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.
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.
The lesion on the right is a superficial spreading melanoma. The one on the left looks as though it may have started this way (see the darker brown area on the right) but now is clearly in a nodular growth phase. In both exampoles note the variability in pigmentation.
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:
- the rate of MM in Australia is around 5 times higher than in the UK 
- those with red hair and pale skin have MM rates 3 times higher than those with dark hair and
- the earlier you move to a climate with high ambient UVR the higher your risk of 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 ).
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)
- Around 10% of MM occur on the palms or soles and the absolute incidence of MM at these (acral) sites is the same in all world populations—whatever the colour of their skin or sun exposure. Given that palmoplantar skin is sun resistant because of the very thick epidermis (particularly the stratum corneum)  it is safe to assume that MM at these particular sites is not UVR related. In fact we are ignorant of any cause for this subgroup of cancers.
- Up to 10% of MM occur in those with a family history of MM. With a tumour that effects around 1% of the population during their life time this clustering will occur due to chance. However in some families MM almost seems to be inherited in an autosomal dominant manner. In some of these kindreds the affected individuals have a larger number of nevi (often several hundred) and these nevi look atypical. Clinical clues therefore are a large number of nevi and the presence of three or more family members with MM. In some of these kindreds the underlying genes have been identified but at present genetic testing is not recommended. 
- Psoralen and UVA (PUVA) therapy: As for SCC there is some evidence that those who have received lots of PUVA are at increased risk of MM. The evidence is far less convincing than for SCC but that a carcinogen like PUVA increases MM rates seems quite plausible .
- Immunosuppression: Evidence here is far less persuasive than for NMSC but there appears some increased risk.
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.
The lesion on the left is a lentigo maligna melanoma. It classically occurs on the face or chronically sun-exposed site, and may develop and change over decades from an insitu lesion or a pigmented precursor. The melanoma on the right is a nodular melanoma that appeared over weeks. Note the small cutaneous metastases towards the left of the picture (righthand image).
The main subtypes of MM we need to consider are as follows:
- Superficial spreading melanoma (SSM). These are flat or almost flat lesions in which
the malignant clones of cells appears to have spread laterally from a central point. They resemble normal flat melanocytic nevi or may even be confused with freckles or lentigines .
- Nodular melanoma. As the name implies these are nodules. Such nodules are inevitably a reflection of a large downward (vertical) collection of malignant cells. It is of course possible to imagine that the nodule represents a later stage of the SSM in which the cells have acquired the propensity to migrate deeper in the skin. They may be confused with normal melanocytic nevi or angiomas .
- Lentigo MM. This refers to MM on continually sun exposed skin most usually the face. They usually present as lesions that develop over many years that show a slow increase in area and gradual darkening in colour. They may be confused with solar lentigines or seborrhoeic keratoses .
- Amelanotic melanoma. Some MM (perhaps ~10%) present as largely amelanotic lesions. In reality such lesions usually contain some melanin but their differential diagnosis is wide.
- Acral MM. These occur on the palms or soles. They occur at the same absolute rate in all populations studies. We have little idea of pathogenesis but UVR for obvious reasons cited above is not thought to play a role. Clinically they usually present as flat pigmented lesions that are confused with normal melanocytic nevi.
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 . 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.
The lentigo maligna melanoma on the left developed in a pigmented macule that had been present for several years and had been treated by a GP with a ‘laser’. Note the darker area which showed a Breslow thickness of 1mm. The image of the right is an amelanotic melanoma. It is a marginally elevated plaque that has lost most, but not all of its pigment, and is easily confused with a superficial BCC or even an area of IEC. Nonetheless the correct diagnosis was made clinically.
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 . 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
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 .
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:
- Asymmetry of shape
- Border irregularity
- Colour variation and a
- Diameter greater than 1cm.
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 .
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?
- If it looks like any MM you have seen before, assume it is a MM and get expert advise. Do not biopsy the lesion—refer to somebody who sees more MM than you do.
- If you cannot diagnose a particular cutaneous lesion, ask yourself could this be a MM? It is missing this diagnosis that has the highest cost attached to clinical error.
- MM are by definition changing or evolving lesions. The problem is that so are lots of normal lesions. Nonetheless, a patient’s history of a change in any pigmented lesion should make you again ask, ‘could this be…..’ Remember that it is normal for pigmented nevi to appear for the first time in young people—advice that every new lesion should be seen by a doctor is impractical, but over the age of 30 the onset of new lesions that are apparently melanocytic nevi becomes rarer and rarer.
- Ugly duckling sign. Experienced skin watchers know that the melanocytic nevi of any one person are much more similar than nevi randomly selected from different people (in statistical parlance, the within person variance is small compared with the between-person variance). A practical corollary of this, called the ‘Ugly Duckling Sign’ is that you should be extra suspicious of ‘melanocytic nevi’ that look very different form the patient’s other nevi: an identical lesion might be viewed with different levels of suspicion in two different patients.
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 . 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 ) 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 . If the patient does have metastases the prognosis is poor as there is in practice no curative treatment for metastatic MM . 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).
- It is a useful shorthand to use Australia as an example of a high UVR location with a pale-skinned population. Of course Brisbane may be viewed as the skin cancer capital of the world, but there is less sun in Melbourne and of course a significant part of the population are Asian or darker skinned.
- MM rates of the tops of the ears are many times higher in men than women, presumably reflecting historical hair fashions. This sexual inequality might change in the future.
- Try burning you palms on a beach holiday, or if you are both patient and a gymnast stand on you hands for 8-10 hours each day. (I am not suggesting you really ….)
- Try burning you palms on a beach holiday, or if you are both patient and a gymnast stand on you hands for 8-10 hours each day. (I am not suggesting you really ….)
- Most human cancers cluster a little in families even without highly penetrant genes. Family members tend to share similar environments and of course tend to be more alike in pigmentation status.
- The increased rate of MM in PUVA patients is largely based on one study. However patients who have received lots of PUVA clinically have odd pigmentary phenotypes so an increase is plausible.
- We will deal with these various mimics of skin cancer in later chapters: freckles are focal areas of overproduction of melanin; lentigines are benign proliferations of melanocytes and angiomas abnormal collection of blood vessels. Melanocytic nevi are ‘moles’.
- LMM increase just like SCC or AK as an exponential function of age, whereas the increase of other types of MM flattens out in later middle age.
- I am cutting corners in the interest of brevity. Palliative care may be very important but cure of advanced MM has not been demonstrated to be due to any therapeutic agent. As discussed later however, at the time of writing, the B-Raf inhibitors show some promise.
- These figures are approximate for a number of reasons including that age and sex influence tumour specific survival, and a number of additional prognostic factors are necessary to provide more precise estimates. MM is notorious for causing late metastasises. The ten year survival is noticeably worse than the five year survival.
- Seborrhoeic keratoses are benign epidermal tumours that are often highly pigmented. They are discussed in the next chapter but their importance is that they are ubiquitous in adulthood and often fulfil the ABCD criteria for melanoma.
- In general treatment of MM has become more and more sensible—or conservative if you are a gung-ho surgeon. Excisions with margins of 1-2cm are the norm, depending on the Breslow thickness and other factors. Students do not need to follow the details here.
- A pyogenic granuloma is an abnormal collection of vessels often thought to represent an abnormal wounding response (dealt with in the next chapter)
- In addition to the Breslow thickness a procedure called the sentinel lymph node biopsy (SNLB) is used by some to further define prognosis.The rationale of this investigation which involves sampling what is thought to be the draining lymph node of a tumour is to see if there is tumour spread to this lymph node. If there is, the lymph nodes are removed. This procedure is quite contentious and discussion of its merit beyond the remit of this book. Suffice to say that there is no evidence that such approaches improve life expectancy.
- Are MM more common than SCC?
- Are melanocytic nevi precursors of MM?
- What is an acral melanoma?
- What type of MM shows a similar age incidence pattern to AK or SCC
- What are the problems with the ABCD(E) system of MM diagnosis
- What does the ugly duckling sign mean?
- Should all new onset pigmented lesions be seen by a doctor?
- Does HPV cause melanoma?
- Where do you find most SCC?
- Is intermittent UVR exposure relevant to relevant to BCC as well as MM?
- Is cryotherapy a suitable treatment for superficial spreading melanomas?
- Define Breslow thickness
(answers are found at the end of the book)