Genetic testing provides accuracy for risk of transformation
Given optometrists’ skills in utilizing and assessing multi-modal imaging, they often direct the management of patients who have retinal conditions, making O.D.s crucial members of the these patients’ health care teams. This is particularly the case with choroidal melanoma.
Early detection of choroidal melanoma is crucial for patient survival, as half of all patients diagnosed with it ultimately develop metastatic disease — primarily to the liver — and many die within a year of their metastatic diagnosis. A total of 4 million cases of choroidal melanoma occur each year, yet 5% to 10% of the general population are diagnosed with choroidal nevi. Differentiation between the two can be challenging. The conditions can share several overlapping features, such as retinal pigment epithelial alterations, and the diagnosis is further complicated by the low rate of transformation — roughly 1 in 8,845 — from nevi to melanoma, reports Ophthalmology. (More information on choroidal nevi and melanoma is available at https://bit.ly/2tO2VRA .)
Established high-risk features, as seen via retinal imaging, can aid in the detection of the transformation of choroidal nevus into melanoma (see “High Risk Features,” p.43), prompting optometrists, the primary eye care providers, to refer the patient to an ocular oncologist for confirmation, via fine-needle aspiration biopsy genetic testing and intervention.
Here, we explain this genetic testing (gene expression profiling and chromosomal analysis) and provide a case in point.
GENE EXPRESSION PROFILING
Also known as GEP, this test identifies the molecular alteration likelihood of metastasis within five years. Specifically, the assay determines the activity or expression of 15 genes, which indicate a patient’s individual risk.
Three distinct tumor prognostic classes can be used to predict metastatic risk and strongly correlate with patient survival. Tumors are now classified as: Class 1A tumors, which have a 2%, five-year tumor-related mortality rate; Class 1B, which have a 21% five-year tumor-related mortality rate; and Class 2, which have a 72% five-year tumor-related mortality rate, reports PLOS Currents. With genetic information, systemic treatment may be initiated in patients who have Class 2 tumors before metastatic lesions are appreciated on imaging studies. While those with low-risk may have routine liver-specific imaging done every six to 12 months.
DecisionDx-UM (Castle Biosciences, Tucson, Ariz.) is the only commercially available CLIA-certified fine-needle aspiration biopsy test routinely used by ocular oncology to provide patients with prognostic information about their tumors.
HIGH RISK FEATURES
OVER THE YEARS, CERTAIN CLINICAL FEATURES HAVE BEEN USED TO PREDICT A NEVI AT HIGH RISK FOR TRANSFORMATION, INCLUDING THIS MNEMONIC, PARTICULARLY WITH SMALL LESIONS:
→ To. Thickness (greater than 2 mm),
→ Find. Fluid (subretinal)
→ Small. Symptomatic (photopsia, floaters, or vision loss)
→ Ocular. Orange pigment (lipofuscin)
→ Melanoma. Margin near the optic nerve (within 3 mm)
→ Using. Ultrasonography
→ Helpful. Hollowness (vs. solid and flat)
→ Hints. Halo absent
→ Daily. Drusen absent
The presence of three or more of these risk factors have been shown to impart a 50% chance or greater for nevi growth into melanoma, according to Ophthalmology. Choroidal nevus with fast growth (≤1 year interval) had a 80% high-risk genetic profile, while those with slow growth (>1 year interval) demonstrate 38% with high-risk genetic profile states the Journal of Ophthalmology.
THE CRITERIA OF THE COLLABORATIVE OCULAR MELANOMA STUDY (COMS) CLASSIFIES MELANOMAS USING APICAL HEIGHT AND LARGEST BASAL DIMENSION IN THREE GROUPS:
→ Small (1 mm to 3 mm/5 mm to 16 mm),
→ Medium (2.5 mm to 10 mm/less than 16 mm)
→ Large (more than 10 mm and 16 mm).
Patients who have medium to large and thicker melanomas have been shown to have worse long-term prognoses, with a five-year mortality rates of 15% to 50% vs. individuals who have smaller melanomas, according to this classifying COMS Study.
CHROMOSOMAL ANALYSIS
In addition to GEP, chromosomal analysis, or cytogenetic screening markers, can further refine the risk of choroidal melanoma.
The most profound chromo-somal alteration associated with a poor prognosis is either a partial or complete loss (monosomy) of chromosome 3, which predicts a three-year survival rate of less than 50%, reports the Eye Journal.
Also, mutations in tumor suppressor gene BAP1 on the short arm of chromosome 3 have been found in 84% of metastasizing choroidal melanoma lesions, according to the Journal of Ophthalmology. Additionally, chromosomal alterations have been noted on chromosomes 1, 6 and 8.
CASE IN POINT
A 75-year-old white male presented for routine monitoring of an asymptomatic amelanotic choroidal nevus OS that was noted 10 years prior. BCVAs were 20/20 OD and OS. Pupils, ocular motilities and confrontation VF testing were unremarkable.
| GENE EXPRESSION PROFILE CLASS | PERCENT METASTASIS-FREE AT 3 YEARS | PERCENT METASTASIS-FREE AT 5 YEARS |
|---|---|---|
| Class 1A | 98% | 98% |
| Class 1B | 93% | 79% |
| Class 2 | 50% | 28% |
| SOURCE: Castle Biosciences Inc. DecisionDx-UM Summary. Accessed March 22, 2017. | ||
Retinal examination OS re-vealed a juxtapapillary dome-shaped choroidal mass that was within 3 mm of the optic nerve, with an overlying neurosensory detachment on SD-OCT and hyper-FAF indicative of orange lipofuscin (See photo on p.42).
The changes suggested a lesion transformation into a melanoma. As a result, the patient was referred to an ocular oncologist who confirmed the small choroidal melanoma (less than 2mm in thickness) and biopsied it for genetic testing. Genetic testing revealed a Class 1A tumor, with a low risk of metastasis. Because the melanoma was small, it was treated with laser photocoagulation and anti-VEGf.
Genetic testing is a valuable addition to choroidal melanoma management, as it plays an important role in accurately identifying risk, as well as prognosis for metastatic disease. OM
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