Uveal melanoma (UM) is a malignant tumor arising from melanocytes of the uvea (iris, ciliary body, choroid). It is the most common primary intraocular tumor in adults, with choroidal origin accounting for over 90%, ciliary body origin about 7%, and iris origin 2%. This article focuses on choroidal and ciliary body melanoma.
The incidence is about 1/20 of that in Western countries, with 0.025 per 100,000 population. In Caucasians, the incidence is 2–8 per million, with a slight male predominance and a peak onset around age 60. Less than 1% of all uveal melanomas occur in individuals under 18 years old. Worldwide, approximately 6 million people are diagnosed with ocular melanoma annually 6).
All metastases are hematogenous (due to the absence of lymphatics in the uvea), with a strong tropism for the liver. Liver metastases are found in 70–90% of cases, and other sites include lung, bone, and skin 6). More than 62% of metastases become clinically apparent within 5 years after treatment of the primary tumor, but the remainder may be detected more than 25 years later. Since metastases may become evident several years to more than 10 years after treatment, long-term monitoring for metastasis is necessary.
The median overall survival (OS) after metastasis is 10–13 months according to a meta-analysis (2494 patients, 78 papers), with approximately 2% surviving more than 5 years and 13% estimated to survive more than 3 years 13). The 1-year survival rate is reported as 43–52%. The 12-year mortality rate is about 40%, which is similar regardless of the choice of local treatment 2). The 5-year survival rate for medium-sized tumors is 70–80% (no difference between eye-preserving therapy and enucleation), indicating that the choice of treatment does not significantly affect life prognosis.
For intermediate- to high-risk patients, it is recommended to continue liver imaging every 6 to 12 months for 10 years14).
In Western countries, the incidence among Caucasians is 2 to 8 per million people per year. Although it is the most common primary intraocular tumor in adults, the absolute number is small. The incidence in Japan is about 1/20 of that in Western countries, estimated at 0.025 per 100,000 population. It is more common in Caucasians and even rarer in Asians.
At the initial visit, approximately 30% of patients are asymptomatic, and the tumor is discovered incidentally during health checkups or examinations for other diseases. When symptoms appear, the breakdown is: decreased visual acuity 38%, photopsia 9%, floaters 7%, peripheral visual field defect 6%, and eye pain 2%.
When the tumor is small and located in the peripheral fundus, it is generally asymptomatic. As it grows, the following symptoms appear.
Symptoms of ciliary body melanoma show the following characteristics due to the peculiarity of its anatomical location5).
Secondary intraocular pressure elevation is observed in up to 17% of patients at the time of ciliary body melanoma diagnosis3).
Choroidal Melanoma
Typical appearance: Unilateral, elevated, dome-shaped, gray-brown choroidal mass with irregular borders.
Pigmentation: 55% heavily pigmented, 30% mixed, 15% amelanotic; color varies.
Mushroom shape: About 20% break through Bruch’s membrane and take on a mushroom (collar button) shape. Rapid growth occurs after Bruch’s membrane rupture.
Subretinal fluid: Frequently accompanied by serous retinal detachment.
Ciliary Body Melanoma
Size at detection: Often relatively large at discovery due to the anatomically hidden location.
Sentinel vessels: Frequently accompanied by dilated and tortuous episcleral vessels directly over the tumor.
Anterior segment changes: Prone to anterior displacement of the lens-iris diaphragm and secondary angle-closure glaucoma.
Extraocular extension: There is a risk of extraocular extension via the emissary canal.
The following 8 items are evaluated to differentiate between choroidal nevus and melanoma.
If there are 0 risk factors, the probability of growth within 5 years is only 3%, but it rises to 38% with 1 factor and over 50% with 2 or more factors.
The size classification according to the COMS protocol is shown below. It is used to select treatment strategy.
| Classification | Apical height | Maximum basal diameter |
|---|---|---|
| Small | 1.0–2.5 mm | 5.0–16.0 mm |
| Medium | 2.5–10 mm | <16 mm |
| Large | >10 mm | >16 mm |
The key points for differentiating the major tumors that occur in the choroid are shown below.
| Malignant Melanoma | Hemangioma | Metastatic Tumor | |
|---|---|---|---|
| Color | Black, gray, brown | Orange-red | Yellow-white |
| Shape | Dome-shaped | Fusiform | Plateau-shaped |
| Retinal detachment | None to moderate | None to mild | Marked |
| Growth | Relatively slow | None | Rapid |
Evaluation is based on the 8 risk factors of TFSOM-UHHD. With 0 factors, the probability of growth within 5 years is only 3%, but with 2 or more factors, it rises to over 50%. Regular follow-up with ultrasound and fundus photography is necessary.
Onset is mainly sporadic. The cause is unknown, but abnormalities in tumor suppressor genes and oncogenes, as well as sun exposure, are suspected to be involved. The main risk factors are shown below.
The correspondence between gene mutations and metastasis risk is shown below.
| Mutated gene | Mutation frequency | Metastasis risk / characteristics |
|---|---|---|
| GNAQ/GNA11 | 83–89% | Mutually exclusive initiating mutations. No direct association with metastasis risk. |
| BAP1 | 45% | Highest metastasis risk (peak at 3.5 years), class 2 |
| SF3B1 | 23% | Intermediate risk. Characterized by late metastasis (major peak at 7 years). |
| EIF1AX | 17% | Lowest risk of metastasis. |
GNAQ/GNA11 mutations are considered early events in tumor formation, and these mutations alone are not significantly associated with tumor size or metastatic risk. Intratumoral heterogeneity exists, and different morphological regions may have different genetic profiles (e.g., monosomy 3 is common across regions, while 6q deletion may be limited to pigmented areas) 2).
BAP1 mutations are associated with the highest risk of metastasis 1), while EIF1AX mutations are associated with the lowest 1).
Histologically, uveal melanoma is classified into spindle cell type and epithelioid cell type. Cases with a higher proportion of epithelioid cells are considered to have a poorer prognosis. Mixed types also exist.
BAP1 mutations carry the highest risk of metastasis (major peak at 3.5 years), SF3B1 mutations are characterized by late metastasis (major peak at 7 years), and EIF1AX mutations indicate the lowest risk. Additionally, detection of chromosome 3 deletion (monosomy 3) is associated with a high rate of metastasis and poor prognosis. These mutation data are obtained via fine-needle aspiration biopsy and are used to individualize metastasis surveillance plans.
Serial fundus photography is extremely important for documenting tumor growth, and the use of wide-angle fundus imaging (such as Optos) is also useful. In fundus autofluorescence, the autofluorescence properties of lipofuscin are used to identify orange fluorescence (orange pigment) that is brighter than drusen.
Ultrasonography is central to the diagnosis of uveal melanoma. Malignant melanoma shows characteristic attenuation.
SD-OCT visualizes neurosensory retinal and RPE changes. Characteristic findings on EDI-OCT (from a study of 37 eyes) are as follows.
It shows high signal on T1-weighted images and low signal on T2-weighted images. It is also used to monitor tumor size after I-125 plaque irradiation7).
In SPECT using 123I-IMP (iodoamphetamine) as a tracer, abnormal accumulation corresponding to the affected eye is observed 24 hours after intravenous injection, making it a highly sensitive and specific test. FDG-PET may also be used for diagnosis.
For intermediate- to high-risk patients, metastasis surveillance every 6–12 months for 10 years is recommended14).
Molecular testing of tumor tissue or cells obtained by needle biopsy is important for stratifying metastatic risk.
Performed in cases where the clinical diagnosis is uncertain. It is usually performed concurrently with plaque brachytherapy insertion. Although there is debate due to the risk of tumor seeding, it is increasingly performed for prognostic stratification by obtaining genetic profiles. Considering intratumoral heterogeneity, sampling from multiple morphologically distinct areas is desirable2).
S-100, HMB-45, MART-1 (MelanA), and vimentin are positive. For confirmation, it is recommended to use at least two melanocytic antibodies in combination with cytokeratin (epithelial marker). Semi-quantitative assessment of the proliferation index by Ki-67 is also performed. In ciliary body melanoma, strong HMB-45 positivity has been confirmed5). BAP1 nuclear staining plays an important adjunctive role in prognostic classification2).
The goals of treatment are: (1) maintaining useful vision in the affected eye, (2) destroying the tumor, and (3) preventing metastasis and recurrence.
When differentiation from choroidal nevus is unclear, strict follow-up is continued with fundus photography and B-mode ultrasound. For choroidal nevus (thickness <2 mm, asymptomatic), re-examination is performed 3 months after the initial examination, followed by observation every 6 months. For lesions <3 mm thick, fundus photography, FA, and A/B-mode ultrasound are performed initially, re-examined after 3–4 months, and then fundus photography is continued every 6–12 months for life. Small tumors with 3 or more risk factors should be treated promptly without waiting for growth documentation.
Brachytherapy
Ruthenium-106 plaque brachytherapy: A plaque containing ruthenium-106 (beta emitter) is sutured onto the sclera over the tumor. Due to beta radiation, the tissue penetration depth is short, making it suitable for small to medium tumors. Facilities where this can be performed are limited.
I-125 plaque: A COMS plaque containing iodine-125 is sutured onto the sclera over the tumor. The prescribed radiation dose to the tumor apex is 90 Gy. Mainly used in North America.
Indications: First-line treatment for small to medium tumors.
Side effects: Radiation maculopathy/retinopathy, cataract, neovascular glaucoma, optic neuropathy, scleral necrosis. Most occur within 5 years after treatment.
Recurrence: 80% of local recurrences occur within 3 years. 98% are detectable on color fundus photography.
Visual prognosis: COMS 3-year data show that 43–49% of patients have visual acuity of 20/200 (equivalent to 0.1) or worse. Radiation retinopathy is the main cause 10).
Proton Beam Therapy
Characteristics: Particle therapy that concentrates radiation dose on the tumor using the Bragg peak effect. Eye-sparing treatment.
Indications: Eye-sparing option for small to medium tumors.
Treatment effect: Complete tumor regression has been reported 6 months after proton beam therapy in some cases.
Advantages: Low radiation dose to surrounding normal tissues.
The indications for external beam radiation therapy such as heavy particle therapy and CyberKnife are expanding. While eye preservation is possible, visual function is often lost due to complications such as optic neuropathy and neovascular glaucoma. Although the number of facilities where it can be performed is limited, it is positioned as one of the treatment options.
Transpupillary thermotherapy (TTT) is indicated for small choroidal melanoma (thickness ≤3 mm). The main parameters are shown below 9).
| Parameter | Setting Value |
|---|---|
| Wavelength | 810 nm (near-infrared) |
| Power | 400–1,000 mW |
| Spot Size | 3,000 μm |
| Irradiation Time | 1–3 minutes per spot |
| Depth | 3–4 mm |
In the “sandwich therapy” combining transpupillary thermotherapy and brachytherapy (plaque), the 5-year recurrence rate is reported as 3% with I-125 and 10% with Ru-106 9).
When the tumor is relatively small and especially located anteriorly, local resection (removing only part of the sclera and the tumor) may be performed.
Enucleation is indicated for large tumors (COMS large classification: apical height >10 mm, largest basal diameter >16 mm) when eye preservation is difficult. It remains one of the treatment options today. For orbital recurrence after enucleation, surgical and radiation treatments are discussed in a multidisciplinary conference. Radiotherapy is recommended at 2 Gy/fraction for a total of 45–50 Gy in 20 fractions.
Systemic treatment options for metastatic uveal melanoma are significantly more limited compared to cutaneous melanoma.
Post-treatment monitoring of the affected eye is performed every 6 months for 2–5 years, then annually thereafter. Patients with complete tumor regression can be transitioned to a local optometrist, and those who underwent enucleation with R0 resection can be transitioned to an ocularist after wound healing.
For metastasis surveillance, liver MRI or ultrasound every 6 months is recommended for high-risk patients, and liver imaging every 12 months for low-risk patients 14). Non-ionizing radiation imaging (MRI, ultrasound) is recommended to avoid radiation exposure. For high-risk patients with monosomy 3, metastasis monitoring should be intensified.
For small to medium-sized tumors, options include brachytherapy (e.g., 106Ru plaque therapy), proton beam therapy, heavy ion therapy, and CyberKnife, often allowing eye preservation. Large tumors may require enucleation, but it has been shown that the choice of treatment does not affect metastasis rate or overall survival. Therefore, while prioritizing life prognosis, the possibility of preserving visual function is considered.
If HLA-A*02:01 positive, tebentafusp is the first-line candidate. It is the first drug shown to significantly improve overall survival in a phase III trial. For liver-limited metastasis, if R0 resection is possible, hepatectomy is considered. Liver-directed therapies (PHP, SIRT, TACE, etc.) are also options. The efficacy of immune checkpoint inhibitors is limited compared to cutaneous melanoma (monotherapy response rate ~5%), and it is important to conduct a multidisciplinary conference at a specialized facility before starting treatment.
The pathogenesis of uveal melanoma involves distinct molecular pathways different from those of cutaneous melanoma.
Mutations at Q209 of GNAQ/GNA11 are most common, and R183 mutations and G48L mutations have also been identified 1). These mutations impair GTPase activity, leading to a constitutively active GTP-bound state 1). GNAQ/GNA11 mutations result in sustained activation of multiple signaling pathways, including the MAPK pathway (Ras/RAF/MEK/ERK) 1). GNAQ/GNA11 mutations are early events in tumorigenesis and are not significantly associated with tumor size or metastasis risk.
Secondary driver mutations (BAP1, SF3B1, EIF1AX) occur almost completely mutually exclusive of each other and have important implications for stratifying metastatic risk. BAP1 mutations are classified as class 2 (high metastatic risk), while patients with SF3B1 mutations have a median overall survival after metastasis of 3.9 years (95% CI 2.3–6.2) and a 12-month overall survival rate of 94%, indicating a relatively favorable course. In metastatic lesions, GNAQ (57%) and GNA11 (36%) are also detected in a mutually exclusive manner.
Rare initiating mutations such as CYSLTR2 and PLCB4 are detected in almost all remaining uveal melanomas.
Since the uvea lacks lymphatic vessels, all metastases occur hematogenously 6). Early-stage lesions are small and flat, but when they become elevated, they break through Bruch’s membrane and grow rapidly. Surrounding serous retinal detachment may occur.
Circulating tumor cells are detected in 10–88% of patients. The notable tropism for the liver is explained by the seed and soil theory. Micrometastases can occur early during the asymptomatic phase of the primary tumor. Monosomy 3 is found in 70–100% of metastases, and BAP1 mutations in 60–80%. Metastases to rare sites such as the thyroid have also been reported 11).
Two growth patterns of liver metastases are known: sinusoidal infiltrative and periportal nodular. In the infiltrative type, collagen production leads to pseudosinusoid formation, while in the nodular type, VEGF-induced angiogenesis is the main mechanism 13).
Intratumoral VEGF concentration is significantly higher than in healthy eyes and positively correlates with tumor basal diameter and height 3). Systemic administration of anti-VEGF drugs (bevacizumab) has shown metastasis-suppressing effects in mouse models, but contradictory results have been reported with intravitreal administration accelerating tumor growth 3).
A case of rapid growth of ciliary body melanoma after intravitreal bevacizumab injection (basal diameter from 2.51 to 18.0 mm, height from 6.23 to 11.0 mm over 7 weeks) has been reported 3). The median doubling time of typical choroidal melanoma is 154–511 days, making this rapid growth unusual.
Intratumoral heterogeneity exists both morphologically and genetically, affecting the prognostic accuracy of biopsy 2). This is why sampling from multiple sites is recommended 2).
An autophagy-related 9-gene signature (9-ARG: IKBKE, BNIP1, ITGA6, FKBP1A, DLC1, PRKCD, GABARAPL1, LMCD1, TUSC1) has been shown to be useful for prognosis prediction in uveal melanoma (validated in TCGA 80 cases + GEO 150 cases)8). In the high-risk group, the IL6-JAK-STAT3 pathway, angiogenesis, and reactive oxygen species pathways are enriched, and although immune cell infiltration (CD8 T cells, activated memory CD4 T cells) is increased, a paradoxical finding has been reported that it is an immunosuppressive phenotype and associated with poor prognosis8). This is thought to be related to the eye being an immune-privileged organ.
Tebentafusp is a T-cell receptor bispecific fusion protein designed for HLA-A02:01-positive patients7). It recognizes the tumor-associated antigen gp100 on the HLA-A02:01 complex and activates T cells to exert antitumor effects.
In a phase III trial, significant improvement in overall survival (median extension of 6 months compared to investigator’s choice control) was shown in HLA-A*02:01-positive metastatic uveal melanoma patients14).
In a case report by Krohn et al. (2025), a patient with metastatic uveal melanoma who received tebentafusp (weekly IV: 20→30→68 mg escalation) based on the phase III trial showed a favorable course with stable liver metastases and no new lesions after 26 months of treatment7). In this patient, the right eye central choroidal thickness decreased by 49% from 241 μm to 123 μm, and fundus depigmentation, poliosis of eyebrows and eyelashes, and skin depigmentation spots were observed.
gp100 is also expressed in normal choroidal melanocytes and is thought to be related to the mechanism of choroidal thinning7). Ocular side effects may be irreversible, and regular ophthalmic monitoring is necessary during administration.
Currently, evidence for adjuvant systemic therapy is insufficient, and administration outside of clinical trials is not recommended14). Families with BAP1 germline mutations (BAP1 tumor predisposition syndrome) are associated with increased risk of multiple cancers (renal cell carcinoma, mesothelioma, cutaneous melanoma, etc.) and are candidates for genetic counseling14).
Wagle et al. (2022) reported a case of tumor necrosis of uveal melanoma after COVID-19 vaccination 12). Necrotic uveal melanoma accounts for 3–6% of all cases and may present diagnostic challenges on pathology.
Combination of a Gαq inhibitor (YM-254890) and a MEK inhibitor (trametinib/binimetinib) has shown synergistic antitumor effects in vitro and in vivo 1). While MAPK signaling recovers within 24 hours with Gαq inhibition alone, the combination with a MEK inhibitor suppresses the recovery of MAPK signaling 1).
In uveal melanoma, immune checkpoint inhibitors have limited efficacy compared to cutaneous melanoma. Monotherapy response rates are approximately 5%, and combination nivolumab plus ipilimumab yields 12–18% 14).
In a cardiac metastasis case reported by Madani et al. (2022), treatment with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (every 3 weeks for 4 cycles) followed by nivolumab maintenance led to disease progression 6). The regimen was then switched to nab-paclitaxel/temozolomide, but the outcome was ultimately poor.
Local approaches for metastatic lesions include hepatectomy, radiofrequency ablation, hepatic artery embolization, percutaneous hepatic perfusion (PHP) with melphalan, yttrium-90 microsphere brachytherapy (SIRT), and MR-guided laser-induced thermotherapy. PHP and SIRT show the longest OS 14).
The 9-ARG prognostic signature may provide insights for personalizing immunotherapy 8). Detection of somatic pathogenic mutations in MBD4 may predict response to checkpoint inhibitors.
It is a T-cell receptor bispecific fusion protein for HLA-A*02:01-positive metastatic uveal melanoma patients. Targeting the tumor-associated antigen gp100, it is the first drug to significantly improve overall survival in metastatic uveal melanoma in a Phase III trial. During administration, attention must be paid to ocular side effects such as choroidal thinning and fundus depigmentation.
