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 mutations
19 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 exists
21 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.