Journal of Pediatric Ophthalmology and Strabismus

Incidence and Survival Characteristics of Retinoblastoma in Singapore From 1968-1995

Seang-Mei Saw, MBBS, MPH, PhD; Nikolle Tan, MBBS; Sao-Bing Lee, MBBS; Kah-Guan Au Eong, MMed(Ophth), FRCS(Edin), FRCS(Glass); Kee-Seng Chia, MMed(OM), MD, FAMS

Abstract

ABSTRACT

Purpose: To describe the incidence and survival of 69 Singapore residents with retinoblastoma in all Singapore hospitals from 1968-1995.

Methods: Data of all Singapore residents diagnosed with retinoblastoma from 1968-1995 were collected by the Singapore Cancer Registry based on notifications from physicians, pathology records, hospital discharge records, and death certificates. The medical records of 46 patients were traced, and information on laterality of tumor, spread of tumor, mode of treatment, and family history of retinoblastoma was obtained. Time trends and survival characteristics of the cohort were described.

Results: The incidence rate of retinoblastoma was 2.4 per 1 million for children <9 years and 11.1 per 1 million for children <5 years. The incidence of retinoblastoma has been almost uniform over time from 1 968-1 995, except for an apparent increase in 1988-1992. The 3-year survival rate for retinoblastoma was 83%. Survival rates were higher in children <2 years because children who present at a younger age may have tumors diagnosed at earlier stages of the disease. There was no difference in survival rates for sex, race, laterality, family history of retinoblastoma, treatment, or year of diagnosis.

Conclusion: Retinoblastoma is the most common eye cancer in children that may cause blindness or death. The incidence rates of retinoblastoma in Singapore have remained fairly stable over 28 years, and the survival rate is higher in younger children. This study will be helpful in monitoring future disease patterns in Asian populations.

Journal of Pediatric Ophthalmology and Strabismus 2000;37:87-93.

Abstract

ABSTRACT

Purpose: To describe the incidence and survival of 69 Singapore residents with retinoblastoma in all Singapore hospitals from 1968-1995.

Methods: Data of all Singapore residents diagnosed with retinoblastoma from 1968-1995 were collected by the Singapore Cancer Registry based on notifications from physicians, pathology records, hospital discharge records, and death certificates. The medical records of 46 patients were traced, and information on laterality of tumor, spread of tumor, mode of treatment, and family history of retinoblastoma was obtained. Time trends and survival characteristics of the cohort were described.

Results: The incidence rate of retinoblastoma was 2.4 per 1 million for children <9 years and 11.1 per 1 million for children <5 years. The incidence of retinoblastoma has been almost uniform over time from 1 968-1 995, except for an apparent increase in 1988-1992. The 3-year survival rate for retinoblastoma was 83%. Survival rates were higher in children <2 years because children who present at a younger age may have tumors diagnosed at earlier stages of the disease. There was no difference in survival rates for sex, race, laterality, family history of retinoblastoma, treatment, or year of diagnosis.

Conclusion: Retinoblastoma is the most common eye cancer in children that may cause blindness or death. The incidence rates of retinoblastoma in Singapore have remained fairly stable over 28 years, and the survival rate is higher in younger children. This study will be helpful in monitoring future disease patterns in Asian populations.

Journal of Pediatric Ophthalmology and Strabismus 2000;37:87-93.

INTRODUCTION

Retinoblastoma is the most common primary intraocular malignancy in childhood. Togedier with malignant melanoma, they form the majority of primary eye cancers.1 Retinoblastoma may occur in one or both eyes, and may be either unifocal or multifocal. It occurs in both sporadic and inherited forms whereby 40% of all cases are inherited and the majority of the eye tumors are bilateral. The inheritance is autosomal dominant with a high penetrance of 90%. 2 The retinoblastoma gene is identified in a segment of chromosome band 13ql4, which is frequently deleted in patients with retinoblastoma. The presenting symptoms include leukokoria, strabismus, decreased visual acuity, and buphdialmos. Despite treatment measures such as enucleation, radiotherapy, cryotherapy, photocoagulation, and chemotherapy, there is still significant morbidity and mortality.

The reported incidence of retinoblastoma (ICD-9 9513 9993 95103) varies in different countries. The average incidence rate of children <5 years is estimated to be 1 1 per 1 million in several major studies in die United States.2"4 The NewTfork State Cancer Registry estimated die average annual incidence rate for children <5 years to be 9.5 per 1 million.' The average annual incidence rate of children <5 years in Great Britain is estimated to be 8.4 per 1 million from local cancer registries.6 There are, however, few estimates of population-based incidence rates in Asia.

This study examined die incidence and survival of retinoblastoma from the records of cases reported to die Singapore Cancer Registry from 1968-1995. This nationwide database with follow-up from 1968-1995 allowed us to determine die incidence trends, demographic patterns, and factors determining survival in retinoblastoma patients in Singapore. To date, there is no published population-based data in Asia diat has longitudinally examined die survival experience of patients with retinoblastoma.

MATERIALS AND METHODS

Data used in this study were obtained from the population-based Singapore Cancer Registry.7 Data from die registry of all Singapore residents diagnosed with retinoblastoma from 1 968- 1995 were obtained. Registrations are based on voluntary notifications from physicians, padiology records, hospital discharge records, and deadi certificates. All padiology departments in government and private hospitals notify histologically proven malignancies. Information captured in die registry include place of residence, sex, race, age at diagnosis, date of diagnosis, primary site of cancer, and histology.

Sixty-eight cases of retinoblastoma were diagnosed histologically while one was diagnosed clinically. The midyear population by age, sex, and race was obtained by interpolation of data from die 1970 and 1990 population census. These estimates were used as die denominator to determine die age-, sex-, and race-specific incidence rates. The 95% confidence intervals of die incidence rates of retinoblastoma were constructed by considering the retinoblastoma cases as a function of die Poisson distribution. The medical records of 67% (46) of die patients were traced in die study, more detailed information on laterality of tumor, spread of tumor, mode of treatment, and family history of retinoblastoma was obtained on diese patients.

The baseline characteristics of patients who survived the follow-up period were compared to those who did not survive using the t test for baseline characteristics that were continuous variables and Fishers exact test for categorical variables. The survival time was calculated from the time of diagnosis of retinoblastoma to death or date of last follow-up if still alive. For patients who died prior to die cutoff date (December 31, 1995), the survival time was calculated from the date of diagnosis to die date of death. For subjects who remained alive at die cutoff date, die survival time was calculated as die time from date of diagnosis to the cutoff date. The date and cause of death of all cases in the Singapore Cancer Registry is constantly updated with records from the Registration of Birrhs and Deaths.

Fifteen patients died before December 30, 1995 and 53 patients remained alive until 1995. None of die patients were lost to follow-up. Kaplan-Meier curves diat depicted the survival experience of die 69 cases of retinoblastoma patients in Singapore were constructed. The Cox proportional hazards model was used to describe the survival experience of die cohort, adjusting for potential confounders including age at diagnosis and stage of die tumor. Hazard ratios of the relative survival of retinoblastoma in two groups, adjusted for potential confounders, were calculated.

RESULTS

Sixty-nine cases were identified from 19681995 from the Singapore Cancer Registry (Table 1). There were 33 boys and 36 girls in die study. There were 55 Chinese, 9 Malay, 3 Indian, and 2 patients of orher races. The age of diagnosis ranged from < 1 year to 8 years. Forty-eight (70.6%) patients were diagnosed at age 2 years. Nine patients were diagnosed at <1 year, 19 children were diagnosed at 1 year, 20 children at 2 years, 13 children at 3 years, 3 children at 4 years, 1 child at 5 years, 2 children at 6 years, and 1 child at 8 years. All deaths occurred within 5 years of diagnosis.

Table

TABLE 1CHARACTERISTICS OF 69 RETINOBLASTOMA CASES FROM 1968-1995, SINGAPORE CANCER REGISTRY

TABLE 1

CHARACTERISTICS OF 69 RETINOBLASTOMA CASES FROM 1968-1995, SINGAPORE CANCER REGISTRY

Figure 1: Time trends in retinoblastoma incidence rates among 69 Singapore residents, 1968-1995 (solid line=males and dotted line=females).

Figure 1: Time trends in retinoblastoma incidence rates among 69 Singapore residents, 1968-1995 (solid line=males and dotted line=females).

Medical records were available for 46 patients whereby 28 patients had unilateral and 8 had bilateral tumors. Thirty-one children had no family history of retinoblastoma, while 2 children had a family history of retinoblastoma. The majority (58.7%) of the children were treated with enucleation, with or without radiotherapy, and 48% of die children had retinoblastoma with no extension beyond the optic nerve head.

Figure 1 shows the trends in retinoblastoma rates from 1968-1995. Although the rates of retinoblastoma have been stable over die 28-year period, there is an apparent increase in the annual incidence of retinoblastoma from 1988-1992. Incidence rates may be affected by changes in ICD (International Classification of Diseases) coding or change in access to health care. Singapore is a small island with good infrastructure, and thus it is unlikely that access to treatment may influence incidence rates over time. Stable trends also may indicate that environmental and possibly genetic factors for retinoblastoma have remained stable over die past 28 years.

The incidence rate of retinoblastoma is 2.4 per 1 million for children <9 years and 11.1 per million for children <5 years. The rate for children between 5 and 9 years is 0.3 per million (Table 2).

The 3-year survival rate, or the proportion who were still alive 3 years after the diagnosis of retinoblastoma, was 83%. During the follow-up period, 15 children died and 53 remained alive at the cutoff date (Table 3). Children who remained alive through 1995 were younger (mean age 1.8 years versus 2.6 years), possibly because die tumor was diagnosed at an earlier stage, and there was a higher proportion of Chinese (83.3% versus 66.7%). The children who remained alive through 1995 had earlier stages of diagnosis and were more likely to have bilateral tumors. There was no difference in gender, family history of retinoblastoma, treatment, or calendar year of diagnosis in 5-year intervals between survivors and those who died.

Table

TABLE 2INCIDENCE OF RETINOBLASTOMA FOR DIFFERENT AGE AND SEX GROUPS

TABLE 2

INCIDENCE OF RETINOBLASTOMA FOR DIFFERENT AGE AND SEX GROUPS

Table

TABLE 3BASELINE CHARACTERISTICS OF 69 RETINOBLASTOMA CASES

TABLE 3

BASELINE CHARACTERISTICS OF 69 RETINOBLASTOMA CASES

Table

TABLE 4HAZARD RATIOS OF CHILDREN WITH RETINOBLASTOMA BY AGE AT DIAGNOSIS, YEAR OF DIAGNOSIS, SEX, AND RACE, ADJUSTED FOR AGE OF DIAGNOSIS AND STAGE OF TUMOR AT DIAGNOSIS, SINGAPORE CANCER REGISTRY, 1968-1995

TABLE 4

HAZARD RATIOS OF CHILDREN WITH RETINOBLASTOMA BY AGE AT DIAGNOSIS, YEAR OF DIAGNOSIS, SEX, AND RACE, ADJUSTED FOR AGE OF DIAGNOSIS AND STAGE OF TUMOR AT DIAGNOSIS, SINGAPORE CANCER REGISTRY, 1968-1995

There was a hazard ratio of retinoblastoma of 0.83 (95% confidence interval [CI] 0.51-1.36) for children whose age at diagnosis was >2 years, after adjustment for tumor stage (Table 4). The hazard ratio of retinoblastoma for children with more advanced stages of disease was 25.6 (95% CI 4.76,138.40) after adjusting for die age of diagnosis of disease. There was, however, no significant relationship between year of diagnosis, sex, race, laterality of the tumor, treatment, or family history even after adjustment for age at diagnosis and tumor stage.

Figure 2 shows the cumulative survival pattern for retinoblastoma for children <1 year and >1 year. The survival curve depicts the probability that a person survives longer than a certain time S(t) against time. The survival of children < 1 year was better than the survival of children > 1 year.

DISCUSSION

This study describes the incidence and survival of population-based data on retinoblastoma in Singapore. The data from the Singapore Cancer Registry are believed to be near complete, and we estimated that only a small number of cases would have been missed as health-care access is not a problem in urban Singapore.

Figure 2: Cumulative survival of children with retinoblastoma whose conditions were diagnosed between 1968-1995 in Singapore, stratified by age at diagnosis (solid line=children <1 year and dotted line= children 5=1 year).

Figure 2: Cumulative survival of children with retinoblastoma whose conditions were diagnosed between 1968-1995 in Singapore, stratified by age at diagnosis (solid line=children <1 year and dotted line= children 5=1 year).

There are several limitations in this study. Approximately 2000 Singapore residents emigrate each year, and this information is not captured in the Cancer Registry. Notification of cancers is not mandatory in Singapore, and cases often may not be notified if enucleation is not performed. As this is a retrospective review, not all information on laterality of tumor, spread, mode of treatment, or family history of retinoblastoma, which predicts retinoblastoma survival, was available from the case sheets. Medical records were not available for 23 patients, the majority of whom were seen by ophthalmologists in private practice.

The average annual incidence rate was 2.4 cases per 1 million children (95% CI of 1.3-4 per 1 million) for children aged 0-9 years. This incidence rate is lower than die annual incidence rate of 5.8 cases per 1 million for children < 10 years from the SEER (Surveillance, Epidemiology, and End Results) database from 1974-1985.2,7 The 4.8 incidence rate per 1 million for children <5 years (95% CI of 2.6 to 8.1 per million) is lower than the incidence rate of 10.62 per 1 million for boys and 11.43 per 1 million for girls <5 years from die Third National Cancer Survey from 1969-1971 in the United States and die SEER data from 1974-1976 with 11.05 cases per million for children <5 years.3,4 The comparison of incidence rates varies with the age of the child, geographic location, and degree of ascertainment of all retinoblastoma cases.

The average annual incidence rate appears to be stable over die 28-year period. However, there is a small increase in the incidence of retinoblastoma from 1988-1992, which may indicate a possible rising trend in retinoblastoma rates over the next few decades or a temporary rise in environmental factors, which does not seem likely. This stable trend is similar to die SEER registry data from 1974-1985.2 A New Zealand survey of retinoblastoma cases reported to a central registry by ophrhalmologists in Christ Church during the 30-year period 19481977 showed a steady trend with time.8 A steady trend also was noted in die West Midlands Health Authority Region (WMHAR) in the United Kingdom from 1960-1989.9 International Classification of Diseases coding, mediods of diagnosis, and possible risk factors for retinoblastoma, such as sex and age of diagnosis, did not change dramatically with time.

It is widely recognized diat die survival rate for leukemia, neuroblastoma, and Wilms' tumor is higher in patients who are diagnosed at a younger age. Children with retinoblastoma who were <2 years had a better survival rate compared to older children in Singapore. However, there was no difference in survival for children <2 years after adjustment for tumor stage. Laterality, family history of retinoblastoma, treatment, sex, and race did not affect the survival patterns of children with retinoblastoma.

The prognostic factors for survival in 431 children diagnosed with retinoblastoma in the United Kingdom from 1969-1980 included sex and age at diagnosis.6 Children aged 2=2 years and who were female had a poorer survival. However, no statistical test was conducted, and there was no adjustment for confounding. In the follow-up of 220 children aged 0-9 years with retinoblastoma from die SEER database from 1974-1985, there was a worsening survival with increasing age at diagnosis through age 2 years, but this relationship is less clear in patients >2 years. The survival rate also varies with die degree of spread and the modality of treatment.10 It is possible that tumors in younger children may be smaller or biologically different. One hypodiesis is that the hereditary component of retinoblastoma is associated with bilateral tumors and dius instead of presenting after birth, there is some delay in diagnosis, and the children present at <~2 years of age. The "two-hit" hypothesis suggests diat for a child with genetically determined retinoblastoma, a child is born with one mutation and only needs one more mutation for cancer to develop, whereas for other nonhereditary forms of retinoblastoma, two mutations are needed.

This is the first evaluation of incidence trends of retinoblastoma over a 28-year period from population-based data in Singapore. This study provides new and interesting information on the pattern, survival, and incidence of retinoblastoma. We are not aware of any population-based data of incidence and survival in other Asian populations, and similar studies conducted in orher countries in Asia would be helpful. Similar results of uniformity of trends are seen in the United States and Great Britain. The major risk factors mat affect survival are die stage and size of die tumor, which may explain why children <2 years old with possibly smaller tumors may have a better survival. Since retinoblastoma is a potentially sight- and Iife-direatening condition, efforts to prevent die onset and rapid progression of the tumor may increase overall survival rates.

Retinoblastoma is the most common eye cancer in children that may lead to subsequent death. Associated morbidity may be enormous, with the loss of an eye if enucleation is done, the side effects of chemotherapy, and the presence of persistent visual symptoms. Complications of retinoblastoma include metastatic lesions, perforation of the eyeball, intracranial extension, and die occurrence of a second tumor. More conservative measures of treatment such as intraocular chemotherapy and radiorherapy have become more important as ophthalmologists attempt to conserve large portions of the eyeball. Genetic counseling and diagnosis may be important for the detection of retinoblastoma in family members. Possible measures such as health education of the public and screening of family members of retinoblastoma patients are possible preventive measures. Further studies in other Asian populations that examine the incidence and survival with age, race, sex , laterality, and treatment modality may lead to a better understanding of die risk factors for retinoblastoma.

REFERENCES

1. Keller AZ. Histology, survivorship and related factors in the epidemiology of eye cancers. Am J Epidemiol 1973;97:386-393.

2. Tamboli A, Podgor MJ, Horm JW. The incidence of retinoblastoma in the United States: 1 974 through 1985. Arch Ophthalmol 1990;108:128-132.

3. Pendergrass TW, Davis S. Incidence of retinoblastoma in the United States. Arch Ophthalmol 1980;98:104-1210.

4. Devesa SS. The incidence of retinoblastoma. Am J Ophthalmol 1975;80:263-265.

5. Mahoney MC, Burnett WS, Majerovics A, Tanenbaum H. The epidemiology of ophthalmic malignancies in New York Sute. Ophthalmology. 1990;97:1143-1147.

6. Sanders BM, Draper GJ, Kingston JE. Retinoblastoma in Great Britain 1969-1980: incidence, treatment, and survival. Br J Ophthalmol 1988;72:576-583.

7. Chia KS, Lee HP, Seow A, Shanmugaratnam K. Trends in Cancer Incidence in Singapore 1968-1992. Singapore: Singapore Cancer Registry; 1996. Report #4.

8. Suckling RD, Fitzgerald PH, Stewart J, Wells E. The incidence and epidemiology of retinoblastoma in New Zealand: a 30-year survey. BrJ Cancer. 1982;46:729-736.

9. Parkes SE, Amoaku WM, Muir KR, Willshaw HE, Mann JR. Thirty years of retinoblastoma (1960-1989): changing patterns of incidence. Paediatr Perinat Epidemiol 1994;8:282-291.

10. Anonymous. Survival rate and risk factors for patients with retinoblastoma in Japan. The Committee for die National Registry of Retinobiastona. Jpn J Ophthalmol 1992;36:121-131.

TABLE 1

CHARACTERISTICS OF 69 RETINOBLASTOMA CASES FROM 1968-1995, SINGAPORE CANCER REGISTRY

TABLE 2

INCIDENCE OF RETINOBLASTOMA FOR DIFFERENT AGE AND SEX GROUPS

TABLE 3

BASELINE CHARACTERISTICS OF 69 RETINOBLASTOMA CASES

TABLE 4

HAZARD RATIOS OF CHILDREN WITH RETINOBLASTOMA BY AGE AT DIAGNOSIS, YEAR OF DIAGNOSIS, SEX, AND RACE, ADJUSTED FOR AGE OF DIAGNOSIS AND STAGE OF TUMOR AT DIAGNOSIS, SINGAPORE CANCER REGISTRY, 1968-1995

10.3928/0191-3913-20000301-07

Sign up to receive

Journal E-contents