Initial management of uveal and conjunctival melanomas

INTRODUCTION — Approximately 85 percent of ocular melanomas arise from the uveal tract (including the iris, ciliary body, and choroid), and the remainder arise in the conjunctiva or (rarely) the orbit. There are significant clinical and genomic differences between melanomas of the uvea, conjunctiva, skin, and other sites.

The initial management of uveal and conjunctival melanoma is discussed in this section. The management of metastatic uveal melanoma is discussed separately. (See "Metastatic uveal melanoma".)

UVEAL MELANOMA — Uveal melanomas can arise in any part of the uveal tract, including the iris, ciliary body, and choroid (figure 1). Approximately 95 percent of uveal melanomas arise from the ciliary body and/or choroid, and approximately 5 percent arise in the iris.

Natural history of uveal melanocytic tumors

Choroidal and ciliary body tumors — Most choroidal and ciliary body melanomas are thought to arise de novo, but they can occasionally develop from preexisting nevi. Research has identified factors that can predict which nevi are most likely to progress to melanoma. Most of these risk factors for choroidal nevus growth were first described in the 1970s [1]. Subsequent studies have validated these factors and have suggested additional potential risk factors [2-5].

The following clinical features are the most commonly used to predict which choroidal nevi are most likely to grow:

●Tumor thickness greater than 2 mm by ultrasound

●Serous subretinal fluid overlying and/or surrounding the tumor

●Orange lipofuscin pigment clumps overlying the tumor

●Tumor location less than 3 mm from the optic disc

●Low internal reflectivity on ultrasound, or acoustic "hollowness"

●Absence of chronic features such as retinal pigment epithelial drusen, fibrosis, and atrophy

●Symptoms attributable to the tumor (eg, visual blurring, distortion, flashes, and/or floaters)

Importantly, the presence of these features and documented tumor growth is not always indicative of malignant transformation [6,7] or of high-risk genetic features [8]. Thus, these features should only be used as management guidelines, and caution is recommended when making clinical decisions based on these features alone, especially if growth is minimal or slow.

Iris tumors — Melanoma of the iris is rare, representing only approximately 5 percent of uveal melanomas [9]. By contrast, iris nevi are relatively common. However, the rate of transformation of iris nevus into melanoma is very low, with an actuarial risk of only approximately 5 percent at 10 years [10]. Risks factors associated with malignancy include larger tumor size, intratumoral vascularity, invasion through the anterior chamber angle to the ciliary body, increased intraocular pressure, and secondary glaucoma [10,11].

Prognosis is much better for melanomas of the iris than for melanomas of the ciliary body and choroid. Earlier diagnosis due to their readily visible location may contribute to this improved prognosis. Because of the less aggressive nature of iris melanomas, these tumors are often managed with close monitoring, although large or fast-growing tumors may require treatment with brachytherapy, proton beam radiation therapy (RT), local excision, or enucleation.

Risk factors — Epidemiologic factors that may increase the risk of uveal melanoma include:

●Host pigmentation factors – Light eye color, fair skin color, and propensity to sunburn may confer increased risk for uveal melanoma [12].

●Cutaneous and iris nevi – Cutaneous nevi, cutaneous freckles, and iris nevi have been associated with an increased risk of uveal melanoma [13,14].

●Ultraviolet light exposure – The role of ultraviolet exposure is unclear. If ultraviolet light is a risk factor for uveal melanoma, its contribution is much weaker than for cutaneous melanoma.

Epidemiologic studies investigating a potential association between ultraviolet light and uveal melanoma have yielded mixed results [15,16]. A meta-analysis of 12 studies found a borderline or nonsignificant association between uveal melanoma and leisure sun exposure, occupational sun exposure, and latitude of birth [17]. Arc welding was found to be a significant risk factor, but it is unclear whether this association can be attributed to ultraviolet light exposure. Next-generation sequencing of primary uveal melanomas does not reveal an ultraviolet-light-associated mutation signature [18].

●Ocular/oculodermal melanocytosis – Ocular/oculodermal melanocytosis is the condition that most strongly predisposes to uveal melanoma, with a lifetime risk of approximately 1 in 400 of developing uveal melanoma [19]. Patients with this condition should undergo periodic ophthalmic examination to rule out uveal melanoma.

Clinical presentation — Uveal melanomas often present without symptoms, being discovered on a routine eye exam. Approximately one-half of patients will present with visual symptoms such as flashes, floaters, or visual field defects.

Diagnosis of the primary tumor — The diagnosis of uveal melanoma is based upon funduscopic examination by an experienced clinician, which is followed by further characterization with specialized noninvasive testing techniques, such as ultrasound, optical coherence tomography, and fluorescein angiography. The most common simulating lesion in the differential diagnosis of uveal melanoma is a uveal nevus, and the two cannot always be distinguished with certainty on clinical examination due to an overlap in size between small melanomas and large nevi [20]. The differential diagnosis of uveal melanoma also includes metastasis to the uvea, especially from lung and breast cancers, which can be the first manifestation of an occult primary tumor [21].

The funduscopic and ultrasonographic features of uveal tumors usually allow the diagnosis to be determined noninvasively. Magnetic resonance imaging (MRI) of the orbit may occasionally be needed to confirm the diagnosis and may also be indicated in patients with tumors that are large, in proximity to nerves, or are suspicious for extraocular involvement. In approximately 5 percent of cases, however, a diagnostic biopsy is needed to distinguish an atypical uveal melanoma from a metastatic tumor, hemorrhagic lesion, or other simulating lesion.

Fine needle aspiration biopsy is now performed in the vast majority of patients with uveal melanoma for molecular prognostic testing, which can be used to customize metastatic surveillance testing and to stratify high-risk patients into clinical trials. The molecular characteristics of the tumor may influence the choice of initial management in selected cases. (See "The molecular biology of melanoma", section on 'Uveal melanomas' and 'Posttreatment systemic surveillance' below.)

Staging of distant (extraocular) disease — The American Joint Committee on Cancer (AJCC) eighth edition tumor, node, metastasis (TNM) staging system is used to stage patients with uveal melanoma (table 1 and table 2).

It is rare for patients diagnosed with uveal melanoma to have detectable metastatic disease at the time of primary tumor diagnosis. For most patients, we offer baseline imaging to assess for distant (extraocular) metastatic disease prior to treating the primary tumor. However, patients with small tumors at low risk for distant metastases may be offered systemic imaging after treatment of the primary lesion. We image the liver using MRI, given the propensity of patients with uveal melanoma to develop hepatic metastases. Alternative options include ultrasound of the liver or computed tomography (CT). However, in patients without evidence of liver metastases, extrahepatic disease is uncommon. Therefore, initial staging for extrahepatic disease using CT of the chest, abdomen, and pelvis may be omitted unless liver metastases are confirmed or the patient is experiencing relevant symptoms. (See "Metastatic uveal melanoma", section on 'Clinical presentation'.)

Prognosis — Local treatment for primary uveal melanoma is effective in preventing local recurrence in over 95 percent of cases, yet up to 50 percent of patients are at risk for metastatic disease. The high risk of metastatic disease is thought to be due to a propensity for early micrometastasis followed by a variable latency period prior to the emergence of overt metastatic disease [22].

The clinical, histopathologic, and molecular features that determine prognosis in uveal melanoma are as follows:

Clinical and histopathologic features — In patients with uveal melanoma, the clinical and histopathologic features of the primary tumor that are associated with poor prognosis include increased patient age, largest basal diameter of the tumor, ciliary body involvement, extrascleral tumor extension, epithelioid cell type, and vasculogenic mimicry patterns [23,24]. The AJCC utilizes several of these prognostic factors for its TNM staging system (table 1 and table 2) [25]. However, the eighth edition TNM system for uveal melanoma is cumbersome and appears to be prognostically equivalent to simply using the largest basal diameter of the tumor [26]. Future simplifications in the system may render it more practical for routine clinical use.

Molecular features — Advances in understanding the molecular pathogenesis of uveal melanoma are providing important information regarding prognosis. Additional studies are required to validate these observations. (See "The molecular biology of melanoma", section on 'Uveal melanomas'.)

●Chromosomal markers – Tumor chromosomal markers (eg, monosomy 3 and 8q gain) have some utility for predicting prognosis [27], but these markers are subject to sampling error due to tumor heterogeneity [28,29], and methods to detect them vary in their accuracy [30].

●Gene expression profiling – Gene expression profiling (GEP) has been shown to be superior to chromosomal markers, as well as clinical and histopathological prognostic factors, for defining groups at high risk for the development of metastatic disease [31-33]. Using primary uveal melanoma samples obtained by fine needle biopsy, GEP classifies tumors as having low (class 1) or high (class 2) metastatic potential depending on the expression of 12 discriminating genes and three control genes [34]. This profile test has been validated in 459 patients in a prospective multicenter study that showed it to be a better prognostic marker than monosomy 3 and the TNM staging system [31].

The use of gene expression profiling to determine posttreatment systemic surveillance in patients with treated uveal melanoma is discussed below. (See 'Posttreatment systemic surveillance' below.)

●Circulating tumor cells/DNA – Detection of circulating tumor cells or circulating tumor DNA may be a risk factor for metastasis and shortened survival in patients with uveal melanoma [35,36].

Management — Management of primary uveal melanoma is guided by many factors, including the size and location of the tumor, presence of extraocular extension, visual potential, patient age and preference, and presence or absence of metastases.

Observation — For asymptomatic patients with small uveal melanocytic tumors (<12 mm in diameter and <2 to 3 mm in height), initial management is often observation for evidence of growth, rather than immediate intervention [37]. (See 'Natural history of uveal melanocytic tumors' above.)

When observation is chosen, initial follow-up at two- to four-month intervals is typical. Imaging modalities commonly used in monitoring a small suspicious uveal melanocytic tumor include fundus photography, ultrasonography, optical coherence tomography, and fundus autofluorescence to identify evidence of tumor growth, subretinal fluid, orange lipofuscin pigmentation, and other risk factors for malignant transformation [8,38].

Radiation therapy — RT is the most common treatment for primary uveal melanoma [3]. Since uveal melanomas are relatively radioresistant, they must be treated with high-dose radiation, usually in the form of plaque brachytherapy or charged-particle RT.

Plaque brachytherapy — Plaque brachytherapy is the most common form of RT used in the treatment of uveal melanoma worldwide. Several radioisotopes have been used, including cobalt-60 (60Co), iodine-125 (125I), iridium-192 (192Ir), palladium-103 (103Pd), and ruthenium-106/rhodium-106 (106Ru/106Rh). The most commonly used isotope is 125I because of its favorable dosimetric characteristics across a broad range of tumor sizes (picture 1) [39] and because of its greater manufacturing accessibility with regards to application in the United States. 106Ru/106Rh is favored by some centers in the treatment of small tumors [40], but this isotope is associated with an increased rate of local treatment failure in larger tumors [41].

Earlier studies reported higher local recurrence rates with brachytherapy compared with charged-particle RT [42], but with the use of intraoperative ultrasonography for plaque localization [43-45], the local recurrence rates with plaque brachytherapy have decreased substantially and are now similar to charged-particle RT [46,47]. These findings suggest that most local recurrences after plaque brachytherapy are due to suboptimal plaque localization and undetected plaque tilting, which can be detected and corrected with intraoperative ultrasonography at plaque insertion and removal [48]. This technique is particularly important for tumors located posteriorly in the eye, where surgical access can be challenging and where the plaque is most prone to tilt [48]. Local tumor recurrence following primary RT is a risk factor for metastasis [49,50]. The importance of local control was illustrated by a study in which cause-specific survival at 10 years was 72 percent for patients with local control following proton beam RT versus 48 percent for those with local recurrence [51].

Consensus opinion guidelines for the use of radioactive plaque therapy have been published by the American Brachytherapy Society (ABS) [52], but research is ongoing into the optimal dosimetric parameters for uveal melanoma [53].

Charged-particle radiation therapy — Charged-particle RT (protons, carbon ions, helium ions) is the second most common form of RT used to treat uveal melanoma [42,54-56]. The physical properties of charged particles allow increased dose targeting at the end of the beam range and a sharp decrease in the dose of the radiation beam beyond the targeted area (the Bragg peak effect) (figure 2) [57]. Nevertheless, charged-particle RT can result in collateral damage to ocular structures such as the lashes, lacrimal gland, cornea, iris, lens, retina, and optic nerve. (See 'Ocular complications of radiation therapy' below.)

In most circumstances, plaque brachytherapy and charged-particle RT render very similar local control rates [58]. Associated ocular radiation complications are slightly different, with greater anterior eye complications with charged-particle RT and with greater visual acuity loss and immediate procedural discomfort with plaque brachytherapy. One circumstance in which charged-particle RT has an advantage over plaque brachytherapy is when the melanoma is encircling the optic nerve in a so-called "circumpapillary" configuration, where it is not possible to place a plaque completely around the tumor. Charged-particle RT also has dosimetric advantages when the tumor basal dimensions are too large to accommodate a plaque. Normally, such large tumors are treated with enucleation, but eye preservation may be desired in occasional situations, especially for patients with poor vision in the contralateral eye.

Photon stereotactic radiation therapy — Linear-accelerator-adapted stereotactic RT has also been used to treat uveal melanomas [59-61]. The total dose is typically between 50 and 70 Gy, delivered in five daily fractions.

While long-term follow-up data for photon stereotactic RT are more limited than for other radiation modalities, the local control and distant metastatic disease rates appear to be similar. However, the complication rate may be higher than for plaque brachytherapy, with approximately two-thirds of patients developing ocular complications within five years after treatment [62,63].

Ocular complications of radiation therapy — All types of RT for uveal melanoma can be associated with ocular complications, including dry eye, cataracts, neovascular glaucoma, vitreous hemorrhage, exudative retinal detachment, uveitis, scleral necrosis, radiation retinopathy, and optic neuropathy [64]. Some complications are more specific to charged-particle and photon stereotactic RT, including lash loss and lacrimal gland dysfunction [65,66].

The severity of ocular radiation damage is related to the increased total radiation dose and dose per fraction, and it may be increased in patients with diabetes or hypertension, or with previous chemotherapy [67]. The threshold dose for developing ocular radiation damage varies by tissue and is approximately 30 to 35 Gy for the retina and optic disc.

Early clinical signs of radiation retinopathy include macular edema and ischemia, which may be demonstrable using optical coherence tomography prior to becoming funduscopically detectable [68,69]. Later manifestations include microaneurysms, telangiectasia, hard (lipid) exudates, and cotton wool spots. Retinal neovascularization and vitreous hemorrhage are more severe but less common manifestations of radiation retinopathy. Radiation optic neuropathy presents initially with optic disc swelling and hemorrhages, and later evolves to optic atrophy with disc pallor.

Risk factors for visually significant radiation retinopathy and optic neuropathy include proximity of the tumor to the optic disc and fovea, increased tumor thickness, tumor-associated retinal detachment, and diabetes [70,71].

The radiation complication most commonly resulting in secondary enucleation is neovascular glaucoma, wherein neovascularization of the iris is caused by the elaboration of angiogenic factors by an ischemic and/or chronically detached retina, leading to closure of the anterior chamber angle and increased intraocular pressure. One study of patients treated with charged-particle RT reported five-year rates of neovascular glaucoma and neovascular-glaucoma-associated enucleation of 12.7 and 4.9 percent, respectively [72]. Risk factors for neovascular glaucoma include larger tumor diameter and thickness, increased patient age, chronic retinal detachment, and greater tumor vascularity [72-74].

Treatment of ocular radiation complications — Radiation-induced cataracts and dry eye can be managed by conventional ophthalmic means [75].

The management of radiation retinopathy, optic neuropathy, and neovascular glaucoma has been more challenging. Radiation causes endothelial cell loss and capillary closure, leading to retinal ischemia and the elaboration of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors [76,77]. Attempted treatments have included photodynamic therapy, laser photocoagulation, oral pentoxifylline, hyperbaric oxygen, periocular or intravitreal injection of corticosteroids, and intravitreal injection of anti-VEGF agents such as bevacizumab, ranibizumab, and aflibercept [78-80].

While none of these treatments is curative or preventative, promising results have been observed for intravitreal anti-VEGF therapy in maintaining or improving visual function in some patients with radiation maculopathy [81]. Intraocular anti-VEGF therapy, often combined with panretinal laser photocoagulation to reduce the production of pro-angiogenic factors from an ischemic retina, has also improved the management of neovascular glaucoma and decreased the rate of secondary enucleation [82]. The risk of neovascular glaucoma can also be reduced by prompt surgical repair of postradiation retinal detachment using vitrectomy techniques [83].

Other noninvasive techniques

Transpupillary thermotherapy — Transpupillary thermotherapy (TTT), also called diode laser hyperthermia, combines three features to induce deep-penetrating tumor necrosis: a modified infrared diode laser, typically at a wavelength of 810 nanometers, that allows deep tissue penetration; a large spot size, which decreases the risk of acute burns to the retina and tumor; and a low-energy, long-duration technique that allows the entire tumor to gradually heat up to approximately 45 to 60°C [84]. Despite these improvements over laser photocoagulation, TTT is only used as a primary treatment in tumors up to approximately 3 mm in thickness, and it is associated with significant complications, such as retinal vascular occlusions, macular edema, epiretinal membrane, vitreous hemorrhage, and retinal detachment [85]. Further, the local recurrence rate is around 30 percent after three years [86].

Consequently, TTT is used today only in highly selected patients for primary treatment of uveal melanoma. By contrast, TTT is often valuable in selected patients as an adjunct after RT to reduce the risk of local tumor recurrence [46]. Further, TTT is often useful at lower energy levels as a nonablative therapy in small borderline uveal melanocytic tumors producing symptomatic subretinal fluid [87].

Photodynamic therapy — Photodynamic therapy comprises intravenous injection of a photosensitive compound followed by light application at a wavelength that activates the photosensitizer, thereby forming singlet oxygen and free radicals that damage endothelial cells and lead to vascular occlusion and tumor necrosis [88]. Photodynamic therapy is not effective in larger tumors and is not generally used as an ablative primary treatment for uveal melanoma. However, it can be useful for drying up subretinal fluid in small, symptomatic macular tumors [89].

Laser photocoagulation — Laser photocoagulation uses high-temperature thermal energy to damage the tumor and its vasculature. However, photocoagulation is associated with visually significant adverse effects, including retinal vascular occlusions, vitreous hemorrhage, and retinal detachment. Furthermore, local recurrences are common due to the inability of this method to destroy tumor cells below the surface. Consequently, photocoagulation is not a common treatment for uveal melanoma in most centers.

Surgery

Local tumor resection — External or internal resection of a uveal melanoma without removing the entire eye is technically challenging, may require risky hypotensive anesthesia, and often results in serious and immediate postoperative complications, such as vitreous hemorrhage, rhegmatogenous retinal detachment, and proliferative vitreoretinopathy [90]. Additionally, local tumor recurrence in the eye and/or orbit is more common with these techniques than with more conventional forms of treatment.

For these reasons, and because modern RT techniques offer a reasonable, if not superior, alternative, enthusiasm for local resection has waned in recent years. Surgeons continuing to use external or internal resection of a uveal melanoma will now often use adjuvant plaque brachytherapy or charged-particle RT in an effort to reduce the risk of recurrence.

Enucleation — Until the 1970s, enucleation was the standard of care for uveal melanoma. However, retrospective studies comparing enucleation with RT did not show a survival advantage for enucleation [91-93].

In a large prospective clinical trial, the Collaborative Ocular Melanoma Study (COMS) compared 1317 patients with medium-sized choroidal melanoma randomly assigned to enucleation versus 125I brachytherapy with overall survival as the primary outcome measure [94]. Five-, 10-, and 12-year rates of death with a histopathologically confirmed melanoma metastasis were 10, 18, and 21 percent, respectively, in the 125I brachytherapy arm and 11, 17, and 17 percent, respectively, in the enucleation arm, and there was no statistically significant difference in survival between the two groups. No comparable study has been performed for charged-particle RT, but it is generally assumed that the outcome would be similar.

Enucleation is now generally reserved for patients who would not be expected to have a favorable outcome with RT, such as those with large tumors, marked extrascleral extension, neovascular glaucoma, extensive retinal detachment, or poor visual potential, or for select patients who prefer enucleation. Fortunately, the quality of life for patients undergoing enucleation appears to be similar to that for those treated with RT [95]. The COMS also confirmed that there is no demonstrable benefit to pre-enucleation RT to the eye and orbit for patients with large uveal melanomas [96].

Posttreatment systemic surveillance — Despite effective treatment of the primary site, many patients with uveal melanoma remain at risk for developing metastatic disease. Therefore, long-term surveillance is necessary to detect late recurrences [54]. (See "Metastatic uveal melanoma", section on 'Clinical presentation'.)

The standard of care in most centers is use molecular prognostic testing to risk-stratify patients and guide surveillance for metastatic disease. Molecular testing is usually obtained at the time of primary tumor treatment based on a fine needle biopsy, among other clinical tumor characteristics [97]. Patients are stratified based on low, medium, and high risk of metastatic disease based on the following criteria. (See "The molecular biology of melanoma", section on 'Uveal melanomas' and 'Prognosis' above.)

●Low risk – Class 1A metastatic potential [31], disomy 3, gain of chromosome 6p, EIF1AX mutation, AJCC T1 disease (table 1 and table 2).

●Medium risk – Class 1B metastatic potential, SF3B1 mutation, AJCC T2 and T3 disease.

●High risk – Class 2 metastatic potential, monosomy 3, gain chromosome 8q, BAP1 mutation, PRAME expression [98], AJCC T4 disease, extraocular extension, ciliary body involvement.

Systemic surveillance imaging for metastasis typically focuses on the liver, the most common site of metastatic disease [99]. While we prefer surveillance with MRI of the liver, other options include abdominal ultrasound for low-risk patients or CT. For all patients, we offer such systemic imaging to evaluate any signs or symptoms of metastatic disease as clinically indicated.

●For patients with low-risk tumors, we offer systemic imaging annually.

●For those with medium-risk tumors, we offer systemic imaging every 6 to 12 months for 10 years, then as clinically indicated.

●For those with high-risk tumors, we offer systemic imaging every 3 to 6 months for years 1 through 5; every 6 to 12 months for years 6 through 10; then as clinically indicated. Clinical trial participation is strongly encouraged in patients with high-risk disease.

The clinical presentation, diagnosis, and treatment of patients who develop metastatic disease while on surveillance is discussed separately. (See "Metastatic uveal melanoma".)

CONJUNCTIVAL MELANOMA

Clinical presentation — Conjunctival melanomas arise from melanocytes located in the basal layer of the conjunctival epithelium, and they represent approximately 5 percent of all ocular melanomas (figure 3) [100]. Risk factors include primary acquired melanosis (PAM) and preexisting conjunctival nevi. Approximately two-thirds of conjunctival melanomas arise from PAM, 16 to 25 percent de novo, and 1 to 6 percent from nevi [101,102]. The incidence of conjunctival melanoma is increasing, suggesting a possible association with ultraviolet light exposure [101,103]. Consistent with this possibility, an ultraviolet mutation signature was identified in conjunctival melanoma samples by whole-exome sequencing [104].

Molecular pathogenesis — The molecular pathogenesis of conjunctival melanoma is distinct from that of uveal melanoma and is more similar to cutaneous and mucosal melanoma. (See "The molecular biology of melanoma", section on 'MAPK pathway'.)

The most common mutations in cutaneous melanoma include BRAF, NRAS, NF1, EGFR, ALK, TERT, and APC, which are rare in uveal melanoma [104]. Common mutations in uveal melanoma, such as GNAQ, GNA11, BAP1, SF3B1, and EIF1AX, are lacking in most conjunctival melanomas. BRAF mutations are found in approximately 35 percent of conjunctival melanomas and are associated with sun-exposed tumor location (bulbar conjunctiva or caruncle), preexisting nevus, and absence of PAM [105]. Gain of chromosome 6p appears to be the most common chromosomal change [104].

Primary treatment — Conjunctival melanoma is typically treated with wide local surgical excision, followed by double freeze-thaw cryotherapy to the margins and possibly alcohol application [100]. Adjunctive plaque radiation therapy after resection has been used successfully [106]. Incisional biopsy and direct manipulation of the tumor should be avoided to prevent tumor cell seeding. Posterior tumor extension may require orbital exenteration [107].

Metastatic disease — The most common sites of metastasis include the regional lymph nodes, lung, liver, skin, and brain [102,108]. In one large series from a single country, tumor-related survival was 86.3 percent at five years, 72 percent at 10 years, and 67 percent at 15 years [102]. Some reports suggest that disseminated conjunctival melanoma may be responsive to targeted molecular therapies, such as BRAF and MEK inhibitors in BRAF-mutant tumors [109], and checkpoint inhibitor immunotherapeutic agents, such as pembrolizumab [110]. Further research is necessary to confirm these findings.

Prognosis — Clinical prognostic factors associated with poor prognosis include extrabulbar location (palpebral conjunctiva, caruncle, plica, or fornices), tumor thickness exceeding 2 mm, origin of the tumor (PAM and de novo versus nevus), involvement of adjacent tissue structures, and local tumor recurrence [102,105,111]. Histopathologic risk factors for tumor-related mortality include tumor infiltration beyond the substantia propria, incomplete surgical excision, and nodular or mixed (nodular and superficial) growth pattern [112]. Conjunctival melanoma can be staged according to the tumor, node, metastasis (TNM) system of the American Joint Committee on Cancer (AJCC) (table 3), which includes most of these risk factors [25].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

SUMMARY AND RECOMMENDATIONS

●Management of small, asymptomatic uveal melanoma – For asymptomatic patients with small uveal melanocytic tumors (<12 mm in diameter and <2 to 3 mm in thickness), an initial period of observation for evidence of growth is generally recommended until evidence of growth is documented. (See 'Natural history of uveal melanocytic tumors' above.)

●Management of larger, symptomatic uveal melanoma – For patients with larger tumors and for those with symptoms, initial treatment is usually indicated:

•For symptomatic patients and those with medium or large tumors, treatment with radiation therapy (RT) is generally recommended. RT can be administered using plaque brachytherapy, the most widely available form of RT, or with charged-particle RT. (See 'Radiation therapy' above and 'Enucleation' above.)

•Enucleation is generally reserved for patients in whom RT is unlikely to achieve adequate local tumor control or is likely to result in unacceptable ocular radiation complications due to large tumor size, extrascleral extension, or risk of neovascular glaucoma. (See 'Enucleation' above.)

●Posttreatment surveillance for uveal melanoma – After treatment of the primary tumor is completed, most centers use molecular prognostic testing to risk-stratify patients and guide surveillance for metastatic disease. (See 'Posttreatment systemic surveillance' above.)

●Management of metastatic uveal melanoma – For patients with metastatic disease, treatment options include liver-directed regional therapies, systemic targeted therapies such as tebentafusp, and immunotherapy. Clinical trial participation is strongly encouraged. (See "Metastatic uveal melanoma".)

●Initial management of conjunctival melanoma – For patients with conjunctival melanoma, initial management focuses upon wide local surgical excision, supplemented by cryotherapy and possibly alcohol application. (See 'Conjunctival melanoma' above.)

●Management of metastatic conjunctival melanoma – The management of metastatic conjunctival melanoma differs from that of uveal melanoma, is based upon molecular pathogenesis, and may include targeted molecular therapy and immunotherapy. (See "The molecular biology of melanoma", section on 'Conjunctival melanoma' and "Overview of the management of advanced cutaneous melanoma".)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Evangelos Gragoudas, MD; Anne Marie Lane, MPH; and Richard D Carvajal, MD, who contributed to earlier versions of this topic review.