PMC9379252_01
(A) Fundus examination of the right eye of patient 1 revealed a large white dome-shaped retinal tumor in the inferonasal quadrant with feeding vessels and a few vitreous cellularities. (B) On fundus fluorescein angiography (FA), multiple areas of the tumor displayed mottled hyperfluorescence in the early phase and hyperfluorescence with intense leakage in the late phase. On indocyanine green angiography (ICGA), the tumor showed hypofluorescence during all stages. (C) Color Doppler imaging (CDI) revealed a pedunculated mass with inconsistent reflectivity of moderate-intensity and no choroidal excavation, as well as arterial blood signals in the tumor. The size of the elevated lesion was 5.2 x 3.9 x 5.9 mm3. (D) Optical coherence tomography (OCT) revealed that the tumor had a sloped dome-shaped elevation, with a hyperreflective anterior surface and vitreous seeds, and normal macular fovea. (E) MRI revealed that the tumor was far from the optic nerve in the right globe, demonstrating a slightly higher hyperintensity (arrow) than vitreous in (a) axial T1-weighted MRI, hypointensity (arrow) in (b) axial T2-weighted MRI, and moderate enhancement of the tumor in axial contrast-enhanced T1-weighted, fat-saturated MRI. (F) At the last follow-up 15 months after the last combination treatment, the retinoblastoma demonstrated complete regression into a partially calcified scar. (G) One day after IV-Melphalan, intravitreal melphalan-hemorrhagic retinopathy toxicity occurred. (H) The patient showed signs of iris atrophy and eventually developed phthisis bulbi.
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A dilated fundus examination of the right eye detected a white mass with feeding vessels located in the inferonasal peripheral fundus, which was surrounded by a few vitreous cellularities ( Figure 1A ). In contrast, the indocyanine green angiography (ICGA) showed hypofluorescence at all stages ( Figure 1B ). The patient underwent color Doppler imaging (CDI), which revealed a pedunculated mass with moderately inconsistent reflectivity and no choroidal excavation, as well as arterial blood signals in the tumor and no obvious calcification ( Figure 1C ). Optical coherence tomography (OCT) revealed that the tumor had a sloped dome-shaped elevation with a hyperreflective anterior surface and vitreous seeds, as well as normal fovea horizontally and vertically ( Figure 1D ). MRI showed the right globe with the tumor located far from the optic nerve, demonstrating a slight hyperintensity (arrow) than vitreous in axial T1-weighted MRI, hypointensity (arrow) in the axial T2-weighted MRI, and moderate enhancement of the tumor in the axial contrast-enhanced T1-weighted, fat-saturated MRI ( Figure 1E ). At the last follow-up, which was 30 months following initial presentation and 15 months since last treatment, the RB completely regressed into a partially calcified scar, with complete resolution of intravitreal seeds and no evidence of tumor recurrence ( Figure 1F ). However, exudative retinal detachment, choroidal detachment, and preretinal hemorrhage had occurred ( Figure 1G ), which were due to toxicity of intravitreal melphalan-hemorrhagic retinopathy. The patient ultimately developed phthisis bulbi ( Figure 1H ) but refused to be enucleated.
PMC9379252_02
(A) Fundus examination of patient 2 revealed a circumscribed, nodular, white lesion of the retina located in the peripheral quadrant, which was associated with tortious feeding vessels and subretinal yellow-white deposits. (B) The lesion was 4.3 mm thick and its largest basal diameter was 6.8 mm, as measured by CDI. (C) SS-OCT revealed multifocal, punctate, or spot subretinal lesions with medium- to hyper-reflectivity involving the lamina cribrosa and the surrounding of the optic nerve, as well as the spot lesions corresponding to subretinal tumor cells in pathological findings. (Green Triangle: superficial retinal detachment; Red Pentagram: tumor cell cluster; Yellow triangle: damaged photoreceptor cell layer and suspended tumor cells; Red triangle: discrete subretinal tumor cells; Blue triangle: tumor cells are implanted in the vitreous cavity; (D) Enucleation was performed and pathological findings revealed no infiltration in the optic nerve head and the sclera. Green Triangle: inner limiting membrane; Red Pentagram: tumor cell cluster; Yellow triangle: damaged photoreceptor cell layer and suspended tumor cells; Red triangle: discrete subretinal tumor cells; Blue triangle: tumor cells are implanted in the vitreous cavity; White pentagram: suspended tumor cell cluster; tumor cell clusters around the optic nerve, subretinal (yellow pentagram) and epiretinal (green pentagram).
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Ophthalmoscopic examination of the right eye revealed a circumscribed, nodular, white lesion of the retina located in the peripheral quadrant, coupled with tortuous feeding vessels and diffused subretinal yellow-white deposits ( Figure 2A ). The lesion was 3.2 mm thick and its largest basal diameter was 5.6 mm, as measured by CDI ( Figure 2B ). Swept source-optical coherence tomography angiography (SS-OCT, VG200D, SVision Imaging, Ltd., China, central wavelength: 1050nm; transverse resolution: 15mum [optical]; longitudinal resolution: 5mum [optical]); B-scan revealed that the multifocal subretinal lesions displayed medium- to hyper-reflectivity and exudative retinal detachment involving the macular ( Figure 2C ). Notably, similar punctate lesions with medium to high reflectivity, such as subretinal deposits observed on the lamina cribrosa, as well as around and within the optic nerve, were observed ( Figure 2C ). Figure 2D ). Furthermore, the subretinal tumor cell clusters shown by pathology corresponded to the multifocal subretinal lesions shown by SS-OCT ( Figure 2C ).
PMC9379252_03
(A) In the fundus of the right eye of patient 3, there was a white, dome-shaped lesion of the retina in the inferotemporal fundus, with fine vitreous hemorrhage. The central portion appeared nodular and fibrotic with subtle tortuous retinal vessels. The vitreous seeds were unclear. (B, C) Pathology and immunohistochemistry results revealed the foci of (B) Flexner-Wintersteiner rosettes that were (C) S100 positive. (D) In the last follow-up, the retina was well-attached and there was slight proliferation in the defect area of the retina.
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The mass was found in the inferotemporal fundus, and the peripheral portion of the lesion was flat, while the central portion appeared nodular and fibrotic with subtle tortuous retinal vessels, as well as associated radial macular traction ( Figure 3A ). The findings revealed the foci of Flexner-Wintersteiner rosettes, confirming the diagnosis of RB in adults ( Figures 3B, C ). Figure 3D ). Furthermore, there was no tumor-related metastasis or death.
PMC9379252_04
(A) The peripheral portion of the lesion in patient 4 was flat and white, while the central portion was elevated. Fine retinal vessels on the surface were observed. (B, C) Pathology and immunohistochemistry results revealed the foci of (B) Flexner-Wintersteiner rosettes that were (C) NSE positive. (D) In the last follow-up, the retina was well-attached and there was slight proliferation in the defect area of the retina.
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The peripheral portion of the lesion was flat and white, but the central portion was elevated, with fine retinal vessels on the surface ( Figure 4A ). The patient had local resection using a 23-gauge micro-invasive vitrectomy, and immunohistochemistry results revealed Homer-Wright rosettes and occasional fleurettes, with positive neuron-specific enolase ( Figures 4B, C ). Figure 4D ). Furthermore, there was no tumor-related metastasis or death.
PMC9379252_05
(A) In patient 5, there was a white, circumscribed lesion of the retina located in the superotemporal peripheral fundus, with retinal exudation and subretinal fluid in the left fundus. The feeding retinal arteriole and venule of the tumor were minimally dilated and convoluted. There was a mild, focal retinal hemorrhage on the nasal aspect of the lesion with no vitreous seeds. (B) Photomicrograph revealed the foci of Flexner-Wintersteiner rosettes. (C) In the last follow-up, the retina was well-attached and there was slight proliferation in the defect area of the retina.
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Figure 5A ). Fluorescein angiography revealed that the mass was nonfluorescent with a trace of overlying retinal hyperfluorescence in the late frames. The patient had local resection using a 20-gauge vitrectomy, and immunohistochemistry results revealed rosette formation and areas of extensive necrosis, but there were no calcific foci ( Figure 5B ). Figure 5C ). Furthermore, there was no tumor-related metastasis or death.
PMC9379252_06
(A) In patient 6, there was a white, circumscribed lesion of the retina in the superotemporal peripheral fundus, with tortious seeding vessels, retinal exudation, and subretinal fluid in the left fundus. Significant vitreous seeds were observed. (B) The slit lamp microscope showed significant tumor seeds floating in the vitreous cavity. (C) The SS-OCT B-scan revealed local exudative retinal detachment surrounding the tumor, as well as subretinal deposition spots with medium to high reflectivity without involving the macular. (Green Triangle: outer limiting membrane; Red Pentagram: tumor cell cluster; Yellow triangle: damaged photoreceptor cell layer and suspended tumor cells; Red triangle: discrete subretinal tumor cells; Blue triangle: tumor cells are implanted in the vitreous cavity; White triangle: superficial retinal detachment) (D) Three months after I-125 plaque brachytherapy, the tumor showed a reduction in size, resolution of subretinal fluid, normalization of the caliber and decrease in the tortuosity of feeding and draining vessels.
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The feeding retinal arteriole and venule of tumor were both minimally dilated and convoluted, with significant vitreous seeds ( Figure 6B ). The mass was 4.8 mm thick and its largest basal diameter was 13.7 mm, as measured by CDI. SS-OCT B-scan revealed a local exudative retinal detachment surrounding the tumor, as well as subretinal deposition spots with medium to high reflectivity, not involving the macular ( Figure 6C ). We then performed I-125 plaque brachytherapy, which resulted in tumor reduction 3 months later ( Figure 6D ) and stable visual acuity.