Malignant Melanoma (All Sites)

Malignant melanoma originates from melanocytes in the basal layer of the epidermis, derived from the neural crest. After malignant transformation, they becomes invasive by penetrating into and beyond the dermis.

The British Association of Dermatologists has produced an evidence based consensus called UK guidelines for the management of cutaneous melanoma.¹

There are separate articles on superficial melanoma and nodular melanoma but they all have similar staging and prognosis to other cutaneous melanoma. There is also an article on choroid melanoma.

Much emphasis is placed on malignant melanoma of the skin as it is by far the commonest form of melanoma but melanocytes can be found at other sites and so too can melanomas. They are all derived from ectoderm of the neural crest.

• Malignant melanoma represents about 3% of all cancers² and 10% of skin cancers.³
• The incidence of new cases is around 10 per 100,000.¹ Hence a practice of 10,000 patients can expect to have, on average, 1 new case each year.
• The incidence in developed countries has increased by 50% in the past 20 years.
• In 2003 there were slightly over 8,100 cases diagnosed in the UK.²
• The incidence rises with age and it is commonest in the over 75s but it is the 3rd commonest cancer in young people.
• In 2002 there were 1,640 deaths from malignant melanoma and 515 from non-melanoma skin cancer. Over 65% of deaths from malignant melanoma were in the over 65s.
• It is commoner in women than in men but men have a worse prognosis.
• The vast majority of melanomas are from the skin although they can metastasise to other sites, including the unusual site of the heart. However, a few do arise from other sources of which choroidal melanoma is the most common primary malignant intraocular tumour and the second most common type of primary malignant melanoma. It remains an uncommon tumour at approximately 6 per million people.
• Malignant melanoma may also occur within the oral cavity. This 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.

• It is 10 times as common in white as non-white populations.
• Excessive exposure to sunlight and especially fair skin that burns is a risk factor. However, some lesions occur on the soles of the feet or the vulva where sunlight would not be a risk factor.
• A strident education programme in Australia has reduced the incidence of malignant melanoma⁴ although the 6-fold increase in melanoma-in-situ may suggest earlier diagnosis.
• A genetic predisposition probably accounts for 1 or 2%.⁵
• 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.⁶
• Between 3 and 5% of all patients with malignant melanoma will develop a further lesion or a different type of skin cancer.
• Risk factors for the rare oral malignant melanoma are unknown. The usual suspects such as smoking, excess alcohol consumption and poor oral hygiene do not appear to increase risk.⁷

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. Early signs to suggest malignant change include darker or variable discoloration, itching, an increase in size or the development of satellites. Ulceration or bleeding are later signs. 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.

The British Association of Dermatologists gives a 7 point check list of 3 major and 4 minor features:¹

• Major:
  • Change in size
  • Irregular shape
  • Irregular colour
• Minor:
  • Largest diameter 7mm or more
  • Inflammation
  • Oozing
  • Change in sensation

The guidelines¹ suggest that the following aspects of history and examination should be recorded in the notes as a minimum requirement:

History

The presence or absence of these changes should be recorded:

• Change in size
• Change in colour
• Change in shape
• Symptoms (itching, bleeding etc.)

Examination

• Site
• Size
• Description (noting irregular margins, irregular pigmentation and ulceration if present)
• Other pigmented lesions
• Any regional lymphadenopathy
• Examination for hepatomegaly

• Suspicious lesions should be excised for histology. Both SIGN and NICE suggest that this should not be done in primary care, unless by a GPwSI, and the patient should be referred intact as a matter of urgency.
• Punch, shave or biopsies that do not attempt to take the full lesion should not be attempted and they may make it impossible to stage the lesion.
• In a number of areas referral can be made to GPs with Special Interests in pigmented lesions. They provide an enhanced service probably through local based commissioning in keeping with the policy of movement from secondary to primary care.

A number of classifications have been used over the years. Classification as superficial spreading, nodular, lentigo maligna, acral lentiginous and miscellaneous unusual types is of historical interest only as it does not classify according to prognosis. The Breslow classification is used to determine the thickness of a lesion. Clark's classification and TMN staging have been used but in 2001 the final version of the American Joint Committee on Cancer staging system for cutaneous melanoma was published.¹⁰ It was an international consensus statement that is recommended by British dermatologists.¹ Quality criteria for pathological reporting are also documented.

Further Investigation and Treatment

• Stage 0, I and IIa do not require further investigation and imaging can produce a low true positive and a high false positive rate.
• Stage IIB and beyond requires CXR, liver ultrasound or CT of chest, abdomen and pelvis. Blood tests include FBC, LFTs and LDH. Bone scans should only be performed if there is indication of bone disease.
• Patients with stage IIB or beyond should be managed at an oncology centre.
• If there is evidence of lymph node involvement, radical dissection should be performed by someone experienced in such surgery.
• Localised metastases may be excised or subjected to radiotherapy for short term benefit.
• Combination with immunotherapy produces no benefit.¹¹
• There is no evidence that pregnancy,¹² hormonal contraceptives¹³ or HRT have an adverse effect on the disease, but especially with pregnancy, consideration should be given to life expectancy.
• Patients should be taught self-examination as many recurrences are found by the patients rather than at the clinic.
• Follow up is not required for carcinoma-in-situ. Where the melanoma was less than 1mm thick follow up should be 3 monthly for 3 years. If it was thicker there should be follow up for a further 2 years.¹⁴

Prognosis tends to be better in women than in men and with peripheral rather than central lesions. A thin lesion with no nodes involved tends to have a 95% survival at 5 years but macroscopic involvement of regional nodes drops this to between 20 and 50%. The table is based on the figures given by SIGN¹⁵ and rounded off.

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

Choroid Melanoma

Choroidal melanomas are the most common primary malignant tumour of the eye and the second most common type of primary malignant melanoma but it is uncommon. It is a form of uveal melanoma. Uveal melanomas can be classified as anterior uveal melanomas, when the tumour arises in the iris, and posterior uveal melanomas, which arise in either the choroid or the ciliary body. Intraocular melanomas can involve more than one uveal structure.

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
• Occasionally, severe ocular pain, including from acute angle-closure glaucoma
• There may be no symptoms and the tumour is found on routine eye examination, perhaps for spectacles.
• The appearance of the tumour can be very variable, depending upon the amount of pigmentation present.
• Proptosis is an unusual presentation in western societies.

Imaging may include ultrasound, CT and MRI. The liver should be checked for metastases.

• Management may include observation for very small tumours less than 10mm in diameter and 2.5mm thick
• Enucleation of the eye is the usual approach for slightly larger tumours
• Brachytherapy, which is implantation of radio-isotopes is usual for medium sized tumours
• External beam radiotherapy is also used
• Orbital exenteration is a radical treatment for larger tumours

At 10 years the survival is between 30 and 50%.

Melanoma of the CNS

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.¹⁷ 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.¹⁸

Melanoma of Oral Mucosa

Melanoma may occasionally arise in the mouth. There are no known risk factors such as smoking or poor dental hygiene. Often a patch of pigmentation has been present for many years before undergoing malignant change. Pigmentation in or around the mouth can occur with Addison's disease and Peutz-Jeghers syndrome.

It tends to be seen in men in their 50s and women in their 60s and is twice as common in men than women.

Presentation 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. Hence outlook is bleak with a 5 years survival of 10 to 25% and a median survival of less than 2 years.

Surgery and radiotherapy may be enhanced by decarbazine.

Prevention of cutaneous melanoma can be achieved by reducing exposure to sunlight. The value of sunscreens is debated. An international convention¹⁹ concluded that sunscreens reduce burn and probably the risk of squamous cell carcinoma but they were less convinced about benefit for basal cell carcinoma and cutaneous melanoma. Another study looked at children, using the presence of naevi as a surrogate for malignancy.²⁰ They concluded that whilst wearing clothes was protective they were concerned that sunscreens permitted longer exposure and hence may increase risk. An American paper²¹ took a quantitative approach to account for confounding factors and concluded that there was no association between melanoma and sunscreen use. Intermittent exposure, perhaps with burning, seems to increase risk rather than occupational exposure.²² High exposure in childhood seems to be a risk.²³

The only widely proposed screening procedure for melanoma is visual examination of the skin, including both self examination and clinical examination.²⁴

The guidelines¹ recommend screening for those at high risk:

• Patients who have already had a melanoma or who have the atypical mole syndrome are at moderately increased risk of another primary, and should be advised of this and taught how to recognize a melanoma.
• Patients with giant congenital pigmented naevi are at increased risk of melanoma and require long-term follow-up.
• The prophylactic excision of small congenital naevi is not recommended.
• Individuals with a family history of three or more cases of melanoma should be referred to a Department of Clinical Genetics for counselling. Those with two cases in the family may also benefit, especially if one of the cases had multiple primary melanomas or the atypical mole syndrome.

This last recommendation is in contrast to SIGN¹⁵ who recommended "genetic testing in familial or sporadic cases is not appropriate in a routine clinical setting and should only be undertaken in the context of appropriate research studies." Both quote the same paper.⁵

There does not appear to be enough evidence of causation to permit advice about prevention of melanoma at other sites.