See also separate article Malignant Melanoma.

Normal melanocytes are found in the basal layer of the epidermis. Melanocytes are found in equal numbers in black and in white skin, but 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:¹

• Lentigo maligna melanoma is where a patch of lentigo maligna develops a papule or nodule, signalling invasive tumour.
• Superficial melanoma is a large flat irregularly pigmented lesion which grows laterally before vertical invasion develops.
  
  
  
  
• Nodular melanoma is 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.

Epidemiology

• Malignant melanoma is more common in women than men. In 2008 it was the sixth most common cancer in females and in males.² Malignant melanoma is much less common than non-melanoma skin cancers (e.g. basal cell carcinoma, squamous cell carcinoma of skin).
• In 2008, the UK age-standardised incidence of melanoma for females was 16.5 (11.7 in 2001) and for males was 15.9 (10.1 in 2001) per 100,000 population. It has been estimated that the lifetime risk of developing malignant melanoma in 2008 was 1 in 61 for men and 1 in 60 for women in the UK.²
• The distribution of melanomas diagnosed between 2006 and 2008 was:²
  • Males: head and neck 22%, trunk 41%, arm 18%, leg 13%.
  • Females: head and neck 14%, trunk 19%, arm 23%, leg 40%.
• The incidence of melanoma has risen over the past 30 years in most white populations.
• Malignant melanoma is rare in children. The incidence of melanoma increases with age in both men and women. The median age of diagnosis of melanoma in men is 62 years and in women 60 years.³
• Superficial spreading melanoma (SSM) is the most common subtype and occurs in approximately 70% of patients with a melanoma.⁴ It is most common on the trunk in men and on the legs in women. Most often, it presents in individuals aged 30-50 years.
• Nodular melanoma represents 15-30% of all malignant melanomas.⁴

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.⁵

Risk factors⁵

• Previous personal primary invasive melanoma.⁶ Between 3 and 5% of all patients with malignant melanoma will develop a further lesion or a different type of skin cancer.
• Naevi:
  • 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, e.g. airline crew, gardeners, cricketers and those involved in other outdoor pursuits.⁶ 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 30.⁶
• 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 about 10 years earlier than others and they have a greater risk of multiple lesions.⁷
  • 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.⁶
• Higher socioeconomic group.⁶

Presentation and differential diagnosis

See separate article Black and Brown Skin Lesions.

Referral

Any skin lesion suspected to be a melanoma should be referred urgently.⁸ The British Association of Dermatologists recommends urgent referral where there is:⁹

• A new mole appearing after the onset of puberty, which is changing in shape, colour or size.
• A long-standing mole which is changing in shape, colour or size.
• Any mole which has three or more colours or has lost its symmetry.
• A mole which is itching or bleeding.
• Any new persistent skin lesion, especially if growing, if pigmented or vascular in appearance, and if the diagnosis is not clear.
• A new pigmented line in a nail, especially where there is associated damage to the nail.
• A lesion growing under a nail.

Lesions which are suspicious for melanoma should not be removed in primary care.⁸

Investigations³

Investigation is primarily by visual inspection and removal for histology where necessary. Diagnosis should be based on a full thickness excisional biopsy.¹⁰

• 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 depth.¹¹
• 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.¹² 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

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 2009.¹³

• Tumour:
  • Tis (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.
• Nodes:
  • N0: no nodal metastases.
  • N1: 1 metastatic node; a: micrometastasis (diagnosed after sentinel node biopsy); 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 4 metastatic nodes, or matted nodes, or in-transit metastases/satellites with metastatic nodes.
• Metastases:
  • M0: no 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:¹

• 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, any M.

Management³

• Cancer networks should establish two levels of multidisciplinary teams: local hospital skin cancer multidisciplinary teams (LSMDTs) and specialist skin cancer multidisciplinary teams (SSMDTs).
• People with precancerous skin lesions should be either treated entirely by their GP or referred for diagnosis, treatment and follow-up to doctors working in the community who are members of the LSMDT/SSMDT.
• If there is any doubt about the diagnosis, people with precancerous lesions should be referred directly to their local hospital skin cancer specialist. Where appropriate, follow-up of these patients may be undertaken by their own GP.
• 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.

Management options¹⁴

• 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:⁹
  • In situ: 5 mm excision margin to achieve complete histological excision.
  • Breslow thickness <1 mm: 1 cm excision margin.
  • 1.01-2 mm: 1-2 cm excision margin.
  • 2.1-4 mm: 2-3 cm excision margin.
  • >4 mm: 3 cm excision margin.
• Completion lymphadenectomy (regional lymph nodes are removed when a sentinel node biopsy is positive) has not been shown to improve overall survival.
• Chemotherapy has limited benefit and response rates are limited. Dacarbazine remains the standard of care. It has a response rate of 5-15% and improves progression-free survival by a few months at best.¹⁴ Patients with elevated LDH are less likely to benefit from currently available systemic treatment.⁹
• Radiotherapy has only a limited role in the management of patients with melanoma but it may be useful and potentially curative in some patients with lentigo maligna and is occasionally used in the palliative treatment of symptomatic metastases, especially in brain and bone.³
• Melanoma vaccines are a theoretically attractive alternative, but have not yet been shown to be beneficial.¹⁵
• For some patients with advanced disease, management may consist entirely of supportive palliative care.

Localised disease¹⁰

• Wide excision of primary tumours with safety margins of 0.5 cm for in situ melanomas, of 1 cm for tumours with a Breslow thickness up to 2 mm and 2 cm for thicker tumours is recommended.
• Sentinel lymph node biopsy (SLNB) in melanoma with a tumour thickness of >1 mm is necessary for precise staging, followed by a complete lymphadenectomy of regional lymph nodes if the sentinel node was found positive for metastases.
• Adjuvant treatment with interferon alfa following resection of the primary tumour has improved recurrence-free survival but without significant effects on overall survival.¹⁶
• Pegylated interferon has been recommended for patients with low tumour burden.
• Radiotherapy for local tumour control should be considered in case of inadequate resection margins of lentigo maligna melanoma or for melanoma metastases when surgery is not feasible.

Locoregional metastatic disease¹⁰

• Surgical removal, including the surrounding lymph node region, is indicated for isolated locoregional lymph node metastases.
• Surgical removal is also recommended in the case of a single organ metastasis, including the central nervous system.
• Non-resectable in-transit metastases or inoperable primary tumours of the limbs without additional metastases may be treated with isolated limb perfusion using, for example, melphalan and/or tumour necrosis factor alpha. Radiation therapy may be used as an alternative.

Systemic metastatic disease¹⁰

• Surgery for visceral metastases may be appropriate for selected patients.
• Palliative therapy for advanced disease with several metastases in different anatomical regions may initially include dacarbazine, taxanes, lomustine, cytokines (interferons, interleukin-2) or combinations of these.
• In aggressive metastatic disease, combination regimens including paclitaxel and carboplatin or cisplatin, vindesine and dacarbazine may produce a partial response but the overall impact of systemic therapy on survival in advanced melanoma patients is unclear.
• Palliative radiotherapy should be considered especially for symptomatic brain or localised and painful bone metastases.

Two recently developed drugs, vemurafenib and ipilimumab, have shown very promising results on survival for patients with advanced melanoma. Both treatments are currently being assessed by European licensing bodies.

See also articles on palliative care.

Follow-up for patients with melanoma⁹

• Patients with in situ melanomas do not require follow up.
• Patients with invasive melanomas have differing risk of relapse according to their stage group.
• Patients with stage IA melanoma should be seen two to four times over up to 12 months, then discharged.
• Patients with stage IB-IIIA melanoma should be seen 3-monthly for 3 years, then 6-monthly to 5 years.
• Patients with stage IIIB and IIIC and resected stage IV melanoma should be seen 3-monthly for 3 years, then 6-monthly to 5 years, then annually to 10 years.
• Patients with unresectable stage IV melanoma are seen according to need.

Prognosis

• Most melanomas that are detected and treated early are cured.¹⁴
• In the UK as a whole, the overall 5-year survival rate is 73% in men and 85% in women.
• Survival among melanoma patients decreases with increasing age and is lower among males.³ The melanoma mortality rate has increased over the last 25 years for men but not women.¹⁰
• Survival in melanoma is strongly correlated with the depth of invasion at diagnosis (Breslow thickness).³
• 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.¹⁴
• 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 2 years of their initial diagnosis.¹⁷ Melanoma patients also have increased risks for other skin tumours. In patients with lentigo maligna melanomas, 35% of the patients developed another cutaneous malignancy within 5 years.¹⁰
• Patients with in-transit metastases (deposits from a focus of cells moving along regional lymphatic channels) have a poor prognosis, with a 5-year survival rate of only 25%. In-transit metastases and nodal metastases are generally treated surgically with palliative intent.¹⁴

Prevention⁵

• 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 (e.g. 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.¹⁴
• 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.

Document references

1. Tan WW; Malignant Melanoma, Medscape, Apr 2011
2. Skin cancer - UK incidence statistics, Cancer Research UK
3. NICE Guidance on Cancer Services; Improving Outcomes for People with Skin Tumours including Melanoma, NICE (Update, May 2010)
4. Swetter SM; Cutaneous Melanoma, Medscape, Apr 2011
5. Bataille V, de Vries E; Melanoma--Part 1: epidemiology, risk factors, and prevention. BMJ. 2008 Nov 20;337:a2249. doi: 10.1136/bmj.a2249.
6. MacKie RM, Hauschild A, Eggermont AM; Epidemiology of invasive cutaneous melanoma. Ann Oncol. 2009 Aug;20 Suppl 6:vi1-7. [abstract]
7. Conrad N, Leis P, Orengo I, et al; Multiple primary melanoma. Dermatol Surg. 1999 Jul;25(7):576-81. [abstract]
8. Referral for suspected cancer, NICE Clinical Guideline (2005)
9. Revised U.K. guidelines for the management of cutaneous melanoma 2010, British Association of Dermatologists
10. Dummer R, Hauschild A, Guggenheim M, et al; Melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and Ann Oncol. 2010 May;21 Suppl 5:v194-7.
11. Morton DL, Thompson JF, Cochran AJ, et al; Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006 Sep 28;355(13):1307-17. [abstract]
12. Wang TS, Johnson TM, Cascade PN, et al; Evaluation of staging chest radiographs and serum lactate dehydrogenase for localized melanoma. J Am Acad Dermatol. 2004 Sep;51(3):399-405. [abstract]
13. Balch CM, Gershenwald JE, Soong SJ, et al; Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009 Dec 20;27(36):6199-206. Epub 2009 Nov 16. [abstract]
14. Thirlwell C, Nathan P; Melanoma--part 2: management. BMJ. 2008 Dec 1;337:a2488. doi: 10.1136/bmj.a2488.
15. Francis SO, Mahlberg MJ, Johnson KR, et al; Melanoma chemoprevention. J Am Acad Dermatol. 2006 Nov;55(5):849-61. Epub 2006 Sep 18. [abstract]
16. Kirkwood JM, Manola J, Ibrahim J, et al; A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004 Mar 1;10(5):1670-7. [abstract]
17. Titus-Ernstoff L, Perry AE, Spencer SK, et al; Multiple primary melanoma: two-year results from a population-based study. Arch Dermatol. 2006 Apr;142(4):433-8. [abstract]

Acknowledgements