Other Prognostic factors

Number of nodes / bulky

Intransit metastasis
Distant metastasis
LDH
Metastasis
Skin
Nodes
Lungs
Liver
Brain
Bone
AJCC Staging Groups for Cutaneous Melanoma: 2009
PROGNOSIS BY STAGE:
Clinical stage 5yr survival
Stage I & II (localized): ~90%
Stage III (regional nodes): ~50%
Stage IV (visceral metastases): <20%
TIME (months to years)
progression
D
e
a
t
h
Early in situ
melanoma
Enlarging
in situ
melanoma
>
Early invasive
radial growth
phase
melanoma
>
>
Vertical growth
phase melanoma
>
1.Regional
metastasis
2.Distant
metastasis
Goal of screening:
1. detect melanomas during this
early stage of tumorgenesis.
2. surgical excision at this stage
offers the patient the best chance
of survival.
Prognosis
determined by
Breslow
depth
Prognosis determined by
number of metastases and
location of metastases
Some melanomas may bypass this
path (i.e., nodular melanoma starts in
the vertical growth phase without an
interveaning radial growth phase).
Early detection!!!!
Key to cure
Examine
Entire
Skin surface!!!!
What to look for?
Analytical recognition
Differential recognition
Comparative recognition
Technology: tools to augment the above
Analytical recognition
Differential recognition
Comparative recognition
Technology: tools to augment the above
Look for a lesion that is out of step
with other moles

Grob JJ, et al. The 'ugly duckling' sign. Arch Dermatol 1998
The UD coin has 2 sides
The UD coin has 2 sides
The UD coin has 2 sides
The UD coin has 2 sides
The UD coin has 2 sides
The UD coin has 2 sides
The UD coin has 2 sides
The UD coin has 2 sides
The UD coin has 2 sides
Ugly Duckling or Outlier
Lesion



This process is hardwired in all of us
Identify the ugly duckling
A
B
C
D
Identify the ugly duckling
A
B
C
D
Identify the ugly duckling
A
B
C
D
Identify the ugly duckling
A
B
C
D
Is melanoma generally apparent as the ugly
duckling to multiple observers (irrespective of
training)?
1- Specificity
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
S
e
n
s
i
t
i
v
i
t
y
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
Experts
Dermatologists
Nurses/Photographers
Dermatology Staff
Joint 95% Confidence Region for diagnostic accuracy
Using the Ugly Duckling for MM detection
Analytical recognition
Differential recognition
Comparative recognition
Technology: tools to augment the above
ABCDE mnemonic
Asymmetry
Border irregularity
Color variegation
Diameter 6 mm
Evolution (change)

2 or more criteria = suspect
The ABCDs of Melanoma Diagnosis
Analytical recognition
Differential recognition
Comparative recognition
Technology: tools to augment the above
ABCD-E mnemonic revised
Emphasize the significance of evolution in the natural
history of melanoma
Calls attention to changes (evolving) of
size
shape
symptoms (itching, tenderness)
surface (especially bleeding)
shades of color
Naheed R et al. JAMA 2004
Patient claims that this new mole appeared approximately 3 weeks ago.
5 / 2003
4 / 2006
4/3/2006
Research Study
Objective
Pre-Film Survey
Video
OSCE: Post-Film Survey
Skin Cancer Exam Video
Which one has changed?
Change is a sensitive marker of melanoma

Photographically assisted follow-up
Interval Professional
Examination
Baseline image
Image taken 3 years
after baseline
5/31/2007
4/17/2001
Analytical recognition
Differential recognition
Comparative recognition
Technology: tools to augment the above
Dermoscopy
Naked eye clinical image Dermoscopy image
Dermoscopy removes surface glare & allows
visualization of structures below the top layer of
the skin.
Melanoma Therapy
Primary cutaneous melanoma
Excision with 1-2 cm margins (+/- SLNB)
Regional lymph node metastasis
Therapeutic lymph node dissection
Consider adjuvant (IFN, vaccine) therapy
Distant metastatic disease
Chemotherapy (DTIC or Cis Platinum)
Palliative XRT
Experimental therapies (eg, biochemotherapy)
RAF

MEK
ERK
Cellular
Proliferation
NRAS
RTK
BRAF
V600E
Abnormal Cellular
Proliferation
Bollag et al. Nature 2010
PET Scans at Baseline and Day 15 after PLX4032

Vemurafenib (Zelboraf)
Mechanism of Action
Ipilimumab Blocks CTLA-4 and Potentiates T-cells
Ipilimumab
T-cell
inactivation
APC
CTLA-4
T-cell
APC
T-cell
activation
T-cell
resting
T-cell
APC
T-cell
activation
CD28
B7
TCR
HLA
APC=antigen-presenting cell; CTLA-4=cytotoxic T-lymphocyte antigen-4;
TCR=T-cell receptor; HLA=human leukocyte antigen
Mechanism of Action
Ipilimumab Blocks CTLA-4 and Potentiates T-cells
Ipilimumab
T-cell
inactivation
APC
CTLA-4
T-cell
APC
T-cell
activation
T-cell
resting
T-cell
APC
T-cell
activation
CD28
B7
TCR
HLA
APC=antigen-presenting cell; CTLA-4=cytotoxic T-lymphocyte antigen-4;
TCR=T-cell receptor; HLA=human leukocyte antigen
Autoimmune
Vitiligo
Enterocolitis
Hepatitis
Endocrinopathies


Pre- and Post-Ipilimumab

Week 1 Week 12
76
11/28/06 1/9/07
Ipilimumab (Yervoy)
Research Study
Objective
Pre-Film Survey
Video
OSCE: Post-Film Survey

How can you lower the risk for developing
skin cancer?
ALMOST ALL
SKIN CANCERS
ARE PREVENTABLE!!!!!

GENETIC
SUSCEPTIBILITY
MOLECULAR
PRECURSOR
CLINICAL
PRECURSOR
RGP
MELANOMA
Metastasis
VGP
MELANOMA
Secondary
Prevention
Melanoma Prevention
Primary Prevention
Chemo?prevention
Sunscreens
retinoids
Beta-carotene
anti-oxidants
Statins
Imiquimod
T4 endonuclease
vaccination
Secondary
Prevention (II)
Precursor
Primary-
Curable
Primary-
Incurable
Attributable
Mortality
Genetic
Susceptibility
Environmental
Exposure
Does UV
exposure cause
melanoma?
Association between UVR and risk of
melanoma
Association between UVR
and risk of melanoma
Relative Risk
Total sun exposure RR = 1.34; (95% CI: 1.02, 1.77)
Intermittent sun exposure RR = 1.61; (95% CI: 1.31, 1.99)
Chronic sun exposure RR=0.95; (95% CI: 0.87, 1.04)
Sunburn history
Sunburn in childhood
sunburns during life

RR=2.24; (95% CI: 1.73, 2.89)
RR= 2.08; (95% CI: 1.70, 2.55)
Gandini, et al. Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure.
Eur J Cancer 2005; 41: 45-60.
Children of the Moon
Impaired UV induced DNA nucleotide excision repair
Experiment of nature (UV linked to skin CA)

More evidence
Supporting the role of UVR in the genesis of melanoma.
Catalogued somatic mutations from a 43yo man with metastatic
melanoma
Identified 33,345 mutations (base substitutions)
Dominant mutation signature reflects DNA damage secondary to both
UVB and UVA
Results are analogous to those for cigarette smoking and lung cancer
in a companion paper
Pleasance, et al. Nature 2010; 463: 191-197.
Does protecting
the skin from UV
prevent
melanoma?
Original Trial
1992-1996
1,621 patients
Subsequently
observed for 10
years (1996-2006)
The two interventions:
sunscreen application
and beta carotene
supplementation,
were evaluated both
alone and in
combination, relative to a
placebo-control group
Melanoma incidence in the Nambour trial:
50% reduction in primary
melanomas (HR=0.50, 95%
CI 0.24 to 1.02; P=0.051).
Substantial reduction in
risk of invasive melanomas
(HR=0.27, 95%CI 0.08-
0.97; P=0.045) when
compared to in situ
melanomas (HR=0.73,
95%CI 0.29-1.81;
P=0.493);
Green A, et al. Reduced melanoma after regular sunscreen use: Randomized Trial Follow-up.
J Clin Oncol 2011 Jan 20;29(3):257-63
Physical sun protection
Clothing
Sun
glasses
Hats
Environmental:
seeking
shade
Topical Sunscreens
Inorganic
(Physical)
Reflect and scatter
UVR and visible
light
Organic
(Chemical)
Absorb UV
radiation.
Topical Sunscreens
Inorganic
(Physical)
Reflect and scatter
UV and visible
light
1. Titanium dioxide
2. Zinc oxide
Organic
(Chemical)
Absorb UV
radiation.
1. UVB filters
2. UVA filters
3. Broadband filters
Micronized Zinc
oxide
Some ingredients have both properties, i.e. micronized ZnO
SLI P on a shirt
SLOP on sunscreen
SLAP on a hat
SLIP, SLOP, SLAP!!!
Avoid
unnecessary sun
exposure
Stay in shaded
areas
Protective Clothing
Rash Guard
Sunglasses
HATS
In addition to all
that, use
sunscreens
regularly
Prudent advice for Individuals at high
risk for melanoma:

Avoid unnecessary sun exposure &
protect your skin when planning
prolonged outdoor activities

Consider supplemental vitamin D 800-
1000 IU/day (especially in the winter)
SLIP, SLOP, SLAP,
AND POP!!!
Thank
you!