Conservative, globe-preserving management of retinoblastoma primarily involves methods of intravenous chemotherapy (IVC) or intra-arterial chemotherapy (IAC) coupled with tumor-targeted consolidation techniques.1 Treatment success relies on several factors, including tumor response to single or combination chemotherapy agent(s) and clinician-related expertise in detection of tumor recurrence at an early point, particularly at a time when additional focal therapies can offer control with avoidance of visual compromise. In most cases, tumor recurrence is visible with indirect ophthalmoscopy and confirmed with fluorescein angiography, ultrasonography, and/or ultrasound biomicroscopy.2,3 In some instances, recurrence is transparent and barely visible on ophthalmoscopy and best delineated as localized hyperfluorescence on fluorescein angiography or other imaging.2 We describe a minimally visible tumor recurrence that was detectable on spectral-domain optical coherence tomography (SD-OCT).
A 2-month-old male infant with a family history of retinoblastoma was referred for evaluation. At presentation, visual acuity was fix-and-follow in each eye. Intraocular pressure and anterior segment examination were normal in both eyes. Fundus examination of the right eye revealed two small tumors in the inferonasal retina, both measuring 3 mm in diameter and 3 mm in ultrasonographic thickness (Figure 1). The left eye showed a single tumor located temporal to the fovea, measuring 3 mm in diameter and 2 mm in thickness. There was no evidence of subretinal fluid, subretinal seed, or vitreous seed. The retina was attached and the macula was intact in both eyes. A diagnosis of bilateral familial retinoblastoma, designated as group A in both eyes, was rendered.
Bilateral familial retinoblastoma classified as group A in the right eye in a 2-month-old male infant. (A) Fundus photograph of the right eye at presentation showing two small retinal tumors located inferonasally. (B) At the 7-month follow-up, fundus photography documenting tumor regression with apparently thin retina down to bare sclera, with no vascularization and surrounded by retinal pigment epithelial hyperplasia. (C) However, hand-held spectral-domain optical coherence tomography (vertical scan indicated by the white arrow) over one of the scars (yellow arrow) disclosed an abrupt transition from a completely flat chorioretinal scar to a thickened recurrent intra-retinal mass measuring 622 µm in thickness and 4.8 mm in diameter.
The child was treated with IVC for six cycles using vincristine, etoposide, and carboplatin.4 Two months into therapy, a new third tumor in the right eye was discovered inferiorly at the ora serrata. Consolidation to all regressed scars in each eye was performed with transpupillary thermotherapy or cryotherapy. At completion of chemotherapy, all scars were completely regressed to a flat appearance.
One month later, despite stable clinical appearance and no evidence of recurrence on ophthalmoscopy or ultrasonography, intraoperative hand-held SD-OCT (Optovue, Inc., Fremont, CA) of the right eye revealed a central recurrence of a single juxtapapillary scar, measuring 622 µm in thickness and 4.8 mm in diameter (Figure 1). A “second-look” ophthalmoscopy confirmed the barely visible, transparent recurrence and cutting cryotherapy was performed. On follow-up examination 12 months later, all tumors were regressed without recurrence in either eye.
Advances in diagnostic imaging and treatment for retinoblastoma have improved the outcomes of patient survival, globe preservation, and long-term visual acuity in the United States, Europe, and Japan over the past 20 years.1 In particular, current methods of chemotherapy have allowed outstanding globe salvage for eyes previously destined for enucleation.5
Kivelä6 provided a retrospective analysis of retinoblastoma patient survival and noted that developed nations (North America, Europe, and Japan) achieved 95% to 97% patient survival compared to 30% in undeveloped regions (Africa). Regarding globe preservation, Shields et al.7 documented that the International Classification of Retinoblastoma was reliable for predicting IVC success, achieving control in 100% of group A, 93% of group B, 90% of group C, and 47% of group D eyes. More recently, globe salvage with IAC has been documented as impressive, with 94% to 100% control for groups A, B, C, and D eyes.8
Retinoblastoma recurrence rates differ depending on the chemotherapy agents, delivery technique, and use of post-chemotherapy consolidation. Following IVC using three agents plus focal tumor consolidation for 457 tumors, Shields et al.9 found solid tumor recurrence in 18% by 7 years of follow-up. Tumors at greatest risk for recurrence were large tumors and those located in the macular region.9 In a study of 158 eyes with retinoblastoma treated with IVC and tumor consolidation, recurrence of at least one solid tumor per eye (51%), one vitreous seed per eye (50%), or one subretinal seed per eye (62%) was documented. In nearly every case, recurrence was detected within 3 years following chemotherapy.10 In our case, the recurrence occurred at 5 months following chemotherapy.
The best method for detection of retinoblastoma recurrence is indirect ophthalmoscopy by an experienced examiner because recurrence typically appears as a solid gelatinous mass with slightly increased vascularity. However, in some cases recurrence can be barely visible, especially when it overlies an atrophic chorioretinal scar, as in our case. In such cases, imaging with fluorescein angiography, ultrasonography, and ultrasound biomicroscopy have been used to confirm recurrences.2,3
There has been little in the literature on the use of OCT for retinoblastoma management. Rootman et al.11 reported the utility of hand-held SD-OCT in identifying small tumors, monitoring treatment response, and detecting edge recurrences in 19 eyes affected by retinoblastoma. Cao et al.12 used the same device in 3 cases of macular retinoblastoma and concluded that the restoration of the foveal anatomy after tumor regression might serve as a predictor of visual potential in preverbal children. Saktanasate et al.13 further demonstrated that subclinical, invisible retinoblastoma could be detected with SD-OCT. Hasanreisoglu et al.14 used hand-held OCT to illustrate a case in which a hidden retinoblastoma, with deep to dense vitreous seeding, was eventually visualized with ophthalmoscopy and SD-OCT following resolution of vitreous seeds. We described another benefit of SD-OCT for retinoblastoma management with early detection of minimally visible recurrence. This early detection permitted treatment with focal therapy and preservation of the globe and visual acuity. We recommend performing SD-OCT, when available, on all eyes with retinoblastoma. This is especially important in eyes with macular tumors to assess macular structure, monitor treatment response, and detect early tumors and recurrences.
Although the hand-held SD-OCT device has several applications, there are limitations to its use for retinoblastoma. First, this device requires a skilled operator to obtain high quality images. Second, the imaging capacity is restricted to small tumors of 3 mm or less in thickness and located in the macular or perimacular region. Third, focusing the equipment to the foveola or specific tumors is challenging because the patient is asleep and gross ocular movement is achieved with manual rotation and stabilization of the globe. Finally, SD-OCT relies on clarity of ocular media.
Intraoperative hand-held SD-OCT can allow for assessment of retinoblastoma response in a non-invasive and effective manner. SD-OCT can assist in documenting tumor localization, tumor response, foveal anatomy, and prediction of ultimate potential visual outcome.12,15 In this report, we documented that SD-OCT identified tumor recurrence before it was clinically obvious by ophthalmoscopy.
- Shields CL, Lally SE, Leahey AM, et al. Targeted retinoblastoma management: when to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Curr Opin Ophthalmol. 2014;25:374–385. doi:10.1097/ICU.0000000000000091 [CrossRef]
- Shields JA, Sanborn GE, Augsburger JJ, Orlock D, Donoso LA. Fluorescein angiography of retinoblastoma. Trans Am Ophthalmol Soc. 1982;80:98–112.
- Paquette LB, Miller D, Jackson HA, et al. In utero detection of retinoblastoma with fetal magnetic resonance and ultrasound: initial experience. AJP Rep. 2012;2:55–62. doi:10.1055/s-0032-1316465 [CrossRef]
- Shields CL, Fulco EM, Arias JD, et al. Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye (Lond). 2013;27:253–64. doi:10.1038/eye.2012.175 [CrossRef]
- Abramson DH, Shields CL, Munier FL, Chantada G. Treatment of retinoblastoma in 2015: agreement and disagreement. JAMA Ophthalmol. 2015;133:1341–1347. doi:10.1001/jamaophthalmol.2015.3108 [CrossRef]
- Kivelä T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol. 2009;93:1129–1131 doi:10.1136/bjo.2008.150292 [CrossRef]
- Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113:2276–2280. doi:10.1016/j.ophtha.2006.06.018 [CrossRef]
- Shields CL, Manjandavida FP, Lally SE, et al. Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the International Classification of Retinoblastoma. Ophthalmology. 2014Jul;121:1453–1460. doi:10.1016/j.ophtha.2014.01.026 [CrossRef]
- Shields CL, Mashayekhi A, Cater J, Shelil A, Meadows AT, Shields JA. Chemoreduction for retinoblastoma: analysis of tumor control and risks for recurrence in 457 tumors. Am J Ophthalmol. 2004;138:329–337. doi:10.1016/j.ajo.2004.04.032 [CrossRef]
- Shields CL, Honavar SG, Shields JA, Demirci H, Meadows AT, Naduvilath TJ. Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol. 2002;120:460–464. doi:10.1001/archopht.120.4.460 [CrossRef]
- Rootman DB, Gonzalez E, Mallipatna A, et al. Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations. Br J Ophthalmol. 2013;97:59–65. doi:10.1136/bjophthalmol-2012-302133 [CrossRef]
- Cao C, Markovitz M, Ferenczy S, Shields CL. Hand-held spectral-domain optical coherence tomography of small macular retinoblastoma in infants before and after chemotherapy. J Pediatr Ophthalmol Strabismus. 2014;51:230–234. doi:10.3928/01913913-20140603-01 [CrossRef]
- Saktanasate J, Vongkulsiri S, Khoo CT. Invisible retinoblastoma. JAMA Ophthalmol. 2015;133:e151123. doi:10.1001/jamaophthalmol.2015.1123 [CrossRef]
- Hasanreisoglu M, Dolz-Marco R, Ferenczy SR, Shields JA, Shields CL. Spectral domain optical coherence tomography reveals hidden fovea beneath extensive vitreous seeding from retinoblastoma. Retina. 2015;35:1486–1487. doi:10.1097/IAE.0000000000000477 [CrossRef]
- Samara WA, Pointdujour-Lim R, Say EAT, Shields CL. Foveal microanatomy documented by SD-OCT following treatment of advanced retinoblastoma. J AAPOS. 2015;19:368–372. doi:10.1016/j.jaapos.2015.02.019 [CrossRef]