Abstract
Purpose: To describe the clinical features and treatment outcomes in eyes with primary macular retinoblastoma (RB). Methods: Patients with primary macular RB were analyzed. Results: Of 41 patients (47 eyes), 20 (49%) were boys and 21 (51%) were girls. The mean age at diagnosis was 16 months (range, 1-60 months). The RB was bilateral in 6 patients (15%). At presentation, the macula was completely covered with the tumor in 22 eyes (47%) and partially covered with the fovea spared in 13 eyes (28%) and the fovea involved 12 eyes (25%). Based on the International Classification of Intraocular Retinoblastoma, 25 (53%), 15 (32%), and 7 (15%) of tumors were in Group B, Group C, and Group D, respectively. The tumor had exophytic features in 36 eyes (77%). The mean tumor basal diameter was 10.0 mm and the mean thickness, 5.6 mm. Associated features included subretinal seeds (10 eyes; 21%) and surrounding subretinal fluid (16 eyes; 34%). Forty-three eyes (92%) were treated with intravenous chemotherapy, 2 (4%) with intra-arterial chemotherapy, and 2 (4%) with transpupillary thermotherapy. Local tumor control was achieved in 45 eyes (96%), with 33 eyes (70%) showing a type III regression pattern. Over a mean follow-up of 23 months (range, 3-48 months), the macular tumor recurred in 5 eyes (11%), the globe was salvaged in all eyes with associated foveal atrophy (36 eyes; 77%), and 1 patient (2%) died. Conclusions: Macular RB has a good prognosis for globe salvage while vision salvage might be compromised as a result of associated foveal atrophy.
Keywords: tumor, retinoblastoma, macula
Introduction
Retinoblastoma (RB) is the most common intraocular tumor in children, accounting for approximately 11% of cancers occurring in the first year of life; 95% are diagnosed before age 5 years. 1 In developed countries, the goal of treatment has shifted from globe salvage to vision preservation. In underdeveloped countries, which account for more than 90% of pediatric RB cases, the intraocular tumor often goes undiagnosed and presents with advanced disease that threatens the globe.2,3 The key to globe salvage and vision preservation in RB depends on early diagnosis and appropriate treatment. 4
Macular RB constitutes an important subset of tumors located entirely or partly in the macular region. Patients presenting with macular RB pose a considerable challenge in management, and there are no clear guidelines or a clear consensus among ophthalmologists regarding its management.
Depending on the tumor location, tumor size, and the availability of resources, treatment options vary from primary systemic intravenous chemotherapy (IVC) 5 with or without focal transpupillary thermotherapy (TTT)6,7 and primary intra-arterial chemotherapy (IAC). 8 General guidelines might not be applicable or macular RB, specifically with treatments such as TTT or laser photocoagulation, because these treatments can directly affect the visual outcomes. Previous studies reported good tumor control using primary IVC without the use of laser treatment, 5 while others advocated the use of IVC for chemoreduction followed by adjuvant laser application to the nonleading edge of the tumor.6,9 –11 Even though the current treatment options achieve excellent local tumor control, the final visual outcomes depend on the size and location of the tumor as well as the administration of adjuvant laser TTT in the macular area.9,10,12,13
In patients treated with laser TTT for macular RB, the visual acuity (VA) after treatment is reported to be 20/200 or better in 20% to 63% of patients.11,13,14 There is little information regarding the outcomes of macular RB in Asian countries. Thus, we report the clinical presentation and treatment outcomes in patients presenting with primary macular RB at a referral center in India.
Methods
A retrospective study was performed at the Operation Eyesight Universal Institute for Eye Cancer, LV Prasad Eye Institute, Hyderabad, India. Institutional review board approval was obtained for the study.
A computerized database search was performed for the diagnosis “retinoblastoma” from January 2017 to April 2021. The medical records of all patients with primary macular RB were reviewed. Patients with adequate data related to clinical presentation and tumor grouping (Groups B to D) at the first visit were included in the study. Those with a minimum follow-up of 3 months or more were included for outcome analysis of actuarial data. Patients with a new tumor in the macular area during the follow-up were not included in the study. Those with inadequate data documentation related to the clinical presentation or tumor filling the entire globe (Group E) or extraocular RB at the first visit were excluded from the study.
The recorded demographic data included sex, age, and tumor laterality. A family history of RB and presenting complaints were recorded. Photographic documentation was performed in all cases using the RetCam II widefield imaging system (Clarity Medical Systems Inc), and all tumors were documented with fundus drawings. Fundus drawings and the widefield images were reviewed for accurate tumor details. Macular tumors were defined as lesions reaching an area of 5.5 mm diameter centered on the fovea. The location of the tumor in the macula (complete/partial; with or without foveal involvement) was recorded. In cases of multifocal tumors, only tumors located in the macular area were considered for analysis. All eyes with an intraocular tumor were classified based on the International Classification of Intraocular Retinoblastoma (ICRB). 15 The presenting signs, nonmacular tumors, and other associated features were also documented.
The details of primary treatment (TTT, cryotherapy, IVC, IAC, external beam radiotherapy, enucleation) were recorded. All cases were managed by the same ophthalmologist (S.K.). As per the institute’s protocol, all bilateral cases were treated with a standard IVC regimen consisting of 6 cycles of vincristine, etoposide, and carboplatin administered every 3 weeks. All unilateral cases were offered the options of IVC and IAC, and the treatment was planned based on the parents’ choice.
Focal TTT was applied at the discretion of the ophthalmologist after 1 to 2 cycles of chemotherapy to the nonleading edge of the tumor in the macular area sparing the fovea or as an adjuvant treatment after completion of 6 cycles of IVC. Laser treatment was delivered with the Iris diode laser (810 nm) (Iridex Corp). The 1.2-mm spot size was aimed through a dilated pupil using the indirect ophthalmoscope and a 20 D lens. The laser was set at 300 mW initially, after which the power was increased as necessary until the tumor had a gray–white appearance. The influence of IVC with adjuvant laser treatment vs IVC alone for macular RB was assessed.
All recurrences and their treatment were recorded. Posttreatment tumor regression patterns and atrophic changes in the macular area were noted. The regression patterns were classified as type 0 (no visible residua), type I (fully calcified tumor), type II (fleshy tissue with without calcification), type III (mixed calcific and fleshy tumor), or type IV (atrophic chorioretinal scar). 16 Partial regression of the tumor was defined as a residual area of active tumor within the nonactive area. Histopathologic features were recorded in eyes that were enucleated.
The main outcome measures were local tumor control, globe salvage, visual potential, and overall survival. The visual potential was assessed based on the anatomic integrity of the fovea. Factors influencing the primary tumor control and visual potential were analyzed.
All statistical analyses were performed using SPSS software (version 17.0, SPSS Inc). A P value of 0.05 or less was considered statistically significant.
Results
Of the 676 patients diagnosed with RB during the study period, 46 (53 eyes) had macular RB classified as Group B, C, or D at presentation. Five patients were excluded for lack of treatment or inadequate follow-up (<3 months), leaving 41 patients (47 eyes) in the study. Table 1 shows the patients’ demographics and clinical presentation. The majority of patients presented with bilateral presentation of RB; however, 25% had bilateral macular tumors. In most cases, the RB did not have a familial origin.
Table 1.
Demographic and Clinical Presentation of Macular Retinoblastoma.
| Characteristic | Value |
|---|---|
| Patients (n) | 41 |
| Eyes (n) | 47 |
| Age (mo) | |
| Mean | 16.4 |
| Median | 11 |
| Range | 1-60 |
| Sex, n (%) | |
| Male | 20 (49) |
| Female | 21 (51) |
| Presentation, n (%) | |
| Unilateral | 7 (15) |
| Bilateral | 40 (85) |
| Laterality of macular tumor, n (%) | |
| Unilateral | 35 (74) |
| Bilateral | 6 (13) |
| Hereditary, n (%) | |
| Familial | 10 (21) |
| Sporadic | 31 (66) |
| Presenting sign, n (%) | |
| Leukocoria | 30 (64) |
| None | 9 (19) |
| Poor vision | 1 (2) |
| Strabismus | 1 (2) |
| Duration of symptoms (wk) | |
| Mean | 8.1 |
| Median | 4 |
| Range | 0, 36 |
| Location of tumor, n (%) | |
| Macula | |
| Complete | 22 (47) |
| Partial | |
| Fovea involved | 12 (26) |
| Fovea spared | 13 (28) |
| Overlying optic disc | |
| Involved | 30 (64) |
| Not involved | 17 (36) |
| Tumor size (mm) | |
| Largest basal diameter | |
| Mean | 10 |
| Range | 3, 18 |
| Thickness | |
| Mean | 5.6 |
| Range | 2, 12 |
| Presence of cavities, n (%) | |
| Type of tumor, n (%) | |
| Exophytic | 36 (77) |
| Endophytic | 6 (13) |
| Mixed | 5 (11) |
| Tumor classification (ICRB), n (%) | |
| Group B | 25 (53) |
| Group C | 15 (32) |
| Group D | 7 (15) |
| Nonmacular tumor present, n (%) | 25 (53) |
| Associated features, n (%) | |
| Subretinal fluid | 16 (34) |
| Subretinal seeds | 10 (21) |
| Vitreous seeds | 2 (4) |
Abbreviation: ICRB, international classification of intraocular retinoblastoma.
The most common presenting complaint was leukocoria. The majority of eyes were in ICRB Group B. Associated features included subretinal fluid, subretinal seeding, and vitreous seeding. Most tumors were of the exophytic variant (Table 1).
Table 1 also shows the characteristics of the tumors (macular, foveal, and optic nerve involvement; basal tumor diameter of macular lesion; tumor thickness). In addition to macular tumors, nonmacular solid tumors were seen in 25 eyes (53%) and the cavitary variant of the RB was noted within the macular tumor in 6 eyes (13%).
Table 2 shows the treatment (type, number of sessions) and outcomes. The most prevalent treatment was IVC with adjuvant TTT. At a mean follow-up of 23 months, 94% of eyes had complete tumor regression, with type III regression pattern being the most common. Small tumors (≤3.0 mm) regressed to type IV in all 3 cases. Medium tumors (3.0 to 8.0 mm; n = 30) regressed most often to type III (n = 22; 73%) or type I (n = 6; 20%) Large tumors (>8.0 mm) regressed to type III in all 5 cases. Figure 1 shows representative case photographs.
Table 2.
Treatment and Outcomes (47 Eyes).
| Feature (n) | Value |
|---|---|
| Primary treatment, n (%) | |
| Systemic IVC | 43 (91) |
| IAC | 2 (4) |
| TTT (fovea sparing) | 2 (4) |
| Adjuvant treatment, n (%) | |
| TTT | 28 (60) |
| None | 19 (40) |
| TTT sessions | |
| Mean | 4 |
| Median | 3 |
| Range | 1, 9 |
| Treatment outcome, n (%) | |
| Partial regression | 2 (4) |
| Regressed | 45 (96) |
| Fovea spared, n (%) | |
| Yes | 16 (34) |
| No | 31 (66) |
| Foveal atrophy, n (%) | |
| Yes | 36 (77) |
| No | 11 (23) |
| Regression pattern, n (%) | |
| Type I | 7 (15) |
| Type II | 4 (9) |
| Type III | 33 (70) |
| Type IV | 3 (6) |
| Visual potential, n (%) | |
| Compromised | 36 (77) |
| Normal | 11 (23) |
| Overall tumor recurrences, n (%) | |
| Yes | |
| Macular | 5 (11) |
| Nonmacular | 13 (28) |
| No | 29 (62) |
| Type of recurrence, n (%) | |
| Solid tumor | 6 (13) |
| SRS | 10 (21) |
| VS | 2 (4) |
| Treatment of recurrence (macula), n (%) | |
| TTT | 1 (2) |
| Repeat IVC | 2 (4) |
| Cryotherapy | 1 (2) |
| IAC followed by plaque | 1 (2) |
| Treatment of recurrence (nonmacular), n (%) | |
| TTT | 9 (19) |
| Repeat IVC | 3 (6) |
| Cryotherapy | 1 (2) |
| Outcomes, n (%) | |
| Globe salvage | 47 (100) |
| Metastases | 1 (2) |
| Death | 1 (2) |
| Lost to FU, n (%) | 3 (6) |
| FU, mo | |
| Mean | 23 |
| Median | 23 |
| Range | 3,48 |
Abbreviations: FU, follow-up; IAC, intra-arterial chemotherapy; IVC, intravenous chemotherapy; SRS, subretinal seeds; TTT, transpupillary thermotherapy; VS, vitreous seeds.
Figure 1.
Macular retinoblastoma: response to treatment. Top row: (A) A 3-month-old boy presented with left-eye Group B exophytic retinoblastoma (RB) involving the macular area. (B) The tumor showed type III regression features with 3 cycles of intravenous chemotherapy (IVC) and (C) remained stable after 6 cycles of IVC with the tumor-bisecting fovea. Middle row: (D) A 3-year-old girl presented with left-eye Group B exophytic RB involving the macular area with (E) dilated feeder vessels. (F) After 1 cycle of intra-arterial chemotherapy (IAC), the tumor reduced to half its size with few areas of intratumor calcification. After III cycles of IAC, the macular tumor showed type III regression partially involving the fovea. Bottom row: (G) A 6-month-old boy presented with multiple tumors in the posterior pole in the right eye with (H) 3 tumors in the macular area. After 2 sessions of transpupillary thermotherapy, all tumors regressed with a flat chorioretinal atrophic scar sparing of fovea.
The 5 eyes (11%) in which the macular tumor recurred were treated with additional cycles of IVC or focal treatments. Factors associated with an increased risk for recurrence were a larger tumor (mean basal dimension 11.0 mm; mean thickness 7.0 mm) and type III regression pattern. The primary visual potential was severely compromised in the 36 eyes with foveal atrophy. None of the eyes had been enucleated by the last follow-up. One child with ICRB classification Group B in the eye with macular RB and orbital extension of tumor in the contralateral eye died.
More eyes in the combination treatment group (IVC + TTT) than in IVC alone group (64% vs 36%) had partial macular involvement (P > .05) (Table 3). At the last follow-up, there was no significant difference between the 2 groups in complete tumor regression or compromised visual potential (both P > .05). The macular tumor recurred in 11% and 0% in the combination group and IVC alone group, respectively (P > .05).
Table 3.
Comparison Between IVC + TTT and IVC Only.
| Parameter | IVC + TTT (n = 28) | IVC (n = 14) | P Value |
|---|---|---|---|
| Age (mo) | |||
| Mean | 15.5 | 13.7 | .856 |
| Median | 10.5 | 9.0 | |
| Range | 2-48 | ||
| Presentation, n (%) | — | ||
| Unilateral | 3 (11) | 3 (21) | |
| Bilateral | 25 (89) | 11 (79) | |
| Eye, n (%) | |||
| Right | 15 (54) | 9 (64) | — |
| Left | 13 (46) | 5 (36) | |
| Presenting sign, n (%) | — | ||
| Leukocoria | 17 (68) | 10 (71) | |
| None | 5 (18) | 4 (29) | |
| Poor vision | 2 (7) | 0 | |
| Strabismus | 2 (7) | 0 | |
| Duration of symptoms (wk) | .609 | ||
| Mean | 7.8 | 10.1 | |
| Range | 0-28 | 0-36 | |
| Location of tumor: macula, n (%) | |||
| Complete | 10 (36) | 9 (64) | .154 |
| Partial: fovea involved | 9 (32) | 2 (14) | .154 |
| Partial: fovea spared | 9 (32) | 3 (22) | .154 |
| Size of tumor (mm) | — | ||
| Largest basal diameter | |||
| Mean | 10 | 10.3 | |
| Range | 3-18 | 6-16 | |
| Thickness | |||
| Mean | 5.5 | 5.8 | |
| Range | 2-10 | 2-12 | |
| Type of tumor, n (%) | |||
| Exophytic | 22 (79) | 12 (86) | .889 |
| Endophytic | 3 (11) | 1 (7) | ≥.999 |
| Mixed | 3 (11) | 1 (7) | ≥.999 |
| Tumor classification (ICRB), n (%) | |||
| Group B | 16 (57) | 6 (43) | .585 |
| Group C | 10 (36) | 3 (21) | .555 |
| Group D | 2 (7) | 5 (36) | .057 |
| Nonmacular tumors, n (%) | 17 (61) | 6 (43) | .442 |
| Associated features, n (%) | |||
| Subretinal fluid | 9 (32) | 7 (50) | .431 |
| Subretinal seeds | 6 (67) | 4 (80) | .898 |
| Vitreous seeds | 1 (11) | 0 (0) | ≥.999 |
| Treatment outcome, n (%) | |||
| Partial regression | 1 (3) | 0 (0) | ≥.999 |
| Regressed | 27 (97) | 14 (100) | .989 |
| Fovea spared, n (%) | |||
| Yes | 10 (36) | 4 (29) | — |
| No | 18 (64) | 10 (71) | |
| Foveal atrophy, n (%) | |||
| Yes | 22 (79) | 11 (79) | ≥.999 |
| No | 6 (21) | 3 (21) | ≥.999 |
| Regression pattern, n (%) | |||
| Type I | 2 (7) | 5 (36) | — |
| Type II | 2 (7) | 2 (14) | |
| Type III | 23 (82) | 7 (50) | |
| Type IV | 1 (4) | 0 (0) | |
| Visual potential, n (%) | |||
| Compromised | 22 (79) | 11 (79) | ≥.999 |
| Normal | 6 (21) | 3 (21) | ≥.999 |
| Overall tumor recurrence, n (%) | — | ||
| Yes | 11 (39) | 5 (36) | |
| No | 17 (61) | 9 (64) | |
| Macula tumor recurrence, n (%) | |||
| Yes | 3 (11) | 0 (0) | .898 |
| No | 25 (89) | 14 (100) | .919 |
| Outcomes, n (%) | |||
| Globe salvage | 28 (100) | 14 (100) | — |
| Metastases | 1 (4) | 0 | |
| Death | 1 (4) | 0 | |
Abbreviations: ICRB, international classification of intraocular retinoblastoma; IVC, intravenous chemotherapy; TTT, transpupillary thermotherapy.
Conclusions
The management of RB has evolved over the past decade as a result of advancements in several techniques, including chemotherapy delivered by intravenous, intra-arterial, or intravitreal routes and focal treatments such as TTT and cryotherapy. The treatment of macular RB poses a serious challenge in terms of a balance between local tumor control and the risk for tumor-related and treatment-related visual loss.
We report our experience treating macular RB with primary systemic/local chemotherapy with or without focal laser treatment. To our knowledge, ours is the first study from India to report the clinical presentation and treatment outcomes of macular RB in which all patients were treated with a uniform, reproducible treatment approach that resulted in excellent local tumor control (94%) and a 100% globe salvage rate without external beam radiation. Our results are consistent with those in previous retrospective studies in a Western population in which excellent tumor control was achieved using IVC.5,6,12 This can be attributed to a higher concentration of chemotherapy delivered to the macula secondary to high choroidal blood flow supplied by the short posterior ciliary vessels. 5
The mean age at presentation in our series was 16 months (median 11 months). In our previous study of RB including all macular and nonmacular tumors, the mean age at presentation of RB was 29 months (median 24 months), 17 suggesting that macular tumors tend to present at a younger age (minimum of 12 months earlier) in eyes with an increased risk of harboring germline RB1 mutation. 18
A study by Abramson and Gombos 19 showed that posterior pole tumors have a more aggressive clinical course than peripheral tumors that present later in life. This might be attributed to 2 factors; that is, tumor location and tumor dimensions. Macular tumors are more difficult to control than extramacular tumors because of the higher rate of recurrence after treatment with chemotherapy and focal therapy.20,21 This is contrary to results in recent studies, which reported excellent outcomes (>84%) of systemic IVC treatment for macular tumors.5 –7,10 In our series, all globes were salvaged without the use of external beam radiotherapy over a median follow-up of 23 months.
In a study by Shields et al, 21 the distribution of regression patterns of RB treated with chemotherapy was 10% to 13% for type I tumors, 3% to 5% for type II tumors, 23% to 33% for type III tumors, and 51% to 57% for type IV tumors. In our study, although the distribution of the regression patterns was similar for type I and type II, a majority of tumors (70%) had a type III regression pattern.
There is no clear consensus on the use of adjuvant TTT for macular RB. Shields et al 21 reported that tumors consolidated with TTT had a type IV regression pattern (57%), which leads to flat scarring and generalized retinal atrophy that can compromise the final VA. In contrast, recent studies found that combining TTT with systemic chemotherapy not only improves the local tumor control rate but also preserves vision with the use of a foveal-sparing laser.6,9,12 In our series, local tumor control (97% vs 100%) and compromised visual potential (79% vs 79%) were comparable between the group treated with IVC + TTT and the group treated with IVC alone. These results could be influenced by the small sample. However, the effectiveness of laser treatment for perifoveal RB cannot be ruled out. A systematic meta-analysis by Fabian et al 22 found that there was no evidence to support or refute the effectiveness and safety of focal laser therapy in children with RB treated with systemic chemotherapy.
In our series, 5 eyes (11%) had solid tumor recurrence in the macular area after an initial good response to chemotherapy. On further analysis, factors associated with the increased risk of recurrence were a larger tumor (mean basal dimension 11.0 mm; mean thickness 7.0 mm) and a type III regression pattern (100%). These results were comparable to those in previous studies of macular tumor recurrence, which ranged from 16% to as high as 34%.5 –7,12
At the last follow-up in our study, the visual potential was compromised in 79% of children as a result of associated foveal atrophy. In a study by Demirci et al 23 of the long-term visual outcomes in children receiving IVC, 55% of patients had compromised VA (<20/200) and a tumor margin at least 3.0 mm from the foveola was the only factor predictive of a good visual outcome. Similarly, a prospective clinical study analyzed the visual outcomes in macular RB treated with primary chemotherapy alone and found that 50% of children had a VA worse than 20/200. 13 Despite complete macular involvement in 22 eyes, 6 eyes (27%) had good visual potential after receiving treatment. This could be related to the finding that larger tumors obscuring the macula at initial examination might shrink after chemoreduction and thus show a normal fovea, leading to good visual outcomes.
Studies have reported better visual outcomes (VA better than 6/60) for perifoveal tumors than for foveal tumors and that laser treatment had no detrimental effect on VA after treatment.9,11,24 In contrast, Chawla et al 25 found that for Group B macular tumors, the VA was worse after laser treatment (median 6/60) than before treatment.
Studies have found that macular RB has an excellent prognosis in terms of globe salvage as well as overall patient survival.6,11 Our findings were similar. One patient died as a result of a distant metastasis secondary to orbital extension of RB in the contralateral eye.
There are several limitations to the present study, including the small sample, possible treatment bias because all cases were managed by the same surgeon, and the retrospective nature. A randomized prospective study would help identify the differences between eyes treated with IVC alone and eyes treated with IVC + TTT. Quantitative visual assessment using best-corrected VA, contrast sensitivity, or visual field testing as parameters could not be performed in our study given the younger age of the patients.
In conclusion, macular RB has a good prognosis in terms of globe salvage, although the vision potential can be compromised as a result of associated foveal atrophy. Adequate tumor control can be achieved with IVC with or without TTT. Recent advances, such as IAC, are becoming more popular and have been shown to provide excellent local tumor control. Prospective future studies comparing systemic IVC with IAC for macular RB would help better refine practice patterns in managing such cases.
Footnotes
Ethical Approval: This study was conducted in accordance with the Declaration of Helsinki. The collection and evaluation of all protected patient health information was performed in a HIPAA (Health Insurance Portability and Accountability Act)–compliant manner.
Statement of Informed Consent: Informed consent was obtained before treatment and included permission for publication of all photographs and images published.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Operation Eyesight Universal Institute for Eye Cancer and Hyderabad Eye Research Foundation, Hyderabad, India.
ORCID iD: Vishal Raval 
https://orcid.org/0000-0002-8446-2696
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