Saskia M. Imhof

Risk of Second Malignancies in Survivors of Retinoblastoma: More Than 40 Years of Follow-up

BACKGROUNDnSurvivors of hereditary retinoblastoma have an elevated risk of developing second malignancies, but data on the risk in middle-aged retinoblastoma survivors (ie, those with more than 40 years of follow-up) are scarce.nnnMETHODSnData from the Dutch retinoblastoma registry were used to analyze risks of second malignancies in 668 retinoblastoma survivors, diagnosed from 1945 to 2005 (median age = 24.9 years) and classified as having had hereditary or nonhereditary disease based on the presence of family history, bilateral disease, or a germline RB1 mutation. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) of subsequent cancers in patients with hereditary and nonhereditary disease were estimated by comparison with Dutch sex-, age-, and calendar year-specific rates. Multivariable Cox regression and competing risk analyses were used to determine associations of treatment with risks of second malignancies. All statistical tests were two-sided.nnnRESULTSnAfter a median follow-up of 21.9 years, the risk of second malignancies in survivors of hereditary retinoblastoma (SIR = 20.4, 95% confidence interval [CI] = 15.6 to 26.1) far exceeded the risk of survivors of nonhereditary retinoblastoma (SIR = 1.86, 95% CI = 0.96 to 3.24). Among patients with hereditary disease, treatment with radiotherapy was associated with a further increase in the risk of a subsequent cancer (hazard ratio = 2.81, 95% CI = 1.28 to 6.19). After 30 years of follow-up, elevated risks of epithelial cancers (lung, bladder, and breast) were observed among survivors of hereditary retinoblastoma. After 40 years of follow-up, the AER of a second malignancy among survivors of hereditary retinoblastoma had increased to 26.1 excess cases per 1000 person-years. The cumulative incidence of any second malignancy 40 years after retinoblastoma diagnosis was 28.0% (95% CI = 21.0% to 35.0%) for patients with hereditary disease.nnnCONCLUSIONnOur analysis of middle-aged hereditary retinoblastoma survivors suggests that these individuals have an excess risk of epithelial cancer. Lifelong follow-up studies are needed to evaluate the full spectrum of subsequent cancer risk in hereditary retinoblastoma survivors.

Second primary tumors in patients with retinoblastoma: a review of the literature

PURPOSEnThe aim of this survey was to review the different studies regarding the occurrence of second primary tumours (SPT) among survivors of retinoblastoma.nnnMETHODSnOvid (Medline, Current contents life, Psychlit, Embase) was searched for the years 1966-1995 using the mesh headings: retinoblastoma, second primary neoplasms, and multiple primary neoplasms. The inclusion criteria were: the study should involve 50 patients or more and should not be limited to one specific SPT. A checklist with criteria regarding the study design and the results was applied to each study.nnnRESULTSnEleven studies were identified which met the inclusion criteria. Thirty-five different types of SPT (Ntotal = 243) were reported. Most of them were osteosarcomas (37.0%), followed by melanomas (7.4%), soft-tissue sarcomas (6.9%), brain tumors (4.5%), fibrosarcomas (3.3%), chondrosarcomas (3.3%), and sarcomas (3.3%). Less frequently reported were leukemias (2:4%), sebaceous cell carcinomas (1.6%), and non-Hodgkin lymphomas (1.6%). Pineoblastoma, which in fact is a trilateral retinoblastoma and not an SPT, was found in 2.4%. Despite the differences, all 11 studies showed a higher incidence of SPT compared to the general population. Only 4 studies were judged to be free from selection bias, reporting a cumulative incidence of SPT of 8.4% 18 years after diagnosis, 15.7% at the age of 20 years, 19% at the age of 35 years, and a relative risk of 15.4 for SPT, respectively.nnnCONCLUSIONnSPT is a serious problem for the survivors of hereditary retinoblastoma and its importance should be recognized in (genetic) counseling of patients.

Second primary tumors in patients with hereditary retinoblastoma: A register-based follow-up study, 1945-1994

The aim of this register‐based follow‐up study was to evaluate the long‐term cumulative incidence of second primary tumors (SPT) among survivors of hereditary retinoblastoma, with special interest for the incidence of pineoblastoma in retinoblastoma patients born after 1970. The Dutch Retinoblastoma Register was completed and updated: in the period 1945–1994, 639 retinoblastoma patients were registered. The vital status of each patient was obtained from the municipal registries and the Central Office of Genealogy. SPT were traced and histopathologically confirmed. Survival curves and cumulative incidence of SPT were calculated by the Kaplan‐Meier method. The survival of patients with hereditary retinoblastoma was significantly shorter than that of patients with non‐hereditary retinoblastoma. The cumulative incidence of SPT in hereditary patients was 3.7 and 17.7% at the ages of 10 and 35 years, respectively. Long‐term follow‐up revealed a high proportion of melanomas (7 melanomas out of 28 SPT). In the sub‐cohort of the hereditary‐retinoblastoma patient group born after 1970, the cumulative incidence of pineoblastomas at the age of 5 years was 9.3%. Our results suggest that patients with hereditary retinoblastoma should have careful follow‐up, and procedures for diagnosing SPT and pineoblastomas at an early and potentially treatable stage should be developed.

Incidence and survival of retinoblastoma in the Netherlands: a register-based study 1862-1995

AIM The aim of this study was to determine the (time trends in) incidence and survival of hereditary (familial and sporadic) and non-hereditary retinoblastoma for male and female patients born in the Netherlands between 1862 and 1995. METHOD The national retinoblastoma register was updated and now consists of 955 patients. The missing dates of death were obtained from the municipal registers and the Central Bureau of Genealogy in The Hague. Mortality was compared with the Dutch vital statistics. RESULTS From 1862 to 1995 no significant differences in incidence for retinoblastoma were found in the hereditary subgroups. Further, no significant differences between males and females were found, both overall and in the hereditary subgroups. The average incidence of retinoblastoma increased untill 1944, probably due to incompleteness of the register, and stabilised after 1945 (1 per 17u2009000 live births). From 1900 to 1995 the standardised mortality ratio increased for hereditary retinoblastoma patients from 2.9 to 9.0 and decreased for non-hereditary retinoblastoma patients from 1.9 to 1.0. CONCLUSION Although survival for retinoblastoma was significantly better after 1945 than before, in comparison with the Dutch population the mortality between 1900 and 1990 increased for the hereditary and decreased for the non-hereditary retinoblastoma patients.

Quantification of orbital and mid-facial growth retardation after megavoltage external beam irradiation in children with retinoblastoma

PURPOSEnThe late side effects of external beam irradiation in patients with retinoblastoma such as orbital bony growth retardation, are a serious problem in adolescence. Therefore, a quantitative study was performed to investigate the late effects of irradiation on orbital growth in patients with retinoblastoma.nnnMETHODSnThe orbits of 68 patients with retinoblastoma, 52 bilateral and 16 unilateral, were divided into two treatment groups: radiotherapy alone, 77 orbits; and radiotherapy + enucleation, 43 orbits. Follow-up time was 12 to 240 months (mean, 95 months) in group 1 and 27 to 216 months (mean, 97 months) in group 2. These groups were subdivided further into age groups at which radiotherapy was given. The morphometric measurements of these groups were compared.nnnRESULTSnThe authors showed that irradiation causes a significant growth retardation when compared with the growth of nonirradiated orbits (P<0.001). They also demonstrated that radiotherapy in children younger than 6 months of age is more damaging to the orbital growth than at an older age (P<0.01). Finally, the authors showed that secondary enucleation does not have an additive growth-retarding effect.nnnCONCLUSIONnOrbital growth retardation in patients with retinoblastoma after radiotherapy is influenced mainly by the age at which irradiation is given and is defined at 6 months. Theoretically, it would be desirable to postpone irradiation in children until they are older than 6 months of age if possible. The irradiation effect on these orbits is not enhanced by enucleation.

High parental age is associated with sporadic hereditary retinoblastoma: the Dutch retinoblastoma register 1862-1994.

Abstract We wished to determine the influence of parental age at the birth of a retinoblastoma patient on the risk of sporadic hereditary retinoblastoma. The parental age at birth of 941 patients of the Dutch retinoblastoma register (1862–1994) was identified and compared between sporadic hereditary and nonhereditary patients. In a subcohort (1936–1994), a comparison was made with parental age at birth in the general population, as obtained from the Central Bureau of Statistics. Missing birth dates of the parents of retinoblastoma patients were traced with the help of the municipal registries and the Central Bureau of Genealogy. The mean paternal age was 10.7 months higher and the mean maternal age was 11.0 months higher in the sporadic hereditary retinoblastoma patients than in parents of nonhereditary patients. In the subcohort, the mean paternal and maternal ages of sporadic hereditary patients were also higher (12.4 and 11.5 months, respectively) than those of the general population. All differences were statistically significant. This study shows that a high parental age is associated with an enhanced risk of sporadic hereditary retinoblastoma.

At what age could screening for familial retinoblastoma be stopped? A register based study 1945–98

AIM To evaluate until what age children in families with retinoblastoma should be screened. METHODS A register based cohort (n= 685) study of Dutch retinoblastoma patients (1945–1998). The records of all familial hereditary retinoblastoma patients from 1945 were reviewed and the age at diagnosis and either they were screened from birth determined. RESULTS 75 patients had the familial hereditary form of retinoblastoma. The mean age at diagnosis in patients with fundus screening (n=50) from birth on was 4.9 months (median 1.9 months; range 1 day to 48 months). Thus, 4 years was the latest onset of familial retinoblastoma properly evaluated from birth. This mean age was significantly different (p<0.0001) from the mean age at diagnosis in patients without fundus screening (n=25) from birth (mean 17.2 months; median 10.0 months; range 1.5–63.0 months). CONCLUSIONS Ophthalmological screening of children and sibs at risk for familial hereditary retinoblastoma is recommended until the age of 4 years in order to detect retinoblastoma as early as possible.

Quantification of lacrimal function after D-shaped field irradiation for retinoblastoma.

To study the quantitative effects of megavoltage external beam irradiation in a D-shaped field in patients with retinoblastoma, biomicroscopy was performed in 61 patients and tear function tests (Schirmer-lactoferrin and lysozyme tests) on 45 eyes in 34 irradiated patients. The results were compared with those obtained in 25 non-irradiated control eyes. The Schirmer test was significantly diminished (p < 0.001) in irradiated eyes, as were the lactoferrin and lysozyme values (p < 0.001). A mild to severe keratitis was found in 17 of the 61 patients (28%). A significant correlation (p < 0.005) was found between the severe keratitis and the mean Schirmer values; the mean lactoferrin and lysozyme values were diminished in all patients but did not correlate significantly with the corneal abnormalities. These quantitative data, obtained in patients treated for retinoblastoma, affirm the qualitative data found in patients irradiated for other reasons such as orbital or sinus tumours. Irradiation for retinoblastoma is not a harmless treatment and serious late side effects have to be considered.

A second primary tumor in a patient with retinoma

Aim: To evaluate the frequency of the co-occurrence of a retinoma and another primary tumor. Method: Presentation of a case report and review of the literature. Results: A cutaneous melanoma was observed in a 52-year-old man, who was known to have two retinomas in the right eye. Five other cases were found in a review of the literature, suggesting the possibility of an increased risk of developing a second primary tumor in patients with retinoma. The occurrence of cutaneous melanoma as a second primary tumor after retinoma and/or retinoblastoma is discussed. Conclusion: There might be an increased risk for patients with retinoma to develop another primary tumor, necessitating regular follow-up of these patients.

Prevalence of mental retardation in patients with hereditary retinoblastoma

Dear Editor, We evaluated the cumulative incidence of mental retardation in patients with hereditary retinoblastomai. Records of the national Dutch retinoblastoma register were used. This register is complete from 1945 through 1994. Cooperation of the hereditary retinoblastoma patients or their parents was solicited by a letter from the ophthalmologist. The patients with hereditary retinoblastoma born between 1945 and 1970 were visited at home in 1985.1 On that occasion, information on mental retardation was collected. In addition, questionnaires were sent in 1993 to the patients parents or caregivers to obtain up-to-date information regarding the patients condition, visual acuity, and second primary tumors.