More than meets the eye13 April 2020
A simple blood test could soon become the latest monitoring tool for the early detection of melanoma in the eye. University of Queensland scientists have discovered markers in the blood that can differentiate between a benign mole and a melanoma, while also identifying if the cancer has spread to other areas of the body. Abi Millar speaks to Mitchell Stark, researcher at the University of Queensland Diamantina Institute, about what this means for clinical practice.
Melanoma in the eye is a rare but serious problem. Also known as ocular melanoma, this is a type of cancer that develops in the melanocytes – the melanin-producing cells that give the eyes their colour. It typically occurs in the uveal region of the eye (the middle layer of tissue) and affects around six in a million people.
One of the most pernicious aspects of eye melanoma is the difficulty of diagnosis. Especially if they occur in the back of the eye, they may not be visible, and the patient may not experience any symptoms at the early stages. Clearly, the longer the cancer evades detection the more likely it is to spread. Outcomes are particularly poor for patients whose cancer has spread to their liver.
On top of that, melanoma can look very similar to a benign eye condition – eye freckles or nevi. Many people (around 5–10%) have at least one nevus in their eye, the vast majority of which are harmless. However, nevi should be monitored by a specialist in case they do become cancerous (one in 9,000 will progress into melanoma). But if certain high-risk features are identified, that risk reaches 69%.
As Mitchell Stark, an early career fellow at the University of Queensland Diamantina Institute, explains, it may not always be immediately obvious whether the mole is malignant or benign.
“A mole at the back of the eye will generally be identified by an optometrist during a routine eye exam,” he says. “In most cases, the patient will be referred to an eye specialist or ophthalmologist who have expertise in identifying the clinical features of a mole versus a melanoma. Often, it is difficult to determine using clinical features if the mole is an early melanoma, so the patient is referred back for monitoring to observe any changes.”
If there is any suspicion that the patient has melanoma, the ophthalmologist may recommend an ultrasound examination of the eye or another imaging test. In some cases, a biopsy will be taken. While there are certain clinical features that do suggest cancer – orange coloration for instance, or a thicker mole than usual – diagnosis remains a challenging process.
Stark’s own work holds up a potential solution to the problem. Together with a team of researchers across multiple institutions, he is developing a blood test that can differentiate between a nevus and melanoma.
“This blood test has the potential to be used as a monitoring tool in conjunction with optometrists, GPs and specialists,” he explains. “If someone went to their optometrist for a regular check-up and a mole was found, you could have this blood test at each routine visit to help monitor mole changes. If the biomarker in the blood had increased, it might be an early warning sign of melanoma.”
A developing vision
Stark’s interest in melanoma began over 20 years ago. Initially, he focused on melanoma of the skin (cutaneous melanoma), which he describes as a ‘very different beast’ to eye melanoma.
“They have the same name, but very different causes,” he says. “What is a common feature of both, as in other cancer types, is that the earlier you detect melanoma the better, as this dramatically increases the chances of successful treatment.”
In his previous work, Stark teamed up with researchers at the QIMR Berghofer Medical Research Institute to develop a panel of biomarkers for skin melanoma. The idea was to track melanoma progression or recurrence with greater accuracy. In studies, these biomarkers performed far better than existing markers, confirming tumour progression among stage-IV patients with a 100% accuracy rate.
In 2017, Stark won a $120,000 grant towards the development of a melanoma biomarker toolkit. This will be used as a rapid, cost-effective diagnostic tool, as well as monitoring disease progression among latestage patients.
His latest study builds on these findings, taking the biomarkers he’d previously identified and applying them to patients with eye melanoma.
“The biomarker panel is similar to the one used previously to detect melanoma of the skin but does have additional markers,” he says. “The test is measuring the expression or amount of microRNA (miRNA) in the blood. These miRNA may be released from the tumour into the blood, or they could be from other cell sources and be released as a response to the tumour in the body. At present, more work needs to be done to determine the source of the miRNA.”
MiRNAs are tiny RNA molecules, which are expressed in every cell type and circulate in the blood. Their patterns of expression tend to look different when the patient is unwell (their volumes might increase or decrease), meaning they hold great promise within cancer detection. In fact, since they are quantifiable and highly stable, they have been touted as an ideal non-invasive biomarker for almost any human disease.
Within cancer research, miRNA biomarkers have been trialled across a number of conditions, including lung cancer, prostate cancer and breast cancer. If researchers can identify a particular miRNA ‘signature’ for a given condition, they should be able to determine who has the disease and who doesn’t simply by doing a blood test. This field of research is in its infancy, but could have a host of clinical applications further down the line.
A work in progress
In Stark’s research, he took blood serum from patients with eye nevi, localised eye melanoma and metastatic eye melanoma. The samples were tested against the panel of miRNA biomarkers, to distinguish the stage of the disease.
“This blood test was able to detect the difference between a benign mole located at the back of the eye and a melanoma in the eye with 100% specificity and 93% sensitivity,” he says. “The test also has the potential to show if the melanoma has metastasised and spread to other areas of the body.”
The study did have some limitations, in particular the small sample size. While it included 50 patients with a localised eye melanoma, only five patients had metastatic eye melanoma and just 10 had a noncancerous mole. On top of that, the miRNA panel was unable to predict or detect cancer recurrence. A larger, longitudinal study would be needed to explore how patients progress over time.
That said, the results are hugely encouraging. Stark believes that, following validation studies, this blood test could become a clinical reality within the next five to 10 years. “The next phase of the research is to increase our collection of specimens to confirm our findings in an independent study,” he says. “Following this, a clinical trial will be designed to assess the clinical utility of the blood test.”
Eventually, the blood test could be used during routine visits to the ophthalmologist. If the patient has an eye nevus, they will receive a regular blood test as part of their check-up, just to ensure any malignancies are caught at the earliest possible stage.
“My research aims to make clinical decision-making a little easier by some day incorporating a blood test that aids in verifying the decision to watch and wait, or to treat,” says Stark. “In most cases, the nevus will not change and regular blood tests in the future may reduce the need for intense surveillance.”
Conversely, if a patient is shown to be high-risk, they can be monitored more closely and accelerated though the healthcare system.
“If an increase of the biomarker panel is detected above a threshold level, then this may indicate metastasis has occurred, before it is eventually diagnosed via radiological imaging,” says Stark. “It will allow for earlier diagnosis, as well as giving doctors an earlier indication of the development of metastatic disease and importantly, a better outcome for patients.”
People have at least one nevus in their eyes, though the vast majority of which are harmless.
National Cancer Institute