Abstract
Objective:
To report the clinical and imaging findings of four patients with benign intraretinal tumors, two of which were associated with retinal pigment epithelium (RPE) hypertrophy. To our knowledge this condition has not previously been described and should be distinguished from retinoblastoma and other malignant retinal neoplasms.
Design:
Retrospective case series
Participants:
Four patients from three institutions
Methods:
Four patients with intraretinal tumors of the inner nuclear layer underwent a combination of ophthalmic examination, fundus photography, fluorescein angiography, optical coherence tomography (OCT), OCT angiography, and whole exome sequencing.
Main Outcomes and Measures:
Description of multimodal imaging findings and systemic findings in four patients with benign intraretinal tumors and whole exome studies in three patients.
Results:
Six eyes of 4 patients ages 5, 13, 32 and 27 years were found to have white intraretinal tumors that remained stable over the follow-up period (range: 9 mo – 4 years). The tumors were unilateral in two cases and bilateral in two cases. The tumors were white, centered on the posterior pole, and multifocal with some consisting of multiple lobules with arching extensions that extended beyond the central tumor mass. OCT demonstrated these lesions to be centered within the inner nuclear layer (INL) at the border of the inner plexiform layer (IPL). In addition, two cases demonstrated congenital hypertrophy of the RPE (CHRPE) lesions. Three out of four patients underwent whole exome sequencing of the blood which revealed no candidate variants that could plausibly account for the phenotype.
Conclusions:
We characterize a novel benign tumor of the inner nuclear layer which in two cases were associated with separate CHRPE lesions. We propose the term Benign Lobular Inner nuclear layer Proliferation (BLIP) to describe these lesions.
Precis
We report a series of four patients with benign intraretinal tumors of the inner nuclear layer which may be associated with congenital hypertrophy of the retinal pigment epithelium.
INTRODUCTION
Retinal tumors arising from the intrinsic cell types of the neurosensory retina are rare and have different implications for prognosis and systemic associations.1 For example, retinal astrocytic hamartomas are typically benign and can be associated with tuberous sclerosis and neurofibromatosis.2, 3 In contrast, retinoblastoma is a malignant cancer thought to arise from cone precursors which presents as unilateral or bilateral retinal masses.4 Although large lesions are visible ophthalmoscopically, smaller lesions that are almost invisible to the eye can be detected on optical coherence tomography (OCT) as growths centered in the outer plexiform layer with variable invasion of the surrounding retinal layers.5, 6 Here we report the clinical and imaging findings of four patients with benign intraretinal tumors which to our knowledge, have not previously been described. In each case, these white intraretinal tumors are centered within the inner nuclear layer (INL) of the retina and in some cases associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE) lesions in the same eye.
METHODS
This study adhered to the tenets of the Declaration of Helsinki and was deemed exempt per 45 CFR46.104(d)(4) by the CHLA Institutional Review Board (CHLA-22–00207). Four patients with intraretinal tumors were identified from three institutions. These patients underwent complete ophthalmologic examination, fundus photography, OCT, and fluorescein angiography or OCT-A. Three of four patients underwent whole exome sequencing of the blood.
RESULTS
Six eyes of four patients ages 5, 13, 32, and 27 years were found to have white INL tumors that remained stable over the follow-up period (range: 9 mo – 4 years). The tumors were unilateral in two cases and bilateral in two cases. The tumors were white, centered on the posterior pole, and multifocal with some containing lobules with arching extensions. Two of the four patients also demonstrated grouped congenital hypertrophy of the RPE (CHRPE) lesions in separate, non-overlapping regions. The details of each case are described below.
Case 1
A 32-year-old female with past medical history significant for anxiety was referred for a macular lesion in the right eye discovered on routine examination. The uncorrected visual acuity was 20/20 in each eye. Anterior segment examination was unremarkable. Funduscopic examination of the right eye revealed white whorled lesions adjacent to the fovea extending temporally (Figure 1A). Funduscopic examination of the left eye was within normal limits. OCT showed hyper-reflective, multi-lobulated lesions connected by thin strands within the INL causing compression and distortion of the adjacent retinal layers (Figure 1B and 1C). OCT angiography demonstrated the lesions to be avascular, though with sufficient decorrelation artifact to appear hyper-reflective (Figure 1D). No changes in the lesion were observed with serial imaging and examination at follow-up two years since presentation.
Figure 1.
Multimodal imaging of the right eye of Case 1. A, Color fundus montage showing a collection of white intraretinal tumors located temporal to the fovea consisting of lobules with thin, arching extensions. B, SD-OCT line scan corresponding to the green dotted line in A, shows a homogenous, hyper-reflective lobular mass lesion compressing the adjacent outer retinal and inner retinal layers. A magnified inlay clearly shows the lateral extension of the tumor residing completely within the INL. C, En face structural OCT with slab through the INL again demonstrates the morphology of the tumor. D-E, OCT-A with slab through the INL shows no intrinsic vascularity, and no identifiably feeder vessels.
Case 2
A 5-year-old male was referred for an unusual macular lesion in the left eye. His medical history was significant for plagiocephaly with right coronal synostosis, left torticollis, and left facial nerve palsy. At six months, he underwent front orbital advancement and calvarial vault remodeling. At three years, he was diagnosed with refractive amblyopia of the left eye and began patching therapy. Upon referral for retinal evaluation at 5 years of age, the best-corrected visual acuity was 20/20 OD and 20/40 OS. Anterior segment examination was unremarkable. Funduscopic examination of the right eye was within normal limits, whereas the left eye revealed three white intraretinal parafoveal lesions (Figure 2A and B). In addition, the left eye had peripheral inferotemporal pigmented lesions consistent with CHRPE or “bear tracks” (Figure 2G). OCT of the left macula revealed hyper-reflective lobular lesions with arching extensions located within the INL causing distortion of the adjacent retinal layers (Figure 2E and 2F). A complete dysmorphology examination revealed no additional findings including skin lesions. In order to determine if there was a genetic basis for these findings and to identify potentially relevant syndromic tumor risk, the patient underwent trio whole exome sequencing of the blood in combination with his unaffected parents. No clinically significant variants were identified, including in the RB1, RBL1, RBL2, or APC genes. Over the course of a four-year follow up, no changes were observed in the INL tumor or the CHRPE lesions on serial examination and imaging.
Figure 2.
Multimodal imaging of Case 2. A, Color fundus photo of the right eye showing clinically normal appearing optic nerve, macula and vasculature. B, Color fundus montage of the left eye demonstrates a large, lobular appearing white intraretinal tumor superior to the fovea with subtle, arching lateral extension emanating from the nasal border. A second, round white lesion is present inferior to the fovea. A third lesion within the maculopapular bundle is difficult to observe because of the prominent ILM sheen. Multiple grouped CHRPE lesions are present within the inferotemporal quadrant. C, SD-OCT through the fovea of the right eye appears normal. D, SD-OCT through the fovea of the left eye demonstrates a normal foveal depression with a subtle linear hyper-reflective lesion extending from the nasal INL across the foveal center to the temporal INL. E-F, High magnification color images show the intraretinal masses in greater detail. The colored dotted lines correspond to SD-OCT line scans. E’, SD-OCT line scan through the lesion in E show two homogenous, round hyper-reflective masses compressing the adjacent retinal layers. These lesions are likely connected by a very thin extension adjacent to the IPL which is slightly hyper-reflective compared to the IPL. F’-F”’, Three SD-OCT line scans through the lesion shown in F show the tumor clearly located within the INL and causing varying degrees of compression to the adjacent tissue layers. G, OCT-A taken at the level of the superficial vascular plexus shows artifactual hyper-reflectivity within the tumors. H, En face structural OCT at the level of the intermediate vascular plexus highlights the morphology of the smaller tumor with thin linear extensions. The superior extension crosses the foveal plane, and can be seen in panel D. I-I’, Magnified color images of the grouped CHRPE lesions and corresponding SD-OCT showing typical findings of CHRPE.
Case 3
An asymptomatic 14-year-old male was referred for evaluation of multiple retinal lesions in both eyes. His past medical history was significant for an accessory navicular bone of the left foot and spondylolisthesis at the S5/L1 vertebrae. Uncorrected visual acuity was 20/20 in both eyes. Anterior segment examination was unremarkable. Funduscopic examination of both eyes revealed multiple white intraretinal lesions and scattered CHRPE lesions in both eyes. These lesions were present in the posterior pole and retinal periphery of the right eye, and posteriorly only in the left (Figure 3A). OCT through the intraretinal lesions of the right eye showed a hyper-reflective lesion within the INL, consisting of multiple interconnected lobules with extensions and intermittent compression of the adjacent retinal layers (Figure 3D and E). OCT through the intraretinal lesions in the left eye showed similar but smaller lobulated and hyper-reflective lesions within the INL. Fluorescein angiography showed blocking from the CHRPE lesions, and the intraretinal lesions were avascular without leakage (Figure 3C and D). A complete dysmorphology examination was externally normal. Trio whole exome sequencing of blood was performed which revealed compound heterozygous variants in the VPS13B gene (VPS13B NM_017890.4:c.11467+1G>T, p.? and VPS13B NM_017890.4: c.10615T>C, p.Tyr3539His). Pathogenic variants have been associated with Cohen syndrome, a highly variable genetic disorder associated with hypotonia, truncal obesity, intellectual disability, dysmorphic facial features and severe retinal dystrophy leading to significant vision loss. These features were not identified on clinical exam and the c.10615T>C variant was interpreted as a variant of uncertain significance. There were no pathogenic variants identified in the RB1, RBL1, RBL2, or APC genes. During 9 months of follow-up, no changes were observed with serial examination and imaging.
Figure 3.
Multimodal imaging of Case 3. A, Widefield pseudocolor photography of both eyes showing a white intraretinal tumor involving the fovea and superior macula consisting of lobules with thin extensions in the right eye. Superonasally, there are multiple lobular areas of retinal whitening corresponding to lesions similar to those in the macula. In addition, there are numerous CHRPE lesions of different sizes seen in both eyes, predominately in the right eye. B, Widefield fundus autofluorescence of both eyes showing hypoautoflourescence corresponding to the areas of CHRPE lesions in both eyes. C, Midphase widefield fluorescein angiography of both eyes shows areas of blocked florescence corresponding to the areas of CHRPE lesions in both eyes. D, SD-OCT testing through the fovea of the right eye show multiple temporal homogenous, hyper-reflective lobular lesions residing in the INL compressing the adjacent outer retinal and inner retinal layers, including the RPE. E, SD-OCT testing through the lesion at the superior macula of the right eye shows a homogenous, hyper-reflective INL mass lesion compressing the adjacent outer retinal and inner retinal layers. F, Higher magnification SD-OCT line scans through the lesion shown in panel D (green bar) and E, (orange bar) show the tumor clearly located within the INL and causing varying degrees of compression to the adjacent tissue layers.
Case 4
A 27-year-old female presented for evaluation of atypical bilateral macular findings and subjective paracentral scotomata. Her past medical history was significant for type 2 diabetes, chronic headache, fibromyalgia, polypectomy for large villous colon polyp, wandering atrial pacemaker, Hashimoto’s disease, joint hypermobility, asthma, and polycystic ovarian syndrome. Corrected visual acuity was 20/25+ OD and 20/20− OS with decreased stereo acuity, but normal color vision and automated visual field testing. Anterior segment examination was unremarkable. Fundoscopic examination revealed bilateral gray-white intraretinal reticular lesions throughout both maculae (Figure 4). Widefield fluorescein / indocyanine green angiography and fundus autofluoresence were unremarkable. OCT revealed discrete homogeneous hyper-reflective lesions within the INL and grade 1–2 fovea plana. OCT angiography revealed absence of the foveal avascular zone and en face OCT highlighted the reticular INL lesions. An inherited retinopathy panel of 942 nuclear genes, hereditary cancer panel of 56 genes, and mitochondrial genome testing of the blood revealed several variants of uncertain significance including BMP4 c.1141A>G (p.Ile381Val), CRB1 c.29T>C (p.Leu10Pro), TENM3 c.4406C>T(p.Ala1469Val), TRNT1 c.667A>G (p.Ile223Val), MT-TP m.15976T>C (2% heteroplasmy), none of which were deemed to be explanatory of her features. In addition, PAX6 sequencing and whole exome sequencing of the blood were unremarkable. These findings have remained stable over 15 months of follow-up.
Figure 4.
Multimodal imaging of Case 4. A-B, Color fundus photo of the right and left eye shows subtle gray-white intraretinal reticular lesions composed of linear extensions criss-crossing the posterior pole. C-D, En Face structural OCT highlights the web-like morphology, and accompanying OCT-A deep retinal slab demonstrates absence of the foveal avascular zone and avascularity of the INL lesions. E-F, SD-OCT shows the tumors localize and extend throughout the INL. Note the absence of a normal foveal depression and central preservation of inner retinal layers. G-H, Combination fluorescein and indocyanine green angiography are unremarkable except for the reduced size of the foveal avascular zones. I-J, The tumors are silent on fundus autofluorescence and without associated RPE lesions.
DISCUSSION
There are only three previously described tumors arising from the intrinsic cells of the neurosensory retina: retinoblastoma (and retinocytoma), retinal astrocytoma, and astrocytic hamartoma.1, 7 In this cases series, we present four patients with apparently benign tumors of the INL that appear to be distinct from any previously described tumor type. The tumors did not exhibit any growth, or invasive features, and were identified in patients as young as 5 years old. They may occur in the absence of any other fundus abnormality; however, two of the four cases presented with separate grouped CHRPE lesions which may support the notion that these patients are predisposed to the development of both lesion types. Because the tumors are benign, lobular, and centered within the inner nuclear layer, we have proposed the descriptive term Benign Lobular Inner Nuclear Layer Proliferation (BLIP).
All patients were children or young adults with tumors discovered incidentally on fundus examination. The majority were asymptomatic, with one patient (Case 2) having coexisting refractive amblyopia in the involved eye, and one patient having decreased stereopsis (Case 4). No patient developed worsening visual symptoms, and no tumor grew or invaded adjacent structures in follow-up ranging from 9 months to 4 years. This stability over time may suggest that the tumors are congenital. In support of this, Case 4 had associated fovea plana with tumors in the fovea that may have precluded normal foveal development. Funduscopically, BLIPs demonstrate several morphologies. Larger lesions appear as smooth, white-opaque masses comprised of multiple lobules connected by thin arches. Smaller round lesions sometimes demonstrated thin extensions. Case 4 was the least similar with a reticular pattern of interlacing strips in the posterior pole. The tumors show a predilection for the posterior pole but were also present in the mid-periphery in Case 3. Fluorescein angiography and OCT angiography demonstrated a lack of feeder vessels and no intrinsic vascularity. Together, these features suggest the tumors are almost certainly benign.
The presence of multiple lesions in all four cases in the absence of tumor growth suggests each tumor likely arose independently, rather than through a seeding or spreading event. If the individual lesions developed independently from one another, this would suggest a predisposition to tumor formation in these patients. This hypothesis is bolstered by the fact that two patients with BLIPs also presented with multiple CHRPE lesions in the same eye. This may suggest an underlying disorder predisposing to both distinct posterior segment lesions. To investigate the possibility of an underlying genetic cause, whole exome sequencing of the blood was performed in cases 2, 3, and 4 which revealed no variants in RB1, APC, or any other genes known to predispose individuals to tumor formation. Notably, this testing does not exclude somatic mosaicism, and due to the benign nature of the lesions, the tissue was not biopsied.
The OCT features of BLIP demonstrate homogenous, hyper-reflective masses similar in reflectivity to the adjacent plexiform layers. There are no significant shadowing artifacts, optically empty spaces, or findings to suggest intralesional calcification. As suggested by their funduscopic appearance, OCT confirms these tumors consist of round lobules connected by thin lateral extensions. The round lobules variably compress adjacent retinal layers, and in these locations, it can be difficult to differentiate the border of the tumor from the adjacent plexiform layer. However, the thin extensions emanating from these lobules clearly reside within the INL (Figure 1B), which suggests these tumors arise from a cell type within the INL. To our knowledge, no other benign tumor has been described that consistently resides completely within the INL. Furthermore, the OCT features of other known intraretinal tumors have been well described.1 For example, retinal astrocytic hamartoma has been shown to arise within the nerve fiber layer and contain optically empty spaces.2, 8 The OCT features of our cases are unique among previously described entities, and no OCT features specific to any other benign retinal tumors were identified.
OCT of small retinoblastoma tumors have been described as lesions of both the INL and ONL. Welch et al. previously described OCT findings in sub-millimeter retinoblastomas where the majority of tumors were found within the INL.6 Berry et al, however, have described ONL-based tumors which extend into the OPL and ONL, but the retina layers tend to drape off the main nodular lesion, which the authors conclude meant origination in the ONL.9 As retinoblastoma lesions are infrequently monitored without treatment there is little known about their growth patterns. However, reports describe splaying of the inner INL around the lateral margins of the tumor as it expands horizontally, and folding of the ONL and OPL as the tumor expands to compress the outer retinal layers, called the “fish tail” and “shark fin” signs.6 Although the INL tumors described here share no other clinical features of retinoblastoma, we observed similar, though less dramatic “fish tail” and “shark fin” signs (Figure 3F” and Figure 2E’). It is likely that the tumors in our patients arose within the INL and followed a similar pattern of growth, but without invasion of adjacent layers. The “fish tail” and “shark fin” signs therefore may not be unique to any specific small retinal tumor, and instead may be seen in any tumor growing within the INL. Because the INL is comprised of the cell bodies of bipolar cells, amacrine cells, horizontal cells, Müller cells, and astrocytes, we suspect the masses described here originate from one or multiple intrinsic retinal cell types.10 Although the clinical and imaging features share no features with astrocytic hamartoma, the possibility of a novel subtype of astrocytic hamartoma arising from peri-vascular astrocytes within the INL cannot be excluded.
To our knowledge, no tumor originating from any of these cell types has previously been described in humans. However, Chen et al and MacPherson et al demonstrated the development of amacrine cell tumors in combined Rb1 and retinoblastoma-like protein 1 (Rbl1) knockout mice and in combined Rb1 / Rbl2 knockout mice.11, 12 Interestingly, mice with Rbl1 and Rbl2 loss also showed skeletal limb and skull abnormalities.13 While none of our patients had congenital limb deformities, the two pediatric cases described did each have separate bony malformations. Case 2 had a history of plagiocephaly secondary to coronal synostosis which required surgery at 6 months. Case 3 was diagnosed with an accessory navicular bone in the foot and spondylolisthesis of L5/S1, neither of which required intervention. None of these abnormalities are rare in the general population; however, isolated cranial synostosis is estimated to occur in 1 out of every 2500 live births, and the vast majority of cases are nonsyndromic.14 Accessory navicular bones occur in up to 21% of the general population and typically have no clinical relevance.15 Likewise, pediatric lumbar spondylolisthesis may affect up to 7% of adolescents.16 It is unclear if these abnormalities are related to the retinal tumors described.
In summary, we have presented four cases of benign tumors of the INL, which to our knowledge have never previously been described or characterized in the literature. These tumors may be congenital and feature unique funduscopic and imaging characteristics distinct from retinoblastoma and astrocytic hamartoma. Our case series demonstrates that affected patients may present with multiple unilateral or bilateral INL tumors. A portion of these patients with multiple tumors also had ipsilateral CHRPE lesions. The presence of two distinct types of posterior segment tumors in the same eye may suggest a predisposition to both types of lesions. We propose the term Benign Lobular Inner nuclear layer Proliferation (BLIP) to describe these lesions which may present with or without CHRPE lesions. We recognize that this study is limited by the small number of cases described and lack of histopathological specimens to definitively characterize these tumors. Additional studies with more patients are therefore necessary to further characterize the features, natural history, and potential associations.
Financial Support:
This study was supported in part by an unrestricted grant to the Department of Ophthalmology at the USC Keck School of Medicine from Research to Prevent Blindness (JLB, DC, AN), NIH K08EY030924 (AN), the Las Madrinas Endowment in Experimental Therapeutics for Ophthalmology (AN), a Research to Prevent Blindness Career Development Award (AN), and a Knights Templar Eye Foundation Endowment (SH, JLB, DC, AN).
Footnotes
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Disclosures: MJ: Consultant, Speaker for Regeneron, Genentech; AN: Consultant for Biogen, Novartis, Atsena, Eyebiotech, and Janssen. The other authors have no disclosures.
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