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Objectives: To assess the diagnostic accuracy of nerve thickening on MRI to predict early-stage postlaminar optic nerve invasion (PLONI) in retinoblastoma. Furthermore, this study aimed to incorporate measurements into a multiparametric model for radiological determination of PLONI., Methods: In this retrospective multicenter case-control study, high-spatial-resolution 3D T2-weighted MR images were used to measure the distal optic nerve. Histopathology was the reference standard for PLONI. Two neuroradiologists independently measured the optic nerve width, height, and surface at 0, 3, and 5 mm from the most distal part of the optic nerve. Subsequently, PLONI was scored on contrast-enhanced T1-weighted and 3D T2-weighted images, blinded for clinical data. Optic nerve measurements with the highest diagnostic accuracy for PLONI were incorporated into a prediction model for radiological determination of PLONI., Results: One hundred twenty-four retinoblastoma patients (median age, 22 months [range, 0-113], 58 female) were included, resulting in 25 retinoblastoma eyes with histopathologically proven PLONI and 206 without PLONI. ROC analysis of axial optic nerve width measured at 0 mm yielded the best area under the curve of 0.88 (95% confidence interval: 0.79, 0.96; p < 0.001). The optimal width cutoff was ≥ 2.215 mm, with a sensitivity of 84% (95% CI: 64, 95%) and specificity of 83% (95% CI: 75, 89%) for detecting PLONI. Combining width measurements with the suspicion of PLONI on MRI sequences resulted in a prediction model with an improved sensitivity and specificity of respectively up to 88% and 92%., Conclusion: Postlaminar optic nerve thickening can predict early-stage postlaminar optic nerve invasion in retinoblastoma., Clinical Relevance Statement: This study provides an additional tool for clinicians to help determine postlaminar optic nerve invasion, which is a risk factor for developing metastatic disease in retinoblastoma patients., Key Points: • The diagnostic accuracy of contrast-enhanced MRI for detecting postlaminar optic nerve invasion is limited in retinoblastoma patients. • Optic nerve thickening can predict postlaminar optic nerve invasion. • A prediction model combining MRI features has a high sensitivity and specificity for detecting postlaminar optic nerve invasion., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Objectives: To validate associations between MRI features and gene expression profiles in retinoblastoma, thereby evaluating the repeatability of radiogenomics in retinoblastoma., Methods: In this retrospective multicenter cohort study, retinoblastoma patients with gene expression data and MRI were included. MRI features (scored blinded for clinical data) and matched genome-wide gene expression data were used to perform radiogenomic analysis. Expression data from each center were first separately processed and analyzed. The end product normalized expression values from different sites were subsequently merged by their Z-score to permit cross-sites validation analysis. The MRI features were non-parametrically correlated with expression of photoreceptorness (radiogenomic analysis), a gene expression signature informing on disease progression. Outcomes were compared to outcomes in a previous described cohort., Results: Thirty-six retinoblastoma patients were included, 15 were female (42%), and mean age was 24 (SD 18) months. Similar to the prior evaluation, this validation study showed that low photoreceptorness gene expression was associated with advanced stage imaging features. Validated imaging features associated with low photoreceptorness were multifocality, a tumor encompassing the entire retina or entire globe, and a diffuse growth pattern (all p < 0.05). There were a number of radiogenomic associations that were also not validated., Conclusions: A part of the radiogenomic associations could not be validated, underlining the importance of validation studies. Nevertheless, cross-center validation of imaging features associated with photoreceptorness gene expression highlighted the capability radiogenomics to non-invasively inform on molecular subtypes in retinoblastoma., Clinical Relevance Statement: Radiogenomics may serve as a surrogate for molecular subtyping based on histopathology material in an era of eye-sparing retinoblastoma treatment strategies., Key Points: • Since retinoblastoma is increasingly treated using eye-sparing methods, MRI features informing on molecular subtypes that do not rely on histopathology material are important. • A part of the associations between retinoblastoma MRI features and gene expression profiles (radiogenomics) were validated. • Radiogenomics could be a non-invasive technique providing information on the molecular make-up of retinoblastoma., (© 2023. The Author(s).)

Background MYCN -amplified RB1 wild-type ( MYCN ) retinoblastoma is a rare but clinically important subtype of retinoblastoma due to its aggressive character and relative resistance to typical therapeutic approaches. Because biopsy is not indicated in retinoblastoma, specific MRI features might be valuable to identify children with this genetic subtype. Purpose To define the MRI phenotype of A retinoblastoma and evaluate the ability of qualitative MRI features to help identify this specific genetic subtype. Materials and Methods In this retrospective, multicenter, case-control study, MRI scans in children with RB1 retinoblastoma and age-matched children with +/+ subtype retinoblastoma were included (case-control ratio, 1:4; scans acquired from June 2001 to February 2021; scans collected from May 2018 to October 2021). Patients with histopathologically confirmed unilateral retinoblastoma, genetic testing ( MYCN A values were calculated. Results A total of 110 patients from 10 retinoblastoma referral centers were included: 22 children with RB1 retinoblastoma and 88 control children with +/+ retinoblastoma. Children in the MYCN A RB1 +/+ retinoblastoma and age-matched children with RB1 -/- subtype retinoblastoma were included (case-control ratio, 1:4; scans acquired from June 2001 to February 2021; scans collected from May 2018 to October 2021). Patients with histopathologically confirmed unilateral retinoblastoma, genetic testing ( RB1/MYCN status), and MRI scans were included. Associations between radiologist-scored imaging features and diagnosis were assessed with the Fisher exact test or Fisher-Freeman-Halton test, and Bonferroni-corrected P values were calculated. Results A total of 110 patients from 10 retinoblastoma referral centers were included: 22 children with MYCN A RB1 +/+ retinoblastoma and 88 control children with RB1 -/- retinoblastoma. Children in the MYCN A RB1 +/+ group had a median age of 7.0 months (IQR, 5.0-9.0 months) (13 boys), while children in the RB1 -/- group had a median age of 9.0 months (IQR, 4.6-13.4 months) (46 boys). MYCN A RB1 +/+ retinoblastomas were typically peripherally located (in 10 of 17 children; specificity, 97%; P < .001) and exhibited plaque or pleomorphic shape (in 20 of 22 children; specificity, 51%; P = .011) with irregular margins (in 16 of 22 children; specificity, 70%; P = .008) and extensive retina folding with vitreous enclosure (specificity, 94%; P < .001). MYCN A RB1 +/+ retinoblastomas showed peritumoral hemorrhage (in 17 of 21 children; specificity, 88%; P < .001), subretinal hemorrhage with a fluid-fluid level (in eight of 22 children; specificity, 95%; P = .005), and strong anterior chamber enhancement (in 13 of 21 children; specificity, 80%; P = .008). Conclusion MYCN A RB1 +/+ retinoblastomas show distinct MRI features that could enable early identification of these tumors. This may improve patient selection for tailored treatment in the future. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Rollins in this issue.

Purpose: To investigate the prevalence and magnetic resonance imaging (MRI) phenotype of retinoblastoma-associated orbital cellulitis. Additionally, this study aimed to identify postlaminar optic nerve enhancement (PLONE) patterns differentiating between inflammation and tumor invasion., Design: A monocenter cohort study assessed the prevalence of orbital cellulitis features on MRI in retinoblastoma patients. A multicenter case-control study compared MRI features of the retinoblastoma-associated orbital cellulitis cases with retinoblastoma controls., Participants: A consecutive retinoblastoma patient cohort of 236 patients (311 eyes) was retrospectively investigated. Subsequently, 30 retinoblastoma cases with orbital cellulitis were compared with 30 matched retinoblastoma controls without cellulitis., Methods: In the cohort study, retinoblastoma MRI scans were scored on presence of inflammatory features. In the case-control study, MRI scans were scored on intraocular features and PLONE patterns. Postlaminar enhancement patterns were compared with histopathologic assessment of postlaminar tumor invasion. Interreader agreement was assessed, and exact tests with Bonferroni correction were adopted for statistical comparisons., Main Outcome Measures: Prevalence of retinoblastoma-associated orbital cellulitis on MRI was calculated. Frequency of intraocular MRI features was compared between cases and controls. Sensitivity and specificity of postlaminar optic nerve patterns for detection of postlaminar tumor invasion were assessed., Results: The MRI prevalence of retinoblastoma-associated orbital cellulitis was 6.8% (16/236). Retinoblastoma with orbital cellulitis showed significantly more tumor necrosis, uveal abnormalities (inflammation, hemorrhage, and necrosis), lens luxation (all P &lt; 0.001), and a larger eye size (P = 0.012). The inflammatory pattern of optic nerve enhancement (strong enhancement similar to adjacent choroid) was solely found in orbital cellulitis cases, of which none (0/16) showed tumor invasion on histopathology. Invasive pattern enhancement was found in both cases and controls, of which 50% (5/10) showed tumor invasion on histopathology. Considering these different enhancement patterns suggestive for either inflammation or tumor invasion increased specificity for detection of postlaminar tumor invasion in orbital cellulitis cases from 32% (95% confidence interval [CI], 16-52) to 89% (95% CI, 72-98)., Conclusions: Retinoblastoma cases presenting with orbital cellulitis show MRI findings of a larger eye size, extensive tumor necrosis, uveal abnormalities, and lens luxation. Magnetic resonance imaging contrast-enhancement patterns within the postlaminar optic nerve can differentiate between tumor invasion and inflammatory changes., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the risk of patients with an early diagnosis of heritable retinoblastoma being diagnosed with TRb (or pineoblastoma) asynchronously in a later stage and its effect on screening., Methods: We updated the search (PubMed and Embase) for published literature as performed by our research group in 2014 and 2019. Trilateral retinoblastoma (TRb) patients were eligible for inclusion if identifiable as unique and the age at which TRb was diagnosed was available. The search yielded 97 new studies. Three new studies and eight new patients were included. Combined with 189 patients from the previous meta-analysis, the database included 197 patients. The main outcome was the percentage of asynchronous TRb in patients diagnosed before and after preset age thresholds of 6 and 12 months of age at retinoblastoma diagnosis., Results: Seventy-nine per cent of patients with pineoblastoma are diagnosed with retinoblastoma before the age of 12 months. However, baseline MRI screening at time of retinoblastoma diagnosis fails to detect the later diagnosed pineal TRb in 89% of patients. We modelled that an additional MRI performed at the age of 29 months picks up 53% of pineoblastomas in an asymptomatic phase. The detection rate increased to 72%, 87% and 92%, respectively, with 2, 3 and 4 additional MRIs., Conclusions: An MRI of the brain in heritable retinoblastoma before the age of 12 months misses most pineoblastomas, while retinoblastomas are diagnosed most often before the age of 12 months. Optimally timed additional MRI scans of the brain can increase the asymptomatic detection rate of pineoblastoma., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

In retinoblastoma, accurate segmentation of ocular structure and tumor tissue is important when working towards personalized treatment. This retrospective study serves to evaluate the performance of multi-view convolutional neural networks (MV-CNNs) for automated eye and tumor segmentation on MRI in retinoblastoma patients. Forty retinoblastoma and 20 healthy-eyes from 30 patients were included in a train/test (N = 29 retinoblastoma-, 17 healthy-eyes) and independent validation (N = 11 retinoblastoma-, 3 healthy-eyes) set. Imaging was done using 3.0 T Fast Imaging Employing Steady-state Acquisition (FIESTA), T2-weighted and contrast-enhanced T1-weighted sequences. Sclera, vitreous humour, lens, retinal detachment and tumor were manually delineated on FIESTA images to serve as a reference standard. Volumetric and spatial performance were assessed by calculating intra-class correlation (ICC) and dice similarity coefficient (DSC). Additionally, the effects of multi-scale, sequences and data augmentation were explored. Optimal performance was obtained by using a three-level pyramid MV-CNN with FIESTA, T2 and T1c sequences and data augmentation. Eye and tumor volumetric ICC were 0.997 and 0.996, respectively. Median [Interquartile range] DSC for eye, sclera, vitreous, lens, retinal detachment and tumor were 0.965 [0.950-0.975], 0.847 [0.782-0.893], 0.975 [0.930-0.986], 0.909 [0.847-0.951], 0.828 [0.458-0.962] and 0.914 [0.852-0.958], respectively. MV-CNN can be used to obtain accurate ocular structure and tumor segmentations in retinoblastoma., (© 2021. The Author(s).)

Topic: To determine the age up to which children are at risk of trilateral retinoblastoma (TRb) developing, whether its onset is linked to the age at which intraocular retinoblastomas develop, and the lead time from a detectable pineal TRb to symptoms., Clinical Relevance: Approximately 45% of patients with retinoblastoma-those with a germline RB1 pathogenic variant-are at risk of pineal TRb developing. Early detection and treatment are essential for survival. Current evidence is unclear regarding the usefulness of screening for pineal TRb and, if useful, the age up to which screening should be continued., Methods: We conducted a study according to the Meta-analysis of Observational Studies in Epidemiology guidelines for reporting meta-analyses of observational studies. We searched PubMed and Embase between January 1, 1966, and February 27, 2019, for published literature. We considered articles reporting patients with TRb with survival and follow-up data. Inclusion of articles was performed separately and independently by 2 authors, and 2 authors also independently extracted the relevant data. They resolved discrepancies by consensus., Results: One hundred thirty-eight patients with pineal TRb were included. Of 22 asymptomatic patients, 21 (95%) were diagnosed before the age of 40 months (median, 16 months; interquartile range, 9-29 months). Age at diagnosis of pineal TRb in patients diagnosed with retinoblastoma at 6 months or younger versus older than 6 months were comparable (P = 0.44), suggesting independence between the ages at diagnosis of intraocular retinoblastoma and pineal TRb. The laterality of intraocular retinoblastoma and its treatment were not associated with the age at which pineal TRb was diagnosed. The lead time from asymptomatic to symptomatic pineal TRb was approximately 1 year. By performing a screening magnetic resonance imaging scan every 6 months after the diagnosis of heritable retinoblastoma (median age, 6 months) until 36 months of age, at least 311 and 776 scans would be required to detect 1 case of asymptomatic pineal TRb and to save a single life, respectively., Conclusions: Patients with retinoblastoma are at risk of pineal TRb developing for a shorter period than previously assumed, and the age at diagnosis of pineal TRb is independent of the age at diagnosis of retinoblastoma. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) level of evidence for these conclusions remains low., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

We present a 6-year-old boy with unilateral retinoblastoma of the left eye. MRI showed an intraocular tumor that extended into the optic nerve beyond the lamina cribrosa. The affected eye was enucleated and the optic nerve resection margin proved to be free. Following protocol, this patient received six courses of adjuvant systemic chemotherapy. Unfortunately, after 5 months this patient returned with the leptomeningeal spread of the tumor and died quickly thereafter.Histopathologic analysis of the enucleated eye and distal optic nerve revealed that the postlaminar tumor cells occupied the entire width of the optic nerve, extending all the way up to the pia mater, whereas, more often the tumor invasion is restricted to the center of the optic nerve. This was also visible on the MR images where contrast enhancement occupied the entire nerve width. A resection margin with tumor cells is recognized as a risk factor for metastasis, but perhaps the proximity of tumor cells to the leptomeninges should also be judged with caution as a potential increased risk for metastatic spread.

Purpose To identify associations between magnetic resonance (MR) imaging features and gene expression in retinoblastoma. Materials and Methods A retinoblastoma MR imaging atlas was validated by using anonymized MR images from referral centers in Essen, Germany, and Paris, France. Images were from 39 patients with retinoblastoma (16 male and 18 female patients [the sex in five patients was unknown]; age range, 5-90 months; inclusion criterion: pretreatment MR imaging). This atlas was used to compare MR imaging features with genome-wide messenger RNA (mRNA) expression data from 60 consecutive patients obtained from 1995 to 2012 (35 male patients [58%]; age range, 2-69 months; inclusion criteria: pretreatment MR imaging, genome-wide mRNA expression data available). Imaging pathway associations were analyzed by means of gene enrichment. In addition, imaging features were compared with a predefined gene expression signature of photoreceptorness. Statistical analysis was performed with generalized linear modeling of radiology traits on normalized log2-transformed expression values. P values were corrected for multiple hypothesis testing. Results Radiogenomic analysis revealed 1336 differentially expressed genes for qualitative imaging features (threshold P = .05 after multiple hypothesis correction). Loss of photoreceptorness gene expression correlated with advanced stage imaging features, including multiple lesions (P = .03) and greater eye size (P < .001). The number of lesions on MR images was associated with expression of MYCN (P = .04). A newly defined radiophenotype of diffuse-growing, plaque-shaped, multifocal tumors displayed overexpression of SERTAD3 (P = .003, P = .049, and P = .06, respectively), a protein that stimulates cell growth by activating the E2F network. Conclusion Radiogenomic biomarkers can potentially help predict molecular features, such as photoreceptorness loss, that indicate tumor progression. Results imply a possible role for radiogenomics in future staging and treatment decision making in retinoblastoma., (© RSNA, 2018 Online supplemental material is available for this article.)

Background: Retinoblastoma is the most common intraocular tumor in childhood with a good prognosis in terms of mortality, but detailed information about tumor morphology and disease extent in retinoblastoma is important for treatment decision making., Purpose: To demonstrate ultrahigh-field MRI tumor morphology and tumor extent in retinoblastoma correlating with in and ex vivo images with histopathology., Study Type: Prospective case series., Population: Six retinoblastoma patients (median age 5.5 months, range 2-14) were prospectively included in this study. Median time between diagnosis and enucleation was 8 days (range 7-19)., Field Strength/sequence: In vivo pre-enucleation at 1.5T MRI with a circular surface coil. Ex vivo imaging (FLASH T 1 -weighted and RARE T 2 -weighted) was performed at field strengths of 9.4T and 17.6T., Assessment: After ex vivo imaging, the eyes were histopathologically analyzed and morphologically matched with MRI findings by three authors (two with respectively 14 and 4 years of experience in ocular MRI and one with 16 years of experience in ophthalmopathology)., Results: Small submillimeter morphological aspects of intraocular retinoblastoma were successfully depicted with higher-resolution MRI and matched with histopathology images. With ex vivo MRI a small subretinal tumor seed (300 μm) adjacent to the choroid was morphologically matched with histopathology. Also, a characteristic geographical pattern of vital tumor tissue (400 μm) surrounding a central vessel interspersed with necrotic areas correlated with histopathology images. Tumor invasion into the optic nerve showed a higher signal intensity on T 1 -weighted higher-resolution MRI., Data Conclusion: Higher-resolution MRI allows for small morphological aspects of intraocular retinoblastoma and extraocular disease extent not visible on currently used clinical in vivo MRI to be depicted., Level of Evidence: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1487-1497., (© 2017 International Society for Magnetic Resonance in Medicine.)

Purpose To assess the correlation of intraocular retinoblastoma tumor size measured with magnetic resonance (MR) imaging in the prediction of histopathologically determined metastatic risk factors (postlaminar optic nerve invasion and massive choroidal invasion). Materials and Methods The ethics committee approved this retrospective multicenter study with a waiver of informed consent. The study population included 370 consecutive patients with retinoblastoma (375 eyes) who underwent baseline MR imaging, followed by primary enucleation from 1993 through 2014. Tumor sizes (maximum diameter and volume) were measured independently by two observers and correlated with histopathologic risk factors. Receiver operating characteristic curves were used to analyze the diagnostic accuracy of tumor size, and areas under the curve were calculated. Logistic regression analysis was performed to evaluate potential confounders. Results Receiver operating characteristic analysis of volume and diameter, respectively, yielded areas under the curve of 0.77 (95% confidence interval [CI]: 0.70, 0.85; P < .0001) and 0.78 (95% CI: 0.71, 0.85; P < .0001) for postlaminar optic nerve invasion (n = 375) and 0.67 (95% CI: 0.57, 0.77; P = .0020) and 0.70 (95% CI: 0.59, 0.80; P = .0004) for massive choroidal tumor invasion (n = 219). For the detection of co-occurring massive choroidal invasion and postlaminar optic nerve invasion (n = 219), volume and diameter showed areas under the curve of 0.81 (95% CI: 0.70, 0.91; P = .0032) and 0.83 (95% CI: 0.73, 0.93; P = .0016), respectively. Conclusion Intraocular tumor size shows a strong association with postlaminar optic nerve invasion and a moderate association with massive choroidal invasion. These findings provide diagnostic accuracy measures at different size cutoff levels, which could potentially be useful in a clinical setting, especially within the scope of the increasing use of eye-salvage treatment strategies. (©) RSNA, 2015 Online supplemental material is available for this article.

Background: While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome-wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes., Methods: We performed SCNA profiling of 45 primary retinoblastoma samples and eight retinoblastoma cell lines by high-resolution microarrays. We combined our data with genomic, clinical and histopathological data of ten published genome-wide SCNA studies, which strongly enhanced the power of our analyses (N = 310)., Results: Comprehensive recurrence analysis of SCNAs in all studies integrated with gene expression data allowed us to reduce candidate gene lists for 1q, 2p, 6p, 7q and 13q to a limited gene set. Besides the well-established driver genes RB1 (13q-loss) and MYCN (2p-gain) we identified CRB1 and NEK7 (1q-gain), SOX4 (6p-gain) and NUP205 (7q-gain) as novel retinoblastoma driver candidates. Depending on the sample subset and algorithms used, alternative candidates were identified including MIR181 (1q-gain) and DEK (6p gain). Remarkably, our study showed that copy number gains rarely exceeded change of one copy, even in pure tumor samples with 100% homozygosity at the RB1 locus (N = 34), which is indicative for intra-tumor heterogeneity. In addition, profound between-tumor variability was observed that was associated with age at diagnosis and differentiation grades., Interpretation: Since focal alterations at commonly altered chromosome regions were rare except for 2p24.3 (MYCN), further functional validation of the oncogenic potential of the described candidate genes is now required. For further investigations, our study provides a refined and revised set of candidate retinoblastoma driver genes.

Purpose: Orbital tumor recurrence is a rare but serious complication in children with retinoblastoma, leading to a high risk of metastasis and death. Therefore, we assume that these recurrences have to be detected and treated as early as possible. Preliminary studies used magnetic resonance imaging (MRI) to evaluate postsurgical findings in the orbit. In this study, we assessed the diagnostic accuracy of high-resolution MRI to detect orbital tumor recurrence in children with retinoblastoma in a large study cohort., Design: Consecutive retrospective study (2007-2013) assessing MRI findings after enucleation., Participants: A total of 103 MRI examinations of 55 orbits (50 children, 27 male/23 female, mean age 16.3±12.4 months) with a median time of 8 months (range, 0-93) after enucleation for retinoblastoma., Methods: High-resolution MRI using orbital surface coils was performed on 1.5 Tesla MRI systems to assess abnormal orbital findings., Main Outcome Measures: Five European experts in retinoblastoma imaging evaluated the MRI examinations regarding the presence of abnormal orbital gadolinium enhancement and judged them as "definitive tumor," "suspicious of tumor," "postsurgical condition/scar formation," or "without pathologic findings." The findings were correlated to histopathology (if available), MRI, and clinical follow-up., Results: Abnormal orbital enhancement was a common finding after enucleation (100% in the first 3 months after enucleation, 64.3% >3 years after enucleation). All histopathologically confirmed tumor recurrences (3 of 55 orbits, 5.5%) were correctly judged as "definitive tumor" in MRI. Two orbits from 2 children rated as "suspicious of tumor" received intravenous chemotherapy without histopathologic confirmation; further follow-up (67 and 47 months) revealed no sign of tumor recurrence. In 90.2%, no tumor was suspected on MRI, which was clinically confirmed during follow-up (median follow-up after enucleation, 45 months; range, 8-126)., Conclusions: High-resolution MRI with orbital surface coils may reliably distinguish between common postsurgical contrast enhancement and orbital tumor recurrence, and therefore may be a useful tool to evaluate orbital tumor recurrence after enucleation in children with retinoblastoma. We recommend high-resolution MRI as a potential screening tool for the orbit in children with retinoblastoma to exclude tumor recurrence, especially in high-risk patients within the critical first 2 years after enucleation., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To estimate the incidence of trilateral retinoblastoma in patients with retinoblastoma., Design: Systematic review and meta-analysis., Methods: We searched Medline and Embase for scientific literature published between January 1966 and July 2015 that assessed trilateral retinoblastoma incidence. We used a random-effects model for the statistical analyses., Results: We included 23 retinoblastoma cohorts from 26 studies. For patients with bilateral retinoblastoma the unadjusted chance of developing trilateral retinoblastoma across all cohorts was 5.3% (95% confidence interval [CI]: 3.3%-7.7%); the chance of pineal trilateral retinoblastoma was 4.2% (95% CI: 2.6%-6.2%) and the chance of nonpineal trilateral retinoblastoma was 0.8% (95% CI: 0.4%-1.3%). In patients with hereditary retinoblastoma (all bilateral cases, and the unilateral cases with a family history or germline RB1 mutation) we found a trilateral retinoblastoma incidence of 4.1% (95% CI: 1.9%-7.1%) and a pineal trilateral retinoblastoma incidence of 3.7% (95% CI: 1.8%-6.2%). To reduce the risk of overestimation bias we restricted analysis to retinoblastoma cohorts with a minimum size of 100 patients, resulting in adjusted incidences of 3.8% (95% CI: 2.4%-5.4%), 2.9% (95% CI: 1.9%-4.2%), and 0.7% (95% CI: 0.3%-1.2%) for any, pineal, and nonpineal trilateral retinoblastoma, respectively, among patients with bilateral retinoblastoma. Among hereditary retinoblastoma we found an adjusted trilateral retinoblastoma incidence of 3.5% (95% CI: 1.2%-6.7%) and a pineal trilateral retinoblastoma incidence of 3.2% (95% CI: 1.4%-5.6%)., Conclusion: The estimated incidence of trilateral retinoblastoma is lower than what is reported in previous literature, especially after exclusion of small cohorts that were subject to overestimation bias in this context., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Retinoblastoma is a pediatric eye cancer associated with RB1 loss or MYCN amplification (RB1 (+/+) MYCN(A) ). There are controversies concerning the existence of molecular subtypes within RB1(-/-) retinoblastoma. To test whether these molecular subtypes exist, we performed molecular profiling., Methods: Genome-wide mRNA expression profiling was performed on 76 primary human retinoblastomas. Expression profiling was complemented by genome-wide DNA profiling and clinical, histopathological, and ex vivo drug sensitivity data., Findings: RNA and DNA profiling identified major variability between retinoblastomas. While gene expression differences between RB1 (+/+) MYCN(A) and RB1(-/-) tumors seemed more dichotomous, differences within the RB1(-/-) tumors were gradual. Tumors with high expression of a photoreceptor gene signature were highly differentiated, smaller in volume and diagnosed at younger age compared with tumors with low photoreceptor signature expression. Tumors with lower photoreceptor expression showed increased expression of genes involved in M-phase and mRNA and ribosome synthesis and increased frequencies of somatic copy number alterations., Interpretation: Molecular, clinical and histopathological differences between RB1(-/-) tumors are best explained by tumor progression, reflected by a gradual loss of differentiation and photoreceptor expression signature. Since copy number alterations were more frequent in tumors with less photoreceptorness, genomic alterations might be drivers of tumor progression., Research in Context: Retinoblastoma is an ocular childhood cancer commonly caused by mutations in the RB1 gene. In order to determine optimal treatment, tumor subtyping is considered critically important. However, except for very rare retinoblastomas without an RB1 mutation, there are controversies as to whether subtypes of retinoblastoma do exist. Our study shows that retinoblastomas are highly diverse but rather than reflecting distinct tumor types with a different etiology, our data suggests that this diversity is a result of tumor progression driven by cumulative genetic alterations. Therefore, retinoblastomas should not be categorized in distinct subtypes, but be described according to their stage of progression.

We demonstrate the value of high-resolution magnetic resonance imaging (MRI) in diagnosing, staging, and follow-up of retinoblastoma during eye-saving treatment. We have included informative retinoblastoma cases scanned on a 3T MRI system from a retrospective retinoblastoma cohort from 2009 through 2013. We show that high-resolution MRI has the potential to detect small intraocular seeds, hemorrhage, and metastatic risk factors not visible with fundoscopy (e.g., optic nerve invasion and choroidal invasion), and treatment response. Unfortunately, however, the diagnostic accuracy of high-resolution MRI is not perfect, especially for subtle intraocular seeds or minimal postlaminar optic nerve invasion. The most important application of MRI is the detection of metastatic risk factors, as these cannot be found by fundoscopy and ultrasound., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To assess the accuracy of high-resolution (HR) magnetic resonance imaging (MRI) in diagnosing early-stage optic nerve (ON) invasion in a retinoblastoma cohort., Methods: This IRB-approved, prospective multicenter study included 95 patients (55 boys, 40 girls; mean age, 29 months). 1.5-T MRI was performed using surface coils before enucleation, including spin-echo unenhanced and contrast-enhanced (CE) T1-weighted sequences (slice thickness, 2 mm; pixel size <0.3 × 0.3 mm(2)). Images were read by five neuroradiologists blinded to histopathologic findings. ROC curves were constructed with AUC assessment using a bootstrap method., Results: Histopathology identified 41 eyes without ON invasion and 25 with prelaminar, 18 with intralaminar and 12 with postlaminar invasion. All but one were postoperatively classified as stage I by the International Retinoblastoma Staging System. The accuracy of CE-T1 sequences in identifying ON invasion was limited (AUC = 0.64; 95 % CI, 0.55 - 0.72) and not confirmed for postlaminar invasion diagnosis (AUC = 0.64; 95 % CI, 0.47 - 0.82); high specificities (range, 0.64 - 1) and negative predictive values (range, 0.81 - 0.97) were confirmed., Conclusion: HR-MRI with surface coils is recommended to appropriately select retinoblastoma patients eligible for primary enucleation without the risk of IRSS stage II but cannot substitute for pathology in differentiating the first degrees of ON invasion., Key Points: • HR-MRI excludes advanced optic nerve invasion with high negative predictive value. • HR-MRI accurately selects patients eligible for primary enucleation. • Diagnosis of early stages of optic nerve invasion still relies on pathology. • Several physiological MR patterns may mimic optic nerve invasion.

Background: About 5% of children with retinoblastoma from germline mutation of the RB1 gene are at risk of developing trilateral retinoblastoma--intraocular retinoblastoma combined with a histologically similar brain tumour, most commonly in the pineal gland. We aimed to provide a systematic overview of published data for trilateral retinoblastoma, and to analyse how survival has changed., Methods: We searched Medline and Embase for scientific literature published between Jan 1, 1966, and April 14, 2014, that assessed trilateral retinoblastoma cases. We undertook a meta-analysis of survival with the Kaplan-Meier method and Cox proportional hazards regression, stratified on the basis of the original study, to account for between-study heterogeneity., Findings: We included 90 studies, with 174 patients with trilateral retinoblastoma. 5-year survival after pineal trilateral retinoblastoma increased from 6% (95% CI 2-15) in patients diagnosed before 1995, to 44% (26-61; p<0·0001) in those diagnosed from 1995 onwards. Before 1995, no patients with non-pineal trilateral retinoblastoma survived, but from 1995 onwards, 5-year survival was 57% (30-77; p=0·035). Hazard ratios (HR) adjusted for the presence of leptomeningeal metastases and trilateral retinoblastoma location, suggested that both conventional (HR 0·059, 95% CI 0·016-0·226; p<0·0001) and high-dose chemotherapy with stem-cell rescue (0·013, 0·002-0·064; p<0·0001) most strongly contributed to this improvement. Absence of leptomeningeal metastases (HR 2·13, 95% CI 0·98-4·60; p=0·055) were associated with improved survival. Non-pineal trilateral retinoblastomas were larger than pineal tumours (median 30 mm [range 6-100] vs 22 mm [7-60]; p=0·012), but both had similar outcomes since 1995., Interpretation: Our results suggest that improvements in overall survival are attributable to improved chemotherapy regimens and early detection of pineal trilateral retinoblastoma. As such, successful treatment of trilateral retinoblastoma should include screening at least at the time of retinoblastoma diagnosis and chemotherapy, which would preferably be a high-dose regimen with autologous stem-cell rescue., Funding: None., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To determine and compare the diagnostic performance of magnetic resonance imaging (MRI) and computed tomography (CT) for the diagnosis of tumor extent in advanced retinoblastoma, using histopathologic analysis as the reference standard., Design: Systematic review and meta-analysis., Participants: Patients with advanced retinoblastoma who underwent MRI, CT, or both for the detection of tumor extent from published diagnostic accuracy studies., Methods: Medline and Embase were searched for literature published through April 2013 assessing the diagnostic performance of MRI, CT, or both in detecting intraorbital and extraorbital tumor extension of retinoblastoma. Diagnostic accuracy data were extracted from included studies. Summary estimates were based on a random effects model. Intrastudy and interstudy heterogeneity were analyzed., Main Outcome Measures: Sensitivity and specificity of MRI and CT in detecting tumor extent., Results: Data of the following tumor-extent parameters were extracted: anterior eye segment involvement and ciliary body, optic nerve, choroidal, and (extra)scleral invasion. Articles on MRI reported results of 591 eyes from 14 studies, and articles on CT yielded 257 eyes from 4 studies. The summary estimates with their 95% confidence intervals (CIs) of the diagnostic accuracy of conventional MRI at detecting postlaminar optic nerve, choroidal, and scleral invasion showed sensitivities of 59% (95% CI, 37%-78%), 74% (95% CI, 52%-88%), and 88% (95% CI, 20%-100%), respectively, and specificities of 94% (95% CI, 84%-98%), 72% (95% CI, 31%-94%), and 99% (95% CI, 86%-100%), respectively. Magnetic resonance imaging with a high (versus a low) image quality showed higher diagnostic accuracies for detection of prelaminar optic nerve and choroidal invasion, but these differences were not statistically significant. Studies reporting the diagnostic accuracy of CT did not provide enough data to perform any meta-analyses., Conclusions: Magnetic resonance imaging is an important diagnostic tool for the detection of local tumor extent in advanced retinoblastoma, although its diagnostic accuracy shows room for improvement, especially with regard to sensitivity. With only a few-mostly old-studies, there is very little evidence on the diagnostic accuracy of CT, and generally these studies show low diagnostic accuracy. Future studies assessing the role of MRI in clinical decision making in terms of prognostic value for advanced retinoblastoma are needed., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Simple Summary: This study investigates the adverse effects of selective intra-arterial chemotherapy (SIAC) on the eyes and optic nerves of retinoblastoma patients using magnetic resonance imaging (MRI). We aim to understand the post-SIAC changes in orbital and ocular structures and evaluate their impact on eye and optic nerve growth. Experienced radiologists analyzed MR images of retinoblastoma eyes treated with SIAC, comparing them to eyes treated with other eye-saving methods and healthy eyes. Results reveal common adverse effects like inflammation and vascular changes, along with significant ocular growth arrest and optic nerve atrophy in eyes treated with SIAC, especially in children treated ≤ 12 months of age. This study underscores the importance of careful consideration when utilizing SIAC, particularly in young patients, due to its potential negative effects on eye and optic nerve development. This retrospective multicenter study examines therapy-induced orbital and ocular MRI findings in retinoblastoma patients following selective intra-arterial chemotherapy (SIAC) and quantifies the impact of SIAC on ocular and optic nerve growth. Patients were selected based on medical chart review, with inclusion criteria requiring the availability of posttreatment MR imaging encompassing T2-weighted and T1-weighted images (pre- and post-intravenous gadolinium administration). Qualitative features and quantitative measurements were independently scored by experienced radiologists, with deep learning segmentation aiding total eye volume assessment. Eyes were categorized into three groups: eyes receiving SIAC (Rb-SIAC), eyes treated with other eye-saving methods (Rb-control), and healthy eyes. The most prevalent adverse effects post-SIAC were inflammatory and vascular features, with therapy-induced contrast enhancement observed in the intraorbital optic nerve segment in 6% of patients. Quantitative analysis revealed significant growth arrest in Rb-SIAC eyes, particularly when treatment commenced ≤ 12 months of age. Optic nerve atrophy was a significant complication in Rb-SIAC eyes. In conclusion, this study highlights the vascular and inflammatory adverse effects observed post-SIAC in retinoblastoma patients and demonstrates a negative impact on eye and optic nerve growth, particularly in children treated ≤ 12 months of age, providing crucial insights for clinical management and future research. [ABSTRACT FROM AUTHOR]

Simple Summary: Retinoblastoma is a rare cancer that develops in the retina of children. Accurate differentiation between retinoblastoma and conditions that show similarities with retinoblastoma (pseudoretinoblastoma or retinoblastoma mimickers) is vital for guiding treatment. The most common pseudoretinoblastoma conditions are Coats' disease and persistent fetal vasculature (PFV). In this study, we aimed to improve pretreatment differentiation between these diseases on MR imaging. We compared pre-treatment MR images of retinoblastoma, Coats' disease and PFV on 20 predefined MR imaging features. An assessment strategy was proposed incorporating MR imaging features that best differentiate retinoblastoma from pseudoretinoblastoma, including three newly identified MR imaging features. Retinoblastoma mimickers, or pseudoretinoblastoma, are conditions that show similarities with the pediatric cancer retinoblastoma. However, false-positive retinoblastoma diagnosis can cause mistreatment, while false-negative diagnosis can cause life-threatening treatment delay. The purpose of this study is to identify the MR imaging features that best differentiate between retinoblastoma and the most common pseudoretinoblastoma diagnoses: Coats' disease and persistent fetal vasculature (PFV). Here, six expert radiologists performed retrospective assessments (blinded for diagnosis) of MR images of patients with a final diagnosis based on histopathology or clinical follow-up. Associations between 20 predefined imaging features and diagnosis were assessed with exact tests corrected for multiple hypothesis testing. Sixty-six patients were included, of which 33 (50%) were retinoblastoma and 33 (50%) pseudoretinoblastoma patients. A larger eye size, vitreous seeding, and sharp-V-shaped retinal detachment were almost exclusively found in retinoblastoma (p < 0.001–0.022, specificity 93–97%). Features that were almost exclusively found in pseudoretinoblastoma included smaller eye size, ciliary/lens deformations, optic nerve atrophy, a central stalk between optic disc and lens, Y-shaped retinal detachment, and absence of calcifications (p < 0.001–0.022, specificity 91–100%). Additionally, three newly identified imaging features were exclusively present in pseudoretinoblastoma: intraretinal macrocysts (p < 0.001, 38% [9/24] in Coats' disease and 20% [2/10] in PFV), contrast enhancement outside the solid lesion (p < 0.001, 30% [7/23] in Coats' disease and 57% [4/7] in PFV), and enhancing subfoveal nodules (38% [9/24] in Coats' disease). An assessment strategy was proposed for MR imaging differentiation between retinoblastoma and pseudoretinoblastoma, including three newly identified differentiating MR imaging features. [ABSTRACT FROM AUTHOR]