Karel E. W. P. Tan

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 17 000 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

PURPOSE The 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. METHODS The 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. RESULTS The 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. CONCLUSION Orbital 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.

Parental Age in Sporadic Hereditary Retinoblastoma

Of 104 children with sporadic hereditary retinoblastoma born between 1945 and 1970, we studied the age of their parents at the birth and compared this age with the mean age of parents at the birth of their children during the same period in The Netherlands. The mean age of fathers at the birth of their children with sporadic hereditary retinoblastoma (33.7 years) was significantly higher than the mean age of fathers at the birth of their children in the general population (32.5 years) (P less than .05, one sided). Similarly, the mean age of mothers at the birth of their children with sporadic hereditary retinoblastoma (31.2 years) was significantly higher than the mean age of mothers at the birth of their children in the general population (29.5 years) (P less than .05, one sided). We further analyzed this parental age factor by measuring the relative risk of age groups and comparing the incidence of sporadic hereditary retinoblastoma in the various parental age groups with the incidence of sporadic hereditary retinoblastoma in the total population. Mothers 35 years of age or older had a relative risk of 1.7 to have a child with sporadic hereditary retinoblastoma compared with mothers in the population in general (P = .006, one sided). Similarly, fathers 50 years of age or older had a relative risk of 5.0 to have a child with sporadic hereditary retinoblastoma compared with fathers in the population in general (P = .04, one sided). No parental age effect was found in children with nonhereditary retinoblastoma. We conclude that a high paternal and a high maternal age are significant risk factors for sporadic hereditary retinoblastoma.

Non-ocular cancer in hereditary retinoblastoma survivors and relatives.

An epidemiological survey has been carried out to establish the incidence of second malignant neoplasms in hereditary retinoblastoma survivors in The Netherlands and the relative risk of cancer in non-affected relatives. The cumulative incidence of second neoplasms was 19% at the age of 35 years. Fathers, unaffected by retinoblastoma, were at risk for pancreatic cancer, the relative risk being 8.3.

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.

Three histopathological types of retinoblastoma and their relation to heredity and age of enucleation.

The histopathology of 61 eyes was studied with special attention to the morphology of the retina adjacent to the main tumour. Three retinal types were distinguished. Retina type 1 (RT-1, 28 specimens) contained a single tumour that was sharply demarcated from surrounding normal retina. In retina type 2 (RT-2, 29 specimens) large parts of the retina were affected and the main tumour mass gradually blended with the adjacent pathological retina. Retina type 3 (RT-3, four specimens) was characterised by a retina almost entirely affected by diffuse tumour growth. RT-1 correlated significantly with early enucleation (0-3 years) both in hereditary and non-hereditary cases. RT-2 was seen in eyes enucleated later (2-5 years). The progressing tumour may release growth factors in the intraocular space that stimulate the cells of the adjacent retina and lead to multiple new primary tumours in the adjacent retinal area. RT-3 was only present in non-hereditary cases with late enucleation (at 2-5 years). Hereditary retinoblastoma cases are usually detected early. Therefore in hereditary cases RT-1 is significantly more common than RT-2. In 25 eyes of the 44 patients with unilateral sporadic retinoblastoma, multifocal tumours of the retina were observed. Such cases should not mistakenly be classified as hereditary cases on the basis of the histological pattern of multifocality of the tumour process.

Hyperthermia in the Treatment of Intraocular Tumors, in Particular Retinoblastoma

The possibility of significant antitumor activity associated with hyperthermia was first documented by Busch, who reported the disappearance of a facial sarcoma following high fever in a patient with erysipelas (Busch 1866). In the last decade interest has been rekindled in the clinical application of this modality because numerous reports and comprehensive reviews have indicated that there may be a significant advantage in the use of heat alone, or combined with radiation or cytotoxic drugs, to enhance the killing of tumor cells (Hall 1988; Overgaard 1989).