Malignant melanoma: Death by image and ignorance, diagnosis by surgical excision and laboratory investigation

British Journal of Biomedical Science, 1999 by Magennis, D P, Orchard, G E

Malignant melanoma: death by image and ignorance, diagnosis by surgical excision and laboratory investigation*

Abstract: Malignant melanoma is now one of the most common cancers in the western world. Across Europe, the rise in annual incidence is 4-7%. The criteria for clinical and histological diagnosis are well established; however, an elaborate range of laboratory investigations can provide valuable supplementary information in difficult cases. In this essay, we highlight the incidence and impact of malignant melanoma worldwide, and outline the range of laboratory investigations that can be performed and are so vital in the diagnosis of problematic cases.

Key words: Diagnosis. Immunohistochemistry. Melanoma.

Introduction

The past few decades have seen a marked increase in the incidence of, and consequently the mortality from, malignant melanoma (MM). As a result of this increase in mortality, efforts have been made to make the public more appreciative of the risk factors leading to the development of MM - particularly excessive exposure to the sun - and the importance of seeking medical advice for suspicious skin lesions.

Laboratory diagnosis plays a crucial role both in the identification of MM and in staging its progress, as this provides vital information to the clinician regarding the optimal treatment strategy for the patient.

Incidence

Cancers of the skin are the most commonly occurring cancers in the West, with 40 000 new cases arising in the UK each year.' There are three main types of skin cancer. Basal cell carcinoma (rodent ulcer) and squamous cell carcinoma are the most common, are rarely fatal and have a cure rate of over 95%. The third type, malignant melanoma, is a malignant tumour of melanocytes. It accounts for approximately 11% of all skin cancers and, as it is a rapidly progressive and metastatic tumour, is the primary cause of death in skin disease.

Malignant melanoma accounts for 1-3% of all cancers2 and increases in importance as its incidence grows faster than that of any other cancer in North America, Europe and the Antipodes.3 In the USA, the incidence of MM has almost tripled in the past four decades,4 and projections suggest that one in 90 Americans will develop MM by the year 2000.5 Adults of all age groups are affected, with a median age of 53 at diagnosis.6 However, MM has the highest incidence of any cancer in Caucasians between the ages of 25 and 29, and in male Caucasians between the ages of 35 and 39.7

There is a difference between the sexes in the incidence and occurrence of MM, with approximately six to seven cases in women for every four in men.l The distribution of MM also varies between men and women (Table 1), and occurs most frequently on the legs in women and on the trunk in men.

Risk factors

The precise cause of MM is unknown,7 although there are a host of risk factors known to affect its development. The most important aetiological factor is excessive exposure to the sun. Ultraviolet (UV) radiation is the part of the sun's radiation that can cause skin damage. Ultraviolet A (UVA, 320400 nm) produces tanning and can cause a very weak inflammatory reaction. This UV wavelength is produced by sunbeds, and the increased incidence of MM associated with these8,9 has cast doubt on the previously held belief that UVA does not cause skin cancer. Ultraviolet B (UVB, 280-320 nm) is regarded as the critical component in the pathogenesis of MM, as prolonged exposure can cause blistering of the skin and sunburn (i.e. a strong inflammatory reaction due to cell damage, and release of histokines and prostaglandins). Melanocyte DNA may be damaged by UVB, causing DNA-protein crosslinks, DNA strand crosslinks, DNA strand breaks, or pyrimidine dimer formation. Indeed, patients with xeroderma pigmentosum, a rare disorder characterised by deficient repair of UVB-damaged DNA (caused by a defect in an endonuclease in excision repair) have a 100-fold increase in the incidence of MM. Ultraviolet C (UVC) rays are even more damaging to the skin than UVB, but are removed by the ozone layer.

Individuals at greatest risk are those with white (particularly fair) skin who are prone to burn in the sun (Table 2).10 There is an increase in the incidence of MM in people of the same skin colour, the nearer they live to the Equator (Table 3).

However, the incidence of MM is relatively low in people with outdoor occupations,11 which supports the hypothesis that the risk of developing MM depends more on intermittent exposure to the sun than on simple cumulative exposure. In particular, blistering sunburn in children under 16 years has been linked with an increased risk of MM in later life.12,13 In the UK, the increase in MM may be linked to an increase in foreign travel, especially that which includes sunbathing. This may explain why it is the only cancer in the UK to show an increased incidence with higher social class and personal income. Patients with giant congenital naevi or dysplastic naevus syndrome also have an increased risk of MM. Dysplastic naevi are abnormal pigmented, roughly symmetrical, flat or slightly raised lesions, usually more than 6 mm in diameter.14 In fact, patients who have dysplastic naevi and two or more first-degree relatives with MM show a significantly increased risk of developing MM during their lifetime. 15 Patients with giant congenital melanocytic naevi have a 6-7% lifetime risk of malignant transformation.16