The incidence of melanoma has risen over the past 30 years but most of this increase involves early melanomas which have less impact on mortality. This may explain why mortality has not changed in parallel with incidence as flat rates and even downturns have been observed in most Caucasian populations.

Early detection has led to a significant improvement in melanoma survival over the past 30 years. But the marked increase in the screening of pigmented lesions over the same period of time has led to the detection of very early melanoma as well as melanoma in situ which has inflated incidence data.¹ These very early borderline melanomas are likely to have a very different biology and many of these early lesions may not have progressed to invasive melanoma if left alone. Melanoma affects 15 to 20 per 100, 000 in the UK. So a GP may never see a case of melanoma in their career and consequently may have difficulty recognising them.

Melanoma has a variety of clinical presentations with different histological features. This is important to recognise as it may affect prognosis as well as management.²

The most common form is the superficial spreading  melanoma (SSM) which in its early stages will be a flat lesion often originating from a flat junctional naevus.³ SSM often has a horizontal growth phase at first followed by a vertical growth phase when atypical melanocytes spread into the dermis. Once SSM progresses it can develop raised areas which often imply a poorer prognosis.

In nodular melanoma, the lesion may present as a very small black nodule growing over weeks or months. These lesions have a vertical growth phase from the onset and are usually more aggressive.²

Lentigo maligna are melanoma seen in older subjects on chronically sun-exposed sites, usually the face. They often originate from a longstanding pre-existing lentigo which slowly becomes darker and larger. There are two forms of lentigo maligna:

• those without invasion in the dermis which have an excellent prognosis

• those with invasion of atypical melanocytes spreading in the dermis. These lesions are regarded as more dangerous and require more aggressive treatment.

Melanoma can also appear on the palms and soles or under the nail and on those sites may present as a vascular non-pigmented lesion which may cause diagnostic problems. These lesions are often diagnosed very late and have a poorer prognosis.

Melanoma is extremely rare in non-Caucasians and, when it does occur, affects the non- pigmented palms and soles but not the pigmented part of the skin.

Women are more likely to develop melanoma on the legs while men are more likely to have melanoma on the trunk.⁴ It is extremely rare in children as melanoma risk increases with age. However, relative to other cancers, melanoma is the most common cancer between the ages of 20 and 35 in Caucasians but it should be remembered that the incidence of melanoma is still very low in that age group.⁵ Common cancers such as breast, and prostate, for example, are around ten times more common than melanoma.

High-risk groups

Subjects with fair skin and hair are at increased risk of melanoma but the magnitude of the risk is only two-fold.⁶ Excessive sun exposure, especially in childhood, may be a risk factor for melanoma but this is often not present in the history. The relationship between melanoma and UVR is very complex and not dose dependent.^{7, 8} The association between sunbeds and melanoma is controversial but sunbeds should be avoided below the age of 18 and in subjects at risk of skin cancer.

Atypical naevi

The most consistent risk factor for melanoma in Caucasians is the number of naevi, see table 1, attached, especially atypical naevi.^9,10 The atypical mole syndrome phenotype is defined as the presence of more than 100 naevi with two or more atypical naevi and/or naevi on unusual sites such as the breasts in women, buttocks, feet and scalp, see figure 1, attached.¹¹ The presence of more than 100 naevi with atypical naevi can increase the risk of melanoma by five- to ten-fold.

Atypical naevi are defined as lesions ≥5 mm in diameter with hazy borders and often irregular pigmentation, see figure 2, attached. These lesions, however, should be regarded as a marker of risk, and not as unstable precursor lesions, as most atypical naevi will never progress to melanoma. There is no need to offer prophylactic excision of atypical naevi as this does not affect long-term risk and is cosmetically unacceptable.

Family history

Family history is also crucial in determining melanoma risk. There is a two-fold increase in risk in subjects with a first-degree relative with melanoma but this risk may change significantly with age of onset and numbers of primaries.^{11, 12}

In the presence of the atypical mole syndrome phenotype and a positive family history, the risk is further increased and these patients should be followed up by a dermatologist. The risk of melanoma increases with the number of melanoma cases in the family and high-risk families should be referred to a cancer genetic clinic for counselling.¹³

There are however, different skin phenotypes associated with melanoma and some melanoma patients have no excess of naevi. These subjects are usually very fair with freckles and may have sun damage with solar lentigines and solar keratoses. This highlights the presence of different at-risk phenotypes in melanoma.^{12, 14}

A family history of other cancers is also important as melanoma can be found in the context of family cancer syndromes. The most common tumours which may cluster in melanoma families are pancreatic cancer, brain tumours and breast cancer, but all types of cancers may be found in melanoma-prone families.⁴ Rare family cancer syndromes such as retinoblastoma and neurofibromatosis also show an increased prevalence of melanoma.

Risk factors for lentigo maligna differ as genetic factors are not as important and chronic sun exposure is more relevant.

What causes melanoma?

As with all cancers, melanoma is likely to be caused by complex interactions between genes and the environment. Recent studies looking at genetic markers throughout the genome are identifying SNPs (single nucleotide polymorphisms) which are associated with melanoma.^15,16 Most of the genes involved in melanoma, so far, are important for pigmentation and naevi formation but are also genes associated with other cancers.

Examining patients with suspicious lesions

It is very important to take a thorough history first and ascertain if the lesion is new or has been there for a long time. Melanomas grow over weeks or months and the lesion will usually have changed in terms of size, shape and colour. Melanomas may grow from a pre-existing naevus but also from normal skin. It is important to determine if naevi have previously been removed and also if relatives are known to have moles.

Family history of melanoma and other cancers should be documented. Skin type can be determined by asking about propensity to burn and ability to tan. This is known as the Fitzpatrick classification and subjects of skin type 1 and 2 (fair) are more prone to melanoma, see table 2, attached.

Once the lesion is clinically examined, there are many features which differentiate a melanoma from a benign naevus.

• Melanoma borders are more likely to be geographical for SSM

• The pigment distribution in the melanoma is often irregular and asymmetrical, see figure 3, attached.²

• Melanomas are usually ≥5 mm but there are obviously exceptions especially for small early nodular melanoma

• There are usually different shades present in a melanoma including brown, black and red with, in some cases, grey and blue

• Early melanoma may have a recent change in pigmentation in one part of the lesion, see figure 4, attached.

Naevi appear in childhood and early adulthood with a plateau in middle age when they start to disappear.¹⁷ This is useful to know as any new mole in a subject above the age of 40 should be regarded by GPs as suspicious unless the patient belongs to a high-risk family with large number of naevi (in high-risk subjects the disappearance of naevi is often delayed).

Lentigo maligna usually presents on the face and has generally been there for many years. The lesion slowly darkens and spreads over time.² It is usually flat but in more advanced cases may have raised areas.

Melanoma of the extremities may be difficult to diagnose especially if the lesions are not pigmented. They may present in the toe webs, under the nails, on the palms or soles.

Dermoscopy

Most clinicians dealing with pigmented lesions acquire training in dermoscopy. The procedure enables the lesion to be examined with high magnification and bright lighting. This reveals the pigment pattern. Characteristic pigment networks can be identified for various lesions. Dermoscopy is especially useful in differentiating seborrhoeic keratoses, see figure 5, below, from naevi but also helpful for diagnosing haemangiomas, see figure 6, attached.

Seborrhoeic keratoses are often a diagnostic challenge for GPs. These lesions usually appear stuck on top of the skin and have a crumbly or greasy surface. The colour also differs, they are usually a dirty brown colour with shades of grey and yellow, see figure 5, attached. However, some seborrhoeic keratoses may be very darkly pigmented and difficult to recognise.

Confirming diagnosis

The diagnosis of melanoma can only be confirmed with a full excision biopsy of the lesion with a narrow margin with histology. This will allow the pathologist to perform a full pathological assessment of the lesion and determine histological subtype and Breslow thickness. Breslow thickness is measured from the top of the epidermis to the last malignant melanocytes in the dermis. This is the most reliable prognostic marker for melanoma.

Melanomas >2 mm thick have a poor prognosis and most melanomas are now picked up below 1 mm in thickness with a much better outcome.¹⁹ In rare instances, punch biopsies are permitted for large suspected melanomas such as lentigo maligna on the face where there is a need to confirm the diagnosis. The other exception for diagnostic punch biopsy may be large melanomas of the extremities where the removal of the lesion is not possible without major surgery.

Referral

All suspicious pigmented lesions should be referred to secondary care via the two-week wait pathway and this is now part of the NICE guidance for the diagnosis and management of melanoma.¹⁹ This will allow rapid access to a dermatologist or plastic surgeon. Some GPs with a special interest may deal with skin cancers but need the right level of accreditation.20 GPs should avoid excising suspected melanomas as these should be removed by experienced specialists.¹⁹

Non-pigmented lesions should also be regarded as suspicious if they are quite vascular and grow over months as these may represent an amelanotic melanoma. Subjects with many junctional and atypical naevi (well above 100) should also be referred to a dermatologist (using the non-urgent pathway) especially if they have a family history of melanoma and/or an excess of cancers in the family.

Treatment

In all cases the melanoma should be fully excised and in most instances this will involve a simple excision with a clear margin of 1 and 2 cm depending on the Breslow thickness. Most patients will not need any further treatment and will be followed up to check for possible recurrence and also for a possible second primary melanoma.

More than 80% of melanoma patients have surgery alone and survive their disease with no other treatments. Some patients may be offered a sentinel node biopsy to assess whether the draining lymph node is positive. This will often, but not always, lead to a complete clearance of the lymph basin if a positive lymph node is identified depending on the type of spread in the sentinel node. However, sentinel node biopsy is regarded as a staging procedure mainly as it has not been shown to provide any significant survival advantage^{.21, 22} In cases of clinical palpable lymph nodes, complete clearance of the nodes will be needed.

Unfortunately, there is no adjuvant therapy in melanoma which offers a survival advantage and most adjuvant treatments are assessed in the research setting.²³ In the palliative setting, there are many chemotherapy regimens which can reduce the bulk of the disease but do not appear to prolong long-term survival.

Follow up needs to include a full body skin examination. Women tend to survive melanoma better than men after adjusting for all possible confounders.²⁴

There is some hope that therapy which targets melanoma genetic pathways such as BRAF/RAS and c-Kit for example will lead to adjuvant treatments with a long-term survival advantage.^25,26 This type of targeted therapy, which depends on the genetic profile of the tumour, is the way forward for melanoma treatments in the future.