International Intraocular Retinoblastoma Classification Research Articles

Aqueous Seeding in Retinoblastoma: Classification and Clinicopathologic Correlation

To correlate the clinical types of aqueous seeds with histopathologic characteristics in primarily enucleated eyes with retinoblastoma (RB). Retrospective study. Twenty-five patients with RB. Clinicopathologic correlation of aqueous seeds in 25 eyes that underwent primary enucleation and showed evidence of aqueous seeds. Histopathologic characteristics of aqueous seeds. All 25 enucleated eyes were classified as group E RB based on the International Classification of Intraocular Retinoblastoma. Clinically, type 1 aqueous seeds were noted in 9 (36%) eyes, type 2 in 8 (32%), and type 3 in 8 (32%). Based on histopathology, type 1 seeds were defined as individual tumor cells admixed with macrophages and nonviable tumor cells. Type 2 seeds were defined as spheres and classified into 2 subtypes: (1) spheres without central necrosis containing solid clusters of tumor cells and (2) spheres with central necrosis containing a central core of necrotic cells surrounded by viable tumor cells. Type 3 seeds were defined as tumor cells admixed with macrophages and red blood cells sedimented at an angle. Aqueous seeding involved both anterior (n= 25; 100%) and posterior (n= 18; 72%) chambers. Significant infiltration of RB into the intraocular tissue (Schlemm canal, trabecular meshwork, ciliary body, choroid, optic nerve, and sclera) was noted in 23 cases (92%). Compared with eyes with type 1 and 2 seeds, eyes with type 3 seeds were more commonly associated with ciliary body infiltration (41% vs. 88%, respectively; P= 0.04). Over a mean follow-up period of 57months (median, 49 months; range, <1-175 months), metastasis and death were noted in 3 patients (12%). Similar to vitreous seeds in RB, aqueous seeds have 3 distinct histopathologic types. Posterior chamber seeds were noted in 72% of cases presenting with anterior chamber (AC) seeds, indicating the need for the treatment of both the chambers whenever conservative treatment is attempted in suitable cases. Most (92%) cases with primary aqueous seeding are associated with other high-risk histopathology features, suggesting acautious approach to conservative management in these cases.

The Effects of Breastfeeding on Retinoblastoma Development: Results from an International Multicenter Retinoblastoma Survey.

Simple SummaryBreastfeeding has been shown to lower the risk of oncogenesis in many pediatric cancers, with longer periods of breastfeeding having the most protective effect. However, an association has not yet been determined for the consequence or benefit of breastfeeding in retinoblastoma (RB), the most common intraocular malignancy of childhood affecting 8000 children worldwide each year. Herein, we aimed to understand the role of breastfeeding in the severity of development of nonhereditary RB, specifically its relationship to age at diagnosis, ocular prognosis, and extraocular involvement. Our analysis of 344 patients indicated that neither breastfeeding nor formula feeding was associated with differences in age at diagnosis, ocular prognosis, or extraocular involvement. More research elucidating the factors affecting the development of RB is warranted both to understand the pathophysiology of tumor development and to develop clinical recommendations for preventive care.The protective effects of breastfeeding on various childhood malignancies have been established but an association has not yet been determined for retinoblastoma (RB). We aimed to further investigate the role of breastfeeding in the severity of nonhereditary RB development, assessing relationship to (1) age at diagnosis, (2) ocular prognosis, measured by International Intraocular RB Classification (IIRC) or Intraocular Classification of RB (ICRB) group and success of eye salvage, and (3) extraocular involvement. Analyses were performed on a global dataset subgroup of 344 RB patients whose legal guardian(s) consented to answer a neonatal questionnaire. Patients with undetermined or mixed feeding history, family history of RB, or sporadic bilateral RB were excluded. There was no statistically significant difference between breastfed and formula-fed groups in (1) age at diagnosis (p = 0.20), (2) ocular prognosis measures of IIRC/ICRB group (p = 0.62) and success of eye salvage (p = 0.16), or (3) extraocular involvement shown by International Retinoblastoma Staging System (IRSS) at presentation (p = 0.74), lymph node involvement (p = 0.20), and distant metastases (p = 0.37). This study suggests that breastfeeding neither impacts the sporadic development nor is associated with a decrease in the severity of nonhereditary RB as measured by age at diagnosis, stage of disease, ocular prognosis, and extraocular spread. A further exploration into the impact of diet on children who develop RB is warranted.

Lenticular changes in eyes with advanced intraocular retinoblastoma: A histopathological study of 48 enucleated eyes

ABSTRACT Purpose To evaluate the lenticular changes in advanced intraocular retinoblastoma (RB) and identify the risk factors for cataract in these eyes. Methods Retrospective analysis of 48 primary enucleations. Results All enucleated eyes were classified either as group D (n = 7; 15%) or group E (n = 41; 85%) tumors based on the International Classification of Intraocular Retinoblastoma. Of the 48 enucleated eyes with RB, cataract was noted clinically in only 5 (18%) cases, while histopathology revealed cataractous changes in 28 (58%) cases. Based on histopathology, the cataractous changes included anterior subcapsular cataract (n = 10; 36%), cortical cataract (n = 6; 21%), posterior subcapsular cataract (n = 10; 36%) and both anterior and posterior subcapsular cataract (n = 2; 7%). Based on multivariate logistic regression, only increased area of necrosis on histopathology was the significant (p = .009) factor predictive of cataractous changes in lens with an odds ratio of 1.08. Conclusion Eyes with advanced RB can harbor cataract in 58% cases, though most of these are subclinical. Clinically significant cataract may be evident in only 18% cases. Increased tumor necrosis is associated with the development of cataractous changes in RB cases.

Aqueous seeding in intraocular retinoblastoma: A review.

The management of retinoblastoma is complex. With increasing treatment modalities and increasing experience with each treatment modality, the globe salvage rates have drastically improved with time. Aqueous seeding in an eye with retinoblastoma is classified as group E based on International Classification of Intraocular Retinoblastoma, and most group E eyes were enucleated a decade earlier. Newer modalities of treatment have improved the globe salvage rates in group E eyes including those with aqueous seeding. Various globe salvage treatment modalities attempted for the management of aqueous seeds include external beam radiotherapy, plaque radiotherapy, intra-arterial chemotherapy, periocular chemotherapy, intravitreal chemotherapy and intracameral chemotherapy. Of all treatment modalities, intracameral chemotherapy holds promise for the management of aqueous seeds in selected patients, but it should be done with the utmost care by a trained ocular oncologist. Enucleation is still the preferred modality of treatment for eyes with advanced retinoblastoma and anterior segment invasion. This review focuses on the current evidence on aqueous seeding, highlighting the pathogenesis, classification, clinical presentation, treatment and outcomes.

LRPPRC regulates metastasis and glycolysis by modulating autophagy and the ROS/HIF1-α pathway in retinoblastoma

Retinoblastoma (RB) is the most common intraocular tumor among children. Leucine-rich pentatricopeptide repeat (PPR)-motif-containing protein (LRPPRC), a suppressor gene of autophagy, has been proven to play a regulatory role in tumor progression. However, little is known about functional roles and mechanisms of LRPPRC in RB progression. First, we performed a detailed analysis for RB and normal control. The expression of LRPPRC in the RB tissues was significantly higher than that in normal tissues. Moreover, LRPPRC suppression could repress tumor cell migration, invasion, glycolysis, and reactive oxygen species (ROS)/hypoxia-inducible factor-1α (HIF1-α) pathway activation by mediating autophagy. Furthermore, overexpression of HIF1-α partially reversed the above changes induced by LRPPRC knockdown. The regulation of LRPPRC on tumor metastasis and glycolysis was also validated by a xenograft tumor assay. In summary, LRPPRC could regulate metastasis and glycolysis of RB by mediating autophagy suppression and further activating the ROS/HIF1-α pathway, and LRPPRC could be a promising prognostic biomarker for RB.

Clinical outcomes and prognosis of Thai retinoblastoma patients.

Retinoblastoma (RB) outcomes in Thailand are unfavorable compared to those of developed countries. This study aims to determine whether the clinical outcomes of patients with RB significantly improved after the implementation of new therapeutic approaches and which clinical factors affect survival and globe-saving outcomes. The medical records of patients newly diagnosed with RB and treated at Siriraj Hospital between January 2005 and December 2018 were reviewed retrospectively. Clinical data, treatments, and outcomes were collected and analyzed. In 194 eyes (144 patients), leukocoria was the most common presenting feature (76.8%); 129 (66.5%) eyes were staged in group E of the International Classification of Intraocular Retinoblastoma. Of the 149 enucleated eyes, 35 had high-risk histopathological features, mostly choroidal invasion; 45 eyes (23.2%) could be salvaged. The 5-year overall survival rate was 90.3%, an improvement compared to the previous study. The 5-year enucleation-free survival rates of Groups A and B, C, D and E were 100%, 83.1%, 36.7% and 16.6% respectively. Factors associated with a lower survival rate were interval from symptom onset to diagnosis >3months (hazard ratio (HR): 5.8: 95% confidence interval (CI): 1.637, 20.579) and buphthalmos (HR: 12.57: 95% CI: 3.936, 40.153). Factors associated with high-risk features were secondary glaucoma (HR: 11.016: 95% CI: 1.24, 98.10) and pseudohypopyon (HR: 14.110: 95% CI: 2.16, 92.05). Survival rates and globe-saving rates appear to have improved; however, advanced-stage presentation remains the major hindrance. Further studies with a larger cohort and longer follow-up are warranted.

The Predictive Value of the Eighth Edition of the Clinical TNM Staging System for the Likelihood of Eye Salvage for Intraocular Retinoblastoma by Systemic Chemotherapy and Focal Therapy.

The American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) cTNM staging is emerging as a universal staging for all cancers, including retinoblastoma. Here we evaluated the predictive value of the eighth edition AJCC/UICC cTNM staging in comparison with the International Intraocular Retinoblastoma Classification for eye globe salvage by primary systemic chemotherapy and focal therapy (CRD) using logistic regression model for the probability of treatment failure. The eye salvage rate for 565 treated eyes was 95% (n=139/147) for T1 tumors (98% for T1a and 93% for T1b), 56% (n=230/410) for T2 (81% for T2a and 53% for T2b), and 0% for T3 tumors, and was 98%, 93%, 76%, and 44% for group A, B, C, and D tumors, respectively. As estimated by odds ratios, T2 were 13.6-fold more likely to fail treatment than T1, and T1b, T2a, and T2b were 2.8-, 9.4-, and 35.1-fold more likely to fail treatment than T1a, respectively. Group B, C, and D tumors were 2.8-, 12.7-, and 50.1-fold more likely to fail treatment than group A tumors, respectively. Eye salvage rate was 62% for eyes with focal seeds (3 mm close to the tumor), and 42% for eyes with diffuse seeds (clouds more than 3 mm from tumor edge) (P<0.0001). Both, the eighth edition cTNM classification and the International Intraocular Retinoblastoma Classification systems, can effectively predict eye salvage rates for retinoblastoma by CRD. Eyes with higher cT stages are more likely to experience treatment failure. Because the cT2b group is very heterogeneous, our findings suggest further division of this group based on the severity of vitreous/subretinal seeds, this should be revised in the next edition of cTNM system.

Risk factors for recurrent retinoblastoma after intravenous chemotherapy.

To analyze the risk factors and estimate the risk period for tumor recurrence in intraocular retinoblastoma (RB). Retrospective study of 60 RB patients. The mean age at presentation with RB was 16months (median 11months; range 1-84months). Tumor was unilateral in 13 (22%) and bilateral in 47 (78%) patients. Of 83 eyes with intraocular RB, group B (n = 27; 33%) tumors were more common based on International Classification of Intraocular Retinoblastoma. All cases received intravenous chemotherapy as a primary treatment. Over a mean follow-up period of 57months (median 38months; range 12-185months) post-primary treatment, 44 (73%) patients developed tumor recurrence. The mean interval between the completion of primary treatment and first tumor recurrence was 5months (median 3months; range 1-24months). The total duration of treatment for complete tumor control including treatment of tumor recurrences was 20months (median 19months; 2-58months). By multivariate analysis, the factors predictive of tumor recurrence were multiple tumors (p = 0.008) and retinal detachment (p = 0.003) at presentation. Kaplan-Meier estimate of tumor recurrence at 6months, 1year, 3years, and 5years was 20%, 31%, 68%, and 73%, respectively. There was no tumor recurrence beyond 5years since primary treatment. Multiple tumors and retinal detachment at presentation are risk factors for tumor recurrence in RB. Close follow-up is mandatory for at least 5years since the initiation of treatment for RB.

Scenario of Retinoblastoma Among Bangladeshi Children – A Single Center Experience of 10 Years

Background: Retinoblastoma is the most common intraocular tumor of childhood and most detected cases are from Indian subcontinent. Here we explore the presentation of retinoblastoma with its histopathological features and treatment outcome in a tertiary eye care center in Bangladesh.&lt;/p&gt; &lt;p&gt;Method: This was a retrospective study of 70 eyes of 60 patients in a ten years period from 2006 to 2016 who had met the criteria regarding demographic profile, clinical presentation, management and histopathology. Tumor was classified based on IIRC (International Intraocular Retinoblastoma Classification) for intraocular tumor and IRSS (International Retinoblastoma Staging System) for extraocular tumor by reviewing the data revealed from EUA, imaging and histopathology.&lt;/p&gt; &lt;p&gt;Result: The mean age of presentation was (Table 1) 31.3 ± 21.68 months, range was 4 months to 96 months and the most frequent presenting age was 12 months. Fifty three percent of children presented between 13 months and 59 months. Mild male predominance was 53.3% (n = 32). Unilateral cases were 71.3% (n = 43) and 6.7% (n = 4) of patients had positive family history. The most common presenting sign was leucocoria (85%) followed by strabismus (18.3%) and proptosis (13.3%). Fifty five (91.6%) children presented with intraocular tumor and 64.9% were with Group E. Enucleation (91.6%) was the prime treatment modality and histopathological risk factor was positive in 51.7% cases among 63.3% cases of primary enucleation. Fifty percent of treated children were in regular follow up.&lt;/p&gt; &lt;p&gt;Conclusion: Most children presented delayed and prime treatment modality was enucleation. Only half of the patients were in regular follow up. Generation of awareness, proper referral, information regarding treatment availability and early detection of cases can increase the survival rate and globe salvage.

Management and Outcomes of Unilateral Group D Tumors in Retinoblastoma.

PurposeRetinoblastoma presents most commonly as advanced unilateral disease, particularly in developing countries for which primary enucleation has been the preferred method of treatment. However, with the evolution of newer treatment modalities including intravitreal chemotherapy, intra-arterial chemotherapy and newer chemotherapeutic combinations, a trend towards more conservative approaches is being observed. Our aim is to evaluate outcomes of group D eyes following conservative and non-conservative treatment options.Patients and MethodsThe ocular oncology database was used to identify eyes with unilateral retinoblastoma that fulfilled the International Intraocular Retinoblastoma Classification (IIRC) group D criteria from August 2010 to August 2018 and these were retrospectively reviewed. Overall, 39 eyes were identified.ResultsNineteen (49%) eyes underwent primary enucleation and 20 (51%) received eye-conserving treatment. Eye salvage was possible in 15 (75%) eyes in the attempted salvage group. None of the patient revealed signs of metastasis. All eyes received conventional chemotherapy (carboplatin, vincristine, etoposide) and focal laser therapy. Additional treatment modalities offered included intravitreal chemotherapy, intra-arterial chemotherapy and topotecan. Three (11%) eyes in the primary enucleation group showed high-risk features on histopathology and none developed metastasis.ConclusionThe results of the study seem promising and conservative measures can be adopted in selected unilateral group D eyes.

Different Types of Clinical Presentations and Stages of Retinoblastoma Among Children.

IntroductionRetinoblastoma (Rb) is the most common intraocular malignant tumor of childhood. The different modes of Rb presentation comprise proptosis, anterior chamber inflammatory signs, spontaneous hyphema, secondary glaucoma, and strabismus. The primary aim of this study was to investigate the different clinical presentations and stages of Rb that may help in early detection and timely diagnosis to prevent the advancement of the disease and increase rates of survival in children. Materials and methodsThis was a descriptive cross-sectional study conducted between December 2019 and May 2020 over a period of six months at a tertiary care hospital in Karachi, Pakistan. The sample size included 68 eyes of children with lesions of Rb at the time of presentation to the hospital. Brightness scans (B-scans), computed tomography (CT) scans, and magnetic resonance imaging (MRI) were performed. The International Intraocular Retinoblastoma Classification (IIRC) was used to stage each eye. In case of enucleation (if necessary) of the eye, the biopsy was performed to evaluate the histological features of cancer. All statistical analysis was performed using Statistical Package for Social Sciences version 17.0 (IBM Corp., Armonk, New York).ResultsThe mean age of the children was 3.21 ± 1.75 years. Leukocoria was the most common clinical presentation observed in more than half (n = 35, 51.47%) of the sample population followed by proptosis reported in nearly two-fifths (n = 25, 36.76%), strabismus and phthisis bulbi observed in equal proportions (n = 3, 4.41%), and hypopyon documented in a minor proportion (n = 2, 2.94%) of patients. Regarding stages of the Rb disease, the most common stages were observed to be stage C and stage E. ConclusionsThis study concludes that the early detection of Rb is possible through a better understanding of presenting features of the disease. It can prevent the progression of the disease to the advanced stages and decrease morbidity and mortality. The early detection of Rb can be made possible through the examination of red reflex on the regular check-ups of children as leukocoria is the most common clinical presentation.

Prognostic Information for Known Genetic Carriers of RB1 Pathogenic Variants (Germline and Mosaic)

To compare the number of tumors per eye for mosaic carriers of RB1 pathogenic variants with full germline variants and the conversion from unilateral to bilateral disease. Retrospective cohort study comparing patients with retinoblastoma and different genetic subtypes: high penetrance (HP), low penetrance (LP), and mosaicism. Data were analyzed between 1992 and 2018 at the Retinoblastoma Unit, Royal London Hospital, London, United Kingdom. All familial patients had a parent with a known pathogenic variant even if the parent did not manifest the disease. Number of tumors per eye in children who developed retinoblastoma in that eye. Other outcomes included total number of tumors per patient, age at diagnosis, laterality at presentation and later, sex, and stage according to International Intraocular Retinoblastoma Classification. A total of 111 patients were included: 64 full germline, familial patients (53 HP and 11 LP) and 47 mosaic patients. Twelve HP patients (23%) were unilateral, and 8 of 12 patients (67%) developed tumors in their previously unaffected eye. A total of 34 mosaic patients (72%) were unilateral, and only 2 (6%) developed tumors in their unaffected eye. Age at diagnosis was higher in mosaic patients (median, 22 months) than in HP patients (median 7) (P < 0.00002). The number of tumors per eye was fewer in patients with mosaic alleles (median, 1.0; range, 1-6) compared with patients with HP alleles (median, 3.0; range, 1-8) (P < 0.0003). All 3 children (4 eyes) with mosaicism and more than 2 tumors per eye had high levels of mosaicism. Children with mosaic alleles have fewer tumors per eye compared with those with known high-penetrant pathogenic variants and are more likely to remain unilateral. The level of mosaicism has an impact on laterality and number of tumors.

Abstract B63: Survivorship, vision, and eye salvage following pars plana vitrectomy for residual active or recurrent retinoblastoma

Abstract Introduction: Intraocular surgery has long been taboo in the management of eyes with retinoblastoma due to concern of extraocular spread that carries poor survivorship. Pars plana vitrectomy (PPV) and tumor endoresection has recently emerged in China as an effective surgical treatment to salvage eyes with tumor resistant to chemotherapy, the current standard of care. To investigate the safety and efficacy of this novel treatment, we studied survivorship, visual acuity, and eye salvage rate of retinoblastoma children/eyes treated with PPV. Methods: Outcomes were reviewed for 227 children (247 eyes) treated with PPV and endoresection for residual active tumor or recurrent tumor following chemotherapy at 29 Chinese centers between 2013 and 2014. Results: At 5 years following PPV, 14 patients died, 8 related to the eye that had PPV. The 5-year overall survival rate following PPV was 93.7% (95% CI: 90.4% to 97.0%). The 5-year PPV eye-related survival rate (PPVSR) was 96.3% (95% CI: 93.8% to 98.9%). Children with PPV for residual active tumor had better survival than those with PPV for recurrent tumor (5-year PPVSR 98.1% vs. 91.4%, P = .021). Children with 1 to 3 cycles of neoadjuvant chemotherapy (intra-arterial or systemic chemotherapy) prior to PPV had similar survival to children with ≥4 cycles of chemotherapy (98.2% vs. 93.7%, P = .093). Children with adjuvant systemic chemotherapy following PPV had 100% (95% CI: 93.5% to 100%) 5-year PPVSR, not significantly higher than those without adjuvant chemotherapy (100% vs. 94.8%, P = .102). Of 94 eyes with partial or no retinectomy and documented visual acuity, the post-PPV visual acuity was 20/20-20/60 (23, 24%); 20/7-20/160 (6, 6%); 20/17-20/400 (9, 10%); counting fingers, hand motion, or light perception vision (42, 45%); and no light perception (NLP) (14, 15%). Complete retinectomy was performed on 93 of 247 (37.7%) eyes that, as expected, had NLP. The 5-year eye salvage rate following PPV was 80.7% (95% CI: 75.5% to 85.9%). PPV for residual active tumor and recurrent tumor had similar eye salvage rate (82.0% vs. 76.8%, P = .372). Eyes with International Intraocular Retinoblastoma Classification (IIRC) A, B, or C staging had better salvage rate than eyes with IIRC D or E staging (100.0% vs. 78.1%, P = .005). Eyes that received 1 to 3 cycles and ≥4 cycles of neoadjuvant chemotherapy had similar salvage rate (81.4% vs. 79.8%, P = .796). Conclusion: We observed that PPV salvaged 80.7% of eyes with residual active tumor after primary chemotherapy or recurrent tumor after remission. The 5-year eye-specific survival was 96.3%, comparable to survivorship using other treatment modalities. More cycles of neoadjuvant chemotherapy did not improve survivorship or eye salvage rate. In this cohort, all children with adjuvant chemotherapy following PPV survived at 5 years. PPV may be a game changer to improve health outcomes of patients with retinoblastoma, with the potential to become the new standard of care. Citation Format: Junyang Zhao, Zhao Xun Feng, Qiyan Li, Songyi Wu, Liwen Jin, Brenda L. Gallie. Survivorship, vision, and eye salvage following pars plana vitrectomy for residual active or recurrent retinoblastoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B63.

Clinical Features of Children with Retinoblastoma and Neuroblastoma.

Purpose Retinoblastoma and neuroblastoma are the most common malignant extracranial solid tumors in children. This study aimed to summarize the clinical features, especially the delayed diagnosis in children with retinoblastoma and neuroblastoma. Methods In a single hospital-based case-control study, a retrospective cohort of 175 children with retinoblastoma and neuroblastoma diagnosed from January 2016 to January 2018 were reviewed. The state of enucleation in retinoblastomas and pathological prognosis in neuroblastomas were outcome indicators. Hereby, the patients were divided into two groups, and clinical features including age at presentation and delayed diagnosis were compared. Results A total of 112 patients with retinoblastoma and 63 with neuroblastoma were included. In the retinoblastoma cohort, the median age at presentation was 17.2 months (0.3–110 months). The mean delay of diagnosis was 1.6 ± 2.3 months, and the rate of enucleation was 61.6%. Unilateral disease, the International Classification of Intraocular Retinoblastoma (IIRC) stage E, and delay of diagnosis over 2.5 months were independent risk factors of ocular outcomes. Notably, the risk of enucleation was increased by 474% when the delay was longer than 2.5 months. In the neuroblastoma cohort, the delay of diagnosis of the unfavorable histology (UH) group was longer than that of the favorable histology (FH) group (1.9 months vs. 1.4 months, P=.487). The levels of serum ferritin and neuron-specific enolase were higher in the UH group than in the FH group (P < .05). Conclusions This study summarized the clinical features and diagnosis biomarkers of retinoblastoma and neuroblastoma patients in China. These results might help to focus on early detection and treatment in children with retinoblastoma and neuroblastoma.

Cataract surgery in treated retinoblastoma eyes: A study of 29 eyes.

To study the outcomes of cataract surgery in treated retinoblastoma (RB) eyes. Retrospective study of 29 eyes of 27 patients. Based on International Classification of Intraocular Retinoblastoma, tumors belonged to group B (n = 3, 10%), C (n = 1, 4%), D (n = 10, 34%), and E (n = 3, 10%). The remaining 12 eyes (41%) had regressed tumors on presentation due to prior treatment. The RB treatment details included intravenous chemotherapy (n = 24, 83%), external beam radiotherapy (n = 14, 48%), and others. The mean time interval between tumor regression and cataract surgery was 51 months (median, 26 months; range, 6-245 months). The post-operative visual acuity was 20/200 or better in 12 (41%) eyes. Overall, 16 (55%) eyes displayed improvement of vision post-cataract surgery, while 13 (45%) eyes had no improvement in vision. The complications of cataract surgery included visual axis opacification (n = 15, 52%), pupillary membrane (n = 4, 14%), hyphema (n = 1, 3%), and extraocular tumor extension (n = 1, 3%). Clearer fundus view post-surgery revealed underlying tumor edge recurrence in 1 (3%) eye, and two (7%) patients had tumor recurrence at a mean interval of 8 months (median, 8 months; range, 7-8 months) following cataract extraction. Globe salvage was achieved in 26 (90%) eyes over a mean follow-up period of 103 months (median, 91 months; range, 19-267 months). Cataract surgery in treated RB is safe with vision salvage in 55% eyes and globe salvage in 90% eyes. Though there is a risk of extraocular tumor extension, its occurrence is rare (3%).

Association Between Genotype and Phenotype in Consecutive Unrelated Individuals With Retinoblastoma

Retinoblastoma (RB) is the most common pediatric intraocular neoplasm. RB is a complex model in which atypical pathogenic variants, modifier genes, imprinting, and mosaicism are known to be associated with the phenotype. In-depth understanding of RB therefore requires large genotype-phenotype studies. To assess the association between genotype and phenotype in patients with RB. This single-center, retrospective cohort study, conducted from January 1, 2000, to September 30, 2017, enrolled 1404 consecutive ascertained patients with RB who consulted an oncogeneticist. All patients had their genotype and phenotype recorded. Statistical analysis was performed from July 1, 2018, to December 31, 2018. RB1 germline and somatic pathogenic variant types, family history, and disease presentation characteristics (ie, age at diagnosis, sex, laterality, and International Intraocular Retinoblastoma Classification group). Among 1404 patients with RB (734 [52.3%] female; mean [SD] age, 20.2 [21.2] months), 866 cases (61.7%) were unilateral and 538 cases (38.3%) were bilateral. Loss of function variants were found throughout the coding sequence, with 259 of 272 (95.2%) somatic pathogenic variants and 537 of 606 (88.6%) germline pathogenic variants (difference, 6.6%; 95% CI, 4.0%-9.2%; P < .001) after excluding tumor-specific pathogenic variants (ie, promoter methylation and loss of heterozygosity); a novel low-penetrance region was identified in exon 24. Compared with germline pathogenic variants estimated to retain RB protein expression, germline pathogenic variants estimated to abrogate RB protein expression were associated with an earlier mean (SD) age at diagnosis (12.3 [11.3] months among 457 patients vs 16.3 [13.2] months among 55 patients; difference, 4 months; 95% CI, 1.9-6.1 months; P = .01), more frequent bilateral involvement (84.2% among 452 patients vs 65.2% among 45 patients; difference, 18.9%; 95% CI, 14.5%-23.3%; P < .001), and more advanced International Intraocular Retinoblastoma Classification group (85.3% among 339 patients vs 73.9% among 34 patients; difference: 11.4%; 95% CI, 6.5%-16.3%; P = .047). Among the 765 nongermline carriers of an RB1 pathogenic variant, most were female (419 females [54.8%] vs 346 males [45.2%]; P = .008), and males were more likely to have bilateral RB (23 males [71.4%] vs 12 females [34.3%]; P = .01). These results suggest that RB risk is associated with the germline pathogenic variant and with maintenance of RB protein and that there is a sex-linked mechanism for nongermline carriers.

Variability in retinoblastoma genome stability is driven by age and not heritability.

Retinoblastoma (RB) is a childhood intraocular cancer initiated by biallelic inactivation of the RB tumor suppressor gene (RB1-/- ). RB can be hereditary (germline RB1 pathogenic allele is present) or non-hereditary. Somatic copy number alterations (SCNAs) contribute to subsequent tumorigenesis. Previous studies of only enucleated RB eyes have reported associations between heritability status and the prevalence of SCNAs. Herein, we use an aqueous humor (AH) liquid biopsy to investigate RB genomic profiles in the context of germline RB1 status, age, and International Intraocular Retinoblastoma Classification (IIRC) clinical grouping for both enucleated and salvaged eyes. Between 2014 and 2019, AH was sampled from a total of 54 eyes of 50 patients. Germline RB1 status was determined from clinical blood testing, and cell-free DNA from AH was analyzed for SCNAs. Of the 50 patients, 23 (46.0%; 27 eyes) had hereditary RB, and 27 (54.0%, 27 eyes) had non-hereditary RB. Median age at diagnosis was comparable between hereditary (13 ± 10 months) and non-hereditary (13 ± 8 months) eyes (P = 0.818). There was no significant difference in the prevalence or number of SCNAs based on (1) hereditary status (P > 0.56) or (2) IIRC grouping (P > 0.47). There was, however, a significant correlation between patient age at diagnosis, and (1) number of total SCNAs (r[52] = 0.672, P < 0.00001) and (2) number of highly-recurrent RB SCNAs (r[52] = 0.616, P < 0.00001). This evidence does not support the theory that specific molecular or genomic subtypes exist between hereditary and non-hereditary RB; rather, the prevalence of genomic alterations in RB eyes is strongly related to patient age at diagnosis.

Clinical Features and Long-term Prognosis of Retinoblastoma according to Age at Diagnosis.

PurposeWe aimed to study the clinical characteristics and long-term prognoses of retinoblastoma according to the age at diagnosis.MethodsA retrospective chart review of non-screened patients newly diagnosed with retinoblastoma between January 2007 and February 2018.ResultsAmong the 20 patients analyzed, 11 were diagnosed at an age younger than 1 year (group 1) and nine at 1 year or older (group 2). The mean lag times until diagnosis were 1.0 ± 0.4 and 5.0 ± 2.1 months for groups 1 and 2, respectively (p = 0.056). The mean follow-up durations were 49.4 ± 12.7 and 58.3 ± 8.8 months, respectively (p = 0.412). Group 1 had a significantly higher proportion of bilateral retinoblastoma than did group 2 (72.7% vs. 11.1%, p = 0.010). Four of five patients (80.0%) with germline RB1 mutations were diagnosed with retinoblastoma at age 3 months or younger. The eyes of patients in group 2 had significantly higher International Intraocular Retinoblastoma Classification stages than did those of patients in group 1 (p for trend = 0.010). The proportion of eyes with optic nerve invasion and those that had undergone enucleation were significantly higher in group 2 (p = 0.033 and 0.046, respectively). Survival did not differ according to the age at diagnosis.ConclusionsEarly onset retinoblastoma does not seem to indicate poor ocular or survival prognosis in Korean children with retinoblastoma.

Combined intra-arterial chemotherapy and intravitreal melphalan for the treatment of advanced unilateral retinoblastoma.

To evaluate the efficacy and safety of combined intra-arterial chemotherapy (IAC) and intravitreal melphalan (IVM) for the treatment of advanced unilateral retinoblastoma. This retrospective study involved 30 consecutive eyes from 30 Chinese patients with advanced unilateral retinoblastoma. All patients were initially treated with IAC combined with IVM. The clinical status and complications were recorded at each visit. The International Intraocular Retinoblastoma Classification groups were D in 23 eyes and E in 7 eyes. All eyes showed severe cloud vitreous seeds at the first visit. The mean number of IAC cycles and intravitreal injections was 3.2 (range, 3-4) and 6 (range, 1-14), respectively. The median follow-up time was 29mo (range, 7-36mo). Treatment success with regression of the retinal tumor and vitreous seeds was achieved in 29 of 30 eyes (96.7%). Globe salvage was attained in 93.3% (28/30) eyes, and enucleation (n=2) was performed due to neovascular glaucoma and persistent vitreous hemorrhage. Complications included retinal pigment epithelium (RPE) atrophy (n=13; 43%), mild lens opacity (n=7; 23%), vitreous hemorrhage (n=5; 17%) and rhegmatogenous retinal detachment (n=1; 3%). No extraocular tumor extension or metastasis occurred. Combined IAC and IVM is effective and safe for the treatment of advanced unilateral retinoblastoma.

Clinical analysis of 66 patients of retinoblastoma

Objective To observe the clinical characteristics of retinoblastoma (RB) in Southwest China. Methods A retrospective clinical study. From January 2010 to December 2017, 66 RB patients diagnosed in Ophthalmology Department of West China Hospital of Sichuan University were included in the study. All the patients underwent ocular B-ultrasound, orbital CT or MRI examination. Ten patients underwent RetCam examination at the same time. Twenty-nine patients were diagnosed by histopathological examination, and 37 patients were diagnosed by clinical symptoms and imaging examination. According to whether the tumor invaded the orbit and optic nerve, it could be divided into extraocular stage and intraocular stage. Intraocular tumors were divided into A-E stages according to the international intraocular RB classification. Treatments were performed according to different stages. The general information, age at diagnosis, course of diseases (the time between onset symptoms and diagnosis), causes of visiting a doctor, classification, treatment methods and eyeball preservation rate were retrospectively analyzed. Results Patients all came from Southwest China (56 patients from Sichuan Province, 2 patients from Yunnan Province, 2 patients from Guizhou Province, and 6 patients from Tibet). The permanent residence were identified in 43 patients, including 27 patients (62.8%) from rural areas. There were 38 males (57.6%); 50 unilateral tumors (75.8%) and 16 bilateral tumors (24.2%); 51 first-visiting patients (77.3%) and 15 re-visiting patients (22.7%). The average diagnostic age of first-visiting patients was 20.9±14.4 months, with 23.2±14.7 and 11.2±7.6 months for unilateral and bilateral tumors, respectively. There were 41 patients had definite course and causes, of whom the average course was 90.6±115.2 days. The most common cause was leucocoria in 32 patients (62.7%), followed by redness and swelling in 4 patients (9.8%), and other causes in 5 patients (12.2%). Among the 15 re-visiting patients, the average diagnostic age was 63.6±46.8 months, the average course was 32.8±45.5 months. Recurrence was occurred in 5 patients (33.3%), leucocoria in 4 patients (26.7%), postoperative complication in 3 patients (20.0%), protrusion in 2 patients (13.3%) and redness in 1 (6.7%) patient, respectively. Fifty out of 82 eyes were admitted to hospital, including 37 eyes of first-visiting patients and 13 eyes of re-visiting patients. Among 37 first-visiting eyes, there were 5 eyes (13.5%) in stage A-C, 26 eyes (70.3%) in stage D-E, 6 eyes (16.2%) in extraocular stage. Five eyes in stage A-C were treated with laser photocoagulation and (or) cryotherapy combined with systemic chemotherapy. Four eyes in stage D were treated with intraocular arterial chemotherapy. Nineteen eyes (51.3%) were performed with enucleation, 2 eyes (5.4%) with evisceration and 7 eyes (18.9%) abandoned treatment. Among 13 re-visiting eyes, 6 eyes (46.2%, with 5 eyes of recurrence) had been enucleated before, 4 eyes (30.8%) were in extraocular stage and 3 eyes (23.1%) in stage D-E. Five eyes (38.5%) were treated with evisceration, 4 eyes (30.8%) with enucleation, 1 eye with oculoplastic surgery and 3 eyes (23.1%) abandoned treatment. The rate of eye preservation was 18.0%, 29.0% for intraocular stage and 0% for extraocular stage, respectively. Conclusion RB patients in Southwest China have a longer course between onset symptoms and diagnosis, more advanced classification and lower rate of eye preservation. Key words: Retinoblastoma; Disease attributes; Chemotherapy, cancer, regional perfusion; Laser coagulation; Cryotherapy