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Gene Expression Profiling for Uveal Melanoma

Policy Number: MP-585

Latest Review Date: February 2019

Category: Laboratory

Policy Grade: D


Uveal melanoma is associated with a high rate of metastatic disease, and survival after the development of metastatic disease is poor. Prognosis following treatment of local disease can be assessed using various factors, including clinical and demographic markers, tumor stage, tumor characteristics, and tumor cytogenetics. Gene expression profiling (GEP) can be used to determine prognosis and gene expression profile testing is commercially available.

Uveal Melanoma

The uveal tract is the middle layer of the wall of the eye, and has three main parts: the choroid (a tissue layer filled with blood vessels), ciliary body (muscle tissue that changes the shape of the pupil and the lens), and the iris (the colored part of the eye). Uveal melanoma arises from melanocytes in the stroma of the uveal tract. Approximately 90% of uveal melanomas arise in the choroid, 7% in the ciliary body, and 3% in the iris.

Uveal melanoma, although rare, is the most common primary intraocular malignancy in adults. Mean age-adjusted incidence of uveal melanoma in the United States is 6.3 per million people among whites, 0.9 among Hispanics, and 0.24 among blacks. Uveal melanoma has a progressively rising, age-specific, incidence rate that peaks near age 70. Host susceptibility factors associated with the development of this cancer include white race, fair skin, and light eye color.


Treatment of primary, localized uveal melanoma can be by surgery or radiotherapy. In general, larger tumors require enucleation surgery and smaller tumors can be treated with radiotherapy, but specific treatment parameters are lacking. The most common treatment of localized uveal melanoma is radiotherapy, which is preferred because it can spare vision in most cases. For smaller lesions, randomized controlled trials have shown that patients receiving radiotherapy or enucleation progress to metastatic disease at similar rates after treatment. Radiotherapy can be delivered by a variety of mechanisms, most commonly brachytherapy and proton beam therapy. Treatment of primary uveal melanoma improves local control and spares vision. However, the five-year survival rate (81.6%) has not changed over the last three decades, suggesting that life expectancy is independent of successful local eye treatment.

Uveal melanomas disseminate hematogenously, and metastasize primarily to the liver and lungs. Treatment of hepatic metastases is associated with prolonged survival and palliation in some patients. Therapies directed at locoregional treatment of hepatic metastases include surgical and ablative techniques, embolization, and local chemotherapy.

Metastatic Disease

It is unusual for patients with uveal melanoma to have distant metastases at presentation, with less than 1% presenting with metastases when they are treated for their intraocular disease, but are at risk for distant metastases, particularly to the liver, for years after presentation. The prospective, longitudinal Collaborative Ocular Melanoma Study (COMS) study followed 2,320 patients with choroidal melanoma with no melanoma metastasis at baseline who were enrolled in randomized controlled trials to evaluate forms of radiotherapy for choroidal melanoma for five to ten years. During follow-up, 739 patients were diagnosed with at least one site of metastasis, of which 660 (89%) were liver. Kaplan-Meier estimates of two-, five-, and ten-year metastasis rates were 10% (95% CI, 9% to 12%), 25% (95% CI, 23% to 27%), and 34% (95% CI, 32% to 37%), respectively.


Metastatic disease is the leading cause of death in patients with uveal melanoma, and approximately 50% of patients will develop distant metastasis. A number of factors may be used to determine prognosis, but the optimal approach is uncertain. The most important clinical factors that predict metastatic disease are tumor size measured in diameter or in thickness, ciliary body involvement, and transcleral extension. Clinical staging according to the American Joint Committee on Cancer (AJCC) recommendations allows risk stratification for metastatic disease. In a retrospective study of 3,377 patients with uveal melanoma, in which staging was performed using AJCC classifications, the rate of metastases-free survival at five years was 97% for Stage I, 89% for Stage IIA, 79% for Stage IIB, 67% for Stage IIIA, 50% for Stage IIIB, and 25% for Stage IIIB.

Genetic Analysis

Genetic analysis of uveal melanoma can provide prognostic information for the risk of developing metastatic disease. In 1996, Prescher et al showed that monosomy of chromosome three correlated strongly with metastatic death, with a five-year survival reduction from 100% to 50%. Subsequent studies reported the initial idea that, based on genetic analysis, there were two distinct types of uveal melanomas—those with monosomy chromosome three associated with a very poor prognosis and those with disomy three and 6p gain associated with a better prognosis. The BAP1 gene has been identified as an important marker of disease type. In one study, 89% of tumors with monosomy three had a BAP1 mutation, and no tumors without monosomy three had a BAP1 mutation.

Gene expression profiling (GEP) determines the expression of multiple genes in a tumor and has been proposed as an additional method to stratify patients into prognostic risk groups.


Effective for dates of service on or after February 24, 2017:

Gene expression profiling for uveal melanoma with DecisionDX-UM may be considered medically necessary for members with primary, localized uveal melanoma.

Gene expression profiling for uveal melanoma is considered not medically necessary and investigational for all other situations.


Effective for dates of service prior to February 24, 2017:

Gene expression profiling for uveal melanoma is considered not medically necessary and investigational.


The most recent literature review was updated through December 4, 2018.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Uveal Melanoma

Clinical Context and Test Purpose

The purpose of using the DecisionDx-UM test in individuals with localized uveal melanoma is to inform a decision about how often patients should undergo follow-up for metastases, based on their likelihood of developing metastases.

The optimal method and interval for surveillance are not well-defined, and it has not been established in prospective trials whether surveillance identifies metastatic disease earlier. Potential methods for metastases include magnetic resonance imaging, ultrasound, liver function testing, and positron emission tomography scans. One retrospective study (2016) of 262 patients estimated that use of hepatic ultrasound and liver function testing every six months in individuals with treated local uveal melanoma would yield a sensitivity and specificity for a diagnosis of metastasis of 83% (95% confidence interval [CI], 44% to 97%) and 100% (95% CI, 99% to 100%), respectively.

Identifying patients at high-risk for metastatic disease might assist in selecting patients for adjuvant treatment and more intensive surveillance for metastatic disease, if such changes lead to improved outcomes. Adjuvant treatment for metastatic disease consists of radiotherapy or systemic therapy, such as chemotherapy, immunotherapy, hormone therapy, biologic therapy, or targeted therapy. Randomized trials of patients with high-risk for uveal melanoma recurrence have shown no differences in survival rates between patients treated with and without adjuvant therapy. However, these trials were reported in 1990 and 1998, and may not represent current treatment and risk stratification methods.

Identifying patients at low-risk for metastatic disease might assist in selecting patients who could safely reduce frequency or intensity of surveillance, which could lead to improved outcomes through reduced burden.

The question addressed in this evidence review is: Does gene expression profile testing to determine the prognosis of patients with uveal melanoma improve the net health outcome?

The following PICOTS were used to select literature to inform this review.


The relevant population of interest is individuals with localized uveal melanoma.

Uveal melanomas may present with visual symptoms or be detected incidentally. The diagnosis is based on funduscopic examination and other noninvasive tests, such as ultrasound and fluorescein angiography. A biopsy may be useful to collect additional information about the molecular characteristics of the tumor. Treatment of primary, localized uveal melanoma can be by surgery or radiotherapy. While treatment is effective at preventing local recurrence, patients are at risk for distant metastases for many years. Approximately 50% of patients will develop distant metastasis, which is the leading cause of death in patients with uveal melanoma.


The test being considered is DecisionDx-UM.

The DecisionDx-UM® test (Castle Biosciences Inc, Phoenix, AZ) is a GEP test intended to assess five-year metastatic risk in uveal melanoma. The test was introduced in late 2009, and claims to identify the molecular signature of a tumor and its likelihood of metastasis within five years. The assay determines the expression of 15 genes, which stratify a patient’s individual risk of metastasis into three classes. The 15 gene signature was originally developed based on a hybridization-based microarray platform; the currently commercially-available DecisionDx-UM test is a polymerase chain reaction (PCR)-based test that can be performed on fine-needle aspiration samples.

Based on the clinical outcomes from the prospective, five-year multi-center Collaborative Ocular Oncology Group (COOG) study, the DecisionDx-UM test reports Class IA, Class I1 and Class II phenotype:

  • Class IA: Very low risk, with a 2% chance of the eye cancer spreading over the next five years;
  • Class IB: Low risk, with a 21% chance of metastasis over five years;
  • Class II: High risk, with 72% odds of metastasis within five years


National Comprehensive Cancer Network guidelines for melanoma do not address the prognosis and management of uveal melanoma. Melanoma Focus (2015), a British medical nonprofit that focuses on melanoma research, published guidelines on uveal melanoma that state that prognostication and risk prediction should be based clinical, morphologic, and genetic cancer features.


The potential beneficial outcome associated with selecting high-risk patients for adjuvant treatment and more intensive surveillance for metastatic disease is improved survival while potential harmful outcomes are related to adverse events of treatment and increased burden of surveillance.

The potential beneficial outcome associated with selecting low-risk patients for less intensive surveillance for metastatic disease is reduced burden; potential harmful outcomes are related to delayed detection of metastasis.


Distant metastasis can develop years or even decades after local treatment of uveal melanoma.


Patients are usually diagnosed by an optometrist or ophthalmologist and referred to a specialist ocular oncologist. The management of uveal melanoma is complex and may require a multidisciplinary team of specialists.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review, and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria For the evaluation of clinical validity of the DecisionDx-UM test, studies that meet the following eligibility criteria were considered:

  • Reported on the accuracy of the marketed version of the technology by score or risk category
  • Included a validation cohort of patient/samples independent of the developmental cohort
  • Included a suitable reference standard (outcome of metastasis or melanoma mortality)
  • Patient/sample clinical characteristics were described
  • Patient/sample selection criteria were described.

Observational studies reported data on the association of GEP score with clinical outcomes; they are summarized in Table 1. All studies showed strong and positive associations between GEP class and clinical outcomes.

The first study was published in 2012 by Onken et al. This prospective, multicenter study evaluated the prognostic performance of a 15-gene GEP assay in patients with posterior (choroidal and ciliary body) uveal melanoma. Prognostic groups were Class I (low risk of metastasis) or Class II (high risk of metastasis). Four hundred fifty nine cases were enrolled from 12 centers between June 2006 and November 2010. The GEP assay rendered a classification in 97.2% of cases. GEP testing results were Class I in 276 (61.9%) cases and Class II in 170 (38.1%) cases. Mean follow-up was 18.0 months (median, 17.4 months). Metastasis was detected in three (1.1%) of Class I cases and 44 (25.9%) of Class II cases (p<0.001). By univariate Cox proportional hazard analysis, factors associated with metastatic disease included advanced patient age (p=0.02), ciliary body involvement (p=0.03), tumor diameter (p<0.001), tumor thickness (p=0.006), chromosome three status (p<0.001), and GEP class (p<0.001). The GEP was associated with a significant net reclassification index (NRI) over TNM classification for survival at two years (NRI=0.37, P=0.008) and three years (NRI=0.43, P=0.001).

Two other studies reporting data on clinical validity were published in 2016. Walter et al evaluated two cohorts of patients at two clinical centers who underwent resection for uveal melanoma. This study had similar methodology to Onken (2012). A primary cohort included 339 patients, of which 132 patients were also included in the Onken et al (2012) study, along with a validation cohort of 241 patients, of which 132 were also included in the Onken et al (2012) study, which was used to test a prediction model using the GEP plus pretreatment largest basal diameter. Cox proportional hazards analysis was used to examine GEP class together with other clinicopathologic factors (tumor diameter, tumor thickness, age, gender, ciliary body involvement, pathologic class). GEP Class II was the strongest predictor of metastases and mortality. Tumor diameter was also an independent predictor of outcomes, using a diameter of 12 mm as the cutoff value. In the validation cohort, GEP results were Class I in 148 (61.4%) patients and Class II in 93 (38.6%) patients. Again, GEP results were most strongly associated with PFS.

Decatur et al (2016) was a smaller, retrospective study of 81 patients who had tumor samples available from resections occurring between 1998 and 2014. GEP was Class I in 35 (43%) patients, Class II in 42 (52%) patients, and unknown in four (5%) patients. GEP Class II was strongly associated with BAP1 mutations (r=0.70; p<0.001). On Cox proportional hazards analysis, GEP Class II was the strongest predictor of metastases and melanoma mortality (see Table 1).

Table 1: Studies of Clinical Validity


Patient Populations

Rates of Metastases

Melanoma Mortality Rates


GEP Class 1

GEP Class 2

GEP Class 1

GEP Class 2

Onken (2012)

459 pts with UM from 12 clinical centers





Walter (2016)

Primary cohort: 339 pts from two clinical centers with UM arising in ciliary body or choroid






Validation cohort: 241 patients from two clinical centers with UM arising in ciliary body or choroid





Decatur (2016)

81 pts from a single center with available tumor samples of UM arising from ciliary body or choroid


(3.1 to 28.5)


(3.6 to 69.1)

GEP: gene expression profile; NR: not reported; pts: patients; UM: uveal melanoma.

a p <0.001

b Reported as relative risk (95% confidence interval) for metastases (or melanoma mortality) in group 2 vs group 1.

Section Summary: Clinically Valid

Three studies published on clinical validity reported rates of metastases or melanoma mortality by GEP class. These studies have reported that GEP Class II is a strong predictor of metastases and melanoma survival. Two studies have compared GEP class to a limited set of clinicopathologic features and have reported that GEP class is the strongest predictor of clinical outcomes.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

There is no direct evidence that the use of DecisionDx-UM for the selection of patients for different surveillance outcomes improves health outcomes. Absent direct evidence, a chain of evidence can be developed based on the clinical validity of the test.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

The GEP test is associated with risk of metastatic disease and melanoma death. Although the three available studies reporting on clinical validity do not all specifically report on rates of survival or metastasis risk by risk group, there is clearly an association of risk category and metastasis and death. For a rare cancer, the studies on clinical validity include a large proportion of annual incident cases.

Plasseraud et al (2016) reported metastasis surveillance practices and patient outcomes using data from a prospective observational registry study of DecisionDX-UM conducted at four centers, which included 70 patients at the time of reporting. Surveillance regimens were documented by participating physicians as part of registry data entry. “High-intensity” surveillance was considered to be imaging and/or liver function testing (LFTs) every 3-6 months and “low-intensity” surveillance was considered to be annual imaging and/or LFTs. The method for following patients for clinical outcomes is not specified. Of the 70 enrolled patients, 37 (53%) were Class 1. Over a median follow up of 2.38 years, more Class 2 patients (36% vs 5%, P=0.002) experienced a metastasis. The three-year metastasis-free survival (MFS) rate was lower for Class 2 patients (63%, 95% CI 43% to 83%) than Class 1 patients (100%, CI not specified; P=0.003). Most Class 1 patients (n=30) had low-intensity surveillance and all (n=33) Class 2 patients had high-intensity surveillance. Strengths of this study include a relatively large population given the rarity of the condition, and an association of management strategies with clinical outcomes. However, it is not clear which outcome measures were prespecified or the manner that data was collected, making the risk of bias high.

Aaberg et al (2014) reported on changes in management associated with GEP risk classification. Aaberg et al analyzed Medicare claims data submitted to Castle BioSciences by 37 ocular oncologists in the United States. Data were abstracted from charts on demographics, tumor pathology and diagnosis, and clinical surveillance patterns. High-intensity surveillance was defined as a frequency of every three to six months and low-intensity surveillance was a frequency of every six to 12 months. Of 195 patients with GEP test results, 88 (45.1%) patients had evaluable tests and adequate information on follow-up surveillance, 36 (18.5%) had evaluable tests and adequate information on referrals, and eight (4.1%) had evaluable tests and adequate information on adjunctive treatment recommendations. Of the 191 evaluable GEP tests, 110 (58%) were Class I and 81 (42%) were Class II. For patients with surveillance data available (n=88), all patients in GEP Class I had low-intensity surveillance, and all patients in GEP Class II had high-intensity surveillance (p<0.001 vs Class I).

It is likely that treating liver metastasis has an effect on local symptoms and survival, for at least a subset of patients. However, it is uncertain whether the surveillance interval has an effect on the time to detection of metastases.

There is the potential for patients considered to be at high risk for metastases to undergo adjuvant treatment, but to date no adjuvant therapies for non-metastasized uveal melanomas have been shown to reduce the risk of metastasis.

Section Summary: Clinical Utility

There are no studies directly showing clinical utility. In the absence of direct evidence, an indirect chain of evidence to determine whether using the results of GEP testing for management decisions improves the net health outcome of patients with uveal melanoma. GEP classification appears be a strong predictor metastatic disease and melanoma death. Aaberg et al (2014) have shown an association between GEP classification and treatment, reporting that patients classified as low risk were managed with less frequent and intensive surveillance and were not referred for adjuvant therapy.

It is uncertain whether stratification of patients into higher risk categories has the potential to improve outcomes by allowing patients to receive adjuvant therapies or through the detection of metastases earlier. However, classification into the low-risk group would allow reduction in the burden of surveillance without apparent harm.

Summary of Evidence

For individuals who have localized uveal melanoma who receive a gene expression profiling (GEP) test for uveal melanoma (DecisionDx-UM), the evidence includes cross-sectional studies of assay validation and clinical validity. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, other test performance measures, functional outcomes, health status measures, and quality of life. One commercially available test identified (DecisionDx-UM) has published data related to its clinical validity, and is the focus of this review. Three studies of clinical validity identified used the GEP score to predict melanoma metastases and melanoma-specific survival. All three reported that GEP class correlated strongly with metastatic disease and melanoma mortality. Two studies compared GEP class to other prognostic markers, and GEP class had the strongest association among the markers tested. GEP class appears to be a strong predictor of metastatic disease and melanoma death. There are no studies directly showing clinical utility. In the absence of direct evidence, an indirect chain of evidence to determine whether using the results of GEP testing for management decisions improves the net health outcome of patients with uveal melanoma. Aaberg et al (2014) have shown an association between GEP classification and treatment, reporting that patients classified as low risk were managed with less frequent and intensive surveillance and were not referred for adjuvant therapy. It is uncertain whether stratification of patients into higher risk categories has the potential to improve outcomes by allowing patients to receive adjuvant therapies or through the detection of metastases earlier. However, classification into the low-risk group would allow reduction in the burden of surveillance without apparent harm. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

National Comprehensive Cancer Network (NCCN) guidelines for uveal melanoma (v.1.2018) state that biopsy specimens 'should be sent for histology, chromosome analysis, and/or gene expression profiling.' The guidelines include DecisionDx-UM classes as one of the factors used to risk stratify patients for systemic imaging.

Melanoma Focus

Melanoma Focus, a British medical nonprofit that focuses on melanoma research, for uveal melanoma was published in 2015. These guidelines, which were created through a process accredited by the National Institute for Health and Care Excellence, contain the following statements related to prognosis and surveillance:

“3.5.1 Prognostic factors/tools

1. Prognostic factors of uveal melanoma are multi-factorial and include clinical, morphological and genetic features. The following features should be recorded:

  • Age
  • Gender
  • Tumour location
  • Tumour height
  • Tumour Largest [sic] basal diameter
  • Ciliary body involvement
  • Extraocular melanoma growth (macroscopic)

The following features should be recorded if tissue is available:

  • Cell type (modified Callender system)
  • Mitotic count (number/40 high power fields in H&E [hematoxylin and eosin] stained sections)
  • Presence of extravascular matrix patterns (particularly closed connective tissue loops; enhanced with Periodic acid Schiff staining). Grade A
  • Presence of extraocular melanoma growth (size, presence or absence of encapsulation).
  • [GRADE A]

3.5.2 Prognostic biopsy

1. There should be a fully informed discussion with all patients, explaining the role of biopsy including the benefits and risks. The discussion should include:

  • Risk of having the biopsy
  • Limitations of the investigation
  • Benefits for future treatments (including possible recruitment to trials)
  • Impact on quality of life
  • Follow-up [GPP]

2. Use of the current (i.e. 7th) Edition of the TN staging system for prognostication is highly recommended. Grade A

3. Use of multifactorial prognostication models incorporating clinical, histological, immunohistochemical and genetic tumour features – should be considered. Grade D

3.6 Surveillance

1. Prognostication and surveillance should be led by a specialist multidisciplinary team that incorporates expertise from ophthalmology, radiology, oncology, cancer nursing and hepatic services. [GPP]

2. Prognostication and risk prediction should be based on the best available evidence, taking into account clinical, morphological and genetic cancer features. [GPP]

3. All patients, irrespective of risk, should have a holistic assessment to discuss the risk, benefits and consequences of entry into a surveillance programme. The discussion should consider risk of false positives, the emotional impact of screening as well as the frequency and duration of screening. An individual plan should be developed. [GPP]

4. Patients judged at high-risk of developing metastases should have six-monthly life-long surveillance incorporating a clinical review, nurse specialist support and liver specific imaging by a non-ionising modality. [GPP] …

5. Liver function tests alone are an inadequate tool for surveillance. Grade C”

Note that Melanoma Focus defined GPP as: recommended best practice based on the clinical experience of the guideline development group.

U.S. Preventive Services Task Force Recommendations

Not applicable.


Uveal melanoma, DecisionDx-UM®, GEP, gene expression profile


Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). The DecisionDx-UM test is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.


Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.


CPT Codes:

Effective 01/01/19 and after, for DecisionDX®-UM:


Oncology (uveal melanoma), mRNA, gene-expression profiling by real-time RT-PCR of 15 genes (12 content and 3 housekeeping genes), utilizing fine needle aspirate or formalin-fixed paraffin-embedded tissue, algorithm reported as risk of metastasis. (Effective 01/01/19)

Prior to 01/01/19:


Unlisted multianalyte assay with algorithmic analysis


Unlisted chemistry procedure


  1. Aaberg TM, Jr., Cook RW, Oelschlager K, et al. Current clinical practice: differential management of uveal melanoma in the era of molecular tumor analyses. Clin Ophthalmol. 2014; 8:2449-2460.
  2. AJCC Ophthalmic Oncology Task Force. International validation of the American Joint Committee on Cancer's 7th Edition Classification of Uveal Melanoma. JAMA Ophthalmol. Apr 2015; 133(4):376-383.
  3. Augsburger JJ, Correa ZM, Augsburger BD. Frequency and implications of discordant gene expression profile class in posterior uveal melanomas sampled by fine needle aspiration biopsy. Am J Ophthalmol. Feb 2015; 159(2):248-256.
  4. Augsburger JJ, Correa ZM, Shaikh AH. Effectiveness of treatments for metastatic uveal melanoma. Am J Ophthalmol 2009; 148(1):119-27.
  5. Choudhary MM, Gupta A, Bena J, et al. Hepatic ultrasonography for surveillance in patients with uveal melanoma. JAMA Ophthalmol. Feb 2016; 134(2):174-180.
  6. Correa ZM, Augsburger JJ. Independent prognostic significance of gene expression profile class and largest basal diameter of posterior uveal melanomas. Am J Ophthalmol. Feb 2016; 162:20-27 e21.
  7. Correa ZM. Assessing prognosis in uveal melanoma. Cancer Control. Apr 2016; 23(2):93-98.
  8. Decatur CL, Ong E, Garg N, et al. Driver mutations in uveal melanoma: associations with gene expression profile and patient outcomes. JAMA Ophthalmol. Apr 28 2016.
  9. Diener-West M, Reynolds SM, Agugliaro DJ, et al. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol. Dec 2005; 123(12):1639-1643.
  10. Desjardins L, Dorval T, Levy C, et al. Etude randomize de chemiotherapy adjuvant par le Delicense dans le melanoma choroidei (Randomized study of adjuvant therapy by DTIC in choroidal melanoma). Ophthalmology. 1998; 12(3):168-173.
  11. Finger PT, AJCC-UICC Ophthalmic Oncology Task Force. The 7th edition AJCC staging system for eye cancer: an international language for ophthalmic oncology. Arch Pathol Lab Med. Aug 2009; 133(8):1197-1198.
  12. Finger RL. Intraocular melanoma. In: DeVita VT, Lawrence TS, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 10th ed. ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2014: 1770-1779.
  13. Francis JH, Patel SP, Gombos DS, et al. Surveillance options for patients with uveal melanoma following definitive management. Am Soc Clin Oncol Educ Book. 2013: 382-387.
  14. Hawkins BS. Collaborative ocular melanoma study randomized trial of I-125 brachytherapy. Clin Trials 2011; 8(5):661-73.
  15. McLean IW, Berd D, Mastrangelo MJ, et al. A randomized study of methanol-extraction residue of bacille Calmette-Guerin as postsurgical adjuvant therapy of uveal melanoma. Am J Ophthalmol. Nov 15 1990; 110(5):522-526.
  16. Nathan P, Cohen V, Coupland S, et al. Melanoma Focus: Uveal Melanoma National Guidelines: Summary. 2015; Available at:
  17. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Melanoma. 2017; Version Accessed January 28, 2019.
  18. Onken MD, Worley LA, Char DH et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology 2012; 119(8):1596-603.
  19. Onken MD, Worley LA, Ehlers JP et al. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res 2004; 64(20):7205-9.
  20. Onken MD, Worley LA, Tuscan MD et al. An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn 2010; 12(4):461-8.
  21. Pereira PR, Odashiro AN, Lim LA, et al. Current and emerging treatment options for uveal melanoma. Clin Ophthalmol. 2013; 7:1669-1682.
  22. Plasseraud KM, Cook RW, Tsai T, et al. Clinical Performance and Management Outcomes with the DecisionDx-UM Gene Expression Profile Test in a Prospective Multicenter Study. J Oncol. 2016; 2016:5325762.
  23. Prescher G, Bornfeld N, Hirche H et al. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996; 347(9010):1222-5.
  24. Spagnolo F, Caltabiano G, Queirolo P. Uveal melanoma. Cancer Treat Rev 2012; 38(5):549-53.
  25. van de Nes JA, Nelles J, Kreis S, et al. Comparing the prognostic value of BAP1 mutation pattern, chromosome 3 status, and BAP1 immunohistochemistry in uveal melanoma. Am J Surg Pathol. Jun 2016; 40(6):796-805.
  26. Walter SD, Chao DL, Feuer W, et al. Prognostic Implications of tumor diameter in association with gene expression profile for uveal melanoma. JAMA Ophthalmol. Apr 28 2016.


Medical Policy Panel, May 2014

Medical Policy Group, February 2015 (3): Creation of individual policy with all references related to Uveal Melanoma removed from medical policy #133-Genetic Testing for Inherited Cancer Predisposition and/or Pharmacogenetics related to Cancer Treatment

Medical Policy Administration Committee, March 2015

Medical Policy Panel, May 2015

Medical Policy Group, May 2015 (3): 2015 Updates to Key Points & Coding; no change in policy statement

Medical Policy Panel, July 2016

Medical Policy Group, July 2016 (3): 2016 Updates to Description, Key Points, Key Words & Coding; no change in policy statement

Medical Policy Panel, February 2017

Medical Policy Group, February 2017 (3): 2017 Updates to Description, Key Points & References; updated policy statements to reflect coverage criteria for GEP for uveal melanoma for members with primary, localized uveal melanoma, effective February 24, 2017

Medical Policy Administration Committee March 2017

Available for comment February 24 through April 9, 2017

Medical Policy Panel, February 2018

Medical Policy Group, March 2018 (2): 2018 Updates to Key Points and References; no change in policy statement.

Medical Policy Panel, February 2019

Medical Policy Group, March 2019 (9): 2019 Updates to Description, Key Points, References; no change in policy statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.