Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003
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Epidemiology of Retinoblastoma |
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If one plots the sums of the yearly incidence figures shown in Figure 1 as a function of age at diagnosis, one obtains the curves shown in Figure 2. Both curves exhibit a rapid rise during the first 3 years, progressive flattening of slope over the next 5 years, and an almost flat slope thereafter for the remainder of life. The curves approach asymptotes of approximately 62.5 and 56.5 cases per million persons respectively. These asymptotic values are known as cumulative lifetime incidence rates of retinoblastoma. By dividing both the numerator and denominator of these cumulative incidence rates by the value of the numerator, one can express these rates as fractions with the value 1 in the numerator. By this transformation, the data presented in Figures 1 and 2 can be shown to correspond with cumulative lifetime incidence rates of approximately 1 in 15,000 to 1 in 18,000 individuals. For reasons unclear to this author, these cumulative lifetime incidence figures are commonly expressed as cases per million live births. Inspection of Figure 2 shows quite clearly that almost all cases of retinoblastoma are diagnosed prior to the age of 10 years, with the majority of cases being diagnosed prior to 3 years.
B.Prevalence of Retinoblastoma
In contrast with incidence, prevalence is an expression of the frequency of a disease or condition in a defined population at a specified point in time. The denominator is the number of individuals evaluated, and the numerator is the number found to have the disease or condition of interest at that evaluation. The specified point or window in time is the period during which all of the evaluations were carried out. This can be the same day relative to the date of birth or death of all subjects, the amount of time
Figure 2 Cumulative lifetime incidence curves for retinoblastoma derived from the annual incidence curves shown in Figure 1. Solid line curve is based on data from the United States, while dashed line curve is hypothetical but approximates cumulative incidence values one would encounter in a third-world country. Asymptote for upper curve is approximately 62.5 cases per million and that for lower curve is approximately 57.5 cases per million.
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required to perform a cross-sectional evaluation of a large population, or some other specified but limited time interval.
When one evaluates the prevalence of retinoblastoma, one must recognize that retinoblastoma is a disease that is almost always either completely cured or fatal within 2 to 3 years following initial diagnosis. Long remissions followed by local or metastatic recurrence of this malignancy are extremely uncommon. Unlike incidence, which relates to occurrence, prevalence falls as individuals who previously had the disease or condition are removed from the ranks of affected persons because of cure or death. An individual who is dead cannot be evaluated in a cross-sectional study of living patients. Similarly, an individual who previously had retinoblastoma but is now cured (e.g., following enucleation of the affected eye in a patient with unilateral intraocular disease) no longer has the disease and cannot be identified as having viable retinoblastoma in a cross-sectional survey. Consequently, the prevalence of retinoblastoma in any randomly selected segment of the population at any point in time will be exceptionally low. To this author’s knowledge, no figures on prevalence of retinoblastoma have ever been published.
III.DEMOGRAPHICS OF RETINOBLASTOMA
A.Age at Diagnosis
As pointed our in the preceding section, retinoblastoma is almost exclusively a disease of childhood. If one plots the cumulative percentage of cases of retinoblastoma already diagnosed in a series of children with retinoblastoma as a function of age of the affected individual at initial diagnosis, one obtains a curve similar to the one shown in Figure 3. This particular curve is bases on data collected in the Retinoblastoma International Collaborative Study [20]. Inspection of Figure 3 reveals that over 90% of all cases of viable retinoblastoma are detected and diagnosed in children under the age of 6 years and approximately 99% of all cases are diagnosed prior to the age of 10 years. The point where the curve crosses the 50% line on the Y axis is referred to as the median age at diagnosis in the evaluated group of retinoblastoma patients. For the data plotted in Figure 3, the median age at diagnosis for the group is approximately 1.5 years (18 months). Retinoblastoma is occasionally detected as a congenital or even intrauterine disorder [21] (i.e., detected by a pelvic imaging study during pregnancy), especially in familial cases. At the other extreme, retinoblastoma is initially diagnosed after the age of 10 years in occasional cases and even after the age of 20 years in exceptional cases [22]. Many of newly diagnosed cases of retinoblastoma in juveniles and adults are currently believed to arise from a pre-existent retinoma (spontaneously arrested retinoblastoma, retinocytoma) that reverted to viable retinoblastoma.
Several factors influence the exact position of the curve on a graph of the cumulative percentage of cases of retinoblastoma already diagnosed versus age of the affected individual at diagnosis. The curve tends to be further to the left in countries with a high-quality health care delivery system and relatively prompt presentation of symptomatic persons to that system and further to the right in countries with a less well developed health care delivery system and relatively delayed presentation of symptomatic persons to eye care professionals. The impact of promptness versus
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Figure 3 Graph showing percentage of cases already diagnosed as a function of age at diagnosis for newly diagnosed patients with retinoblastoma. Median age at diagnosis in group is approximately 18 months.
lateness of presentation of symptomatic patients to eye care professionals is reflected by the finding of a substantially higher proportion of patients with more advanced retinoblastoma at initial diagnosis in countries with a poorly developed health care delivery system for a substantial portion of their citizens [1].
B.Sex
Retinoblastoma affects males and females almost equally. Curves of cumulative percentage of cases already diagnosed versus age of the affected individual at initial diagnosis for males and females are virtually identical.
C.Race
Retinoblastoma occurs in all ethnic and racial groups. The cumulative lifetime incidence of the disease appears to be similar in all of these groups [16]. For reasons mentioned above, however, annual incidence curves and the exact positions of curves of the cumulative percentage of cases already diagnosed versus age of the affected individual at diagnosis for various racial groups may differ to some extent in different geographic locations.
D.Socioeconomic Group
Retinoblastoma appears to affect individuals in various socioeconomic groups equally. However, because patients of lower socioeconomic groups do not present as early on average for health care evaluations following onset of symptoms as do those from higher socioeconomic groups, the percentage of patients with more advanced
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forms of the disease at initial diagnosis and the median age at diagnosis both tend to be substantially higher among those of lower socioeconomic status [1].
E.Number of Eyes Affected
Retinoblastoma occurs in both unilateral and bilateral forms. In most large series, approximately 70% of cases are unilateral and 30% are bilateral. Most bilateral cases already exhibit bilateral ocular involvement when the disease is first detected, but occasional cases that are unilateral at initial diagnosis eventually become bilateral during follow-up [20]. Among individuals with unilateral retinoblastoma at initial diagnosis, the younger the child at the time of diagnosis, the higher the probability of subsequent conversion to bilaterality [23].
If one divides a group of patients with retinoblastoma into subgroups according to unilaterality or bilaterality of disease and then plots the cumulative percentage of cases already diagnosed as a function of age of the affected individual at initial diagnosis for each subgroup, one obtains curves similar to those shown in Figure 4. The data on which these curves are based again comes from the Retinoblastoma International Collaborative Study (RICS) [20]. Inspection of Figure 4 reveals a shift of the ascending limb of the curve of the bilateral cases to the left compared with the curve for unilateral cases. The median age at diagnosis of retinoblastoma in the RICS patients with bilateral ocular involvement was approximately 12 months, while that in the RICS patients with monocular ocular disease was approximately 24 months.
Figure 4 Graph showing percentage of cases already diagnosed as a function of age at diagnosis for patients with monocular retinoblastoma (solid line curve) and binocular retinoblastoma (dashed line curve). Median age at diagnosis is approximately 12 months for binocular cases and 24 months for monocular cases.
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F.Number of Discrete Tumors
Retinoblastoma occurs in unifocal and multifocal forms in affected eyes. Individuals with bilateral disease have a much higher frequency of multifocal involvement in one or both eyes than do individuals with unilateral disease. Most persons with unilateral disease also have unifocal disease in the affected eye. In contrast, most persons with bilateral disease develop multifocal tumors in both eyes.
IV. RISK FACTORS FOR RETINOBLASTOMA
A risk factor is a feature or characteristic of persons in the general population that is strongly associated with a disease or condition of interest. Risk factors are generally identified by case-control studies in which the frequency of a feature or characteristic in individuals with the disease or condition of interest is compared with the frequency of the feature or characteristic in similar individuals without the disease or condition. Although risk factors are by definition strongly associated with the disease or condition of interest, they are not necessarily causative of the disease or condition.
Several risk factors for retinoblastoma have been identified over the years. These factors include a positive family history of retinoblastoma, deletion or inactivation of one allele of the retinoblastoma gene in somatic retinoblasts, advanced parental age at the time of an affected child’s conception, and early-onset primitive neuroectodermal tumors in the pineal, suprasellar, or parasellar regions of the brain. Environmental factors such as intense sunlight exposure and ultraviolet light exposure have been linked by some investigators [24,25] but have not been confirmed by most researchers.
A.FAMILY HISTORY OF RETINOBLASTOMA
The risk of retinoblastoma is substantially increased if either of a child’s parents had prior retinoblastoma [26]. The risk is most pronounced if the family member had bilateral disease, multifocal intraocular disease, or both. If one plots the cumulative percentage of cases already diagnosed versus age of the affected patient at the time of initial diagnosis for subjects with a positive versus negative family history of retinoblastoma, one obtains curves similar to those shown in Figure 5. Once again, these particular curves are based on data from the Retinoblastoma International Collaborative Study (RICS) [20]. Inspection of Figure 5 reveals that the median age at diagnosis in the patients with a positive family history of retinoblastoma was about 9 months, while that in the patients with a negative family history was approximately 1.7 years.
B.Loss or Inactivation of Retinoblastoma Gene in Somatic Cells
Whenever one allele of the retinoblastoma gene on the long arm of chromosome 13 is lost or inactivated in all somatic cells, the retinoblasts in the developing retina have a substantially increased risk of developing retinoblastoma by undergoing a deletion, translocation or other mutation of the remaining retinoblastoma gene allele.
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Figure 5 Graph showing percentage of cases already diagnosed as a function of age at diagnosis for patients with a positive family history of retinoblastoma (solid line curve) and a negative family history of retinoblastoma (dashed line curve). Median age at diagnosis is approximately 9 months for familial cases and 1.7 years for nonfamilial cases.
Estimates suggest that the average number of retinoblasts likely to undergo a spontaneous mutation of the intact retinoblastoma gene allele leading to retinoblastoma in the presence of loss or inactivation of one allele of the retinoblastoma gene in all somatic cells is approximately five to six per eye [27]. Methods of detection of such gene defects are described in Chapter 7.
If a relatively major portion of the long arm of chromosome 13 is deleted from the either the sperm or the egg or does so in the early stages of development following fertilization, a child may be born with both a dysmorphic syndrome, the chromosome 13q deletion syndrome [28–30], and a predisposition to develop retinoblastoma. A spectrum of dysmorphic features can occur, the nature and severity of which appear related to the extent and location of the deletion. The most commonly reported dysmorphic features are prominent eyebrows, broad nasal bridge, bulbous tipped nose, large mouth, and a thin upper lip and long philtrum [30]. The recognized association between deletions of the long arm of chromosome 13 and retinoblastoma should remind ophthalmologists to recommend karyotype analysis whenever a dysmorphic syndrome is noted in a child with retinoblastoma and alert neonatalogists and pediatricians to request ophthalmic evaluation of any child with a dysmorphic syndrome associated with a deletion of the long arm of chromosome 13.
C.Advanced Parental Age
The parents of children who develop sporadic hereditary retinoblastoma tend to be slightly but significantly older on average than parents of age and sex-matched children who do not develop this disease [31,32]. Some investigators have suggested that increased chromosomal fragility exists in older parents and such parents are therefore more likely to generate spermatocytes or oocytes having various
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chromosomal defects, including deletions or other defects that inactivate the retinoblastoma gene [32].
D.Early-Onset Primitive Neuroectodermal Intracranial Tumors
Development of a primitive neuroectodermal neoplasm in the pineal gland or in parasellar or suprasellar regions of the brain occasionally precedes development of intraocular retinoblastoma in children with hereditary disease. Because of this association, every child with an early onset primitive neuroectodermal tumor of the types mentioned above should probably be examined for retinoblastoma and followed as a retinoblastoma suspect. More information about such tumors is contained in the following section.
V.IMPORTANT EXTRAOPHTHALMIC LESIONS AND DISORDERS ASSOCIATED WITH RETINOBLASTOMA
A.Ectopic Intracranial Retinoblastoma
Ectopic intracranial retinoblastoma is a malignant central nervous system neoplasm that resembles intraocular retinoblastoma both histomorphologically and immunohistochemically [33–35]. It arises either from the immature pineal gland, in which case it is termed pineoblastoma, or from ectopic suprasellar or parasellar rests of immature neuroectodermal tissue. This type of tumor is almost exclusively associated with germinal retinoblastoma. Because individuals with germinal retinoblastoma usually have bilateral ocular disease, the association of ectopic intracranial retinoblastoma with germinal retinoblastoma is commonly referred to as trilateral retinoblastoma. Approximately 6–10% of individuals with germinal retinoblastoma eventually develop trilateral retinoblastoma. If one evaluates a series of patients with trilateral retinoblastoma and plots the cumulative percentage of intraocular and ectopic intracranial retinoblastomas already diagnosed as a function of age at diagnosis of each form of this malignancy, one obtains a curve similar to that shown in Figure 6. Inspection of Figure 6 reveals that the median age at diagnosis of ectopic intracranial retinoblastoma in patients with germinal retinoblastoma is approximately 1.8 years. Note also that the median age at diagnosis of the intraocular retinoblastoma in these patients was only about 4.0 months.
In the majority of cases, ectopic intracranial retinoblastoma is diagnosed subsequent to detection and diagnosis of the intraocular tumors. In a metanalysis of reported cases of trilateral retinoblastoma, Kivela and coworkers [35] found a median interval between diagnosis of the retinal and central nervous system tumors of 21 months. However, the range was from 6 months prior to diagnosis of the retinal tumors to 141 months after diagnosis of the intraocular lesions.
The usual presenting symptoms of ectopic intracranial retinoblastoma (when the lesion is not detected at an asymptomatic stage by neuroimaging at the time of diagnosis of intraocular retinoblastoma) are somnolence, lethargy, vomiting, and failure to thrive. Older children may complain of headaches. In children with clinically apparent intraocular retinoblastoma, the finding of a pineal, suprasellar, or
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Figure 6 Graph showing percentage of cases of retinoblastoma (solid line curve) and ectopic intracranial retinoblastoma (dashed line curve) already diagnosed as a function of age at diagnosis for patients with trilateral retinoblastoma. Median age at diagnosis of retinoblastoma is about 4 months while that at diagnosis of ectopic intracranial retinoblastoma is about 1.8 years.
parasellar mass on central nervous system neuroimaging is usually considered sufficient for diagnosis of ectopic intracranial retinoblastoma. Lumbar puncture for cerebrospinal analysis and detection of malignant small round cells is indicated in such children to determine whether the ectopic intracranial retinoblastoma has been disseminated up and down the spinal cord within the cerebrospinal fluid. In contrast, in children without familial, bilateral, or multifocal intraocular retinoblastoma in whom the cerebrospinal fluid is negative for malignant cells, establishing the diagnosis of ectopic intracranial retinoblastoma generally entails neurosurgical biopsy of the mass. The survival prognosis for children with disseminated ectopic intracranial retinoblastoma via the cerebrospinal fluid is currently poor [35].
B.Second Primary Malignant Neoplasms
Survivors of germinal retinoblastoma have long been recognized to have a substantially increased risk of one or more extraophthalmic primary malignant neoplasms other than ectopic intracranial retinoblastoma [36–42]. These neoplasms are commonly referred to as second primary tumors. The most frequent of these neoplasms (in descending order, as identified by Moll and coworkers [37] in a large series of cases) are osteogenic sarcoma, various soft tissue sarcomas, and malignant melanomas of the skin. The cumulative incidence of a second primary malignant neoplasm of any type (excluding ectopic intracranial retinoblastoma) in survivors of germinal retinoblastoma, as estimated by Wong and coworkers [39], is shown in Figure 7. Inspection of this figure shows that the vast majority of second primary tumors develop in survivors of germinal retinoblastoma.
External-beam radiation therapy for retinoblastoma, especially if performed prior to the age of 6 months, appears to substantially increase the risk for a second
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Figure 7 Cumulative incidence curves for second primary malignant neoplasms in patients with somatic retinoblastoma (solid line curve) and germinal retinoblastoma (dashed line curve). Cumulative incidence of second primary tumors is over 10 times as high in the germinal cases as in the somatic cases. The germinal case subgroup includes patients treated by externalbeam radiation therapy for retinoblastoma early in life (see Fig. 8).
primary malignant neoplasm within the field of radiation. This effect is illustrated graphically in Figure 8. Inspection of this figure and comparison of the curve for unirradiated germinal retinoblastoma cases with that for somatic cases in Figure 7 reveals that the risk of second primary tumors is increased in germinal retinoblastoma by a factor of about 5. This added risk is attributable to the loss
Figure 8 Cumulative incidence curves for second primary malignant neoplasms in survivors of germinal retinoblastoma if external-beam radiation therapy was employed as retinoblastoma treatment (dashed line curve) and if it was not (solid line curve). Cumulative incidence of second primary tumors in unirradiated germinal subgroup is about four times as high as the rate in the somatic cases (Fig. 7) but less than half the cumulative incidence in the irradiated germinal subgroup.
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or inactivation of one allele of the retinoblastoma gene in virtually all somatic cells of such patients. Further inspection of Figure 8 shows that treatment by external-beam radiation therapy more than doubles the inherent added risk of second primary tumors in survivors of germinal retinoblastoma. This adverse effect of irradiation is less pronounced in children with germinal retinoblastoma treated after 6 months of age and appears to be extremely small in individuals with germinal retinoblastoma who underwent external-beam radiation therapy after the age of 1 year [41,42].
If one plots the percentage of retinoblastomas and second primary tumors already diagnosed as a function of age at diagnosis of the respective neoplasms in a group of retinoblastoma survivors who developed at least one second primary tumor, one obtains curves similar to those shown in Figure 9. These curves are based in part on data reported by Draper and coworkers [36]. Inspection of Figure 9 reveals that the curve for second primary tumors is displaced considerably to the right of that for retinoblastoma. The median age at diagnosis of retinoblastoma in this group of patients who developed a second primary tumor is approximately 1 year while that for initial diagnosis of a second primary tumor is about 15 years. Recent evidence suggests that retinoblastoma survivors who develop a second primary tumor and survive that tumor also have an extremely high risk of developing one or more subsequent second primary tumors.
The long-term impact of currently employed chemotherapy regimens for retinoblastoma on the cumulative incidence of second primary malignant neoplasms is unknown. This uncertainty is attributable to the fact that chemotherapy as primary treatment for germinal retinoblastoma only began to be used widely after the mid-1990s.
Although second primary tumors usually follow diagnosis, treatment, and eradication of retinoblastoma by months to years in survivors of germinal
Figure 9 Graph showing percentage of cases of retinoblastoma (solid line curve) and second primary malignant neoplasm (dashed line curve) already diagnosed as a function of age at diagnosis in retinoblastoma survivors who developed at least one second primary tumor. Median age at diagnosis of retinoblastoma in this subgroup is about 1 year while that at diagnosis of the second primary tumor is about 15 years.