Abstract
Background
To determine the unique clinical characteristics and treatment outcomes of diffuse infiltrating retinoblastoma (DIR).
Methods
This international, multicentre, registry-based retrospective case series analysed pooled data from January 2001 to December 2013, including 132 eyes from 132 patients with DIR.
Results
Among 2854 eyes with retinoblastoma, 132 (4.6%; 95% CI, 3.9 to 5.5) had DIR. The median age at diagnosis for DIR patients was 24 months (IQR, 15–33), with no bilateral cases of DIR. The American Joint Committee on Cancer staging showed 4.5% cT2 and 95.5% cT3 categories, with no cT1 or cT4 cases. Clinical features associated with DIR included secondary glaucoma (67%), retinal detachment (38%), diffuse vitreous seeds (37%), anterior segment involvement (24%), vitreous haemorrhage (50%) and hyphema (6%). Primary enucleation was the predominant treatment (81%), while 19% initially received systemic chemotherapy, with 6% requiring subsequent enucleation. The 5-year Kaplan-Meier survival rate for cT3 DIR was 82% (95% CI, 78 to 86), significantly lower than the 94% (95% CI, 93 to 95) for cT3 non-DIR cases (p<0.001). Cox proportional hazards regression returned a higher risk of metastatic death for DIR cT3 compared with non-DIR cT3 (HR, 3.3; 95% CI, 1.8 to 5.9; p<0.001). High-risk pathological features were more frequent in DIR (41% vs 28%, p=0.004). There was no association between DIR and local treatment failure.
Conclusions
Approximately 1 in 20 patients with retinoblastoma had DIR, which often presented with glaucoma, anterior segment involvement or intraocular bleeding. DIR was more lethal than non-DIR cT3, with enucleation revealing high-risk pathology.
Keywords: Neoplasia, Pathology, Retina, Hemorrhage, Uveitis
WHAT IS ALREADY KNOWN ON THIS TOPIC
Diffuse infiltrative retinoblastoma (DIR) is a rare variant of retinoblastoma characterised by widespread neoplastic infiltration of the retina. It can masquerade as uveitis with pseudohypopyon, anterior chamber flare, iris heterochromia, vitreous cells and intraocular haemorrhage, often leading to delayed or incorrect diagnosis. Previous literature on DIR is limited, with some studies describing it as a slow-growing tumour with a more favourable prognosis.
WHAT THIS STUDY ADDS
Multicentre international registry-based studies are crucial for gathering extensive patient data, especially to address rare tumours like DIR. Contrary to earlier perceptions, DIR was found to be more lethal than non-DIR cT3 retinoblastoma. Primary enucleation frequently revealed high-risk pathological features, emphasising the aggressive nature of DIR.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The findings call for heightened awareness among eye care specialists regarding DIR as it can mimic less severe ocular pathologies, leading to diagnostic delays and poor outcomes. DIR may not show calcification on imaging or ultrasound, making it challenging to detect. Therefore, paediatric patients with unexplained unilateral glaucoma, intraocular bleeding or uveitis should undergo thorough evaluation under anaesthesia to rule out retinoblastoma, including DIR. This approach can facilitate earlier diagnosis and improve patient outcomes.
Introduction
Diffuse infiltrating retinoblastoma (DIR) presents unique challenges for establishing the diagnosis, predicting outcomes and thus guiding therapeutic decisions.1 While retinoblastoma (RB) is typically diagnosed clinically, staging focuses on the identification of clinical factors that can be used to predict high-risk pathology and thus metastasis.2 3 Clinical studies of advanced RB have identified iris neovascularisation, increased intraocular pressure (glaucoma), buphthalmos and intraocular haemorrhage as adverse prognostic indicators, establishing a precedent.4 5 In that DIR is characterised by many of these features, it is no wonder that the diagnosis of DIR is an adverse prognostic factor for both eye salvage and survival.4 5 This contradicts older literature that portrayed DIR as a slowly growing cancer with a relatively favourable prognosis.6 7
First documented by Ashton and Schofield in 1958,1 DIR is characterised by a flat but widespread ‘diffuse’ neoplastic infiltration of the retina, with small tumorous masses and diffuse dispersion of tumour cells in the vitreous, anterior chamber, iris surface and trabecular meshwork. Compared with the much more common non-DIR tumours, this unique clinical presentation predisposes to delayed or misdiagnosis. The literature documents DIR may masquerade as a pseudohypopyon, anterior chamber flare, iris heterochromia, vitreous cells and intraocular haemorrhage, all of which can suggest uveitis.8 Furthermore, inadvertent attempts at diagnostic taps are thought to add risk for tumour dissemination and thus systemic metastasis.
In our PubMed review using the terms retinoblastoma, diffuse and infiltrating, the largest DIR case series included 77 DIR eyes.9 This highlights the scarcity of systematic data on presentation and outcomes in DIR.
Controversies persist regarding the optimal treatment approach and outcome for DIR. While some advocate for a favourable prognosis due to slow growth,6 7 conflicting evidence from previous studies on advanced RB contradicts that notion.4 5 10 11 Our study aims to add medical evidence from a multicentre, international registry to explore the nuanced differences between DIR and non-DIR eyes. By investigating presenting features, the risk of systemic metastasis, high-risk pathology and local treatment failure, our research contributes to a better understanding and management of this less frequent RB subtype.
Methods
A retrospective chart review encompassed patients diagnosed with RB between 5 January 2001 and 31 December 2013. Conducted in collaboration with 18 RB centres spanning 13 countries on 6 continents, this international registry-based study adhered to the ethical principles outlined in the Declaration of Helsinki and the Health Insurance Portability and Accountability Act of 1996.
The registry data fields were formulated by an American Joint Committee on Cancer-Ocular Oncology Task Force (AJCC-OOTF) committee, ensuring comprehensive coverage of relevant information. Subsequently, anonymised data were meticulously entered into a secure online database. Detailed descriptions of the database structure and security measures can be found in prior registry publications, providing transparency and reassurance regarding the integrity of the collected data.45 12,15
Definitions
The inclusion criteria for this study comprised exclusively internationally recognised ophthalmic oncology subspecialty sites, ensuring a high standard of expertise. The classification of countries by national income level, derived from the 2017 World Population Prospects (the United Nations, Department of Economic and Social Affairs), categorises participating centres into high-income countries, upper-middle-income countries and lower-middle-income countries.14 16 However, no centres from lower-income countries contributed to the registry. Patient management adhered to the best practices defined at each centre, and clinical data were collected through retrospective record reviews.
-
DIR1 9 was defined as
Flat infiltration of the retina or small tumorous masses.
Associated with diffuse spread of tumour cells in the vitreous, iris surface, trabecular meshwork and anterior chamber.
Presence of pseudohypopyon.
In cases with limited fundus visibility due to intraocular haemorrhage, absence of distinct masses was confirmed on B-scan ultrasonography or MRI.
Primary enucleation was defined as the removal of a treatment-naive eye containing RB.
Secondary enucleation was defined as removal of the eye after an attempted salvage, regardless of the reason (eg, significant residual disease, recurrent tumour).
Of note, diffuse anterior RB is described in the literature as a variant of DIR, originating from a peripheral intraretinal tumour that spreads into the aqueous humour and ciliary body. However, none of the cases in our cohort exhibited features consistent with diffuse anterior RB. As a result, we did not classify it as a distinct entity for our study.17
A total of 132 eyes met the criteria for inclusion in the DIR group. Within this cohort, 4.5% of eyes were classified as American Joint Committee on Cancer (AJCC) cT2 and 95.5% as cT3. No patient had DIR in both eyes. Given that cT3 RB has clinical high-risk features associated with increased metastatic risk,4 5 a control group was established, comprising non-DIR cT2 and cT3 patients. In cases of bilateral RB in the control group, the AJCC category of the more severely affected eye was used for patient-level survival analysis, and only the worse eye was included in eye-level analysis. This yielded a control group of 1284 eyes from 1284 patients. To reduce potential bias, comparisons were stratified by AJCC category: cT2 DIR eyes were compared with cT2 non-DIR controls and similarly for cT3 cases. Some DIR eyes presented with intraocular haemorrhage. Although detailed information on haemorrhage extent was unavailable within the registry data, contributing centres classified cases as DIR based on morphology of visible tumour and only when imaging modalities, such as B-scan ultrasound or MRI, confirmed the absence of a distinct tumorous mass.
The 8th edition of the AJCC Cancer Staging Manual provided the framework for defining primary tumour extent (cT2 and cT3) and high-risk pathological features (pT3 and pT4).18 Final patient outcomes included survival status, metastasis, date of the last follow-up and duration of follow-up. Patients who developed central nervous system metastasis and were then lost to follow-up were considered deceased and were thus included in the metastasis-related mortality analysis. Patients whose treatment was discontinued by request of their guardians and were then lost to ophthalmic follow-up but eventually recorded as having died of RB were also included as deaths for analysis of metastasis-related mortality. All other non-metastasis-related deaths were censored observations in analysis and thus not modelled as competing risk events. Local treatment failure after conservative treatment was defined as the need for external beam radiotherapy or secondary enucleation.
Patient selection criteria excluded eyes with missing or inconsistent key variables essential for RB classification, treatment data or outcome information. Eyes that were secondarily enucleated were excluded from the analysis of high-risk pathological features because of potential downstaging effects of primary treatment.19 AJCC cT1 and cT4 category eyes were excluded for being non-comparable to DIR, with the former being candidates for globe-conserving therapies, and the latter associated with limited options for globe salvage and worse systemic outcome because of orbital extension. The registry contained completed data for 2854 eyes from 2190 patients. Of these, 1416 eyes from 1416 patients were included in statistical analysis, and 132 (9.3%) were DIR eyes and 1284 were cT2 and cT3 non-DIR eyes with RB in the control group (figure 1).
Figure 1. Consolidated Standards of Reporting Trials flow diagram of all patients with diffuse infiltrating retinoblastoma (DIR) and non-DIR.
Statistical analysis
The data were summarised following the AJCC 8th edition RB staging system.18 Continuous variables were described using median, mean and IQR, whereas categorical variables were presented as frequencies and percentages. χ2 test was used to examine the difference between categorical variables. Mann-Whitney U test was used to compare means for non-normally distributed data. We assessed the relationship between DIR and non-DIR with respect to metastasis-related mortality using Kaplan-Meier plots, log-rank tests for trend and Cox proportional hazards regression models. The statistical analysis was performed using SPSS software, V.26.0 (IBM). Statistical significance was set at p<0.05.
Results
Considering the entire cohort of 2854 eyes, the frequency of DIR was 4.6% (95% CI, 3.9 to 5.5). Of the 132 DIR eyes, 99 (75%; 95% CI, 67 to 82) were unilateral and 33 represented the worse eye of bilateral RB. No child had DIR in both eyes. Conversely, of the 1284 non-DIR eyes, 80% were unilateral (table 1). Nearly 80% (105) of DIR were from Asia, followed by 17% (22) from North America (online supplemental table 1). Based on national income, 32% of DIR came from high-income, 63% from upper-middle-income and 5% from lower-middle-income countries (online supplemental table 1). Of note, the numbers presented in online supplemental table 1 represent only the DIR cases and their matched controls, rather than the total RB cases from each geographic region in the registry. Consequently, these figures do not reflect the actual incidence of DIR in these regions.
Table 1. Comparison of DIR with non-DIR.
| DIR (%) | Non-DIR (%) | P value | |
|---|---|---|---|
| Number | 132 | 1284 | |
| Median age in months (mean±SD, IQR) | 24 (27.2, 21.75, 15–33) | 21 (24.53, 21.71, 11–32) | 0.10* |
| Follow-up in months (mean±SD, IQR) | 30 (41.6, 41, 9–64) | 46.5 (54.7, 41.6, 21–81) | |
| cT2 | 6 (4.5) | 804 (62.6) | <0.001† |
| cT2a | 1 (0.8) | 137 (10.7) | |
| cT2b | 5 (3.8) | 667 (51.9) | |
| cT3 | 126 (95.5) | 480 (37.4) | |
| cT3a (pre-phthisis/phthisis) | 1 (0.8) | 7 (0.5) | |
| cT3b (anterior chamber involvement) | 20 (15.2) | 114 (8.9) | |
| cT3c (glaucoma) | 33 (25.0) | 261 (20.3) | |
| cT3d (intraocular haemorrhage) | 68 (51.5) | 85 (6.6) | |
| cT3e (orbital cellulitis) | 4 (3.0) | 13 (1.0) | |
| H0 | 99 (75) | 1021 (79.5) | 0.224† |
| H1 | 33 (25) | 263 (20.5) | |
| Unilateral | 99 (75) | 1027 (80) | 0.177† |
| Bilateral | 33 (25) | 257 (20) | |
| Alive | 112 (84.8) | 1239 (96.5) | |
| Metastatic death | 20 (15.2) | 45 (3.5) | |
| Primary enucleation | 107 (81.1) | 823 (64.1) | <0.001† |
| Systemic chemotherapy+secondary enucleation | 8 (6.1) | 208 (16.2) | |
| Systemic chemotherapy+eye salvage | 17 (12.8) | 253 (19.7) |
Mann-Whitney U test for comparing means.
χ2 test for trends.
DIR, diffuse infiltrating retinoblastoma.
The median age of the 132 patients with DIR was 24 months (mean, 27; IQR, 15–33) at diagnosis. Their median follow-up duration was 30.0 months (mean, 42; IQR, 9–64). In contrast, 1284 patients with non-DIR were diagnosed at a median age of 21 months (mean, 24; IQR, 11–32, p=0.10, Mann-Whitney U test). There was no statistically significant difference in the median age at diagnosis between DIR and non-DIR among different national income group cohorts (online supplemental table 1). Their median follow-up was 46 months (mean, 55; IQR, 21-81).
For the 132 DIR eyes, AJCC clinical categories were cT2 in 6 eyes (4.5%) and cT3 in 126 eyes (95.5%). Associated clinical features included secondary glaucoma in 89 (67%), retinal detachment with subretinal seeds in 50 eyes (38%), diffuse vitreous seeds in 49 (37%), anterior segment involvement in 31 eyes (24%), vitreous haemorrhage in 66 (50%) and hyphema in 8 (6%).
As regards the 1284 non-DIR eyes, 804 (62.6%) were cT2 and 480 (37.4%) were cT3. Online supplemental table 1 provides the AJCC clinical category distribution of patients with DIR based on national income groups.
Treatment outcomes
Of the 132 eyes diagnosed with DIR, 107 (81%) were managed with primary enucleation and 25 (19%) were first treated with systemic chemotherapy. In the latter group, 8 eyes (32%) required secondary enucleation and 17 (68%) eyes were salvaged. In comparison, of the 1284 non-DIR eyes, 823 (64.1%) underwent primary enucleation and 461 eyes (35.9%) received primary systemic chemotherapy. Then after chemotherapy, 208 eyes (45.1%) required secondary enucleation and 253 eyes (54.9%) were salvaged. When analysed by the AJCC cT category, there was no significant difference between the approach to treatment for DIR versus non-DIR eyes (p=0.35 and p=0.11 for cT2 and cT3, respectively, online supplemental table 2). Online supplemental table 1 provides the approach to treatment for DIR eyes based on national income groups.
Within the DIR cohort, 15% of patients (20 of 132) developed systemic metastasis, resulting in mortality. Of those, 19 patients with data on time to metastasis, the median interval to metastasis was 7.0 months (mean, 8.7; IQR, 2.0–13.0). In the non-DIR cohort of 1284 patients, 45 patients (3.5%) died from metastasis. Of those, 38 non-DIR patients had data on the time to metastasis, where the median interval to metastasis was 10.0 months (mean, 15.3; IQR, 6.0–22.0).
The 5-year Kaplan-Meier cumulative probability of survival for DIR patients was 83% (95% CI, 60 to 87), which was worse than the 96% (95% CI, 95 to 97) noted for non-DIR patients (table 2, figure 2A). No patient died after 5 years in either group. DIR carried a higher risk of metastasis-related death and a shortened overall survival (p<0.001, log-rank test for trend) compared with non-DIR cases. Cox proportional hazard analysis revealed that patients with DIR faced almost a five times higher risk of metastasis-related death compared with non-DIR cases (HR, 4.7; 95% CI, 2.8 to 8.0; p<0.001, table 2).
Table 2. Kaplan-Meier cumulative proportion of surviving without death from metastasis in 1416 children with advanced retinoblastoma comparing DIR with non-DIR by AJCC clinical category.
| Kaplan-Meier estimate, % (95% CI) | Log-rank test (p value) | |||
|---|---|---|---|---|
| 1 year | 5 years | 10 years | ||
| All patients | ||||
| Non-DIR (n=1284) | 98 (97 to 99) | 96 (95 to 97) | 96 (95 to 97) | <0.001 |
| DIR (n=132) | 85 (82 to 88) | 83 (70 to 87) | 83 (70 to 87) | |
| AJCC cT2 | 0.689 | |||
| Non-DIR (n=804) | 98 (97 to 99) | 97 (96 to 98) | 97 (96 to 98) | |
| DIR (n=6) | 100 | 100 | 100 | |
| AJCC cT3 | <0.001 | |||
| Non-DIR (n=480) | 94 (93 to 95) | 94 (93 to 95) | 94 (93 to 95) | |
| DIR (n=126) | 83 (80 to 86) | 82 (78 to 86) | 82 (78 to 86) | |
| Cox proportional hazards regression model for retinoblastoma variants associated with metastatic mortality in 1416 patients with retinoblastoma | ||||
| Variable | Patients (n=1416) | Reference | HR (95% CI) | P value |
| DIR | 132 | Non-DIR | 4.7 (2.8 to 8.0) | <0.001 |
| Age (in months) | ||||
| 8.0–17.0 | 309 | <8.0 | 0.5 (0.2 to 1.5) | 0.223 |
| 17.0–29.0 | 423 | <8.0 | 1.5 (0.7 to 3.3) | 0.278 |
| >29.0 | 416 | <8.0 | 1.8 (0.9 to 4.0) | 0.098 |
| AJCC cT3 only (n=606) | ||||
| DIR | 126 | Non-DIR | 3.3 (1.8 to 5.9) | <0.001 |
| Age (in months) | ||||
| 8.0–17.0 | 107 | <8.0 | 0.3 (0.1 to 1.7) | 0.183 |
| 17.0–29.0 | 211 | <8.0 | 1.0 (0.4 to 2.8) | 0.996 |
| >29.0 | 218 | <8.0 | 1.8 (0.7 to 4.6) | 0.249 |
AJCC, American Joint Committee on Cancer; DIR, diffuse infiltrating retinoblastoma.
Figure 2. (A) Kaplan-Meier curves showing cumulative survival estimates for patients with advanced retinoblastoma based on tumour variant. (B) Kaplan-Meier curves showing cumulative survival estimates for American Joint Committee on Cancer (AJCC) cT2 patients with retinoblastoma based on tumour variant. (C) Kaplan-Meier curves showing cumulative survival estimates for AJCC cT3 patients with retinoblastoma based on tumour variant. (D) Kaplan-Meier curve of cumulative proportion of salvaged retinoblastoma eyes based on tumour variant.
A secondary analysis based on the AJCC cT category revealed a significant difference between DIR and non-DIR for cT3 category (p<0.001, log-rank test for trend) but not for cT2 (p=0.689, log-rank test for trend, table 2 and figure 2B,C). Cox proportional hazard analysis revealed that cT3 patients with DIR were associated with a 3.3 times higher risk of metastasis-related death compared with non-DIR cT3 cases (HR, 3.3; 95% CI, 1.8 to 5.9; p<0.001, table 2).
Presence of high-risk pathology
Among the 107 primarily enucleated eyes with DIR, the AJCC pathological pT category was pT1 in 20 (19%), pT2 in 43 (40%), pT3 in 32 (30%) and pT4 in 12 (11%) eyes. High-risk pathological features were identified in 44 of 107 (41%) eyes (table 3).
Table 3. Pathological features in 107 primarily enucleated DIR.
| Feature | DIR | Non-DIR | ||
|---|---|---|---|---|
| N | % | N | % | |
|
High-risk pathology |
44 | 41 | 63 | 28 |
|
Optic nerve |
||||
| None | 36 | 34 | 352 | 45 |
| Optic nerve head involvement | 36 | 34 | 305 | 38 |
| Retrolaminar optic nerve involvement | 25 | 23 | 120 | 15 |
| Optic nerve cut end positive | 10 | 9 | 19 | 2 |
| Choroid | ||||
| None | 62 | 58 | 506 | 64 |
| Focal | 29 | 27 | 189 | 24 |
| Massive | 16 | 15 | 101 | 12 |
|
Scleral involvement |
||||
| None | 98 | 92 | 741 | 93 |
| Partial thickness | 3 | 3 | 44 | 6 |
| Full thickness | 6 | 6 | 11 | 1 |
| Comparison of primarily enucleated DIR with non-DIR for the presence of high-risk pathological features | |||
|---|---|---|---|
| DIR (%) | Non-DIR (%) | P value | |
| N | 107 | 796 | |
|
High-risk pathology |
|||
| Present | 44 (41.1) | 221 (27.8) | 0.004* |
| Absent | 63 (58.9) | 575 (72.2) | |
χ2 test for trends.
DIR, diffuse infiltrating retinoblastoma.
Of the 823 non-DIR eyes that were primarily enucleated, histopathology data were missing for 27. Of the remaining 796 eyes, the pT categories were classified as pT1 in 266 (33%), pT2 in 309 (39%), pT3 in 194 (24%) and pT4 in 27 (3%) eyes. High-risk pathological features were identified in 221 (28%) eyes (table 3). Thus, DIR eyes were more likely to exhibit high-risk pathological features (χ2=8.117, p=0.004, table 3). Online supplemental table 3 provides the AJCC pathological category for DIR eyes based on national income groups. While there was a significant difference in high-risk pathology in non-DIR cases by national income group (χ2=12.7, p=0.002), the difference was not significant for DIR cases (χ2=4.57, p=0.101).
Local treatment outcome
Among the 132 eyes with DIR, only 25 were primarily treated with systemic chemotherapy, of which 17 (68%) were salvaged. Among the 17, presenting clinical features included 4 eyes (23.5%) with diffuse vitreous seeds, 12 eyes (70.6%) with glaucoma, 9 eyes (52.9%) with intraocular haemorrhage and 3 eyes (17.6%) with anterior chamber seeds. The 5-year Kaplan-Meier cumulative proportion of eyes salvaged was 65% (95% CI, 54 to 76) and 91% (95% CI, 89 to 93) for DIR and non-DIR eyes, respectively. The Kaplan-Meier survival rates were comparable for both groups (p=0.086, log-rank; online supplemental table 4, figure 2D). No local failures occurred after 5 years.
Discussion
Our multicentre, international, internet-based data-sharing registry of incident RB revealed a 4.6% frequency of DIR, which is notably higher than the previously reported 1–2%.9 17 This disparity may be attributed to the inclusion of tertiary referral centres in our registry, managing more complex cases with diagnostic uncertainties. Consequently, the incidence reported in our study may represent an overestimate relative to the actual prevalence of DIR in the general population. Multiple case reports suggest that DIR occurs in older patients aged 1–16 years.6 8 11 20 21 Our study was not able to confirm (p=0.10) an overall age difference in the median age at diagnosis that was 24 months for DIR compared with 21 months for non-DIR patients.
Clinical features
Previous literature has reported grouping by international classification.22 For 34 eyes, they found 18% and 82% in groups D and E, respectively.10 In contrast, 95% of DIR eyes were classified as advanced RB or cT3 compared with only 37% among non-DIR eyes. In our cohort, 75% of DIR patients had unilateral RB, which was not significantly different from the 80% in non-DIR patients, but contrasts with 85–92% of DIR patients who had unilateral RB in prior studies.9 10 Notably, a quarter of DIR eyes exhibited anterior segment seeds, over a third diffuse vitreous seeds and over a third retinal detachment that is associated with subretinal seeds. While 25% of DIR eyes belonged to cT3c (glaucoma or buphthalmos), about 67% had glaucoma, many being included in a higher AJCC clinical category because of the concomitant presence of other clinical features. This agrees with a review of 34 DIR eyes, 50% of which had glaucoma.10
In our study, vitreous haemorrhage was observed in 50% of eyes and hyphema in 6%. This frequency was higher than in the previous series where vitreous haemorrhage and hyphema were found in 4–24% of DIR eyes.7 10 Importantly, our methodology prevented misdiagnosis of DIR despite media obscuration due to our strict inclusion criteria. This increased incidence of intraocular haemorrhage may be explained by findings from recent fluorescein angiographic studies on DIR, which revealed tortuous, dilated retinal vessels with complex branching patterns in tumour-affected areas and such vascular changes that could contribute to vitreous haemorrhage.21 These findings underscore the importance of maintaining a high index of suspicion for DIR in cases suspected to have uveitis but also for those with unexplained paediatric and adolescent intraocular haemorrhage.21 The absence of an apparent mass or calcification should not be used to rule out DIR. Additionally, emerging liquid biopsy techniques could provide a valuable diagnostic tool for such cases.23
Pathology
Of the 107 primarily enucleated eyes with DIR, 41% exhibited high-risk pathological features compared with 28% from non-DIR eyes. Earlier reports on DIR suggested a good prognosis despite the absence of differentiated histopathological features.1 4 Our pathology findings, along with other studies, challenge that optimism.3 8
Survival outcomes
In contrast to reports suggesting DIR is slow growing and, thus, has a favourable prognosis,1 6 7 our study uncovered a 3.3 times higher risk of metastatic disease for patients with DIR compared with non-DIR in cT3 patients (p<0.001). This is consistent with recent reports documenting DIR as a cause of death.11 20 The results of our study call for a paradigm shift that challenges conventional perceptions of DIR.
Local treatment outcomes
Our analysis did not find medical evidence that primary treatment with systemic chemotherapy either increased or decreased the risk of local treatment failure in DIR eyes compared with non-DIR eyes. However, due to the timing of our data collection, we did not include newer treatments like intra-arterial therapy. The literature includes one study of 34 DIR eyes, all managed with primary enucleation,10 whereas another reported successful globe salvage after conservative treatment in three patients.24 Within the evolving landscape of new local therapeutics, it is crucial to consider that DIR eyes are at a greater risk of containing high-risk pathological features and, thus, are at a higher risk for metastatic disease.
Strengths and limitations
Limitations of our study include its retrospective nature, select data points and the period of data collection. For example, gender data were not collected, where the literature suggests a biological male preponderance.9 We have no information on tumour calcification, the absence of which is considered a hallmark of DIR.10 25 Because of the timing of our data collection, we could not include newer treatments like intra-arterial chemotherapy. The registry did not include the detailed descriptions of the predominant intraretinal growth patterns, which in hindsight would have been valuable for study of DIR. The timing of data collection also precluded specific genetic analyses or biomarkers for prognostication, especially exploring potentially unique genetic features of DIR.26 Such may have allowed for a better understanding of its distinctive diffuse infiltrating growth pattern for which various mechanisms have been proposed, including immune response variations,27 mutation of precursor cells28 and/or specific mutations in tumorous adhesive molecules.29
Strengths of our study include its extensive, multicentre, global scope, enabled by its online registry-based approach.30 We used the AJCC staging system, which enhanced both the reliability and future comparability of findings across the diverse RB patient population.12,14 In addition, this study included the largest number of reported patients with DIR who contributed significantly to the body of medical evidence, offering valuable insights into critical clinical aspects of this rare paediatric tumour.
Conclusion
Presenting with unique, atypical findings, the diagnosis of DIR remains a major challenge for eye cancer specialists, particularly when differentiating it from conditions like uveitis and vitreous haemorrhage in children. DIR is complicated by a higher frequency of high-risk pathological features and metastasis-related death. All eye care specialists (eg, paediatric, retina, uveitis and ophthalmic oncology) need a high index of suspicion for this variant because it can masquerade as more innocuous pathology, thus delaying diagnosis and resulting in poor outcomes. Furthermore, new liquid biopsy techniques and using tumour biomarkers offer a promising diagnostic tool to aid in the timely detection of DIR while also providing valuable insights into the biological and clinical behaviour of RB.23 26
Supplementary material
The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
Footnotes
Funding: The John and Myrna Daniels Charitable Trust, the Paul T. Finger Fund and The Eye Cancer Foundation provided monetary support to the Princess Margaret Cancer Centre’s Internet Technology Program, which has (in turn) participated in the design, construction and maintenance of this retinoblastoma registry. AST received an ophthalmic oncology fellowship grant to study with Dr Finger (from The Eye Cancer Foundation).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Collaborators: The American Joint Committee on Cancer Ophthalmic Oncology Task Force (AJCC-OOTF) members appear in the supplemental appendix file. The writing committee consisted of AST, PTF, BG, TK and AM.
Ethics approval: The Institutional Review Board (IRB) and Ethics Committee of Princess Margaret Comprehensive Cancer Center (PMCCC) participated in and supervised the design of the retinoblastoma registry. Each participating centercentre was required to adhere to, or exceed, a PMCCC-approved protocol meeting IRB and Ethics Committee standards. The Ethics Committee ID for this study is REB ID # 11-0233-AE. Given that no patient identifiers were collected, individual patient consent was deemed unnecessary, a determination supported and approved by the participating centres and by the Princess Margaret Cancer Center, Toronto, Ontario, Canada. This study does not involve animal subjects.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
References
- 1.SCHOFIELD PB. Diffuse infiltrating retinoblastoma. Br J Ophthalmol. 1960;44:35–41. doi: 10.1136/bjo.44.1.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Finger PT, editor. Finger’s essential ophthalmic oncology: principles and practice. The Netherlands: Kugler Publications; 2024. Chapter 32: diagnosis of retinoblastoma; pp. 451–64. Available. [DOI] [Google Scholar]
- 3.Finger PT, editor. Finger’s essential ophthalmic oncology: principles and practice. The Netherlands: Kugler Publications; 2024. Chapter 33: treatment of retinoblastoma; pp. 465–80. Available. [DOI] [Google Scholar]
- 4.Tomar AS, Finger PT, Gallie B, et al. Metastatic Death Based on Presenting Features and Treatment for Advanced Intraocular Retinoblastoma: A Multicenter Registry-Based Study. Ophthalmology. 2022;129:933–45. doi: 10.1016/j.ophtha.2022.04.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Tomar AS, Finger PT, Gallie B, et al. High-risk Pathologic Features Based on Presenting Findings in Advanced Intraocular Retinoblastoma: A Multicenter, International Data-Sharing American Joint Committee on Cancer Study. Ophthalmology. 2022;129:923–32. doi: 10.1016/j.ophtha.2022.04.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Morgan G. Diffuse infiltrating retinoblastoma. Br J Ophthalmol. 1971;55:600–6. doi: 10.1136/bjo.55.9.600. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Bhatnagar R, Vine AK. Diffuse infiltrating retinoblastoma. Ophthalmology. 1991;98:1657–61. doi: 10.1016/s0161-6420(91)32072-4. [DOI] [PubMed] [Google Scholar]
- 8.Materin MA, Shields CL, Shields JA. Diffuse Infiltrating Retinoblastoma Simulating Uveitis in a 7-Year-Old Boy. Arch Ophthalmol. 2000;118:442. doi: 10.1001/archopht.118.3.442. [DOI] [PubMed] [Google Scholar]
- 9.Traine PG, Schedler KJ, Rodrigues EB. Clinical Presentation and Genetic Paradigm of Diffuse Infiltrating Retinoblastoma: A Review. Ocul Oncol Pathol. 2016;2:128–32. doi: 10.1159/000441528. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Shields CL, Ghassemi F, Tuncer S, et al. Clinical spectrum of diffuse infiltrating retinoblastoma in 34 consecutive eyes. Ophthalmology. 2008;115:2253–8. doi: 10.1016/j.ophtha.2008.07.003. [DOI] [PubMed] [Google Scholar]
- 11.Khetan V, Al-Kharusi N, Ganesh A. Diffuse Infiltrating Retinoblastoma With Central Nervous System Metastasis. Arch Ophthalmol. 2011;129:373. doi: 10.1001/archophthalmol.2011.28. [DOI] [PubMed] [Google Scholar]
- 12.Tomar AS, Finger PT, Gallie B, et al. A Multicenter, International Collaborative Study for American Joint Committee on Cancer Staging of Retinoblastoma: Part I: Metastasis-Associated Mortality. Ophthalmology. 2020;127:1719–32. doi: 10.1016/j.ophtha.2020.05.050. [DOI] [PubMed] [Google Scholar]
- 13.Tomar AS, Finger PT, Gallie B, et al. A Multicenter, International Collaborative Study for American Joint Committee on Cancer Staging of Retinoblastoma: Part II: Treatment Success and Globe Salvage. Ophthalmology. 2020;127:1733–46. doi: 10.1016/j.ophtha.2020.05.051. [DOI] [PubMed] [Google Scholar]
- 14.Tomar AS, Finger PT, Gallie B, et al. Global Retinoblastoma Treatment Outcomes: Association with National Income Level. Ophthalmology. 2021;128:740–53. doi: 10.1016/j.ophtha.2020.09.032. [DOI] [PubMed] [Google Scholar]
- 15.Tomar AS, Finger PT, Gallie B, et al. Retinoblastoma seeds: impact on American Joint Committee on Cancer clinical staging. Br J Ophthalmol. 2023;107:127–32. doi: 10.1136/bjophthalmol-2021-318892. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.United Nations, Department of Economic and Social Affairs World population prospects: the 2017 revision. volume i: comprehensive tables. 2017 https://www.un.org/development/desa/pd/content/world-population-prospects-2017-revision-volume-i-comprehensive-tables Available.
- 17.Jijelava KP, Grossniklaus HE. Diffuse anterior retinoblastoma: A review. Saudi J Ophthalmol. 2013;27:135–9. doi: 10.1016/j.sjopt.2013.06.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Mallipatna AC, Gallie BL, Amin MB, et al. AJCC cancer staging manual. 8th. Springer; 2017. Chapter 68: retinoblastoma ophthalmic sites: part xv; pp. 819–31. edn. [Google Scholar]
- 19.Zhao J, Feng ZX, Wei M, et al. Impact of Systemic Chemotherapy and Delayed Enucleation on Survival of Children with Advanced Intraocular Retinoblastoma. Ophthalmol Retina. 2020;4:630–9. doi: 10.1016/j.oret.2020.02.015. [DOI] [PubMed] [Google Scholar]
- 20.Kase S, Yoshida K, Suzuki S, et al. Diffuse infiltrating retinoblastoma invading subarachnoid space. Clin Ophthalmol. 2011;5:861–3. doi: 10.2147/OPTH.S20913. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Fernandez MP, Al-Holou SN, Fischer O, et al. Fluorescein angiography findings in diffuse retinoblastoma: two case reports with clinicopathologic correlation. J AAPOS. 2017;21:337–9. doi: 10.1016/j.jaapos.2017.03.013. [DOI] [PubMed] [Google Scholar]
- 22.Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113:2276–80. doi: 10.1016/j.ophtha.2006.06.018. [DOI] [PubMed] [Google Scholar]
- 23.Berry JL, Pike S, Shah R, et al. Aqueous Humor Liquid Biopsy as a Companion Diagnostic for Retinoblastoma: Implications for Diagnosis, Prognosis, and Therapeutic Options: Five Years of Progress. Am J Ophthalmol. 2024;263:188–205. doi: 10.1016/j.ajo.2023.11.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Stathopoulos C, Moulin A, Gaillard MC, et al. Conservative treatment of diffuse infiltrating retinoblastoma: optical coherence tomography-assisted diagnosis and follow-up in three consecutive cases. Br J Ophthalmol. 2019;103:826–30. doi: 10.1136/bjophthalmol-2018-312546. [DOI] [PubMed] [Google Scholar]
- 25.Brisse HJ, Lumbroso L, Fréneaux PC, et al. Sonographic, CT, and MR imaging findings in diffuse infiltrative retinoblastoma: report of two cases with histologic comparison. AJNR Am J Neuroradiol. 2001;22:499–504. [PMC free article] [PubMed] [Google Scholar]
- 26.Liu J, Ottaviani D, Sefta M, et al. A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression. Nat Commun. 2021;12:5578. doi: 10.1038/s41467-021-25792-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Kao LY. Diffuse infiltrating retinoblastoma: an inherited case. Retina (Philadelphia, Pa) 2000;20:217–9. doi: 10.1097/00006982-200002000-00021. [DOI] [PubMed] [Google Scholar]
- 28.Herwig MC, Hubbard GB, Wells JR, et al. Diffuses anteriores Retinoblastom. Ophthalmologe. 2011;108:969–72. doi: 10.1007/s00347-011-2369-y. [DOI] [PubMed] [Google Scholar]
- 29.Schedler KJE, Traine PG, Lohmann DR, et al. Hereditary Diffuse Infiltrating Retinoblastoma. Ophthalmic Genet. 2016;37:95–7. doi: 10.3109/13816810.2014.921315. [DOI] [PubMed] [Google Scholar]
- 30.Finger PT, editor. Finger’s essential ophthalmic oncology: principles and practice. The Netherlands: Kugler Publications; 2024. Chapter 8: a review of intraocular and orbital tumor registry studies; pp. 101–8. [Google Scholar]
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Data Availability Statement
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