Tumor Profiles of Late Presentation Uveal Ring Melanoma With Novel Characteristics – A Case Series

Abstract

Purpose: The purpose of this study was to investigate the clinical features, tumor characteristics, including histopathology and cytogenetic analysis, and management of patients with uveal ring melanoma in New Zealand.

Methods: A retrospective review was conducted on all uveal melanoma cases treated in a single national oncology center in New Zealand. The study period was from January 1, 2013 to December 31, 2022 (10 years). Written consent was obtained from all patients included in this case series.

Results: Uveal ring melanoma of ciliary body origin (n = 4) comprised 0.7% of all uveal melanomas (n = 571). Ethnicity distribution was three patients of New Zealand European ancestry and one patient of Chinese/Pasifika ancestry. Three patients (75%) were symptomatic at presentation (spontaneous hyphema, glaucoma, and cataract), whereas one was asymptomatic but subsequently developed painful refractory glaucoma. All eyes underwent enucleation. Three eyes had primary iris biopsies with subsequent enucleation for refractory glaucoma and pain and one eye underwent primary enucleation. All cases demonstrated malignant tumor characteristics including diffuse 270 to 360-degree ciliary body ring growth pattern, epithelioid-cell type and presence of either BAP-1 expression loss or gain of MYC gene. Two cases (50%) developed distant organ metastasis – liver, parotid gland, and breast. Of those, one patient was deceased at the time of follow-up whereas one had completed treatment for metastases.

Conclusions: Uveal ring melanoma is a rare tumor that is highly invasive and malignant. When detected, prompt definitive treatment should be advocated, and patient counselling should be given regarding the high risk of developing a painful, blind eye with increased risk of metastasis in the absence of treatment.

Uveal melanoma, first described by Ernst Fuchs in 1882 as “sarcom des uveal tractus,” is the most common primary intraocular malignancy in the adult eye.¹ Uveal ring melanoma is an extremely rare variant representing approximately 0.3% of uveal melanomas.² It was first described by Ewetzky in 1898,³ who observed an unusual pattern of uveal melanoma growth where the tumor extended circumferentially, involving the entire ciliary body and iris. Due to its rare entity, uveal ring melanoma descriptions have largely been limited to case reports and the largest study to date (n = 49) was published by Markiewicz et al. in 2001.⁴ The characteristic circumferential pattern of growth means that tumor spread is typically insidious and tumor detection often occurs at an advanced stage. The primary presentation may occur due to secondary sequelae, such as refractory unilateral glaucoma,^5–7 hyphaema,⁸ cataract,² or extraocular extension.⁹ Although typically asymptomatic, the most common presenting symptom is blurred vision.² 

There are no published data on uveal ring melanoma in New Zealand, a country with an estimated age-standardized annual uveal melanoma incidence of seven to eight cases per million population per year.¹⁰ This case series provides the first written report on the clinical presentations, tumor characteristics, and management of uveal ring melanoma in a national oncology center serving a national population of five million. 

Methods

This was a 10-year (January 1, 2013, to December 31, 2022), retrospective review, of all uveal melanoma cases referred to a national ocular oncology center, Greenlane Clinical Centre, Te Whatu Ora Health New Zealand. Our national oncology center treats all uveal melanomas in New Zealand and therefore the data assessed is a complete national representative. A subset population diagnosed with uveal ring melanoma was identified. Written consent was obtained from each patient prior to inclusion in this case series. Information was collected on patient demographics, medical and ocular history, presenting features, management, tumor characteristics, including histopathology and cytogenetic investigations, and outcome, including metastatic status, morbidity, and mortality where relevant. This study was approved by the Health and Disability Ethics Committee (Reference 2023 EXP 15100), received institutional approval from Auckland District Health Board (Reference AH22023), and adhered to the tenets in the Declaration of Helsinki. 

Statistical Analysis

Descriptive statistical analysis was completed on the Excel Spreadsheet. Due to the small number of cases, further statistical analysis was not possible. 

Clinical Assessment and Investigations

Clinical assessment following referral into the anterior segment clinic (all patients were reviewed by anterior segment specialist, authors C.N.J.M. or A.C.) comprised the following: visual acuity (VA), intraocular pressure (IOP), a thorough history followed by a comprehensive slit lamp examination, including gonioscopy and anterior segment photography, further investigation where relevant with anterior segment optical coherence tomography (AS-OCT) and/or ultrasound biomicroscopy (UBM), if indicated or available, and B-scan when there was obstruction of view to the posterior segment (i.e. cataract or hyphema). Following diagnosis, all patients received a baseline systemic workup, including full blood count, urine and electrolytes, liver function tests, chest x-ray, and liver ultrasound. Any abnormalities detected on the baseline workup were further investigated (i.e. liver lesions detected on ultrasound received further investigation with computed tomography [CT] or magnetic resonance imaging [MRI] scans). 

Surgical Management – Iris Biopsies

All iris biopsies were completed by anterior segment subspecialist (authors C.N.J.M. or A.C., in conjunction with C. N. J. McGhee). Using the Minimal Iris Touch Excision (MITE) technique.¹¹ All excision biopsies were conducted with a tumor margin of ≥1 mm of macroscopically uninvolved tissue. After incisions free the iris biopsy, the tissue passes from the anterior chamber, by capillary action and pressure differential, into an IOL cartridge (without touching the corneal incision or ocular surface), and is then gently flushed onto pre-cut filter paper, gently spread flat, and secured under a second sheet of filter paper in a cartridge. Immediately, the cartridge is placed into a specimen bottle and submerged in formalin and delivered directly to the pathology laboratory for processing. All iris biopsies were sent to the pathology service at Te Whatu Ora Health New Zealand Auckland Region for histological confirmation and immunohistochemistry analysis (as described below). 

Surgical Management – Enucleation

Unless contraindicated, all enucleations were carried out with the patient under general anesthetic by the next available oculoplastic surgeon within the patient's local district health board at the time the decision for treatment was made. The affected globe was separated from all attachments and removed from the orbit with a margin of the optic nerve. The eye specimens were delivered in formalin to the pathology service on the same day. Simultaneous implantation of a scleral-wrapped orbital acrylic implant was performed, and all patients received a conformer to allow for subsequent ocular prosthetic fitting, typically 6 to 8 weeks following surgery. 

Histopathology – Methods and Reporting

All biopsied specimens (iris biopsy or enucleated eye) were examined and reported in accordance with the College of American Pathologists “Protocol for the Examination of Specimens From Patients With Uveal Melanoma” version: 4.1.0.0 (authors: Tatyana Milman, MD; Patricia Chevez-Barrios, MD; Ralph C. Eagle, Jr., MD; Hans E. Grossniklaus, MD, MBA; and Dan S. Gombos, MD, FACS). The samples were all fixed in neutral buffered formalin for a minimum of 24 hours. 

All biopsy specimens were first examined macroscopically followed by transillumination of the globe (if enucleated). Enucleated specimens were orientated by identification of extraocular muscle insertions, optic nerve, vortex vein, and long posterior ciliary artery. The globe is sliced into three parts, two calottes, and a pupil-optic nerve slice. Care is taken to cut the tumor in the meridian to include the largest (or the most informative) portion of the tumor. Melanoma cells are identified by morphology on hematoxylin staining and eosin counterstains. Histological determination is based on the modified Callender classification for determining cell type. The American Joint Committee on Cancer (AJCC) defined the histopathologic types as follows: 

• 1. Spindle cell melanoma, (>90% spindle cells)
• 2. Mixed cell melanoma, (>10% epithelioid cells and <90% spindle cells)
• 3. Epithelioid cell melanoma, (>90% epithelioid cells)

Immunohistochemistry Methods

Following histopathology verification, the uveal melanoma specimen is sent for immunohistochemistry analysis. Immunohistochemistry is performed using the Leica Biosystems BOND Polymer Refine Detection kit and BOND Polymer Refine Red Detection (protocols available in the Appendix). All samples were counterstained with hematoxylin to allow visualization of cell nuclei. For primary uveal melanoma, BAP-1 is detected with BAP-1(C-4) mouse monoclonal antibody, whereas the preferentially expressed antigen in melanoma (PRAME) protein is detected with the PRAME (EP461) rabbit monoclonal primary antibody. Both BAP-1 and PRAME are prognostic markers. For metastatic uveal melanoma, presence of melanocytic differentiation antigen (Melan A) is detected with MART-1 (Melan A; M2-7C10) mouse monoclonal antibody and presence of SOX-10 transcription factor protein is detected using SOX-10 (EP268) rabbit monoclonal primary antibody. 

Fluorescence In Situ Hybridization Methods

Fluorescence in situ hybridization (FISH) was conducted on paraffin embedded tissue. This method is useful in confirming or excluding histological diagnosis, differentiating tumor subtypes, used as a confirmatory tool where there is poor tissue morphology or when the immunohistochemistry is uninformative. The protocol for FISH testing in our center has previously been described by authors Duffy et al.¹² For all uveal melanomas, the following probe panel was used: 3p21.1 BAP1 (spO)/CCP3 (spG) gene probe (Cytotest), t(8; 14)(q24; q32) IGH (spG)/CMYC(spO)/cen8 (spA) (D8Z2) df gene re-arrangement probe (Vysis) 6p25 (RREB1)/6q23 (MYB)/6p11.1-q11 (CEP 6)/11q13 (CCND1). For uveal melanomas identified prior to 2021, the 3p14.2 FHIT/CEN3 gene probe (Zytovision) was used instead of BAP1. 

Results

Over the 10-year study period, 4 cases (0.7%) of histologically confirmed uveal ring melanoma were identified, among 571 cases of uveal melanoma in New Zealand. Table 1 provides a complete summary of the patients’ demographics, presenting symptoms, initial and final management, and metastatic status. Table 2 summarizes tumor characteristics, including histology and immunohistochemistry findings. 

Table 1.

 

Uveal Ring Melanoma in New Zealand: Summary of Patient Demographics, Clinical Presentations, and Tumor Characteristics Between 2013 and 2022

 

Table 2.

 

Uveal Ring Melanoma in New Zealand: Summary of Tumor Histopathology and Immunohistochemistry Findings

 

Mean age at diagnosis was 64.3 (± 10.7) years and mean follow-up was 39.7 (± 29.4) months. One patient (25%) was asymptomatic at the time of presentation. The most common symptom was pain secondary to elevated IOP (n = 2 cases, 1 from hyphema) and loss of vision from cataract (n = 1). Only one patient had evidence of systemic metastasis at initial diagnosis – this was the only patient who elected for primary enucleation for diagnostic purposes (case 3). The remaining three patients proceeded for primary diagnostic iris biopsies. All three were initially resistant to the concept of enucleation but ultimately required enucleation after developing painful blind eyes from refractory secondary glaucoma. Two patients underwent transscleral cyclodiode laser, but the IOP was refractory to treatment. Two patients developed uveal melanoma metastases to distant organs, including liver, parotid gland, and breast. One patient was deceased at the time of follow-up due to secondary metastasis to the liver. All four melanomas were of epithelioid cell type with diffuse 270 to 360-degree ciliary body ring growth pattern. 

Case One: Asymptomatic But Aggressive Presentation of Uveal Ring Melanoma

A 75-year-old New Zealand European man was referred from an Optometry clinic following an incidental finding of a right pigmented iris lesion. His medical history was significant for concurrent prostate adenocarcinoma (Gleason Grade 4+3) requiring intermittent chemotherapy and hormone therapy. He was asymptomatic, with no significant ocular history and a nonsmoker. The presenting best corrected visual acuity (BCVA) in the affected eye was 6/7.5 with a baseline IOP of 19 mm Hg. On examination, he had a diffusely pigmented lesion in the inferior right iris occupying 2 clock hours with associated corectopia (Fig. 1). Heavy pigmentation of the angle was observed on gonioscopy. Routine investigations, including chest x-ray, liver ultrasound, and liver function tests, to screen for metastasis were negative. 

Figure 1.

 

Case One – Initial presentation in 2016 (left) with growth noted in 2017 after patient opted for a period of observation (right).

Despite advice that the lesion was suspicious for iris melanoma and recommendations for excision biopsy, the patient declined surgical management and opted for observation. He was reviewed every 3 months. The lesion continued to exhibit a circumferential growth pattern associated with incremental elevations in IOP that was managed with topical ocular antihypertensive medications. He was counseled for further definitive treatment, however, the patient continued to decline treatment. 

Two years following initial presentation, the patient consented to an iris biopsy (Fig. 2A). Histology confirmed a uveal melanoma with positive involvement of all biopsy margins (cell type not confirmed in pathology report and no immunohistochemistry or FISH performed). The patient was again strongly counseled for further definitive treatment with either proton beam radiotherapy or enucleation, both of which were declined. His postoperative recovery was complicated by elevated IOP (30–40 mm Hg) refractory to maximal medical treatment. Over the course of the subsequent 12 months, his vision declined from 6/7.5 to no perception of light due to refractory secondary glaucoma. However, as the eye was comfortable, the patient continued to decline further intervention apart from one cycle of cyclodiode to manage his elevated IOP. During this time, he unfortunately developed concurrent metastatic castrate-resistant prostate adenocarcinoma requiring intensive radiotherapy and hormone treatment, which resulted in unavoidable delay in a number of follow-up appointments that were further complicated due to the coronavirus disease 2019 (COVID-19) pandemic restrictions and rescheduling. 

Figure 2.

 

Case One – (A) Post diagnostic iris biopsy confirming malignant melanoma of the iris. (B) Subsequent tumor extension with gross cataract and neovascularization. (C) Extrascleral extension manifesting as superior scleral pigment. (D) Close-up slit lamp examination demonstrating diffuse pigmentation on anterior lens capsule, iris margins, and on corneal endothelium.

Five years following the initial ocular presentation, extraocular scleral extension of uveal melanoma was identified associated with diffuse, 360 degree episcleral sentinel vessels, with diffuse pigmentation of the anterior segment structures (Figs. 2B, 2C, 2D). Following an in-depth discussion, the patient consented to an enucleation. Histology confirmed diffuse epithelioid uveal ring melanoma of the ciliary body and iris, pT4d. Immunohistochemistry demonstrated BAP-1 loss of expression and positive PRAME expression. No evidence of uveal melanoma metastasis was detected at the latest follow-up (March 2023). 

Case Two: Uveal Ring Melanoma in a Chinese-Samoan Patient With Subsequent Parotid Gland and Breast Tissue Metastasis

A 51-year-old woman of Chinese and Pasifika (Samoan) ethnicity presented to the emergency eye service with acute right eye pain and loss of vision to hand movements. She had no significant ocular or medical history and was an exsmoker. The right ocular examination was remarkable for a large >50% hyphema with secondary elevated IOP (76 mm Hg) and a suspicious iris lesion described as a “gelatinous amelanotic mass with deep fronds of blood vessels in the cornea and iris, associated with iris distortion and overlying plaque-like sheet” (Fig. 3). There was no view posteriorly and the B-scan examination revealed no posterior segment abnormalities. 

Figure 3.

 

Case Two – (A) Initial presentation with spontaneous hyphema and elevated intraocular pressure in the right eye. Note the gelatinous mass at the corneal endothelium (red arrow). (B) Slow resolution of hyphema following anterior chamber washout demonstrating an amelanotic lesion at 7 to 8 o'clock (white arrow).

Due to the unusual appearance, the lesion was deemed suspicious for malignancy but not typical for melanoma with differential diagnoses of infectious versus noninfectious granulomatous diseases. The patient proceeded for a combined anterior chamber washout and iris biopsy using the MITE technique,¹¹ a technique used in our center for excision of iris lesions to minimize tumor seeding during surgery. The histology was reported as iris spindle cell melanoma. On immunohistochemistry, BAP-1 was retained. FISH showed gain of MYC gene locus, no monosomy 3, or MYB deletion. 

The postoperative recovery was complicated by ongoing persistent hyphema and elevated IOP refractory to topical medical treatment (corticosteroids and ocular antihypertensive medications). Enucleation was strongly recommended as the treatment of choice; however, this was declined due to cosmetic and cultural reasons. Two cycles of cyclodiode were performed but other glaucoma drainage procedures were contraindicated due to the risk of melanoma dissemination. 

Over 18 months, the vision continued to decline due to chronic inflammation and refractory secondary glaucoma. Two years following initial ocular presentation, the patient developed a painful, blind eye not amenable to any medical therapy and she consented to enucleation. The final histology revealed a 360-degree epithelioid uveal ring melanoma involving the iris, ciliary body, and anterior choroid with extrascleral extension, pT4d. BAP-1 nuclear expression was retained and PRAME was negative by immunohistochemistry. FISH demonstrated gain of MYC gene locus, no monosomy 3, or MYB deletion. 

Within 12 months of enucleation, the patient presented with a biopsy-confirmed, regressed, uveal melanoma metastasis in her right breast and proceeded for partial mastectomy. She was subsequently found to have enlarged pre-auricular lymph nodes on surveillance positron emission tomography (PET)-CT scan (Fig. 4) and proceeded for parotidectomy and lymph node dissection that confirmed metastatic uveal melanoma in the parotid gland with microscopic extra nodal extension. Histopathology of the parotid lesion demonstrated atypical spindle cells with a focus of cells with epithelioid appearance. On immunohistochemistry, the lesion showed a strong staining for SOX10, positive staining for Melan A and S100, retained BAP-1, negative BRAF, and negative staining for CKAE1/AE3, SMA, and desmin, which is consistent with metastatic uveal melanoma.^13–16 A further pigmented nodule was identified on the skin of the right cheek following surgery and she proceeded for wide local excision which confirmed metastatic uveal melanoma to the skin overlying the parotid gland (similar appearances on immunohistochemistry to parotid lesion). She received further postoperative radiotherapy to the surgical bed and right neck (48 Gray in 20 fractions over 4 weeks). At the time of the latest review (May 2023), no further evidence of metastasis was found. 

Figure 4.

 

Case Two – PET-CT scan demonstrating uveal metastases to preauricular lymph node (red arrow) and lymph node deep to parotid (white arrow).

Case Three: Uveal Ring Melanoma With Extrascleral Extension and Liver Metastasis

A 68-year-old New Zealand European man was referred by his general practitioner for left cataract assessment due to loss of vision. His medical history included being a current smoker with a 20-pack year history. He had no significant ocular history. On examination of the left eye, BCVA was no perception of light and IOP elevated at 50 to 60 mm Hg. His anterior segment examination demonstrated a large diffuse pigmented iris lesion with extraocular scleral extension, widespread iris neovascularization, shallowing of the anterior chamber, and a dense cataract. Gonioscopy demonstrated 360 degrees of angle pigmentation. A large scleral pigmented lesion was observed on the superior globe with a small adjacent satellite lesion (Fig. 5). 

Figure 5.

 

Case Three – (A) Initial presentation to cataract assessment clinic with large iris pigmented mass with associated rubeosis iridis, cataract, diffuse pigmentation involving anterior chamber angle, corneal endothelium, and anterior lens capsule. (B) Extrascleral extension visible as sclerolimbal pigmentation.

He was immediately referred to the oncology specialist service with a presumed diagnosis of uveal melanoma with extraocular extension. Systemic imaging with CT and MRI scans revealed multiple, probable, liver metastases. He was counseled on the diagnosis and consented for enucleation within 1 week of diagnosis. The histology report confirmed a diffuse uveal, epithelioid cell, ring melanoma affecting approximately 270 degrees of the ciliary body and iris root with extrascleral extension, pT4d. On immunohistochemistry, BAP1 expression was lost and PRAME was equivocal. 

Ultrasound-guided liver biopsy confirmed metastatic uveal melanoma in the liver. Further CT-PET scan demonstrated focal uptake in the distal esophagus suspicious for metastasis. Next generation sequencing revealed a microsatellite stable tumor with 0.0 mutations/Mb: BAP1 slice site 1729+1G>A (VAF 53%), GNA 11 Q209L (VAF 23%). Unfortunately, there were no recommended clinical trials or treatments based on these results. He was subsequently referred to hospice and palliative care for ongoing management of pain and ascites secondary to metastatic disease. Sadly, this patient died 8 months following the initial ocular diagnosis. 

Case Four: Uveal Ring Melanoma Presenting as Iris Heterochromia

A 61-year-old New Zealand European man was referred to our service by an ophthalmologist with secondary left ocular hypertension related to a melanocytic iris lesion. The patient initially presented with unilateral ocular pain and was unaware of the presence of iris heterochromia. There was no significant ocular history. His medical history was significant for Alzheimer's dementia, and he was an exsmoker. On initial examination, BCVA was 6/9 and IOP 47 mm Hg OD. The iris demonstrated significant diffuse pigmentation with a focus of dense pigmentation between 9 o'clock and 4 o'clock (Fig. 6). On gonioscopy, pigmented lesions were observed within the angle. Routine investigations revealed no evidence of systemic metastasis. 

Figure 6.

 

Case Four – Diffuse uveal ring melanoma affecting 360 degrees of iris causing heterochromia.

He consented for an iris biopsy and histology demonstrated an epithelioid iris melanoma with positive margins. On immunohistochemistry, BAP1 was lost. FISH results showed monosomy 3, MYC gain, and no MYB loss. Following diagnosis, he was strongly recommended to undergo enucleation but declined, as he preferred to retain the eye, despite being aware of the risks of metastasis. Over the course of 20 months, he developed refractory secondary glaucoma (50 mm Hg) despite maximum medical therapy and his BCVA declined to no perception of light. He eventually consented to an enucleation 2 months later, which confirmed a diffuse, epithelioid, uveal ring melanoma involving the iris and ciliary body, pT4d. No immunohistochemistry results were available but FISH demonstrated monosomy 3, MYC gain, and MYB loss. 

Twelve months following enucleation, he was found to have a hypo-enhancing liver lesion measuring 32 × 36 mm and bilateral solid, mildly enhancing renal cortex lesions. At the time of this report, the patient was still awaiting further investigations with a CT scan. 

Discussion

We report the clinical course, histopathology, genetics based on immunohistochemistry, and management of four cases of advanced uveal ring melanoma (iris and ciliary body) in New Zealand. This case series also highlights the first report of uveal ring melanoma in a patient of Pasifika ethnicity with rare metastases to the ipsilateral breast and parotid gland via regional and extra-regional lymph nodes. The following discussion will focus on management considerations in this rare and potentially deadly eye malignancy. 

The prevalence of uveal ring melanoma in New Zealand is approximately 0.7%, which is twice as high as the rate found in current literature (0.3%).² All patients developed a blind eye with refractory secondary glaucoma and enucleation was the final definitive treatment for all cases. Epithelioid cell type was identified in all cases, and this is known to be the most malignant of the three known cell types for uveal melanoma.¹ In one case, we observed a change in the histopathology report from a low malignant spindle cell type at the time of iris biopsy to a highly malignant epithelioid-cell type on subsequent enucleation. Whether this represents a change in tumor aggression with time or a sampling bias in a heterogeneous tumor is inconclusive, but it was interesting to note that the immunohistochemistry findings did not change between initial iris biopsy and final enucleation. 

We noted that BAP-1 expression was lost in all cases of New Zealand European ethnicity (75%) with pigmented lesions in light-colored iris (blue and green) whereas BAP-1 was retained in the patient of mixed Chinese and Pasifika ethnicity with an amelanotic lesion in a brown iris. However, this did not correlate with the metastatic status of the cases at the time of last follow-up. Indeed, of those with BAP-1 expression loss, only one case developed uveal metastases to distant organs (case 3) whereas the remaining two developed local tumor extension due to a delay in definitive treatment with enucleation. BAP-1 expression and chromosome 3p loss are known to be strong prognostic predictors of high risk metastasis in uveal melanoma.^17–20 As many as 84% of metastasizing tumors have been demonstrated to harbor BAP-1 mutations¹⁹ and the presence of BAP-1 mutations carry a 10-fold increased risk of metastasis and a 9-fold increased risk of melanoma-specific mortality.²⁰ In our center, BAP-1 expression is carried out using manual assessment by anatomical pathologists. Despite analyzing BAP-1 expression in the largest surface area of tumor, it has been recognized that substantial intratumor heterogeneity exists²¹ and this may impact the final results. 

Considering current literature, we believe case two represents the first case report of uveal ring melanoma in a young patient of Pasifika ancestry. Uveal melanoma is rare in Pacific patients and we were only able to identify two large registry studies that identified Pacific patients within their study cohort. One study by Hu et al.²² used data from the Surveillance, Epidemiology, and End Results (SEER) program in the United States identified only 0.7% of those affected by uveal melanoma in the US population were of Asian or Pacific People ancestry. The second, more recent study was conducted in our center in New Zealand identified that Pacific People only made up 0.4% of those affected by uveal melanoma between 2000 to 2020.¹⁰ In this same study, we recognized earlier presentation of uveal melanoma (iris, ciliary body, and choroid) in our non-European cohort, consistent with global observations. Historically, it has been observed that uveal melanoma in Asian, Black, Pacific, and Hispanic populations presented earlier^1,22,23 and we do note that case two also identifies with Asian ancestry. Further research is required to elicit causes for the earlier development of this disease in the non-European cohort. 

We also report an unusual route of metastasis to regional and extra-regional lymph nodes and organs (parotid gland and ipsilateral breast) without liver involvement. Lymph node metastases arising from uveal melanomas are very rare owing to the lack of lymphatic drainage from the eye and only scattered reports are found in the literature.^24–29 However, the classical route of hematogenous dissemination may be compromised in uveal melanoma cases that have developed extrascleral spread where lymphatic dissemination can occur via the conjunctiva. There are only two prior reports of uveal melanoma metastasis to the parotid gland.^25,28 These occurred in young individuals with a history of filtering procedures prior to a diagnosis of uveal melanoma. The first case was a 22-year-old man (ethnicity not reported) who had an initial diagnosis of unilateral glaucoma mistakenly attributed to a childhood eye trauma.²⁵ The second case was a 12-year-old White girl with an initial diagnosis of iritis with secondary glaucoma. Both cases eventually required enucleation and were diagnosed with advanced epithelioid uveal melanoma with metastatic disease to the parotid gland and surrounding superficial parotid lymph nodes.²⁸ Furthermore, there have only been two documented cases of breast metastases (both bilateral) from primary uveal melanoma.^30,31 Therefore, to our knowledge, this is the first report of ipsilateral (unilateral) breast and parotid gland metastasis from primary uveal melanoma. 

In larger uveal ring melanoma studies (including ring melanomas of angle and ciliary body), the primary location of metastasis was through the hematogenous route to the liver (up to 100%), followed by bone (25%) and skin (8%).^2,4,6 It has been theorized that glaucoma surgery/procedures, such as filtering procedures, may allow a route of metastasis through the lymphatic drainage system, which is classically absent from intraocular structures.^24,25 The route of metastasis is presumed to be from invasion of emissary channels or the trabecular meshwork and subsequent drainage through the conjunctival/orbital lymphatic vessels.^24,28,32 Interestingly, we note that case two received transscleral cyclodiode, as this modality was thought to be minimally invasive and less likely to cause tumor dissemination. However, at the time of treatment, the status of the ciliary body was unknown and may have already been infiltrated with melanoma (as later confirmed on enucleation; see Table 2). Theoretically, transscleral cyclodiode may liberate malignant cells from the ciliary body into the trabecular meshwork with subsequent seeding through the conjunctival lymphatic vessels, thereby providing a pathway for metastases. Consequently, we currently advocate against pursuing any form of glaucoma procedures in cases of refractory glaucoma where uveal ring melanoma has not been excluded. In these cases, prior to transscleral treatment, use of investigations, such as ultrasound biomicroscopy, to rule out ciliary body malignancies may prove to be diagnostic.³³ Ultimately, in cases of suspected uveal ring melanoma with refractory glaucoma, the definitive treatment is with an enucleation,^2,6 and this should be pursued early in the management course due to the aggressive nature and risk of dissemination. 

This case series highlights real-world challenges in managing advanced uveal ring melanoma. Three patients were highly resistant to the concept of enucleation despite strong treatment recommendations. The concept of enucleation may be unpalatable for several reasons. Patients may be asymptomatic with normal vision and therefore refrain from invasive interventions in the early stages of the disease. Paradoxically, this may mean that the window for a less invasive treatment is lost. In our case series, all patients ultimately required an enucleation for a blind painful eye. As treatment is time-critical, discussion of treatment options should follow soon after diagnosis, allowing for a period of adjustment. In uveal ring melanoma, where treatment options are limited and the malignant course of the disease is known, it is pertinent that a thorough discussion on the prognosis, systemic risks, and eventual outcomes of eye retention are provided to allow the patient to make an informed decision on treatment. Furthermore, the clinician should fully engage with the patient in relation to the reasons for declining recommended treatments and, where appropriate, provide support and resources regarding any cultural and cosmetic reasons that may arise following enucleation. 

In conclusion, uveal ring melanoma represents a potentially deadly variant of uveal melanoma, and the index of suspicion should be high in cases with refractory glaucoma or hyphema despite maximum medical therapy. Any glaucoma procedures should be considered carefully to avoid potential tumor seeding, as enucleation remains the definitive treatment. Patients should be counseled empathetically regarding the high risk of metastases and informed on the risk of developing a painful, blind eye from this variant of tumor, which ultimately will require enucleation. 

Acknowledgments

The authors thank their patients for generous participation in research and consent to share their anonymized clinical images for medical education. The authors thank Amanda Charlton, anatomic pathologist with a special interest in ocular melanomas, for her input and expertise in analyzing the tumor specimens, Annie Jo, pathologist liaison and Lisa Duffy, technical specialist scientist from the FISH laboratory for inputs regarding uveal melanoma FISH analysis, and Regie Iñigo, head of immunohistochemistry, for providing detailed protocols on the immunohistochemistry analysis of uveal melanomas. The authors also thank the following consultant ophthalmologists who were involved in the care of the patients above: ocular oncology subspecialist Peter Hadden, uveitis subspecialist Rachael Niederer, oculoplastic subspecialists Brian Sloan, Catherine McMurray, Richard Hart, and Kent Chow, senior corneal fellow Bia Kim, and all ophthalmology trainees who provided care for the patients included in this study. 

J.Z.L. is funded by an unrestricted Health Research Council New Zealand Clinical Research Training Fellowship. 

Consent: Written informed consent was obtained from all patients for inclusion of clinical photographs in this case series. 

Disclosure: J.Z. Lim, None; A.Z. Crawford, None; C.N.J. McGhee, None