Controversies in the Genetics of Choroidal Melanoma

Intervention is vital, but fraught with challenges


Controversies in the Genetics of Choroidal Melanoma

Intervention is vital, but fraught with challenges.

Tara A. McCannel, MD • Barry L. Burgess, MD

Care is evolving for patients with choroidal melanoma, the most common primary intraocular cancer of adults. Molecular discoveries have established access to prognostic information for patients. However, providing molecular prognostic information remains controversial because no effective treatment for metastatic disease to the liver currently exists.


Among the many new complex scientific and therapeutic discoveries comes the ability to provide personalized molecular prognostic information to patients about their disease. Genetic or molecular profiling may allow for individualized treatment with drugs targeting a specific mutation, for counseling regarding the risk of developing a heritable condition, or for providing prognostic information about risk of metastasis, such as with choroidal melanoma.

Today, patients are often healthcare consumers, armed with an array of information from the Internet, including the latest news about diseases, scientific reports and other patients' experiences or opinions. Empowered with knowledge, they desire to know how molecular information of their disease may influence their prognosis, even in the absence of consensus about how molecular prognostic information should be used. The patient's desire for prognostic information regarding choroidal melanoma—despite the lack of effective treatments—remains an important aspect of whole-patient care.


The challenge of choroidal melanoma is metastatic disease. Local control of the primary cancer can almost always be achieved through radiation or enucleation. However, metastasis is what kills the patient; death from metastases occurs in approximately half of choroidal melanoma patients.1,2

Despite what we have learned about choroidal melanoma, fundamental questions remain unanswered: Why do people get this cancer? Why does choroidal melanoma almost always go to the liver? By what mechanism is the liver invaded? Although we may attempt to slow metastatic death by local treatments to the liver, we are as yet unable to effectively treat or prevent metastatic choroidal melanoma.3

While it is true that our knowledge of the basic biology of choroidal melanoma continues to grow, effective management remains elusive. Ultimately, targeted therapies toward specific sets of mutations may be required to control metastatic disease.


For the past two decades, we have known that choroidal melanoma falls into two largely exclusive cytogenetic groups: those patients who will go on to develop fatal metastasis (monosomy 3 of the tumor) and those patients who will not (absence of monosomy 3). This knowledge was established in work examining the outcomes of patients who underwent enucleation and in whom chromosome analysis established the poor prognosis in tumors of those patients with loss of one copy of chromosome 3, or monosomy 3, in the tumor tissue.4,5 Research into this field by ourselves and others has identified distinct molecular and cytogenetic profiles that have further defined these two groups of patients.6-8

More recently, specific mutations involved in tumorigenesis have been identified in many cancers, including choroidal melanoma. GNAQ and GNA11 mutations, believed to be important in the development of choroidal melanoma, may require an individualized, targeted approach for a successful treatment strategy.9-10 Therefore, metastasis will likely not be a one-size-fits-all treatment. Knowledge of the individualized molecular characteristics of each primary choroidal melanoma will not only be needed for the patient's prognosis, but will also be required to determine a customized, molecular-based treatment for the patient of the future.


Prognosticating the risk of developing metastatic choroidal melanoma has traditionally been based on clinical and histopathologic characteristics of the primary tumor. However, for the past five years, analysis of molecular and cytogenetic information from choroidal melanoma fine-needle aspiration biopsy (FNAB) has become possible and increasingly common.11-14

Both DNA and RNA can be analyzed from the tumor. Cytogenetic testing can be performed for chromosomes of interest using fluorescence in situ hybridization (FISH). FISH testing may be performed in a hospital clinical cytogenetics laboratory, similar to other laboratory investigations covered by insurance providers. However, other assessment techniques that are investigational and less widely available include whole genome single-nucleotide polymorphism (SNP), multiplex ligation-dependent probe amplification (MLPA) and microsatellite analysis (MSA).

Whole genome SNP assesses all regions of all chromosomes; however, MLPA and MSA examine a limited number of foci of chromosomes that are believed to be of interest. Although SNP provides information across the entire genome, with less likelihood of missing key information than MLPA or MSA, SNP is considerably more costly to perform. Most insurance companies do not cover these latter investigational techniques, which may be an additional cost to a patient who is not part of a research study.

The only reported RNA-based assay for choroidal melanoma prognosis is a commercially available assay by Castle Biosciences, known as the “class 2 gene test.”15 A challenge with RNA-based assay for gene expression profiling is sample degradation because of the labile nature of RNA. Furthermore, the biological relevance to metastasis of the genes in the class 2 gene test have not been demonstrated. Until such a time that these genes are shown to have biological relevance, class 2 gene testing remains limited to prognosis.

A loss of one copy of chromosome 3 or a class 2 gene expression profile portends a higher risk of developing metastasis. All of the aforementioned tests can be performed on specimens obtained by FNAB of the primary tumor at the time of surgery.

Influence on Current Medical Care

Although FNAB may provide information regarding a patient's risk for developing metastasis, the result does not yet alter a patient's medical management. Because there are no effective treatments available for metastatic disease, the clinical impact of obtaining routine biopsy on choroidal melanoma is controversial, with many experts arguing against this practice.

However, cancer treatment involving targeted therapy to specific mutations continues to evolve. We expect that the discovery of genes whose functions influence metastasis may represent targets against which tumor-specific therapies may be directed in the future. Because the mutations tend to be of somatic rather than of germline origin (ie, originating only within the primary tumor, not identifiable by an analysis of patient blood or other nontumor tissue), FNAB will eventually be a requirement to devise the most appropriate individualized treatment strategy for a given tumor.

Risks of Biopsy

The most common method of obtaining tissue for prognostication, cytopathology and/or research purposes at the time of brachytherapy is FNAB. FNAB may be performed trans-sclerally or by a trans–pars plana, transvitreal approach. The trans-scleral approach, which is the simplest and most commonly performed, involves placing the needle through the sclera and into the tumor. The plaque is then placed over both the biopsy site and the tumor. A trans–pars plana transvitreal approach involves placing the needle through the pars plana opposite the tumor, passing it through the vitreous and then into the tumor with binocular indirect visualization.

Potential complications of the procedure, including rhegmatogenous retinal detachment and endophthalmitis, have been reported as rare isolated cases in the literature.16-19 Two cases of endophthalmitis have been reported after FNAB, one of which was performed via a trans–pars plana transvitreal approach with indirect ophthalmoscopy.18,19 We reported local complications in a series of macular tumors biopsied using a trans-scleral approach, which resolved without intervention and without consequence to short-term visual outcome and which included vitreous hemorrhage and submacular hemorrhage.20

Short-term follow-up of patients who have undergone FNAB for prognostic purposes at the time of brachytherapy have demonstrated no risk of local recurrence over a mean follow-up period of less than one year.21 Higher rates of orbital dissemination, increased local recurrence, and increased risk of metastatic development are often speculated with FNAB, but their true occurrence has not been reported. Furthermore, the risk of metastatic development is believed to be related to the molecular make-up of the tumor, rather than any physical manipulation of the tumor at the time of treatment.

Giving Patients Bad News

While the scientific merits of prognostic assays continue to be debated, the psychological effect of providing information obtained from a prognostic test has received considerable attention. In the absence of effective metastatic treatment therapies, the nonmedical implications of prognostication may have the most impact on patients. Could this impact be psychologically detrimental?

To answer this question, we reported the results of a questionnaire sent to patients who had been treated for choroidal melanoma, asking if they would have wanted to know their cytogenetic test results despite the absence of any effective therapies for metastasis. Motivation for the test was for future planning purposes, despite the fact that it would not influence their medical management. We and others have shown that a bad prognostic test result does not result in psychological morbidity or depression.22,23

Toward a Cure for Metastasis

Although controversy exists, biopsies of primary choroidal melanoma will become increasingly important. Biopsies are necessary (1) to provide prognostication to patients, (2) for continuing research and (3) in the future, for customized, directed treatment based on defined molecular characteristics of the primary melanoma.

A forward-looking approach at future treatment of choroidal melanoma will involve identifying specific mutations within the primary tumor that may be specifically targeted to control the cancer and prevent the onset of metastasis in those patients who are identified by biopsy as susceptible. The first reason is to satisfy the desire of the patient to receive prognostic information regarding the tumor, beyond the traditional but less accurate clinical indicators of size, location and cell type.

The second reason is to continue to build upon scientific discoveries made possible by studies of material obtained through biopsy. When weighed against the minimal risk associated with trans-scleral biopsy, routine FNAB to include material for research and prognostication, is essential to further our understanding of the biology of metastasis. Access to live tumor material provides cytopathologic confirmation of diagnosis, DNA, RNA and cells for culture to create in vivo models for studying biologic pathways and for testing drugs. The current and future state of molecular knowledge and treatments will be heavily influenced by biopsy-driven studies.8,24

Here to stay is fine-needle aspiration biopsy of primary choroidal melanoma, and those practitioners who are considering biopsy must look ahead to what the future may hold for mutation-specific targeted cancer treatments. Once targeted therapies are available to prevent metastasis, it may be necessary to sample every tumor for which the patient consents to be tested. For the time being, however, biopsy of primary tumors continues to offer those affected with much wanted prognostic information and is the foundation of research programs targeting cures. RP


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Tara A. McCannel, MD, PhD, is assistant professor of ophthalmology and director of the Ophthalmic Oncology Center at the Jules Stein Eye Institute. Barry L. Burgess, BA, is faculty research specialist in the Ocular Oncology Center at Jules Stein. Neither author reports any financial interest in any product mentioned in this article. Dr. McCannel can be reached at