Late-Onset Bilateral Retinoblastoma in Adolescence with Successful Globe Salvage

Abstract

Introduction

Retinoblastoma (RB) is the most common intraocular malignancy in children, known to occur within 5 years of age. The occurrence of RB after the first decade of life is rare and is usually unilateral. Owing to its varied and delayed presentation with advanced stages, enucleation is advocated in most cases of late-onset RB. However, with the advent of multiple treatments, such as local therapies, the chances of globe salvage can still be attempted, even in late-onset RB.

Case Presentation

We report a case of a 14-year-old boy who had active RB in the right eye and retinomas in the left eye. The child was given systemic three-drug chemotherapy (standard VEC regimen) along with intravitreal injection of topotecan for vitreous seeds in the right eye and cryotherapy for the retinomas in the left eye. By 1 year, the right eye lesion had shown stable type II regression and no recurrence of vitreous seeds, while the left eye lesions showed type IV regression.

Conclusion

This case highlights a case of bilateral late-onset RB with a rare combination of active RB in one eye and retinoma in the other eye. Successful globe salvage was achieved by combining local and systemic approaches, resulting in good anatomical and functional outcomes.

Introduction

Retinoblastoma (RB) is the most common intraocular malignancy in children under 5 years of age, with an incidence ranging from 1 in 15,000 to 1 in 18,000. Presentation of RB after the first decade of life is infrequent and may pose a challenge in diagnosis and management. Till date, there are around 50 cases of late-onset RBs reported [1]. Late-onset RB can occur due to de novo tumors arising out of persistent embryonal cells that get mutated or due to malignant transformation of the benign form of RB (retinocytoma or retinoma) [1]. We present a case of late-onset RB in a child in his early second decade who had active RB in 1 eye, probably due to malignant transformation of retinoma, with the presence of retinomas in the fellow eye.

Case Report

A 14-year-old male child presented with complaints of progressive diminution of vision in the right eye for the past 1 month. There were no associated symptoms like flashes/floaters. The child had no systemic issues with no previous ocular complaints. On examination, the best-corrected visual acuity in the right eye was finger counting close to face, and the left eye was 20/20. There was a whitish pupillary reflex with grade 2 relative afferent pupillary defect in the right eye. Anterior segment examination in both eyes was unremarkable. The right eye fundus examination showed multiple pearl-like vitreous opacities (vitreous seeds) with diffuse irregular yellowish mass lesion occupying the inferior hemiretina with exudative retinal detachment (Fig. 1a). Disc and macula details could not be made out. The left eye showed two grayish white deep retinal lesions with smooth surface and defined margins, with retinal vessels crossing the lesions (and not dipping into it). The lesions were about 4-disc diameters in size in the superonasal quadrant (Fig. 1b) and about 3-disc diameters in size in the inferotemporal quadrant. There was neither evidence of activity (subretinal fluid, vitreous seeds) nor features of spontaneous regression, i.e., retinocytoma (surrounding retinal pigment epithelial alterations or chorioretinal atrophy). Ultrasound B scan showed an ill-defined mass lesion with associated internal calcification in the right eye (Fig. 1c). Based on clinical appearance and ultrasound findings, a diagnosis of group D RB was made in the right eye and retinomas in the left eye. Magnetic resonance imaging revealed a relatively hyperintense lesion in the posterior aspect of vitreous cavity in the right eye with no evidence of optic nerve involvement. Genetic analysis revealed a heterozygous contiguous deletion of size ∼1,585.29 KB on chromosome 13 (chr13:g.[?_47943371]_[49528665_?]del) encompassing multiple genes was observed. This mutation has been previously reported in patients affected with RB [2]. Fundus examination of both parents and the younger sister of the patient was normal. Workup for metastasis (chest X-ray, abdominal ultrasound, bone marrow examination, and cerebrospinal fluid analysis) was negative. The child was put on 6 cycles of chemotherapy regimen of vincristine (0.05 mg/kg), etoposide (5 mg/kg), and carboplatin (18.6 mg/kg). After 4 cycles of chemotherapy, the right eye exudative retinal detachment had resolved completely. A solid mass lesion was seen inferior to the disc with a reduction in vitreous seeds (Fig. 2a), and the left eye showed persistence of the lesions (Fig. 2b). Intravitreal injection of topotecan (20 μg/0.1 mL) was given in the right eye for the treatment of residual vitreous seeds. Even after 4 cycles of chemotherapy, the left eye lesions did not show any regression and thus pointing again in favor of a benign nature of the lesion (retinoma). In view of a possible risk of malignant transformation of the left eye lesions in the future, cryotherapy was applied to both lesions. The right eye lesion received transpupillary thermotherapy (TTT). Post-local therapy, both eyes showed regression of lesions with complete resolution of vitreous seeds. By 1 year, the right eye lesion had shown stable type II regression (homogenous grayish appearance) and no recurrence of vitreous seeds, while the left eye lesions showed type IV regression (flat scar with pigmentary changes) (Fig. 2c, d). Dimensions of the right eye lesion remained stable on ultrasound throughout the follow-up of 1 year (shown in Fig. 2c inset). The vision was maintained at 20/200 and 20/20 in the right and the left eye, respectively.

Fig. 1.

a Right eye fundus examination showing multiple vitreous seeds with diffuse yellowish mass lesion occupying the inferior hemiretina with exudative retinal detachment. b Left eye fundus showing a grayish white deep retinal lesion about 4 disc diameter size in the superonasal quadrant (a similar looking lesion of about 3 disc diameters was noted in the inferotemporal quadrant, not seen in the figure). c Right eye ultrasound B scan showing an ill-defined mass lesion with associated internal calcification. d Computed tomography of orbits showed a large mass lesion in the right eye with internal calcifications.

Fig. 2.

a Post-4 cycles of chemotherapy, the right eye shows resolution of exudative retinal detachment, and the mass lesion appears partly regressed along with reduction in vitreous seeds. b Left eye showing persistence of the tumor lesion. c Right eye post-TTT and post-intravitreal topotecan showing type IV pattern of regression and disappearance of vitreous seeds. USG B scan revealing a clear vitreous in the right eye with a regressed calcified mass at 1 year of initiating treatment. d Left eye post-cryotherapy showing type IV pattern of regression.

Discussion

Retinoblastoma is a neuroectodermal tumor arising from photoreceptor precursor cells. It classically affects toddlers and is rare after 5 years of age. Late presentation of RB beyond the first decade of life is extremely rare. The mean age of presentation in late-onset RB is around 30 years and presents as mostly unilateral lesions [3]. Diminution of vision is the most common presenting symptom in late-onset RB, as seen in our case, in contrast to leukocoria and strabismus in childhood RB [4].

Two of the commonly described mechanisms for the pathogenesis of late-onset RB are de novo RB without antecedent lesion due to persistence of rare embryonal retinal cells, which undergo malignant transformation in later life [5], or as a sequela of oncogenetic mutations in a pre-existing retinocytoma or a retinoma [6]. The left eye of our patient had features suggestive of retinoma, and the active RB seen in the right eye was possibly related to reactivation of a retinoma. It is postulated that a second mutation occurring in immature retinoblast cells results in RB, whereas a second mutation in mature retinoblast cells results in retinocytoma [7, 8]. Singh et al. [9] stated that long-term risk of malignant transformation of a retinocytoma into an RB is approximately 4%. The rate of retinocytoma/retinoma transformation into RB is reported to be 2.7% by 2 years, 9.2% by 5 years, and 15.3% by 10–20 years [10]. Hence, it is imperative to screen these patients regularly for possible malignant transformation [10]. Late-onset RBs are usually unilateral [2, 11] and the occurrence of retinoma in the contralateral eye is extremely rare [11]. Kaliki et al. [3] reported 8 cases of newly diagnosed active RB in adults and found that patients were on average aged 30 years; all 8 patients had unilateral RB and had advanced RB (>group D). Masoomian et al. studied patients of a much younger age-group (average age 16.4 years) and found that 92% of these children had unilateral RB with only 1 patient having a contralateral retinoma and all of them having advanced RB (>group D) [11]. Our patient (aged 14 years) likewise had a group D lesion in the eye with active RB and the contralateral eye had 2 retinomas.

RB lesions are usually solitary or multiple solid whitish retinal masses resulting in the appearance of leukocoria in childhood RB. Some of the commonly considered differential diagnoses for whitish mass lesions in an adult ocular fundus include metastatic carcinoma, amelanotic melanoma, lymphoma, astrocytoma, and endophthalmitis (chorioretinal abscess). RB is rarely considered in such situations owing to its rarity after the first decade of life [12]. RB needs to be considered once the common causes are ruled out. Ultrasonography may not show characteristic calcification in late-onset RB, which is a classical finding in childhood RB [12]. In strongly suspected cases, genetic analysis, fine-needle aspiration cytology, and immunohistochemistry with neuron-specific enolase help in confirmation [13]. To our fortune, calcification was picked up on the ultrasound B scan at the initial evaluation of our patient, and the genetic testing confirmed the diagnosis of RB.

Treatment of late-onset RB depends on the size and location of the tumor, laterality, visual prognosis, threat of metastatic disease, and systemic status [13]. Considering the delayed presentation, advanced form of the disease, and recurrences, enucleation has been advocated in most of the cases of late-onset RBs [3, 11]. With the advent of newer modalities like TTT, intravitreal chemotherapy, and selective intra-arterial chemotherapy, globe salvage rates have tremendously increased in pediatric RBs. Our case also had advanced disease (group D in the right eye) with extensive vitreous seeds. Since there was no evidence of extraocular spread, we decided to proceed with systemic chemotherapy supplemented with local therapy (TTT and intravitreal topotecan) to aid in regression and stabilization of the tumor, and no recurrence was detected after more than a year of follow-up. Intra-arterial chemotherapy in combination with other local therapies can also be considered for recurrence in patients of late-onset RB [3]. In a case series of 8 patients with newly diagnosed active RB in adults, 3 patients had primary enucleation. Subsequently during follow-up, 2 patients in whom globe salvage therapy was opted as primary treatment required enucleation for recurrence [3]. Thus, our case also needs close follow-up to detect recurrence through serial fundus examinations, fundus photo documentation, and ultrasound B scan. For the left eye, cryotherapy was opted for the retinoma lesions as they were in the periphery and easily accessible with a cryotherapy probe. TTT is also a good option for such lesions, and TTT is associated with lesser chorioretinal scarring compared to cryotherapy. However, multiple treatment sessions might be needed with TTT [14].

Conclusion

Our case presents a rare presentation of bilateral late-onset RB with active RB in one eye and retinomas in the other eye. These tumors are often manifest at an advanced stage. Globe salvage in late-onset RB can still be achieved with careful ocular and systemic evaluation and utilization of all available modalities of treatment. However, long-term follow-up is needed in such cases for the detection of recurrence and appropriate management.

The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546983).

Statement of Ethics

This retrospective review of patient data did not require ethical approval in accordance with the guidelines of the institute’s Ethics Committee. Written informed consent was obtained from the father and assent from the child for the publication of the details of the medical case and accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Shreyas Temkar, Nirupama Kasturi, and Renu Puthenvilayil Rajan: clinical care, drafting of the text, and critical revision. Nirupama Kasturi, Amit Kumar Deb, Hemanth Ramachandar, and Krishna Murali: clinical care, data collection, sourcing, and editing of clinical images and investigation results. Shreyas Temkar, Nirupama Kasturi, Amit Kumar Deb, Hemanth Ramachandar, Krishna Murali, and Renu Puthenvilayil Rajan: final approval of the manuscript.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.