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Other Prognostic factorsNumber of nodes / bulkyIntransit metastasisDistant metastasis LDH

MetastasisSkinNodesLungsLiverBrainBone

AJCC Staging Groups for Cutaneous Melanoma: 2009

PROGNOSIS BY STAGE:Clinical stage 5yr survivalStage I & II (localized): ~90%Stage III (regional nodes): ~50%Stage IV (visceral metastases):

Early detection!!!!Key to cure

ExamineEntireSkin surface!!!!

What to look for?

Analytical recognitionDifferential recognitionComparative recognitionTechnology: 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

Ugly Duckling or Outlier Lesion

This process is hardwired in all of us

Identify the ugly ducklingABCD

Is melanoma generally apparent as the ugly duckling to multiple observers (irrespective of training)?

Joint 95% Confidence Region for diagnostic accuracyUsing the Ugly Duckling for MM detection

ABCDE mnemonicAsymmetryBorder irregularityColor variegationDiameter 6 mmEvolution (change)

2 or more criteria = suspectThe ABCDs of Melanoma Diagnosis

ABCD-E mnemonic revisedEmphasize 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 / 20034 / 2006

4/3/2006

Research StudyObjectivePre-Film SurveyVideoOSCE: 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 imageImage taken 3 years after baseline

5/31/20074/17/2001

Dermoscopy

Naked eye clinical imageDermoscopy image Dermoscopy removes surface glare & allows visualization of structures below the top layer of the skin.

Melanoma TherapyPrimary cutaneous melanomaExcision with 1-2 cm margins (+/- SLNB)Regional lymph node metastasisTherapeutic lymph node dissectionConsider adjuvant (IFN, vaccine) therapyDistant metastatic diseaseChemotherapy (DTIC or Cis Platinum)Palliative XRTExperimental therapies (eg, biochemotherapy)

RAFMEKERKCellularProliferationRTKBRAFV600EAbnormal CellularProliferationARRESTEDBollag et al. Nature 2010

PET Scans at Baseline and Day 15 after PLX4032

Vemurafenib (Zelboraf)

Mechanism of ActionIpilimumab Blocks CTLA-4 and Potentiates T-cellsAPC=antigen-presenting cell; CTLA-4=cytotoxic T-lymphocyte antigen-4; TCR=T-cell receptor; HLA=human leukocyte antigen

AutoimmuneVitiligoEnterocolitisHepatitisEndocrinopathies

Pre- and Post-Ipilimumab

Week 1 Week 12*

11/28/061/9/07

Ipilimumab (Yervoy)

Research StudyObjectivePre-Film SurveyVideoOSCE: Post-Film Survey

How can you lower the risk for developing skin cancer?ALMOST ALLSKIN CANCERSARE PREVENTABLE!!!!!

GENETIC SUSCEPTIBILITYMOLECULAR PRECURSORCLINICAL PRECURSORRGP MELANOMAMetastasisVGP MELANOMAMelanoma Prevention

PrecursorPrimary- CurablePrimary- IncurableAttributable Mortality

Does UV exposure cause melanoma?

Association between UVR and risk of melanoma Gandini, et al. Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. Eur J Cancer 2005; 41: 45-60.

Association between UVR and risk of melanoma Relative RiskTotal sun exposureRR = 1.34; (95% CI: 1.02, 1.77)Intermittent sun exposureRR = 1.61; (95% CI: 1.31, 1.99)Chronic sun exposureRR=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)

Children of the MoonImpaired UV induced DNA nucleotide excision repairExperiment 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 melanomaIdentified 33,345 mutations (base substitutions)Dominant mutation signature reflects DNA damage secondary to both UVB and UVAResults are analogous to those for cigarette smoking and lung cancer in a companion paperPleasance, et al. Nature 2010; 463: 191-197.

Does protecting the skin from UV prevent melanoma?

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

Topical Sunscreens

Topical SunscreensSome ingredients have both properties, i.e. micronized ZnO

SLIP on a shirtSLOP on sunscreenSLAP on a hatSLIP, SLOP, SLAP!!!

Avoid unnecessary sun exposure

Stay in shaded areas

Protective ClothingRash Guard

Sunglasses

In addition to all that, use sunscreens regularly

SLIP, SLOP, SLAP,

Thank you!

*******Scope,Burroni paperScopes ugly duckling paper**********9/16/2008Frank Surita00530501

*35178661

*9/20/2006Lynn Montag

*****Point estimate of diagnostic accuracy with surrounding 95% CI. The point estimate is in the center of each box.

**2 or more = new JAMA Kopf article on ABCD***********CCND1=cyclin D1Most melanocytic nevi and melanoma have somatic activating BRAF or RAS mutationsThis cyclin D1 forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb and the expression of this gene is regulated positively by Rb.BRAF mutations are associated with intermittent sun exposed skin (59%MM in these locations as compared to mucosal MM 11% or acral 23%). PTEN tumor suppressor inhibits PI3K (mutation in Cowdens syndrome though melanoma not commonly associated.)C-KIT proto-oncogene, receptor for stem cell factor, targeted therapiessorafenib

***telford*The primary end points used in the evaluation of these interventions were the incidence of basal cell carcinoma and the incidence of squamous cell carcinoma after 4.5 years of follow-up. In their current report, the authors focus on the incidence of in situ and invasive melanoma during the 15 yearsof trial participation as a secondary end point, and use it to test the hypothesis that regular sunscreen use by white adults prevents the occurrence of primary cutaneous melanoma, with a possible latent effect of up to 10 years.

Here, the study population was comprised of adults living in Nambour, a township in Queensland, Australia, where there is high solar UV radiation, with the UV index frequently climbing to higher than 12, classified as 'extreme'. Half of the subjects were given a sunscreen (sun protection factor [SPF] 16) with instructions to apply this every morning to the head, neck, arms and hands during the trial period of 4 years. The other half used sunscreen of any SPF at their usual discretionary frequency, which was once or twice a week (35%), or in some cases not at all (38%). Sun exposure was similar in the two groups. Monitoring was carried out for new skin cancers, including melanomas, for 10 years after the trial had been completed. While 22 people out of 428 participants developed new primary melanomas in the discretionary group, of which 11 were invasive, only 11 people out of 418 participants developed melanomas in the daily sunscreen group, of which three were invasive. Although these figures are striking, it should be noted that the difference between the two groups was of borderline statistical significance. The decrease in melanomas was found on all body sites, not just the ones where sunscreen had been used, suggesting that the application had been extended to the trunk and lower limbs by those in the daily sunscreen group. The conclusions are that excessive sun exposure is a major risk factor for melanoma in adults and that this can be reduced by the regular use of sunscreen. *Issue was raised regarding contradiction between the P-values reported and the authors conclusions because both of those P values could be considered to be a borderline significance.

P-values have historically been considered in two different conceptual frameworks:1) The first is that it is an index or measure of evidence that can be used to measure disagreement between what is observed and expected under a null hypothesis. The weakness in this case is that it does not consider the effect size. P for large effect in small sample = P for small effect in large sample.

2) The second framework is the more commonly understood approach and involves defining two hypothesis (null and alternative) and the statistical test defines one of two behaviors (reject null or accept alternative). This second framework considers the power of the statistical test. In this case, they presented HRs to describe the incidence of melanoma in the two groups.

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Documents

sidesthe ud coin

ugly ducklingabcdidentify

ugly ducklingabcdis

ugly duckling sign

clinical stage

sidesugly duckling

tenderness surface

surface glare