Melanocytic lesions and moles: management in primary care

Melanomas are cancers which arise from naevi or within normal looking skin. They are becoming increasingly common and urgent excision is the best hope of cure for affected patients. Although melanoma is more common than in the past, many GPs will see relatively few in their working life, so that diagnosis may be challenging. Moreover, moles do change through life (slowly) and a key guide to diagnosis in primary care is to make oneself familiar with how common naevi evolve and therefore to be able to recognise when something is different.

Melanocytic lesions may be broadly classified as congenital or acquired according to their time of onset. Melanocytes originate from neural crest cells; they subsequently proliferate and migrate to the skin, central nervous system, eyes and the ears during embryogenesis.

When these melanocytes proliferate excessively, hamartomatous growths known as congenital melanocytic naevi (CMN) result. This can happen in all of these body sites. Common melanocytic naevi (moles) are acquired naevi. These start to appear in the first year of life and may continue to develop up to the age of 40 years. New melanocytic lesions (ML) developing after the age of 40 are less common and should therefore be treated with some caution.

High risk factors for melanocytic lesions

The assessment of risk factors predisposing patients to melanoma is important in the complete evaluation of a ML. Even relatively banal appearing naevi with subtle atypia or a history of change should be treated with caution in high-risk patients. Melanomagenesis may be contributed to by external or genetic factors.

External factors in melanomagenesis

Environmental factors such as signicant sun exposure and sunbed usage causes ultra violet radiation related melanocyte DNA damage which is a well known precursor for melanoma. The most robust measure of this damage is a history of sunburn. Other external causative factors include immunosuppression, due to underlying medical conditions such as lymphoma or HIV/AIDS or secondary to drugs such as tumour necrosis alpha inhibitors.^1,2

Genetic factors in melanomagenesis

Most melanomas (90%) are sporadically inherited, i.e. indicating damage to a gene after the patient is born – therefore conferring no risk to their offspring. Melanoma itself is not inherited; however the risk of developing melanoma is passed on from one generation to the next, i.e. familial melanoma (FM).1 Melanoma results from genetic changes in melanocytic cells in the skin in response to sunburn, and people with familial inherited red hair, freckles, fair skin with a tendency to burn and multiple moles are considered to be at an increased risk of melanoma. Some specic gene mutations in CDK4 and CDKN2A are associated with increased melanomagenesis. Genetic testing may be considered for patients with in excess of 50 atypical moles and a family history of two or more rst degree relatives with melanoma or pancreatic cancer, as they carry a higher risk for FM. These patients are often referred to as having familial atypical multiple melanoma mole syndrome (FAMMM), or atypical naevus syndrome.

Mole development

Normal moles arise early in life and the cells undergo a relatively ordered phase of proliferation, then they age and the naevus matures. During this process they change from !at brown lesions to dome shaped lesions or they may simply fade away over time. They are usually less than 5mm in diameter. As the proliferation is ordered the naevi are symmetrical and evenly coloured (even blue naevi). In cases where the proliferation carries on for a longer period, the naevi are larger, and as the proliferation is more disordered then the naevus will be irregular in shape. The host may respond to that proliferation, so the mole may become pinker. This is then termed an atypical naevus.
Atypical naevi are more likely to change into a melanoma and should be treated with caution. When melanocyte proliferation becomes severely disorderly an irregularpigment network and shape is visible, suggestive of the development of melanoma.

Commonly presenting benign melanocytic lesions

Banal melanocytic naevus

These are usually pale brown to dark brown dependent on the Fitzpatrick skin type, symmetrical with a regular outline and usually found scattered over the body. They may be multiple and usually remain dormant. They may be macules, papules or nodules.

Lentigo/lentigines

Lentigines are usually small, pigmented macular or papular lesions with well defined margins occurring anywhere on the body. They are identified pathologically by an increase in normal appearing melanocytes in the epidermis. The basal layer of the epidermis also shows keratinocytes replaced by melanocytes. There are differing types of lentigenes:

Lentigo simplex: This is a uniformly pigmented, small macule usually present since childhood or birth which may have a dry scaly surface. These lesions may not result directly from sun exposure and are benign.
Solar lentigo: Solar lentigines occur on sun-damaged sites and present as uniformly pigmented macules or patches. They are commonly referred to as age or liver spots and present commonly with darkening of pigmentation after sunny holidays (Figure 2a).

Ink spot lentigo: As the name suggests these are darkly pigmented (often black) pigmented macules, appearing as an ink splash on the skin on a background of sun damaged skin, often on the shoulders after sunburn. They occur commonly on pale Fitzpatrick type 1 skin.

Labial melanotic macules

These are benign brown macules often occurring on the lower lip although they may occur anywhere on the lip or the buccal mucosa.

Similar pigmented macules may be found on the penile shaft or glans in men and on the vulva in females and are termed penile and vulvar lentigo respectively. As the latter are less common such patients should be referred to the pigmented lesion clinic for review.

Syndrome associated lentigines

Some very rare genetic syndromes are characterised by multiple lentigines, e.g. xeroderma pigmentosum, LEOPARD, myxoma syndromes (LAMB, Carney, NAME).

Dysplastic naevi

Moles usually greater than 5mm in diameter with variegated pigment and an irregular or diffuse edge are termed dysplastic naevi or atypical naevi. Dysplastic naevi often have a ‘fried egg’ appearance, with a pale papule in the centre and adjacent vairable pigment in a symmetrical distribution.

Spitz naevi

These are melanocytic naevi but are unusual, being usually pink coloured papules or nodules. They are most common in children. They are benign but are difficult to distinguish from melanomas clinically, so they cause concern especially when seen in older children or adults. As a result of this diagnostic uncertainty affected patients should be referred for review in the pigmented lesion clinic where they are commonly removed.

Blue naevi

Deep dermal pigmented lesions appear blue on the skin surface due to the Tyndall effect, i.e. the differential reection of different wavelengths of life by deep melanin in the skin. These are benign, and malignant transformation is very rare.

Naevus of Ota and Ito

Deep dermal proliferation of melanocytes from birth may result in blue-slate grey pigmented patches around the eye (Naevus of Ota) or on the shoulder or upper arm (Naevus of Ito). These are a form of birthmark and the pigment may become more apparent later on in life.

Other commonly presenting non-melanocytic pigmented lesions

Seborrheic keratosis (basal cell papiloma)

Seborrheic keratoses are benign pale to dark brown warty lesions, which commonly present when inamed and itchy. They appear as a ‘stuck on’ lesion and have a rough surface. They are not due to sebum production as the name suggests, but in fact are an overproduction of keratin on ageing skin. The exact etiology has not yet been elucidated. These lesions are universal over the age of 50 but may occur much earlier in life. They do cause diagnostic concern when pigmented and indeed melanomas may rarely simulate pigmented, seborrheic keratoses.

Dermatogibromas

These are commonly occurring benign !brous lesions and mostly present as small nodules on the extremities. They are usually skin coloured with a characteristic ‘pellet under the skin’ like consistency on palpation, although they may become pigmented or inamed over time. Dermato!bromas are histiocytic lesions, which may occur at sites of trauma.

Managing pigmented lesions in primary care When presented with a pigmented lesion (PL) the most important question is: ‘Is this benign or malignant?’ Unfortunately the answer may not always be straightforward as malignant lesions (MLs) may vary in their presentation. A number of direct questions may help in the assessment, enabling the astute GP to discern suspicious lesions from banal and to appropriately streamline referrals to secondary care. These questions include:

• How long has the lesion been present? Congenital melanocytic naevi (CMN) are present from birth. However, most moles are acquired de novo in childhood or early adult life, therefore new moles occurring later in life (i.e. above the age of 40) should be treated with caution.
• Has it changed recently? Melanocytic lesions may change gradually over years in tandem with the patient’s growth. If a ML changes rapidly – that is, over a few weeks or months without any other contributing factors – this should raise concern.
• Has there been any change in size? If a ML grows two or more times its original size over a period of few weeks or months, this may be a sign of abnormal melanocyte proliferation and should raise alarm.
• Has the shape changed? Melanocyte proliferation in malignant melanoma occurs in a disorderly manner, which may present clinically as an irregularly shaped mole and is often asymmetrical.
• Has the colour of the mole changed? Both atypical or dysplastic naevi may have different shades of colour ranging from red to brown-black and are usually less than 5mm in size. When moles change in colour over a short period of time and display areas of noticeable dark brown or black pigment, which is out of keeping with the patient’s other moles, this may signify malignant change. The loss of pigment within a mole – so-called ‘pigment regression’ – may also be a concerning feature (see Figure 6), although this should be distinguished from the slow steady uniform loss of pigment which occurs as benign naevi ‘mature’ or dermalise over time. Partial regression of a mole may be a feature of primary malignant melanoma and results from the body’s immune response to invasive melanoma cells in the vertical growth phase. Complete regression of melanoma is a rare though recognised phenomenon. The differentiation of loss of pigment in benign dermalising moles from regression of pigment is demonstrated in Figure 6.
• Has the mole been itching or bleeding? Moles may bleed for various reasons, such as external trauma, or itch if inflammation occurs around a hair arising within the mole. This is particularly so if the naevus is on a site where it might be irritated, such as the hairline and scalp (from brushing hair), the neck and wrists (from jewellery, collar or cuffs) or the torso, waistband or groin (from brassieres or underpants). When moles itch or bleed spontaneously with no apparent external causative factors and have changed in appearance, they warrant further evaluation.

When clinically evaluating a mole, the ABCDE mnemonic (see below) may be useful in highlighting ‘red flags’.

 

 

Most melanomas will display one or more of the above features of change. If one or more high risk factors are present in association with concerning findings on examination, then an urgent referral to secondary care should be considered.

Groups at risk

It is worth noting that melanomas are more common in fair skinned individuals, particularly in those of Celtic descent. Melanoma is rare in Asian and Afro- Caribbean skin, although acral lentiginous melanoma (palm and sole and nail melanoma) occurs in all ethnic groups. After the completion of a tailored history the ML in question should be examined. A thorough clinical examination includes inspection and palpation in most cases. A total cutaneous examination (TCE: patient undressed down to their underclothes) is gold standard for the evaluation of moles, especially with one or more of the above risk factors. Atypical moles in particular warrant a TCE to evaluate their abundance and range of atypia. This may facilitate the timely detection of melanoma. While it is not always necessary to perform a TCE, especially if the presenting ML appears banal, thorough examination is advisable if the patient has multiple moles (see Figure 7) or has an atypical mole with a previous history of melanoma.

Melanoma

Malignant melanoma (MM) has been identified as the fifth most common cancer in the UK, accounting in 2010 for 4% of all new cases. 4 Among the 12,818 new cases of malignant melanoma that were detected in the UK in 2010, 48% were male and 52% were female giving a male: female ratio of 10:11. The European age standardised melanoma incidence rates are higher in Wales in comparison to England, Scotland and Northern Ireland in males. 4 An average of 27% of new MM cases were diagnosed between 2008 and 2010 in patients

 

• Superficial spreading melanoma (SSM). This is the commonest subtype, accounting for almost 70% of all cutaneous melanomas. It usually displays a radial growth phase, characterised by a horizontal growth pattern, predominantly within the epidermis. This subtype carries less invasive potential in comparison to vertical growth pattern. Both patterns however are possible in SSM, and this subtype typically exhibits change in shape, size and colour.
• Nodular melanoma (NM). This subtype occurs in 15-30% of patients and exhibits a vertical growth phase, hence possessing higher metastatic potential. These are less likely to display typical appearances of changing size, shape and colour, and may commonly be misdiagnosed as pyogenic granuloma, basal cell carcinoma, or even angiomas.
• Acral lentiginous melanoma (ALM). This is a rare form of melanoma accounting for 2-8% of MM cases. These melanomas occur on the palms, soles or under the nail plate (subungual variant, characterised by Hutchison’s sign, where pigment spill is noted across the proximal or lateral nail fold and may be associated with nail dystrophy). Although rare, this form is the most common form of MM in dark skinned individuals. Figure 10 shows a benign acral lentiginous naevus.
• Lentigo maligna melanoma (LMM). This occurs typically on the head, neck and arms in over 65 year olds with chronically sun damaged skin. The in situ precursor lesion is usually large (>1- 3cm) and is termed lentigo maligna. LMM may vary in colour from light brown or red to black. Histopathologically, the atypical melanocytes track down adnexal structures, i.e. hair follicles, and background solar elastosis is invariably notable.
• Amelanotic melanoma (AM). This variant is extremely rare and constitutes less than 5% of all melanomas. AM usually presents as pink to flesh coloured nodules, mimicking basal cell carcinoma, squamous cell carcinoma or even a dermatofibroma; however the history of rapid evolution or change would suggest AM. The melanocytes in AM are poorly differentiated and lack the ability to synthesise melanin, thus leading to its amelanotic appearance.
• Desmoplastic melanoma (DM). This is another rare variant, which clinically resembles non-melanoma skin cancer and presents as a firm flesh coloured nodule, or in association with a patch of lentigo maligna, typically in older patients. DM lesions exhibit greater risk of local recurrence and perineural invasion and are therefore treated more aggressively.

Dermoscopy

The use of a dermatoscope is a helpful tool in the identification of melanin and its pattern of distribution and therefore in the early detection of melanoma. ⁵ Special training in the use of a dermoscope is required and beginners may have a higher false positive referral rate. Developing experience with its use, however, may convert this into an invaluable tool in the differentiation of benign from malignant lesions and identification of melanoma. It is an essential tool for the dermatologist.

Referral pathways

Once confronted with an atypical PL or a suspicious PL the next step for the GP is to refer to a local dermatology service for specialist evaluation. The route of referral depends largely on the degree of suspicion regarding the PL in question. For a ML with definite suspicion of melanoma a two week cancer referral should be made to a local dermatology service. Differing systems are in place to facilitate urgent review of PL, which is region specific; however, most dermatology services have specific cancer waiting target forms, which require completion. Once a suspicious ML is referred via the fast track cancer target pathway, the patient should receive an appointment to see a dermatologist within two weeks of their referral.

If the lesion is deemed suspicious for melanoma then their initial treatment – a diagnostic excision biopsy with 2mm margins – is usually performed by a dermatologist within 31 days of the confirmatory diagnosis being made, and completion of treatment should be achieved within 62 days of confirmed diagnosis. If the excision biopsy is confirmatory of a melanoma then staging is done within a specialist skin cancer multidisciplinary team, involving dermatologists, dermatopathologists, specialist skin cancer nurses, plastic surgeons, medical oncologists and radiologists, where further management of the melanoma is planned.

This usually involves further wide local excision of the melanoma scar site and if indicated further sentinel lymph node biopsy and scans, depending on the stage at presentation. If there is uncertainty about the exact aetiology of a ML, further referral to secondary care may be discussed with a local dermatologist or melanoma expert. The duration of waiting times for such referrals is variable from weeks to months, and it is worthwhile enquiring about these and informing patients in turn. For patients with less concerning moles, where a degree of uncertainty regarding diagnosis exists, routine referrals may be considered. Most regional centres run specialist pigmented lesion clinics at least once a week for evaluation of PL, and timings and referral methods can clarified by liaising with the local skin cancer lead for melanoma or the skin cancer multidisciplinary team coordinator.

Treatment of melanoma

The treatment of a melanoma is largely dependent on the stage at presentation. The revised UK guidelines for the management of cutaneous melanoma uses the American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma and outlines stage specific treatment. ⁶ Novel mutations in cutaneous melanoma have been found – namely BRAF, NRAS and KIT – and new drugs targeting these mutations have revolutionised the treatment of metastatic melanoma. Melanomas arising on intermittently sun damaged skin tend to be associated with BRAF mutations, with melanomas arising on chronically sun damaged skin exhibiting NRAS mutations and non sun exposed skin, such as acral and mucosal sites, more frequently exhibiting the KIT mutation. ⁷

It has become routine practice across many centres in the UK to test for the BRAF-V600E mutation in cases of metastatic melanoma, i.e. stage IV disease. If the mutation is found, a BRAF inhibiting drug such as vemurafenib may be given after patient counselling. vemurafenib has been shown to increase tumour progression free survival (PFS) by 5.3 months and overall survival by 6 months. A trial comparing vemurafenib with dacarbazine demonstrated 84% survival in the vemurafenib group in comparison to 64% in the dacarbazine group at 6 months. ⁸ Research is ongoing in the management of melanoma, and targeted therapies and vaccines are undergoing evaluation.

Summary

Since no definitive screening programme exists in the UK for melanoma skin cancer, it is vitally important to detect atypical ML early and appropriately refer these to the local skin cancer multidisciplinary team where both effective and timely management of these lesions can be performed. Having a simple yet effective method for the evaluation of ML, which can be easily reproducible, is essential to early melanoma detection. Most patients can be taught how to self examine their skin for change in their moles with the ABCDE technique.

High-risk patients should be advised to do this on a monthly basis. For sites such as the back, which are difficult to visualise, a partner, friend or family member may be recruited for regular assessment. Early detection of melanoma and minimising risky behavioural patterns may be lifesaving and therefore should be the focus point for all those involved in evaluating a ML. For further information on the evaluation of melanocytic and other skin lesions the GP skin cancer referral toolkit is an invaluable resource and available at www.doctors.net.uk. ⁹

Further information on mole assessment (clinical and dermoscopic) and melanoma can be found at www.genomel.org.

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Dr Sweta Raithe

Professor Julia Newton-Bishop

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References

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2 Kouklakis G, Efremidou EI, Pitiakoudis M et al; Drug Des DevelTher. 2013;7:195-9. doi:10.2147/DDDT.S41889. Epub 2013 Mar 27.
3 Bishop JN, Harland M, Randerson-Moor J, Bishop DT. Lancet Oncol. 2007 Jan;8(1):46-54.

4 www.Cancerresearchuk.org/cancer-info/uk-skin-cancer-incidencestatistics

5 M.E. Vestergaard, P. Macaskill, P.E. Holt et al; Dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting; DOI: 10.1111/j.1365-2133.2008.08713.

6 Puntervoll HE, Yang XR, Vetti HH et al. J Med Genet . 2013 Apr;50(4):264-70. doi: 10.1136/jmedgenet-2012-101455. Epub 2013 Feb 5

7 Maldonado JL, Fridlyand J, Patel H, et al. J Natl Cancer Inst. Dec 17 2003;95(24):1878-90

8 Chapman PB, Hauschild A, Robert C, et al. N Engl J Med . Jun 30 2011;364(26):2507-16.

9 http://www.doctors.net.uk/client/cruk/cruk_skin_toolkit_b09/