NCCN临床实践指南：葡萄膜黑色素瘤（2025.V1）

Overview

Uveal melanoma is the most common type of primary intraocular

malignancy in adults, with new cases occurring in 5 to 10 people per

million per year.1-9 Uveal melanomas can arise anywhere in the uveal

tract, with less than 75% arising in the choroid, and the remainder arising in the iris or ciliary body.1,3,6,10,11

The distribution of uveal melanoma by sex, race, and geography differs

from that of cutaneous melanoma.1,3,12 Most uveal melanomas are

localized at first presentation, and only a small percentage of cases

present with metastases (<3%).6,12-16 Risk of metastasis varies by stage at presentation, with 5-year risk of metastasis ranging from 3% to 5% for

stage I to 44% or greater for stage III.10,15 Large population-based

analyses have reported disease-specific survival (DSS) between 70% to 81% at 5 years.2,5,6,12,14,15,17-20 For those with early-stage disease (stage I–II), 5-year DSS is 85% or better.15,17,20 For those with distant metastatic

disease, most studies report estimated 5-year survival of less than

20%,15,17,21-24 which has not improved over the past few decades.25

These NCCN Guidelines include recommendations for management of

melanomas arising in the choroid or ciliary body. Recommendations for iris melanomas are not included in these guidelines, because iris melanomas are rare (3%–5% of uveal melanomas),3,10,11,26,27 have a low rate of

systemic metastasis (~5% at 5 years compared with 15%–20% for ciliary body or choroidal melanomas),28 10,29-32 have a better prognosis than other types of uveal melanoma,27,32 have a different AJCC staging system,33 and have a different molecular signature.34-38 Treatments for iris melanoma

may differ from other types of uveal melanoma due to these factors, as

well as anatomic considerations, ease of resection,39-42 and the negative

effects of radiation to the iris.43-48 Moreover, patients with iris melanomas were excluded from many of the large randomized trials that inform

treatment recommendations for uveal melanomas.16,49,50

The patterns of presentation and prognosis for uveal melanoma are

different from cutaneous melanoma. The AJCC Staging Manual 8th Edition includes separate staging systems for cutaneous, uveal, and conjunctival

melanoma.33 The staging system for uveal melanoma is further subdivided into separate T-staging for iris versus choroidal or ciliary body

melanoma.33 Each of these staging systems is based on survival data

from large epidemiologic studies, with more data independently validating

the staging system for melanoma of the choroid and ciliary body14,15,20

compared with the iris31 or conjunctiva.51,52

Cutaneous, uveal, and conjunctival melanomas also have different

molecular signatures.36,53-63 Whereas BRAF, NRAS, KIT, and TERT

promoter mutations are extremely rare in uveal melanoma,36,53-56,62,64,65

they are more common in conjunctival and cutaneous melanomas.57-63

Molecular markers common in uveal melanomas that may have prognostic significance are not often found in conjunctival or cutaneous melanoma.

These include chromosomal abnormalities (particularly chromosomes 3

and 8),14,66-70 and mutations in GNAQ or GNA11 (>80% of uveal

cases),36,53,68,71,72 BAP1,73,74 SF3B1, and EIFAX.38,75,76

Risk Factors for Uveal Melanoma

Literature Search Criteria and Guidelines Update

Literature Search Criteria and Guidelines Update Methodology

Methodology

Prior to the update of this version of the NCCN Guidelines for Melanoma: Uveal, an electronic search of the PubMed database was performed to

obtain key literature using the following search term: uveal melanoma. The PubMed database was chosen as it remains the most widely used

resource for medical literature and indexes peer-reviewed biomedical

literature.77

The search results were narrowed by selecting studies in humans

published in English. Results were confined to the following article types: Clinical Trial; Guideline; Meta-Analysis; Randomized Controlled Trial;

Systematic Reviews; and Validation Studies.

The data from key PubMed articles as well as articles from additional

sources deemed as relevant to these guidelines and discussed by the

panel have been included in this version of the Discussion section (eg,

e-publications ahead of print, meeting abstracts). Recommendations for

which high-level evidence is lacking are based on the panel’s review of

lower-level evidence and expert opinion.

The complete details of the Development and Update of the NCCN

Guidelines are available at www.NCCN.org.

Risk Factors for Uveal Melanoma

Choroidal Nevi

Choroidal Nevi

Large population-based studies have found that choroidal nevi occur in

1.9% to 6.5% of the population, depending on the population studied.78-80 Choroidal nevi can transform into choroidal melanoma,81,82 and one study

reported that of uveal melanomas diagnosed, 8% arose from a previously documented nevus.81 Others have argued that the fraction of uveal

melanomas that arise from nevi may in fact be much higher, as many

patients diagnosed with uveal melanoma have not had an ophthalmologic

exam for many years.83 The rate of transformation from nevi to uveal

melanoma is an issue of much debate.79,84-90 Besides, choroidal nevi can

be difficult to distinguish from choroidal melanoma, as there is evidence

that many small lesions presumed to be nevi may actually be

melanoma.91,92 Due to uncertainty regarding uveal melanoma diagnosis, studies have looked at the likelihood of lesion growth in patients with

untreated melanocytic choroidal lesions (Table 1).93,86,87,94-100 Documented growth has been correlated with progression to uveal melanoma94 and risk

of metastasis,94 even though some growing choroidal nevi do not undergo malignant transformation.86,93,97,98,101,102 It is important to note that for

patients with small lesions presumed to be nevi or indeterminate, who are

observed and treated upon evidence of transformation, the risk of

metastasis and death is low.87,94,98 However, these risks increase with

increasing baseline tumor size.87 Patient characteristics that increase the likelihood of choroidal nevi growth or choroidal/ocular melanoma include

Birt-Hogg-Dubé syndrome,103,104 myotonic dystrophy,105-107 and

immunocompromise.108,109

Ocular/Oculodermal Melanocytosis

Ocular/Oculodermal Melanocytosis

The rate of ocular/oculodermal melanocytosis, which causes

hyperpigmentation of the episclera, uvea, and skin, is much higher in patients with uveal melanoma than in the general population.110-115

Familial Uveal Melanoma

Familial Uveal Melanoma

Although only a small percentage of patients with uveal melanoma have at least one family member with uveal melanoma,116,117 this rate is higher

than would be expected, given the very low incidence of uveal melanoma in the population as a whole.118,119 Having a family member with uveal

melanoma is therefore considered a risk factor for melanoma. Studies of families with more than one member with uveal melanoma have shown

that there are several family cancer syndromes associated with increased risk of uveal melanoma.

Certain BAP1 germline mutations have been associated with

predisposition for uveal melanoma, malignant mesothelioma, cutaneous

melanoma, renal cell carcinoma, and cholangiocarcinoma.74,119-129 Some families with BAP1 tumor predisposition syndrome also tend to have

atypical Spitz tumors, which are benign/precursor melanocytic lesions with distinctive clinical and pathologic features.119,123,126,130-132 In individuals with germline BAP1 mutations associated with this syndrome, the risk of uveal melanoma is high (up to ~30%),126,132,133 uveal melanoma tends to develop at a younger age,125,132 primary lesions tend to be larger and involve the

ciliary body,74 and the disease has a more aggressive course.74,134 Some individuals with this syndrome develop more than one type of primary

cancer,132,133,135 and there is a high likelihood of BAP1-associated cancers in first- or second-degree relatives.119,132

Mutations in PALB2 have been associated with increased risk for

developing breast, ovarian, and pancreatic cancer. Pathogenic variants leading to biallelic inactivation of PALB2 were identified in tumors of two patients with familial uveal melanoma.136 This finding from a

retrospective case series might warrant further investigation into PALB2 as a uveal melanoma susceptibility gene.

MBD4 deleterious mutations have been identified in uveal melanoma

tumors at increased incidence compared with the general population and

The Relationship Between Uveal and Cutaneous Melanoma

associated with high tumor mutational burden.137,138 Questions remain

whether MBD4 germline variants or somatic loss predisposes individuals to uveal melanoma.139 How MBD4 inactivation might affect

immunotherapy response is also worth further investigation.137,140

Based on case reports of uveal melanomas developing in patients with

neurofibromatosis,141-148 neurofibromatosis type 1 (NF-1) is thought to be a risk factor for uveal melanoma, although population statistics supporting

this claim are lacking.149

Other Potential Risk Factors

Other Potential Risk Factors

Patient characteristics associated with increased uveal melanoma risk are lighter skin and eye color and propensity to sunburn.150-153 Occupational

history of welding and a dose-response relationship with job duration have also been associated with increased uveal melanoma risk.154

In conclusion, the NCCN Panel recommends evaluation for evidence of

hereditary syndrome and referral for genetic counseling and testing in

case of: early age of diagnosis (<30 years of age), history of other primary cancers in the patient, or family or personal history of other cancers known to be associated with a hereditary syndrome.

The Relationship Between Uveal and Cutaneous Melanoma

Clinic-based studies (N < 250) evaluating the likelihood of finding

concurrent cutaneous melanoma in patients with ocular melanoma

suggest a relationship between these two cancers.155-158 Most large

population-based studies reveal no relationship between preexisting

cutaneous melanoma and the subsequent development of uveal

melanoma.159-163 However, one SEER-based study revealed a potential relationship between these two cancers.164 For patients who present with uveal melanoma as their first primary cancer, some population-based

studies have shown increased risk of subsequent cutaneous

melanoma,160-162,165 and others have not found the risk to be significantly

higher than in the general population.163,166 Currently the NCCN Panel does not consider cutaneous melanoma to be a risk factor for uveal

melanoma, and patients with cutaneous melanoma do not need more frequent ocular screening than the general population.

Diagnosis and Workup

Diagnosis and Workup

Characteristics, Detection, and Differential Diagnosis

Characteristics, Detection, and Differential Diagnosis

Uveal melanoma typically presents as a pigmented lesion.167 One study of 8033 eyes with uveal melanoma found that the lesion was pigmented in

55%, nonpigmented in 15%, and 30% had a mixture of pigmented and

nonpigmented areas.168 Uveal melanoma most often presents as a domeshaped tumor (75%), but approximately 20% present with a mushroom

shape due to the rupture of Bruch’s membrane and growth into the subretinal space.168 A small number of cases present as a diffuse, flat,

plateau-shaped tumor (6%) or have a multinodular tapioca appearance

(<1%).168 Subretinal fluid is present in the majority of cases (75%).168

The majority of uveal melanomas are symptomatic at

presentation,11,81,169,170 but studies have reported 13% to 30% of patients were asymptomatic at diagnosis (and are discovered by routine eye

exam).11,81,167,170 The most common symptom is blurred vision; other

common symptoms include visual field defect/loss, photopsia, irritation

and pain, metamorphopsia, floaters, redness, and pressure.11,81,170

Although current imaging techniques provide high accuracy of diagnosis of medium to large uveal melanomas,171,172 real-world studies have reported relatively high rates of delay in diagnosis and treatment (23%–37%) due to failure to detect these lesions in the initial ophthalmologic exam.11,81,170,173 Surprisingly, the rate of delayed diagnosis is also high in symptomatic

patients.11,81 Furthermore, conditions such as choroidal nevus, congenital hypertrophy of the retinal pigment epithelium (RPE), and choroidal

hemangioma can be mistaken for uveal melanoma.174-177 Therefore, full

dilation of the pupil and meticulous examination of the fundus in any

patient presenting with symptoms is critical.83

Ciliary body melanoma can be difficult to detect,11 as it is often hidden

behind the iris,178 and symptoms often do not develop until the tumor is

large.11,43,48,178 Ciliary body melanoma can cause lens tilting or

displacement,48,178 cataract development,48,178,179 and elevated intraocular pressure,48 and is often associated with dilated episcleral “sentinel”

vessels.178 Ciliary body melanomas usually present with a dome

shape,48,178 but occasionally have a circumferential ring shape.178,180

As described above, several risk factors have been identified that may

increase the risk of uveal melanoma. When a pigmented lesion on the

ciliary body or choroid is discovered, these factors should be evaluated, as they may inform the index of suspicion.

It is also important to rule out metastasis to the uvea from other cancers— either known cancers based on patient history or occult primary cancer.

Among patients with metastases to the eye or orbit, the most common

primary cancer diagnosis is breast cancer, followed by lung cancer, which together account for over half of the cases.181-183 The remainder of uveal metastases can arise from cancers of the kidney, gastrointestinal (GI)

tract, skin, prostate, thyroid, pancreas, and others.182,183

Initial Workup of Suspicious Pigmented Uveal Lesion

Initial Workup of Suspicious Pigmented Uveal Lesion

Upon discovery of a suspicious pigmented lesion in the ciliary body or

choroid, clinical evaluation should include a complete history and physical

(H&P), including personal or family history of prior or current cancers

Comprehensive Eye Exam (biomicroscopy)

(outside the eye), as this may help determine whether the lesion is primary uveal cancer or a metastasis from another primary cancer. A wide variety of imaging and clinical exam techniques have been tested for their utility in diagnosis and characterization of uveal melanoma. In most cases, the

diagnosis of uveal melanoma and characterization for treatment planning (or follow-up) can be achieved based on comprehensive exam of the front and back of the eye including biomicroscopy and dilated fundus exam

(indirect ophthalmoscopy).47,48,83,184 In some cases, additional imaging may be needed to confirm diagnosis or better characterize the tumor for

treatment planning (or monitoring). Additional imaging options that may be

• Treatment Dosing Information

Using iodine-125 Collaborative Ocular Melanoma Study (COMS) plaques, 85 Gy should be prescribed to the tumor apex at low dose-rate

(≥0.6 Gy/h). Dose adjustments may need to be made for non-COMS plaques.5-7 The plaque margin on the tumor border should be

≥2 mm when feasible (diameter of plaque ≥4 mm larger than largest basal diameter of tumor). The exception is for tumors near the optic

nerve where it may be impossible to achieve adequate coverage of the margins. The largest commercially available brachytherapy plaque

is 23 mma in diameter; thus, plaque brachytherapy is recommended only for tumors with largest basal diameter ≤19 mm.

▲Using other radioisotopes (eg, ruthenium-106, palladium-103, strontium-90, cobalt-60, cesium-131), or non-COMS iodine-125 plaques,

60–100 Gy may be prescribed at low dose-rate to the tumor apex; alternatively, a minimum dose may be prescribed to the tumor base. The

plaque margin on the tumor border may vary for other radioisotopes.

PRINCIPLES OF RADIATION THERAPY

Continued References

a The cutoff for largest basal diameter depends on the dimensions of the largest brachytherapy plaque available, so may depend on the type of plaque and isotope selected if brachytherapy is used.

Particle Beam Therapy

Particle beam therapy is a common form of definitive radiotherapy for the primary tumor.1 A prospective trial found no difference in causespecific survival among patients with tumors ≤15 mm in maximum basal diameter and ≤11 mm in apical height randomized to plaque

brachytherapy or particle beam therapy.8

’Particle beam therapy is appropriate as upfront therapy after initial diagnosis, after margin-positive enucleation, or for intraocular or orbital

recurrence.

Particle beam therapy should be performed by an experienced multidisciplinary team including an ophthalmic oncologist, radiation

oncologist, and particle beam physicist.9

Tumor localization for particle beam therapy may be performed using indirect ophthalmoscopy, transillumination, and/or ultrasound

(intraoperative and/or preoperative), MRI, and/or CT.

For intraocular tumors:

◊ Using protons, 50–70 cobalt Gray equivalent (CGyE) in 4–5 fractions should be prescribed to encompass the planning target volume

surrounding the tumor.9-11,b

◊ Using carbon ions, 60–85 CGyE in 5 fractions should be prescribed to encompass the planning target volume surrounding the tumor.12◊ Fiducial markers (tantalum clips) are encouraged to permit eye and tumor position verification for image-guided radiotherapy delivery.

◊ Volumetric planning in 3 dimensions (with or without CT and/or MRI) is encouraged to maximize radiation delivery to tumor and minimize radiation delivery to organs and tissues at risk of injury from radiation.

UM-B 2 OF 4 Continued

b The prospective trial showing no difference in local control for 50 CGyE and 70 CGyE in 5 fractions was for tumors <15 mm in diameter and <5 mm in height and near the optic disc or macula (within 4 disc diameters of either structure) (Gragoudas ES, Lane AM, Regan S, et al. A randomized controlled trial of varying radiation doses in the treatment of choroidal melanoma. Arch Ophthalmol 2000;118:773-778).

Proton Beam Therapy

• Tumor localization for proton beam therapy may be performed by indirect ophthalmoscopy, transillumination, and/or ultrasound(intraoperative or postoperative but before proton beam), x-ray, MRI, and/or CT.13

ComprehensiveNCCN Guidelines Version 1.2025 1 NCCNCancer

UM-B 3 OF 4

Stereotactic Radiosurgery (SRS)

SRS is the least often used form of definitive radiotherapy for the treatment of primary or recurrent intraocular tumors.14,15

Few prospective studies have assessed the efficacy and safety of radiosurgery.16,17

Tumor localization, fiducial marker use, and planning for SRS are generally consistent with particle beam therapy approaches.

Using fractionated SRS: 45–70 Gy in 2–5 fractions should be prescribed.

Using single-fraction SRS: 18–45 Gy in 1 fraction should be prescribed.

Photon Beam Radiotherapy

• Treatment/Dosing Information

Photon beam radiotherapy is a preferred option as an adjuvant to surgery for orbital involvement.

◊ Adjuvant radiotherapy can be used in patients at risk for local recurrence (margin-positive enucleation or exenteration) or regional

recurrence (resected regional metastases).

– Adjuvant RT Dosing

▪ A dose of 20–30 Gy in 5 fractions should be prescribed to the clinical target volume at risk for recurrence18,19 using intensitymodulated RT (IMRT) with image guidance.

For symptom palliation, photon beam radiotherapy can be used for treatment of distant metastases at risk for causing symptoms or for

palliation of symptomatic distant metastases.

– RT Dosing for Distant Metastases

▪ Doses of 8–30 Gy in 1–10 fractions should be prescribed to the appropriate target volume20 using appropriate 3D or IMRT techniques with or without image guidance.

▪ For ablative therapy of oligometastases, doses of 16–24 Gy/1 fraction or 24–60 Gy/2–8 fractions should be prescribed to the

appropriate target volume using appropriate stereotactic body RT (SBRT) techniques with image guidance.21-24

Radioembolization

• Selective internal RT for patients with liver metastases using yttrium-90 has been reported in retrospective studies and in one prospective study.25,26

• Further study is required to determine the appropriate patients for and risks and benefits of this approach.

UM-B 4 OF 4

1 Abrams MJ, Gagne NL, Melhus CS, Mignano JE. Brachytherapy vs. external beam radiotherapy for choroidal melanoma: Survival and patterns-of-care analyses.

Brachytherapy 2016;15:216-223.

2 Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and

prognostic factors: COMS report No. 28. Arch Ophthalmol 2006;124:1684-1693.

3 American Brachytherapy Society - Ophthalmic Oncology Task Force. The American Brachytherapy Society consensus guidelines for plaque brachytherapy of uveal

melanoma and retinoblastoma. Brachytherapy 2014;13:1-14.

4 Almony A, Breit S, Zhao H, et al. Tilting of radioactive plaques after initial accurate

placement for treatment of uveal melanoma. Arch Ophthalmol 2008;126:65-70.

5 Rivard MJ, Chiu-Tsao ST, Finger PT, et al. Comparison of dose calculation methods for brachytherapy of intraocular tumors. Med Phys 2011;38:306-316.

6 Kheir WJ, Stinnett SS, Meltsner, et al. Preliminary results of uveal melanoma

treated with iodine-125 plaques: Analysis of disease control and visual outcomes with 63 Gy to the target volume. Adv Radiat Oncol 2022;7:100869.

7 Echegaray JJ, Bechrakis NE, Singh N, et al. Iodine-125 brachytherapy for uveal

melanoma: A systematic review of radiation dose. Ocul Oncol Pathol 2017;3:193-

198.

8 Mishra KK, Quivey JM, Daftari IK, et al. Long-term results of the UCSF-LBNL

randomized trial: Charged particle with helium ion versus iodine-125 plaque therapy for choroidal and ciliary body melanoma. Int J Radiat Oncol Biol Phys 2015;92:376-383.

9 Hrbacek J, Mishra KK, Kacperek A, et al. Practice patterns analysis of ocular proton therapy centers: The International OPTIC Survey. Int J Radiat Oncol Biol Phys

2016;95:336-343.

10 Hartsell WF, Kapur R, Hartsell SO, et al. Feasibility of proton beam therapy for

ocular melanoma using a novel 3D treatment planning technique. Int J Radiat Oncol Biol Phys 2016;95:353-359.

11 Gragoudas ES, Lane AM, Regan S, et al. A randomized controlled trial of

varying radiation doses in the treatment of choroidal melanoma. Arch Ophthalmol

2000;118:773-778.

12 Tsuji H, Ishikawa H, Yanagi T, et al. Carbon-ion radiotherapy for locally advanced

or unfavorably located choroidal melanoma: a phase I/II dose-escalation study. Int J Radiat Oncol Biol Phys 2007;67:857-862.

13 Lu JE, Welch RJ, Mishra KK, et al. Ultrasonography and transillumination for uveal melanoma localisation in proton beam treatment planning. Eye (Lond) 2019;33:1904-1910.

14 Muller K, Naus N, Nowak PJ, et al. Fractionated stereotactic radiotherapy for uveal melanoma, late clinical results. Radiother Oncol 2012;102:219-224.

15 Dunavoelgyi R, Georg D, Zehetmayer M, et al. Dose-response of critical structures in the posterior eye segment to hypofractioned stereotactic photon radiotherapy of

choroidal melanoma. Radiother Oncol 2013;108:348-353.

16 Muller K, Nowak PJ, de Pan C, et al. Effectiveness of fractionated stereotactic

radiotherapy for uveal melanoma. Int J Radiat Oncol Biol Phys 2005;63:116-122.

17 Zehetmayer M, Kitz K, Menapace R, et al. Local tumor control and morbidity after

one to three fractions of stereotactic external beam irradiation for uveal melanoma. Radiother Oncol 2000;55:135-144.

18 The Collaborative Ocular Melanoma Study (COMS) randomized trial of preenucleation radiation of large choroidal melanoma III: local complications and

observations following enucleation COMS report no. 11. Am J Ophthalmol

1998;126:362-372.

19 Ang KK, Peters LJ, Weber RS, et al. Postoperative radiotherapy for cutaneous

melanoma of the head and neck region. Int J Radiat Oncol Biol Phys 1994;30:795-

798.

20 Huguenin PU, Kieser S, Glanzmann C, et al. Radiotherapy for metastatic

carcinomas of the kidney or melanomas: an analysis using palliative end points. Int J Radiat Oncol Biol Phys 1998;41:401-405.

21 Curti B, Crittenden M, Seung SK, et al. Randomized phase II study of stereotactic body radiotherapy and interleukin-2 versus interleukin-2 in patients with metastatic melanoma. J Immunother Cancer 2020;8:e000773.

22 Palma DA, Olsen R, Harrow S, et al. Stereotactic ablative radiotherapy for the

comprehensive treatment of oligometastatic cancers: Long-term results of the

SABR-COMET phase II randomized trial. J Clin Oncol 2020;38:2830-2838.

23 Palma DA, Olsen R, Harrow S, et al. Stereotactic ablative radiotherapy for the

SABR-COMET phase II randomized trial. Lancet 2019;393:2051-2058.

24 Chalkidou A, MacMillan T, Grzeda MT, et al. Stereotactic ablative body

radiotherapy in patients with oligometastatic cancers: a prospective, registrybased, single-arm, observational, evaluation study. Lancet Oncol 2021;22:98-106.

25 Jia Z, Jiang G, Zhu C, et al. A systematic review of yttrium-90 radioembolization

for unresectable liver metastases of melanoma. Eur J Radiol 2017;92:111-115.

26 Gonsalves CF, Eschelman DJ, Adamo RD, et al. A prospective phase II trial of

radioembolization for treatment of uveal melanoma hepatic metastasis. Radiology 2019;293:223-231.

PRINCIPLES OF RADIATION THERAPY REFERENCES

|Table 1. Definitions for Choroidal and Ciliary Body |Table 1. Definitions for Choroidal and Ciliary Body |T, N, M Melanomas |

|T Primary |T Primary |Tumor |

|TX Primary tumor |TX Primary tumor |cannot be assessed |

|T0 No evidence of |T0 No evidence of |primary tumor |

|T1 Tumor size |T1 Tumor size |category 1 |

|T1a Tumor size |T1a Tumor size |category 1 without ciliary body involvement and extraocular extension |

|T1b Tumor size category |T1b Tumor size category |1 with ciliary body involvement |

|T1c |Tumor size category 1 without ciliary body involvement but with extraocular extension ≤5 mm in largest diameter |Tumor size category 1 without ciliary body involvement but with extraocular extension ≤5 mm in largest diameter |

|T1d |Tumor size category 1 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter |Tumor size category 1 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter |

|T2 |Tumor size category 2 |Tumor size category 2 |

|T2a |Tumor size category 2 without ciliary body involvement and extraocular extension |Tumor size category 2 without ciliary body involvement and extraocular extension |

|T2b |Tumor size category 2 with ciliary body involvement |Tumor size category 2 with ciliary body involvement |

|T2c |Tumor size category 2 without ciliary body involvement but with extraocular extension ≤5 mm in largest diameter |Tumor size category 2 without ciliary body involvement but with extraocular extension ≤5 mm in largest diameter |

|T2d |Tumor size category 2 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter |Tumor size category 2 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter |

|T3 |Tumor size category 3 |Tumor size category 3 |

|T3a |Tumor size category 3 without ciliary body involvement and extraocular extension |Tumor size category 3 without ciliary body involvement and extraocular extension |

|T3b |Tumor size category 3 with ciliary body involvement |Tumor size category 3 with ciliary body involvement |

|T3c |Tumor size category 3 without ciliary body involvement but with extraocular extension ≤5 mm in largest diameter |Tumor size category 3 without ciliary body involvement but with extraocular extension ≤5 mm in largest diameter |

|T3d |Tumor size category 3 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter |Tumor size category 3 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter |

|T4 |Tumor size category 4 |Tumor size category 4 |

|T4a |Tumor size category 4 without ciliary body involvement and extraocular extension |Tumor size category 4 without ciliary body involvement and extraocular extension |

|T4b |Tumor size category 4 with ciliary body involvement |Tumor size category 4 with ciliary body involvement |

|T4c |Tumor size category 4 without ciliary body involvement but with extraocular extension ≤5 mm in largest diameter |Tumor size category 4 without ciliary body involvement but with extraocular extension ≤5 mm in largest diameter |

|T4d |Tumor size category |4 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter |

|T4e Any tumor size category with extraocular extension >5 mm in largest diameter Notes |T4e Any tumor size category with extraocular extension >5 mm in largest diameter Notes |T4e Any tumor size category with extraocular extension >5 mm in largest diameter Notes |

|1. Primary ciliary body and choroidal melanomas are classified according to the four tumor size categories defined in Figure 1. (ST-3) |1. Primary ciliary body and choroidal melanomas are classified according to the four tumor size categories defined in Figure 1. (ST-3) |1. Primary ciliary body and choroidal melanomas are classified according to the four tumor size categories defined in Figure 1. (ST-3) |

|2. In clinical practice, the largest tumor basal diameter may be estimated in optic disc diameters (DD; average: 1 DD = 1.5 mm), and tumor thickness may be estimated in diopters (average: 2.5 diopters = 1 mm). Ultrasonography and fundus photography are used to provide more accurate measurements. 3. When histopathologic measurements are recorded after fixation, tumor diameter and thickness may be underestimated because of tissue shrinkage. |2. In clinical practice, the largest tumor basal diameter may be estimated in optic disc diameters (DD; average: 1 DD = 1.5 mm), and tumor thickness may be estimated in diopters (average: 2.5 diopters = 1 mm). Ultrasonography and fundus photography are used to provide more accurate measurements. 3. When histopathologic measurements are recorded after fixation, tumor diameter and thickness may be underestimated because of tissue shrinkage. |2. In clinical practice, the largest tumor basal diameter may be estimated in optic disc diameters (DD; average: 1 DD = 1.5 mm), and tumor thickness may be estimated in diopters (average: 2.5 diopters = 1 mm). Ultrasonography and fundus photography are used to provide more accurate measurements. 3. When histopathologic measurements are recorded after fixation, tumor diameter and thickness may be underestimated because of tissue shrinkage. |

|Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, (2017) published by Springer International Publishing. |Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, (2017) published by Springer International Publishing. |Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, (2017) published by Springer International Publishing. |

Color Fundus Photography

useful include color fundus photography, conventional ocular ultrasound (US), autofluorescence of the ocular fundus, optical coherence

tomography (OCT), retinal fluorescein angiography of the ocular fundus, transillumination, and MRI.

Features that are essential to measure and document as part of workup include visual acuity (VA), location and size of the tumor (ie, diameter,

thickness), distance from the tumor to the disc and to the fovea, ciliary

body involvement, and subretinal fluid and orange pigment, if present.

Biopsy may be considered if needed to confirm diagnosis or for prognostic analysis for risk stratification. Biopsy is usually not necessary for initial

diagnosis of uveal melanoma and selection of first-line treatment, but may be useful in cases of uncertainty regarding diagnosis, such as for

amelanotic tumors or retinal detachment. Biopsy of the primary tumor may provide prognostic information that can help inform frequency of follow-up and may be needed for clinical trial eligibility. If biopsy is performed,

molecular/chromosomal testing for prognostication is preferred over

cytology alone. The risks/benefits of biopsy for prognostic analysis should be carefully considered and discussed.

Imaging Methods

Imaging Methods

Comprehensive Eye Exam (biomicroscopy)

Meticulous analysis of the fundus after full pupil dilation will allow detection of most choroidal melanomas,83 and can be used to record many of the

relevant features needed for diagnosis and treatment planning. Whereas ciliary body melanomas can be difficult to detect by this method, fundus

exam with good indentation can sometimes help.43

Color Fundus Photography

Color fundus photography is useful for documenting the clinical features of lesions, with the advantage of giving the most identical appearance to

clinical examination.185 Color fundus photography can be used to evaluate

Ocular Ultrasound

##### A-Scan Ultrasonography

the borders of the lesion, and thereby record the location and shape;

calculate lesion basal diameter and area; and be used to detect orange pigment, drusen, and halo.83,185-187 Areas of orange pigment seen by color fundus photography have been shown to correlate with those seen by

fundus autofluorescence.186,187 It is important to note that color fundus

photography alone is not sufficient for a differential diagnosis, and

diagnostic accuracy based on color fundus photography has wide

interobserver variation.188

Ocular Ultrasound

In addition to comprehensive clinical ophthalmologic exam and color

fundus photography, US of the eye (ocular echography) is one of the most useful tools for diagnosis of choroidal melanomas.47,189-191 In experienced hands, US in combination with complete ophthalmologic clinical exam

results in a high level of diagnostic accuracy (>99%) for studies of medium to large uveal melanomas.171,172,192 Melanomas tend to exhibit low internal

##### B-Scan Ultrasound

reflectivity as well as an intrinsic acoustic quiet zone on US,191 features

that distinguish them from a variety of other intraocular conditions. US is

particularly useful when a mass cannot be visually inspected due to

opacity or pathology of structures in the anterior portion of the eye such as corneal scars, cataract, or blood in the vitreous.47

US can help in the detection of ciliary body melanomas that may be

missed by fundoscopy.193 US is particularly useful for determining the

thickness of the tumor,179,189 and has been shown to have a high level of accuracy compared with tumor height measurements based on

histopathology of enucleated specimens.194,195 By facilitating measurement of tumor dimensions, US is useful for detecting lesion growth.178,190 US can also be used to detect extraocular extension,47 which shows

hyporeflectivity on US.83 There are two modes of US to evaluate the eye, A-mode and B-mode. Uveal melanomas show low reflectivity on both Ascan and B-scan ultrasonography, although other features differ.83

A-Scan Ultrasonography

Uveal melanomas typically show low to medium internal reflectivity on Amode US,43,47,178,190,196 which further decreases toward the sclera.47,83

Other A-scan US hallmarks specific to uveal melanoma are: 1) a regular internal structure with similar height of the inner tumor spikes or regular

decrease in height (positive angle kappa sign); 2) solid consistency with no aftermovement of tumor spikes; and 3) echographic sign of

vascularization with a fast, spontaneous, continuous, flickering vertical

motion of single tumor spikes.43,196 In contrast, choroidal metastases from other types of cancer typically show an irregular structure on A-mode

US,196 hemangiomas show much higher reflectivity,47,190,196 and nevi and melanocytomas show higher reflectivity and more irregular structures than malignant melanoma.196 Fresh choroidal hemorrhages may have similar structure and reflectivity as melanomas, but will show aftermovement

following small eye movements.196

B-Scan Ultrasound

On B-scan US, posterior uveal melanomas appear as hyperchromic mass with lower reflectivity than the surrounding choroid, thus giving an

acoustically hollow appearance.43,47,83,178 Posterior uveal melanomas,

particularly the larger ones, show choroidal excavation and orbital

shadowing on B-scan US.43,47,178,190 These features help confirm clinical

diagnosis, and are distinct from hemangiomas or metastases to the eye, which typically show high reflectivity.178,197 However, some other lesions that may show choroidal excavation include: hemangiomas, long-standing nevi, and choroidal metastases.192 B-scan US is used for obtaining tumor dimensions, extent, and shape,43,190,197 and is useful for characterizing

larger ciliary body tumors.43 Extraocular extension can be observed by Bscan US as areas of hyporeflectivity compared to normal orbital

tissue.83,178

Autofluorescence of Ocular Fundus

Autofluorescence of Ocular Fundus

Fundus autofluorescence has been proposed as a method to help in the diagnosis and characterization of uveal melanomas.179,186,198,199 Choroidal

melanoma generally shows slight intrinsic hyperautofluorescence and the brightness increases with tumor pigmentation and disrupted RPE.200,201

Orange pigment is the most highly autofluorescent uveal melanoma

feature.198,200-205 Drusen can also be detected by autofluorescence,204 and

have increased, normal, or decreased autofluorescence.198,202,205 Fibrous metaplasia also shows elevated autofluorescence.201,202,204

Autofluorescence can be used to distinguish orange pigment from drusen in both pigmented and non-pigmented tumors.178 Unlike uveal melanoma

and choroidal nevi, melanocytomas show hypofluorescence.206

Comparative studies have shown that the autofluorescence pattern often

matches that of orange pigment and hyperpigmentation seen by color

fundus photography.47,187,202 Based on comparative studies, it is not clear

that fundus autofluorescence increases the detection rate of orange

pigment relative to standard ophthalmologic exam.207

Optical Coherence Tomography

OCT is another imaging method proposed for assisting diagnosis of uveal melanoma.47,179 Spectral domain OCT (SD-OCT) allows the detailed

evaluation of the retina and RPE, changes in which are more common in choroidal melanoma versus choroidal nevi.47,198 OCT can help identify

overlying retinal detachment or edema, even before clinically apparent.198 OCT can detect subretinal and intraretinal fluid, subretinal lipofuscin,

retinal epithelium atrophy and degeneration, shaggy photoreceptors, and structural loss of photoreceptors in the neurosensory retina.47,178,198,208,209

These features are more likely in choroidal melanoma than in choroidal nevi, although some features are more useful than others for differential

diagnosis, especially in small lesions.47,208,210-212 Results differ across

comparative studies regarding whether OCT is more sensitive than

Transillumination

standard ophthalmologic exam plus US for detecting subretinal

fluid.207,212,213

In OCT, the structure of the lesion differed between choroidal nevi,

melanomas, hemangiomas, and metastases.209 Optical density ratio based on OCT can also be used to distinguish choroidal melanomas from

choroidal metastases.214 Enhanced depth imaging OCT (EDI-OCT) is

particularly useful for detecting small lesions, and distinguishing small nevi from small choroidal melanoma.43 OCT angiography (OCT-A) can be used to distinguish choroidal nevi from choroidal melanoma based on margin

characteristics (well-delimited vs. imprecise), reflectivity of choroid

capillary vasculature (hyper vs. hypo), and characteristics of lesion

vasculature.215,216 Compared to US biomicroscopy, OCT provides better

resolution of the anterior segment anatomy and margin, while the former provides better overall visualization and resolution of the posterior

margin.217

Optical Coherence Tomography

Retinal Fluorescein Angiography

Retinal Fluorescein Angiography

Retinal fluorescein angiography can be used to characterize lesion

vasculature, which can aid in diagnosis because choroidal melanomas

may have intrinsic tumor circulation, sometimes called “double circulation,” in addition to normal choroidal vasculature.43,47,83,178,190,191,218 Observation

of the tumor vasculature is helpful in distinguishing melanomas from

choroidal nevi, hemorrhagic degeneration, or choroidal melanoma.47,83,219

After treatment with brachytherapy, fluorescein angiography is also useful for detection of complications such as radiation retinopathy.47,83

Transillumination

Transillumination has been tested as a method for detecting and

measuring uveal melanomas that may be difficult to detect or fully

characterize by other techniques. Examples include large ciliary body

melanomas,43,47,83 or tumors obscured by cataracts.220 Compared with tumor dimension measurements based on histology of enucleated eyes,

MRI

Features to Record

Visual Acuity

Size

transillumination tends to overestimate both the thickness and diameter of tumors, and is prone to shadowing artifacts.195,221 Therefore, it is only used if other methods have proven inadequate.

MRI

MRI is generally not needed for diagnosis and workup, but occasionally is necessary with features that may make other imaging methods difficult,

such as secondary vitreous hemorrhage, extensive retinal detachment, or cataract.47,83 MRI may be useful in determining whether cataract is caused by an underlying ciliary body melanoma, and can help distinguish uveal

melanomas from hemangiomas.47 Uveal melanomas usually have high

signal intensity in T1-weighted MRI images and low signal intensity in T2-weighted images.43,47,83,178 Although similar signal pattern can be caused by hemorrhage or necrosis,47,83 hemangiomas typically have hyperintense signal on T-weighted images and T2-weighted images are isointense with the vitreous.47 MRI is useful for detecting and characterizing extraocular extension,47,83,178,189,222,223 and is also used for radiation therapy (RT)

planning.83,178,189,224,225

Features to Record

Location, Distance from Disc and Fovea, Ciliary Body Involvement

Visual Acuity

It is important to measure VA during workup, as many uveal melanomas can disturb vision, and changes in VA can be an indication of progression, response to treatment, or a side effect of certain treatments. VA or

changes in VA can contribute to the differential diagnosis, as benign nevi rarely cause visual impairment,79,226 whereas malignancy does.11,81,90,99 In patients with uveal melanoma, VA in the affected eye tends to be worse

than in the fellow eye.16 A baseline measure of VA is also important to

determine effects of uveal melanoma treatment. RT can cause a decline in VA, although the effects are highly variable.227-229 Larger tumor size and

tumor location near the optic disc are associated with greater loss of VA

and higher rates of local complications.230-232

Size

Although size alone does not determine diagnosis, it can contribute to

differential diagnosis, as uveal melanomas are generally larger than

choroidal nevi, and size (thickness >2 mm, tumor diameter >5 mm) is

predictive of growth in melanocytic lesions.97,99 For lesions thought to be

nevi, or small lesions with uncertain diagnosis, accurate measurements of size are important for monitoring for growth, as rapid growth is a sign of

likely malignancy.94 Baseline tumor size is needed to determine the T

stage of the tumor, which helps determine the prognostic risk category

used to inform post-treatment surveillance. Tumor size is also important for selecting and planning treatment. For brachytherapy, selection of the

appropriate size plaque is important to ensure that the lesion is fully

covered, and alternative or additional treatment options need to be

considered for tumors that exceed the size of the largest commercially

available plaque. Selection of alternative treatment options (eg, particle

beam RT, stereotactic radiosurgery [SRS], enucleation) should also

depend on tumor size. Accurate measurements of size and shape of the

tumor are also needed for monitoring response or progression after

treatment.

Location, Distance from Disc and Fovea, Ciliary Body Involvement

Lesion location is one of the features that can contribute to diagnosis.

Proximity to the optic disc is considered a diagnostic feature of uveal

melanomas, as it is correlated with likelihood of growth in melanocytic

choroidal lesions.93-95,97 Lesion location, including distance from disc and fovea, and ciliary body involvement, can impact imaging results, such as the ability to detect certain diagnostic features and accurately discern

borders for measurement of tumor size. In some cases, color fundus

photography, US, and complete clinical exam may not be sufficient for

detection and/or characterization of ciliary body involvement; this is a

feature that may require additional imaging approaches.184 Lesion location can help explain visual symptoms and may impact the efficacy and safety

of specific treatments. Ciliary body involvement is one of the elements that determines the T stage of the tumor and prognostic risk category used to inform post-treatment follow-up surveillance.

Subretinal Fluid

Subretinal fluid is a feature that supports the diagnosis of uveal

melanoma, as it is rare in benign choroidal nevi,88,102 and has been shown to develop during growth of choroidal nevi and transformation to

melanoma.82,89 The presence of subretinal fluid has been shown to be

predictive of growth in choroidal nevi or small indeterminate melanocytic lesions.89,94,95,97,233 One study of a large number of uveal melanomas (N = 8033) reported that subretinal fluid was present in 75% of cases.168

However, ocular metastases from other primary cancers (eg, breast, lung) can also give rise to subretinal fluid.182

Orange Pigment

Orange Pigment

Orange pigment, also called lipofuscin, can be present in benign choroidal nevi;88,102 however, it has been shown to develop during nevi growth and transformation to uveal melanoma.82,89 In nevi or indeterminate small

lesions, the presence of orange pigment is predictive of future growth and increases the likelihood of a future uveal melanoma diagnosis.86,89,93-99

Biopsy

The use of biopsy as part of workup for uveal melanoma is an issue of

some debate. Potential benefits of biopsy during workup are: 1)

cytologic/histologic confirmation of diagnosis; 2) potential for molecular

analysis that may impact eligibility for current or future clinical trials; and 3) potential for molecular analyses that may provide more accurate

prognostic assessment for risk of metastasis, which may inform future

follow-up surveillance. Potential harms of biopsy of the primary tumor

include: 1) risk of complications from the procedure that damage the eye; 2) risk of tumor seeding leading to local or distant recurrence; and 3) risk

Biopsy

Fine-Needle Aspiration Biopsy

of inadequate sampling resulting in misdiagnoses or inaccurate or

inconclusive molecular testing results. The likelihood of these potential benefits and harms is debated and may vary across practitioners.

Subretinal Fluid

There are a wide variety of biopsy techniques that have been tested and are sometimes used for choroidal or ciliary body tumors. Some involve a

transscleral (direct) approach while others use a transvitreal (indirect)

approach.234,235 Tumor location is a major determinant of which approach

is likely to be successful and safe. Table 2 provides a list of techniques for biopsying choroidal and ciliary body tumors that have been used to assist

with diagnosis and/or prognostication in primary uveal melanomas. Any of these biopsy procedures can result in intraocular complications/morbidities

(eg, hemorrhage, decrease in VA, retinal detachment, retinal perforation, hypotony, endophthalmitis) which if severe may require secondary

procedures or other interventions for management.236-247 Longitudinal

population-based studies have shown that biopsy does not impact allcause mortality or disease-specific death (DSD) in patients with uveal

melanoma.248-250

Fine-Needle Aspiration Biopsy

Fine-needle aspiration biopsy (FNAB) is the simplest, most inexpensive, and most commonly used method for biopsy of choroid or ciliary body

tumors presumed to be melanoma.234,251,252 Details of the technique are

described in several review articles,234,251,252 as well as multiple primary

reports from many different centers.91,236,237,239,253-255 FNAB can be done

via a transvitreal or transscleral approach depending on the location of the tumor. The transvitreal approach is generally easier due to better

intraoperative illumination and visualization options.234,252

The disadvantage to FNAB is that multiple passes may be needed to

obtain enough material for cytologic and molecular genetic

analysis.236,240,255,256 The yield from FNAB varies across

studies.91,236,237,239,240,249,250,253-262 Some studies suggest that transvitreal

(vs. transscleral) approach is associated with improved FNAB yield, but

some studies disagreed.236,237,239,260,262,263 It has also been postulated that FNAB yield is higher for larger and thicker tumors,237,250,254,260-262 but a

recent study showed that high yields can be obtained even in thin tumors (<3.5-mm thick), with both the transscleral and transvitreal approach.236

FNAB can help distinguish between uveal melanoma and borderline or

benign melanocytic nevus, even among small lesions,91,261 and between a primary uveal melanoma versus metastasis from another cancer, another type of primary ocular tumor, a melanocytoma, or RPE proliferation.255

Concerns about FNAB causing tumor seeding have been raised based on findings of melanoma cells left in the needle track,257,259,264-266 and some

have suggested procedure adjustments for reducing the likelihood of

tumor cell seeding by FNAB.252,257,265 A few case reports found local

recurrences at FNAB entry sites.267-269 However, multiple follow-up studies with large patient populations have revealed no local recurrences after

FNAB,91,236,239,249,250,254,255,258,259,263 and one case series found no increased risk of metastasis among untreated patients who had post-biopsy

evidence of melanoma cell dissemination inside the eye.264 FNAB is

therefore generally thought to be safe and to have low risk of seeding.

Other Biopsy Techniques

Other biopsy techniques that have been tested in large uveal melanoma populations use tools from vitrectomy systems to access tumor via a

transvitreal/transretinal approach and to extract tumor tissue using the

vitreous cutter and aspiration through the canula. These procedures do

not necessarily include a vitrectomy. There are a variety of procedures

that fall into this category, and are described in a series of publications

based on clinical practices both in the United States and

Europe.234,241,242,244,252,271,272 These techniques have been used

successfully on anterior, posterior, equatorial, and peripapillary lesions.241-244,270 They generally result in larger sample sizes than FNAB, although

like FNAB multiple passes may be necessary.241,242,271,272 For this reason it

Other Biopsy Techniques

has been suggested that these methods may be useful in patients with

tumors that are too small or inaccessible for FNAB, or for tumors where

FNAB has failed. One study reported that for choroidal melanomas with

thickness of 2.0 mm or less, sufficient sample for prognostic evaluation

was obtained in 100% of patients.241 Reported yields from these

procedures range from 89% to 99% for diagnosis of choroidal lesions, and 97% to 100% for prognostic testing on uveal melanomas.241-244,270,271

Studies have shown that these biopsy techniques can be used to

diagnose tumors that are unclassifiable based on standard noninvasive

diagnostic techniques, and can differentiate uveal melanoma from benign nevus, metastases from other cancers, vasoproliferative tumor,

hemorrhage, gliosis, and scleritis.244,270

Generally, these approaches are less broadly used than FNAB, are more expensive, and require additional expertise.234,252 Like FNAB, hemorrhage is the most common complication with these biopsy procedures, is

normally localized, and usually resolves without intervention.241,243,244

Since these techniques are more invasive, however, retinal detachment

and severe hemorrhage are more common, and more patients require

intervention for management.238,242-244,252 Decrease in VA due to these

procedures is not uncommon.242,243

Like FNAB, studies have published evidence that these procedures may leave tumor cells along the access pathways. Nevertheless, most studies, including those with large patient samples, have not observed local

recurrence during follow-up.243,244 There are a few case reports of local

recurrences at biopsy entry sites.268,270,284,285

Incisional biopsy techniques are more invasive than vitrectomy systemassisted biopsies, and likewise yield more material, but also are more

likely to lead to complications.245-247 These methods have been used for

cases that are particularly hard to diagnose. Excisional biopsy, using

either transscleral resection or endoresection, was also explored as an

NCCNCancer

option for both biopsy and primary treatment,286 but is not included in

Table 2 because it is no longer used due to technical challenges, risk of complications, and concerns about tumor seeding.178,273-283

Observation for Uncertain Diagnosis in Patients with Low Risk

Findings from the clinical workup should be used to determine initial

management. Observation may be appropriate for patients with uncertain diagnosis and/or fewer than three risk factors for lesion growth (Table 1). Studies have found that for patients with small choroidal lesions presumed to be nevi or indeterminate, deferring treatment until evidence of growth or features of malignancy develop (eg, orange pigment, subretinal fluid,

symptoms) is associated with a very low risk of metastasis,94,98 and even lower risk of death from uveal melanoma.87 For patients who meet the

criteria for observation, regular follow-up is recommended to periodically re-evaluate for growth or features of malignancy. Follow-up tests should include the same tests recommended for initial workup and diagnosis that would help clarify if there is progression and determine the natural history of the indeterminate lesion. Initially, these patients should be re-evaluated every 2 to 6 months to determine rate of growth (if any) and to monitor for other changes indicative of malignancy. Close follow-up for 5 years is

recommended to firmly establish whether or not there is any growth or

progression; some lesions that initially seem stable may suddenly begin to grow and transform. The frequency of re-evaluation should depend on the index of suspicion, patient age, and medical frailty. For example, the

presence of one to two risk factors for growth (Table 1), or evidence of

changes would increase suspicion. If the size and features of a lesion

appear static after 5 years of follow-up, the patient can be followed

annually thereafter. Lesions that demonstrate growth or develop additional risk factors for growth (>3 total) should be managed as uveal melanoma, even if diagnosis is still uncertain.

Observation for Uncertain Diagnosis in Patients with Low Risk

Further Workup Prior to Treatment

Further workup prior to treatment may be needed in some cases to aid in treatment selection and planning. For example, for tumors that are large, close to the optic nerve, or have suspected extraocular extension, MRI

should be performed, if not previously done, to confirm extraocular

extension, determine whether RT or enucleation is needed, and for RT

planning.47,83,178,189,222-224 MRI should be performed with and without

contrast unless contraindicated. Ciliary body involvement or extraocular

extension should be assessed and documented, as these features may

impact the feasibility, safety, and efficacy of certain treatment options.

Biopsy is typically performed before the tumor is irradiated and can often be performed at the time of primary treatment depending on the procedure modality. There is some evidence to suggest that RT may alter molecular genetic features of the tumors, reducing the accuracy of prognostication

based on samples taken after RT treatment.287

Baseline imaging to screen for systemic disease is also recommended

prior to treatment. Unless there is a specific contraindication to the

administration of IV contrast, all cross-sectional imaging studies should be performed with and without IV contrast. Despite lack of treatment options for patients with distant metastatic disease, NCCN favors staging before primary treatment. For patients who have small, low-risk tumors, deferring extraocular baseline imaging until after primary treatment can be

considered. The most frequent site of metastasis is the liver, and other

sides include the lungs, skin/soft tissue, and bones.23 At minimum, all

patients should have contrast-enhanced MR or US of the liver, with

modality preference determined by expertise at the treating institution.

Additional imaging modalities may include chest/abdominal/pelvic CT with contrast. However, screening should limit radiation exposure whenever

possible.

Treatment for Localized Primary Uveal Melanoma

Treatment for Localized Primary Uveal Melanoma

Most uveal melanomas are localized at first presentation, and only a small percentage of cases present with metastases (<3%).6,12-16 Local treatment for primary uveal melanoma is effective in preventing local recurrence in greater than 85% of cases,273,288 yet the rate of metastasis within 20 years after treatment is approximately 20% to 70% for patients who present with localized uveal melanoma, depending on tumor stage/size at

diagnosis.10,15,28,289 Whereas surgical approaches historically are the

mainstay of treatment for localized cutaneous melanoma, the field has

moved away from using surgery in all patients.2,290 Different modalities,

primarily various forms of RT, have been found to be just as safe and

effective for those with limited disease, and can preserve the affected eye. 291-303 Some surgical approaches are still used in patients with extensive

local disease, but most patients with localized primary uveal melanoma

are treated with some form of RT.2,304 There are a number of other ablative techniques that are occasionally used for localized primary melanoma,

including laser therapy, cryotherapy, and photodynamic therapy.

Selection among these techniques is guided by many case-specific

factors, including the size and location of the tumor, presence of

extraocular extension, visual potential, patient age, and preference. The recommended treatment options are largely based on data from choroidal melanomas. For small ciliary body and iris tumors (<3 clock hours),

surgical excision may be considered.

doses higher than in COMS also reported recurrence rates that compared favorably with other treatment modalities (eg, TTT, proton beam RT).330,359 In contrast, studies using iodine-125 brachytherapy doses of less than or equal to 80 Gy reported recurrence rates higher than with particle beam

RT.49,336,360-362 Whereas a few studies have associated a lower iodine-125 brachytherapy dose with local tumor recurrence and decreased systemic control,340,363-365 others have found no such correlation.349,356,366,367

Another issue of debate is the relationship between brachytherapy dose

and long-term complications. Several studies have found correlations

between increasing iodine-125 dose and loss of VA, risk of RT-related

complications (eg, cataract, optic neuropathy, glaucoma), and the need for secondary enucleation.347,356,364,366-371 Results are mixed, however, and

retrospective analyses did not always find significant correlations between dose and these negative outcomes.369,372,373

Studies testing a wide range of doses for brachytherapy plaques made of other radioisotopes, such as ruthenium-106, palladium-103, strontium-90, and cobalt-60, have reported mean/median dose to the apex between 80 and 130 Gy.228,332,342,353,359,374-381 Although there is evidence to suggest that results differ between isotopes,359,375 the optimal dose has not been

determined for any of these isotopes. Results are inconsistent across

retrospective studies that evaluated the impact of dose on local/distant

failure rate,374,379 or the impact of dose on RT-related complications and

VA loss.228,378

Particle Beam Radiation Therapy

Particle beam RT includes radiation with protons, carbon ions, or helium ions, and is a common form of definitive RT for the primary tumor.327

Prospective studies, a systematic review, and a retrospective study found that DSS in patients with uveal melanoma treated with particle beam RT was similar or better than for plaque brachytherapy.49,336,362,382 Compared with brachytherapy, particle beam RT was associated with higher rates of local control and similar or lower rates of enucleation during followup.49,336,362 Specifically, local control for particle versus plaque treatment

was 100% versus 84% at 5 years, and 98% versus 79% at 12 years,

respectively (P = .0006). Enucleation rate was 11% versus 22% at 5

years, and 17% versus 37% at 12 years, respectively (P = .01).49 Across studies, local recurrence rates with charged particle therapy ranged from 3% to 10%.273,383 Tumor regression following particle beam RT can begin within 6 months of treatment, and tumor shrinkage may continue to occur throughout 5 years of follow-up.383,384 As with brachytherapy, local

recurrence after particle beam RT as treatment for primary localized uveal melanoma occurs over a long time range, as early as 2 months after

treatment and as late as 12 years.385-387 Prospective studies have found

that most local recurrences occurred in the first 4 to 5 years, with median time to recurrence of less than 2 years.49,385-387 Multivariate analysis of a

real-world database found that treatment with protons was associated with

Particle Beam Radiation Therapy

Stereotactic Radiation

poorer overall survival (OS) compared with brachytherapy treatment (5-

year OS 51% vs. 77%; P = .008).388

Decrease in VA and loss of vision, similar to brachytherapy, can occur with particle beam RT.383,386,389 Commonly reported toxicities include vitreous

hemorrhage, subretinal exudation in macula, posterior subcapsular

opacity, radiation keratopathy, rubeosis/neovascular glaucoma, retinal

detachment, radiation maculopathy, and papillopathy.383,385,389,390

Stereotactic Radiation

Stereotactic RT (SRT) includes both single-fraction and hypofractionated stereotactic techniques, referred to collectively as SRS in these NCCN

Guidelines. Compared with brachytherapy and particle beam RT, there are fewer prospective comparative study data on SRS for treatment of primary uveal melanoma.227,273,358,380,391-408 Studies using SRT as primary treatment for uveal melanoma have reported local failure rates ranging between 2% to 16%.227,273,358,380,392-405,409 Following SRT of the primary tumor, many

uveal melanomas showed a transient increase in tumor height, volume, or both.398 Responses to SRT first began to appear 6 months after treatment, with progressive decreases in tumor height and volume continuing for at

least 3 years.227,394,396,398,399,402-405,410

Available data suggest that SRS may be as effective as other RT

modalities, albeit with a higher risk of complications. 358,392,394,395,397-407,410-418 One series that compared SRS with iodine-125 brachytherapy found that rates of tumor recurrence, distant metastasis, and secondary enucleation were similar across treatments.358 Risk of cataract appeared similar across treatments, but SRS appeared to be associated with higher rates of

neovascular glaucoma, radiation retinopathy, and radiation

papillopathy.358,413 Another study also reported similar rates of local control with brachytherapy versus SRS.380 A retrospective study comparing

ruthenium-106 brachytherapy versus SRS found a nonsignificant trend

toward increased secondary glaucoma after SRS.377 Retrospective studies

comparing SRS versus proton beam RT reported similar rates of local

control and eye retention across treatments, but higher rates of VA decline and vitreous hemorrhage with SRS.392,419

RT Toxicity (Ocular)

RT Toxicity (Ocular)

In order to avoid secondary enucleation, a variety of methods for

preventing or managing RT-associated complications have been tested in prospective studies. Toxicity management methods tested include

panretinal photocoagulation for ocular ischemia,420 transscleral local

resection for exudative retinal detachment,421 and intravitreal anti-vascular endothelial growth factor (VEGF) (eg, bevacizumab, ranibizumab,

aflibercept) or intravitreal corticosteroids (eg, triamcinolone,

dexamethasone) for treating optic neuropathy, macular radiation

vasculopathy, or papillopathy or macular edema.422-429 These intravitreal therapies have also been tested for prophylaxis.430-432 The NCCN

Guidelines for Melanoma: Uveal do not currently have recommendations for management of RT side effects.

Other Ablative Techniques

Other Ablative Techniques

Laser photocoagulation has been used for treatment of primary or

recurrent uveal melanomas, sometimes as monotherapy but more often as an adjunct to RT or surgery.47,48,179,278,282,387,433-447 The sparse data

available suggest that laser photocoagulation is associated with high rates of recurrence if used as the sole primary therapy,433,438 but that when used as a supplement to brachytherapy can increase rate of tumor

regression.443

TTT, also called diode laser hyperthermia, can be used to treat a large

spot and has deep tissue penetration. TTT has been tested in prospective studies as the sole primary treatment for uveal melanoma tumors, but

local recurrence rates varied widely across studies, with some studies

reporting high rates of recurrence (>50%), even for small tumors.273,330,448-

Treatment for Extraocular Extension

453 TTT has also been tested as an adjunct therapy to RT to reduce the

risk of local recurrence.332,334,335,343,345,363,390,454,455 One prospective

randomized trial found that TTT administered at 1, 6, and 12 months after proton RT reduced the likelihood of retinal detachment and lowered the

secondary enucleation rate.390 A retrospective study found that addition of

TTT to brachytherapy improved rate of tumor regression, 5-year tumor

recurrence rate, eye-globe preservation, and recurrence-free survival.456

There was no impact on metastasis-free survival, OS, rate of

complications, or visual outcomes.456 However, two other studies showed

that adding TTT to brachytherapy did not improve the rate of globe

conservation, and was associated with greater loss of VA.332,457 The larger

of these studies (N = 449) also showed that rate of local failure, distant

metastasis, and cause-specific death were not improved by TTT.332

Use of cryotherapy for treatment of primary or recurrent uveal melanomas, either alone or in conjunction with other therapies, has been described in

case reports and case series in the literature.452,458-464 Retrospective

reports and review articles suggest that this method is occasionally being used in clinical practice.28,298,465

Treatment for Extraocular Extension

Extraocular extension has been reported to be present in approximately 3% of patients at diagnosis of uveal melanoma,167,168,195,466 is more

common among tumors with higher T stage (12% of T4 tumors),289 and is associated with poor prognosis.20,28,288,467-469 Extraocular extension can be detected by preoperative imaging, or found or confirmed at the time of

enucleation.306,470 In the COMS trial of patients with large uveal

melanomas, unexpected extrascleral extension was found in 2% of

patients who underwent enucleation, despite extensive clinical and

imaging workup.306,319

Sometimes the evidence of extraocular extension is microscopically

positive or close margins after enucleation, without clinical, intraoperative, or radiographic evidence of gross residual disease to the orbit. In this

case, the patient can be observed, and map biopsy and/or RT using

particle beam or proton beam to the orbit can be considered. In other

cases, extraocular tumor is visible intraoperatively or intraoperative

findings suggest that there may be gross disease to the orbit. In this case, biopsy of the extraocular tissue should be carried out, if possible, with

consideration of one or more of the following options: intraoperative

cryotherapy, orbital exenteration, or RT using particle beam or photon

beam to the orbit.

For cases with extraocular extension and/or orbital invasion, orbital

exenteration, the surgical removal of the globe and adjacent orbital

contents, is recommended.43,191,229,439,442,471 Retrospective studies of large databases suggest that exenteration is used in less than 1% of patients,28

and among patients undergoing enucleation, 2.5% need orbital

exteneration.472 The value of orbital exenteration is disputed in the

literature, largely based on low-quality data such as case reports and

retrospective studies. Some studies support orbital exenteration because it provided superior outcomes compared with other (nonsurgical)

approaches,473 whereas others report poor outcomes after orbital

exenteration, arguing that it may not be justified.474,475

A retrospective study (N = 202) found that in patients treated with

enucleation, postoperative RT improved survival, particularly in young

patients (age <30 years) and those with choroidal tumor height greater

than 3 mm.472 Another small retrospective study reported a local

recurrence rate of 6% in patients with extrascleral extension who were

treated with enucleation followed by adjuvant external beam RT to the

orbit.476

Follow-up

Follow-up

For patients whose primary uveal melanoma was treated with RT or

surgery, the subsequent disease-free interval is highly variable, ranging from a few months to many years.335,336,338,341,343,386,403 Uveal melanoma is characterized by early micrometastasis (often before treatment) followed by variable latency period before emergence of overt metastasis.477 Local recurrence is rare, occurring in less than 10% of patients after treatment with the modalities recommended in these guidelines.49,231,273,306-308,330-342 Development of detectable distant metastatic disease is much more

common than local recurrence, and happens in up to 70% of patients,

depending on the stage and other risk factors at the time of

diagnosis.10,15,28,289

Follow-up for the Treated Eye

Follow-up for the Treated Eye

At NCCN Member Institutions, standard follow-up in the affected eye

includes imaging with color fundus photography and ultrasonography

every 3 to 6 months for 3 to 5 years, then every 6 to 12 months thereafter, if stable. Serial orbital MRI may be used as clinically indicated. The

frequency of follow-up should depend on the size and location (eg,

juxtapapillary location, ciliary body involvement) of the tumor at

presentation, as these factors impact the risk for recurrence. Radiationrelated retinopathy and other treatment-related complications may occur at any time following treatment.

For patients treated with enucleation in the COMS trial, there were followup clinical and ophthalmologic exams at 1 to 2 weeks after surgery to

assess healing status, and at 6 months, 12 months, and annually

thereafter, in which the eye socket and eyelids were examined for possible recurrence or complications, and the fit of prosthesis checked.291,319,478

For patients treated with RT in prospective studies, follow-up exams

typically included complete ophthalmologic exam of the treated eye, with

indirect ophthalmoscopy, slit-lamp exam, tonometry, color fundus

photography, A-scan and B-scan US, and measurement of VA and visual field. Many prospective studies also included fluorescein angiography in

follow-up exams, either at regular intervals or as needed.49,227,230,231,330-

332,334,336,338,341-343,345,346,379,383-385,395,398,399,402-404,410,478-480 A few prospective

studies used gonioscopy,231,403 OCT,332,345,346 or MRI.398,410 For patients

who were treated with brachytherapy in the COMS study, follow-up

included an exam within 6 weeks of surgery, at 6 months after treatment, then every 6 months for 5 years, and every 12 months thereafter.291

Patients with suspected tumor growth had more frequent follow-up exams. Whereas some prospective studies in patients treated with brachytherapy had follow-up protocols similar to COMS,331,338,379 others used more

frequent follow-up, with more than 2 exams per year during the first year or first few years after treatment, and exams every 6 to 12 months during later years.49,330,334-336,341-343,347,480 Prospective studies following patients

after particle beam RT or SRT sometimes had frequent follow-up during

the first 6 months after treatment (eg, 3–5 exams in the first 6

months),227,394,395,398,399,481 and most had follow-up exams at least every 3 to 4 months during the first year or two.49,227,336,389,394,399,402-404 A few studies switched to the 6-month follow-up interval starting early (<1 year) from

treatment.383,384,395,410,479,481 Long-term follow-up intervals ranged between 4 to 12 months.49,227,336,383,389,394,395,398,399,402,403,410,481

Risk in Contralateral (Fellow) Eye

All patients should receive follow-up for the affected eye. In patients with uveal melanoma, the contralateral eye is not at increased risk of uveal

melanoma,12,307,482,483 and should be followed with routine ophthalmologic care including routine eye protection for the remaining eye (eg,

polycarbonate glasses).

In the COMS trials of patients with medium or large primary uveal

melanoma tumors, prospective monitoring showed that less than 1% of

Sites of Metastasis

patients developed disease in the contralateral eye during follow-up after primary treatment.307,482,483 Moreover, for the majority of patients who did not develop disease in the contralateral eye, results from regular

ophthalmologic exams showed that good VA was retained in their fellow

eye throughout the 10 years of follow-up, regardless of the modality used to treat the primary lesion.484 Analysis of 8165 patients with ocular

melanoma in the SEER database found bilateral involvement in 0.1% of

patients.12 One retrospective study of 52 cases of bilateral uveal

melanoma suggests prognosis is similar to that of unilateral cases.485 Rare instances of uveal melanoma metastasizing to the contralateral eye are

described in case studies.486-494

Risk in Contralateral (Fellow) Eye

Patterns of Metastases

Patterns of Metastases

Most uveal melanomas are localized at first presentation, and only less

than 3% of cases have detectable metastatic disease at the time of

diagnosis.6,12-16,167,495 Development of distant metastatic disease is much more common, occurring in ~20% to 70% of patients within 20 years after

treatment for primary uveal melanoma, depending on stage/size and

genetic characteristics of the tumor at diagnosis.10,15,28,50,69,289 Large

retrospective studies (N > 7000) found that after long-term follow-up, 20% of patients with stage I disease at diagnosis developed metastasis, in

contrast to ~70% for those with stage III disease.15,289 Prospective studies have shown that the cumulative rate of development of distant metastatic

disease steadily increases even after 6 to 20 years of followup.49,331,332,335,336,341,343,385,386,394,396,402,403,482,483 In the COMS studies, the

Kaplan-Meier estimates of 2-, 5-, and 10-year metastasis rates were 10%, 25%, and 34%.483

Sites of Metastasis

Uveal melanoma most often metastasizes to the liver (90% of the

time).21,23,24,167,307,482,483,496-503 Other common sites of metastasis, listed in

order of decreasing prevalence, are lung, bone, skin/soft tissue, and lymph

nodes.13,23,167,307,389,394,482,483 In large prospective studies following patients after treatment for primary uveal melanoma, metastasis to the lung was

observed in 20% to 30% of patients who developed distant metastasis, to the bone in 16% to 18%, to skin/soft tissue in 11% to 12%, and to lymph nodes in 10% to 11%.307,482 Retrospective studies show similar trends.23,503 A few studies reported brain metastases in 4% to 5% of patients who

developed distant metastases.23,307,482 Most patients who develop

metastasis ultimately have multiple sites involved; however, the first site is typically the liver. 21,23,24,307,482,499

Risk Factors for Metastasis

Risk factors for metastasis include a variety of genetic markers as well as tumor size at presentation. The NCCN Guidelines list specific risk factors to be used for risk stratification to determine the frequency of surveillance imaging during follow-up. The NCCN Guidelines recommend using AJCC T stage for risk stratifying according to primary tumor size. T1 is

considered low risk, T2 and T3 medium risk, and T4 high risk. For patients who had a biopsy of their primary tumor, certain molecular features have been shown to be prognostic for risk of distant spread, and should be used for risk stratification. Gene expression profiling (GEP) as described by

Onken et al50 is recommended to determine whether the tumor is Class 1A (low risk), Class 1B (medium risk), or Class 2 (high risk) to inform

frequency of follow-up.504-506 It has been shown that Class 2 was

associated with a 5-fold to 20-fold higher risk of metastasis than Class

1.50,256,507-517 The following chromosomal abnormalities are also considered risk factors that should inform frequency of follow-up: disomy 3 (low risk), gain of chromosome 6p (low risk), monosomy 3 (high risk), and gain of

chromosome 8q (high risk). Mutations in several genes have also been

shown to be prognostic for distant metastasis, and should be used for risk stratification: EIF1AX (low risk), SF3B1 (medium risk), and BAP1 (high

risk). PRAME expression is also an indicator of high risk to be used to

inform frequency of follow-up. If biopsy was not performed, medium- or

For thin tumors (<2.5 mm) with largest diameter ranging from 5 to 19 mm, the recommended primary treatment options are plaque brachytherapy or particle beam RT. For highly select patients who are not good candidates for brachytherapy or particle beam RT, other options to consider include

laser therapy or enucleation. Brachytherapy with scleral patch graft is

recommended for cases with limited extraocular extension (See Principles of Radiation Therapy in the algorithm).

Enucleation

For tumors with largest diameter 19 mm or smaller and thickness 2.5 mm

to 10 mm, brachytherapy and particle beam RT are also options. If there is concern that adequate response was not achieved from initial RT,

additional treatment with resection, laser ablation, transpupillary

thermotherapy (TTT), or cryotherapy can be considered. Although there is a trend toward avoiding enucleation, it is recommended for patients with

neovascular glaucoma, tumor replacing greater than 50% of globe, or

blind, painful eyes. Enucleation should also be considered in cases of

extensive extraocular extension. Pathologic evaluation should follow the uveal melanoma synoptic report recommendations by the College of

American Pathologists (available at:

http://documents.cap.org/protocols/cp-uveal-melanoma-17protocol4000.pdf).305

Given the limitations in the size and RT penetrance of commercially

available brachytherapy plaques (diameter ≤23 mm), this method is not

recommended for tumors that are too large in diameter (>19 mm; any

thickness), too thick (>10 mm; any diameter), or have optic nerve

involvement and thickness (>8 mm; any diameter). RT options for such

tumors include particle beam RT and SRS. The choice between these two RT modalities usually depends on which modality is available at the

treating institution. In the rare scenario that the institution has both SRS

and particle beam facilities, some practitioners would opt for particle beam

because there are more data supporting its efficacy (See Guidelines

section UM-B Principles of Radiation Therapy in the algorithm).

Enucleation is recommended for cases with extensive extraocular

extension, neovascular glaucoma, tumor replacing greater than 50% of

globe, or blind, painful eyes.

Enucleation is historically the most widely used treatment for uveal melanoma. Results from the Collaborative Ocular Melanoma Study

(COMS) prospective randomized trial suggest that enucleation is

associated with a very low risk of local recurrence (~1%),306-308 notably

lower than the rate of local recurrence reported for retrospective studies in patients treated with primary local resection.273-276,309-314 The few patients who developed local recurrences after enucleation all had distant

metastases before the local recurrence developed.306 Retrospective

studies reported similar findings, suggesting that development of distant metastasis is due to micrometastasis that developed prior to

enucleation.308

Postoperative complications include pain, hemorrhage, nausea/vomiting, cardiovascular or pulmonary problems, urinary retention, fever, and local surgical problems.306 Enucleation procedures have been standardized;

they involve complete removal of the eye and in most cases include

insertion of an orbital implant.178,282,315,316 Both porous and nonporous

implants have been shown to result in similar outcomes, although there

may be a higher incidence of ptosis with acrylic implants, and a greater need for ocularists’ treatment (eg, topical antibiotics, polishing or refitting of prosthesis) with hydroxyapatite implants.317

Pre-enucleation RT is generally not used. Results from the COMS

randomized trial in large tumors (height ≥2 mm and diameter ≥16 mm; or

height ≥10 mm and any diameter; or height ≥8 mm, any diameter, if

proximal tumor border <2 mm to optic disc) showed that pre-enucleation RT had no impact on survival compared with enucleation alone,306,318,319 confirming results of prior retrospective studies.320 The 5- and 10-year

DSD reported in this trial were 28% and 40%, respectively, for patients

treated with enucleation.318

In the COMS randomized trial in small-to-medium choroidal melanomas (2.5–10.0 mm in apical height [2.5-8.0 mm if peripapillary] and ≤16 mm in maximum basal diameter, no extrascleral extension ≥2.0 mm thick),

survival outcomes for enucleation were similar to those with iodine-125

Plaque Brachytherapy

brachytherapy.291,292 The 5- and 10-year DSD reported in this trial were

11% and 17%, respectively, for patients treated with enucleation,

compared with 10% and 18%, respectively, for the brachytherapy arm.292 Even after adjustment for age and maximum basal diameter, there were no treatment-dependent differences in all-cause mortality or mortality with confirmed melanoma metastasis at time of death.292 One prospective and several retrospective studies also found that survival was similar after

enucleation versus cobalt plaque brachytherapy,293-297 or a mix of

brachytherapy plaque types,298 versus proton beam RT,299 or versus

SRS.300-303 Relative to RT, enucleation is associated with worse effects on certain visual functions and physical and functional well-being. However, some studies have found that overall quality of life was similar between

the two treatment modalities.321-326

Radiation Therapy

Radiation Therapy

Brachytherapy and charged particle RT are considered appropriate for primary therapy for most cases of uveal melanoma, whereas photon RT and SRT are less often used as primary treatment for uveal melanoma. SRS is sometimes used for large primary tumors, and photon RT is

generally only used as an adjuvant to surgery.

Plaque brachytherapy is a commonly used form of definitive RT for the

primary tumor.290,304,327-329 Prospective studies in patients with small

choroidal tumors found that iodine-125 brachytherapy resulted in tumor

regression in most cases (98%) and 98% rate of globe conservation.330,331 DSD at 5 years was 3.9%.331 As discussed previously, results from the

COMS trial showed that long-term outcomes were not significantly

different with plaque brachytherapy versus enucleation for patients with

small- to medium-sized choroidal melanomas.291,292 Local recurrence after brachytherapy, although rare, is more common than with enucleation.

Prospective studies have reported local failure rates ranging from 0% to

~20%, with most studies reporting rates of less than 10%.49,231,330-342 A

systematic review (N >3000) found that the weighted mean rate of local

failure after brachytherapy was 9.45%.273 Whereas some studies report

median time to local recurrence between 2 and 4 years,335,338,341,343 most also show curves that never really plateau, with recurrences developing as late as 12 years or more after treatment.49,231,332,335,338,341,343

More serious postoperative complications commonly reported for

brachytherapy include radiation retinopathy, optic neuropathy,

papillopathy, maculopathy, neovascular glaucoma, retinal detachment,

and various types of hemorrhages and vascular abnormalities.331,335,341,344 The 5-year cumulative rate of enucleation as a result of brachytherapy

complications or growth of tumor was approximately 12% in prospective trials, most often due to treatment failure during the first 3 years after

brachytherapy, and to eye pain beyond 3 years after treatment.

49,230,231,291,332,335,338,341,343,345 Loss of VA and cataracts are common longterm complications of brachytherapy, with approximately half of patients having lost six or more lines of VA after 3 years of followup.230,331,332,336,341,346-348

Risk Factors for Metastasis

high-risk pathways should be followed, depending on whether any highrisk features are present.

Although the AJCC staging system is based on survival data from large

epidemiologic studies,14,15,20 characteristics used for AJCC staging have

also been shown to be prognostic for development of distant metastasis. T stage is based on the largest basal diameter and thickness of the primary tumor, as well as the presence or absence of ciliary body involvement and presence and size of extraocular extension.33 Multiple prospective studies and several large retrospective studies (N > 1000) have shown that

primary tumor diameter and/or thickness is associated with risk of

metastasis after primary treatment.94,328,336,341,386,467,511 Additionally, several retrospective studies on large patient populations have found that risk of metastasis is correlated with AJCC T stage and with AJCC

staging.10,15,288,503,516,518-521

Multiple tumor molecular markers have been shown to be associated with increased risk and/or shorter time to development of distant metastases. Chromosomal changes were among the first molecular markers to be

found to be associated with risk of distant metastasis in patients with uveal melanoma.522 Multiple studies have found that monosomy 3 and gain of

chromosome 8q, especially when numerous copies are found, in the

primary uveal melanoma is associated with increased risk of

metastasis.26,38,50,69,328,508,517,523-537 Risk of metastasis is even higher when both of these abnormalities are present.26,69,524,527,529,533 Some studies have identified additional chromosomal abnormalities associated with increased risk of metastasis, such as loss of 8p,26,524,526,527,529 loss of 1p,529 loss of

16q,524 and loss of 6q.26 Gain of 6q may be protective against

metastasis,529 at least in the context of monosomy 3 and gain of 8q.26

Mutation and expression of certain genes have also been associated with risk of metastasis in patients with uveal melanoma. Multiple studies have found that BAP1 mutation/deletion (observed in approximately half of

uveal melanomas) and loss of BAP expression in the primary tumor is

associated with increased risk of metastasis.38,74,512,517,518,520,534,538,539 One study showed that risk of metastasis is highest with BAP1 somatic

mutation, and somewhat elevated with BAP1 germline mutation.531 Other studies found that BAP1 mutation was associated with early

metastasis.540,541 Mutation in EIF1AX, found in up to 20% of uveal

melanomas,38,512,536,542 has been associated with lower risk of distant

metastasis.520,540,541 SF3B1 mutation, which is present in approximately

20% of uveal melanomas, was associated with lower risk of

metastasis,38,75 while some studies reported that patients with this

mutation developed late metastases.520,540,541 PRAME expression, present in about a third of uveal melanomas, has also been associated with

increased risk of metastasis.513,516,543

Follow-up for Distant Metastasis

Given the lack of high-quality data to inform the frequency or modality of follow-up screening for distant metastatic disease, the NCCN

recommendations are based on clinical practice at NCCN Member

Institutions. Patients with no evidence of disease (NED) after treatment for uveal melanoma should be followed for signs of metastatic disease. The most frequent site of metastasis is the liver and other sites include lungs, skin/soft tissue, and bones. Recommended follow-up for distant metastatic disease includes imaging to evaluate signs or symptoms of distant

metastasis, and may include regular surveillance imaging. Liver function tests (LFTs) may be considered as a component of follow-up visits,

although some studies showed poor sensitivity for early detection of liver metastases.

For patients who elect to have surveillance imaging to screen for distant

metastatic disease, options include contrast-enhanced MR or US of the

liver, with modality preference determined by expertise at the treating

institution. Additional imaging modalities may include

Follow-up for Distant Metastasis

chest/abdominal/pelvic CT with contrast, or dual-energy subtraction chest x-ray. However, screening should limit radiation exposure whenever

possible. Scans should be performed with IV contrast unless

contraindicated. Recommendations for imaging modality are based on

clinical practice at NCCN Member Institutions, as there are very few data to inform selection of modality. Providers may also want to discuss mental health resources with patients. See the NCCN Guidelines for Survivorship(www.NCCN.org). Participation in a clinical trial is strongly encouraged.

For those choosing to have regular surveillance, the recommended

frequency is based on the risk of distant metastasis. The NCCN

Guidelines recommend risk stratifying patients into low, medium, and high risk of distant metastasis based on the highest risk factor present. For

patients with high risk of distant metastasis who opt to have surveillance imaging, the recommended frequency is every 3 to 6 months for 5 years, then every 6 to 12 months for years 6 through 10, then as clinically

indicated. For patients with medium risk of distant metastasis who opt to have surveillance imaging, the recommended frequency is every 6 to 12 months for 10 years, then as clinically indicated. For patients with low risk of metastasis who opt to have surveillance imaging, consider imaging

every 12 months. Adjusting follow-up frequency based on risk of

metastasis is based on clinical practice at NCCN Member Institutions, and this approach has not been prospectively tested to determine whether it results in better yield from imaging or better outcomes.

There are few data to inform the frequency and modality of follow-up

screening for development of metastatic disease. Prospective studies

have typically monitored for development of distant metastasis using

complete cancer-oriented physical exams, and one or more of the

following: chest x-ray, liver US, and serum LFTs. Most of these studies

followed patients every 6 months for at least the first 5 years.

21,23,24,49,167,307,319,330,332,336,338,379,395,399,403,479,482,483,499 For these studies, the

total number of patients who developed distant metastases was usually too small to produce meaningful results regarding the sensitivity and

specificity of different surveillance modalities. The value of surveillance

imaging and tests is also controversial because it is unclear whether early detection of distant metastases improves outcomes, given that most

treatments for distant metastatic disease are relatively ineffective. Some retrospective studies found that survival was better for patients whose

distant metastases were asymptomatic at the time of detection,497,544

whereas other studies observed no such correlation.23,545,546

The utility of LFTs for early detection of liver metastases is an issue of

ongoing debate. In the COMS trials for patients with medium and large

tumors, the sensitivity, specificity, positive predictive value, and negative predictive value associated with at least one abnormal LFT before first

diagnosis of metastasis at any site was 14.7%, 92.3%, 45.7%, and 71.0%, respectively. Of the LFTs, APH had the highest diagnostic attributes.

These results suggest that the use of LFT results followed by other

diagnostic tests has high specificity and predictive values, but low

sensitivity.482 Whereas 739 patients had distant metastases detected

during follow-up, 13 did not have their metastasis discovered until time of death.483 While some analyses supported LFTs as one of the most useful

methods for screening,498,547-551 others argue that the specificity and

sensitivity of these tests is too low to warrant routine use.501,502,552

The optimal strategy for imaging surveillance is also an issue of debate. Each of the methods commonly used (ie, chest x-ray, CT, US, MRI,

PET/CT) has produced varying results.498-502,549,553-564 Due to the low

probability of metastasis at any specific time point, the yield of these tests

is low, and there is concern regarding cumulative radiation exposure due to the long-term follow-up.565 Therefore, imaging is usually focused on the

liver, and liver US and MRI are favored over CT or PET/CT. Some studies have found MRI to be moderately better than CT or PET/CT,553,557,559 and

Risk of Developing Secondary Cancers During Follow-up

in high-risk patients, showed promising results for early detection of liver metastases.502,560

Risk of Developing Secondary Cancers During Follow-up

Due to the long-term surveillance needed for detection of distant

metastatic disease in patients with uveal melanoma, it is not uncommon

for screens to identify other primary cancers.13,162,163,165,563,566-569 The two

COMS randomized trials in patients with medium to large primary uveal

melanomas showed that the proportion of patients with secondary cancers increased steadily over the entire duration of follow-up (median 10 years, range 5–16 years).567 Various types of secondary malignancies were

observed.162,567 Uveal melanoma may increase the risk of developing other cancers,163 especially in patients with familial uveal melanoma or other

familial cancers.116,117

Management of Ocular Recurrence

Management of Ocular Recurrence

Workup for Ocular Recurrence

Workup for Ocular Recurrence

If a recurrence is detected, workup should include H&P to identify any

signs or symptoms associated with recurrence or metastasis. Biopsy may also be appropriate. Whereas intraocular recurrence can often be

diagnosed and managed without a biopsy, additional prognostic FNA

biopsy may be valuable to determine whether the tumor has developed

any high-risk features that warrant more frequent surveillance. Extraocular recurrence or metastasis should be confirmed histologically whenever

possible or if clinically indicated. Appropriate biopsy techniques in this

setting may include FNA or core biopsy. For patients with metastasis who are considering treatment with targeted therapy, tissue should be obtained for genetic analysis (screening for mutations that may be potential targets for treatment or to determine eligibility for a clinical trial) from either biopsy of the metastasis (preferred) or archival material. Broader genomic

profiling may be considered if the results could inform future treatment

decisions or eligibility for clinical trials.

Patients with local recurrence should have ocular orbital imaging (if not

recently previously done or as clinically indicated) to evaluate the extent of local recurrence. Patients who develop distant metastatic disease after

treatment of primary uveal melanoma should have ocular orbital imaging as part of workup to check for local recurrence, since asymptomatic local recurrences may be present at the time distant metastasis is discovered. Workup for patients with recurrence should include broader imaging to

evaluate the extent of local recurrence/distant metastasis, and/or for

baseline staging. Since the most frequent site of metastasis is the liver

and other sites include lungs, skin/soft tissue, and bones, imaging options for baseline staging in patients with recurrence or metastasis include

contrast-enhanced MR or US of the liver, with modality preference

determined by expertise at the treating institution. Additional imaging may include chest/abdominal/pelvic CT with contrast and/or whole-body FDG

Treatment for Ocular Recurrence

PET/CT; however, screening should limit radiation exposure whenever

possible. Brain MRI with IV contrast may be performed if neurologic

symptoms are present, but routine CNS imaging is not recommended. All scans should be performed with IV contrast unless contraindicated.

Treatment for Ocular Recurrence

The recommended treatment options for local recurrence depend on the extent of disease. For intraocular recurrence (limited to the eye, without

orbital involvement), the recommended options include RT, either by

plaque brachytherapy or particle beam, enucleation, or laser ablation. For small recurrences in patients who cannot undergo RT or surgery, TTT is recommended. TTT is usually reserved for small recurrences, particularly when recurrence is likely due to incomplete plaque coverage during

primary brachytherapy; it is generally not appropriate for recurrences

occurring within the RT field or recurrences that may be too thick (>3 mm) for laser treatment to reach the base. If there is extraocular involvement, surgical resection is needed, but can be coupled with RT to the orbit

(particle beam or photon beam) and/or cryotherapy to the orbital tumor.

Surgical resection may potentially include partial orbital tumor resection, enucleation, or exenteration. Besides surgical resection, RT with plaque brachytherapy or particle beam alone might be offered. If there is orbital involvement and the patient has had prior enucleation, options include

surgical resection or cryotherapy to the orbital tumor, and/or RT to the

orbit (particle beam or photon beam) (See Principles of Radiation Therapy in the algorithm).

Given the rarity of local recurrence after treatment of primary uveal

melanoma, data on treatment of local recurrences are scant, and it is

unclear which approaches result in the best outcomes. Most studies had fewer than 10 patients with local recurrence, and many studies either

managed all local recurrences with enucleation or did not report on

retreatment approaches. In the few studies that reported outcomes after

treatment of local recurrence (N ≥ 10),361,387,403,440,455,570-574 reasonably high rates of local control were achieved with the following globe-conserving

modalities: laser photocoagulation,361,387 TTT,455,573 proton-beam

RT,387,440,571-573 and plaque brachytherapy RT.403,455,573,574 Similar to the

primary treatment setting, some patients treated with globe-conserving

therapy for local recurrence subsequently underwent enucleation due to (suspected or confirmed) tumor regrowth or complications such as pain

and neovascular glaucoma. 361,387,440,570,571,573,574 Results from one

retrospective study of 73 patients with local recurrence suggest that

treating recurrence with proton-beam RT (N = 31) versus enucleation (N = 42) may result in similar metastasis-free survival and OS.572 Another

retrospective analysis of 51 patients with local recurrence found that local control after treatment of recurrence was more likely in those with longer intervals between primary treatment and development of recurrence.361

Management of Metastatic Disease

Management of Metastatic Disease

Survival after detection of distant metastatic disease varies widely across studies, including those with large patient samples (N > 100), with median OS ranging from 3 to 30 months.23-25,483,497,575-578 Several studies have

found that a small percentage of patients with uveal melanoma metastasis experience long-term survival (≥5 years) after development of distant

metastatic disease.21,23,483 Others have shown a bimodal distribution of

separate populations with short-term survival (median OS <1 year) and

long-term survival (median OS >2 years).21,23,579 Conflicting data exist for a wide range of factors that have been associated with OS after detection of metastasis including older age, male sex, and poor performance status.21-24,483,499,503,545,575,578,580-582 Other factors include the presence of symptoms

versus asymptomatic metastasis detected by surveillance, shorter

disease-free interval before metastasis, higher number of anatomic sites involved, involvement of the liver, and greater disease volume.21-

24,499,503,544-546,558,575,578,580-587 In addition, elevated liver enzymes at the time of diagnosis of metastasis, particularly lactate dehydrogenase (LDH) and alkaline phosphatase (APH), have been associated with shorter

OS.21,22,24,499,575,578,580-582,585

Whereas in recent years the options for treating metastatic cutaneous

melanoma have dramatically improved, treatment of distant metastases

from uveal melanoma still presents a major clinical challenge. Several

retrospective studies suggest that treatment for distant metastases from

uveal melanoma improves survival, although it is unclear whether these

results are influenced by selection bias.23,25,503,582,586 Other studies did not find that treatment improved survival.483,581 Patients treated with supportive care reported a median OS ranging from 1.7 to 4.9 months, although

those opting for supportive care are more likely to have risk factors for

poor survival.25,503,586 For treatment of distant metastasis from uveal

melanoma, a wide variety of approaches have been tested, including

surgery, RT, ablative approaches, vaccines, systemic therapies

(chemotherapies, immunotherapies, targeted therapies, and combined

regimens), and localized chemotherapy/immunotherapy.24,575-577,587-589

Systematic reviews, meta-analyses, and retrospective studies suggest that the best outcomes are seen in patients who received liver-directed

treatments, particularly those treated with surgery when complete

resection was achieved.21,24,502,544,545,575,576,580,582,583,587,590,591 It is unclear

whether these effects are due to other factors, such as lower volume of

metastatic disease, which would make a patient eligible for surgery and/or liver-directed treatments, and more likely to have complete resection. One

phase III randomized trial (EORTC 10821) found no difference in OS in

171 patients with liver metastasis from uveal melanoma treated with IV

fotemustine versus hepatic arterial infusion (HAI) with fotemustine, despite the HAI approach showing higher response rates and longer progressionfree survival (PFS).592 A few studies suggest that better survival was seen in those who had a response to therapy for metastatic disease,23,575 but

some did not find an association.21

Workup for Distant Metastatic Disease

Workup for distant metastatic disease includes biopsy if clinically

appropriate. Similar to workup for ocular recurrence, metastasis should be confirmed histologically whenever possible or if clinically indicated. Biopsy techniques may include FNA or core. Tissue should be obtained for

genetic analysis (screening for mutations that may be potential targets for treatment or determine eligibility for a clinical trial) from either biopsy of the metastasis (preferred) or archival material if the patient is being

considered for targeted therapy. Broader genomic profiling should be

considered if the test results might guide future decisions or eligibility for participation in a clinical trial. Imaging can be considered for baseline

staging and to evaluate specific signs and symptoms. Since the most

frequent site of metastasis is the liver and other sites include lungs,

skin/soft tissue, and bones, imaging options include contrast-enhanced

MR or US of the liver, with modality preference determined by expertise at

Workup for Distant Metastatic Disease

Treatment for Distant Metastatic Disease

the treating institution. Additional imaging may include

chest/abdominal/pelvic CT with contrast and/or whole-body FDG PET/CT; however, screening should limit radiation exposure whenever possible.

Brain MRI with IV contrast may be performed if neurologic symptoms are present, but routine CNS imaging is not recommended. All scans should be performed with IV contrast unless contraindicated. Testing of LFTs,

including LDH, and alkaline phosphatase should be considered for their potential prognostic value.

Treatment for Distant Metastatic Disease

Given that there are no treatments for metastatic uveal melanoma, except for the recently FDA-approved tebentafusp, that have clearly and

consistently been shown to improve outcomes, it is important to consider all clinical trial options carefully, and when available and clinically

appropriate, enrollment in a clinical trial is recommended. For those who are not appropriate for treatment in the context of a clinical trial, the

recommended options are largely based on clinical practice at NCCN

Member Institutions. It is important to be aware that even among therapies often used at NCCN Member Institutions, efficacy is limited, and it is not

clear which approaches are most effective. Therefore, the guidelines

indicate that a combination of approaches may be needed, and it is

important to consider each patient’s prognosis and treatment goals to

determine whether palliative care is the most appropriate option.

Selection of treatment should depend on the location and extent of

disease. For patients with metastasis to the liver, liver-directed therapies should be considered. Options include: hepatic isolation perfusion,

embolization (ie, chemotherapy, radiation, immunotherapy), and ablative procedures (ie, thermal ablation, cryotherapy). For patients with

extrahepatic disease or hepatic disease that is not amenable to liverdirected therapy, systemic therapy can be considered. A recently reported phase III randomized trial was conducted in previously untreated HLA-

A*02:01-postive patients with metastatic uveal melanoma. Patients were randomized to tebentafusp (a bispecific protein) or investigator’s choice of either pembrolizumab, ipilimumab, or dacarbazine. Results showed that treatment with tebentafusp resulted in longer OS compared with control therapy.593 The literature is not directive regarding other systemic

therapies. However, individual patients may derive benefit on occasion

from agents used to treat metastatic melanoma of cutaneous origin.

Clinical trials are preferred given the lack of data.

For both hepatic and extrahepatic metastases, patients with limited or

symptomatic disease should consider resection and/or RT by photon

beam or SRS. Recommendations for treating uveal melanoma metastases with RT can be found within Principles of Radiation Therapy in the

algorithm and within Principles of Radiation for Metastatic Disease in the NCCN Guidelines for Melanoma: Cutaneous (available at

www.NCCN.org).

Following treatment for metastatic disease, patients should receive

imaging to assess response or progression. The recommended crosssectional imaging modalities are the same as those recommended for

workup. Those with NED after treatment for metastases may be eligible for clinical trials testing adjuvant therapies. If they opt to forgo adjuvant

treatment, then the recommended follow-up surveillance is similar to the

follow-up for patients with NED after treatment of localized disease (Refer to Guidelines section UM-4 Follow-up in the algorithm). If post-treatment imaging shows residual or progressive disease, the NCCN Panel

recommends trying other options for treatment of distant metastatic

disease.

Resection of Metastases

As mentioned above, multiple prospective and retrospective studies and meta-analyses have found that among patients with metastatic uveal

Regional Isolation Perfusion

melanoma, those who can be treated with surgery have the best

outcomes, especially if complete resection is achieved.23,544,545,575-

577,583,587,591,594-598 Multiple studies have reported median OS greater than 20 months after resection of uveal melanoma

metastases.23,544,545,577,587,591,594,595,597-602 For liver metastases, rates of

complete resection ranged from 27% to 88%.23,545,583,587,594,595,598,600

Multiple studies reported on combination therapy with resection and

hepatic arterial infusion, radiofrequency ablation (RFA), transarterial

chemoembolization (TACE), or adjuvant systemic

therapy.544,545,577,587,594,599,603-605

Resection of Metastases

Liver-Directed Therapy

Liver-Directed Therapy

Regional Isolation Perfusion

Several techniques have been developed for localized delivery of

pharmaceutical therapy to the liver since theoretically, higher doses can

be administered locally than would be feasible systemically due to toxicity. Methods include isolated hepatic infusion (IHP), percutaneous hepatic

perfusion (PHP), HAI, and embolization techniques. Liver metastases

derive most of their blood supply from the hepatic artery, whereas the

blood source for benign hepatocytes is primarily the portal vein.606 IHP and HAI both deliver therapy via the hepatic artery to maximize drug delivery to liver metastases while limiting exposure to healthy parenchyma.607

Whereas IHP is done during surgery, has risk of morbidity, and usually

can only be done once, HAI and PHP are less invasive techniques, with

lower risk of morbidity, and have the potential to be performed multiple

times to increase depth of response. 577,591,607-609

IHP is an open surgical procedure involving vascular isolation of the liver, allowing high doses of heated chemotherapy to be directly delivered to the organ through an arterial catheter.591 Several small prospective studies (n < 40)610-614 and a few retrospective studies (N = 19-68) 615-618 have tested hyperthermic IHP in patients with liver metastasis from uveal melanoma.

The agent most commonly used in these studies was melphalan, with or without tumor necrosis factor alpha (TNF-alpha) or cisplatin.610-614 Good

response rates to IHP have been reported in some of these prospective

studies (overall response rate [ORR], 50%–68%),610-613 as well as

retrospective studies (ORR, 67%–83%).615-617 However, the IHP procedure is often lengthy (>8 hours),577,591,609-611 involves significant blood loss

(median 2–3.5 L),577,610,611 involves long hospital stays (7–10 days),591,609-611,617,618 can result in significant complications/morbidities (eg, portal vein

thrombosis, transient grade 3/4 hepatic toxicity),591,609-612,615-618 and

mortalities from the procedure were also observed.609,610,615,618 For these

reasons IHP is not widely used.

PHP is a simpler, less invasive alternative to IHP that can be

repeated.591,608 It uses a double-balloon catheter inserted into the inferior vena cava to isolate hepatic venous blood that is then filtered

extracorporeally.591,608 Several prospective studies tested PHP in patients with liver metastases from uveal melanoma, but efficacy results are

Hepatic Embolization

lacking.619-621 Retrospective studies suggest good response rates (>40%), especially if multiple rounds are used.622-625 In all these studies melphalan was the agent used.619-625 PHP appears to be somewhat better tolerated than IHP, with no treatment-related fatalities, but many patients still

experienced hematologic grade 3–4 events, some had non-hematologic

grade 3–4 adverse events (AEs) (eg, bleeds, thromboembolism), and

some had extended hospital stays (4–5 days) or had to be readmitted.621-

623,626

HAI is a technique using catheters in the hepatic artery to deliver

chemotherapy directly to the liver.591 The number of times HAI can be

repeated depends on the type of catheter used.591 Efficacy of HAI for liver metastases from uveal melanoma has been reported in several small

prospective studies (N = 8–31)627-631 and several retrospective studies (N = 10–100).632-636 Most of these studies used fotemustine,628,629,632,633,635 but

More recent studies have reported local failure rates ranging from 0% to 20% for patients treated with iodine-125, ruthenium-106, palladium-103,

and cesium-131 brachytherapy plaques.273,337,338,349-352 It is important to

note that late treatment failures (up to 12 years) after brachytherapy have

been observed.338 One prospective and several retrospective studies also found that survival was similar after enucleation versus cobalt plaque,293-

297 or a mix of brachytherapy plaque types.298 A meta-analysis of studies

testing Ru plaques reported a 5-year DSD of 6% for small and medium

tumors (T1/T2), and 26% for large tumors (T3).353 Palladium-103

brachytherapy plaques appear to perform similarly to iodine-125

plaques.342

##### Plaque Brachytherapy Dosing Considerations

When evaluating patients for brachytherapy, it is important to consider the entry criteria and treatment parameters used in the COMS trial. The

COMS trial included only patients with tumors that were choroidal;291 those with tumors contiguous with the optic disc were excluded, as were those with metastases from melanoma or another cancer (except nonmelanoma skin cancers).292 Only 16% of patients had tumors less than 2.0 mm from the optic disc.291

Plaque Brachytherapy Dosing Considerations

Using iodine-125 COMS plaques, 85 Gy should be prescribed to the apex of the tumor at low dose-rate (≥0.6 Gy/h), as this was the dose used in the COMS study of medium-sized uveal melanomas, showing similar survival with brachytherapy versus enucleation.291,292 Other prospective and

retrospective studies using iodine-125 brachytherapy dosing similar to

COMS have reported similarly high rates of local control,338,350,354-357 and a retrospective study found that efficacy outcomes were similar to those in patients treated with SRT.358 Studies using iodine-125 brachytherapy

##### Hepatic Chemoembolization

other agents tested include carboplatin;627,635 nab-paclitaxel;630

decitabine;631 a combination of cisplatin, vinblastine and dacarbazine;634

and melphalan.636 Response rates to HAI were lower and more variable

than for IHP in both prospective (ORR, 0%–44%)627-631 and retrospective studies (16%–36%).632,635 In the phase III randomized trial EORTC 10821 in patients with liver metastasis from uveal melanoma, no difference in OS was observed for IV fotemustine versus HAI fotemustine (median OS, 13.8 vs. 14.6 months), despite the HAI approach showing higher response

rates (2.4 vs. 10.5%) and longer PFS (median 3.5 vs. 4.5 months; HR,

0.62; 95% CI, 0.45–0.84, P = .002).592 Complication rates varied widely

across studies, but in general appear to be lower than those reported for IHP, and are manageable.592,627-629,632,633,635,636 Grade 3/4 AEs were mostly hematologic (eg, anemia, leukopenia, thrombocytopenia,

neutropenia).592,627,631-633 Grade 3–4 catheter-related complications

occurred in a minority of patients (≤12%), as did liver toxicity (<10%).592,632 Deaths from toxicity were reported in one study,592 but not in others.

Hepatic Embolization

Hepatic arterial embolization is a method for delivering to the liver

chemotherapy, immunotherapy, or radioactive agents, while increasing dwell time and providing selective ischemia.591,609

Hepatic Chemoembolization

There are no standard protocols for hepatic chemoembolization, also

called hepatic TACE or hepatic arterial chemoembolization (HACE). In

general, two approaches have been used for treatment of uveal melanoma metastases to the liver. One involves HAI with the active agent, followed by addition of either a transient or permanent embolic agent.591,609 The

active agent is usually mixed with ethiodized oil (to increase dwell time),

and embolization agents include absorbable gelatin sponge or polyvinyl

alcohol particles.591,609 The other approach uses drug-eluting beads

produced from a polyvinyl alcohol hydrogel that has been modified with

sulfonate groups for the controlled loading and delivery of chemotherapy agents.609 These beads provide localized drug delivery and serve as an

embolic agent to render tumors ischemic.609

Multiple retrospective637-644 as well as a few prospective studies645-648 have evaluated chemoembolization for the treatment of hepatic metastasis in

patients with uveal melanoma. Using traditional methods (active agent

infusion + addition of embolic agent), response rates varied widely, but

could be as high as 57%.637,638,640,641,643-649 Chemotherapies used included BCNU, mitomycin C, fotemustine, cisplatin, carboplatin, doxorubicin, and

1,3-bis (2-chloroethyl)-1-nitrosourea; embolic agents used included gelatin sponge, polyvinyl sponge, resorbable microspheres, and polyvinyl alcohol particles.637,639,640,642-649 Only a few studies reported outcomes for patients with liver metastases from uveal melanoma that were treated with transarterial chemotherapy-eluting beads.650-652 One phase II study reported

100% ORR in the 10 patients treated with irinotecan-loaded polyvinyl

alcohol microspheres.650 In contrast, a retrospective study of irinotecanloaded beads in 28 patients reported much lower response rates.652 A

retrospective study including 58 patients treated with TACE using

irinotecan-charged microbeads reported an ORR of 27.5% (all partial

responses).653 Another prospective noncontrolled study testing beads

loaded with doxorubicin only reported toxicity and quality of life.651

Comparisons of hepatic chemoembolization with other treatments for

uveal melanoma liver metastasis are limited. One retrospective study

compared cisplatin-based chemoembolization (TACE) versus HAI or

systemic therapy, and found that chemoembolization was associated with

the best response rate, although OS did not differ between the groups.638 However, those who responded to TACE had better OS than those who

did not respond and better than those treated with HAI or systemic

therapy.638 Other studies also reported that OS was better in responders to

##### Hepatic Immunoembolization

chemoembolization versus non-responders,638,641,642,644,645,647 whereas

others did not find a significant association.646,653

Chemoembolization seems to be generally well tolerated, with few or no treatment-related deaths.640,646,648,649,651-654 AEs reported in more than one study include abdominal pain, fever, nausea, vomiting, liver dysfunction, and thrombocytopenia.637,640,643,644,648,650,652,653 Some studies recommend supportive treatment with antibiotic and antiemetic prophylaxis, IV

hydration, and major analgesic before and after the procedure.648,650

##### Hepatic Radioembolization

Hepatic Radioembolization

Hepatic radioembolization, also called hepatic transarterial

radioembolization (TARE) or selective internal RT (SIRT), is a procedure in which glass or resin yttrium-90 microspheres are introduced to the

hepatic artery, both as a mechanism for radiation delivery and for

embolization.609 Response rates from retrospective studies varied widely (6%–100%), but disease control rate was consistently greater than

50%.655-660 A phase II study reported ORR of 39% in the 23 patients who received radioembolization as first-line treatment for liver metastasis, and ORR of 33% in the 24 patients who received radioembolization after

progression on immunoembolization, with disease control rates of 87% and 58%, respectively.661 Across studies, radioembolization was well

tolerated, with most toxicities being grade 1–2 and self-limiting, and no

treatment-related deaths.655-659 AEs included abdominal pain/discomfort, nausea and vomiting, LFT elevation (sometimes due to progression),

transient lymphopenia, and gastric ulcer.656-659,661

Hepatic Immunoembolization

Hepatic immunoembolization involves infusion of an immunologic

stimulant into the hepatic artery, followed by addition of an embolizing agent.609 Several studies have tested immunoembolization using

granulocyte-macrophage colony-stimulating factor (GM-CSF) ethiodized

oil plus a gelatin sponge.662,663 A phase I trial with 34 uveal melanoma

patients and unresectable liver metastases occupying less than 50% of

total liver volume reported an ORR in the liver of 32%, and response

correlated with better OS.662 A phase II randomized trial with 52 patients with uveal melanoma and hepatic metastases only (also <50% liver

volume) reported an ORR of 21.2% for the 25 patients treated with

immunoembolization versus 16.7% for the 27 who received bland

embolization (GM-CSF replaced with saline).663 In this study hepatic

response was not correlated with OS, but was associated with better PFS. AEs associated with immunoembolization in these studies included

abdominal pain, fever, nausea, and transient increases in hepatic

enzymes and there were no treatment-related deaths.662,663

Ablative Procedures for Liver Metastases

Although ablative procedures such as thermal ablation and cryotherapy

have been used with some success for liver metastases from other kinds of cancer, there are very few reported clinical data on the efficacy of these techniques for liver metastases from uveal melanoma. 599,604,664-667 The

supposed advantage of ablative techniques is that these techniques can be useful for tumors that are difficult to resect, and compared to surgery, are tissue-sparing, less invasive, cost-saving, and have lower rates of

complications, while still being potentially curative.668 The most commonly used methods of thermal ablation for liver tumors include RFA and

microwave ablation (MWA).668-670 Both methods use heat induction and

destroy tissue through thermally induced coagulative necrosis. Based on data from other (non-uveal) types of liver tumors, safety of MFA and RFA

appears similar with rare major complications (<3%).670-674 On the other hand, cryoablation dehydrates and causes irreversible cell damage and cell death by using rapid gas expansion at a probe tip to quickly cool

surrounding tissues to as low as -140°C.668,669,675-677 Complications may include pain, infection (eg, wound infection, pneumonia), hemorrhage, biliary injury, thrombocytopenia, pleural effusion, and renal

External Beam Radiation for Uveal Melanoma Metastases

impairment.669,675,677,678 Whereas some studies found that cryoablation was more likely to cause complications compared with RFA, other analyses

suggest that complication rates are similar to RFA, especially in more

recent studies.668,669,675,676,678-680

Outcomes have been reported for patients with liver metastases from

uveal melanoma treated with RFA599,604,665,667 and laser-induced interstitial thermotherapy (LITT).664 The efficacy and safety of ablative techniques is difficult to ascertain, because most of these studies contained fewer than 20 patients with uveal melanoma,604,664-667 combined results for patients

with uveal melanoma and other types of melanoma,665,666 or combined

results for the ablative therapy with other therapies.599,604,664,667

Nonetheless, several retrospective studies reported relatively long median

Ablative Procedures for Liver Metastases

OS of greater than 20 months in cohorts of uveal melanoma patients with

liver metastases treated with LITT (±TACE),664 RFA,665 or percutaneous thermal ablation (± systemic therapy).666 In a retrospective study of uveal

melanoma patients with liver metastases treated with surgery alone (N = 57) or a combined approach in which some metastases were resected and others treated with RFA (N = 13), those treated with the combination

approach had similar disease-free survival as those treated with surgery

alone (median 7 vs. 10 months) and OS (median 28 vs. 27 months).599

Moreover, there were no recurrences at the 22 sites treated with RFA after a median follow-up of 63 months.599 These results suggest that RFA may

be as effective as surgery, and could be used in lieu of surgery for

metastases that are difficult to resect.

External Beam Radiation for Uveal Melanoma Metastases

Published data on external beam RT for uveal melanoma metastases are extremely scant with no study reporting outcomes or palliative effects.

Systemic Therapy for Distant Metastatic Disease

Many systemic therapies have been tested in prospective trials as

treatment for metastatic uveal melanoma, including immunotherapies,681-694 chemotherapies,592,695-705 targeted therapies,702-704,706-716 and systemic

therapy combinations.698,701,717-735 For treatment of metastatic uveal

melanoma, systemic therapies have largely been tested in small phase II studies and most have shown little activity (response rate

<10%),589,591,593,736-738 especially compared with the efficacy of checkpoint immunotherapies and BRAF/MEK inhibitor combinations in metastatic

cutaneous melanoma.739-747 The few larger randomized phase II/III trials comparing systemic therapies for metastatic uveal melanoma have failed to identify any systemic therapies that are consistently more effective than chemotherapy,698,701-704,710,712,731 except recent data for tebentafusp.593 As noted above, meta-analyses suggest that for metastatic uveal melanoma, systemic therapy appears to result in worse outcomes than localized

treatment (surgery or liver-directed therapies), although differing patient selection criteria across studies may be a confounding factor in these

analyses.24,576,577,591 For patients who are not appropriate for localized

therapy, selection of systemic therapy is very challenging, necessitating further study into better options.

Immunotherapy

Immunotherapies for which there are efficacy data from prospective

studies in metastatic uveal melanoma include tebentafusp (formerly

IMCgp100),681,758 dendritic cell vaccination,683 adoptive transfer of TILs,682 or bleomycin/vincristine/lomustine/dacarbazine (BOLD) in combination

with IFNα-2b727,728,730 or in combination with IFNα-2b and IL-2.729 Most

recently and notably, tebentafusp was tested in a large phase III

randomized trial (N = 378) in previously untreated HLA-A*02:01-positive

patients with metastatic uveal melanoma. Patients were randomized 2:1 to receive tebentafusp or investigator’s choice of single-agent

pembrolizumab, ipilimumab, or dacarbazine (control group). OS at 1 year

Immunotherapy

was significantly higher in the tebentafusp group versus the control group

(73% vs. 59%; HR for death, 0.51; 95% CI, 0.37–0.71; P < .001). The

same was true for PFS (31% vs. 19%; HR for disease progression or

death, 0.73; 95% CI, 0.58–0.94; P = .01). The OS advantage but relatively low response rate (9% in the tebentafusp group vs. 5% in the control

group) suggests that recipients of tebentafusp live longer but there might not be tumor shrinkage. Therefore, patients who present with symptomatic

liver metastases may prefer to start with liver-directed therapies or

nivolumab/ipilimumab. Treatment-related events infrequently led to

discontinuation of the trial treatment (2%) and no treatment-related death was reported.593 Tebentafusp was associated with cytokine-release

syndrome, at least for the first few cycles; therefore, hospitalization to

monitor for and treat this condition should be indicated.

Checkpoint immunotherapies tested in prospective studies for metastatic uveal melanoma include anti-CTLA-4 agents ipilimumab and

tremelimumab,685,686,693 anti-PD-1 agents nivolumab and

pembrolizumab,688-691 and nivolumab/ipilimumab combination

therapy.692,694,748,749 In prospective trials,685,686,693 expanded access

programs (EAPs),750-755 and a named patient program,756 anti-CTLA-4

agents resulted in response rates ranging between 0% to 6.5%, median

PFS between 2 to 4 months, and median OS of less than 13 months.

Meta-analyses have concluded that anti-CTLA-4 systemic therapy results

in outcomes that are similar or worse than conventional systemic

chemotherapy.576,589,737 Results for other immune checkpoint inhibitor

regimens in patients with metastatic uveal melanoma look somewhat more promising. Although one prospective study reported no responses in 17

patients treated with anti-PD-1 systemic therapy,689 three other

prospective trials and one EAP reported ORRs between 6% to 38%, with

eight responses among a total of 81 patients treated (8%).688,690,691,757

Median PFS ranged from 2.3 to 11 months.688-690,757 Two phase II trials

testing nivolumab/ipilimumab in patients with metastatic uveal melanoma

have reported ORRs of 11.5% and 18%, respectively. 692,694,748,749 The median OS and PFS were 12.7 and 3.0 months, respectively, in one

study749 and 19.1 and 5.5 months, respectively, in the other.748

Comparative studies are needed to determine whether combination antiCTLA-4/anti-PD-1 consistently improves outcomes in patients with

metastatic uveal melanoma.

Cytotoxic Regimens

Cytotoxic Regimens

A wide variety of chemotherapies have been tested in prospective trials in patients with metastatic uveal melanoma, and outcomes have been

reported for the following single-agent chemotherapies: dacarbazine,701-704

paclitaxel, 697 temozolomide,695,702,704 DHA-paclitaxel,696 fotemustine,592

bendamustine,699,700 treosulfan,698 liposomal vincristine,700 arsenic

trioxide,705 and lenalidomide.759 Most studies evaluated patients for

response to treatment, but responses to these therapies were rarely

observed.592,695-705,759 The few responses observed were in patients treated with fotemustine (2/83),592 liposomal vincristine (1/4),700 dacarbazine

(3/36),703 and DHA-paclitaxel (1/22).696 For the studies that measured PFS and OS with these single-agent chemotherapy regimens, median PFS was

always less than 4 months,592,695,696,698,701-704 and median OS was nearly

always greater than 10 months.592,695,696,702-704 EORTC 10821, a phase III

randomized trial, reported a median OS of 13.8 months for patients treated with IV fotemustine, but this longer OS is likely due to the trial including

only patients with liver metastases (no extrahepatic metastases).592 It

remains unclear whether any single-agent chemotherapy improves

survival relative to best supportive care.

Combination chemotherapies that have been tested in prospective trials

for metastatic uveal melanoma include gemcitabine/treosulfan,698,717-721

dacarbazine/treosulfan,723 cisplatin/gemcitabine/treosulfan,722,760

cisplatin/dacarbazine/vinblastine,724 docetaxel/carboplatin,725 and

tirapazamine/cisplatin.726 All of these were tested in pilot, phase I, or

Targeted Therapy

phase II studies, most of which reported response rates of less than 5%. Due to an early pilot study that reported a response rate of nearly 29% for patients with metastatic uveal melanoma (n = 14),721

gemcitabine/treosulfan was tested in multiple studies, but in the five

subsequent studies the response rate was much lower, ranging from 0% to 4.2%.698,717-720 Four of these studies (including the pilot) reported PFS and OS data, with median PFS ranging from 2.5 to 6.7 months, and

median OS ranging from 7.5 to 14.2 months.698,717,718,720,721 Results from

one phase II study suggested that higher treosulfan doses (≥3500 mg/m2) provided better outcomes with this combination. Nonetheless the response rate at these higher doses was only 5.2%.717 A randomized phase II study found that gemcitabine/treosulfan combination, using the higher treosulfan dose, did provide better PFS and a trend for better response compared

with treosulfan alone, but the overall response was still relatively low

(4.2% in the combination arm), and the PFS relatively short (mean 3

months in the combination arm).698 Addition of cisplatin to

gemcitabine/treosulfan did not improve results—there were no responses in both of the studies that tested this triplet.722,760 There were also no

responses seen in the phase II trials that tested dacarbazine/treosulfan,723 docetaxel/carboplatin,725 and tirapazamine/cisplatin.726 The one phase II

study testing cisplatin/dacarbazine/vinblastine reported a surprisingly high ORR of 20%, with median PFS of 5.5 months and median OS of 13.0

months.724 This result needs to be repeated, and may be a product of

patient selection.

Meta-analyses combining results across studies that tested chemotherapy in patients with metastatic uveal melanoma report ORRs ~4%,589 median PFS of 2.6 months,24 and median OS ranging from 9 to 11 months.24,576

Targeted Therapy

Targeted therapies that have been tested in prospective studies as singleagent therapy for patients with metastatic uveal melanoma include the

tyrosine kinase inhibitors (TKIs) imatinib706,707,761 and sunitinib,703,709 the

mitogen-activated protein kinase (MEK) inhibitors trametinib710,711 and

selumetinib,702 the multi-kinase inhibitor sorafenib,708 the receptor TKI

cabozantinib,704,712 the VEGF inhibitor aflibercept,715 the HSP90 inhibitor

ganetespib,713 and the topoisomerase inhibitor 9-nitro-camptothecin.716

Targeted therapy combinations that have been tested in prospective trials include trametinib plus uprosertib, an inhibitor of protein kinase B (AKT);710 binimetinib (MEK inhibitor) plus sotrastaurin (PKC inhibitor);738 and

everolimus (mTOR inhibitor) plus pasireotide (IG1FR inhibitor).714

Prospective studies in patients with metastatic uveal melanoma have also tested combinations of chemotherapy plus targeted therapy, including

carboplatin/paclitaxel/sorafenib,734 fotemustine/sorafenib,762

dacarbazine/selumetinib,701 temozolomide/bevacizumab,735 and

carboplatin/paclitaxel/bevacizumab ± everolimus.731 These prospective

studies were pilot studies, phase I trials, and phase II trials, and in most of them the overall response was less than 10%.702,706-708,710-716,761 Taken

together, most meta-analyses concluded that targeted therapy did not

improve outcomes relative to conventional chemotherapy.24,576,589,738

Although uveal melanomas often express KIT, they rarely harbor the c-KIT mutations associated with response to imatinib in other cancers.61,706,761,763 It is thus perhaps not surprising that response rates to imatinib were low in patients with metastatic uveal melanoma.706,707,761 Two studies reported no responses,706,707 and 8% response was observed in a third study that

selected patients with high KIT expression.761 Given the unimpressive

median PFS (2.8 months) and OS (6.9 months) for the 25 patients in this study, imatinib is not considered a good option for patients with metastatic uveal melanoma.761 Results were similar for the other TKI, sunitinib. A pilot study in 20 patients with metastatic uveal melanoma expressing KIT

reported an ORR of 5% for patients treated with sunitinib,709 but a

subsequent larger phase II randomized study reported no response in the 38 patients treated with sunitinib (vs. ORR of 8% with dacarbazine), and

PFS and OS with sunitinib were no better than the comparator

dacarbazine.703

Although BRAF mutations are rare in uveal melanoma,36,53,55,56,62,64,65 most uveal melanomas carry mutations in GNAQ or GNA11 that result in

constitutive activation of the RAS/RAF/MEK/ERK

pathway.36,37,53,66,68,71,72,764 Prospective studies of MEK inhibitors have

yielded mixed results in patients with metastatic uveal melanoma.702,710,711 A large phase II randomized trial in 101 patients with metastatic uveal

melanoma reported responses in 14% of the 50 patients treated with

selumetinib, and no responses in the 51 patients in the comparator arm

(chemotherapy with temozolomide or dacarbazine).702 Selumetinib

modestly improved PFS compared with chemotherapy (median 3.7 vs. 1.6 months; P < .001), although the effect on OS was not significant (median

11.8 vs. 9.1 months; P = .09).702 However, in a phase III randomized trial in 129 patients with metastatic uveal melanoma that compared selumetinib plus dacarbazine versus placebo plus dacarbazine, selumetinib did not

improve response (3% vs. 0%) or PFS (median 2.8 vs. 1.8 months).701

Results from other MEK inhibitors were not impressive. No responses to trametinib were observed in the 16 patients with metastatic uveal

melanoma in a phase I trial, and the median PFS was unremarkable (1.8 months).711 In a subsequent phase II study, 1 of 18 (5.6%) patients with

metastatic uveal melanoma responded to single-agent trametinib, and

PFS was slightly better (median 3.6 months).710 Addition of uprosertib, an AKT inhibitor, yielded very similar results (ORR 4.8%, PFS median 3.6

months).710 A phase Ib/II trial of combination binimetinib and sotrastaurin yielded no responses in patients with metastatic uveal melanoma.738

Across studies it appeared that GNAQ and GNA11 mutation status did not impact response rate or outcomes in patients treated with MEK

inhibitors.701,702,711 Taken together, these data show that some patients

with uveal melanoma may respond to the MEK inhibitor selumetinib, and there are limited data suggesting that trametinib may also be marginally

effective. Although the data are strongest for selumetinib, it was not FDA approved for use in humans at the time of the most recent Guidelines

update, so it could not be included as a recommended option. Trametinib is included as a recommended option based on the positive data for

selumetinib and the general lack of systemic therapy options for patients with uveal melanoma. Further study of trametinib for uveal melanoma is needed.

Network"

Table 1. Risk Factors for Growth in Small Intraocular Melanocytic Lesions

Table 1. Risk Factors for Growth in Small Intraocular Melanocytic Lesions

|Risk Factor |Risk Factor |Studies Demonstrating Correlation with Tumor Growth |Detection Method(s) | |---|---|---|---|

|Symptoms |Symptoms |Augsburger, 198993; Butler, 199498; Shields, 199594; Shields, 200095; Singh, 200696; Shields, 200997; Lane, 201087 |History and physical |

|Lesion thickness (>2 mm) |Lesion thickness (>2 mm) |Augsburger, 198993; Butler, 199498; Shields, 199594; COMS 199786; Shields, 200095; Singh, 200696; Lane, 201087; Shields, 200997; Dalvin, 201999 |Ultrasound |

|Lesion diameter (>5 mm) |Lesion diameter (>5 mm) |COMS 199786; Dalvin, 201999 |Comprehensive eye exam, color fundus photography, ultrasound |

|Subretinal fluid |Subretinal fluid |Shields, 199594; Shields, 200095; Shields, 200997 |Color fundus photography, comprehensive eye exam Ancillary option: OCT |

|Orange pigment (lipofuscin) |Orange pigment (lipofuscin) |Augsburger, 198993; Butler, 199498; Shields, 199594; COMS 199786; Shields, 200095; Singh, 200696; Shields, 200997; Dalvin, 201999 |Color fundus photography, comprehensive eye exam Ancillary options: ocular fundus autofluorescence, OCT |

|Proximity to optic (tumor margin <3 |disc mm) |Augsburger, 198993; Shields, 199594; Shields, 200095; Shields, 200997 |Comprehensive eye exam, color fundus photography |

|Ultrasound hollowness |Ultrasound hollowness |Shields, 200997; Dalvin, 201999 |Ultrasound (A- and B-scan) |

|Absence of halo |Absence of halo |Shields, 200997 |Comprehensive eye exam, color fundus photography |

OCT, optical coherence tomography

|Table 2. Biopsy Options for Choroidal or Ciliary Body Tumorsa,234,252 |Table 2. Biopsy Options for Choroidal or Ciliary Body Tumorsa,234,252 |Table 2. Biopsy Options for Choroidal or Ciliary Body Tumorsa,234,252 |Table 2. Biopsy Options for Choroidal or Ciliary Body Tumorsa,234,252 |Table 2. Biopsy Options for Choroidal or Ciliary Body Tumorsa,234,252 |Table 2. Biopsy Options for Choroidal or Ciliary Body Tumorsa,234,252 | |---|---|---|---|---|---|

|Biopsy Type |Surgical Approachb |Tumor Locationc |Sample Analysisd |Studies Describing Technique, Reporting Yield or Safetye (number of patients biopsied) |Studies Describing Technique, Reporting Yield or Safetye (number of patients biopsied) |

|Fine-needle aspiration biopsy (FNAB) |Transscleral |Anterior |Cytopathology |Glasgow, 1988265 (n=6) Eide, 1999255 (n=50) Shields, 2007263 (n=73) Shields, 2007262 (n=24; ≤3 mm thick) McCannel, 2012250 (n=170) Chang, 2014260 (n=38) |Grixti, 2014238 (n=291) Sellam, 2016239 (n=185) Singh, 2016237 (n=71) Kim, 2018236 (n=11) Matet, 2019253 (n=24) |

|Fine-needle aspiration biopsy (FNAB) |Transvitreal |Posterior |Cytopathology |Glasgow, 1988265 (n=15) Eide, 1999255 (n=14) Cohen, 2001254 (n=83) Augsburger, 200291 (n=34; diameter ≤10 mm; thickness, ≥1.5 mm but ≤3 mm) Shields, 2007263 (n=67) Shields, 2007262 (n=32; ≤3 mm thick) Correa, 2014256 (n=159) |Chang, 2014260 (n=38) Augsburger, 2015240 (n=80) Singh, 2016237 (n=64) Sellam, 2016239 (n=32) Kim 2017259 (n=10) Kim, 2018236 (n=33) Reddy 2017258 (n=57) Singh, 2017257 (n=20) |

|Vitrectomy system (vitreous-cutter)- assisted biopsyf |Transvitreal/ transretinal |Posterior or equatorial |Cytopathology or Histopathology (depends on exact technique used) Jensen, |1997244 (n=92) Bechrakis, 2002270 (n=23) Sen, 2006271 (n=14) Bagger, 2013 243 (n=123) Grixti, 2014238 (n=448) |Bagger, 2015272 (n=39) Nagiel 2017241 (n=17; ≤2.0 mm thick) Grewal, 2017242 (n=18) |

|Incisional biopsyg with Essen forceps |Transvitreal |Anterior |Histopathology |Akgul, 2011246 (n=20) |Akgul, 2011246 (n=20) |

|Incisional biopsyg (standard forceps) |Transvitreal |Posterior |Histopathology |Kvanta, 2005247 (n=10) Seregard, 2013245 (n=46) |Kvanta, 2005247 (n=10) Seregard, 2013245 (n=46) |

Table 2. Biopsy Options for Choroidal or Ciliary Body Tumorsa,234,252

a Although review articles include excisional biopsy,234,252 and historical literature includes reports of transscleral resection or endoresection being used for uveal melanoma biopsy, these

methods are not included in this table because they are no longer commonly used due to technical challenges, risk of complications, and concerns about tumor seeding.178,273-283

b The transscleral (direct) approach involves approaching the tumor from the outside, with the needle first puncturing the sclera over the tumor, then the tumor itself, leaving the retina

intact.234 The transvitreal (indirect) approach involves anterior entry through the pars plana opposite the tumor, going through the vitreous body and retina to reach the tumor.234

c Although each biopsy method may be used successfully in a range of locations, the feasibility and success rate vary based on tumor location. The table lists the tumor location(s) for

which the biopsy method was developed and/or is most often used.

d Sample Analysis: Some methods provide cellular aspirate that can be used for cytopathology; others provide tissue samples that can be sectioned for histopathology. The table reflects

the type of sample usually obtained by each of the biopsy methods listed. Both types of samples can be used for molecular analyses for prognostication.

e For each biopsy method, the table lists representative studies including at least 10 cases that reported at least one of the following: detailed description of biopsy technique used,

analysis of yield and safety, risk assessment of tumor seeding. Note that inclusion criteria varied across studies listed in the table. Whereas some studies included only patients with

suspected or confirmed uveal melanoma, others included patients with other intraocular conditions.

f Vitrectomy system (vitreous-cutter)-assisted biopsy: Includes a variety of methods that use vitrectomy tools both to access tumor via a transvitreal/transretinal approach and to extract

tumor tissue using the vitreous cutter and aspiration through the canula. These procedures do not necessarily include a vitrectomy.

g Incisional biopsy techniques described in the literature sometimes included use of a vitreous cutter, vitrectomy, and other procedures to access the biopsy site, wherein the tumor tissue

was incised with a diamond knife and removed with forceps.

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|520. Drabarek W, Yavuzyigitoglu S, Obulkasim A, et al. Multi-Modality |520. Drabarek W, Yavuzyigitoglu S, Obulkasim A, et al. Multi-Modality |520. Drabarek W, Yavuzyigitoglu S, Obulkasim A, et al. Multi-Modality |520. Drabarek W, Yavuzyigitoglu S, Obulkasim A, et al. Multi-Modality |

|Analysis Improves Survival Prediction in Enucleated Uveal Melanoma|Analysis Improves Survival Prediction in Enucleated Uveal Melanoma|Analysis Improves Survival Prediction in Enucleated Uveal Melanoma|Analysis Improves Survival Prediction in Enucleated Uveal Melanoma|

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|Cancer Genome Atlas Classification vs American Joint Committee on |Cancer Genome Atlas Classification vs American Joint Committee on |Cancer Genome Atlas Classification vs American Joint Committee on |for Predicting Risk of Metastasis in Uveal Melanoma. Invest Ophthalmol |

|Cancer Classification for Prediction of Metastasis in Patients With Uveal |Cancer Classification for Prediction of Metastasis in Patients With Uveal |Cancer Classification for Prediction of Metastasis in Patients With Uveal |Cancer Classification for Prediction of Metastasis in Patients With Uveal |

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|uveal melanoma is simple and highly predictive using The Cancer |uveal melanoma is simple and highly predictive using The Cancer |uveal melanoma is simple and highly predictive using The Cancer |Melanoma Metastatic Rate With Stochastic Mutation Rate and Type of |

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||||541. Yavuzyigitoglu S, Koopmans AE, Verdijk RM, et al. Uveal |

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|National|National|NCCN Guidelines Version 1.2025||

|Comprehensive|Comprehensive|||

|NCCN Cancer Network®|NCCN Cancer Network®|Melanoma: Uveal ||

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|helpful for early diagnosis of metastatic uveal melanoma. Ophthalmology |helpful for early diagnosis of metastatic uveal melanoma. Ophthalmology |helpful for early diagnosis of metastatic uveal melanoma. Ophthalmology |helpful for early diagnosis of metastatic uveal melanoma. Ophthalmology |

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|https://www.ncbi.nlm.nih.gov/pubmed/17553818. ||||

|Version 1.2025 © 2025 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-72 ||||

https://www.ncbi.nlm.nih.gov/pubmed/20413675.

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|MS-77 |MS-77 |MS-77 |

|Version 1.2025 © 2025 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. |Version 1.2025 © 2025 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. |Version 1.2025 © 2025 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. |

|NCCN Cancer Network®|NCCN Cancer Network®|Melanoma: Uveal |Melanoma: Uveal | |---|---|---|---|

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|NCCN Cancer Network®|Melanoma: Uveal |||

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