Follow-up report of fundus findings of tuberous sclerosis-associated retinal astrocytoma of two siblings.

A late adolescent with tuberous sclerosis (TS) presented with reduced vision in one eye to our tertiary care university hospital 4 years ago. Fundus examination revealed multiple retinal astrocytic hamartomas (RAHs) in both eyes. His younger sibling, who also had TS, was found to have RAH on retinal screening. The swept-source optical coherence tomography (SS-OCT) findings were typical of RAH. We further noted that some of the RAH lesions showed segmental whitening of the outer walls of the arterioles, which traversed through them. The segmental whitening may suggest the enveloping of normal retinal vessels by the tumour. En-face and B-scan SS-OCT angiography of patients with TS showed vascularity within the tumour. The vessels within the tumour appeared to be in continuity with the retinal vasculature. Both siblings were reviewed annually. At the end of 4 years, there was no change in visual acuity, tumour size, number, vascularity and behaviour.

Swept-source optical coherence tomography angiography findings in a case of primary vitreoretinal lymphoma over a three-year follow-up.

BACKGROUND: Vitreoretinal lymphoma (VRL) still represents a diagnostic challenge for retinal specialists. Early diagnosis and treatment are critical for a better prognosis. Several diagnostic tools have proven helpful in the identification of VRL abnormalities. However, swept-source OCT angiography (SS-OCT-A) findings and their long-term follow-up are yet to be explored. CASE PRESENTATION: a 42-year-old man presented with blurred vision in his left eye for 2 weeks. He denied any systemic symptoms. A multimodal imaging examination was performed, raising the clinical suspicion of VRL and guiding the ensuing diagnostic procedures. The patient underwent treatment and at the last FU visit three years later, no disease signs were present on fundus examination, nor on oncologic evaluation. Some novel SS-OCT-A features were identified, and uncommonly reported findings were examined over a long-term follow-up. At baseline multiple hyperreflective alterations were detected on the enface outer retina slabs and choriocapillary analysis revealed low reflectance areas in the foveal and parafoveal areas. One month after the first presentation, multiple hyperreflective retinal lesions in a vertical shape were detected on OCT which appeared on midretinal slabs of enface SS-OCT-A as hyperreflective spots mainly located near second-order retinal vessels. These alterations remarkably reduced after treatment. CONCLUSION: SS-OCT-A may be a useful imaging technique in the detection of VRL, providing ophthalmologists additional findings that assist the diagnosis and follow-up of this disease. This may prove useful for a more timely and precise diagnosis, prompt therapy, and treatment response monitoring. The original aspects found in this case may provide grounds for future studies, ultimately fostering a better understanding of the disease.

Diagnostic Imaging for Retinoblastoma Cancer Staging: Guide for Providing Essential Insights for Ophthalmologists and Oncologists.

Retinoblastoma is the most common cause of all intraocular pediatric malignancies. It is caused by the loss of RB1 tumor suppressor gene function, although some tumors occur due to MYCN oncogene amplification with normal RB1 genes. Nearly half of all retinoblastomas occur due to a hereditary germline RB1 pathogenic variant, most of which manifest with bilateral tumors. This germline RB1 mutation also predisposes to intracranial midline embryonal tumors. Accurate staging of retinoblastoma is crucial in providing optimal vision-, eye-, and life-saving treatment. The AJCC Cancer Staging Manual has undergone significant changes, resulting in a universally accepted system with a multidisciplinary approach for managing retinoblastoma. The authors discuss the role of MRI and other diagnostic imaging techniques in the pretreatment assessment and staging of retinoblastoma. A thorough overview of the prevailing imaging standards and evidence-based perspectives on the benefits and drawbacks of these techniques is provided. Published under a CC BY 4.0 license. Test Your Knowledge questions for this article are available in the supplemental material.

Orbital Development in Children with Retinoblastoma: An Imaging-Based Study.

PURPOSE: To examine whether children treated for Retinoblastoma (Rb) have impaired orbital development. METHODS: A retrospective case series was performed among children with Rb treated at a single medical center from 2004 to 2020. Orbital volumes and measurements were assessed by 3-dimensional image processing software. The main outcome measures were differences in orbital growth between Rb and non-Rb eyes assessed at last follow-up. RESULTS: Among 44 patients included (mean age 16.09 ± 18.01 months), a positive correlation between age and orbital volume was observed only in the uninvolved, healthy eyes (p = .03). In unilateral cases, orbital growth in the horizontal, vertical, and depth planes was smaller on the affected side compared to the healthy eyes (p < .05). Orbits that underwent enucleation showed decreased growth over time compared to those treated conservatively (p = .017). CONCLUSIONS: Orbital growth rate is slower in the orbits of children treated for Rb compared to healthy orbits. Enucleation negatively affects orbital growth.

Role of apparent diffusion map in the evaluation of retinoblastoma.

PURPOSE: This study aimed to analyze the association between magnetic resonance imaging apparent diffusion coefficient map value and histopathological differentiation in patients who underwent eye enucleation due to retinoblastomas. METHODS: An observational chart review study of patients with retinoblastoma that had histopathology of the lesion and orbit magnetic resonance imaging with apparent diffusion coefficient analysis at Hospital de Clínicas de Porto Alegre between November 2013 and November 2016 was performed. The histopathology was reviewed after enucleation. To analyze the difference in apparent diffusion coefficient values between the two major histopathological prognostic groups, Student's t-test was used for the two groups. All statistical analyses were performed using SPSS version 19.0 for Microsoft Windows (SPSS, Inc., Chicago, IL, USA). Our institutional review board approved this retrospective study without obtaining informed consent. RESULTS: Thirteen children were evaluated, and only eight underwent eye enucleation and were included in the analysis. The others were treated with photocoagulation, embolization, radiotherapy, and chemotherapy and were excluded due to the lack of histopathological results. When compared with histopathology, magnetic resonance imaging demonstrated 100% accuracy in retinoblastoma diagnosis. Optic nerve invasion detection on magnetic resonance imaging showed a 66.6% sensitivity and 80.0% specificity. Positive and negative predictive values were 66.6% and 80.0%, respectively, with an accuracy of 75%. In addition, the mean apparent diffusion coefficient of the eight eyes was 0.615 × 103 mm2/s. The mean apparent diffusion coefficient value of poorly or undifferentiated retinoblastoma and differentiated tumors were 0.520 × 103 mm2/s and 0.774 × 103 mm2/s, respectively. CONCLUSION: This study revealed that magnetic resonance imaging is useful in the diagnosis of retinoblastoma and detection of optic nerve infiltration, with a sensitivity of 66.6% and specificity of 80%. Our results also showed lower apparent diffusion coefficient values in poorly differentiated retinoblastomas with a mean of 0.520 × 103 mm2/s, whereas in well and moderately differentiated, the mean was 0.774 × 103 mm2/s.

Construction of a Functional Nucleic Acid-Based Artificial Vesicle-Encapsulated Composite Nanoparticle and Its Application in Retinoblastoma-Targeted Theranostics.

Retinoblastoma (RB) is an aggressive tumor of the infant retina. However, the ineffective targeting of its theranostic agents results in poor imaging and therapeutic efficacy, which makes it difficult to identify and treat RB at an early stage. In order to improve the imaging and therapeutic efficacy, we constructed an RB-targeted artificial vesicle composite nanoparticle. In this study, the MnO2 nanosponge (hMNs) was used as the core to absorb two fluorophore-modified DNAzymes to form the Dual/hMNs nanoparticle; after loaded with the artificial vesicle derived from human red blood cells, the RB-targeted DNA aptamers were modified on the surface, thus forming the Apt-EG@Dual/hMNs complex nanoparticle. The DNA aptamer endows this nanoparticle to target the nucleolin-overexpressed RB cell membrane specifically and enters cells via endocytosis. The nanoparticle could release fluorophore-modified DNAzymes and supplies Mn2+ as a DNAzyme cofactor and a magnetic resonance imaging (MRI) agent. Subsequently, the DNAzymes can target two different mRNAs, thereby realizing fluorescence/MR bimodal imaging and dual-gene therapy. This study is expected to provide a reliable and valuable basis for ocular tumor theranostics.

ZEISS PLEX Elite 9000 Widefield Optical Coherence Tomography Angiography as Screening Method for Early Detection of Retinal Hemangioblastomas in von Hippel-Lindau Disease.

Purpose: To evaluate early detection of retinal hemangioblastomas (RHs) in von Hippel-Lindau disease (VHLD) with widefield optical coherence tomography angiography (wOCTA) compared to the standard of care in ophthalmologic VHLD screening in a routine clinical setting. Methods: We conducted prospective comparisons of three screening methods: wOCTA, standard ophthalmoscopy, and fluorescein angiography (FA), which was performed only in uncertain cases. The numbers of detected RHs were compared among the three screening methods. The underlying causes for the lack of detection were investigated. Results: In 91 eyes (48 patients), 67 RHs were observed (mean, 0.74 ± 1.59 RH per eye). FA was performed in eight eyes. Ophthalmoscopy overlooked 25 of the 35 RHs detected by wOCTA (71.4%) due to the background color of the choroid (n = 5), small tumor size (n = 13), masking by a bright fundus reflex (n = 2), and masking by surrounding retinal scars (n = 5). However, wOCTA missed 29 RHs due to peripheral location (43.3%). The overall detection rates were up to 37% on the basis of ophthalmoscopy alone, up to 52% for wOCTA, and 89% for FA. Within the retinal area covered by wOCTA, the detection rates were up to 46.7% for ophthalmoscopy alone, up to 92.1% for wOCTA, and 73.3% for FA. Conclusions: The overall low detection rate of RHs using wOCTA is almost exclusively caused by its inability to visualize the entire peripheral retina. Therefore, in unclear cases, FA is necessary after ophthalmoscopy. Translational Relevance: Within the imageable retinal area, wOCTA shows a high detection rate of RHs and therefore may be suitable to improve screening for RHs in VHLD.

Microvascular flow ultrasound imaging for retinoblastoma.

PURPOSE: To present the results of a pilot study of microvascular flow imaging (MFI) in characterizing tumor vasculature of retinoblastoma. METHODS: The medical records of consecutive patients with retinoblastoma presenting at our institution between July 2019 and June 2022 that were imaged using MFI were reviewed retroactively. Each patient underwent diagnostic evaluation according to standard of care by examination under anesthesia with fluorescein angiography and ocular ultrasound imaging, including color Doppler and MFI. RESULTS: Thirteen eyes of 10 patients with retinoblastoma were included. MFI showed a prominent feeder vessel in 8 eyes, basket vasculature in 6 eyes and tumor bed vascularity in 10 eyes. MFI showed a more extensive vascular branching pattern that was not visible on color Doppler and fluorescein angiography in all eyes. CONCLUSIONS: MFI of retinoblastoma patients could add information about tumor vascularity not detectable by color Doppler or fluorescein angiography. Further study is needed to determine whether this information could be used to predict prognosis for ocular salvage and tumor response to treatment.

Comparison of HASTE versus EPI-Based DWI for Retinoblastoma and Correlation with Prognostic Histopathologic Parameters.

BACKGROUND AND PURPOSE: Non-EPI-based DWI has shown better performance in head and neck pathologies owing to lesser susceptibility artifacts compared with EPI-DWI. However, only sporadic studies have investigated the feasibility of non-EPI-based DWI in retinoblastoma (RB). We qualitatively and quantitively compared EPI-DWI and HASTE-DWI in RB and correlated the tumor ADC values obtained from these 2 techniques with histopathologic markers. MATERIALS AND METHODS: Twenty-one treatment-naive patients with RB underwent 1.5T orbital MR imaging. EPI-DWI and HASTE-DWI were acquired at 3 b-values (0, 500, and 1000 s/mm2). All patients subsequently underwent surgical enucleation. For qualitative image assessment, scoring of overall image quality, artifacts, tumor sharpness, and tumor conspicuity was done by using a 5-point Likert scale. Quantitative assessment included calculations of SNR, contrast-to-noise ratio (CNR), geometric distortion, and ADC. Qualitative scores were compared by using the Wilcoxon signed-rank test, and quantitative parameters were analyzed with a t test. RESULTS: All 21 patients had unilateral RB; 15 were male and 6 were female with a median age of 36 months (range, 9-72 months). On histopathology, patients had either poorly differentiated (n = 13/21) or moderately differentiated (n = 8/21) RB. Other poor prognostic markers evaluated were optic nerve invasion (n = 10/21), choroidal invasion (n = 12/21), and anterior eye segment enhancement on MRI (n = 6/21). HASTE-DWI demonstrated higher image quality scores than EPI-DWI (P < .01), except for tumor conspicuity score, which was higher for EPI-DWI (P < .001). HASTE-DWI showed lower SNR, CNR, and geometric distortion than EPI-DWI (P < .001). The average acquisition times of EPI-DWI and HASTE-DWI were ∼1 and 14 minutes, respectively. The mean tumor ADC value on EPI-DWI was 0.62 ± 0.14 × 10-3 mm2/s and on HASTE-DWI was 0.83 ± 0.17 × 10-3 mm2/s. A significant correlation between EPI-DWI and HASTE-DWI ADC values (r = 0.8; P = .01) was found. Lower ADC values were found in tumors with poor prognostic markers, but none reached a statistically significant difference. CONCLUSIONS: HASTE-DWI shows improved overall image quality; however, it lacks in terms of tumor conspicuity, SNR, CNR, and longer acquisition time compared with EPI-DWI. ADC values derived from HASTE-DWI show no advantage over EPI-DWI in correlation with histopathologic prognostic markers.

Correlation of gene expression with magnetic resonance imaging features of retinoblastoma: a multi-center radiogenomics validation study.

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.

An atypical location of pineoblastoma RB1 subgroup without pineal or retinal tumor.

PURPOSE: To describe the clinical and imaging features of a sellar-suprasellar pineoblastoma RB1 subgroup without pineal or retinal involvement. CASE REPORT: An 11-month-old girl presented to the emergency department with fever, rhinorrhea, vomiting, altered level of consciousness, and one seizure. Head CT and brain MRI demonstrated a large lobulated mass with calcifications and heterogeneous enhancement in the suprasellar region causing mass effect to the ventricular system and hydrocephalus. Histology revealed a CNS embryonal tumor not otherwise specified (NOS) with small round nuclei with mitotic activity and necrosis. DNA methylation analysis classified the tumor in the pineoblastoma RB1 subgroup. CONCLUSION: Pineoblastoma RB1 subgroup should be considered in the differential diagnosis of large sellar-suprasellar masses with calcifications and heterogeneous enhancement in children younger than 18 months even in cases of absent pineal or retinal involvement. Molecular analysis with DNA methylation profiling is critical for diagnosis and management.

[Angioarchitecture of small retinoblastomas: the role of optical coherence tomography angiography]. / Angioarkhitektonika malykh retinoblastom: rol' opticheskoi kogerentnoi tomografii-angiografii.

Optical coherence tomography angiography (OCTA) is a non-invasive diagnostic method used in children and adults. Features of angioarchitecture of small retinoblastoma are not sufficiently covered. PURPOSE: The study investigated the angioarchitecture of small retinoblastomas using OCTA. MATERIAL AND METHODS: The study included 10 children with binocular retinoblastoma aged 2.7±0.5 months with small tumors of central localization (10 foci). The tumors were divided into 3 groups: group 1 (n=4) - tumor thickness 0.8±0.2 mm; group 2 (n=3) - 1.6±0.5 mm; group 3 (n=3) - 2.4±0.8 mm. OCTA was performed on Spectralis HRA+OCT (2460 scans in total). Vessels were identified in the superficial, deep and outer layers of the tumor on En Face images. Their average number was estimated by visualization of yellow pixels in the superficial layers on 10 sagittal sections. Statistical analysis was done using Microsoft Excel, Statistica 8.0. The Kruskal-Wallis H test was used for comparative analysis of independent variables with more than two samples. RESULTS: Retinal vessels with feeding anastomoses connecting them to multiple small tortuous tumor vessels in the superficial layers were identified in group 1. Number of yellow pixels - 16.5±0.5. In the deep layers - single chaotic vascular arcades. In flat small retinoblastomas the vascular component was not evaluated. In group 2 in the superficial layers of the tumor we found multiple geniculate vessels of large and small caliber anastomosing between themselves and the retinal vessels. Number of yellow pixels was 21±0.8. A few vessels were identified in the deep and outer layers. In group 3 we identified single convoluted vessels in the superficial layers with glow and quantity increasing in the deep layers. In the deep layers - emergence of a small number of vessels. The maximum number of multiple own tumor vessels was determined in the outer layers. Number of yellow pixels - 10±0.8. CONCLUSION: The obtained results confirm the possibility to preclinically identify the angioarchitecture of small retinoblastomas in order to determine the activity of tumor growth and serve as a marker of neoplasm regression in the future, after organ-preserving treatment.

Semi-supervised segmentation of retinoblastoma tumors in fundus images.

Retinoblastoma is a rare form of cancer that predominantly affects young children as the primary intraocular malignancy. Studies conducted in developed and some developing countries have revealed that early detection can successfully cure over 90% of children with retinoblastoma. An unusual white reflection in the pupil is the most common presenting symptom. Depending on the tumor size, shape, and location, medical experts may opt for different approaches and treatments, with the results varying significantly due to the high reliance on prior knowledge and experience. This study aims to present a model based on semi-supervised machine learning that will yield segmentation results comparable to those achieved by medical experts. First, the Gaussian mixture model is utilized to detect abnormalities in approximately 4200 fundus images. Due to the high computational cost of this process, the results of this approach are then used to train a cost-effective model for the same purpose. The proposed model demonstrated promising results in extracting highly detailed boundaries in fundus images. Using the Sørensen-Dice coefficient as the comparison metric for segmentation tasks, an average accuracy of 93% on evaluation data was achieved.

MRI Features for Identifying MYCN-amplified RB1 Wild-type Retinoblastoma.

Background MYCN-amplified RB1 wild-type (MYCNARB1+/+) 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 MYCNARB1+/+ 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 MYCNARB1+/+ 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 MYCNARB1+/+ retinoblastoma and 88 control children with RB1-/- retinoblastoma. Children in the MYCNARB1+/+ 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). MYCNARB1+/+ 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). MYCNARB1+/+ 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 MYCNARB1+/+ 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.

A Multi-Thresholding-Based Discriminative Neural Classifier for Detection of Retinoblastoma Using CNN Models.

Cancer is one of the vital diseases which lead to the uncontrollable growth of the cell, and it affects the body tissue. A type of cancer that affects the children below five years and adults in a rare case is called retinoblastoma. It affects the retina in the eye and the surrounding region of eye like the eyelid, and sometimes, it leads to vision loss if it is not diagnosed at the early stage. MRI and CT are widely used scanning procedures to identify the cancerous region in the eye. Current screening methods for cancer region identification needs the clinicians' support to spot the affected regions. Modern healthcare systems develop an easy way to diagnose the disease. Discriminative architectures in deep learning can be viewed as supervised deep learning algorithms which use classification/regression techniques to predict the output. A convolutional neural network (CNN) is a part of the discriminative architecture which helps to process both image and text data. This work suggests the CNN-based classifier which classifies the tumor and nontumor regions in retinoblastoma. The tumor-like region (TLR) in retinoblastoma is identified using the automated thresholding method. After that, ResNet and AlexNet algorithms are used to classify the cancerous region along with classifiers. In addition, the comparison of discriminative algorithm along with its variants is experimented to produce the better image analysis method without the intervention of clinicians. The experimental study reveals that ResNet50 and AlexNet yield better results compared to other learning modules.