A.C. Moll

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.

Single-Shot Turbo Spin-Echo Diffusion-Weighted Imaging for Retinoblastoma: Initial Experience

BACKGROUND AND PURPOSE: Retinoblastoma may exhibit variable hyperintensities on DWI, resulting in different values in the ADC maps, depending on their histology and cellularity. However, EP-based DWI has susceptibility artifacts and image distortions, which make DWI of the orbit a challenging technique. The aim of this study was to investigate the feasibility of single-shot turbo spin-echo (HASTE) DWI in the evaluation of children with retinoblastoma and to assess the value of ADC maps in differentiating viable and necrotic tumor tissue. MATERIALS AND METHODS: Two radiologists assessed conventional MR images, DWI, and ADC maps of 17 patients with retinoblastoma (n = 17 eyes). Non-EP DWI was performed by using a HASTE sequence with b-values of 0 and 1000 s/mm2. ADC values were measured for enhancing and nonenhancing tumor tissue. ADC maps were compared with histopathologic findings regarding tumor differentiation and viability. RESULTS: On DWI, vital tumor tissue showed hyperintensity with negligible intensity of surrounding vitreous. The difference in mean (range) ADC values between enhancing (1.03 [0.72–1.22] × 10−3 mm2 s−1) and nonenhancing (1.47 [0.99–1.80] × 10−3 mm2 s−1) parts of retinoblastoma was statistically significant (P < .0005). Nonenhancing tumor parts showed a significantly lower ADC compared with vitreous (2.67 [2.24–3.20]×10−3 mm2 s−1) (P < .0005) and subretinal fluid (2.20 [1.76–2.96] × 10−3 mm2 s−1) (P < .0005). Histopathologically, low ADC values (enhancing tumor part) correlated to viable tumor tissue, whereas intermediate ADC values (nonenhancing tumor parts) correlated to necrotic tumor tissue. CONCLUSIONS: HASTE DWI allowed adequate characterization of retinoblastoma, and ADC is a helpful tool to differentiate viable and necrotic tumor tissue and might be valuable in monitoring the response to eye-preserving therapies.

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.

Brain Abnormalities on MR Imaging in Patients with Retinoblastoma

BACKGROUND AND PURPOSE: Although pineoblastoma is the main brain abnormality associated with hereditary retinoblastoma, recent studies suggest an association with pineal cysts. This association is important because some pineoblastomas mimic pineal cysts. If there is a relationship, then radiologists should be aware of it because diagnostic confusion is possible. Mental retardation and congenital brain anomalies are also reported in patients with retinoblastoma, mostly in combination with 13q deletion syndrome. In this retrospective study, the presence of brain abnormalities on MR images in a large group of consecutive patients with retinoblastoma is evaluated. MATERIALS AND METHODS: Brain MR images of 168 patients with retinoblastoma from 1989 to 2009 were evaluated by 2 radiologists for tumors, structural anomalies, myelinization, and coincidental findings. Clinical records were reviewed for laterality, heredity, and the presence of the 13q deletion syndrome. RESULTS: The hereditary group (patients with bilateral and unilateral proved RB1-germline mutation) included 90 (54%) of 168 patients. Seven patients had 13q deletion syndrome. Normal findings on brain MR images were seen in 150 (89%) patients. Five pineoblastomas were detected, all in patients with hereditary retinoblastoma (5.5% in the hereditary subgroup). Nine pineal cysts were detected (2.2% in the hereditary subgroup). Corpus callosum agenesis was found in 1 patient and a Dandy-Walker variant in 1 patient, both in combination with 13q deletion syndrome. CONCLUSIONS: Pineoblastoma is associated with hereditary retinoblastoma, and structural brain abnormalities are restricted to patients with the 13q deletion syndrome. The incidence of pineal cysts in patients with retinoblastomas is similar to that in healthy children and is not associated with hereditary retinoblastoma.

Contrast-Enhancement of the Anterior Eye Segment in Patients with Retinoblastoma: Correlation between Clinical, MR Imaging, and Histopathologic Findings

BACKGROUND AND PURPOSE: AES contrast-enhancement is recognized in a substantial number of retinoblastoma-affected eyes. We retrospectively investigated the histopathologic basis of AES contrast-enhancement on MR images in retinoblastoma. MATERIALS AND METHODS: Pretreatment contrast-enhanced MR images were obtained from 42 children with retinoblastoma. Forty-two enucleated eyes were included in this study, AES enhancement was evaluated by using a 3-point score, and these data were correlated with clinical, MR imaging, and histopathologic findings. Additionally, 14 specimens were immunohistochemically analyzed for CD31, VEGF, and Flt-1 expression. Statistical correlations with AES enhancement were assessed by using a linear-by-linear association test and univariate and multivariate ordinal regressions. RESULTS: The degree of abnormal AES enhancement was moderate in 15 (36%) eyes and strong in 14 (33%) eyes, whereas 13 (31%) eyes showed normal AES enhancement. In multivariate analysis, the degree of AES enhancement showed statistically significant correlations with iris surface-vessel count (P = .05) and optic nerve invasion (P = .04) in the enucleated eye and with tumor volume (P = .02) as detected on MR imaging. No significant associations between AES enhancement and VEGF expression in the iris were observed. Flt-1 (P = .04) staining in iris stroma and IA as detected with CD31 staining (P = .009) both yielded a statistically significant positive correlation with abnormal AES enhancement. CONCLUSIONS: The degree of abnormal AES enhancement on MR imaging in retinoblastoma reflects angiogenesis in the iris. AES enhancement is also a hallmark of advanced retinoblastoma because its degree correlates with tumor volume and optic nerve invasion.

Reproductive behavior of individuals with increased risk of having a child with retinoblastoma.

Dommering CJ, Garvelink MM, Moll AC, van Dijk J, Imhof SM, Meijers‐Heijboer H, Henneman L. Reproductive behavior of individuals with increased risk of having a child with retinoblastoma.

Retinoblastoma: Value of Dynamic Contrast-Enhanced MR Imaging and Correlation with Tumor Angiogenesis.

Fifteen patients with retinoblastoma were assessed with dynamic contrast-enhanced MRI over a period of 8 minutes; late contrast enhancement was also studied. The authors found that during the early phase of the perfusion studies the time curve correlated with microvessel density whereas late enhancement correlated with tumor necrosis. Thus, dynamic contrast-enhanced MRI may be used to assess angiogenesis and necrosis and may be used to monitor treatment. BACKGROUND AND PURPOSE: Noninvasive evaluation of retinoblastoma treatment response has become more important due to increased use of eye-sparing treatments. We evaluated the relation between DCE-MR imaging and histopathologic parameters to determine the value of DCE-MR imaging in assessing tumor angiogenesis and prognostic features. MATERIALS AND METHODS: Fifteen consecutive patients with retinoblastoma (mean age, 24 months; range, 2–70 months) undergoing enucleation as the primary treatment (15 eyes) were scanned at 1.5T by using dedicated surface coils. Pretreatment DCE-MR imaging of the most affected eye was evaluated by 2 observers by using curve-pattern analysis, with the first 5 minutes of each curve and the full time-series described as κ5min and κ17min, respectively. Assessed histopathologic and immunologic parameters included optic nerve invasion, choroid invasion, MVD, tumor necrosis, and expression of VEGF and Flt-1. RESULTS: The median value of κ5min was 1.28 (range, 0.87–2.07) and correlated positively with MVD (P = .008). The median value of κ17min was 1.33 (range, 0.35–3.08) and correlated negatively with tumor necrosis (P = .002). Other histopathologic and immunohistopathologic parameters did not correlate with DCE-MR imaging parameters. Interobserver agreement was 0.53 for κ5min and 0.91 for κ17min. CONCLUSIONS: In retinoblastoma, the early phase of the DCE time curve positively correlates with MVD, while the presence of late enhancement is correlated with necrosis. Thus, the potential for DCE-MR imaging to noninvasively assess tumor angiogenesis and necrosis in retinoblastoma is promising and warrants further investigation.

Retinal Dysplasia Mimicking Intraocular Tumor: MR Imaging Findings with Histopathologic Correlation

SUMMARY: We report a 6-month-old boy who presented with unilateral leukocoria, retinal detachment, and a retrolental mass in a microphthalmic eye based on retinal dysplasia with concurrent optic nerve aplasia. Dysplastic retinal tissue, a rare congenital defect, may create a clinical and radiologic picture of an intraocular mass closely resembling tumor tissue. MR imaging findings with histopathologic correlation are presented to facilitate discrimination of the more common causes of leukocoria.