Cutaneous Malignant Melanoma

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Cutaneous Malignant Melanoma
Donato Calista Unità Operativa di
Dermatologia Ospedale M. Bufalini, Cesena
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The Italian age-adjusted incidence of CM is 4.6
cases/100,000 person-years for males and
5.5/100,000 person-years for females.
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Risk Factors for Cutaneous Melanoma
Sun exposure, particularly at a young
age Artificial ultraviolet radiation

• Environmental
• Constitutional
• Genetic

Caucasian Poor tanning ability Freckling, red or
blonde hair, light eyes Multiple nevi Presence of
dysplastic nevi
Family history of melanoma or dysplastic
nevi Rare hereditary syndromes albinism,
Li-Fraumeni syndrome, Werners syndrome,
Xeroderma p.
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• UV radiations induce the initial transformation
  of benign melanocytes having direct and indirect
  mutagenic effects on DNA
• by stimulating the keratinocytes to produce
  growth factors
• by reducing cutaneous immune surveillance
• by promoting reactive oxygen species in the
  impact with melanin.
• The altered melanocytes that do not undergo
  apoptosis provide the substratum for the
  selection of malignant phenotypes.

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• CM develops as a result of the accumulation of
  abnormalities within melanocyte DNA

These events are either
Genetic gene mutation, deletion, amplification,
or translocation
Epigenetic heritable changes other than in DNA
sequence, generally transcriptional modulation by
DNA methylation or chromatin alterations
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Dorothy C Bennett How to make a melanoma what
do we know of the primary clonal events? In press

• Not all CM show the same set of primary clonal
  events.
• Every one of these genes encodes some kind of
  regulatory molecule, which controls either cell
  proliferation, senescence, or apoptosis.
• Probably no single genetic change is crucial.

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• It seems that the following steps are needed to
  develop a CM
• Changes that induce clonal expansion
  Mutational
  activation of NRAS or BRAF oncogenes.
  
• NRAS is known to promote proliferation and
  malignant transformation, however, BRAF gene has
  recently become the centre of attention.
• Changes needed to overcome melanocyte senescence
  Through inactivation of p16-RB
  pathway and activation of telomerase.
• Changes that suppress apoptosis

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On the basis of the aspect of the skin
surrounding the area of CM onset, epidemiologic
and molecular studies suggest that at least two
types of melanoma can develop.
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• The first
• is related to melanocyte instability
• It occurs on skin with few or no signs of chronic
  sun-induced damage, particularly in younger
  individuals with multiple nevi.

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On the basis of the aspect of the skin
surrounding the area of CM onset, epidemiologic
and molecular studies suggest that at least two
types of melanoma can develop.
2

• The second
• is related to chronic solar exposure
• It occurs on skin with chronic sun-induced
  damage, particularly in older people.
• Such patients have a low number of melanocytic
  nevi.
• and a large number of solar keratoses and other
  keratinocytic malignancies.

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Whiteman DC, Parson PG, Green AD. P53 expression
and risk factors for cutaneous melanoma a
case-control study. Int J Cancer 199877843-48.

• p53-positive CMs
• were strongly
• associated with
• inability to tan
• history of non CM skin cancer
• site of melanoma head, neck and lower
  extremities

• p53-negative CM
• were related to
• nevi density

p53 The Guardian of the Genome is a molecule
that is central to protection of DNA damage from
UVR.
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Maldonado JL, Fridlyand J, Patel H, et al.
Determinants of BRAF mutations in primary
melanomas. Natl Cancer Inst 2003171878-90.

• A higher frequency of BRAF mutations (81) has
  been detected in melanomas occurring on skin with
  minor histopathological signs of chronic solar
  damage (CSD) as compared to melanoma onset on
  chronically photo-exposed skin (17).

CSD CLASSIFICATION
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Since the year 2000 BRAF gene becomes a focal
genetic issue.

• The most common BRAF mutation (90 of cases) is
  glutamic acid for valine substitution at position
  600 (V600E), which is not a typical sun induced
  signalling.
• So the role of BRAF mutation in the
  cancerogenesis is probably the consequence of
  secondary events to the UVR induced damage
• the presence of highly toxic oxidizing agents
  produced by pheomelanin
• the inflammation that accompanies sunburn
• or TNFa secreted by monocytes and macrophages

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MCIR Germline Variants Confer Risk for
BRAF-Mutant MelanomaMaria Teresa Landi, Jürgen
Bauer, Ruth M. Pfeiffer, David E. Elder, Benjamin
Hulley, Paola Minghetti, Donato Calista, Peter A.
Kanetsky, Daniel Pinkel, Boris C.
BastianScience 2006313521-2.

• Some studies have suggested the existence of
  susceptibility loci which make it more likely
  that some individuals will acquire these
  mutations than others.
• One of these susceptibility genes is MC1R.

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Melanocortin-1 receptor (MC1R) an intriguing
candidate gene for CM susceptibility
16q24.3
UVR
UVR
UVR
UVR
UVR
UVR
UVR
a-MSH
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MC1R gene is highly polymorphic in Caucasians
with specific variants linked to the red hair
colour phenotype.
V92M
K278E
F45L
MC1R gene missense variants
D294H
R163Q
V60L
D84E
R142H
R160W
R151C
I155T
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Variants of MC1R can result in partial r or
complete R loss of the receptors signalling
ability. In the absence of funtional MC1R,
eumelanin production is shifted to pheomelanin.
16q24.3
UVR
UVR
UVR
UVR
UVR
UVR
UVR
a-MSH
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• The r and R variants are associated with
  phenotypic traits such as red hair, fair skin,
  freckles, and increased sensitive to the UV
  light.

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MCIR Germline Variants Confer Risk for
BRAF-Mutant MelanomaMaria Teresa Landi, Jürgen
Bauer, Ruth M. Pfeiffer, David E. Elder, Benjamin
Hulley, Paola Minghetti, Donato Calista, Peter A.
Kanetsky, Daniel Pinkel, Boris C.
BastianScience 2006313521-2.

• Variants of the MC1R gene have recently been
  reported to be associated with BRAF mutation
  status in subjects with melanoma onset on skin
  without signs of chronic solar damage.
• In subjects with BRAF-mutant melanoma, the odds
  ratio increased from 7.2 for individuals with one
  MC1R variant allele, to 17.0 for those with
  multiple variant alleles, when compared with
  individuals with no MC1R variants.

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Sporadic Cutaneous Melanoma
SSM right arm 55y
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Sporadic Cutaneous Melanoma

• In cases in which there are no at risk
• phenotypical characteristics

Patients can be reasonably sure that their family
runs no hereditable risk of CM.

• In cases in which at risk phenotypical
• characterictics are present

The risk of CM can naturally be transmitted
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OR
(95 CI)


dark
Risk Factors for Melanoma



1.0

-

medium
high/medium
1.8

(1.0
-
3.0)

light
low
2.4

(1.1
-
5.1)

dark


2.6

(1.4
-
4.7)

medium
4.5

(2.0
-
10.3)

light
6.1

(2.3
-
16.7)
dark


high/medium
dark-olive
2.4

(0.9
-
6.6)

medium
4.3

(1.4
-
13.3)

light
5.8

(1.7
-
20.3)

low
dark
medium


6.3

(2.0
-
19.9)

medium
11.1

(3.1
-
39.7)

light
15.0

(3.7
-
60.2)

dark
light


high/medium
3.8

(1.4
-
10.7)

medium
7.0

(2.2
-
20.5)

light
9.0

(2.6
-
31.4)

dark
low


9.9

(3.3
-
29.5)

no

medium

(5.3
-
56.6)

light
17.3

(6.3
-
86.7)

Eye colour
23.4
Ability to tan
Phototype
dark


Atipical nevi
high/medium


4.2

(2.4
-
7.4)

medium
7.4

(3.3
-
16.7)

light
10.0

(3.8
-
26.5)

low

dark
yes


10.9

(4.6
-
25.5)

medium
19.1

(6.7
-
54.3)

light
25.8

(7.9
-
84.2)

dark


dark-olive
high/medium
10.3

(3.4
-
30.8)

medium
18.0

(5.2
-
62.6)

light
24.4

(6.4
-
93.8)

medium
dark
low


medium
26.5

(7.6
-
92.9)

light
46.6

(
11.6
-
187.2)

63.1

(14.2
-
279.3)

dark
light


16.1

(5.2
-
49.9)

medium
high/medium
28.2

(8.2
-
97.1)

light
38.1

(10.0
-
146.0)

dark
low


Landi et al., Br J Cancer 2001
41.6

(12.4
-
138.8)

medium
72.8

(19.6
-
270.5)

light
98.5

(23.8
-
406.9)



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Familial Cutaneous Melanoma
SSM leg 63y
SSM back 55y
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Hereditary Familial Melanoma
SSM leg 63y
MN trunk 55y
Ca Pancreas 61y
SSM back 17y SSM foot 18y
SSM trunk 18y SSM arm 20y
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Two major melanoma susceptibility genes have been
identified.Both are inherited in an autosomal
dominant pattern showing vertical transmission of
the disease.
Chrom 9p21
Chrom 12q13
Mutations in different genes can cause the same
disease
CDKN2A
CDK4
Hereditary Melanoma
Goldstein et al., 2001
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CDKN2A and CDK4 account for 5 to 50 of the
inherited forms of melanoma, depending on the
number of patients affected, the geographical
area, and the possibility of finding a founder
gene.
From 45 to 95 of high risk families do not show
any genetic mutation of the known susceptibility
genes. Probably different mutation genes have
still to be detected.
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CDKN2A

• The first gene, CDKN2A, is located on the short
  arm of chromosome 9 (9p21).
• It is a complex tumour suppressor gene that
  encodes 2 distinct proteins, p16 and p14ARF.
• The p16 protein negatively regulates cell growth
  by arresting cells at G1 phase of the cell cycle.
  
• The p14ARF protein, acts via the p53 pathway to
  induce cell cycle arrest or apoptosis.

p16INK4A
CDKN2A
p14ARF
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CDK4
Chrom 12q13

• The second identified melanoma susceptibility
  gene, CDK4, functions as an oncogene, and maps to
  the long arm of chromosome 12 (12q13).
• CDK4 mutations are very rare as they have been
  detected in only 11 melanoma-prone families
  worldwide.
• In such families all the mutations were detected
  at the codon 24 Arg

CDK4
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CM can also occur in the context of some family
cancer syndromes such as

• RETINOBLASTOMA
• LI-FRAUMENI CANCER SYNDROME
• LYNCH SYNDROME TYPE II
• XERODERMA PIGMENTOSUM
• ALBINISM
• WERNERS SYNDROME

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Diagnosis of Melanoma

• CM presents as an Asymmetric lesion, with
  irregular Borders, dark brown to bluish black in
  Colour, often with different colour tones, and
• (D) larger than 6 mm in size.

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1994
Although all pigmented lesions will change over
time....
1999
2004
This is the naevus of a 14 year old boy and its
evolution over a 10 year period.

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....CM do so much more rapidly
1997
1998
April 14th 2000
December 20th 2000
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Diagnosis of Melanoma
A low number of CM does not show any at risk
morfologic aspects.
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Diagnosis of Melanoma

• A substantial fraction of CM does not show any at
  risk clinical aspects.
• Symmetrically shaped lesions with regular
  borders, sometimes 3-4 mm in diameter.

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Superficial Spreading Melanoma

• SSM accounts for 70 of cases.
• SSM are most often found on areas of the skin
  that are intermittently exposed to the sun, such
  as the upper back of men and the lower legs of
  women.

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Nodular Melanoma

• NM accounts for 10 to 15 of all melanomas, and
  is solely made up of cells showing a tumourigenic
  vertical growth pattern.
• Because of the rapid growth, these lesions are
  often quite thick at the time of removal and
  hence have a poor prognosis.

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Lentigo Maligna/ Lentigo Maligna Melanoma

• LM/LMM represents about 10 of all melanomas.
• It usually occurs on the most chronically sun
  exposed skin of older people.
• They tend to remain non-invasive for many years,
  then become invasive which evidently influences
  the prognosis.

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Acral-Lentiginous Melanoma
ALM arise on the hairless skin of the palms and
soles and on mucosal surfaces. When located in
the nail matrix, the development of a
longitudinal pigmented band in the nail plate may
herald its presence. This kind of melanoma is
the predominant form in coloured people.
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• Some patients have hundreds of nevi, and in these
  cases changes are nearly impossible to detect.
• In these subjects identification of the
  appropriate pigmented lesions to remove (if any)
  requires considerable clinical expertise.

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Total body photographic surveillance may be a
useful technique to document baseline nevi for
comparison at follow-up sessions.
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Efficient digital systems are also available in
most Dermatological Units
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Surgical treatment of Melanoma
The AAD Guidelines Committee recommend the
following excision margins

• After histopathological diagnosis
• re-excision is required, and the
• resection margin is determined by the
• thickness of the primary tumour.

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Sentinel lymph node biopsy

• Sentinel lymph node biopsy (SLNB) has become a
  standard diagnostic procedure for CM with a
  thickness 1 mm and over and without clinically
  detectable lymph node metastases (stage I,II).
• The sentinel node can be identified in more than
  96 of cases.
• The procedure is safe.
• Adverse events related to the technique appear to
  be low 1-3.
• False negative SLN rate (defined as LF metastases
  detected in the previously negative biopsy
  basins) is about 6 at a 5-year-follow up.

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Sentinel lymph node biopsy

• Although SLN involvement is a poor prognostic
  factor for CM, controversy still exists as to
  whether or not SLN biopsy alters a patients
  survival.
• The final proof of a survival benefit or lack,
  awaits the completion of the Multicenter
  Selective Lymphadenectomy Trial.
• Although SLN biopsy may be able to identify
  patients who may benefit from adjuvant therapy,
  currently no therapies have been shown to have an
  effect on survival in patients with high risk
  melanoma.

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Conclusions

• Early detection and treatment of CM is of vital
• importance for the patient.
• Therefore, patients must be taught
• to be aware of the damage of sun exposure
• the importance of self-examination
• that contacting expert dermatologists is
  essential for the early detection of the cancer
  and a good prognosis.

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