Simultaneous Bilateral Primary Choroidal Melanoma Linked to Bilateral Ocular Melanocytosis: A Rare Case Study

Introduction

Ocular melanomas can affect several structures of the eye. Of the melanomas affecting the uvea, 90% arise from the choroid [1]. Choroidal melanoma is the most common primary intraocular tumor in adults. It mainly affects people of Caucasian origin and has an incidence of 5.1 per million, per year [2]. Primary choroidal melanoma can arise from a preexisting nevus or de novo growth. It can be associated with risk factors such as light skin pigmentation [3,4] or even rarely can be associated with genetic predisposition, such as the BRCA-associated protein 1 (BAP1) gene [5]. Furthermore, it has been demonstrated that patients with pre-existing oculodermal melanocytosis have a predisposition to developing primary choroidal melanoma in their lifetime, with a risk of 1 in 400 Caucasian individuals [6].

Most primary choroidal melanomas are unilateral and unifocal. Bilateral primary choroidal melanomas are considered to be a rare occurrence, reported in approximately 0.2% of cases [5,7,8]. Bilateral primary choroidal melanomas can present sequentially or simultaneously, the former being more common.

Case Report

Our patient was a 78-year-old man who presented to the Emergency Department of the 1st University Clinic of Ophthalmology at the General Hospital of Athens “G. Gennimatas”. His symptoms were floaters and a reduction in visual acuity in his left eye. His symptoms started a week earlier. The patient received medication for arterial hypertension. Medical history included previous diagnoses of hepatitis B and colorectal carcinoma, which had been treated surgically and with chemotherapy 10 years ago, with no known recurrence to date. No occupational risk factors were found. The patient reported a previous vascular incident in his right eye years ago, which caused severe loss of vision. Upon clinical examination, visual acuity in the right eye was counting fingers and the left eye was 2/10. His intraocular pressures were 9 mmHg in the right eye and 7 mmHg in the left eye.

Upon macroscopic examination, the patient displayed bilateral pigmentation on the sclera, which was consistent with ocular melanocytosis (Figure 1). Both eyes had relatively advanced nuclear cataracts. Fundoscopy of the left eye revealed a massive choroidal protrusion next to the area of the optic disc, which was itself obscured by the mass. Fundoscopy further displayed an inferior wedge-shaped retinal detachment. Fundoscopy of the right eye displayed a pale optic disc, denoting the possibility of a previous ischemic optic neuropathy. When examining the inferonasal retina, an elevated mass of roughly 10 disc diameters of measured area was found, with stippled yellow pigment overlying its surface (Figure 2).

Upon optical coherence tomography examination the macula of the right eye was without any pathology, whereas the optic disc displayed extensive atrophy. This was correlated with his reported history, possibly indicating a past episode of nonarteritic ischemic optic neuropathy. The macula of the left eye displayed subretinal fluid under the fovea, with a sliver of sub-retinal fluid extending temporally. As confirmed with optical coherence tomography, the retinal detachment in the left eye began at the inferior temporal arcade (Figure 3). Ultrasound examination was performed to observe the echogenicity of the lesions and measure their size. The right eye lesion was dome-shaped and hypoechogenic, and its measured height was 4.5 mm. Ultrasound of the left eye displayed a mushroom-shaped lesion with a height of 11 mm and confirmed the existence of a retinal detachment inferiorly (Figure 4). In addition, we performed fundus autofluorescence (Figure 5), fluorescein angiography (Figure 6), and indocyanine green angiography (Figure 7). The examinations performed confirmed the diagnosis of simultaneous bilateral primary choroidal melanomas. Systemic evaluation and imaging did not reveal any metastasis from the choroidal melanomas, nor did it reveal any other primary tumor source.

The patient was referred for radiation therapy in both eyes. His left eye was treated with proton beam therapy at Paul Scherrer Institute in Switzerland, a month earlier. In addition, his left eye received intravitreal bevacizumab and triamcinolone. In a second session, his right eye was also going to receive radiation therapy.

Discussion

The initial incidence, as described by Shammas and Watzke, of bilateral primary uveal melanoma was estimated to be 1 case every 18 years [9]. Following this publication, Singh et al reported the incidence to be much greater, approximately 0.2%, by reviewing charts of 4500 patients with a diagnosis of primary uveal melanoma, spanning 17 years. The bilaterality of primary choroidal melanomas can be paralleled to the genetic predisposition found in primary occurring bilateral tumors in other paired organs. This can warrant specific genetic testing [5].

Scott et al [10] reviewed databases from 1973 to 2016, identifying a total of 52 cases of primary bilateral uveal melanoma, with 16 of these cases being bilateral. The authors concluded that bilaterality does not equate to a more aggressive course of disease or shorter survival. Although this review does not account for risk factors, such as oculodermal melanocytosis or BAP1 mutation, the authors make note of the publication of Eide et al [11], who detected a discordance between the expression of BAP1 in each eye of a case of bilateral uveal melanoma. Scott et al, based on this result, questioned the possibility of genetic tendency for bilateral uveal melanoma and suggested further research that would include genetic testing. In addition, Scott et al excluded patients with concurrent or preceding non-ocular malignancies, to avoid mimicry of choroidal melanoma by paraneoplastic syndromes, or malignancies that can cause diffuse uveal melanocytic proliferation. The aforementioned criteria exclude cases of bilateral uveal melanoma associated with other primary malignancies. In our opinion, this can be a confounding factor in the detection of a genetic predisposition of bilateral choroidal melanoma or a possible tumor predisposition syndrome.

Yu et al [12] described 2 cases of sequentially bilateral primary uveal melanoma with BAP1 positivity. BAP1 mutation has been documented as a high penetrance gene for hereditary uveal melanoma [13]. Based on these cases and other previous publications, Yu et al proposed BAP1 testing in specific patient groups, including those with bilateral uveal melanoma. The authors explained that this could help identify sequential involvement of the contralateral eye. Furthermore, BAP1 germ-line mutation is associated with 29% risk for developing uveal melanoma and poor survival, with significantly greater risk of metastasis [12]. According to Gupta et al [14], risk of metastasis in BAP1 germline mutation-positive patients with uveal melanoma is 71%. These patients also had more frequent ciliary body involvement and larger tumor diameters. A study on Finnish patients diagnosed with uveal melanoma concluded that the overall frequency of BAP1 germline mutations in these patients was 2% [15].

Other genes may be associated with bilateral uveal melanoma, as stated by Silva-Rodríguez et al [16], who proposed TERF2IP and BAX as candidates for predisposition to uveal melanoma.

Bilateral oculodermal melanocytosis, a known risk factor for primary uveal melanoma, can be associated with an increased risk for bilateral primary uveal melanoma [5,12,17,18]. Melanocytosis was significantly more common in bilateral uveal melanoma than in unilateral [5].

Our patient presented with bilateral ocular melanocytosis and simultaneous bilateral primary choroidal melanoma. To the best of our knowledge, this is the first case in Greece to date. This patient had a history of colorectal carcinoma 10 years earlier, which was successfully treated. The patient upon examination showed no signs of metastatic disease or recurrence of the primary colorectal tumor.

In our case, the patient was of an advanced age. Simultaneous bilateral disease can present in older patients, due to the rather slow nature of the disease. The lesion of the left eye measured 11 mm, which possibly suggested a growth over a long period of time. The patient came in to the Emergency Department because of decreased visual acuity presenting 7 days earlier, when the tumor caused subretinal fluid to migrate under the fovea, making the choroidal melanoma an incidental finding. The fellow eye was examined, without any signs or symptoms, as part of routine examination upon presentation, making the melanoma of the right eye also an incidental finding. This condition, although presented simultaneously bilaterally, most likely had not been diagnosed for a while in the left eye. This could mean that the interval from the initial presentation of the choroidal melanoma of the left eye and the initial presentation of the right eye could have been a significant time frame. Considering the aforementioned assumptions, this patient’s developing choroidal melanoma of one eye most likely had a large interval with no choroidal melanoma in the fellow eye.

A limitation in our publication is that despite the fact that the existing literature recommends genetic testing for BAP1, in our case it was not performed, even though the patient had a known history of another primary tumor in his past medical history.

Conclusions

This case illustrates the necessity of always examining the fellow eye on initial presentation and follow-up, and of always bearing in mind that choroidal melanoma, albeit a very rare occurrence, could be a bilateral disease. Furthermore, based on our knowledge from previous publications, the interval between presentation of the 2 eyes could be very large. This is even more critical in cases such as ours, in which there was preexisting bilateral ocular melanocytosis, which has an increased risk of uveal melanoma.