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Childhood Intraocular (Uveal) Melanoma Treatment (PDQ®)–Health Professional Version

Incidence and Risk Factors

Uveal melanoma (iris, ciliary body, choroid) is the most common primary intraocular malignancy (about 2,000 cases are diagnosed each year in the United States) and accounts for 5% of all cases of melanoma.[1] This tumor is most commonly diagnosed in older patients, and the incidence peaks at age 70 years.[2]

Pediatric uveal melanoma is extremely rare and accounts for 0.8% to 1.1% of all cases of uveal melanoma.[3] A retrospective, multicenter, observational study conducted by the European Ophthalmic Oncology Group from 1968 to 2014 identified 114 children (aged 1–17 years) and 185 young adults (aged 18–25 years) with ocular melanoma at 24 centers.[3] The median age at the time of diagnosis for children was 15.1 years. The incidence of disease increased by 0.8% per year between the ages of 5 and 10 years and 8.8% per year between the ages of 17 and 24 years. Other series have also documented the higher incidence of the disease in adolescents.[4,5]

Risk factors include the following:[6-8]

  • Light eye color.
  • Fair skin color.
  • Inability to tan.
  • Oculodermal melanocytosis.
  • Presence of cutaneous nevi.

In a European Oncology Group study, 57% of the pediatric patients were females and four had a preexisting condition that included oculodermal melanocytosis (n = 2) and neurofibromatosis (n = 2).[3] In a review of 13 cases of uveal melanoma in the first 2 years of life, four patients had familial atypical melanoma mole syndrome, one patient had dysplastic nevus syndrome, and one patient had café au lait spots.[9]

  1. Field MG, Harbour JW: Recent developments in prognostic and predictive testing in uveal melanoma. Curr Opin Ophthalmol 25 (3): 234-9, 2014. [PUBMED Abstract]
  2. Singh AD, Bergman L, Seregard S: Uveal melanoma: epidemiologic aspects. Ophthalmol Clin North Am 18 (1): 75-84, viii, 2005. [PUBMED Abstract]
  3. Al-Jamal RT, Cassoux N, Desjardins L, et al.: The Pediatric Choroidal and Ciliary Body Melanoma Study: A Survey by the European Ophthalmic Oncology Group. Ophthalmology 123 (4): 898-907, 2016. [PUBMED Abstract]
  4. Shields CL, Kaliki S, Arepalli S, et al.: Uveal melanoma in children and teenagers. Saudi J Ophthalmol 27 (3): 197-201, 2013. [PUBMED Abstract]
  5. Pogrzebielski A, Orłowska-Heitzman J, Romanowska-Dixon B: Uveal melanoma in young patients. Graefes Arch Clin Exp Ophthalmol 244 (12): 1646-9, 2006. [PUBMED Abstract]
  6. Weis E, Shah CP, Lajous M, et al.: The association between host susceptibility factors and uveal melanoma: a meta-analysis. Arch Ophthalmol 124 (1): 54-60, 2006. [PUBMED Abstract]
  7. Weis E, Shah CP, Lajous M, et al.: The association of cutaneous and iris nevi with uveal melanoma: a meta-analysis. Ophthalmology 116 (3): 536-543.e2, 2009. [PUBMED Abstract]
  8. Singh AD, De Potter P, Fijal BA, et al.: Lifetime prevalence of uveal melanoma in white patients with oculo(dermal) melanocytosis. Ophthalmology 105 (1): 195-8, 1998. [PUBMED Abstract]
  9. Yousef YA, Alkilany M: Characterization, treatment, and outcome of uveal melanoma in the first two years of life. Hematol Oncol Stem Cell Ther 8 (1): 1-5, 2015. [PUBMED Abstract]

Prognostic Factors

Prognostic factors for uveal melanoma include the following:[1,2]

  • Tumor size.
  • Age.
  • Ciliary body involvement.
  • Tumor outside the sclera.
  • Metastasis.
  • Genetic changes.
  1. Al-Jamal RT, Cassoux N, Desjardins L, et al.: The Pediatric Choroidal and Ciliary Body Melanoma Study: A Survey by the European Ophthalmic Oncology Group. Ophthalmology 123 (4): 898-907, 2016. [PUBMED Abstract]
  2. Shields CL, Kaliki S, Arepalli S, et al.: Uveal melanoma in children and teenagers. Saudi J Ophthalmol 27 (3): 197-201, 2013. [PUBMED Abstract]

Molecular Features

Uveal melanoma is characterized by activating mutations of GNAQ and GNA11, which lead to activation of the mitogen-activated protein kinases (MAPK) pathway. In addition, mutations in BAP1 are seen in 84% of metastasizing tumors, whereas mutations in SF3B1 and EIF1AX are associated with a good prognosis.[1-6]

  1. Van Raamsdonk CD, Griewank KG, Crosby MB, et al.: Mutations in GNA11 in uveal melanoma. N Engl J Med 363 (23): 2191-9, 2010. [PUBMED Abstract]
  2. Harbour JW, Onken MD, Roberson ED, et al.: Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330 (6009): 1410-3, 2010. [PUBMED Abstract]
  3. Gupta MP, Lane AM, DeAngelis MM, et al.: Clinical Characteristics of Uveal Melanoma in Patients With Germline BAP1 Mutations. JAMA Ophthalmol 133 (8): 881-7, 2015. [PUBMED Abstract]
  4. Harbour JW, Roberson ED, Anbunathan H, et al.: Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat Genet 45 (2): 133-5, 2013. [PUBMED Abstract]
  5. Martin M, Maßhöfer L, Temming P, et al.: Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. Nat Genet 45 (8): 933-6, 2013. [PUBMED Abstract]
  6. Van Raamsdonk CD, Bezrookove V, Green G, et al.: Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457 (7229): 599-602, 2009. [PUBMED Abstract]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[1] Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric surgeons.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child-life professionals.
  • Psychologists.

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[3] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[4] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[5,6] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:

  • A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than 2 cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than 2 cases per 1 million people were also included in the very rare group because there is a lack of knowledge and expertise in the management of these tumors.[7]
  • The Children's Oncology Group defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancer, melanoma and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinoma, nasopharyngeal carcinoma, and most adult-type carcinomas such as breast cancer, colorectal cancer, etc.).[8] These diagnoses account for about 4% of cancers diagnosed in children aged 0 to 14 years, compared with about 20% of cancers diagnosed in adolescents aged 15 to 19 years.[9]

    Most cancers in subgroup XI are either melanomas or thyroid cancer, with other types accounting for only 1.3% of cancers in children aged 0 to 14 years and 5.3% of cancers in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the low number of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack of clinical trials for adolescents with rare cancers.

Information about these tumors may also be found in sources relevant to adults with cancer, such as the PDQ summary on adult Intraocular (Uveal) Melanoma Treatment.

  1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
  2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed June 7, 2022.
  3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  4. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr. [PUBMED Abstract]
  5. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017. [PUBMED Abstract]
  6. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017. [PUBMED Abstract]
  7. Ferrari A, Brecht IB, Gatta G, et al.: Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126, 2019. [PUBMED Abstract]
  8. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010. [PUBMED Abstract]
  9. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2012. National Cancer Institute, 2015. Also available online. Last accessed May 25, 2022.

Treatment and Outcome of Childhood Intraocular (Uveal) Melanoma

Treatment options for childhood intraocular (uveal) melanoma include the following:

  1. Surgery.
  2. Radiation therapy.
  3. Laser surgery.
  4. Bispecific fusion proteins (tebentafusp).

(Refer to the PDQ summary on adult Intraocular [Uveal] Melanoma Treatment for information on the treatment of uveal melanoma in adults.)

Survival of children appears to be more favorable than that of young adults and adults, suggesting that the biology of ocular melanoma might be different in children.[1,2]

A retrospective single-institution review identified 18 patients younger than 21 years with uveal melanoma.[3][Level of evidence: 3iiA] Eight of these patients (44%) developed metastatic uveal melanoma, and all of these patients died of metastatic disease. The median overall survival (OS) of the 18 patients after treatment of the primary intraocular tumors was 11.9 years (95% CI, 7.3–16.5). In the eight patients who developed metastatic disease, the median survival time after detection of metastasis was 2.3 months (95% CI, 0.0–5.2).

An open-label, randomized, phase III trial of adult patients with previously untreated HLA-A*02:01–positive metastatic uveal melanoma investigated treatment with tebentafusp. Tebentafusp is a bispecific restricted T-cell receptor for the glycoprotein 100 peptide; it is fused to a CD3 single-chain variable fragment. Patients were randomly assigned to receive either tebentafusp or treatment according to the investigator's choice. Patients who received tebentafusp had an OS rate of 73%, compared with 50% for patients in the control group (hazard ratio for death, 0.51; P < .001). The progression-free survival rate was also significantly higher for the tebentafusp group (31% vs. 16% at 6 months; hazard ratio for progression or death, 0.71; P = .01). The most common toxicities for patients who received tebentafusp were cytokine release syndrome, mostly grades 1 and 2, and rash.[4]

  1. Al-Jamal RT, Cassoux N, Desjardins L, et al.: The Pediatric Choroidal and Ciliary Body Melanoma Study: A Survey by the European Ophthalmic Oncology Group. Ophthalmology 123 (4): 898-907, 2016. [PUBMED Abstract]
  2. Shields CL, Kaliki S, Arepalli S, et al.: Uveal melanoma in children and teenagers. Saudi J Ophthalmol 27 (3): 197-201, 2013. [PUBMED Abstract]
  3. Fry MV, Augsburger JJ, Corrêa ZM: Clinical Features, Metastasis, and Survival in Patients Younger Than 21 Years With Posterior Uveal Melanoma. JAMA Ophthalmol 137 (1): 75-81, 2019. [PUBMED Abstract]
  4. Nathan P, Hassel JC, Rutkowski P, et al.: Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med 385 (13): 1196-1206, 2021. [PUBMED Abstract]

Treatment Options Under Clinical Evaluation for Childhood Intraocular (Uveal) Melanoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.

    Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and website.

Changes to This Summary (02/25/2022)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric intraocular (uveal) melanoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Intraocular (Uveal) Melanoma Treatment are:

  • Denise Adams, MD (Children's Hospital Boston)
  • Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
  • Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
  • Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
  • Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
  • Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
  • Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Intraocular (Uveal) Melanoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: Accessed <MM/DD/YYYY>.

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on on the Managing Cancer Care page.

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