CT scan, there was no evidence of intracranial disease. He was treated with chemotherapy for the extraocular disease, which responded dramatically. External beam radiotherapy was given for the intraocular disease in the left eye with approximately 60% of the dose delivered across the midline to the right orbit. Subsequently, the right eye became shrunken and phthisical. The eye was then removed. Fortunately, the disease had extended only anteriorly and had not invaded the optic nerve or the retrobulbar space. (B) Patient is wearing his ocular prosthesis and safety glasses. Five years later he was free of retinoblastoma recurrence but had developed an osteosarcoma of the left arm.
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patients (Fig. 9-10). The earliest lesions do not appear to have tumor vascularization. These very small lesions may be virtually transparent, but as they enlarge they become more opaque. Once a retinoblastoma has reached one disc diameter in size, it usually has the characteristic appearance of frozen yogurt. Untreated tumors are fairly uniform. This opacity distinguishes them from treated and inactive tumors that are “gauzy” or partially transparent (type II regression).
As tumors enlarge, clonal overgrowth frequently leads to an asymmetrical spread away from the original tumor base; this can be particularly evident in tumors of the posterior pole, which frequently “overhang” the disk or macula. During the course of treatment, it is often a pleasant surprise to see the macula or disc appear from beneath the retreating tumor mass.
As tumors grow and their demand for a blood supply increases, the nearest retinal vessels are recruited as tumor “feeder” vessels. As the flow increases, the size and tortuosity of these vessels increase. During tumor therapy, a decrease in the size and tortuosity of these vessels is a positive sign that the treatment is at least partially successful.
With endophytic growth (growth into the vitreous as a single mass), two things eventually happen. As the base expands and as more incompetent tumor vessels form, fluid accumulates beneath the retina and a serous retinal detachment appears around the base of the tumor. As the fluid increases, it tends to move dependently. With large tumors, it is not uncommon to see a total serous retinal detachment.59 In the presence of a tumor-associated detachment, it is common for the tumor to “seed” the subretinal space. Where these small clumps of malignant cells attach to the retinal pigment epithelium (RPE) or the underside of the detached retina, new tumors may appear in the distribution of the retinal detachment even if the fluid resolves with treatment. Visibly detectable tumor nodules on the underside of the detached retina at the time of diagnosis make the salvage of the eye unlikely.
With continued expansion of an endophytic tumor, the pseudocapsule surrounding the tumor eventually breaks down, allowing the loosely adherent tumor cells access to the vitreous cavity. Initially, their growth is stunted by lack of oxygen and nutrients in this new environment. Eventually, however, they coalesce into spheres consisting of an inner core of necrotic tumor cells and an outer shell composed of only two viable cell layers. The thickness of the vitreous “seeds” is determined by
FIGURE 9-9A–D. A 7-year-old child was evaluated in an emergency room following minor head trauma. The ER physician noted poor acuity in the left eye and also noted an afferent pupillary defect on the left. Subsequent ophthalmologic evaluation revealed multifocal inactive retinoblastoma in the left fundus. The child had no previous diagnosis or treatment of retinoblastoma lesions. (A) Appearance of the larger lesion at age 7 years. This lesion shows a type II regression pattern (gray, semitransparent). Adjacent to it is a rather large section of RPE depigmentation. (B) Image of a second lesion demonstrating a type I regression pattern in which the residual mass is composed entirely of calcium, giving the tumor a cottage cheese-like appearance. (C,D) Photographs of the same two lesions 3 years later show an absence of growth and the maturing of the regression patterns. The typical pattern of regression and the associated depigmentation of the RPE supports the diagnosis of retinoma or retinocytoma. (Courtesy of Dr. I. Hsu, Portland, OR.)
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FIGURE 9-9A–D. (continued)
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FIGURE 9-10. Fundus photograph of a child with multifocal, bilateral retinoblastoma. With the exception of one reported case, tumor has not been documented to spread from one eye to the other; these tumors have all arisen independently of each other. The findings in this child would be statistically impossible unless he is genetically predisposed to develop the tumor. Without genetic predisposition, each of these tumors could only have arisen as a result of two chance DNA events in the same retinal cell. Each of those events occurs spontaneously with a frequency approaching once per 1 million retinoblasts. The frequency of even one tumor arising in the absence of genetic predisposition is the product of the individual frequencies or once per 1,000,000,000,000 retinoblasts. In contrast, if this child is genetically predisposed, he carries one of the two DNA events necessary for tumor formation in every cell. Only one additional “once per million” event must occur for a tumor to arise. Because children have approximately 3 million retinoblasts at birth, a second tumorigenic event would be expected to occur in an average of three retinal cells in each eye. Three tumors is about the average number seen in each eye in patients with genetically predisposed retinoblastoma.
the oxygen diffusion gradient in the vitreous. The use of the term seeds to describe these structures is most appropriate because these are relatively dormant carriers ready to “seed” tumor wherever they can reattach and recruit a blood supply (Fig. 9-11). An eye with diffuse extensive vitreous seeding is almost impossible to treat successfully.
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FIGURE 9-11. Retinoblastoma can break through its smooth surface and spread tumor cells into the vitreous. Not infrequently, the early stages of vitreous “seeding” is a localized event, occurring just over the surface of an individual tumor. In this figure, the localized vitreous seeding is arising from a “nipple” or candy kiss-like structure on the surface of a previously smooth tumor mass. This geographic feature is likely the result of the rapid overgrowth of a clone of daughter cells, all arising from one tumor cell, which happened to undergo a mutation that further releases restraints on growth rate. These spontaneous mutations within tumors that confer growth advantages are frequently the result of chromosome rearrangement during tumor cell mitosis and are collectively known as “progression of malignancy.” As clones of these cells overgrow their cousins, the nature of the entire malignancy rapidly changes character toward a more aggressive and life-threatening tumor.
Diffuse infiltrating retinoblastoma is a rare subtype of the disease that may be diagnosed in older children (average age,
6.1 years). There is no definite mass and the condition is frequently misdiagnosed as a posterior uveitis. Pseudohypopyon is common.5
WORKUP
The only essential laboratory study in the systemic workup of a newly diagnosed retinoblastoma is an imaging study to demonstrate the presence of calcium in the eye, either a CT scan with contrast or echography or both. Magnet resonance imaging (MRI) is helpful if the retinoblastoma is suspected to be present outside
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the eye, either in the optic nerve or in the orbit. It is unnecessary to order bone scans, extensive blood studies (including liver function studies), a lumbar puncture, or a bone marrow aspiration and biopsy in the typical case of intraocular retinoblastoma in which the classic fundus picture is present and calcification is clearly demonstrable with an imaging study (Fig. 9-12).
Because retinoblastoma most commonly metastasizes to bone and bone marrow, any unusual bone lesion should be suspected to be caused by metastatic retinoblastoma or, if the patient is genetically predisposed, by a second malignant neoplasm (most commonly osteogenic sarcoma) (Fig. 9-13).59 One of our patients with bilateral retinoblastoma was treated in another hospital for several months for a nonhealing bone abscess in the mandible. Eventually, this lesion was shown to be an osteogenic sarcoma.
An inflammatory reponse can obscure the classic features of retinoblastoma. Figure 9-6 shows findings in a 7-year-old patient whose clinical diagnosis of toxocara granuloma was made at grand rounds in a major teaching center. An intraocular mass was present without clear evidence of calcium on CT scan. After 3 days of high-dose systemic steroids, the vitreous cleared dramatically and revealed a typical endophytic retinoblastoma. Repeat echography showed clear evidence of calcification in the mass, and a correct diagnosis of retinoblastoma was made.
FIGURE 9-12. Precontrast CT demonstrates a bright spot of calcification within the tumor mass in the left eye. Preand postcontrast scans both show calcification, but contrast may be very useful in demonstrating extraocular involvement. MRI scans do not define calcification but may prove to be useful in demonstrating optic nerve involvement.
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FIGURE 9-13A,B. This 12-year-old child had a history of bilateral retinoblastoma diagnosed at age 2 years. The right eye was removed at the time of diagnosis, and the left eye was treated with external beam radiotherapy and cryotherapy. There was no history of ocular tumor recurrence. At age 11, the child began complaining of a “fullness” behind her left eye. An ophthalmologist examined her three times during the subsequent 8 months and noted no active retinoblastoma. She then developed orbital aching, headaches, nausea, vomiting, and a 15-pound weight loss. Multiple pediatricians evaluated her and thought she was suffering from a “chronic viral syndrome.” She then developed proptosis and the inability to move her left eye. (A) Patient’s clinical appearance at this time. The left eye was proptotic and there was conjunctival congestion and chemosis. In this photograph she is attempting to look up but cannot. The right orbit contains a prosthesis. (B) CT appearance at the same time. A large mass is present in the ethmoid sinus and left orbit inside the radiated field. Biopsy confirmed the clinical diagnosis of osteosarcoma. This child had symptoms for 8 months before diagnosis. The delay was primarily caused by the failure of her physicians to consider the possibility of a second malignant neoplasm and to order an imaging study of the left orbit. Similar cases have prompted the development of a medi-alert card.
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Genetic Counseling
Genetic counseling is becoming a more integrated part of the management of retinoblastoma. Genetic counseling requires a team approach. The need for fresh tumor tissue for adequate genetic counseling is one of the best arguments for the treatment of all retinoblastoma, including the primary enucleation of unilateral sporadic retinoblastoma, at a major ocular oncology center. Experienced genetic counselors will have all the necessary information about which blood and tumor specimens are needed and to which labs they should be sent. Turnaround time is improving in most of the laboratories; results may now be available in 8 to 12 weeks. Costs associated with these DNA tests have not decreased, but more insurance companies are now paying these charges.
The genetics of retinoblastoma is well understood, and our tools for affordable, reliable, gene-based genetic counseling are improving. The “retinoblastoma” gene was cloned almost simultaneously in Boston14 and Los Angeles.15 Most people have two normal copies of the Rb gene in each cell. Individuals genetically predisposed to retinoblastoma have only one normal copy. The second copy is defective and does not produce an active protein. If the single good copy is mutated or otherwise becomes defective, then the cell is completely released from the growth restraint imposed by this system. The loss of both copies of the growth-suppressing gene is required for retinoblastoma to develop. The loss of both copies of this gene also occurs in some cases of other malignancies, including breast, lung, and prostate.63 In these tumors, the two Rb mutations are not involved in tumor initiation but are part of the cascade of events known as progression of malignancy. Gene products that target and bind the Rb gene protein, such as the SV40 large T antigen, the E6 antigen of human papilloma virus, and the E1A antigen of adenovirus, can also cause malignant transformation of cells.16 Homologues of these genes (human oncogenes) are present in normal cells. Because the Rb gene product binds to oncogene products, the Rb gene seems to function as an anti-oncogene.
Histopathological Risk Factors for
Metastatic Disease
Unlike choroidal melanoma, the most differentiated retinoblastomas appear to have the same metastatic potential as the least
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differentiated ones. However, histological examination of the enucleated specimen is important for another reason. If there is tumor in the optic nerve past the lamina cribrosa, or massive invasion of the choroid, or both, then prophylactic chemotherapy is recommended. However, if the nerve is free of tumor past the lamina cribrosa, and if there is no evidence of spread through the choroid into the sclera, then additional treatment is not necessary. Efforts should be made to obtain as long a piece of optic nerve as possible. Clinical follow-up is especially important in patients with a genetic predisposition.
Treatment of Intraocular Retinoblastoma
The treatment of intraocular retinoblastoma has evolved significantly in the last decade and since the first edition of this textbook. The primary use of traditional teletherapy (external beam radiotherapy) in the treatment of intraocular tumor is rare. Enucleation of eyes with advanced intraocular retinoblastoma in unilaterally affected patients is appropriate and common. Retinoblastoma in patients with bilateral disease or only moderately advanced unilateral disease diagnosed today are treated with a protocol of systemic chemotherapy (generally carboplatin, etoposide, and vincristine) given intravenously every 3 to 4 weeks followed by consolidation (the use of a different dose of the same drug, a different drug, or different treatment modality) with the focal surgical techniques of direct tumor photocoagulation or cryotherapy or both.40
One of the authors (ALM) first suggested the use of the term chemoreduction for what we were beginning to do in the treatment of retinoblastoma in the Franschescetti Lecture at the International Symposium on Retinoblastoma in Switzerland in 1992. At the time, he thought it might be a convenient shorthand way to describe the use of primary systemic chemotherapy to reduce the volume of the tumor followed by local surgical modalities (laser or cryo) to consolidate the initial massive, but incomplete, tumor cell kill by the chemotherapy.
We no longer use that term, because it implies that in treating retinoblastoma we are using an approach unique to this tumor. That is not the case. In fact, every effective treatment regimen for solid tumors that includes primary systemic chemotherapy requires consolidation to accomplish complete tumor destruction. Systemic chemotherapy alone, in virtually no solid tumor, will sterilize the tumor. A better terminology