Progressive Vision Loss From Uveal Melanoma with Extraocular Extension: A Case Report

Introduction

Intraocular melanoma accounts for 5% of all melanomas, with approximately 85% originating in the uveal tract [1]. Uveal melanoma is the most common primary malignant tumor in adult patients [1], occurring most frequently in males over 50 years old [1]. Diagnosis is made through a combination of clinical ophthalmologic examination, B-mode ultrasound, and histopathologic study [2].

Research suggests a genetic predisposition and increased risk among people of White race. Hematogenous metastasis, particularly to the liver, is a known complication [3]. Available treatments for uveal melanoma include enucleation, local resection, and the application of episcleral radioactive plaques [4]. The 5-year prognosis after enucleation ranges from 16% to 53%, depending on tumor size, with 90% of tumor-related deaths occurring within the first 15 years [1].

Uveal melanoma with extra-scleral extension is a rare presentation often linked to poor prognosis. Similar cases have been described in the literature, including 1 reported by Kimura et al, in which treatment refusal led to rapid tumor progression and extensive extraocular spread within 7 months [5]. Kaliki et al and Shome et al also reported extra-scleral extension following local intraocular procedures, suggesting possible iatrogenic dissemination [6,7].

In contrast to previously reported cases, our patient presented with a prolonged disease course lasting over 3 years, without any prior intraocular interventions aside from cataract surgery. This suggests the possibility of spontaneous extra-scleral extension in untreated uveal melanoma. We report the case of a 67-year-old woman who experienced ocular pain and progressive vision loss in the right eye. Clinical evaluation revealed an inferomedial uveal melanoma. She underwent enucleation, and no evidence of metastatic disease was found.

Case Report

A 67-year-old brown-skinned female patient was examined at the Ophthalmology Department of the University Hospital of Brasília in February 2023, reporting progressive vision loss associated with pain and a pigmented lesion in the inferomedial region of her right eye for 3 years. She had been taking acetazolamide to control eye pressure. She underwent phacoemulsification with intraocular lens implantation in the right eye in 2021 and had a history of chagasic cardiomyopathy, for which amiodarone is currently being taken.

At the time, she presented with the following examination findings: visual acuity with best correction was light perception in the right eye and 20/20 in the left eye. Biomicroscopy revealed a dark pigmented lesion with irregular borders in the lower nasal quadrant of the ocular conjunctiva in the right eye, along with the presence of a large-caliber nourishing vessel, edematous cornea 2+/4 with pigments in the endothelium, pseudophakic, and left eye without noteworthy alterations (Figure 1). The intraocular pressure was 38 mmHg in the right eye and 13 mmHg in the left eye, with tonometry performed using a Goldman applanation tonometer. Fundoscopy of the right eye was unfeasible due to opacity, while fundoscopy of the left eye was normal.

Complementary exams included an eye ultrasound in January 2023 showing high-intensity hyperechogenic echoes and a kappa angle corresponding to a large choroidal tumor (approximately 70% of the vitreous volume). Based on ocular ultrasound findings, the tumor appeared to originate from the choroid, given its posterior location and the pattern of a dome-shaped choroidal elevation with well-defined contours, convex toward the vitreous cavity, and showing continuity with the posterior scleral wall, suggestive of a solid intraocular lesion.

A complete systemic evaluation, including advanced imaging studies to rule out distant metastases, was performed after the therapeutic intervention. Prior to that, the diagnostic assessment was limited to the biomicroscopic and ultrasonographic examinations, due to the patient’s clinical condition and the resources available at the time. Based on these findings, a presumptive diagnosis of ocular melanoma was made, although histopathological classification had not yet been established.

The patient underwent enucleation of the right eye in March 2023 with placement of an intra-orbital prosthesis covered in donated sclera. The anatomopathological analysis showed a 3.0×3.5 cm material with an intraocular lesion located from the most posterior portion of the eyeball, around the insertion of the optic nerve, advancing to the anterior chamber and connected to the scleral lesion. The tumor had a vegetating, blackened, friable appearance and was irregular in size with a basal diameter of 1.0 cm and 1.9 cm in its longest axis, which coincided with the greatest tumor thickness (Figure 2). It was classified as stage T4 according to the American Joint Committee on Cancer (AJCC) [8] and large according to the Collaborative Ocular Melanoma Study (COMS) [3]. Microscopy revealed a mixed-cell type uveal melanoma, with direct invasion of the sclera, surgical margins free of neoplasia, and pathological staging pT4a (Figures 3–6).

After the ocular enucleation performed in March 2023, the patient began regular outpatient follow-up with the Ophthalmology Department. Staging tests were requested to investigate possible metastases, including a CT scan.

The diagnosis of primary uveal melanoma was based on the characteristic clinical and imaging findings, including a large, pigmented intraocular mass with high-intensity hyperechogenic echoes originating from the choroid, as seen on ocular ultrasound, and histopathologic confirmation of a mixed-cell-type melanoma with direct scleral invasion. The absence of prior history of cutaneous or mucosal melanoma, combined with a thorough systemic evaluation, including CT of the chest, abdomen, and pelvis, showed no evidence of a primary tumor elsewhere or distant metastases, supporting the diagnosis of a primary ocular origin.

Since then, she has been undergoing periodic follow-ups with bi-annual ophthalmologic consultations, during which the condition of the anophthalmic socket and any clinical signs that might indicate local recurrence or systemic progression of the disease are evaluated. So far, there has been no clinical evidence of tumor recurrence or the emergence of metastases, and the patient remains asymptomatic.

Currently, 2 years after diagnosis and surgical treatment, she is in good general health and leading a normal life. However, it has not yet been possible to fit a definitive ocular prosthesis due to the unavailability of supplies in the public healthcare system.

Discussion

This case underscores the significant challenges associated with the diagnosis and management of uveal melanoma in resource-limited settings, emphasizing the critical importance of early detection and the role of enucleation in advanced-stage disease. It further illustrates the urgent need for increased public awareness and the establishment of efficient referral pathways to facilitate timely and accurate diagnosis and access to appropriate treatment.

The present case aligns with previous reports describing uveal melanoma with extra-scleral extension, a relatively rare manifestation often associated with poor prognosis. Kimura et al reported a similar case in which a patient refused initial treatment, resulting in rapid tumor progression and massive extraocular extension within 7 months [5]. Unlike that case, our patient had a much longer course of disease, with symptoms persisting for over 3 years before diagnosis and without prior therapeutic intervention. Kaliki et al and Shome et al documented extra-scleral extension occurring after local treatments such as plaque brachytherapy or fine-needle aspiration biopsy, suggesting that some iatrogenic factors can contribute to tumor dissemination [6,7]. However, our patient had not undergone any prior intraocular procedures other than cataract surgery, supporting the hypothesis that spontaneous extraocular extension can occur in the natural history of untreated uveal melanoma.

The incidence of uveal melanoma is approximately 4 to 10 cases per million people per year. The age-adjusted average in the United States is approximately 5.1 cases/million [4,9,10]. The established risk factors for ocular melanoma include light-colored irises, congenital ocular and oculodermal melanocytosis, cutaneous nevi, iris nevi, and cutaneous ephelides [11]. Patel et al further emphasized that while these risk factors increase susceptibility, ocular melanoma can also arise sporadically without any identifiable predisposition [9].

The established risk factors for ocular melanoma include light-colored irises, congenital ocular and oculodermal melanocytosis, cutaneous nevi, iris nevi, and cutaneous ephelides [11]. However, these risk factors are not always present, as illustrated by our patient, who lacked both a family history of the condition and the common risk factors typically associated with the disease.

Although a small percentage of ocular melanoma cases are familial, with a germline mutation in the BAP1 gene, this mutation is not observed in all patients. It is estimated that individuals carrying this mutation have a 29% risk of developing uveal melanoma [12].

Genomic testing has become an important tool for evaluating prognosis and treatment response in various types of cancer, including cutaneous melanoma. For instance, the BRAF mutation serves as a predictor of response to therapies targeting RAF proteins. Additionally, the overall mutational burden in cutaneous melanoma offers valuable insights into potential treatment outcomes. Specific gene alterations, such as BAP1 mutations, are significantly associated with poorer survival rates, whereas mutations in other genes, such as EIFAX1, have been correlated with a substantially reduced risk of metastasis [13].

In addition to genetic factors, several clinical and histopathological characteristics are critical for predicting the risk of metastasis in ocular melanoma. Clinically, features such as the T stage, involvement of the ciliary body, and presence of extraocular extension markedly influence disease progression. Histopathologically, cell type – spindle versus epithelioid – is a key determinant, with epithelioid cells associated with a worse prognosis. Furthermore, cytogenetic analyses, particularly involving chromosomes 3, 5, and 8, offer essential information for risk stratification and guide clinical decision-making [14].

When comparing these data to the present patient, several important considerations emerge. Although genomic testing was not performed due to financial constraints within the Brazilian public healthcare system, clinical findings are consistent with established risk factors for uveal melanoma. These include a dark, irregularly pigmented lesion on the ocular conjunctiva, elevated intraocular pressure, and corneal changes – features commonly associated with advanced disease. The clinical suspicion was reinforced by imaging, with ultrasound (the preferred method due to availability) revealing high-intensity hyperechogenic echoes and a kappa angle consistent with a large choroidal tumor, thus supporting the biomicroscopic findings suggestive of uveal melanoma [13]. The diagnosis is usually made by physical examination using fundoscopy or imaging tests such as OCT, angiography, and ocular ultrasound. In selected cases, a biopsy may be performed [4–6].

Although genetic analysis was not conducted, features such as direct scleral invasion and the presence of a mixed-cell-type tumor suggest a poor prognosis, consistent with findings in other studies of large uveal melanomas. These factors, combined with clinical and imaging results, underscore the relevance of staging systems such as the American Joint Committee on Cancer (AJCC) [8] and Collaborative Ocular Melanoma Study (COMS) [3] for assessing metastatic risk and informing therapeutic decisions.

The management of uveal melanoma has evolved significantly, with a growing emphasis on preserving visual acuity whenever feasible. Enucleation, historically the treatment of choice, is increasingly reserved for large tumors or blind and painful eyes. Local tumor control is typically achieved via radiotherapy or surgical intervention. Radiotherapy can be in the form of brachytherapy (radioactive plates) or teletherapy (proton beams/charged particles) [15].

Recent studies highlight the potential of targeted therapies and immunotherapies to improve treatment outcomes [16]. However, despite these advances, early diagnosis remains critical given the potential for metastasis and associated mortality. This variability in risk and presentation is reflected in our patient, who lacked classic risk factors and family history, underscoring the complexity of this disease [9]. Recent research also emphasizes the importance of early diagnosis and the identification of novel biomarkers to enhance prognosis and inform treatment strategies [17].

Although the Collaborative Ocular Melanoma Study (COMS) large tumor trial found no significant difference in survival between neoadjuvant radiotherapy (RT) followed by enucleation and enucleation alone, it did report a reduced risk of orbital recurrence in patients receiving neoadjuvant RT [3]. Nonetheless, enucleation was chosen in our case due to limited treatment availability in the public healthcare system. This approach is traditionally reserved for advanced cases because it was deemed the most appropriate under the circumstances.

It is essential to closely monitor patients following a diagnosis of uveal melanoma, given the significant risk of metastatic spread. The liver is the most common site of metastasis, followed by the lungs, bones, skin, and lymph nodes [4,18]. In the present case, the patient presented with stage IV disease, which, along with factors such as increased tumor size and thickness, larger basal diameter, ciliary body involvement, and extra-scleral extension, is associated with a higher risk of multi-organ dissemination [19]. Fortunately, she was able to undergo comprehensive screening, which revealed no evidence of metastasis.

The latest National Comprehensive Cancer Network (NCCN) guideline classified as high-risk patients those who have class 2 uveal melanoma or monosomy 3 or gain of chromosome 8q or BAP1 mutation or T4 classification according to the AJCC and recommended monitoring this group with surveillance images every 3–6 months for 5 years, then 6–12 months up to 10 years, then as clinically indicated [3,8]. This screening can be done using radiographs, abdominal ultrasounds, CT scans, MRI, or positron emission tomography-computed tomography [19,20].

Conclusions

This case highlights the critical importance of early recognition and evaluation of suspicious pigmented ocular lesions to prevent delayed diagnosis of uveal melanoma. In resource-limited settings, late presentation often restricts therapeutic options and can lead to enucleation in advanced cases. Although advanced imaging and genetic testing were not available, clinical and histopathological findings supported a high-risk diagnosis. Fortunately, the patient had no evidence of metastasis. This case underscores the critical need for public awareness, early detection, and effective referral of pigmented ocular lesions to preserve vision, expand therapeutic options, and ensure timely access to specialized care.