Elsevier

The Lancet

Volume 365, Issue 9460, 19–25 February 2005, Pages 687-701
The Lancet

Seminar
Cutaneous melanoma

https://doi.org/10.1016/S0140-6736(05)17951-3Get rights and content

Summary

Episodic exposure of fair-skinned individuals to intense sunlight is thought to be responsible for the steadily increasing melanoma incidence worldwide over recent decades. Rarely, melanoma susceptibility is increased more than tenfold by heritable mutations in the cell cycle regulatory genes CDKN2A and CDK4. Effective treatment requires early diagnosis followed by surgical excision with adequately wide margins. Sentinel lymph node biopsy provides accurate staging, but no published results are yet available from clinical trials designed to assess the therapeutic efficacy of early complete regional node dissection in those with metastatic disease in a sentinel node. Magnetic resonance spectroscopy is one technique under investigation for non-invasive, in-situ assessment of sentinel nodes. Localised metastatic disease is best treated surgically. No postoperative adjuvant therapy is of proven value for improving overall survival, although numerous clinical trials of vaccines and cytokines are in progress. Medical therapies have contributed little to the control of established metastatic disease, but molecular pathways recently identified as being central to melanoma growth and apoptosis are under intense investigation for their potential as therapeutic targets.

Introduction

Melanoma has become a major public health problem in many countries. Since the mid 1960s, melanoma incidence has risen by 3–8% per year in most people of European background, with the greatest increases in elderly men.1 Despite this increase, and an overall rise in mortality due to melanoma, the survival rate has improved substantially.2 Roughly 60% of those diagnosed with melanoma in the 1960s died of the disease, compared with just 11% more recently, an improvement attributed mainly to early detection.2

Section snippets

Epidemiology

Table 1 shows international trends in melanoma incidence and mortality rates. 5-year survival has steadily improved over recent decades, and is now greater than 85%,8 but melanoma causes disproportionate mortality in those of young and middle age, such that an average of 18·6 years of potential life are lost for each melanoma death in the USA, one of the highest rates for adult-onset cancers.4, 9 The evidence of a causative link with sunlight exposure is compelling, with severe episodic sunburn

Pathogenesis

Ultraviolet solar radiation promotes malignant change in the skin by having direct mutagenic effects on DNA, by stimulating the cellular constituents of the skin to produce growth factors, by reducing cutaneous immune defences, and by promoting reactive oxygen species of melanin that cause DNA damage and suppress apoptosis.25 Melanoma develops as a result of accumulated abnormalities in genetic pathways within the melanocyte. These abnormalities promote cell proliferation and prevent normal

Sun-protective behaviour

Physical protection from exposure to sunlight is generally accepted as the most important element of melanoma risk reduction.48 When shade is not available, sun-protective clothing and hats should be worn, peak hours of sun intensity should be avoided, and sunburn should be prevented. These measures may be especially important in children and adolescents.49, 50, 51 Large changes in attitude and behaviour towards sun protection in Australia have been attributed to the success of widespread

Recognition of early melanoma

The most important factor for successful management of melanoma is early diagnosis, allowing treatment to be undertaken at a stage when cure is readily achievable. Most melanomas can be identified clinically by careful examination with good lighting and magnification. Several characteristics are usually present and recognisable, including asymmetry, border irregularity, colour variegation, and a diameter greater than 6 mm. These features have been used as the so-called ABCD system of diagnosis.

Lymphatic mapping and sentinel node biopsy

Until the early 1990s, controversy had existed for decades about the value of elective lymph-node dissection (ELND) for patients who presented with a primary melanoma but who had no clinical evidence of regional node metastasis. Several large retrospective studies appeared to show a survival benefit,116 but randomised trials did not.89, 117, 118 The short-term and long-term morbidity of ELND was substantial, and only 20% of patients had nodal metastases. Then, in 1992, sentinel node (SN) biopsy

Metastatic melanoma

Little progress has been made in medical treatment of metastatic melanoma because of the absence of effective systemic therapies. Most patients with metastatic disease confined to skin, subcutis, and lymph nodes will survive for 12 months, whereas those with visceral involvement or an elevated concentration of LDH in serum have a median survival of only 4–6 months.91

Conclusions

Steady improvements in early detection rates and the surgical management of early disease have resulted in cure for most patients who present with primary melanoma. Substantial advances have also been made in understanding of the molecular pathogenesis of melanoma and the interaction between sunlight and host risk factors that underpin it. Advanced melanoma evolves with an extensive repertoire of molecular defences against immunological and cytotoxic attack—a challenge to the development of

Search Strategy and Selection Criteria

We searched the medical databases PubMed, MEDLINE, EMBASE, and The Cochrane Library (from January, 1985, to October, 2004) using the term “melanoma”, with relevant subheadings. We also searched the reference lists in articles identified by this strategy and selected additional articles that we judged to be relevant. Several review articles and book chapters were included as references because they provided comprehensive overviews of topics that are beyond the scope of this Seminar.

Conflict of

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