Seminar

Cutaneous melanoma
John F Thompson, Richard A Scolyer, Richard F Kefford Lancet 2005; 365: 687–701
Sydney Melanoma Unit,
Episodic exposure of fair-skinned individuals to intense sunlight is thought to be responsible for the steadily University of Sydney at Royal
Prince Alfred Hospital
increasing melanoma incidence worldwide over recent decades. Rarely, melanoma susceptibility is increased more
(Prof J F Thompson FRACS,
than tenfold by heritable mutations in the cell cycle regulatory genes CDKN2A and CDK4. Effective treatment R A Scolyer FRCPA), and
requires early diagnosis followed by surgical excision with adequately wide margins. Sentinel lymph node biopsy Westmead Hospital
provides accurate staging, but no published results are yet available from clinical trials designed to assess the (Prof R F Kefford FRACP),
Sydney, Australia
therapeutic efficacy of early complete regional node dissection in those with metastatic disease in a sentinel node.
Correspondence to:
Magnetic resonance spectroscopy is one technique under investigation for non-invasive, in-situ assessment of
Prof J F Thompson, Sydney
sentinel nodes. Localised metastatic disease is best treated surgically. No postoperative adjuvant therapy is of proven Melanoma Unit, Royal Prince
value for improving overall survival, although numerous clinical trials of vaccines and cytokines are in progress. Alfred Hospital, Missenden Road,
Medical therapies have contributed little to the control of established metastatic disease, but molecular pathways Camperdown, New South Wales
2050, Australia
recently identified as being central to melanoma growth and apoptosis are under intense investigation for their
thompson@smu.org.au
potential as therapeutic targets.

Introduction lated abnormalities in genetic pathways within the

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 diag-
nosed with melanoma in the 1960s died of the disease,
compared with just 11% more recently, an improvement
attributed mainly to early detection.2
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 in
early life correlating best with melanoma risk.10,11 Even in
those predisposed to melanoma by inheritance of
mutations in the cyclin dependent kinase inhibitor 2A
(CDKN2A) gene, incidence is markedly higher in people
living at lower latitudes.12 This fact indicates close
interactions between genetic susceptibility and environ-
mental ultraviolet (UV) exposure in the genesis of
melanoma. Other risk factors for melanoma are shown
in table 2.
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 accumu-
melanocyte. These abnormalities promote cell prolifer-
ation and prevent normal pathways of apoptosis in
response to DNA damage. The altered melanocyte is
thereby predisposed to cumulative DNA damage,
resulting in the selection for genetic mutations that
allow all aspects of the malignant phenotype, including
stimulation of blood vessel growth, evasion of the
immune response, tumour invasion, and metastasis.26
Although the mechanisms of differential cancer cell
killing are poorly understood,27 selection of cells that are
resistant to apoptotic mechanisms might contribute to
the resistance of melanoma cells to the cytotoxic effects
of chemotherapy, radiotherapy, and immunotherapy,
especially through the expression of apoptosis inhibitors
like B-cell lymphoma derived protein 2 (Bcl-2) and Bcl-
xL.28 Growth factors such as stem cell factor, fibroblast
growth factor, and transforming growth factor  are
produced by the action of solar radiation on melanocytes
and surrounding keratinocytes and fibroblasts (figure 1).
Resulting signals are transduced via the Ras/RAF
pathway, ultimately triggering the transcription of a
suite of genes involved in cellular proliferation and
migration. Solar radiation also stimulates production of
melanocortin (-MSH), the ligand for the melanocortin-1
receptor (MC1R), which signals via cyclic AMP to induce
production of sun-protective pigment (eumelanin).
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.

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 Seminar

Age-standardised Age-standardised Lifetime risk Incidence trend Mortality trend Most common
incidence (105/year) mortality (105/year) (incidence) over 10 years over 10 years cancers (ranking)
Australia (2001)3
Men 41·4 (world) 5·1 (world) 1 in 25 22% increase 2% increase (1991–2001) 4th
Women 31·1 (world) 2·6 (world) 1 in 35 12% increase 0% increase (1991–2001) 3rd
USA (2001) 4,5

Men 21·4 (world) 3·9 (world) 1 in 53 31% increase 0% increase (1991–2001) 5th
Women 13·8 (world) 1·8 (world) 1 in 78 25% increase 1% decrease (1991–2001) 7th
The Netherlands (1998)6
Men 11·5 (Europe) 3·1 (Europe) ·· 21% increase 24% increase (1989–98) ··
Women 14·8 (Europe) 2·1 (Europe) ·· 11% increase 5% increase (1989–98) ··
UK (2000)7
Men 9·7 (world) 2·7 (world) 1 in 147 59% increase 20% increase (1991–2001) 12th
Women 11·2 (world) 1·9 (world) 1 in 117 41% increase 3% increase (1991–2001) 7th

Table 1: Melanoma statistics in four countries

Variants in MC1R result in production of pheomelanin, Inherited susceptibility to melanoma

which is not sun-protective and produces red hair. By- The risk of an individual developing a melanoma is
products of melanin biosynthesis can themselves cause greatly increased if there is a family history of the
oxidative stress and contribute to malignant change. disease.13,14 Very occasionally, however, melanoma is due
Constitutive activating mutations in NRAS occur in to the presence of identifiable, heritable mutations in
21% of melanoma cell lines.29 Activating v-raf murine highly penetrant genes. The proportion of all
sarcoma viral oncogene homologue B1 (BRAF) melanomas that is due to these genes is unknown, but is
mutations are the most common oncogene mutations in estimated to be less than 2%.40 The genes known to
melanoma,30 indicating the importance of this pathway function in this way are CDKN2A and, rarely, CDK4
in the deregulation of melanocyte growth. Such (figure 1).41 A locus on chromosome 1p22 is strongly
mutations occur in 10–30% of primary melanomas.31,32 linked with melanoma susceptibility42 but the respon-
There is complementarity between the presence of sible gene has not yet been identified.
NRAS and BRAF mutations in any individual melanoma Inactivating mutations in CDKN2A confer on carriers
since each has the same effect of causing unrestrained a risk of melanoma of between 50% and 90% by age
cell proliferation. 80 years.12 Inherited mutations in this gene are present
BRAF mutations are also present in 60–80% of benign in 30–40% of families with three or more members
melanocytic naevi,31,33,34 which suggests that the complex affected by melanoma.41 Although some but not all
molecular machinery that provides checks and balances in melanoma-prone families have multiple atypical naevi,
the cell normally protects against the unrestrained growth the various terms used for these families in medical
stimuli that are propagated through such abnormalities in publications43 cause confusion and are of little practical
the Ras/RAF pathways, possibly preventing the vast
majority of benign naevi from undergoing malignant Relative risk
change. One source of these cell cycle brakes is the protein for melanoma*
products of the CDKN2A gene: p16 and p14ARF. This Genetic
genetic locus is frequently targeted for disruption in Strong family history (3 first degree relatives affected) 35–7013
Weak family history 314
melanomas, and is inherited in mutated form in certain
Naevi
melanoma-prone families.35 When defective, p16 is Multiple benign naevi (100) 1115,16
unable to inactivate CDK4 and CDK6, which Multiple atypical naevi 1117,18
phosphorylate Rb, releasing the transcription factor E2F Previous skin cancer
Previous melanoma 8·519
and leading to cell cycle progression.36
Previous non-melanoma skin cancer 2·920
The molecule that is usually central to protection Immunosuppression
against DNA damage, p53, is rarely mutated early in Transplant recipients 321
melanoma, which is possibly one of several adaptations Patients with AIDS 1·522
Surrogates of sun sensitivity
to permit survival of cells responsible for generating Type I skin (burns without tanning) 1·723,24
sun-protective pigment.37 However, mutations in Freckling 2·523,24
p14ARF allow degradation of p53 by releasing its Blue eyes 1·623,24
binding partner hdm2.38 As a further defence, melanoma Red hair 2·423,24
UV exposure
cells frequently express high levels of the antiapoptotic History of blistering sunburn 2·523,24
molecules Bcl-2 and Bcl-x.28 These are important
*CIs for estimates of relative risk given in references cited.
potential targets for therapeutic attack on the tumour.
Advanced melanomas also frequently inactivate the Table 2: Clinical risk factors for melanoma
apoptosis effector Apaf-1.39

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 Seminar

Melanocortin Growth factors

Receptor
3 tyrosine
Cell surface MC1R kinase

CDKN2A gene 4
cAMP Ras PTEN
p53
hdm 2 ARF p16
p53 p53 Melanin RAF PI3K
synthesis

p21 5 MEK Akt

Bax Bcl-2 1 Cyclin ERK mTOR 6

CDK
2
Mitf Translation
Apoptosis P P
growth
Rb Rb P regulators
E2F P Tyr, Bcl2, cell-cycle genes
P

Cell-cycle progression
E2F

Figure 1: Selected prominent molecular pathways in the genesis and regulation of melanoma
Targets undergoing experimental inhibition in melanoma therapy (green diamonds): (1) antisense oligonucleotide to Bcl-2 (oblimersen); (2) CDK inhibitors
(flavopiridol); (3) receptor tyrosine kinase inhibitors; (4) farnesyl transferase inhibitors; (5) RAF inhibitors (BAY 43-9006); (6) mTOR inhibitors. Barred lines indicate
inhibition. SCF=stem cell factor. FGF=fibroblast growth factor. Ras=rous avian sarcoma homologue. BRAF=v-raf murine sarcoma viral oncogene homologue B1.
MEK=mitogen-activated protein kinase kinase (MAP2K). ERK=extracellular signal-regulated kinase. MAPK=mitogen-activated protein kinase. Mitf=microphthalmia
transcription factor. PI3K=phosphatidylinositol-3 kinase. Akt=murine v-akt oncogene homologue. mTOR=mammalian target of rapamycin. CDKN2A=cyclin
dependent kinase inhibitor-2A. CDK=cyclin dependent kinase. Rb=retinoblastoma protein. p16=16 000 MW protein. ARF (p14ARF)=14 000 MW alternate reading
frame protein. cAMP=cyclic AMP. Bcl=B-cell lymphoma derived protein. hdm=human double minute chromosome-associated protein. E2F: E2F cell cycle regulated
transcription factor. MSH=melanocyte stimulating hormone (melanocortin). MC1R=melanocortin-1 receptor.

value. The presence of multiple naevi in an individual, Use of sunscreens

whether atypical or not, is a strong marker for Because much of the solar UV radiation reaching the
melanoma risk irrespective of family history (table 2 and earth’s surface is UV-A, and older sunscreen
figure 2), and the presence of naevi cannot be used to formulations were most effective at blocking UV-B, a
predict the presence of CDKN2A mutations.44
Some inherited variants of the melanocortin-1
receptor gene confer increased UV-sensitivity and a
twofold to fourfold elevation in melanoma risk.45
Although commonly mutated as somatic events in
deregulating melanocyte proliferation (figure 1), the
BRAF and NRAS genes are not associated with inherited
melanoma susceptibility.46,47

Prevention and screening

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.49–51 Large changes
in attitude and behaviour towards sun protection in
Australia have been attributed to the success of
widespread public education programmes,52 and the
reduction in the rate of rise of melanoma incidence in
Australian and US birth cohorts since the 1960s suggests
that primary prevention strategies are effective.2 Figure 2: The back of an individual with multiple atypical naevi

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 Seminar
theoretical concern has been that sunscreen use could
increase the risk of melanoma by giving false security
from potentially damaging sun exposure.53 However, a
meta-analysis of 18 studies concluded that there was no
evidence of an increase in melanoma risk with
sunscreen use.54 It will take many years to assess the
protective effect of newer sunscreen formulations that
block both UV-A and UV-B, but most current guidelines
on melanoma prevention advocate their use as a
supplement to physical protection.
Population screening for melanoma
A number of US cancer organisations recommend
routine screening for melanoma, but the International
Union Against Cancer and Australian guidelines do not,
because of the lack of any evidence of its value from
randomised controlled trials. Such trials are underway.55
Approach to high-risk groups
Individuals can be identified as high risk on the basis of
factors summarised in table 2. Algorithms combining
these factors divide individuals into low, moderate, or
high risk categories.56 Many guidelines recommend that
those at high risk engage in programmes of increased
surveillance and prevention.57,58 These programmes
involve education about the need for sun protection,
routine self-examination and examination by a partner
or family member, regular screening of individuals and
first degree relatives of those with a positive family
history or multiple primary melanomas, and regular
dermatological review. Such recommendations,
although clinically prudent, still need validation by
appropriate intervention studies.
The Melanoma Genetics Consortium recommends
that genetic testing for melanoma should be confined to
carefully designed research protocols.35 This is because
of the low predictive value of positive tests, the elevated
background risk in these families, probably due to
coinheritance of unidentified melanoma susceptibility
genes, and the uncertain benefit of medical
interventions for carriers.35
Figure 3: Melanoma features shown by skin surface microscopy
A: multiple colours, radial streaming, peripheral black dots and globules, and a blue white veil. B: These features
not visible to naked eye.
690
Diagnosis
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.59 Clinical suspicion should
additionally be aroused by any significant change in an
existing naevus or skin lesion, because some
melanomas do not display the classical features. It has
long been recognised, for example, that about 5% of all
melanomas are non-pigmented, with the reported
incidence varying from 1·6% to 10%.60–63 As a result,
amelanotic melanomas are sometimes mistaken for
basal cell or squamous cell carcinomas, or even benign
inflammatory lesions, seborrhoeic keratoses, or
common warts. Nodular melanomas are more likely
than superficial spreading melanomas to lack evident
pigmentation, and in a recent study, more than 50% of
the nodular melanomas were predominantly amelanotic
(red or pink),64 whereas almost all melanomas of
superficial spreading type were mainly black or brown.
Nodular melanomas often fail to fulfil the ABCD
diagnostic criteria in other respects too, and can
therefore be particularly difficult to recognise in the early
stages of their evolution.64
When diagnosis is uncertain, the safest course of
action is to perform an excision biopsy. An alternative
but less reliable approach is to review the lesion in
2–3 months. Monitoring with high-resolution
photography may assist in assessing change.65
Skin surface microscopy and computerised imaging
Hand-held instruments for skin surface microscopy
(dermoscopy, dermatoscopy) are now available, and have
made differentiating between benign and malignant skin
lesions more reliable.66–69 These instruments all rely on
the principle of epiluminescence, using either polarised
light or a film of liquid that prevents normal scattering of
light at the stratum corneum of the skin and thereby
allows clear display of the structures beneath it.
Skin surface microscopy allows differentiation
between melanocytic and non-melanocytic lesions with
high confidence. Having established that a lesion is
melanocytic, skin surface microscopy then assists in
recognition of the characteristic features of a melanoma,
which include a broadened pigment network, the
presence of a blue-white veil, multiple colours, radial
streaming, pseudopods, and peripheral black dots and
globules (figure 3).70 The accuracy of melanoma
diagnosis both by specialist dermatologists and by
general practitioners is greater when skin surface
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Panel 1: Example of a synoptic pathology report for a
primary cutaneous melanoma on the right thigh of a
34-year-old man
Site Right thigh
Diagnosis Melanoma
Histological subtype Superficial spreading
Breslow thickness 1·9 mm
Ulceration Present (3·6 mm diameter)
Dermal mitotic rate (per mm2) 8
Clark level IV
Vertical growth phase Present
Vascular or lymphatic invasion Absent
Neurotropism Absent
Desmoplasia Absent
Satellites Absent
Features of regression
Early (TILs): Mild and focal
Intermediate (angiofibroplasia with or without TILs): Absent
Late (fibrosis and loss of rete ridges): Absent
Predominant cell type Epithelioid
Associated naevus Dermal naevus
Nearest lateral margin to in-situ or invasive component
1·7 mm
Distance from tumour to deep margin 4·5 mm
TILs=tumour infiltrating lymphocytes.
microscopy is used in addition to standard clinical
examination.71–73 Computerised monitoring systems that
allow comparison between new and previous images are
now widely available. These systems can also provide an
estimate of the probability that an individual lesion is a
melanoma by comparing its features with those of a
bank of lesions known to be benign or malignant.74
Histological confirmation of diagnosis
If the clinical diagnosis of a skin lesion is uncertain and
melanoma cannot be excluded, the appropriate course of
action is to excise the entire lesion for histological
examination, with a 2-mm clearance margin. This
approach allows definitive treatment to be planned
appropriately if the diagnosis of melanoma is confirmed.
The biopsy will provide details of the thickness of the
tumour and any unfavourable features such as
ulceration, regression, or a high mitotic rate. Even if a
confident clinical diagnosis of melanoma is made, it is
important to perform an excision biopsy with narrow
margins, so that subsequent definitive treatment options
are not compromised. If an excessively wide margin is
taken, or if complex flap reconstruction is done,
subsequent wider excision with adequate margins might
be difficult to plan, and lymphatic mapping (with a view
to sentinel node biopsy or simply to guide follow-up)
could well be inaccurate. When a pigmented lesion is
large, however, an incision biopsy or a punch biopsy
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Seminar
may need to be considered, to establish a definite
diagnosis. However, such biopsies are always more
difficult for the pathologist to interpret because they
represent only a small part of the entire lesion. As a
general rule, shave biopsies of pigmented lesions should
not be done, because if a diagnosis of melanoma is
established, it is often impossible to establish either the
true depth of invasion or the completeness of
excision.75–77 This has obvious implications for clinical
management. The potential problems associated with
shave, incision, and punch biopsies also have medico-
legal implications; in one study, more than 80% of
medical malpractice claims in relation to melanoma
involved incomplete biopsy specimens.78
Pathology
Rational and effective treatment of a melanoma is
possible only if an accurate histological diagnosis is
available. However, diagnostic difficulties often occur,
particularly for pathologists who are not experienced in
assessing and reporting melanocytic lesions.79,80 For this
reason, pathologists should be encouraged to seek
second and third opinions when there is uncertainty, as
many already do. This process is of great value in
eliminating incorrect diagnoses.79
Panel 2: The 2002 AJCC staging system
0 Melanoma in situ
IA Tumour thickness 1·0 mm without ulceration and
Clark level II or III.
IB Tumour thickness 1·0 mm with ulceration or Clark
level IV or V, or tumour thickness 1·01–2·0 mm without
ulceration.
IIA Tumour thickness 1·01–2·0 mm with ulceration or
tumour thickness 2·01–4·0 mm without ulceration.
IIB Tumour thickness 2·01–4·0 mm with ulceration or
tumour thickness 4·0 mm without ulceration.
IIC Tumour thickness 4·0 mm with ulceration.
IIIA Any tumour thickness with no ulceration and
1–3 microscopic nodes.
IIIB Any tumour thickness with ulceration and
1–3 microscopic nodes, or any tumour thickness without
ulceration and 1–3 macroscopic nodes, or any tumour
thickness with or without ulceration and either
satellite(s) or in-transit metastasis(es) without
metastatic node(s).
IIIC Any tumour thickness with ulceration and either
1–3 macroscopic nodes or satellites or in-transit
metastases without metastatic nodes or any tumour
thickness with 4 metastatic nodes or satellites/
in-transit metastases with metastatic nodes.
IV Any tumour thickness, any number of nodes and any
distant skin, subcutaneous, nodal or visceral metastases.
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 Seminar
5-year survival
Stage I (primary tumour 1mm) 93%
Stage II (primary tumour 1mm) 68%
Stage III (regional node metastasis) 45%
Stage IV (systemic metastasis) 11%
Table 3: Melanoma-specific survival estimates, according to the 2002
AJCC staging system88
As well as an accurate diagnosis, an appropriately
detailed histopathology report is needed by the surgeon
undertaking treatment of a melanoma, and review of
histology slides should be requested if important
features of the primary melanoma are not described. A
standardised synoptic reporting system for melanomas
can ensure that key elements of histopathological
assessment are not overlooked.81 An example of a
synoptic report is shown in panel 1. Such a report not
only includes essential information about tumour
thickness and ulceration, but also describes features
such as desmoplasia, neurotropism, tumour mitotic
rate, growth phase, lymphatic invasion and vascular
invasion, each of which might have important
implications for management and prognosis.82–84
A detailed description of melanoma histopathology is
beyond the scope of this Seminar, but the topic is fully
discussed elsewhere85 Also important are special
pathological diagnostic techniques such as immuno-
histochemistry86 and molecular assessment.87
Prognosis and staging
The prognosis for a patient with a newly diagnosed
cutaneous melanoma depends mainly on two factors—
the thickness of the primary tumour and the presence or
absence of metastasis to regional lymph nodes.
However, other prognostic factors are very important,
including tumour ulceration, mitotic rate, and presence
of regression, as well as sex and age of the patient, and
tumour site.
A new American Joint Committee on Cancer (AJCC)
staging system for melanoma was introduced in 2002,
and is now in international use (panel 2).88 It was based
on the details of 17 600 patients from 13 melanoma
treatment centres around the world.89–92 Table 3 shows
5-year and 10-year survival predictions for patients
according to stage.
The new AJCC staging system incorporated several
important changes. For T staging, patients with stage I
Microscopic nodal involvement
1 positive node 2–3 positive nodes
Melanoma ulceration
Absent 69% 63%
Present 52% 50%
Based on data from Balch et al.91
Table 4: Diversity of 5-year survival probabilities for stage III melanoma
692
10-year survival
disease were designated as those with primary tumours
less than or equal to 0·75 mm in thickness (whereas an
85%
55% arbitrary cut off of 0·75 mm had been used in previous
36% versions). Ulceration was included as a criterion for
6% T staging, except in patients with tumours less than or
equal to 1 mm in thickness, where Clark level retained
its prognostic significance. However, the prognostic
variables considered in the AJCC analysis to determine
T stage did not include tumour mitotic rate, which has
since been shown to be an important independent
prognostic indicator in two large studies,83,93 and possibly
more powerful than ulceration.83 This example
highlights the fact that no staging system should be
regarded as static or final, and future melanoma staging
systems may need to incorporate not only mitotic rate
but also other parameters that prove to have prognostic
significance, including gene expression profiles.94,95
For N staging, the number of nodal metastases and
whether they were microscopic or macroscopic was used
in the new AJCC system, rather than the dimensions of
nodal metastases used previously. In the new system, a
clear distinction was drawn for the first time between
clinical and pathological staging. This distinction has
particular relevance to the revolution in nodal staging
that has happened over the past decade with
introduction of the sentinel node biopsy technique.96 The
finding of even a small focus of metastatic disease in a
sentinel node has very important prognostic
implications, and sentinel node status has emerged as
the most powerful prognostic indicator at the time a
patient presents with a primary melanoma.97 On the
basis of evidence from the AJCC prognostic factors
analysis, primary tumour ulceration was also included
as a criterion for N staging in the new system. For
M staging, patients with an elevated serum lactate
dehydrogenase concentration were assigned to a
separate, worse prognosis category because of
convincing evidence that the serum concentration of this
enzyme is a powerful predictor of outcome in patients
with metastatic melanoma.98,99
The prognostic factors analysis undertaken by the
AJCC Melanoma Staging Committee91 provided new
insights into several aspects of the natural history of
melanoma. One of the most important of these was that
the prognosis for patients with stage III disease (ie,
metastatic disease in regional lymph nodes) varied very
greatly. Prognosis depended not only on the number of
involved nodes, but also on whether that involvement
Macroscopic nodal involvement
3 positive nodes 1 positive node 2–3 positive nodes 3 positive nodes
27% 59% 46% 27%
37% 29% 25% 13%
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was microscopic or macroscopic, and on whether the
primary tumour had been ulcerated (table 4). This new
understanding may help explain the inconclusive results
of previous clinical trials of adjuvant therapies, in which
results for all stage III patients were considered
together.100
Initial investigations
At initial presentation, most patients with melanoma
have disease that is confined to the primary site on the
skin, and extensive staging investigations are
inappropriate because of the extremely low detection
rate of distant metastases. In a large study,101 for
example, a chest radiograph revealed evidence of
metastatic disease in only one of 876 patients (0·1%),
whereas false positive results were obtained in 15% of
the patients, requiring clarification with further costly
and sometimes invasive investigations. In another
study,102 a positive result was obtained from computed
tomographic (CT) scans in only 1·3% of newly
diagnosed patients, a false positive result in 15·8%, and
a second primary tumour was identified in 2%. Even
lower positive rates for metastatic melanoma have been
reported for bone scans and other nuclear medicine
scans, including liver scans and brain scans.103 High-
resolution ultrasound examination of the regional
lymph nodes at the time of presentation is unlikely to
reveal metastatic disease, even when present,104,105
because tumour deposits smaller than 4 mm in
diameter cannot reliably be detected by ultrasound, and
few patients with a primary melanoma but clinically
normal lymph nodes will have a nodal tumour focus
larger than 4 mm.105 Positron emission tomographic
(PET) scanning with fluorodeoxyglucose detected only
two of 26 patients with positive sentinel nodes in one
study,104 and is not recommended for initial staging. For
patients with thick primary tumours (4 mm), CT
scans can be useful before recommending radical
lymph node surgery, because such surgery might be
inappropriate in the presence of widespread
dissemination of disease.
If there is clinical evidence of metastatic disease in
regional lymph nodes at presentation, CT scans can
assist in assessing the extent of lymph node
involvement, and can also indicate whether systemic
metastatic disease is present. However, the yield in
patients with only microscopically positive sentinel
lymph nodes is very small.106 If evidence of systemic
metastasis is found on presentation or at a later date, full
staging with CT, MRI, or PET scans is warranted,
because sometimes metastases that may be resectable
with curative intent will be identified. In any case,
baseline staging is valuable if systemic treatment is to be
undertaken, so that the effects of therapy can be
monitored. Detailed practical recommendations for
staging evaluation based on critical analysis of available
evidence have been proposed by Buzaid et al.103
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Initial surgical management—excision margins
Despite many attempts over the past 25 years to
determine the appropriate excision margins for primary
cutaneous melanomas of varying thicknesses, the matter
remains controversial. There is no doubt that the 5-cm
clearance margins that were considered appropriate for
all melanomas only three or four decades ago are
unnecessary, because they do not affect long-term
survival and do not produce lower recurrence rates than
more conservative margins. Large retrospective studies
reported in the 1980s showed that local recurrence was
very uncommon with excision margins of 2 cm or
greater. However, it became apparent that primary
tumour thickness was of significance in determining the
risk of local recurrence. In a retrospective study of
1839 patients with 5 years of follow up, the local
recurrence rate for thick tumours (3 mm) was 21%
with margins less than 2 cm, and 9% when wider
margins were used. For thin tumours (0·1–0·7 mm),
recurrence rates were 2% and less than 1%,
respectively.107
A randomised trial undertaken by the WHO
Melanoma Program108 compared the outcomes for
612 patients with primary melanomas less than 2 mm in
thickness who were randomised to excision margins of
either 1 cm or 3 cm. Disease free or overall survival rates
did not differ, but the trial did indicate that melanomas
1 mm or less in thickness were adequately treated by
excision with 1-cm margins. A subsequent Intergroup
study109 randomly assigned 486 patients with melanomas
of intermediate thickness (1–4 mm) to excision with
either 2-cm or 4-cm margins. Local recurrence rates
were similar for the two groups, and overall 5-year
survival rates did not differ significantly. However,
treatment morbidity and length of hospital stay were
significantly greater in the 4-cm margin group.
Two randomised trials have compared 2-cm and
5-cm excision margins. The Swedish Melanoma Study
Group110 did so for 989 patients with melanomas
0·8–2·0 mm in thickness, and the French Group for
Research on Malignant Melanoma111 undertook the
comparison for 326 patients with primary tumours less
than 2·1 mm thick. Neither study indicated that
5-cm margins resulted in a lower local recurrence rate or
a better survival rate than 2-cm margins.
Further information about excision margins for higher
risk (2 mm thick) melanomas comes from results of a
900-patient British collaborative trial112 in which 1-cm and
3-cm excision margins were compared. The conclusion
from this study was that a 1-cm margin for melanomas
thicker than 2 mm was associated with a slightly greater
risk of local recurrence than was a 3-cm margin, but with
no significant difference in overall survival.
Thus, some uncertainty remains about optimum
excision margins. However, for invasive melanomas
1 mm or less in thickness, the broad consensus is that a
1-cm margin is adequate.113 For tumours between 1 mm
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 Seminar
Figure 4: Metastatic tumour cells in sentinel node (immunohistochemical
staining for S100 protein)
and 2 mm thick, there is suggestive but not conclusive
evidence that excision margins greater than 1 cm are
desirable.114 Melanomas thicker than 2 mm seem to
require an excision margin of at least 2 cm, but whether
this margin is adequate or 3 cm is needed remains an
open question. Most trials have not included melanomas
on the head, neck, and distal extremities, and thus no
reliable data exist to provide guidelines for their
treatment. Even if excision margins of 2 cm or more for
Left posterior right Left anterior right
Initial Initial
Delay Delay
Figure 5: Lymphoscintigraphy in a patient with a melanoma on the central upper back
Top: summed 10-min dynamic images in posterior and anterior projections after injection of technetium-99m
antimony sulphide colloid intradermally at melanoma site. Dominant lymphatic channels pass laterally to both
axillae and upwards to interval nodes on back. Delayed scans 2 h later show single sentinel node in each axilla and
three interval nodes (also sentinel nodes in this patient) on upper back.
694
intermediate thickness and thick melanomas do
produce slightly lower local recurrence rates, this
possible benefit must be weighed against the
undoubtedly increased likelihood of surgical morbidity
and disfigurement associated with wider excision
margins. Some compromise on margins is probably
reasonable when the risk of causing morbidity and
disfigurement is high.115
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 was proposed as a minimally
invasive procedure that provided accurate assessment of
regional node status in melanoma patients,119 allowing
full regional node dissection to be avoided in the 80% of
patients who had negative SNs. Within 3 years of that
landmark publication by Morton et al,120 confirmation of
the accuracy of such assessment was provided by studies
in the USA120 and Australia.121 These studies both
involved SN biopsy with immediate complete node
dissection so that all remaining nodes in the node field
could be examined histologically.
The SN concept is simple: lymph draining from a
tumour site passes first to a so-called sentinel node
before onward passage to other nodes in the regional
node field. Thus the SN is most likely to contain tumour
cells, and if none are present in this node, tumour cells
are unlikely to be present in other nodes in the node
field (figure 4).
In early studies, blue dye was injected intradermally at
the primary melanoma site and each SN was identified by
tracing blue-stained afferent lymphatics to a blue-stained
lymph node in the regional node field. Preoperative
lymphoscintigraphy, involving injection of a radiolabelled
colloid at the primary melanoma site, was soon found to
provide valuable information preoperatively,122,123 and to
make the SN biopsy procedure quicker and more accurate
than without this technique. The development of hand-
held gamma probes allowed even faster and more precise
intraoperative localisation of such nodes, and it proved
possible to use residual radioactivity in the SN after the
preoperative lymphoscintigram for identification of such
a node.124 It soon became clear, however, that
identification of this node was most accurate if all three
methods were used—a preoperative lymphoscintigram,
injection of blue dye around the primary melanoma site
immediately preoperatively, and the use of a hand-
held gamma probe intraoperatively. Preoperative
lymphoscintigraphy for many melanoma patients before
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 Seminar

SN biopsy provided important new insights into A B

cutaneous lymphatic drainage pathways,125,126 and this new
information highlighted the importance of preoperative
lymphoscintigraphy before undertaking a SN biopsy
procedure (figure 5).
The prognostic value of determining SN status has
now been shown in several large studies.127–134 All show a
large difference in probability of 5-year survival between
patients who are SN positive and those who are SN
negative, independently of other prognostic variables.
Results from the Sydney Melanoma Unit135 are typical,
with a 5-year survival rate of 56% for SN positive patients
(n=145) and 90% for SN negative patients (n=846).
Prognostic information from SN biopsies may be
further refined by PCR to detect melanoma-specific
mRNA in lymph nodes that are negative by standard
histopathological techniques.136
Although it has become clear that SN assessment
provides important prognostic information, there is no
evidence that removal of these nodes, with complete
ppm 4 3 2 1 ppm 4 3 2 1
regional node field dissection if micrometastatic
melanoma is found, improves survival. The results of
large multicentre trials that will assess this question123,137 Figure 6: Magnetic resonance spectra
are awaited with great interest. It is expected that initial A: normal skin. B: melanoma, showing prominent choline and taurine peaks.
results of the Multicentre Selective Lymphadenectomy
Trial122 will be presented in May, 2005. The next attention is already focusing on non-surgical methods of
important question is whether it is always necessary to SN assessment. For example, rapid and accurate results
undertake a complete regional node field clearance can be obtained by examination of fine needle aspiration
when a sentinel node is positive, since there is no biopsies of such nodes with magnetic resonance
evidence of metastatic disease in non-sentinel nodes in spectroscopy.148 The spectra obtained when melanoma is
87% of patients. A new multicentre, international trial present in an SN aspirate contain characteristic peaks of
that will examine this question has recently commenced. choline, taurine, and other metabolites that are absent
when melanoma is not present (figure 6). Studies are in
Present role of sentinel node assessment progress to determine the feasibility of completely non-
It has been suggested that it is inappropriate, even invasive in-vivo SN assessment with surface coils.149,150
improper, to perform SN biopsy procedures routinely
because there is no clinical trial evidence that it is of Systemic adjuvant therapy
therapeutic value.138–141 However, this suggestion has More than 80% of patients who develop a melanoma will
been rebutted by others, on the basis that even if trials do die from other causes.2 However, some patients are
not show a survival benefit, the value of SN biopsy for intermediate (51–64% 10-year survival) or high risk
accurate staging will remain.142,143 A knowledge of SN (50% 10-year survival).92 Patients at greatest risk include
status also provides the patient with a more reliable those with primary tumours thicker than 4 mm, and
estimate of prognosis, and allows more accurate those with lymph node involvement. Adjuvant systemic
stratification for entry into adjuvant therapy trials. If therapy aimed at minimum residual tumour burden
effective adjuvant therapies are found, of course, would be potentially valuable for these patients, as well as
knowledge of SN status will be needed to identify those for those with totally resected metastatic disease.
at greatest risk and therefore most in need of those Multiple clinical trials of adjuvant therapies have been
treatments. done in melanoma patients with chemotherapy,
The SN biopsy procedure has also been criticised on vaccines, biological drugs, and combinations of these.151
the basis of isolated reports that in-transit metastasis The only substance yet shown to affect disease behaviour
rates are increased.139–141,144 However this increase was not reproducibly in large randomised controlled clinical trials
apparent in two large series,145,146 and analysis of all is high-dose intravenous interferon-alpha. Low-dose or
available evidence indicates that regional node surgery intermediate-dose interferon offered no overall survival
does not increase the risk of in-transit metastasis. benefit in several trials.100,152,153 At a dose of 5 million units
Rather, primary tumour biology alone seems to thrice weekly for 2 years, subcutaneous interferon-alpha
determine that risk.147 Although clinical trial results showed a delay to time of first distant metastasis, but this
must be awaited before final conclusions are reached, delay did not result in a survival advantage.154

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 Seminar
A pooled analysis of trials155 at median follow-up times
of 2·1–12·6 years showed significant improvement in
relapse-free survival for patients treated with high-dose
interferon-alpha of about 10% at 5 years, but no clear
benefit in terms of overall survival, compared with
patients randomly allocated to observation or vaccine
therapy. The toxicity of interferon-alpha is high,156 and in
view of the absence of evidence for an overall survival
benefit, it cannot be regarded as standard adjuvant
therapy, although it remains the sole US Food and Drug
Administration (FDA) approved substance for this
purpose. Active participation of intermediate or high
risk patients in prospective observation-controlled
clinical trials is therefore to be encouraged. Many such
trials are underway and are testing a wide variety of
melanoma-derived vaccines alone or in combination
with cytokines such as interferon-alpha, interleukin 2
and granulocyte-macrophage colony-stimulating factor.
A combination of cytotoxic drugs, interferon-alpha, and
interleukin-2 is also being compared with high-dose
interferon-alpha therapy alone.
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
Staging patients with metastatic disease
If surgery is planned for apparently resectable
metastatic disease, a sensitive screening test for
metastatic disease in other sites, such as PET scanning,
might be particularly useful.157 However, when clinical
examination and simple imaging have established the
presence of inoperable metastatic disease, the addition
of PET scanning is of questionable value. Serial CT
scans are the best method for assessing response to
treatment. Although not recommended for routine
screening, MRI is the most sensitive test for detection
of cerebral metastases because the combination of
haemorrhage and the presence of melanin combine to
give a very high signal intensity on T1 weighted
images.158
Surgery and radiotherapy
Local recurrences and in-transit metastases are most
effectively treated by surgical excision. Clinically evident
metastatic disease in regional lymph nodes should be
treated surgically, by complete regional node dissection,
since between 13% and 59% of these patients will not
develop further metastatic disease.91 The role of adjuvant
postoperative radiotherapy to the node field is not clear,
although there is much evidence that it improves long-
term local disease control.159 The results of randomised
696
trials (in progress) that may confirm this possibility are
awaited.
Surgery can also be valuable for patients with
metastatic disease beyond the regional nodes, and those
with surgically resectable disease in up to three visceral
sites are frequently offered surgical resection. 5-year
survival can be more than 20% after complete resection
of pulmonary metastases,160,161 and 28–41% after complete
resection of gastrointestinal metastases.162–164 These
patients are highly selected, and it is unlikely that there
will ever be randomised clinical trial data to prove the
effectiveness of such interventions. Surgical resection
and radiation therapy also offer valuable palliation in
specific circumstances and radiotherapy remains the
treatment of choice for palliation of multiple cerebral
metastases,165 and for non-resectable bone metastases.166
Isolated limb perfusion and isolated limb infusion
Occasionally, patients develop extensive recurrent
disease in a limb, but have no clinically detectable or
symptomatic systemic metastases. Such patients can be
treated by hyperthermic isolated limb perfusion with a
cytotoxic drug (usually melphalan), with complete
response rates of 50% or better.167,168 However, this
procedure is complex and involves open surgical
canulation of major limb vessels, and an extracorporeal
cardiopulmonary bypass circuit. A simplified version,
done without oxygenation via percutaneous catheters, is
known as isolated limb infusion.169 This procedure
achieves response rates similar to those from isolated
limb perfusion, but is less invasive and uses fewer
resources.170 Clinical trials are planned to establish its
value as an alternative to isolated limb perfusion.
Although both techniques are undoubtedly of value for
management of recurrent limb melanoma that cannot
be controlled by simple surgical means, no survival
benefit for prophylactic isolated limb perfusion was
evident in a large international multicentre trial.171
Immunotherapy
Immunotherapy continues to be investigated intensively
in both adjuvant and advanced disease settings, and
attempts are being made to target the major defences
that melanoma mounts against an effective immune
response. These defences include development of host
tolerance to melanoma antigens, production of
immunosuppressive factors by melanoma cells, and
clonal selection of melanoma cells that are resistant to
apoptosis.172 Despite the presence of detectable immune
responses in 30–60% of patients, tumours regress in
only a few vaccine-treated patients with metastatic
disease.173 The cytokine interleukin 2 has FDA approval
for high-dose intravenous use in treating metastatic
melanoma, on the basis of durable responses in some
patients.174,175 However, the overall response rate is low
(16%), and systemic toxicity is high (hypotension,
capillary leak syndrome, sepsis, and renal failure),
www.thelancet.com Vol 365 February 19, 2005

restricting this treatment to highly specific patients and
institutions. Innovative immunotherapy approaches
include the use of immunotoxins to eliminate regulatory
T cells (thereby allowing tumour-specific T cells to be
activated), monoclonal antibodies such as MDX-010 to
inhibit immunosuppressive cell signalling,176–178 and ex-
vivo expanded tumour-specific T cells in combination
with chemotherapy.179
Chemotherapy and biological therapy
Single agent dacarbazine, temozolomide, and fotemus-
tine continue to be widely used in systemic therapy of
metastatic melanoma because of their fairly low toxicity
and simplicity of administration, and because more toxic
combination therapies do not improve survival.180 These
single drugs have response rates of 18–24%, with
complete response rates of less than 5%.181,182 However,
response rates to dacarbazine and temozolamide in
randomised trials183,184 were less than 10% and more
effective systemic therapies are urgently needed. A phase
III trial of three-drug chemotherapy versus the same
drugs plus interferon-alpha and interleukin 2
(biochemotherapy)185 produced slightly higher response
rate and progression-free survival for biochemotherapy,
but this benefit was not associated with either improved
quality of response or better overall survival.
The molecular pathways identified as being central to
melanoma growth are the subjects of intense
investigation for their potential as therapeutic targets
(figure 1). Oblimersen (Genasense, Genta Incorporated,
New Jersey, USA) is an antisense oligonucleotide to the
antiapoptotic molecule Bcl-2, which is overexpressed in
many melanomas. This drug sensitised melanoma cells
to chemotherapy in preclinical studies.186 Phase III testing
of dacarbazine plus oblimersen versus dacarbazine alone
showed significant incremental benefits in progression-
free survival,187 but this benefit was insufficient to justify
FDA listing. As with many similar new anticancer drugs,
there is major concern that small signals of activity in this
heterogeneous population of patients with very advanced
disease might be inadvertently overlooked, causing
potentially valuable drugs to be abandoned. The RAF
inhibitor BAY 43-9006 has minimum activity on its own,
but in combination with the cytotoxic drugs carboplatin
and paclitaxel it gave 14 of 35 partial responses (Flaherty
KT, oral presentation, 40th Ann Meeting American
Society of Clinical Oncology, New Orleans, USA,
June 5–8, 2004), and response did not depend upon the
presence of an activating RAF mutation.188 The prospect of
using a number of targeted inhibitors in combination
with chemotherapy provides some optimism and is the
subject of planned phase III trials.
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
www.thelancet.com Vol 365 February 19, 2005
Seminar
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 effective adjuvant and
systemic therapies that is being met vigorously by a new
international organisation of melanoma researchers.189
Conflict of interest statement
RK has on two occasions received payment to attend expert advisory
meetings of the scientific and clinical research sections of Novo Nordisk
and Actelion who are developing novel drugs for phase I and II trials in
melanoma. Neither these companies, their products, the clinical trials
concerned, or any ideas or concepts relating to them are referred to in
this article, nor do any views expressed in it have any relation to these or
any other commercial activity. The other authors declare that they have
no conflict of interest.
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