What does molecular prognostic testing in uveal melanoma change?

Surveillance and counselling, not eye treatment Prognostic testing estimates metastatic risk; it does not change treatment of the eye but informs surveillance and counselling, and no adjuvant therapy is yet proven to improve survival.

The choice between plaque and enucleation

The radiation dose to the tumor

Access to a proven adjuvant cure

Which is the best-known cytogenetic marker of metastatic risk in uveal melanoma?

Monosomy of chromosome 3 Monosomy 3 is the best-known marker and is strongly associated with metastasis; gain of 8q also worsens the outlook, especially with monosomy 3.

Which chromosomal change in uveal melanoma is associated with a better outlook?

Gain of chromosome 6p Gain of chromosome 6p is associated with a better outlook, in contrast to monosomy 3 and 8q gain.

On gene expression profiling of uveal melanoma, which class carries a high metastatic risk?

Class 2 Gene expression profiling assigns tumors to class 1A, 1B or 2; class 1A had a low five-year metastasis rate and class 2 a high rate in prospective validation.

BAP1 mutations in uveal melanoma are linked to which feature?

Loss of one copy of chromosome 3 and high risk BAP1 mutations are frequent in metastasizing tumors and are linked to loss of one copy of chromosome 3 and a high risk.

Early driver status with no prognostic value

Intermediate risk similar to SF3B1

Which mutation in uveal melanoma is associated with low metastatic risk?

EIF1AX SF3B1 and EIF1AX mutations are associated with intermediate and low risk respectively, while BAP1 marks high risk.

What is the prognostic value of GNAQ and GNA11 mutations in uveal melanoma?

They are early drivers that do not predict outcome GNAQ and GNA11 are early driver mutations that do not predict outcome, unlike BAP1, SF3B1 and EIF1AX.

They mark the highest-risk tumors

They predict liver-only metastasis

Why may a low-risk result from a uveal melanoma biopsy fail to represent the whole tumor?

Tumors are heterogeneous, so sampling error occurs Sampling error is a concern because tumors are heterogeneous, so a normal result may not represent the whole tumor; the sample may also be too small for testing.

Fine-needle aspiration denatures RNA

Plaque radiation alters the tumor genes

How are patients with high-risk uveal melanoma usually followed after prognostic testing?

Liver imaging and examination every three to six months High-risk patients usually have liver imaging by ultrasound, MRI or CT and examination at three- to six-month intervals, while low-risk patients can be followed less often.

No surveillance until symptoms appear

Uveal Melanoma Prognostic Testing: GEP and BAP1

Uveal melanoma prognostic testing estimates the risk that a tumor will metastasize, using molecular features of the tumor cells.

It does not change the treatment of the eye, but it informs surveillance and counselling.

Because there is no proven treatment to prevent metastasis, experts debate the benefits and the ethics of testing.

Why Uveal Melanoma Prognostic Testing Is Done

About half of patients with uveal melanoma eventually develop metastases, most to the liver.

The interval can be many years.

Clinical features such as tumor size, ciliary body involvement, and extraocular extension predict risk, but they are imprecise (see choroidal melanoma).

Molecular tests identify tumors with high-risk biology.

They can also distinguish patients who need close monitoring from those at lower risk.

Uveal Melanoma Prognostic Testing: Cytogenetic Features

Monosomy of chromosome 3, the best-known marker, strongly associated with metastasis
Gain of chromosome 8q, also associated with a worse outlook, especially with monosomy 3
Gain of chromosome 6p, associated with a better outlook

Laboratories can test chromosomes on tumor tissue obtained by fine-needle biopsy or after enucleation.

Test your knowledge 10 questions from this article

Gene Expression Profiling

Onken and colleagues described two molecular classes of uveal melanoma on the basis of gene expression: class 1, with low metastatic risk, and class 2, with high risk.

A commercial assay measures the expression of a panel of genes and assigns the tumor to class 1A, 1B, or 2, with a corresponding risk of metastasis.

A prospective multicenter study validated the test, showing that class 1A tumors had a low rate of metastasis at five years, and class 2 tumors had a high rate (see the references).

Uveal Melanoma Prognostic Testing: Mutational Markers

BAP1 mutations, found in a large share of metastasizing tumors, linked to loss of one copy of chromosome 3 and to a high risk
SF3B1 and EIF1AX mutations, associated with intermediate and low risk respectively
GNAQ and GNA11, early driver mutations that do not predict outcome
PRAME expression, an additional marker used with gene expression profiling in some assays

Harbour and colleagues found frequent BAP1 mutations in metastasizing uveal melanomas, which helped to explain the biology.

How the Sample Is Obtained

Fine-needle aspiration biopsy of the tumor, usually at the time of plaque placement or in an office setting
Enucleation specimen from a removed eye
Transscleral or transvitreal approaches, according to the tumor location

Biopsy carries small risks, including hemorrhage, retinal detachment, and tumor seeding, and the sample may be too small for testing.

Sampling error is a concern, since tumors are heterogeneous, and a normal result may not represent the whole tumor.

What the Result Changes

Surveillance intensity: patients with high-risk tumors usually have liver imaging, by ultrasound, MRI, or CT, and examination at intervals of three to six months, while low-risk patients can be followed less often
Counselling: it gives patients and families a realistic estimate of the risk
Clinical trials: high-risk patients may also be eligible for adjuvant trials
Reassurance: a class 1A result may also spare a patient anxiety and over-testing

Currently, no adjuvant therapy has been proven to improve survival, so a high-risk result does not lead to a proven treatment.

Uveal Melanoma Prognostic Testing: Limitations and Ethics

Not all patients want to know their risk, so offer testing after counselling
Results can cause distress, particularly when no preventive treatment exists
The test has limited value for small, low-risk tumors, where the chance of metastasis is already small
Costs and availability vary between centers

Testing is best done at a center with experience.

The results should be discussed with the patient by a team that includes an ocular oncologist.

Practical Advice

Document the clinical features and the testing results in the chart, and arrange regular surveillance with a clear schedule.

Also, provide the patient with information about the disease and support resources.

Communicating the Result

Discuss the result with the patient in terms of probabilities and what they mean for follow-up, and not as a prediction of fate.

Also, allow time for questions and for the patient to bring a family member, and provide information from a reliable organization.

Offer psychological support to those who are also distressed, and remind them that the test describes a risk and that many patients with high-risk features live for years.

In addition, make sure that the patient knows who will coordinate the surveillance imaging and how the team will communicate results.

References

Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64:7205-7209.
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;119:1596-1603.
Harbour JW, Onken MD, Roberson EDO, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330:1410-1413.
American Academy of Ophthalmology. Basic and Clinical Science Course, Section 4: Ophthalmic Pathology and Intraocular Tumors. AAO; current edition.

Test yourself

A few questions straight from this article.

1 / 10 0 correct

What does molecular prognostic testing in uveal melanoma change?
Prognostic testing estimates metastatic risk; it does not change treatment of the eye but informs surveillance and counselling, and no adjuvant therapy is yet proven to improve survival.
What proportion of patients with uveal melanoma eventually develop metastases, and where do most go?
About half of patients eventually develop metastases, most to the liver, and the interval can be many years.
Which is the best-known cytogenetic marker of metastatic risk in uveal melanoma?
Monosomy 3 is the best-known marker and is strongly associated with metastasis; gain of 8q also worsens the outlook, especially with monosomy 3.
Which chromosomal change in uveal melanoma is associated with a better outlook?
Gain of chromosome 6p is associated with a better outlook, in contrast to monosomy 3 and 8q gain.
On gene expression profiling of uveal melanoma, which class carries a high metastatic risk?
Gene expression profiling assigns tumors to class 1A, 1B or 2; class 1A had a low five-year metastasis rate and class 2 a high rate in prospective validation.
BAP1 mutations in uveal melanoma are linked to which feature?
BAP1 mutations are frequent in metastasizing tumors and are linked to loss of one copy of chromosome 3 and a high risk.
Which mutation in uveal melanoma is associated with low metastatic risk?
SF3B1 and EIF1AX mutations are associated with intermediate and low risk respectively, while BAP1 marks high risk.
What is the prognostic value of GNAQ and GNA11 mutations in uveal melanoma?
GNAQ and GNA11 are early driver mutations that do not predict outcome, unlike BAP1, SF3B1 and EIF1AX.
Why may a low-risk result from a uveal melanoma biopsy fail to represent the whole tumor?
Sampling error is a concern because tumors are heterogeneous, so a normal result may not represent the whole tumor; the sample may also be too small for testing.
How are patients with high-risk uveal melanoma usually followed after prognostic testing?
High-risk patients usually have liver imaging by ultrasound, MRI or CT and examination at three- to six-month intervals, while low-risk patients can be followed less often.

Ahmed Ophthalmologist

Writes and reviews the clinical articles on Educate. Every post is checked against peer-reviewed sources before it goes live.