Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Retinal Disease_Wright, Spiegel, Thompson_2006

FIGURE 9-2. Fundus photograph of typical endophytic retinoblastoma: right eye of an 18-month-old child who presented with a 2-month history of an “unusual glint or reflex” in the right pupil. There is no tumor in the left eye, and the family history is entirely negative for evidence of retinoblastoma or other childhood cancers. This tumor has the smooth, regular margins that are characteristic of endophytic retinoblastoma. Calcium inclusions can sometimes be seen in these tumors, and they are present in this case. The “lacunae” or clear spaces within the tumor mass are areas of glial differentiation. The creamy, yellow-white, yogurt-like appearance indicates viable retinoblastoma. The initial diagnosis made well into the second year of life, the unifocal, uniocular nature of the tumor, and the absence of a family history are strongly suggestive of sporadic, nonhereditary retinoblastoma. However, these clinical findings do not allow one to be absolutely certain about the genetic status of this child because 15% of genetically predisposed individuals develop retinoblastoma in only one eye.

retinoblastoma are of concern because they can be confused with other disorders. Traumatic hyphema, vitreous hemorrhage, or glaucoma can obscure an underlying retinoblastoma. Such misdiagnoses can lead to an inappropriate surgical intervention. Opening an eye containing an unsuspected retinoblastoma dramatically increases the risk of tumor spread outside the eye.

FIGURE 9-4. Fundus photograph of a 5-year-old child with tuberous sclerosis. This whitish elevated lesion, slightly smaller than one disc in diameter, looks very much like retinoblastoma. This is the early form of the astrocytic hamartoma associated with tuberous sclerosis. Eventually such lesions take on the typical mulberry appearance characteristic of tuberous sclerosis. At this point, however, it could be confused with an active or regressed retinoblastoma.

coma by pushing the lens–iris diaphragm forward and occluding the anterior chamber angle. A surgical procedure for glaucoma should not be undertaken in a child without either a clear view of the posterior pole or an imaging study that rules out the presence of an intraocular mass. In most cases, the presence of a retinoblastoma in an eye does not cause pain. If, however, there is associated hemorrhage or angle-closure glaucoma, then pain may be a presenting symptom.

Epidemiology

Retinoblastoma is a rare disease but is disproportionately important because its misdiagnosis is one of the few errors in the practice of ophthalmology that can lead to the death of a child. The prevalence of retinoblastoma in the developed world seems to be about 11 cases per 1 million children under 5 years of age. A less useful but more commonly used measure is the incidence rate. The incidence is expressed as a ratio of the number of cases

FIGURE 9-6A,B. A 7-year-old boy presented with pain and redness of the left eye of 1 week duration. (A) Physical examination revealed hand motions vision, a mild anterior chamber reaction, and an intense vitreous reaction. The other eye was normal. Because of the child’s age and the presence of anterior and posterior chamber inflammation, toxocara and toxoplasmosis were high on the list of differential diagnoses. (B) Ultrasound and CT demonstrated a posterior pole mass but no evidence of calcification. Because of the presence of the mass (even without calcification), a diagnosis of retinoblastoma was under consideration.

newly diagnosed in any given year to the number of live births recorded in that year. Obviously not all new cases of retinoblastoma are diagnosed in the first year of life, but the ratio is a useful one. The incidence rate most commonly cited is 1 case of retinoblastoma per 15,000 to 18,000 live births.11,33,45,62

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FIGURE 9-6C. (C) The child was treated with a short 3-day course of oral corticosteroids, and the vitreous cleared, revealing a classic retinoblastoma. A repeat CT scan showed calcification for the first time. All the presenting findings in this child were “out of character” for retinoblastoma. A correct diagnosis would not have been made without a high index of suspicion.

The estimate, from several decades ago, of 1 in 15,000 to 1 in 18,000 either is an underestimate or the perceived total number of new cases today is an overestimate. An overestimate could result when the family of a child with retinoblastoma seeks treatment advice in several ocular oncology centers and is counted several times. According to the 2000 census figures, there were 4,340,000 live births in the United States and Canada during that year. If the number of new cases of retinoblastoma generally agreed upon (300 in the United States and 50 in Canada) are, in fact, diagnosed annually, then the incidence figure for retinoblastoma in North America is 1 in 12,400 live births. The incidence rate more commonly cited of 1 in 15,000 require that only 289 cases of retinoblastoma be newly diagnosed in the United States and Canada. There is a great need for a national registry to answer questions such as this. The newly organized Children’s Oncology Group (COG), formed from a merger of the Children’s Cancer Group (CCG) and the Pediatric Oncology Group (POG), is interested in establishing a national retinoblastoma registry.

Worldwide there is evidence that unilateral retinoblastoma may be much more common in some underdeveloped countries, particularly in Mexico and Central America, in the countries of central Africa, and on the Indian subcontinent. There is evidence in one study reported from Mexico that a high incidence of

endemic human papilloma viral (HPV) infection may be associated with the larger than expected number of cases of retinoblastoma.43a It is known that one of the HPV proteins can bind with and inactivate the Rb-1 protein pRb. Inactivating the protein could have the same effect as a mutation in the gene manufacturing the protein: insufficient active protein is available to the cell to halt cell division.

In Los Angeles, the number of Rb patients with Latino surnames is higher than would be expected based on population. We will be studying this issue in collaboration with the author of the report on the HPV as a possible causal factor for the increased number of unilateral cases of retinoblastoma.

Etiology

The protein product of the gene (Rb-1) associated with retinoblastoma is known to be an indispensable component of the normal cell machinery for regulation of its own growth. The normal role of this growth suppressor gene product can be thought of as a stoplight to the traffic of cell growth. For the cell to divide, it must change the light to green (which it accomplishes by attaching a phosphate group and temporarily inactivating the suppressor protein). After completion of one cell division, the traffic light again turns to red (the phosphate group is removed, reactivating the growth suppressor protein). We now know that loss or inactivation of the product of the retinoblastoma gene, RB-1, is required for transformation of a retinoblast into a malignant cell.39 This protein may be missing or defective as a result of either an inactivating mutation or deletion of both maternal and paternal alleles of the Rb gene in chromosomal region 13q14. Knudson predicted that two mutational events were required for the appearance of retinoblastoma, but there was no evidence at that time that the mutational events were allelic (present in both the maternal and paternal copies of the gene).32 It was not until Cavenee and colleagues demonstrated the presence of recessive cancer genes through reduction to homozygosity that the allelic nature of the retinoblastoma mutations was clearly delineated.9

The nongenetic form of retinoblastoma (unifocal, unilateral disease) can result when two independent, inactivating mutations happen by chance to occur together in a single retinal cell. Another possible etiology, as already discussed, is the presence of a viral protein that inactives the Rb-1 gene product. In both scenerios, the germline is uninvolved and thus genetic trans-

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mission of a predisposition to Rb is impossible. Approximately 60% of all retinoblastoma cases are of the unilateral, nonhereditary type. A basic hypothesis of Knudson’s classic publication was that two independent mutational events would take a longer time to occur than a single one, which would explain the observation that children with unilateral, nonheritable retinoblastomas are older on the average than those with an inherited predisposition.30,31,32

In the other 40% of patients, an inactivating mutation or deletion in one of the two alleles of the RB-1 gene (we refer to this event as the “predisposing mutation”) is either inherited from one parent who is known to be affected (10%), or occurs spontaneously in the sperm or egg (90% of spontaneous new mutations are paternal in origin) at or near the time of conception. This event accounts for the common clinical finding of a negative family history of retinoblastoma following the birth of a child with bilateral retinoblastoma. Regardless of whether the predisposing mutation was inherited from a parent or occurred de novo in a sperm or egg, all the cells of the developing child carry the predisposing mutation and have only one normal copy of the Rb gene.

The presence of a single predisposing, inactivating mutation is not, however, sufficient to cause the tumor. A second inactivating mutation is required for tumor formation and occurs in one or more individual retinal cells in each eye, usually as a result of an error at mitosis. Because the frequency of such an event is approximately 1 per million developing retinal cells, and there are several million cells at risk in each eye, several discrete, independently arising retinoblastomas would be expected to occur in each eye of genetically predisposed “gene carriers,” and this is exactly what is observed.

As the second (tumorigenic) mutation occurs by chance alone, the number of tumors in each eye assumes a normal distribution, and about 15% of patients who “carry the gene” develop tumors in only one eye. Such individuals are at risk for transmitting the disease to their children even though they have only unilateral disease. If the tumorigenic mutation does not occur in either eye, the individual is a nonexpressing “gene carrier.”

In approximately 3% of retinoblastoma cases, a karyotypically visible deletion of chromosomal region 13q14 is present. The clinical appearance or phenotype of these patients relates to the extent of the deletion (Fig. 9-7).

A

B

FIGURE 9-7A,B. This 2-year-old child was diagnosed with bilateral retinoblastoma at 4 months of age. (A) Chromosomal analysis demonstrated a significant deletion of one of the two chromosome 13s, including region 13q14, the site of the retinoblastoma gene. (B) The facial photograph shows the features of the 13 q-syndrome: low-set ears and facial dysmorphism. The child was developmentally delayed. At 25 months of age, a preauricular mass was noted on the left side of the child’s face. Excisional biopsy confirmed a primitive neuroectodermal tumor. This second malignant neoplasm occurred within the field of the previous external beam radiotherapy.

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Staging of Retinoblastoma

The terminology in this area is treacherous. “Staging” is generally used in oncology to define how extensively a tumor has become disseminated throughout the body. Because spread of retinoblastoma outside the eye is rare in the developed world, the use of the word staging should be reserved for the child with known metastatic disease. In ocular oncology, because we are almost always contending with tumor confined to the eye when retinoblastoma is first diagnosed, the term grouping is more appropriate.

The currently available Reese–Ellsworth grouping of retinoblastoma is outdated and needs revision. The Reese– Ellsworth (R-E) classification was originally developed in the late 1960s and early 1970s as a guide to predicting visual prognosis in eyes treated primarily with external beam radiotherapy.47 Both tumor size and location were assigned major roles in the R-E grouping. More than 10 years ago, most ocular oncology centers treating this disease began using chemotherapy as primary therapy.

With primary chemotherapy, tumor size and location is less important than the presence of intraocular dissemination of the tumor in predicting ultimate outcome. The beta version of a new classification for intraocular retinoblastoma is currently being evaluated in a number of major centers internationally. Publication is expected soon.

Clinical Presentation

NATURAL HISTORY

The natural history of retinoblastoma is to fill the eye, then continue local expansion into the periocular tissues (Fig. 9-8), and finally the brain. Bloodborne metastases may occur before, during, or after local extension and spread the tumor to distant sites, primarily bone and bone marrow. The disease is uniformly fatal if left untreated. Occasionally, an apparent retinoblastoma (retinoma) may display evidence of involution and appear as a treated scar (Fig. 9-9).

Early retinoblastoma lesions are barely perceptible, round elevations in the retina, and are sometimes found only by detecting the circular retinal reflex formed by their shape. Multiple lesions appear at various times in genetically predisposed