See also the separate Malignant Melanoma article.
Normal melanocytes are found in the basal layer of the epidermis. Melanocytes are found in equal numbers in black and in white skin; however, the melanocytes in black skin produce much more melanin. People with dark brown or black skin are very much less likely to be damaged by ultraviolet (UV) radiation than those with white skin. Non-cancerous growth of melanocytes results in moles (benign melanocytic naevi) and freckles (ephelides and lentigines).
Most skin melanomas spread out within the epidermis. If all the melanoma cells are confined to the epidermis then the lesion is a melanoma in situ, which can be cured by excision because it has no potential to spread around the body. When the cancer has grown through the dermis it is known as invasive melanoma. Four clinical types of skin melanoma exist:
- Lentigo maligna melanoma: a patch of lentigo maligna develops a papule or nodule, signalling invasive tumour.
- Superficial melanoma: a large flat irregularly pigmented lesion which grows laterally before vertical invasion develops.
- Nodular melanoma: the most aggressive type. It presents as a rapidly growing pigmented nodule which bleeds or ulcerates. Rarely, they are amelanotic (non-pigmented) and can mimic pyogenic granuloma.
- Acral lentiginous malignant melanoma: arises as pigmented lesions on the palm, sole or under the nail and it usually presents late.
Once the melanoma cells have reached the dermis, they may spread to other tissues via the lymphatic system to the local lymph nodes or, via the bloodstream, to other organs. Metastases can occur virtually anywhere and at any time after a diagnosis of melanoma. Common sites for metastases are lymph nodes, liver, lung, bone and brain. In-transit metastases are deposits from a focus of cells moving along regional lymphatic channels.
- Malignant melanoma is more common in women than in men. In 2011 it was the fifth most common cancer in females and in males.
- Malignant melanoma is much less common than non-melanoma skin cancers (eg, basal cell carcinoma, squamous cell carcinoma of skin).
- In 2011, the UK age-standardised incidence of melanoma for females was 17.6 (11.7 in 2001) and for males 17.5 (10.1 in 2001) per 100,000 population.
- It has been estimated that the lifetime risk of developing malignant melanoma in 2010 was 1 in 55 for men and 1 in 56 for women in the UK.
- The distribution of melanomas diagnosed between 2008 and 2010 was:
- Males: head and neck 22%, trunk 41%, arm 19%, leg 13%.
- Females: head and neck 14%, trunk 20%, arm 24%, leg 39%.
- The incidence of melanoma has risen over a period of 30 years in most white populations.
- Malignant melanoma is rare in children. The incidence of melanoma increases with age, both in men and in women.
- Superficial spreading melanoma (SSM) is the most common subtype.
BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signalling pathway. It is encoded on chromosome 7q34. About 50% of melanomas have activating BRAF mutations. BRAF V600 has been implicated in different mechanisms underlying the development of melanomas.
The reported incidence has been inflated by early lesions that have little potential to spread and have a low impact on mortality. Early melanomas are increasingly being excised and mortality data suggest that many borderline lesions may never progress if not removed.
- Previous personal primary invasive melanoma.Between 3% and 5% of all patients with malignant melanoma will develop a further lesion or a different type of skin cancer.
- Naevi are the most powerful predictor of risk of melanoma. An individual with more than 100 common naevi or more than two atypical naevi has a 5- to 20-fold increased risk of melanoma.
- Two twin studies suggest that naevi are under considerable genetic control, with a 60% concordance in numbers of naevi in identical twins.
- In younger individuals, atypical naevi on the trunk and limbs are more predictive of superficial melanoma than of nodular melanoma or lentigo maligna melanoma, which affect older individuals with more sun damage and fewer naevi.
- The presence of multiple common naevi and atypical naevi denotes the phenotype for atypical mole syndrome, which may indicate a genetic susceptibility to melanoma (this phenotype is found in about 2% of a healthy population in the UK). Atypical mole syndrome includes:
- More than 100 common naevi (2 mm in diameter).
- More than two atypical naevi (5 mm in diameter).
- Naevi on unusual sites, such as breasts in females, buttocks, scalp, ears, dorsum of feet, hands and irises.
- Sun exposure:
- Sun exposure has long been suspected to be a risk factor; however, a meta-analysis of melanoma case-control studies found:
- Low relative risks associated with various measures of exposure to UV radiation and the relation with sunshine was not dose-dependent.
- Sharp, short bursts of acute exposure in childhood, and severe sunburn, were most strongly associated with melanoma.
- Occupation and leisure - eg, airline crew, gardeners, cricketers and those involved in other outdoor pursuits.However, cumulative moderate occupational exposure seems to be protective in some white populations.
- Host response to UV radiation appears to be more important than dose of sun exposure.
- Past sunbed use, especially before age 30.
- Sun exposure has long been suspected to be a risk factor; however, a meta-analysis of melanoma case-control studies found:
- Skin pigmentation:
- Pale Caucasian skin (skin type 1 or 2): having fair skin with a poor ability to tan, or a freckled complexion with or without red or blond hair, doubles a person's risk of melanoma.
- The risk of a black person developing a malignant melanoma is 20 times less and the risk for Hispanic people is 6 times less than white people.
- Non-white people more often present with lentiginous and nodular melanoma on the palms and soles and rarely on other parts of the body.
- Family history of melanoma and genetic factors:
- People with a first-degree relative with melanoma are at increased risk of developing melanoma.
- 5-10% of individuals with melanoma have a family history of melanoma. About a quarter of all families with melanoma have been linked to mutations in the tumour suppressor gene CDKN2A/p16 on chromosome 9p21.
- Patients with numerous atypical lesions and a personal or family history of malignant melanoma are at increased risk. They tend to develop the disease earlier than others and also have a greater risk of multiple lesions.
- In some families with melanoma, susceptibility to some other cancers, such as pancreas, brain and breast, is increased.
- Solar keratoses carry a relative risk for melanoma of 2 to 4.
- Past pesticide exposure.
- Higher socio-economic group.
Presentation and differential diagnosis
See the separate Black and Brown Skin Lesions article. The National Institute for Health and Care Excellence (NICE) recommends using the weighted 7-point checklist for assessing pigmented skin lesions. An alternative aide-mémoire to the 7-point checklist described below is the 'ABCDE' list:
- Border irregular.
- Colour irregular.
- Diameter greater than 7 mm.
Refer people - using a suspected cancer pathway referral (for an appointment within two weeks) - for melanoma if they have a suspicious pigmented skin lesion with a weighted 7-point checklist score of three or more:
Weighted 7-point checklist:
- Major features of the lesions (scoring two points each):
- Change in size.
- Irregular shape.
- Irregular colour.
- Minor features of the lesions (scoring one point each):
- Largest diameter 7 mm or more.
- Change in sensation.
Refer people - using a suspected cancer pathway referral (for an appointment within two weeks) - if dermoscopy suggests melanoma of the skin.
Consider a suspected cancer pathway referral (for an appointment within two weeks) for melanoma in people with a pigmented or non-pigmented skin lesion that suggests nodular melanoma.
Lesions which are suspicious for melanoma should not be removed in primary care.
Investigation is primarily by visual inspection and removal for histology where necessary. Diagnosis should be based on a full-thickness excisional biopsy.
All pigmented skin lesions that are either referred for assessment or identified during follow-up in secondary or tertiary care should be assessed using dermoscopy. For clinically atypical melanocytic lesions that do not need excision at first presentation in secondary or tertiary care, baseline photography should be used with review after three months.
Genetic testing of stage IIC primary melanoma or the nodal deposits or in-transit metastases should be considered for people with stage III melanoma.
All pigmented lesions that are not viewed as suspicious of melanoma but are excised should have a lateral excision margin of 2 mm of clinically normal skin and cut to include subcutaneous fat. All excised lesions should be sent for histology.
- The dermatoscope can be used to examine skin lesions and may make distinguishing benign from malignant pigmented lesions more accurate.
- Sentinel lymph node biopsy (SLNB), identifying and removing the lymph node(s) immediately draining the area of the primary tumour for histological analysis, provides prognostic information. An SLNB for pathological staging is particularly important for primary tumours greater than, or equal to, 1 mm in depth.
- Further investigations include CXR and liver ultrasound, or CT scan of the chest, abdomen and pelvis.
- Blood tests include FBC, LFTs and lactate dehydrogenase (LDH).
- However, CXRs and LDH lack significant impact on early detection of metastases and survival.They should therefore not be part of routine investigation and staging.
- Bone scans should only be performed if there is indication of bone disease.
Staging of primary melanoma is based on the histological features of the lesion. Accurate staging is vital to determine appropriate treatment, follow-up and calculation of risk of recurrence. The American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma was revised in 2009.
- TX: primary tumour cannot be assessed.
- T0: no evidence of primary tumour.
- Tis: tumour in situ.
- T1: thickness 1 mm or less; a: without ulceration and mitosis <1/mm2; b: with ulceration or mitoses 1/mm2 or larger.
- T2: thickness 1.01-2.00 mm; a: without ulceration; b: with ulceration.
- T3: thickness 2.01-4.00 mm; a: without ulceration; b: with ulceration.
- T4: thickness >4.00 mm; a: without ulceration; b: with ulceration.
- NX: regional lymph nodes cannot be assessed.
- N0: no nodal metastases.
- N1: one metastatic node; a: micrometastasis (diagnosed after SLNB); b: macrometastasis (clinically detectable nodal metastases confirmed pathologically).
- N2: 2-3 metastases; a: micrometastasis; b: macrometastasis; c: in-transit metastases/satellites without metastatic nodes.
- N3: more than four metastatic nodes, or matted nodes, or in-transit metastases/satellites with metastatic nodes.
- M0: no detectable evidence of distant metastases.
- M1a: distant skin, subcutaneous, or nodal metastases.
- M1b: lung metastases.
- M1c: all other visceral metastases; any distant metastasis with elevated serum LDH.
The AJCC stages based on 'Tumour, Node, Metastasis' (TNM) classification are:
- Stage 0 - Tis, N0, M0.
- Stage IA - T1a, N0, M0.
- Stage IB - T1b, N0, M0; T2a, N0, M0.
- Stage IIA - T2b, N0, M0; T3a, N0, M0.
- Stage IIB - T3b, N0, M0; T4a, N0, M0.
- Stage IIC - T4b, N0, M0.
- Stage III - any T, N 1-3, M0.
- Stage IIIA - pathological (p) T1-4a, N1a, M0; pT1-4a, N2a, M0.
- Stage IIIB - pT1-4b, N1a, M0; pT1-4b, N2a, M0; pT1-4a, N1b, M0; pT1-4a, N2b, M0; pT1-4a/b, N2c, M0.
- Stage IIIC - pT1-4b, N1b, M0; pT1-4b, N2b, M0; any T, N3, M0.
- Stage IV - any T, any N, M1a, M1b or M1c.
- Imaging or SLNB should not be offered to people who have stage IA melanoma or those who have stage IB melanoma with a Breslow thickness of 1 mm or less.
- SLNB should be considered as a staging rather than a therapeutic procedure for people with stage IB-IIC melanoma with a Breslow thickness of more than 1 mm.
- CT staging should be offered to people with stage IIC melanoma who have not had sentinel lymph node biopsy, and to people with stage III or suspected stage IV melanoma.
- The brain should be included as part of imaging for people with suspected stage IV melanoma.
- Whole-body MRI should be considered for children and young people (from birth to 24 years) with stage III or suspected stage IV melanoma.
Cancer networks should establish two levels of multidisciplinary teams: local hospital skin cancer multidisciplinary teams (LSMDTs) and specialist skin cancer multidisciplinary teams (SSMDTs). All patients with a suspicious pigmented skin lesion or a malignant melanoma, or where the diagnosis is uncertain, should be referred to a doctor trained in the specialist diagnosis of skin malignancy. Patients with a high risk of recurrence of their skin cancer or of new primary cancers should normally be followed up in hospital but should still be instructed in self-examination and provided with written and photographic information.
The primary treatment for malignant melanoma is wide local excision. Re-excision should be performed for proven melanomas if the margins are inadequate. Recommended surgical excision margins:
For some patients with advanced disease, management may consist entirely of supportive palliative care.
Vitamin D levels should be measured at diagnosis in all people with melanoma. People whose vitamin D levels are thought to be suboptimal should be given advice on vitamin D supplementation and monitoring.
Minimising or avoiding immunosuppressants should be considered for people with melanoma.
Managing stages 0-II melanoma
- Consider a clinical margin of at least 0.5 cm when excising stage 0 melanoma.
- Offer excision with a clinical margin of at least 1 cm to people with stage I.
- Offer excision with a clinical margin of at least 2 cm to people with stage II melanoma.
- Imiquimod for stage 0 melanoma:
- Topical imiquimod should be considered to treat stage 0 melanoma in adults if surgery to remove the entire lesion with a 0.5 cm clinical margin would lead to unacceptable disfigurement or morbidity.
- Consider a repeat skin biopsy for histopathological assessment after treatment with topical imiquimod for stage 0 melanoma, to check whether it has been effective.
Managing stage III melanoma
- Completion lymphadenectomy:
- Consider completion lymphadenectomy for people whose sentinel lymph node biopsy shows micro-metastases.
- Lymph node dissection:
- Therapeutic lymph node dissection should be offered to people with palpable stage IIIB-IIIC melanoma or nodal disease detected by imaging.
- Adjuvant radiotherapy:
- Adjuvant radiotherapy should not be offered to people with stage IIIA melanoma. It should also not be offered to people with stage IIIB or IIIC melanoma unless a reduction in the risk of local recurrence is estimated to outweigh the risk of significant adverse effects.
- Palliative treatment for in-transit metastases:
- If palliative treatment for in-transit metastases is needed, palliative surgery should be offered as a first option if surgery is feasible.
- If palliative surgery is not feasible for people with in-transit metastases, other options include systemic therapy, isolated limb infusion, isolated limb perfusion radiotherapy, electrochemotherapy, CO2 laser or a topical agent such as imiquimod.
- Palliative treatment for superficial skin metastases:
- Topical imiquimod should be considered to palliate superficial melanoma skin metastases.
- Electrochemotherapy may be considered as a palliative treatment for metastases in the skin from tumours of non-skin origin and melanoma.
Managing stage IV melanoma
Management of oligometastatic stage IV melanoma
Surgery or other ablative treatments (including stereotactic radiotherapy or radioembolisation) should be considered to prevent and control symptoms of oligometastatic stage IV melanoma in consultation with site-specific multidisciplinary teams (eg, for the brain or for bones).
Systemic anticancer treatment
Ipilimumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma in people who have received prior therapy.
Dacarbazine can be considered for people with stage IV metastatic melanoma if immunotherapy or targeted therapy are not suitable.
Further cytotoxic chemotherapy should not be offered for stage IV metastatic melanoma to people previously treated with dacarbazine.
See also articles on palliative care.
Follow-up for patients with melanoma
- Follow-up after stage IA melanoma:
- Consider follow-up 2-4 times during the first year after completion of treatment and discharging them at the end of that year.
- Do not routinely offer screening investigations (including imaging and blood tests) as part of follow-up.
- Follow-up after stages IB-IIB melanoma or stage IIC melanoma (fully staged using SLNB):
- Consider follow-up every three months for the first three years after completion of treatment, then every six months for the next two years and discharging them at the end of five years.
- Do not routinely offer screening investigations (including imaging and blood tests) as part of follow-up to people who have had stages IB-IIB melanoma or stage IIC melanoma with a negative SLNB.
- Follow-up after stage IIC melanoma with no SLNB or stage III melanoma:
- Consider follow-up every three months for the first three years after completion of treatment, then every six months for the next two years, and discharging them at the end of five years.
- Consider surveillance imaging as part of follow-up for people who have had stage IIC melanoma with no SLNB or stage III melanoma and who would become eligible for systemic therapy as a result of early detection of metastatic disease.
- Follow-up after stage IV melanoma:
- Offer personalised follow-up to people who have had stage IV melanoma.
- Most melanomas that are detected and treated early are cured.
- In the UK as a whole, the overall five-year survival rate is 73% in men and 85% in women.
- Survival among melanoma patients decreases with increasing age. The melanoma mortality rate has increased over a period of 25 years for men but not for women.
- Survival in melanoma is strongly correlated with the depth of invasion at diagnosis (Breslow thickness).
- The risk of death from a primary melanoma increases dramatically with increasing stage. Patients with metastatic disease have a median survival of six to nine months.
- Women have thinner tumours and survive melanoma better than men even after adjustment for Breslow thickness, ulceration and body site.
- 8% of all melanoma patients develop a second melanoma within two years of their initial diagnosis.Melanoma patients also have increased risks for other skin tumours. In patients with lentigo maligna melanomas. In one study, 35% of patients developed another cutaneous malignancy within five years.
- Patients with in-transit metastases (deposits from a focus of cells moving along regional lymphatic channels) have a poor prognosis, with a five-year survival rate of only 25%. In-transit metastases and nodal metastases are generally treated surgically with palliative intent.
- A reduction in people's exposure to sun has not led to a significant reduction in the incidence of melanoma and sun avoidance may be detrimental (eg, as a cause of vitamin D deficiency).
- Although large-scale primary prevention programmes, such as public health education campaigns aimed at reducing exposure to sun, may lead to reduced incidence, such programmes have not yet been proved effective.
- Avoiding sunburn and excessive sun exposure without protection seems to be the most important message in skin cancer prevention without advocating keeping away from the sun altogether.
- Sunbed use: current recommendations are that sunbeds should be avoided, especially in relation to premature skin ageing. Individuals with red hair and freckles, or multiple atypical naevi, should avoid sunbeds since their risks of developing both melanoma and non-melanoma skin cancer are already significantly increased.
- Secondary prevention with early detection of melanoma saves lives. Educating the public and health professionals to recognise melanoma early is crucial. Rapid referral for surgery and further management are imperative to improve outcomes.
- Individuals with multiple atypical naevi, a family history of melanoma and/or multiple cancers should be referred to a dermatologist for screening, as their risk of melanoma is significantly increased.
Further reading and references
; NICE Guidance (February 2016)
; Scottish Intercollegiate Guidelines Network (January 2017)
; NICE Technology Appraisal Guidance, February 2016
; NICE Quality Standard, September 2016
; Cancer Research UK
; The role of BRAF V600 mutation in melanoma. J Transl Med. 2012 Jul 910:85. doi: 10.1186/1479-5876-10-85.
; Melanoma--Part 1: epidemiology, risk factors, and prevention. BMJ. 2008 Nov 20337:a2249. doi: 10.1136/bmj.a2249.
; Epidemiology of invasive cutaneous melanoma. Ann Oncol. 2009 Aug20 Suppl 6:vi1-7.
; NICE Clinical Guideline (2015 - last updated July 2017)
; NICE Guidance (July 2015)
; Melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010 May21 Suppl 5:v194-7.
; Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006 Sep 28355(13):1307-17.
; Evaluation of staging chest radiographs and serum lactate dehydrogenase for localized melanoma. J Am Acad Dermatol. 2004 Sep51(3):399-405.
; Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009 Dec 2027(36):6199-206. Epub 2009 Nov 16.
; British Association of Dermatologists
; NICE Interventional Procedure Guidance, Mar 2013
; NICE Technology Appraisal Guidance, October 2014
; NICE Technology Appraisal Guidance, December 2012
; NICE Technology Appraisal Guidance, December 2012
; Melanoma--part 2: management. BMJ. 2008 Dec 1337:a2488. doi: 10.1136/bmj.a2488.
; Multiple primary melanoma: two-year results from a population-based study. Arch Dermatol. 2006 Apr142(4):433-8.
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