Chapter 7

Melanoma (MM)

Of all skin cancers malignant melanoma is the most feared by both patients and doctors. The former, because MM is a significant cause of mortality; the latter because the diagnosis of MM is difficult and relies on the ability to distinguish between the rare suspicious lesions and the ubiquitous harmless pigmented lesions that are found on all of us. Clinicians who claim certitude in this area are likely deluded.

Clinical Vignette

The wife of a 60 year old gentleman noticed a brown lesion on his upper back that she thought may be new although she couldn’t be certain. She felt it looked very different from the other moles and blemishes on his skin, was about 1cm across, and was totally asymptomatic. She thought it was changing.

Melanoma is a malignancy of the neural crest derived melanocytes. Most MM are pigmented and may be confused with benign melanocytic nevi (‘moles’) or other being pigmented lesions of the skin. Some moles develop into MM. Melanoma unlike virtually all other skin cancers metastasises early, and it is these metastases that lead to death.

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Epidemiology

The incidence of MM in Northern Europe is close to 15:100,000 with a median age of 53. Rates in men and women are fairly similar. The majority of deaths from skin cancer are a result of malignant melanoma with a death rate of approximately 3:100,000. Melanoma is therefore much less common than non-melanoma skin cancer (NMSC) but has a much higher case fatality (10-20% at 10 years).

Causes of melanoma

The principal cause of MM as for other skin cancers is the combination of UVR and sun sensitive skin. Therefore, as expected, MM is more common in Northern Europeans with pale skin living in areas of high ambient UVR such as Australia or sub-Saharan Africa. The role of UVR is, as for other skin cancers, supported by the abnormally high rates of MM in patients with xeroderma pigmentosum.

However there are complications in the relation between UVR and skin cancer (including BCC) that I have skipped over in the previous sections and I will discuss here before returning to our list of causes of melanoma.

Melanoma and the puzzle of the body site distributions of skin cancers

In earlier sections we learned that AKs and SCCs are most common on body sites that receive the most cumulative UVR, sites such as the scalp in bald headed males, the backs of the hands and some parts of the face. However keen readers will have noticed that for BCC I pointed out that most occur on the middle third of the face. If BCC are caused by UVR why is this? For MM the picture is yet even more confusing. Although, as we will learn later, there are various subtypes of MM, MM are most common on body sites that are usually protected from the sun—sites such as the back and the legs. Yet, we see that more MM occur on these protected sites than on the back of hand. Does this mean that MM is not related to UVR?

The conventional arguments for the importance of UVR in skin cancers are that cancers occur frequently in xeroderma pigmentosum, that those with less melanin in the skin are more at risk, and that those exposed to the most UVR have the highest incidence. These statements all apply to MM:

So why the odd body site distribution of MM and BCC?

I will deal with BCC first. Although UVR is a necessary cause for BCC it is not sufficient. BCC are likely tumours of the appendage or appendage related cells. This means that since the density of appendages (both pilosebaceous units and eccrine glands) is very high on the middle third of the face then, tumour density may well be highest here.

For MM we need to remember that different body sites have different surface areas and if, for the sake of simplicity, we assume that the precursor cells of MM (melanocytes or other products of the neural crest) are spread at an even density across the body then we would expect that MM body site distribution would reflect both (1) area of skin and (2) the influence of exposure to UVR.

The data we see is at least compatible with these two statements. On larger areas of skin (such as the back or legs) we see more tumours than areas such as the back of hands that have a lower surface area. In fact if we calculate the rate of MM per unit area of skin we see that the rate of MM is highest on the top of the ear (and much higher in men than women at this site [2]).

This line of reasoning only gets us so far however. We have made a case for keeping our favourite hypothesis about skin cancer causation (i.e UVR) and justifying the differences in body site distribution between BCC and MM. However, why don’t these arguments hold for AK and SCC? For these lesions we still see the highest numbers on the back of hands or the scalp despite the area being relatively low?

The easiest and most popular explanation is to assume that the exact nature of the relation between the various cancer types and UVR differs. Whereas AK and SCC are related to cumulative UVR exposure, BCC and MM may relate to intermittent exposure. The caricature here is the office worker who only goes to the beach at the weekend and gets burned on sites that are normally protected such as the back and the legs. Conversely, the sites that receive the more continuous exposure such as the face and the hands have lower rates (in comparison with SCC body site figures).

This intermittent sun exposure risk for BCC and MM is widely believed and receives some support from the fact that rates of MM are lower in some occupational groups such as outdoor workers that receive UVR more continuously than our stereotypical office worker who descends on the beach with his surfboard at the weekend.

Causes of melanoma (continued)

Clinical presentation and clinical subtypes

So far, we have discussed MM as though it were a homogenous entity with the exception of the 10% of lesions that appear on the palms or soles and are unrelated to UVR. Early diagnosis for melanoma means distinguishing MM from a range of much more common pigmented lesions (such as melanocytic nevi and seborrhoeic keratoses). Diagnosis is however made much more difficult because MM can present in a number of different morphological forms—and so can its mimics. Here is the issue that makes dermatology so difficult: there is not a one-to-one correspondence between a single diagnostic entity and how something looks.

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The main subtypes of MM we need to consider are as follows:

It is a mistake to think the above are watertight compartments or that different observers do not sometimes classify the same lesion differently. Recourse to the pathologist does not always help either. For instance, any MM—say a lentigo MM or acral MM—may develop into a nodular morphology.

Given what I have just said it is worth continuing with these categories? I would give a guarded ‘yes’ answer to this question. First, some of the differences reflect differences in causation. We have already mentioned acral MM where UVR does not play a role. But lentigo MM is typically found on continuously exposed skin such as the photodamaged face and shows a change in incidence with age different from the other MM [7]. SSM by contrast are often seen in younger persons and with a history of change of a preexisting mole or a presentation like a new onset mole, whereas nodular MM seem to occur more often in the elderly on sites and appear ‘suddenly’ out of nowhere.

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Another key reason for being aware of these morphological subtypes is that some of the advice to help both doctors and patients spot early warning signs at best only works for some MM and not others. The most well known of such methods is the ABCD(E) rule and we will discuss this below as it leads to much confusion both amongst medical students and the lay public.

The problem of diagnosing MM

The management of MM is focussed on early diagnosis. The reasons for this are
straightforward. If a primary MM is excised before it has spread then the patient will survive.
By contrast, if a MM has metastasised, then there is no curative therapy available [8]. When
you diagnose a cutaneous melanoma however, unless metastases are clinically obvious or
seen on imaging, then you do not know whether clinically undetectable metastases have
already occurred (i.e. that is, the tumour has already spread but you cannot detect the
spread).

The best single indicator of whether metastases have already occurred is the Breslow thickness of the primary lesion. This is a simple measurement in mm of the distance from the granular layer to the bottom of the abnormal melanocytic proliferation, made by the pathologist on the excised primary MM. A Breslow thickness of less than 1mm or less predicts a 90% 5 year survival; a thickness of between 2 and 4mm denotes a survival of 40-60% at the same time point [9].

The logic of the data on the Breslow thickness is that we should focus on detecting MM at the thinest Breslow thickness. Diagnosis as in so much of medicine is much harder early in the course of the disease than later on. For MM one system to help you remember the features of early MM is the ABCD(E) rule. This acronym stands for:

Depending on the authority the E can refer to either Elevation or Evolution (‘change’). Despite the wide promulgation of this approach, evidence that it is effective is scant. There are a number of particular issues that are worth discussing.

The ABCD systems was originally designed to help doctors distinguish MM from melanocytic nevi. It was never designed to be a system that allowed doctors or lay persons to distinguish MM from any other mimic of melanoma. In practice the lay public and many doctors cannot distinguish between melanocytic nevi and seborrhoeic keratoses, and most seborrhoeic keratoses will fulfil the criteria for melanoma using the ABCD system [10].

Students needs to be able to comment on the ABCD rule, but my own view is that the best way to know what MM look like is to look at as many pictures of them as you can and try and come up with your own internal representations.

Clues to MM

Beyond epidemiological clues (sun sensitive skin, high UVR exposure, positive family history) what strategy can I recommend for detecting early MM?

Finally, many patients seem to have an uncanny ability to detect that something serious may be amiss. Patients may be wrong a lot of the time: but doctors are not perfect either.

Treatment of melanoma

The treatment of melanoma is excision of the primary lesion with the overall clinical goal to diagnose MM at an early stage before spread has occurred. Lesions should be excised with a 2mm margin, the sample examined by the histopathologist, and a further excision carried out based on the Breslow thickness which might mean that 1-2cm margins are required [11]. If the lesion turns out to be benign, the patient is left with a (relatively) small scar; if the clinical suspicion is confirmed, the patient does not suffer due to the delay of the ‘two stage approach’.

Deliberate incisional biopsies: Avoid deliberately taking incisional biopsies of MM. First, the depth in terms of then Breslow thickness may be misleading and second it is rarely necessary, except for very large lesions. It used to be held (mainly, it is true, by surgeons) that the mere act of incising a MM would increase the risk of metastasis, but this seems rather implausible. Nonetheless, if you are uncertain about the merits of an incisional biopsy, you should not be doing it—refer.

‘Accidental’ incisional biopsies: By this I do not mean that your hand slipped while holding a scalpel, but that you didn’t consider the diagnosis in the first place. It is in the nature of human fallibility that MM will be sometimes misdiagnosed as something else (e.g seborrhoeic keratoses or pyogenic granulomas [12]) and treated with surgical procedures such as curettage and cautery. If this happens, refer on to organise prompt complete excision—the tumour will likely have a high Breslow score.

Prognosis for advanced disease

The Breslow thickness provides the single best prognostic information for patients who do not have metastases at presentation [13]. If the patient does have metastases the prognosis is poor as there is in practice no curative treatment for metastatic MM [8]. Palliative therapy using most commonly dacarbazine and radiotherapy may be used. These patients require expert oncological support from the appropriate specialists. There are however new treatments that are coming on stream and appear better and less toxic that the ones we have currently available. Most notably are inhibitors of the B-Raf signalling pathway (a growth signalling pathway in melanocytes and some other cell types).