The Pediatric and Young Adult Choroidal and Ciliary Body Melanoma Genetic Study, A Survey by the European Ophthalmic Oncology Group.

Purpose: To explore the genetic background of choroidal and ciliary body melanoma among children and young adults, with special focus on BAP1 germline variants in this age group. Methods: Patients under the age of 25 and with confirmed choroidal or ciliary body melanoma were included in this retrospective, multicenter observational study. Nuclear BAP1 immunopositivity was used to evaluate the presence of functional BAP1 in the tumor. Next-generation sequencing using Ion Torrent platform was used to determine pathogenic variants of BAP1, EIF1AX, SF3B1, GNAQ and GNA11 and chromosome 3 status in the tumor or in DNA extracted from blood or saliva. Survival was analyzed using Kaplan-Meier estimates. Results: The mean age at diagnosis was 17 years (range 5.0-24.8). A germline BAP1 pathogenic variant was identified in an 18-year-old patient, and a somatic variant, based mainly on immunohistochemistry, in 13 (42%) of 31 available specimens. One tumor had a somatic SF3B1 pathogenic variant. Disomy 3 and the absence of a BAP1 pathogenic variant in the tumor predicted the longest metastasis-free survival. Males showed longer metastasis-free survival than females (P = 0.018). Conclusions: We did not find a stronger-than-average BAP1 germline predisposition for choroidal and ciliary body melanoma among children and young adults compared to adults. Males had a more favorable survival and disomy 3, and the absence of a BAP1 mutation in the tumor tissue predicted the most favorable metastasis-free survival. A BAP1 germline pathogenic variant was identified in one patient (1%), and a somatic variant based mainly on immunohistochemistry in 13 (42%).

IC3D Classification of Corneal Dystrophies-Edition 3.

PURPOSE: The International Committee for the Classification of Corneal Dystrophies (IC3D) was created in 2005 to develop a new classification system integrating current information on phenotype, histopathology, and genetic analysis. This update is the third edition of the IC3D nomenclature. METHODS: Peer-reviewed publications from 2014 to 2023 were evaluated. The new information was used to update the anatomic classification and each of the 22 standardized templates including the level of evidence for being a corneal dystrophy [from category 1 (most evidence) to category 4 (least evidence)]. RESULTS: Epithelial recurrent erosion dystrophies now include epithelial recurrent erosion dystrophy, category 1 ( COL17A1 mutations, chromosome 10). Signs and symptoms are similar to Franceschetti corneal dystrophy, dystrophia Smolandiensis, and dystrophia Helsinglandica, category 4. Lisch epithelial corneal dystrophy, previously reported as X-linked, has been discovered to be autosomal dominant ( MCOLN1 mutations, chromosome 19). Classic lattice corneal dystrophy (LCD) results from TGFBI R124C mutation. The LCD variant group has over 80 dystrophies with non-R124C TGFBI mutations, amyloid deposition, and often similar phenotypes to classic LCD. We propose a new nomenclature for specific LCD pathogenic variants by appending the mutation using 1-letter amino acid abbreviations to LCD. Pre-Descemet corneal dystrophies include category 1, autosomal dominant, punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) ( PRDX3 mutations, chromosome 10). Typically asymptomatic, it can be distinguished phenotypically from pre-Descemet corneal dystrophy, category 4. We include a corneal dystrophy management table. CONCLUSIONS: The IC3D third edition provides a current summary of corneal dystrophy information. The article is available online at https://corneasociety.org/publications/ic3d .

Functional assay for assessment of pathogenicity of BAP1 variants.

BACKGROUND: Pathogenic germline variants in BRCA1-Associated Protein 1 (BAP1) cause BAP1 tumor predisposition syndrome (BAP1-TPDS). Carriers run especially a risk of uveal (UM) and cutaneous melanoma, malignant mesothelioma, and clear cell renal carcinoma. Approximately half of increasingly reported BAP1 variants lack accurate classification. Correct interpretation of pathogenicity can improve prognosis of the patients through tumor screening with better understanding of BAP1-TPDS. METHODS: We edited five rare BAP1 variants with differing functional characteristics identified from patients with UM in HAP1 cells using CRISPR-Cas9 and assayed their effect on cell adhesion/spreading (at 4 h) and proliferation (at 48 h), measured as cell index (CI), using xCELLigence real-time analysis system. RESULTS: In BAP1 knockout HAP1 cultures, cell number was half of wild type (WT) cultures at 48 h (p = 0.00021), reaching confluence later, and CI was 78% reduced (p < 0.0001). BAP1-TPDS-associated null variants c.67+1G>T and c.1780_1781insT, and a likely pathogenic missense variant c.281A>G reduced adhesion (all p ≤ 0.015) and proliferation by 74%-83% (all p ≤ 0.032). Another likely pathogenic missense variant c.680G>A reduced both by at least 50% (all p ≤ 0.032), whereas cells edited with likely benign one c.1526C>T grew similarly to WT. CONCLUSIONS: BAP1 is essential for optimal fitness of HAP1 cells. Pathogenic and likely pathogenic BAP1 variants reduced cell fitness, reflected in adhesion/spreading and proliferation properties. Further, moderate effects were quantifiable. Variant modelling in HAP1 with CRISPR-Cas9 enabled functional analysis of coding and non-coding region variants in an endogenous expression system.

Does Corneal Topography Using 3-Dimensional Optical Coherence Tomography Suggest Different Subtypes of Terrien Marginal Degeneration?

PURPOSE: The aim of this study was to analyze corneal topography relative to astigmatism, higher order aberrations, and corneal curvatures in Terrien marginal degeneration using 3-dimensional anterior-segment optical coherence tomography. METHODS: Twenty-nine eyes of 15 Finnish patients from a tertiary referral center had topographic axial power maps classified into 4 patterns by visual grading: crab claw (CC), mixed (M), arcuate (A), and normal. Regular astigmatism, keratometry, higher order aberrations, maximal corneal thinning, apex thickness, and curvature changes relative to best fit sphere toward maximal peripheral thinning were compared. RESULTS: Four, 9, and 12 eyes were classified as CC, M, and A, respectively; 1 as normal with clinical disease; and 3 as normal with unilateral disease. Median follow-up was 2.3 (range, 0-7.2) years. Three eyes changed pattern. Patients with the CC pattern were the youngest when diagnosed, progressed more rapidly, exhibited cavities in superior quadrants with anterior bulging, and had greater higher order posterior aberrations. Patients with the M pattern were older, progressed slower, and showed superonasal asymmetric corneal steepening extending centrally, often with asymmetric bow tie. Patients with pattern A showed little progression and were the oldest when diagnosed, with maximal corneal thinning equally in all quadrants. According to the Wang classification, the median stage was 4, 2, and 2 in CC, M, and A patterns, respectively, whereas it was always 2 by the Süveges classification. CONCLUSIONS: Terrien marginal degeneration is characterized by distinct corneal topographic patterns that differ in tomographic features, suggesting existence of subtypes in addition to different stages of disease. Patients representing CC and M patterns might benefit from more frequent monitoring.

Epithelial recurrent erosion dystrophy (ERED) from the splice site altering COL17A1 variant c.3156C>T in families of Finnish-Swedish ancestry.

PURPOSE: To describe four Finnish families with epithelial recurrent erosion dystrophy (ERED) caused by the pathogenic variant c.3156C>T in collagen type XVII alpha 1 chain gene (COL17A1). METHODS: Eleven affected and two unaffected individuals underwent clinical ophthalmological examination, anterior segment photography, and corneal topography. Two of them underwent phototherapeutic keratectomy (PTK). Genetic analysis included both next-generation and Sanger sequencing. Specimens from the manual keratectomy of one patient were available for ophthalmic pathologic examination, including immunohistochemistry. RESULTS: The common splice-site altering synonymous variant c.3156C > T, p.(Gly1052=) in COL17A1 was confirmed in 15 individuals with ERED from the four families. Subepithelial corneal scarring grades varied and increased with age, leading to decreased best-corrected visual acuity. PTK improved vision in 58- and 67-year-old individuals without reactivating the disease. The keratectomy specimens showed an uneven epithelium and a spectrum of basement membrane abnormalities, including breaks, fragmentation, multiplication and entrapment within the subepithelial scar, reflecting recurrent erosions. The stromal cells consisted of varying proportions of bland and activated fibroblasts and myofibroblasts, reflecting different ages of scars. The family with the largest number of known affected generations originated from Southern Sweden. CONCLUSION: The phenotype in the Finnish ERED families is consistent with earlier reports of the c.3156C > T variant, although the severity has varied between reports. The phenotype may be modulated by other genes. This study suggests a likely founder effect of the variant in both Finnish and Swedish populations due to their shared population histories. If vision is compromised, PTK can be considered especially in older patients.

Cutaneous squamous cell carcinoma of the eyelid in northern latitudes, a 25-year experience in Finland.

PURPOSE: To evaluate the incidence, clinical features, diagnostic challenges, management and prognosis of cutaneous squamous cell carcinoma of the eyelid (ecSCC) in southern Finland, northern Europe, latitude 62° N. METHODS: Patients were identified from the Finnish Cancer Registry and the Helsinki University Hospital databases during a 25-year period (1998-2022). Age, sex, location, clinical and histopathological diagnosis, treatment and outcome were retrieved. RESULTS: Cutaneous squamous cell carcinoma of the eyelid (ecSCC) was diagnosed in 58 patients. The mean age-standardized incidence was 1.03 per 100 000. Median age at the time of histopathological diagnosis was 79 (range 55-93) years; sex ratio was 0.52. Clinical diagnosis in the referral was ecSCC in only three patients. The most frequent misdiagnosis (38%) was basal cell carcinoma (BCC). One or more of the known risk factors (smoking, history of extensive sun exposure, systemic immunosuppression and previous in situ cSCC/cSCC) were documented in 71% of the patients. More than one third (38%) of the patients developed in situ SCC elsewhere on the skin; one third (31%) of the patients had invasive cSCC elsewhere. During the median follow-up time of 24 months, three patients experienced local recurrence, four patients developed metastatic disease (median 19 months) and two patients died of metastatic ecSCC. CONCLUSION: The estimated incidence of ecSCC in Finland (predominantly white Caucasian) was higher than in a previous study from Europe. Clinical diagnosis of ecSCC is difficult and often misdiagnosed as BCC. Immunosuppression as a risk factor should noticed. Recurrences of ecSCC, which may be lethal, were infrequent.

Pediatric ocular melanoma: a collaborative multicenter study and meta-analysis.

PURPOSE: To investigate clinical manifestations and prognoses in pediatric patients (≤12 years old) with ocular melanoma. METHODS: This was a retrospective, multicenter cohort study with individual participant data (IPD) meta-analysis pooling available published cases, and unpublished cases from an international collaboration of seven ocular oncology centers. RESULTS: There were 133 eyes of 133 pediatric patients with choroidal or ciliary body (n = 66 [50%]), iris (n = 33 [25%]), conjunctival (n = 26 [19%]), and eyelid (n = 8 [6%]) melanoma. Overall, the mean patient age at presentation was 7 years (median, 8; range, 1-12 years), with 63 males (49%). The mean age by tumor site was 6.50 ± 3.90, 7.44 ± 3.57, 9.12 ± 2.61, and 5.63 ± 2.38 years, for choroid/ciliary body, iris, conjunctiva, and eyelid melanoma, respectively (P = 0.001). Association with ocular melanocytosis was seen in 15%, 11%, 4%, and 0%, respectively (P = 0.01). Frequency of ocular melanoma family history did not vary by tumor site (7%, 17%, 9% and 12%, resp. [P = 0.26]). After mean follow-up of 74, 85, 50, and 105 months (P = 0.65), metastasis was seen in 12%, 9%, 19%, and 13% of choroid/ciliary body, iris, conjunctiva, and eyelid melanoma, respectively. Death was reported in 5%, 3%, 8%, and 0%, respectively, with survival analysis indicating higher mortality in choroidal/ciliary body and conjunctival melanoma patients. CONCLUSIONS: Ocular melanoma in the pediatric population is rare, with unique clinical features and outcomes. Iris melanoma accounts for about one-third of pediatric uveal melanoma cases.

Cataract surgical training in Europe: European Board of Ophthalmology survey.

PURPOSE: To survey recently graduated European ophthalmologists concerning cataract surgery (CS) training opportunities. SETTING: Countries affiliated to the European Board of Ophthalmology (EBO). DESIGN: Cross-sectional study of anonymous survey results. METHODS: A 23-question online survey was emailed to candidates who sat the EBO Diploma Examination as residents between 2018 and 2022. RESULTS: 821 ophthalmologists from 30 countries completed the survey. The mean residency duration was 4.73 (SD 0.9) years. The mean reported number of entire CS procedures performed was 80.7 (SD 100.6) at the end of residency, but more than 25% of respondents (n = 210) had received no live CS training during their residency. The self-confidence (scale, 1 to 10) to perform a simple case or challenging case, manage posterior capsular rupture, and realize a corneal stitch were rated 4.1, 3.2, 4.2, 2.4, respectively. We observed extensive variation in clinical exposure to CS and self-reported confidence to perform CS between European trainees. Females reported a mean of 18% fewer entire procedures than their male colleagues and were also less confident in their surgical skills (P < .05). Trainees in residency programs longer than 5 years performed fewer procedures and were less confident than trainees in residences of shorter duration (P < .001). The importance of fellowships to complete surgical education was rated 7.7 out of 10. CONCLUSIONS: CS training across European countries lacks harmony. Female ophthalmology trainees continue, as in other specialties, to experience apparent gender bias. European level recommendations seem necessary to raise and harmonize competency-based CS training programs and promote post-residency fellowship training programs.

Analysis of glaucoma genes in Finnish patients with juvenile open-angle glaucoma.

PURPOSE: To identify germline variants in myocilin (MYOC) and other known monogenic glaucoma genes in Finnish patients with juvenile open-angle glaucoma (JOAG). METHODS: Finnish patients with JOAG treated between 2010 and 2018 at the Department of Ophthalmology, Helsinki University Hospital, Finland, were enrolled. We sequenced all exonic regions and flanking splice sites of MYOC for five patients and one healthy relative using Sanger sequencing. In 48 patients, we performed exome sequencing to identify variants also in 28 other glaucoma-related genes. RESULTS: Fifty-three individuals with JOAG from 50 pedigrees, and one healthy relative, participated. The mean age at diagnosis was 30.8 years [SD 7.6; range 11 to 39]. Five probands had probably pathogenic variants in MYOC: c.1102C>T p.(Gln368Ter), c.1109C>T p.(Pro370Leu), c.1130C>T p.(Thr377Met), c.1132G>A p.(Asp378Asn) and c.1456C>T p.(Leu486Phe). Four of these patients had a family history of dominantly inherited JOAG. The frequency of MYOC variants was 10% (5 of 50 families). One patient and his mother with JOAG had a novel loss-of-function variant in the FOXC1 gene, c.366G>A p.(Trp122Ter). A patient with sporadic JOAG had a homozygous likely pathogenic variant in the LTBP2 gene, c.3938G>A p.(Cys1313Tyr). The genetic variants explained 14% (7 out of 50 families; 95% CI, 6%-23%) of JOAG in our cohort. CONCLUSIONS: The frequency of pathogenic variants in previously known glaucoma-associated genes is low in Finnish patients with JOAG. Because of the distinct genetic background of Finns, it might be possible to identify novel glaucoma genes through our JOAG series in the future.

Clinical and Histopathologic Characteristics and Template of the TGFBI p.(His626Arg) Missense Variant Lattice Corneal Dystrophy.

PURPOSE: The aim of this study was to define, following the IC3D template format, the clinical and histopathologic phenotype of the p.(His626Arg) missense variant lattice corneal dystrophy (LCDV-H626R), the most common variant lattice dystrophy, and to record long-term outcome of corneal transplantation in this dystrophy. METHODS: A database search and a meta-analysis of published data on LCDV-H626R were conducted. A patient diagnosed with LCDV-H626R who underwent bilateral lamellar keratoplasty followed by rekeratoplasty of 1 eye is described, including histopathologic examination of the 3 keratoplasty specimens. RESULTS: One hundred forty-five patients from at least 61 families and 11 countries diagnosed with LCDV-H626R were found. This dystrophy is characterized by recurrent erosions, asymmetric progression, and thick lattice lines that extend to corneal periphery. The median age is 37 (range, 25-59) years at the onset of symptoms, 45 (range, 26-62) years at the time of diagnosis, and 50 (range, 41-78) years at the time of the first keratoplasty, suggesting a median interval from the first symptoms to diagnosis and to keratoplasty of 7 and 12 years, respectively. Clinically unaffected carriers have been of age 6 to 45 years. Central anterior stromal haze and centrally thick, peripherally thinner branching lattice lines in the anterior to midstroma of the cornea were noted preoperatively. Histopathology of the host anterior corneal lamella showed a subepithelial fibrous pannus, a destroyed Bowman layer, and amyloid deposits extending to the deep stroma. In the rekeratoplasty specimen, amyloid localized to scarring along the Bowman membrane and to the margins of the graft. CONCLUSIONS: The IC3D-type template for LCDV-H626R should help diagnose and manage variant carriers. The histopathologic spectrum of findings is broader and more nuanced than what has been reported.

Determinants of Long-Term Survival in Metastatic Choroidal and Ciliary Body Melanoma.

PURPOSE: To build and validate a prognostic model that predicts long-term overall survival (OS) in metastatic choroidal and ciliary body melanoma (CCBM) to facilitate patient counseling and planning, reporting, and interpreting clinical trials. DESIGN: Retrospective cohort study with validation. METHODS: We analyzed predictors of intermediate (IMT; 25-<42 months) and long-term (LT; ≥42 months) OS in a Finnish nationwide cohort of 330 patients with metastatic CCBM. Short-term (<25 months), IMT, and LT survival were compared with pairwise and ordinal logistic regression. A single-center cohort of 259 patients from Italy was used for validation. Models were compared with a deviance test. RESULTS: Median OS was 12 and 17 months in the building and validation datasets, respectively; 40 (12%) and 31 (9%) compared with 44 (17%) and 32 (12%) patients were IMT and LT survivors, respectively. Alkaline phosphatase or lactate dehydrogenase level never exceeded 2 times the upper normal limit (UNL) in either LT cohort. Conditional to both being ≤2 times the UNL, distant metastasis-free interval (DMFI) >42 months (odds ratio [OR] 4.09-4.64; P < .001) paired with age <60 years (OR 3.23; P = .002), having no symptoms (OR 4.19; P = .005), and the largest diameter of the largest metastasis <30 mm (Tumor, Node, Metastasis stage M1a; OR 3.05; P = .001) independently predicted higher odds of surviving longer (IMT or LT) without model preference. These results were confirmed in the validation dataset. CONCLUSIONS: Alkaline phosphatase or lactate dehydrogenase >2 times the UNL essentially precluded LT survival. The most robust predictor otherwise was DMFI >42 months, followed by age <60 years, absence of symptoms, and Tumor, Node, Metastasis stage M1a.

Trends in Keratoplasty Procedures During 2 Decades in a Major Tertiary Referral Center in Finland: 1995 to 2015.

PURPOSE: The purpose of this study was to analyze trends in number, age-adjusted frequency, and type of keratoplasty in a major tertiary referral center, relative to patient and graft characteristics. METHODS: A retrospective registry study of 1574 patients who in 1995 to 2015 underwent keratoplasty in the Helsinki University Eye Hospital (HUEH). Graft type and sequence, patient characteristics, and date of surgery were recorded. Main outcome measures were annual number, type, and age-adjusted frequency of keratoplasty; patient and graft characteristics; graft procurement; and national population-adjusted frequency of keratoplasty. RESULTS: In HUEH, from 1995 to 2015, a total of 2191 keratoplasties were performed with 48% of the grafts procured intramurally; 76% were primary and 24% regrafts. The age-adjusted frequency of primary penetrating keratoplasty decreased by 52% from 0.96 to 0.46 per 100,000. The corresponding frequency of primary Descemet stripping automated endothelial keratoplasty increased by 367% from 0.3 to 1.4 after 2006, finally accounting for 68% of primary grafts. Men underwent primary penetrating keratoplasty (median 48 vs. 67 yrs, P = 0.0001) and anterior lamellar keratoplasty (median 37 vs. 46 yrs, P = 0.0015) at a younger age than women. Interval to the first regraft was comparable between sexes (median 2.2 vs. 1.9 yrs, respectively, P = 0.17). The national median population-adjusted frequency of keratoplasties was 3.2 per 100,000 from 2009 to 2015, and HUEH accounted for a median of 69% of them. CONCLUSIONS: The increased frequency of keratoplasty in HUEH resulted from rapid adoption of Descemet stripping automated endothelial keratoplasty after 2006 and was facilitated by centralizing graft procurement to HUEH and the National Cell and Tissue Center Regea.

Presumed incipient choroidal melanoma: proposed diagnostic criteria and management.

AIMS: To propose diagnostic criteria for a presumed incipient choroidal melanoma based on tumour growth rate and tumour doubling time (TDT) and to describe management of such tumours with transpupillary thermotherapy (TTT). METHODS: Retrospective interventional case series of nine consecutive presumed incipient uveal melanomas diagnosed and treated with TTT in 2010-2017. Growth rate in mm/year and per cent/year in largest basal diameter (LBD) and TDT were compared with published data for uveal melanomas and growing naevi that did not transform to melanoma under long-term follow-up. RESULTS: The median LBD and thickness were 1.6 mm (range 0.9-2.3) and 0.20 mm (range 0.15-0.29), respectively. The median age was 57 years (range 47-78). Seven tumours were classified as de novo melanomas and two as transformed naevi. The median time from first observation to diagnosis was 3.3 years (range 2.2-7.3), LBD growth rate 0.25 mm/year (range 0.11-0.72) and 34 per cent/year (range 10-1437), and TDT 609 days (range 97-1612). The estimates matched those reported for uveal melanoma (median TDT 521 days, 90th percentile 2192) and exceeded those for growing naevi (median growth rate 0.04 mm/year, 90th percentile 0.12; 1.1 per cent/year, 90th percentile 2.6). The predicted median age at de novo appearance was 51 years (range 32-63). No tumour grew after TTT during a median follow-up of 2.1 years (range 0.6-8.7). CONCLUSIONS: In this series, relative growth rate and TDT best qualified as diagnostic criteria for an incipient choroidal melanoma. Too small for brachytherapy, they could be managed with TTT.

Incidence and Risk Factors for Secondary Glaucoma in Eyes with Uveal Melanoma.

PURPOSE: To estimate incidence of and analyze risk factors for developing secondary glaucoma in eyes with uveal melanoma before and after diagnosis. DESIGN: A cross-sectional, population-based cohort study. PARTICIPANTS: Seven hundred eighty-one patients (median age, 64 years; range, 14-93) consecutively diagnosed with uveal melanoma from 1997 to 2012 in a national ocular oncology service, 708 (91%) of whom received ruthenium (50%) or iodine (50%) brachytherapy. METHODS: Patient, tumor, treatment, and follow-up data were collected prospectively. Frequency and associations of melanoma-related glaucoma at tumor diagnosis were assessed. Incidence of developing secondary glaucoma after diagnosis was estimated by Kaplan-Meier analysis. Independent risk factors were modeled using Cox regression. MAIN OUTCOME MEASURES: Melanoma-related glaucoma and related risk factors. RESULTS: Forty-five patients (5.8%; 95% confidence interval [CI], 4.2-7.6) had tumor-related secondary glaucoma at diagnosis, 34 (76%) from a narrow-to-closed angle (25 had direct angle invasion) and 10 (22%) from anterior neovascularization. Synchronous metastases were common in patients with initial secondary glaucoma (11% vs. 1.2% with incident glaucoma, P = 0.005). Patients with secondary glaucoma were often male (58% vs. 48% without glaucoma; P = 0.010) and had larger tumors (median thickness, 9.1 vs. 4.0 mm; P < 0.001) involving the ciliary body (43% vs. 21%; P < 0.001) with retinal detachment (53% vs. 30%; P < 0.001). One hundred and sixty-eight patients 165 of which were treated with brachytherapy developed incident tumor- or treatment-related secondary glaucoma a median of 1.7 years (range, 0.1-13.6) after tumor diagnosis. Cumulative proportion of developing secondary glaucoma was 23% (95% CI, 20-27) at 5 years. The most common mechanism was neovascularization in 119 patients (71%; 95% CI, 63-78). By multivariable regression, initial retinal detachment 3 to 4 quadrants (hazard ratio [HR], 2.18; P < 0.001), initial intraocular pressure 17 mmHg or higher (HR, 1.64; P = 0.01), and tumor thickness predicted incident secondary glaucoma. CONCLUSIONS: Secondary glaucoma at initial uveal melanoma diagnosis predicts high risk of synchronous metastases. Although anterior neovascularization is the most common mechanism for secondary glaucoma after diagnosis, other mechanisms such as angle narrowing and anterior chamber hemorrhage are not infrequent. Initial retinal detachment and intraocular pressure with tumor thickness could inform interim assessments of intraocular pressure and neovascularization.

Metastatic Death Based on Presenting Features and Treatment for Advanced Intraocular Retinoblastoma: A Multicenter Registry-Based Study.

PURPOSE: To evaluate presenting features, tumor size, and treatment methods for risk of metastatic death due to advanced intraocular retinoblastoma (RB). DESIGN: International, multicenter, registry-based retrospective case series. PARTICIPANTS: A total of 1841 patients with advanced RB. METHODS: Advanced RB was defined by 8th edition American Joint Committee on Cancer (AJCC) categories cT2 and cT3 and new AJCC-Ophthalmic Oncology Task Force (OOTF) Size Groups (1: < 50% of globe volume, 2: > 50% but < 2/3, 3: > 2/3, and 4: diffuse infiltrating RB). Treatments were primary enucleation, systemic chemotherapy with secondary enucleation, and systemic chemotherapy with eye salvage. MAIN OUTCOME MEASURES: Metastatic death. RESULTS: The 5-year Kaplan-Meier cumulative survival estimates by patient-level AJCC clinical subcategories were 98% for cT2a, 96% for cT2b, 88% for cT3a, 95% for cT3b, 92% for cT3c, 84% for cT3d, and 75% for cT3e RB. Survival estimates by treatment modality were 96% for primary enucleation, 89% for systemic chemotherapy and secondary enucleation, and 90% for systemic chemotherapy with eye salvage. Risk of metastatic mortality increased with increasing cT subcategory (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of metastatic mortality in categories cT3c (glaucoma, hazard ratio [HR], 4.9; P = 0.011), cT3d (intraocular hemorrhage, HR, 14.0; P < 0.001), and cT3e (orbital cellulitis, HR, 19.6; P < 0.001) than in category cT2a and with systemic chemotherapy with secondary enucleation (HR, 3.3; P < 0.001) and eye salvage (HR, 4.9; P < 0.001) than with primary enucleation. The 5-year Kaplan-Meier cumulative survival estimates by AJCC-OOTF Size Groups 1 to 4 were 99%, 96%, 94%, and 83%, respectively. Mortality from metastatic RB increased with increasing Size Group (P < 0.001). Cox proportional hazards regression analysis revealed that patients with Size Group 3 (HR, 10.0; P = 0.002) and 4 (HR, 41.1; P < 0.001) had a greater risk of metastatic mortality than Size Group 1. CONCLUSIONS: The AJCC-RB cT2 and cT3 subcategories and size-based AJCC-OOTF Groups 3 (> 2/3 globe volume) and 4 (diffuse infiltrating RB) provided a robust stratification of clinical risk for metastatic death in advanced intraocular RB. Primary enucleation offered the highest survival rates for patients with advanced intraocular RB.

High-risk Pathologic Features Based on Presenting Findings in Advanced Intraocular Retinoblastoma: A Multicenter, International Data-Sharing American Joint Committee on Cancer Study.

PURPOSE: To determine the value of clinical features for advanced intraocular retinoblastoma as defined by the eighth edition of the American Joint Committee on Cancer (AJCC) cT3 category and AJCC Ophthalmic Oncology Task Force (OOTF) Size Groups to predict the high-risk pathologic features. DESIGN: International, multicenter, registry-based retrospective case series. PARTICIPANTS: Eighteen ophthalmic oncology centers from 13 countries over 6 continents shared evaluations of 942 eyes enucleated as primary treatment for AJCC cT3 and, for comparison, cT2 retinoblastoma. METHODS: International, multicenter, registry-based data were pooled from patients enrolled between 2001 and 2013. High-risk pathologic features were defined as AJCC categories pT3 and pT4. In addition, AJCC OOTF Size Groups were defined as follows: (1) less than half, (2) more than half but less than two thirds, (3) more than two thirds of globe volume involved, and (4) diffuse infiltrating retinoblastoma. MAIN OUTCOME MEASURES: Statistical risk of high-risk pathologic features corresponding to AJCC cT3 subcategories and AJCC OOTF Size Groups. RESULTS: Of 942 retinoblastoma eyes treated by primary enucleation, 282 (30%) showed high-risk pathologic features. Both cT subcategories and AJCC OOTF Size Groups (P < 0.001 for both) were associated with high-risk pathologic features. On logistic regression analysis, cT3c (iris neovascularization with glaucoma), cT3d (intraocular hemorrhage), and cT3e (aseptic orbital cellulitis) were predictive factors for high-risk pathologic features when compared with cT2a with an odds ratio of 2.3 (P = 0.002), 2.5 (P = 0.002), and 3.3 (P = 0.019), respectively. Size Group 3 (more than two-thirds globe volume) and 4 (diffuse infiltrative retinoblastoma) were the best predictive factors with an odds ratio of 3.3 and 4.1 (P < 0.001 for both), respectively, for high-risk pathologic features when compared with Size Groups 1 (i.e., < 50% of globe volume). CONCLUSIONS: The AJCC retinoblastoma staging clinical cT3c-e subcategories (glaucoma, intraocular hemorrhage, and aseptic orbital cellulitis, respectively) as well as the AJCC OOTF Size Groups 3 (tumor more than two thirds of globe volume) and 4 (diffuse infiltrative retinoblastoma) both allowed stratification of clinical risk factors that can be used to predict the presence of high-risk pathologic features and thus facilitate treatment decisions.