Malignant Melanoma (All Sites)

Normal melanocytes are found in the basal layer of the epidermis. The melanocytes produce melanin, which protects the skin by absorbing ultraviolet (UV) radiation.

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 UV radiation than those with white skin.

Non-cancerous growth of melanocytes results in moles (benign melanocytic naevi) and freckles (ephelides and lentigines). Cancerous growth of melanocytes results in melanoma. The vast majority of melanomas are from the skin but a minority of melanomas arise from other sites, including:

• Choroidal melanoma
• Melanoma of the central nervous system
• Mucosal melanoma arising on lips, eyelids, vulva, penis, anus or oral mucosa

There is a separate article on Choroidal Melanoma.

Malignant melanoma of the skin originates from melanocytes in the basal layer of the epidermis, derived from the neural crest. After malignant transformation, they become invasive by penetrating into and beyond the dermis. Four clinical types of skin melanoma exist:

• 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.

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.

• Most melanomas spread out within the epidermis; the radial or horizontal growth phase.
• If all the melanoma cells are confined to the epidermis, it is melanoma in situ, which can be cured by excision because it has no potential to spread round the body.
• When the cancer has grown through the dermis, it is known as invasive melanoma. This is the vertical growth phase, which is potentially more dangerous than the horizontal growth phase.
• 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 blood stream to other organs.

Epidemiology¹

• Malignant melanoma, is much less common (10% of skin cancers) than non melanoma skin cancers (e.g. basal cell carcinoma, squamous cell carcinoma of skin). However it is the third most common tumour in people aged 15–39.²
• In 2001, the age-standardised incidence of melanoma for females was 11.7, and for males was 10.1 per 100,000 population.
• The incidence of melanoma has risen over the past 30 years in most white populations. However recent data suggests that in some parts of the US, Australia, and the United Kingdom, incidence of melanoma may have reached a plateau and even started to decrease.
• The reported incidence has been inflated by early lesions that have little potential to spread and have a low impact on mortality. In countries with health education campaigns related to skin cancer, much of the rise in incidence can be attributed to very thin melanoma lesions or melanomas in situ.
• Early melanomas (often in situ tumours) are increasingly being excised, and comparisons of incidence and mortality data suggest that many borderline lesions may never progress if left alone.
• The incidence of melanoma increases with age in both men and women, rising steadily in both sexes from age 15 years onwards. The median age of diagnosis of melanoma in men is 62 years and in women 60 years.²
• Superficial spreading melanomas, usually thinner tumours, are seen in younger individuals.
• Nodular melanoma and lentigo maligna melanoma tend to affect older individuals.
• Men and women are generally equally likely to be diagnosed with melanoma, but in some countries it is commoner in women than in men; men have a worse prognosis.

Risk factors¹

• 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 ultraviolet 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.
    • Cumulative occupational exposure seemed to be protective in some white populations.
  • Host response to ultraviolet radiation appears to be more important than dose of sun exposure.
  • Sunbed use seems to be most detrimental before the age of 20.
• Skin pigmentation:
  • Having fair skin with a poor ability to tan, or a freckled complexion with or without red 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.
  • Five to ten per cent 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.³
  • In some families with melanoma, susceptibility to some other cancers such as pancreas, brain and breast cancer is increased.
• Solar keratoses carry a relative risk for melanoma of 2 to 4.
• Between 3 and 5% of all patients with malignant melanoma will develop a further lesion or a different type of skin cancer.

Presentation

• Most melanomas arise in the skin but they can arise from mucosal surfaces.
• More than half of the cases arise in apparently normal areas of skin.
• Melanomas may have a variety of colours including tan, dark brown, black, blue, red and occasionally light grey.
• An alternative aide-memoir to the 7-point checklist described below is the ABCDE list:
  • Asymmetry
  • Border irregular
  • Colour irregular
  • Diameter greater than 7mm
  • Evolving
• Change in size: naevi may change in size over years, but any change over weeks or months is suspicious.
• Change in colour:
  • Melanomas often show irregular pigment in a lesion, with shades of black, brown, grey, and pink. In nodular melanoma the lesion is often black throughout.
  • Rarely a melanoma can present as a non-pigmented red nodule (amelanocytic melanoma), which is more likely on hands and feet.
• Change in outline: melanomas often show a geographical outline with a sharp cut-off from normal skin.
• Itching may be a late sign and is often unreliable as many benign naevi intermittently itch.
• Bleeding is also a late sign and is often present in advanced melanoma.
• Melanoma in women occurs more commonly on the extremities and in men on the trunk or head and neck, but it can arise from any site on the skin surface.
• When there are multiple atypical naevi, check them all.⁴
  
  
  
  Multiple lesions with irregular pigmentation and edge
  
  
  
• Examination of suspicious lesions should include a thorough assessment for other suspicious skin lesions, palpation for regional lymph nodes and examination of the abdomen for enlarged liver and/or spleen.

Multiple cutaneous melanomas

• About 3-5% of melanoma patients present with a second primary melanoma.⁴
• Subsequent melanomas may appear at the same time or up to decades after the first primary melanoma, emphasising the need for thorough complete skin examination and continued careful self-examination and follow up.^5,6
• The incidence of a second primary invasive melanoma has been shown to be increased in men and for initial melanoma thickness greater than 2 mm.⁷
• Lesions may be classified as synchronous if they present at the same time or within 2 months, or metachronous if the second melanoma presents later.⁶

Referral⁸

• Use the 7-point weighted checklist for assessment of pigmented skin lesions:
  • Major features of lesions (2 points each):
    • Change in size
    • Irregular shape
    • Irregular colour
  • Minor features of lesions (1 point each):
    • Largest diameter 7 mm or more
    • Inflammation
    • Oozing
    • Change in sensation
• Lesions scoring 3 points or more in the 7-point checklist above are suspicious (if you strongly suspect cancer any one feature is adequate to prompt urgent referral).
• For low-suspicion lesions, undertake careful monitoring for change using the 7-point checklist (see below) for 8 weeks. NICE recommends ideally making measurements with photographs and a marker scale and/or ruler.
• Refer urgently patients with a lesion suspected to be melanoma (excision in primary care should be avoided).
• Send all excised skin specimens for pathological examination.
• When referring a patient in whom an excised lesion has been diagnosed as malignant, send a copy of the pathology report with the referral correspondence.

Differential diagnosis¹

There is a separate article on Black and Brown Skin Lesions.

• Unlike melanoma, atypical naevi are usually symmetrical and do not have a sharp edge with geographical border; asymmetry and sharp edged borders are clear signs of malignant transformation.¹
• Naevi remain static whereas melanoma change in size, shape, or colour over weeks or months.²

Investigations²

• Investigation is primarily by visual inspection and removal for histology where necessary.
• 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 (identifying and removing the lymph node(s) immediately draining the area of the primary tumour for histological analysis) provides prognostic information. A sentinel lymph node biopsy (SLNB) for pathological staging is particularly important for primary tumours greater than or equal to 1 mm depth.⁹
• Further investigations include chest x-ray and liver ultrasound, or CT of chest, abdomen and pelvis.
• Blood tests include full blood count, liver function tests and lactate dehydrogenase (LDH).
• However chest x-rays and serum lactate dehydrogenase lack significant impact on early detection of metastases and survival.¹⁰ They should therefore not be part of routine investigation and staging.
• Bone scans should only be performed if there is indication of bone disease.

Staging¹¹

• 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.
• In 2001 the American Joint Committee on Cancer staging system for cutaneous melanoma was published.¹²
• The current American Joint Committee on Cancer (AJCC) staging is based on measurement of the invasive component of the tumour (the Breslow thickness) and the presence or absence of microscopic ulceration.
• The staging system is in the process of being revised and an update is expected in 2009.

Management²

• 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 options¹¹

• The primary treatment for malignant melanoma is wide local excision. Re-excision should be performed for proven melanomas if the margins are inadequate. Recommended excision margins:¹³
  • Stage pT1 (melanoma less than 1 millimetre): margin 1 centimetre
  • Stage pT2 (melanoma 1 to 2 millimetres): margin 1-2 centimetres
  • Stage pT3 (melanoma 2 to 4 millimetres): margin 2 centimetres
  • Stage pT4 (melanoma over 4 millimetres): margin 2 centimetres
• Completion lymphadenectomy (regional lymph nodes are removed when a sentinel node biopsy is positive) has not been shown to improve overall survival.
• Adjuvant treatments:
  • Several adjuvant therapies have been tried for the treatment of localised cutaneous melanoma after complete surgical removal. Survival benefit has only been demonstrated for adjuvant interferon (IFN) alfa-2b,¹⁴ and no adjuvant treatment has yet been shown to be sufficiently effective to become routine.
  • Chemotherapy is often used for patients with metastatic melanoma but there is no evidence to support the use of adjuvant chemotherapy following surgery.²
  • There is some evidence that interferon alfa improves recurrence-free survival, but not overall survival, when given as an adjuvant treatment after surgery.²
  • Melanoma vaccines are a theoretically attractive alternative,¹⁵ but have not yet been shown to be beneficial.
• Metastatic disease:
  • All patients diagnosed with distant metastases should be referred to a specialist oncologist and have access to a clinical nurse specialist and palliative care team.²
  • In advanced disease, no intervention has been shown to have a significant effect on overall survival.
  • Chemotherapy:¹¹
    • Chemotherapy in melanoma is unsatisfactory; few drugs are available 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.
    • Patients with raised lactate dehydrogenase are less likely to benefit from systemic treatment.
    • Adding interferon alfa and interleukin-2 to chemotherapy increases response rates and toxicity, but does not significantly improve overall survival and so is therefore not recommended.
  • Metastases to the central nervous system carry a poor prognosis. Surgery may be indicated for isolated lesions if amenable. Stereotactic radiotherapy can also be used but no survival benefit has been proved for whole brain radiotherapy or chemotherapy.
  • Radiotherapy otherwise 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.²
  • Metastasectomy in oligometastatic relapse may be considered in highly selected patients who have been disease free for a long time.
  • In-transit metastases from malignant melanoma (deposits from a focus of cells moving along regional lymphatic channels):²
    • Patients with in-transit metastases have a poor prognosis, with a 5-year survival rate of only 25%.
    • Cutaneous metastases, in-transit metastases and nodal metastases are generally treated surgically with palliative intent.¹¹
    • Treatment options include surgery and intra-lesional therapy for individual lesions.
    • Carbon dioxide laser therapy is valuable for multiple small-volume deposits that are too numerous to excise individually.
  • Multiple cutaneous deposits in a single limb (with no distant metastases):²
    • Can be treated by isolated limb perfusion or infusion using melphalan as a single agent or combined with other cytotoxic and biological agents.¹¹
    • Isolated limb perfusion (ILP) may be an option for selected patients, especially those at risk of limb loss, with remission rates of up to 60% for periods of up to 2 years.
    • This option should be reserved for advanced in-transit disease when simpler and safer methods have been exhausted.
    • Isolated limb infusion (ILI) is a relatively new technique that appears to be of equal efficacy; it is less invasive and easier to repeat, but toxicity is similar to ILP.
  • Occasionally, for some patients, no active treatment may be the most appropriate course of action. Supportive care and observation may be a suitable alternative in selected cases after full discussion of the options available.
  • For some patients with advanced disease, management may consist entirely of supportive palliative care.

Prognosis

• Most melanomas that are detected and treated early are cured.¹¹
• 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.²
• Survival in melanoma is strongly correlated with the depth of invasion at diagnosis (Breslow thickness).²
• Mortality rates for melanoma have been fairly flat over the past 30 years in most white populations and have even begun to fall in the US, Australia, Scandinavia, and the UK.
• 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.¹¹
  

  Prognosis of Malignant Melanoma by stage & 5 years survival13 Stage O IA IB IIA IIB IIC IIIA IIIB IIIC IVM:1 IVM:2 IVM:3 5 years survival % 100 95 90 78 65 45 69 59 27 19 7 10

• Women have thinner tumours and survive melanoma better than men even after adjustment for Breslow thickness, ulceration and body site.
• People who have more than 1 lesion, whether synchronous or metachronous, fare better than may be feared. Subsequent primary lesions tend to be discovered early. This may be because both the patient and doctor are more alert to the risk. If a patient has synchronous lesions, the prognosis is as for the deepest lesion.¹⁶

Prevention¹

• 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 relating 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.¹¹
• 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.

Melanomas from sites other than the skin are much less common but do occur.

Choroidal melanoma¹⁷

Choroidal melanoma is a subtype of uveal melanoma, which can be classified as anterior uveal melanomas (arise in the iris) or posterior uveal melanomas (arise in either the choroid or the ciliary body). Choroidal melanomas most often metastasise to the liver. Other organs include lung, bone, skin, and central nervous system. Less frequently they metastasise locally into the orbit or rarely the conjunctiva.

• Choroidal melanomas are the most common primary malignant tumour of the eye and the second most common type of primary malignant melanoma. It remains an uncommon tumour at approximately 6 per million people.
• The incidence is much higher in countries with large numbers of people of northern European descent than elsewhere in the world.
• The tumour is most common in those of North European descent. It tends to be slightly more frequent in men than women and the peak incidence is around 55 years old.
• Presentation may include:
  • Blurred vision. This may result from a variety of factors, including growth of the melanoma, macular oedema, retinal detachment, vitreous haemorrhage, cataract, and obstruction of the visual axis by the tumour.
  • Painless and progressive visual field defect.
  • Floaters.
  • It is not uncommon for patients to present with a brief ball of light moving across their vision, which may occur 2 or 3 times a day.
  • Occasionally severe ocular pain, including from acute angle-closure glaucoma.
  • There may be no symptoms and the tumour is found on routine eye examination.
  • The appearance of the tumour can be very variable depending upon the amount of pigmentation present.
  • Proptosis is an unusual presentation in western societies.
• Examination and investigation aim to exclude metastases to the choroid (most frequently from the bronchus in both sexes and the breast in women, but may also be from the kidney or gastrointestinal tract) and from the choroid (liver is by far the most frequent site) as this influences management.
• Investigations therefore include ultrasound, CT/MRI and biopsy.
• Management is very variable depending on exact individual circumstances:
  • Observation (e.g. small slow growing tumours in the elderly)
  • Transpupillary thermotherapy (small tumours)
  • Radiotherapy (slightly larger tumours)
  • Brachytherapy (implantation of radio-isotopes for medium sized tumours)
  • Local resection (small anterior tumours)
  • Enucleation (large tumours, optic nerve involvement, or blind or painful eyes)
  • Orbital exentration (controversial; for massive tumours)
• Prognosis:
  • The 10 year survival is between 30 and 50%.
  • Death is usually secondary to distant metastases, and the risk is greatest in larger tumors.
  • Choroidal melanoma normally leads to partial or total visual loss in the affected eye but patients with small or medium sized choroidal melanomas may be able to preserve very good central vision, even after treatment.

Melanoma of the central nervous system¹⁸

• The commonest form of melanoma in the CNS is metastases of cutaneous melanoma.
• Primary intracranial melanoma can arise from the leptomeninges or dura mater.
• It is rare as a primary malignancy of the CNS and accounts for about 1% of melanomas.
• Spread to the meninges gives a worse prognosis.¹⁹
• Neurocutaneous melanoma is a congenital disorder in infants with giant hairy melanocytic naevi. The leptomeningeal tissues are invaded, involving the brain or spinal cord. Severe neurological compromise or death results.
• Very rarely, primary melanoma of the pineal has been reported.²⁰
• Melanomas that metastasise to the CNS are incurable. Treatment is aimed at reducing the size of the tumour by surgery and/or palliative radiotherapy and supportive palliative care. The use of steroids provides symptom relief by decreasing cerebral oedema.

Mucosal melanoma²¹

• Melanoma of oral mucosa is very uncommon and accounts for less than 1% of all melanomas.
• Unlike cutaneous melanoma, the incidence has remained static over the past 20 years.
• There are no known specific risk factors.²²
• Tends to present in patients older than 40 years and is rare in patients younger than 20 years.
• Melanoma of oral mucosa is twice as common in men than in women.
• Often a patch of pigmentation has been present for many years before undergoing malignant change.
• Pigmentation in or around the mouth can also occur with Addison's disease and Peutz-Jeghers syndrome.
• Presentation:
  • Usually macular but nodular and even pedunculated lesions occur.
  • Pain, ulceration, and bleeding are rare until late in the disease.
  • Pigmentation varies from dark brown to blue-black, with erythema when the lesions are inflamed.
  • Mucosa-coloured and white lesions are occasionally seen and amelanotic melanoma accounts for up to one third of oral melanomas.
  • Approximately one third of patients have lymph node involvement at presentation.²³
• Diagnosis tends to be late as it is often thought to be a benign pigmentation process. They tend to be more aggressive than other oral tumours and rapidly metastasise.
• Treatment:
  • The primary treatment is surgery but radiotherapy may be an effective adjunct.
  • Chemotherapy (dacarbazine), therapeutic radiation and immunotherapy have not been proven to benefit patients with oral melanoma. Dacarbazine is not effective alone but may be beneficial in conjunction with interleukin-2.
• Outlook is poor with a 5 years survival of 10 to 25% and a median survival of less than 2 years.