Retinoblastoma and Persistent Fetal Vasculature in the Same Eye: Case Report

Retinoblastoma is the leading differential diagnosis for leukocoria in pediatric patients, posing a direct life-threatening risk. It is the most common intraocular neoplasm in this age-group, affecting 1 in 16,000–18,000 live births. Its genetic cause involves RB1 tumor suppressor gene mutation, occurring germinally or somatically. Germline mutations account for 1/3 of cases, often presenting bilaterally in the first year. Somatic mutations make up 2/3, typically unilateral and diagnosed later, between 2 and 5 years [1].

Fetal vasculature persistence predominantly occurs sporadically and unilaterally, with no known genetic association. It occurs due to failed fetal vitreous conversion and shows variable clinical signs (Mittendorf’s dot, Bergmeister’s papilla), sometimes links to systemic conditions (trisomy 13, Walker-Warburg, Norrie disease) [2, 3]. The association of both pathologies in a single eye is a rare event reported only a few times in the literature, with different etiologies at first, and sometimes reported as mutually exclusive pathologies since retinoblastoma would occur in eyes of normal to increased axial length when associated with infantile glaucoma, while persistence of the fetal vasculature would affect microphthalmic eyes [4‒7].

A 2-year-old girl, referred by the pediatric oncology team, has exhibited fixed convergent strabismus in her left eye for the past 4 months, with an altered red reflex noted 2 months after the onset of strabismus. Initial examination showed preserved visual acuity in the right eye, while the left eye retained only light perception. She exhibited 10° esotropia by the Hirschberg test, with a formed anterior chamber and clear lens showing iris neovascularization in the lower periphery. Biomicroscopy identified a yellow retrocrystalline lesion with whitish dots, suggestive of calcification and hemorrhage, obstructing fundoscopic view in the left eye. The right eye appeared normal on examination (Fig. 1a, b).

The patient was born in São Paulo, Brazil, at 39 weeks via vaginal delivery without needing extra oxygen. Prenatal care was uneventful, and there were no issues in the red reflex test at birth. There is no family history of retinoblastoma or other eye diseases. On weekends, the patient visits a rural property and interacts with animals but has not been around puppies since birth.

Laboratory tests were normal, including negative serology for Toxocara canis. Ocular ultrasound of the left eye showed reduced axial length (19 mm), a hyperechogenic septal lesion connecting the papillary to the retrocrystalline region, hyperechogenic punctate lesions with posterior acoustic attenuation indicating calcification in the retrocrystalline area, posterior tented retinal detachment with peripapillary retina adhered to the septal structure causing traction, and subretinal punctate echoes suggestive of cellular material (Fig. 1c). Doppler examination identified internal flow within the intraocular septal structure (Fig. 1d).

MRI reveals retrolental septal structure with intermediate T1 signal, low T2 signal, contrast enhancement, and subretinal cellular material indicating hemorrhage. Bilateral optic nerves show preserved diameter and signal (Fig. 1e).

The patient’s initial diagnosis was group E retinoblastoma with the presence of neovessels in the anterior segment. The decision was made to perform enucleation surgery on the left eyeball with reconstruction using a dermoadipose graft to treat the patient.

Anatomopathological examination (Fig. 2, 3) revealed retinoblastoma cells with mixed growth pattern and G2 histological differentiation, characterized by Homer-Wright and Flexner-Wintersteiner rosettes. The tumor exhibited 30% necrosis and 1% calcification, along with vitreous seeds and involvement of the optic nerve in its prelaminar and laminar portions. Additionally, the examination identified capillaries and larger vessels in the retrolental area, tumor embolization extending to the optic papilla, and traction effects on the ciliary processes and adjacent retina, indicative of retinal dysplasia consistent with persistent fetal vasculature (PFV). Immunohistochemistry was negative for glial fibrillary acidic protein (GFAP).

Following the histopathological examination of the left eye, which revealed laminar invasion by retinoblastoma, a decision was made to initiate six cycles of intravenous chemotherapy. The treatment regimen included vincristine, etoposide, and carboplatin.

Leukocoria in pediatric patients should prompt ophthalmologists to initially consider retinoblastoma as the primary differential diagnosis, given its significant threat to life. During diagnostic evaluation, detecting intralesional calcium is crucial, prevalent in up to 85% of retinoblastomas [8]. While in acute cases of persistence of fetal vasculature, Coats disease, and ocular toxocariasis the presence of intraocular calcium is not an expected finding, but rarer neoplasms such as medulloepithelioma and retinocytoma may also present some degree of calcification [3].

Ocular ultrasound is highly sensitive (91–95%) for detecting intralesional calcium, though sensitivity may decrease in cases with retinal detachment or vitreous hemorrhage [9]. Computed tomography offers high sensitivity for detecting intralesional calcification. Still, it is not recommended for patients with suspected retinoblastoma due to concerns about exposure to ionizing radiation without genetic status being known. MRI, although less sensitive in routine image acquisition sequences for identifying intralesional punctate calcifications, has acquisition sequences weighted in magnetic susceptibility that can assist in the objective, such as T2*WI or SWI [3].

PFV is often present in pediatric patients with leukocoria, typically with microphthalmia and a persistent hyaloid artery. The hyaloid artery can be identified as a fibrovascular tissue that connects the papillary region to the retro-crystalline region, forming in this region a mass that can have a tractional effect on the peripheral ocular wall, retina, and ciliary processes in a centripetal direction to the visual center, whether or not be associated with cataracts [2].

The hyaloid artery can be seen directly if the visual axis is clear. Ultrasound may show a septal formation linking the optic disc to the lens with medium-high heterogeneous echogenicity. Doppler may or may not show blood flow, depending on the involution of the fetal vasculature. MRI may reveal a tubular or funnel-shaped structure in the Cloquet canal with hypersignal on T1- and T2-weighted sequences and gadolinium enhancement, indicating blood flow.

In Brazil, the red reflex test is mandatory for all newborns before discharge from the maternity ward. The Brazilian Society of Pediatric Ophthalmology also recommends that it be repeated during well-child visits within the first year of life. In this patient’s case, the test was performed in the maternity ward with a normal result. It is known that PFV can present with a range of clinical manifestations, sometimes with subtle signs that make detection, diagnosis, and screening challenging. Nevertheless, it is essential to emphasize the importance of systematic red reflex screening in children to enable the early diagnosis of various ocular pathologies, including retinoblastoma. In our patient’s case, early diagnosis might have prevented the need for enucleation and systemic chemotherapy.

Despite the distinct etiologies of retinoblastoma and the persistence of the fetal vasculature and its simultaneous occurrence, initially occurring randomly, it is valid to question the influence of the neoplasia’s vasogenic factors on the process of natural involution of the fetal vasculature, especially in cases of clinical emergence during the gestational period. Another question that we need to keep in mind is whether the presence of embolic tumor invasion of these vessels could lead to an increase in the risk of metastatic lesions to the point of justifying the need for complementary treatment with intravenous chemotherapy [10].

The concomitant presence of retinoblastoma and persistence of the fetal vasculature in the same eye is an uncommon event. A careful multimodal assessment is important in cases of leukocoria in pediatric patients as pathologies can overlap, making correct diagnosis difficult. Furthermore, the differential nosological entity is crucial as each has different treatments and managements. 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/10.1159/000542987).

This study protocol was reviewed and approved by Comitê Nacional de ética em Pesquisa (CONEP) (Approval No. 6.944.368). Written informed consent was obtained from participants parents for publication of the details of their medical case and accompanying images.

The following authors have no financial disclosures: F.B., L.G.C., P.P., P.V.A.S., and M.T.B.C.B.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Felipe Baccegea, Laura Goldfarb Cyrino, Patricia Picciarelli, Paulo Vigga Alves e Silva, and Maria Teresa Brizzi Chizzotti Bonanomi contributed to the conceptualization, investigation, data curation, and writing and revising this case report.

The authors confirm that the data supporting the findings of this study are available within the article. Further inquiries can be directed to the corresponding author.