Advances in diagnostic devices in melanoma screening

Dr Alessandro Testori - European Institute of Oncology, Milan, Italy

I will talk about two completely different aspects of the big novelties that we have been developing in the last years which are some from the diagnostic point of view and some others from the therapeutic point of view. Starting with the diagnosis, we know since ever that as early as we could get the diagnosis of a primary melanoma, the better the prognosis would have been. This has been discussed and developed from the research for decades that brought us to understand the importance of recognising and excising a primary melanoma when this is at the early stages of the development of the disease.

This means that we pass from a, let’s say, optical evaluation of the skin to some more technical developments of the clinical diagnosis which pass through, first of all, the use of a dermatoscope that, using the methodology of epiluminescence, permits to the clinician to see some of the features of the pigmented lesions. And this has certainly helped us in improving enormously the capacity to recognise a benign versus a suspicious or malignant primary melanoma. It’s not only dedicated to melanoma, this kind of diagnosis, the importance is also for other skin tumours, basal cell carcinomas, squamous cell carcinomas, starting from the development of actinic keratosis to the progression into epidermoid cancer of course. But certainly melanoma is the most important because the great majority of deaths for skin cancer are linked to melanoma. We should say that around 75-80% of deaths for skin cancer are due to melanoma. The earlier we can obtain the diagnosis the better it is.

This kind of evaluation has now a new device which is the confocal laser microscopy. This is a completely different device; it’s a device that through the evaluation of a laser ray permits to study 250 microns from the surface to the deeper part of the lesion. In early situations where maybe you are not so sure whether this lesion is suspicious or not it helps you in an incredible way to do in a certain way a histological evaluation of the skin lesion before excising it. Because with this laser evaluation you can really see the cells and you perform a sort of histological evaluation of the skin lesion that you have in front of you. The association of these two methodologies, dermoscopy from one side which helps you to screen the great majority because of dermatopical evaluation, it takes three seconds to be done, while instead laser microscopy, confocal laser microscopy evaluation, takes some, let’s say, 15-20 minutes to be done and then you have to analyse all the scans that the computer has obtained and it takes it a bit more time but of course it’s of great help, in particular in the difficult lesions, for example in the lesions which have very little pigment because the so-called achromic lesions, pigmented lesions, are very difficult to be diagnosed and a differential diagnosis in between a benign and a malignant lesion it’s not so easy. We have, of course, some particular peculiarities like the vascularisation but these are not really strong aspects to help us from a dermoscopical point of view to recognise when benign vessels in malignant lesions. So the confocal microscopy laser evaluation is of great help. It is, of course, an expensive device but in the big centres we have it at disposition and this certainly has helped us in selecting patients for excision or just a normal control of the skin.

I think that we have more or less between twenty and thirty of these devices in different hospitals in Italy and I should say one hundred or more around Europe. On the therapeutic I should say that we don’t have enormous novelties from the surgical point of view, surgery it’s the standard things for some decades. The very last important novelty has been the sentinel node biopsy concept which is a very diffuse practice in the great majority of institutions working on these kinds of pathologies and treating patients with melanoma, breast cancer. It’s really something on which we have been discussing and proposing it from an educational point of view in the last years. Nowadays, of course, it’s very important that you co-ordinate well the therapeutic surgical aspects of melanoma patients so that, for example, the nuclear medicine department is in the same hospital where then you conduct the surgical and the pathological evaluations of the specimen that you excise. Of course the processing of the sentinel node that you have excised is a completely different and very intensive evaluation compared to a normal node that you excise from patients. But it’s clearly very important that everything is established into a melanoma unit, let’s say a multidisciplinary melanoma unit. This is the important message that now we are trying to communicate to the different institutions. It’s not the best situation where you have a dermatologist in one department then the dermatology calls the surgeon, the surgeon maybe asks for which kind of operation he should do to this patient because he knows how to operate but he doesn’t know what kind of procedure to perform, and the discussion is in between three different entities ending with the medical oncologist who will then follow the patient and eventually treat him if he requires to be treated from the medical point of view. So these are, of course, very standard aspects nowadays but the important aspect is that they are very well co-ordinated. Every patient should be discussed and an approved treatment plan should be designed for each patient when the situation is a bit complex. If you are just talking of primary melanoma where you need just a wide … this is a straightforward operation and every dermatologist, or surgical dermatologist, is absolutely able to manage this kind of situation.

The important novelties are instead from the medical point of view. From the medical point of view nowadays we have completely changed the opportunities that we can offer to our patients. Specifically when you have a stage 4 non-operable melanoma patient the first evaluation comes from the molecular biology aspect. We need to study the patients for the possible different mutations that the tumour presents and these are the famous BRAF mutation, the NRAS mutation or the c-KIT mutation. BRAF is something that happens in between 40-60%, depending on the different populations, of patients with melanoma. NRAS encodes nearly 15-20% and 15% for c-KIT which is mainly linked to the acral melanomas and to the mucosal melanomas.

The most important results in terms of clinical efficacy using the inhibitors of these pathways are related to the BRAF mutation and the trend now is to treat patients with both a BRAF inhibitor and MEK inhibitor. We have different companies working on these new drugs and I should say that the average is, of course, of an equivalent efficacy, a little bit of difference in toxicity from one drug to the other one but at least we can say that we obtain up to 60% of clinical responses while the big question is how long do these responses last. So after six months, eight months, one year in the majority of patients unfortunately we see progression of the disease again which is often a very rapid progression of the disease.

This is the topic of targeted therapy, the other important aspect comes from immunotherapy. Where we talk of immunotherapy we talk first of all of ipilimumab, which was the very first drug to be approved in terms of improving overall survival of advanced melanoma patients. But here we are talking of maybe less than 30% of benefit. The new drug is PD1 and this drug is under, let’s say, evaluation from the concept of waiting for the results of the phase III studies where we have been studying both the combination of PD1 plus ipilimumab, PD1 alone or ipilimumab alone in a very important phase III study. The results should be ready within maybe one or two years maximum so that we have the possibility to treat our patients at least with PD1 but I really think that the combination of PD1 and ipilimumab will give the best response rate and overall survival results to these patients who are really in a very, very delicate situation from the clinical point of view. Because if they, for example, would be characterised by disease without any mutation like those that I mentioned before, BRAF, NRAS or c-KIT, then the only other alternative that these patients have to be treated is through either the standard chemotherapy, 5% of survival at five years, or these new drugs which are, of course, PD1 and ipilimumab. Until we have the commercial use we could treat patients under clinical studies, now the majority of these clinical studies are under evaluation of the results so we are really waiting hopefully for the possible commercial use of these new products as soon as possible.

Can these immunomodulatory drugs be offered to all patients?

For immunotherapy so far there is no selection criteria to be identified in terms of which patient could benefit and which could less benefit. This is a very important question, this is a very important aspect of research but so far we are offering this kind of approach to all the patients who may need it.