Subretinal Exudation: The First Presentation of Untreated Choroidal Melanomas

Abstract

Introduction

This case series aims to present the unusual clinical manifestation of subretinal exudation in patients diagnosed with untreated choroidal melanoma. A total of 886 patients were diagnosed and treated for primary choroidal melanoma between November 2017 and June 2023 at St. Paul’s Eye Unit, Royal Liverpool University Hospital, UK. The fundus photographs were screened for lipid exudates by two independent clinical experts. The patients’ demographics, clinical manifestations, and imaging features were analysed, whereas the location of exudation was documented with fundus photographs and optical coherence tomography (OCT). The histopathological and genetic results were also analysed in cases with tumour biopsy available.

Case Presentations

Eight cases with subretinal exudates were identified (n = 8/886, 0.90%). No gender predilection was noticed (male/female 1:1), whereas the mean age was 51 years (range 39–79). Four patients were asymptomatic at presentation, 2 patients reported reduced visual acuity, and 2 patients presented with photopsia. OCT scans revealed the presence of subretinal fluid and subretinal exudates, while the ultrasound showed medium or low internal reflectivity in 7 out of 8 cases. The biopsy analysis was available in 4 cases, all showing low-risk spindle cell choroidal melanoma with disomy 3.

Conclusion

Lipid exudates are an atypical fundoscopic finding in patients with untreated choroidal melanoma. The subretinal location could differentiate them from other retinal vascular conditions and facilitate early diagnosis and intervention. Interestingly, all cases tested cytogenetically were of low metastatic risk; these exudates may, therefore, be a positive clinical prognostic sign.

Introduction

Uveal melanoma is the most frequent primary intraocular tumour in the adult population, with the age-adjusted incidence being 5.1 per million [1]. The choroid is the most common presentation site, with approximately 85% of cases located posterior to the equator [2]. A unilateral dome-shaped elevated lesion with a greyish-brownish colour and irregular margins arising from the choroid is the common fundoscopic appearance of choroidal melanoma. However, non-pigmented choroidal melanomas appear at approximately 15%. Subretinal fluid and lipofuscin at the retinal pigment epithelium (RPE) level appeared as an orange pigment are some frequent fundoscopic characteristics [3, 4].

Hard exudates do not represent a typical fundoscopic feature in untreated choroidal melanomas, although it is more common after radiotherapy treatment [5]. They consist of yellow-white lipid and proteinaceous deposits with indistinct margins related to excessive vascular permeability from damaged capillaries and leakage into the extracellular space; the role of retinal ischaemia and the subsequent vascular endothelial growth factor (VEGF) release in vascular abnormalities, angiogenesis induction, and vascular permeability has been well investigated in the literature [6]. Exudates are primarily deposited within the outer plexiform retinal layer in diseases such as diabetic or hypertensive retinopathy, Coat’s disease, retinal macroaneurysm, retinal capillary haemangiomas, and choroidal neovascularisation.

In the literature, very few isolated case reports provide insight into this clinical finding and mention retinal exudation as one of the presenting clinical manifestations of untreated uveal melanomas [7–10]. The aim of this case series was to highlight the presence of the subretinal exudates as an uncommon fundoscopic appearance in patients with primary untreated choroidal melanoma. The awareness of this rare clinical manifestation could contribute to reducing confusion in the early diagnosis of these tumours.

Case Report

A retrospective analysis of images of 886 patients diagnosed with choroidal melanoma was conducted at the Liverpool Ocular Oncology Centre between November 2017 and June 2023. The fundus photographs and optical coherence tomography (OCT) scans were screened for hard exudates, with eight cases being identified (Table 1). The demographic information, the ophthalmic history, and the clinical findings, such as symptoms, best-corrected visual acuity (VA), and tumour location, were extracted from the electronic medical records. The ultrasound and OCT findings were also recorded from all cases. In patients who underwent tumour biopsy or enucleation, the histopathological features were evaluated following cytospin preparation and May-Grunewald-Giemsa staining. The genetic analysis was conducted by microsatellite analysis (MSA) and/or multiplex-ligation-dependent probe amplification. The data collection was conducted in accordance with the Declaration of Helsinki.

Table 1.

Case series of untreated choroidal melanomas presented with subretinal exudation

	Age/sex	Eye	PMHx/POHx	Presenting VA	Final VA	Presenting symptoms	Location	SRF/IRF	U/S	OCT	Primary treatment	Histology genetics	Complication treatment
Case 1	39/M	RE	Unremarkable	6/4	6/18	Shadow in the visual field	SN	+	Medium reflectivity	Intraretinal and subretinal foci	Ruthenium plaque and transretinal biopsy	Spindle cell	Radiation maculopathy
									No Doppler				Anti-VEGF
									5.5 × 4.5 (3.0) mm	Subretinal exudates		Disomy 3 (MSA)
Case 2	52/F	RE	Spondylarthritis	6/7.5	6/7.5	Asymptomatic	SN	+	Low-medium reflectivity	Subretinal exudates	Ruthenium plaque and trans-scleral biopsy	Spindle cell	–
									Positive Doppler			Disomy 3
			Thyroid Cancer						11.98 × 10.78 (5.36) mm			(MLPA and MSA)
Case 3	47/F	LE	Unremarkable	6/6	N/A	Asymptomatic	Temporal to the macula	+	Low-medium reflectivity	Subretinal exudates	Ruthenium plaque	N/A	–
									7.58 × 7.60 (4.71) mm
Case 4	47/M	RE	Unremarkable	6/6	6/9	Asymptomatic	ST	+	Low reflectivity	Subretinal exudates	Ruthenium plaque	N/A	Radiation maculopathy
													Anti-VEGF
Case 5	41/M	LE	LE oculodermal melanosis	6/18	N/A	VA decrease	IT	+	Low reflectivity	Diffuse posterior pole exudates	Proton beam radiotherapy and transretinal biopsy and anti-VEGF	Spindle cell	Increased intraocular pressure
			LE CSCR						Positive Doppler				Vitreous haemorrhage
			RE amblyopia						10.77 × 8.66 (5.34) mm	Asteroid hyalosis		Disomy 3 (MSA)	Antiglaucoma drops
Case 6	55/F	RE	POAG	6/9	6/15	Asymptomatic	ST	+	Medium reflectivity	Subretinal haemorrhage and exudates	Proton beam radiotherapy	N/A	Radiation maculopathy and retinopathy
									10.67 × 9.54 (3.42) mm	Pigmented retinal infiltration			Pigmented vitreous infiltrates Ocular surface problems
Case 7	49/F	LE	LE choroidal naevus	6/6	6/7.5	Photopsias	Inferior juxtapapillary	+	Low reflectivity	Subretinal material and exudates	Proton beam radiotherapy	N/A	–
			Endometriosis
			Migraine						4.8 × 4.3 (1.42) mm
Case 8	79/M	LE	Hypertension	6/30	NLP	VA decrease, photopsias, floaters	S	+	Variable reflectivity	Retinal infiltration	Enucleation	Spindle cell	–
									(Apex medium-high, base medium-low)	Vitreous pigment
									10.1 × 7.8 (8.1) mm	Inferior subretinal exudates		Disomy 3 (MLPA and MSA)

M, male; F, female; RE, right eye; LE, left eye; SN, superonasally; ST, superotemporally; IT, inferotemporally; S, superiorly; MLPA, multiplex-ligation-dependent probe amplification; MSA, microsatellite analysis; VEGF, vascular endothelial growth factor; POAG, primary open-angle glaucoma; CSCR, central serous chorioretinopathy; NLP, no light perception; N/A, not available.

Case 1

A 39-year-old male was referred for a posterior segment lesion in his right eye (RE). The patient reported RE shadow, while he denied previous surgery or trauma. His medical and ophthalmic history was unremarkable. The best-corrected VA in the RE and left eye (LE) was 6/4 and 6/3, respectively. The LE examination was normal, whereas the RE fundoscopy revealed a pigmented lesion with subretinal fluid and exudates at the superonasal quadrant (as shown in Fig. 1a). The fundus autofluorescence demonstrated the absence of lipofuscin. There was also a flat-pigmented choroidal naevus with a small pigment epithelium detachment at the RE macula.

Fig. 1.

Cases 1–8: pigmented choroidal melanomas with hard yellowish exudates (a, d, e, g–k). Case 1 shows medium reflectivity on ultrasound (b) and subretinal fluid and exudates on OCT scan (c). The OCT scans confirm the subretinal location of hard exudates in case 3 (f) and in case 8 (l).

The ultrasound showed a medium reflectivity lesion with negative spontaneous vascularity on the colour Doppler. The lesion was measured at 5.5 × 4.5 mm with a 3.0 mm thickness (as shown in Fig. 1b). The OCT scans revealed a choroid-originated lesion with an abnormal overlying retina and hyperreflective intraretinal and subretinal foci (as shown in Fig. 1c).

Due to potential suspicion of choroidal melanoma, the patient was treated with ruthenium plaque brachytherapy, and post-treatment transretinal biopsy was performed on the day of plaque removal. The histology reports showed a spindle cell-type choroidal melanoma, whereas the MSA confirmed the diagnosis with disomy 3. Twelve months after the treatment, the choroidal melanoma showed significant regression, while the radiation-induced maculopathy was treated with good final anatomical and visual outcomes.

Case 2

A choroidal lesion was detected in a 52-year-old female upon routine eye examination. Past medical history revealed axial spondylarthritis and thyroid cancer, treated with surgery and radiotherapy 9 years ago. The patient was asymptomatic with presenting VA of 6/7.5 in both eyes (BE). The fundus examination showed a large pigmented choroidal tumour at the RE superonasal mid-periphery (as shown in Fig. 1d), while the OCT scans demonstrated intraretinal fluid with subretinal exudates surrounding the lesion and extending along the inferior periphery.

The ultrasound demonstrated a low-medium reflectivity lesion with positive Doppler. The tumour was measured at 11.98 × 10.78 with a thickness of 5.36 mm. The tumour was treated with ruthenium plaque for 4 days, and the trans-scleral choroidal biopsy reported a choroidal melanoma, predominantly of spindle cell type and disomy 3.

Case 3

A 47-year-old woman attended a routine eye test. The VA was 6/6 in BE, and the dilated LE fundoscopy showed a raised pigmented choroidal lesion with a collar stud formation associated with subretinal fluid. The rest of the ophthalmic examination appeared normal. There was no past medical or ophthalmic history of significance. The choroidal tumour was located temporal to the macula without affecting the fovea (as shown in Fig. 1e). The OCT showed significant subretinal fluid with subretinal exudates, whereas the ultrasound findings were consistent with a low-medium reflectivity lesion, measuring 7.58 × 7.60 (4.71) mm (as shown in Fig. 1f). The diagnosis of choroidal melanoma was based on the fundoscopic appearance and the imaging features of the lesion, and thus, it was treated with a 4-day course of ruthenium plaque radiotherapy; no biopsy was performed according to the patient’s will.

Case 4

A 47-year-old male was referred for a large pigmented choroidal lesion at the superotemporal quadrant of RE. The patient did not mention any eye-related symptoms, and the VA in the affected eye was 6/6. The fundoscopy revealed a normal macula and a large pigmented choroidal melanoma, with the subretinal location of the exudates at the inferior border of the tumour being confirmed by OCT scans (as shown in Fig. 1g). The ultrasound showed a low-reflectivity lesion, suggesting the clinical diagnosis of choroidal melanoma. The tumour was treated with ruthenium plaque, and although radiation maculopathy developed, the final VA was 6/9 following the six weekly anti-VEGF treatment.

Case 5

A 41-year-old man presented with a 3-month history of VA decrease in the LE. The medical history revealed left nevus of Ota, LE central serous chorioretinopathy, and RE amblyopia. The VA was 6/18 in BE, and the RE examination was normal. The LE anterior segment examination demonstrated oculodermal melanosis, hyperpigmented sclera, and clear crystalline lens. The posterior segment showed asteroid hyalosis, and a non-pigmented choroidal lesion located inferotemporal to the macula associated with inferior serous retinal detachment. Yellowish subretinal deposits were present in all quadrants of the fundus (as shown in Fig. 1h). The lesion was of low reflectivity with a positive Doppler on the ultrasound. The tumour was measured at 10.77 × 8.66 (5.34) mm.

Tantalum marker insertion for proton beam radiotherapy treatment (PBRT) preparation, transretinal biopsy, and intravitreal anti-VEGF injection were performed the following day. The histology and MSA chromosomal analysis revealed a spindle cell-type lesion and the presence of disomy 3, respectively, confirming the diagnosis of low-risk choroidal melanoma. One week after treatment, the patient developed a mild vitreous haemorrhage and high IOP, which were successfully managed conservatively.

Case 6

A 55-year-old lady was referred to our department for an asymptomatic RE fundus lesion showing a slow growth tendency. The patient was under topical treatment for primary open-angle glaucoma in BE. On examination, the VA was 6/9 and 6/6 in the RE and LE, respectively, with normal IOP. The RE had a choroidal pigmented lesion along the superotemporal vascular arcade. Subretinal haemorrhage and exudates appeared at the inferior and inferonasal lesion borders, respectively. There was also pigmented retinal infiltration over the surface of the lesion (as shown in Fig. 1i). On ultrasound, the lesion had a medium reflectivity and measured 10.67 × 9.54 mm with a thickness of 3.42 mm. Considering the documented enlargement of the lesion and the imaging features, we made the diagnosis of choroidal melanoma which was treated with PBRT. Although it was offered, the patient decided not to proceed with the transretinal biopsy.

Upon the last follow-up visit, the patient reported ocular surface symptoms, whereas fundoscopy showed pigmented vitreous infiltrates with signs of radiation retinopathy and maculopathy. Taking into account that there was no sign of tumour recurrence or progression and permanent macular damage, no further treatment was considered.

Case 7

A 49-year-old female was monitored for an inferior juxtapapillary choroidal nevus in the LE for at least 16 years. Past medical history revealed endometriosis and many episodes of migraine. The patient complained about flashing lights; the VA was 6/6 in BE. There was a documented increase in size and presence of new subretinal fluid and subretinal exudates inferior to the lesion (as shown in Fig. 1j). Fundoscopy demonstrated a slightly elevated pigment choroidal lesion with low reflectivity on ultrasound, dimensions of 4.8 × 4.3 mm, and a thickness of 1.42 mm. The history of naevus progression and the acoustic hollowness on ultrasound contributed to the diagnosis of choroidal melanoma. The tumour was treated successfully with PBRT without any signs of recurrence at the 6-month follow-up visit.

Case 8

A 79-year-old male was referred to our department with a 4-month history of LE VA deterioration, flashing lights, and floaters. The patient was diagnosed with a choroidal nevus superior to the LE macula 6 years ago without being monitored since then. The ophthalmic examination showed a partially pigmented choroidal melanoma, with retinal infiltration, vitreous seeding of pigmented cells, and subretinal fluid. The inferior retina appeared detached with an extended area of subretinal exudates (as shown in Fig. 1k). The OCT scans also showed sub-macular material and fluid (as shown in Fig. 1l). The tumour was measured 10.1 × 7.8 (8.1) mm on ultrasound and had variable internal acoustic reflectivity with positive Doppler. The patient was finally treated with LE enucleation, which demonstrated spindle cell choroidal melanoma. The multiplex-ligation-dependent probe amplification/MSA testing showed disomy 3, confirming the low risk of metastasis.

Discussion

The typical clinical features of choroidal melanoma have been thoroughly described in the literature [4]. However, our case series highlights the unusual manifestation of subretinal exudates as a presenting fundoscopic finding in patients with untreated choroidal melanomas. We found that hard exudates appear in approximately 0.9% of the cases, with their subretinal location documented with the OCT.

The hard exudates are included in the differential diagnosis of various intraocular tumours, such as vasoproliferative tumour, retinal angioma, combined hamartoma of retina and RPE, and adenoma and adenocarcinoma of the RPE [4, 11–13]. There is reasonable overlap in these conditions’ clinical and imaging features, making the clinical diagnosis sometimes challenging. A case of an intraocular tumour with subretinal exudation arising from the site of congenital hypertrophy of RPE was reported by Williams et al. [10]. The initial diagnosis of RPE adenoma or adenocarcinoma was made, but the remarkable enlargement of the tumour along with the cytopathologic and cytogenetic biopsy results supported the diagnosis of high-risk choroidal melanoma.

In 1992, Kremer et al. [7] also reported a case of massive lipid exudates in a 75-year-old female with choroidal tumour and diffuse metastatic hypernephroma. The patient presented with serous retinal detachment and subretinal and retinal lipid exudates. Although the initial hypothesis was a possible metastatic disease with intraocular spread, the histopathologic analysis showed malignant epithelioid choroidal melanoma with lipid-laden macrophages.

The aetiology of hard exudates and vascular changes related to uveal melanoma is unclear. Although exudation is a frequent post-radiotherapy fundoscopic feature in uveal melanomas due to vascular endothelial damage [14, 15], their presence is uncommon in untreated cases. Minija et al. [8] reported a case of dome-shaped choroidal melanoma showing lipid exudation at the posterior border of the tumour. The authors hypothesised that vascular incompetence, subretinal neovascularisation, or resolving serous retinal detachment may be the reason for lipid exudation. However, the subretinal location of exudates was not documented by the OCT scan.

In 1984, Cantrill et al. [16] used fluorescein angiography to describe the vascular changes in patients with malignant choroidal melanoma. They investigated 41 angiographies and found 8 patients with abnormal retinal capillaries (19.5%), four with microaneurysms (9.7%), and one with lipid exudation (2.4%). These vascular changes look like the vascular abnormalities seen in diabetic retinopathy patients, with various proposed explanations. Mechanical factors such as deformation and stretching of the overlying retina, ischaemia due to choriocapillaris obliteration, or tumour-related releasing growth factors are some of the hypotheses regarding vascular incompetence [17, 18].

Besides intraocular tumours, there are also non-neoplastic lesions with uncommon characteristics mimicking choroidal melanomas that may pose a diagnostic challenge. In the literature, many reports of cases such as eccentric choroidal neovascularisation and scleritis were erroneously diagnosed as choroidal melanoma [4, 19]. Recently, Furashova et al. [9] published a choroidal melanoma case presenting with subretinal exudation that was initially diagnosed as an infectious chorioretinal disease.

In our study, an interesting finding was also the location of the exudation. Blood-retinal barrier breakdown is an early sign of vascular leakage, leading to retinal oedema and extravasated lipid and proteinaceous material. This has been thoroughly investigated in patients with diabetic retinopathy. This forms the hard exudates that are primarily located in the outer plexiform retinal layer [20]. In our case series, however, the hard exudates were accumulated in the subretinal space. This is probably related to the discontinuity of the barrier function of the external limiting membrane, allowing fluid to flow into the subretinal space. The longstanding serous retinal detachment, along with protein and lipid material, forms the hyperreflective subretinal exudates [21, 22].

In addition, we cannot exclude that the accumulation of hard exudates in the subretinal space may also be related to Bruch’s membrane disruption, local tumour invasion, and fluid lipid-proteinaceous material extravasation. The rupture of Bruch’s membrane occurs in approximately 87.7% of patients diagnosed with choroidal melanoma [23]. The association between Bruch’s membrane incompetence and tumour-related lipid exudation has been proven after plaque radiotherapy in patients with uveal melanoma [24]. Unfortunately, this study did not investigate the origin of exudates based on histochemical analysis and their correlation to the final visual outcome/prognosis. Further studies are required to investigate the role and the predictive value of subretinal exudation.

Surprisingly, despite the potential invasive aetiology of vascular incompetence, all cases with cytogenetic analysis demonstrated low-risk profiles for metastatic disease (spindle cell, disomy 3). Clearly, there is a limitation with low numbers and not all patients choosing to undergo a prognostic biopsy. However, there is certainly a trend.

In conclusion, this case series points out that the presence of a choroidal tumour associated with subretinal lipid exudation does not exclude the diagnosis of choroidal melanoma. Awareness and early recognition of this uncommon clinical finding could contribute to the early diagnosis and timely treatment and could potentially be utilised as a clinical marker of low-risk choroidal melanoma tumours.

Statement of Ethics

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patients themselves for publication of the details of their medical case and any 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

Mrs. Rumana Hussain and Prof Heinrich Heimann devised the project and supervised the research activity planning and execution. Mrs. Harriet Williams and Mr. Ayodeji Ajanaku reviewed all the patient’s photos and OCT scans. Mr. Asterios Diafas contributed to the data collection and presentation and has written the original draft of the manuscript. Patients’ examinations and diagnoses were performed by all doctors. All authors commented on the final version of the manuscript and read and approved the final manuscript.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

This article includes all data generated for the study. Further enquiries can be directed to the corresponding author.