Suraj Venna, MD Director, Pigmented Lesion Clinic Assistant Clinical Professor, Dermatology

ABC News Flash November 2007 Melanoma Update and Other Neoplasms of the Skin Botox May Beat Cancer Concern in Race to Dermatologist. Wait Times Shorter for Patients Seeking Wrinkle Injections Than Those With Suspicious Moles.. Suraj Venna, MD Director, Pigmented Lesion Clinic Assistant Clinical Professor, Dermatology 8 days median wait time for Botox 26 days median wait time for changing mole Resneck et al. J Am Acad Dermatol. 2007 Dec;57(6):985-9. Epub 2007 Aug 27. Outline Melanoma epidemiology Risk factors Moles and Melanoma Early Diagnosis Role and Indication for SLNBx Surgical Management of Melanoma Tanning and Vitamin D Other skin tumors Lifetime Risk Invasive Melanoma 1/1500 1/250 1/100 1/62 1/50 Projected 1935 1950 1980 1985 1993 2000 2005 2006 2010 *Rigel, D et al. CA Cancer J Clin 1996:46:195-198 198 **American Academy of Dermatology Annual Meeting, 2008 1

Top 10 Malignancies Male Prostate 218,890 (29%) Lung and Bronchus 114,760 (15%) Colon and Rectum 79,130 (10%) Urinary Bladder 50,040 (7%) NHL 34,200 (4%) Melanoma 33,910 (4%) Kidney 31,590 (4%) Leukemia 24,800 (3%) Oral Cavity 24,180 (3%) Pancreas 18,830 (2%) Estimated New Cases* Female Breast 178,480 (26%) Lung and Bronchus 98,620 (15%) Colon and Rectum 74,630 (11%) Uterine Corpus 39,080 (6%) NHL 28,990 (4%) Melanoma 26,030 (4%) Thyroid 25,480 (4%) Ovary 22,430 (3%) Kidney 19,600 (3%) Leukemia 19,440 (3%) Melanoma ranks second among all cancers in years of productive life lost, 2nd only to leukemia Productive years lost/fatality 25 20 15 10 5 ALL SITES 766,860 (100%) ALL SITES 668,470 (100%) Adult leukemia Melanoma Cervical Breast Ovarian *Excludes basal and squamous cell skin cancers and in situ carcinoma except urinary bladder. Note: Percentages may not total 100% due to rounding. 2007, American Cancer Society, Inc., Surveillance Research Cancer Facts & Figures 2007. Source: Journal of the American Academy of Dermatology, Volume 23, Number 2, Part 1, August 1990x Approximately $1.5 billion is spent in the United States each year on treatment of melanoma. Cancer Trends Progress Report (http://progressreport.cancer.gov), in 2004 dollars, based on methods described in Medical Care 2002 Aug; 40 (8 Suppl): IV-104 17. 17. Trends in Cancer Incidence: 1950-2000 (whites) Melanoma Liver Lung Multiple Myeloma Prostate NHL Thyroid Kidney Testis CNS Bladder Breast All Sites Larynx Pancreas Leukemia Hodgkin's Disease Colorectal Uterus Esophagus Ovary -31.2-74.3-77.6 295 294.3 291.6 282.9 252 240.8 196.1 167.6 159.7 96.9 90.6 88.7 43 36.5 21 31.5 20.4 18.5 16 15.7 Oral Stomach Cervix 619.1-100 0 100 200 300 400 500 600 700 % Change SEER Data, 1950 2000, Table I 3 2

Annual Change of Cancer Incidence 1995-2004 http://seer.cancer.gov/csr/1975_2004/results_merge d/topic_inc_trends.pdf All sites -0.5 Prostate -0.4 Breast -1.1 Lung -1.3 Colon -1.6 Bladder 0.1 Melanoma 1.8 NHL 0.2 Kidney 2.3 Uterus -1.2 Leukemia -1.1 Pancreas 0.3 Oral Cavity -1.3 Thyroid 5.7 Ovary -1.4 Stomach -1.4 Annual Percent Change Estimated New Melanoma Cases & Deaths: US, 2007 70000 60000 50000 40000 30000 20000 10000 0 59940 8110 Total 58% vs 42% 33910 5220 Male 26030 2890 Female Death 65% 35% Cases Deaths American Cancer Society. Cancer Facts & Figures 2007. 60,000 / year Melanoma Incidence The majority (65%) of patients present with low risk or thin melanomas Type Number (%) Distant 1900 (3.5%) Regional 5000 (9%) 4+ mm 2400 (3%) 1-4 mm 12,300 (23%) < 1mm ~40,000 (65%) Clark s Level vs Breslow s Depth Clark s level refers to the anatomic layer of the skin Breslow s depth refers to the absolute thickness of the melanoma in millimeters Epidermis Dermis Clark s I II,III, IV +50,000 In-Situ Melanomas Over 100,000 melanomas! Adipose V 3

Doctor, I have Stage 3 melanoma Melanoma Thickness Stage 3C melanoma, 5yr survival < 25% Clark s level III and < 1mm is Stage 1A = 95% 5-year survival Thin Intermediate Thick < 1mm 1-4mm > 4mm Stage I low risk for metastases Stage II Staging intermediate risk for metastases Stage III Regional metastasis Stage IV Distant metastasis * Presence of ulceration up-stages the prognosis Survival 5-year 10-year MMIS 100% 100% Stage IA 95% 88% Stage IB 90% 80% Stage IV 10% 8% 4

Melanoma Incidence Rates: US, 1975-2000 Incidence (per 100,000) 30 25 20 15 10 5 0 1975 1980 1985 1990 1995 2000 White Men All Men Overall Women Ries LAG, et al, eds. SEER Cancer Statistics Review, 1975 2000. Bethesda, MD: National Cancer Institute; 2003: Tables XVI-1 9. The Challenge The Clark Model of Melanoma Progression Incidence of melanoma continues to rise Screening efforts have lead to capture of thinner melanomas Mortality from melanoma continues to rise 4% of all skin cancers 80% of deaths from skin cancer 14% metastatic disease survive 5 years SSM Patch Raised Nodular Miller & Mihm: MELANOMA; NEJM 2006 5

Primary site Extremities females, trunk in males Acral lentiginous melanoma Any ethnic origin No history of significant sun exposures Regional lymph nodes Skin, soft tissues, lung, liver Can develop in people of Risk Factors darker complexion Fair skin History of sunburn Excessive sun exposure Sunny or high-altitude Moles FH FAMMM Immunodeficiency Carcinogen exposure Hereditary conditions The greatest damage seems to occur before you're 18 but sunburn in adulthood also are a risk factor One dysplastic nevus doubles risk of MM coal tar, the wood preservative creosote, arsenic compounds in pesticides and radium 6

Risk Factors * RR PEOPLE AT HIGH RISK OF MELANOMA Fair skin 2-18 Freckles 3-20 Blonde hair 2-10 Red hair 2-6 Inability to tan 2-5 Blue eyes 2-5 Constant Sun 2-5 Intermittent Sun 2-3 Immunosupp 2-8 NMSC 3-17 PH of 1 melanoma 9-10 FH of melanoma 8 50-100 common nevi 2-64 1 or 2 atypical moles 2-11 AMS No PH/FH 2-92 PH, no FH 8-127 1 family member w/mm 2 family member w/mm 33-444 85-1269 Prior history of melanoma Familial melanoma (pancreatic cancer) Atypical mole syndrome 50 common nevi 5 atypical nevi Multiple melanocytic nevi 100 common nevi Kopf & Bart. AMS. JAAD 1995 Moles and melanoma risk Are Moles Precursors to Melanoma? 7

Evil Mole May 1978: Origin of familial malignant melanomas from heritable melanocytic lesions. 'The B-K mole syndrome' W. H. Clark Jr, R. Reimer, M. Greene, A.Ainsworth and M. Mastrangelo Described distinct mole syndrome in 6 melanoma prone families with a total of 37 patients B-K mole syndrome designation based on last names of 1 st two families studied The transformation of two B-K moles into malignant melanomas was documented photographically ttp://bristle.files.wordpress.com/2007/08/blogmoletweak.jpg Nov. 98 Jul. 01 Sequential dermatoscopic images from Drs. Garbe and Bauer Jan. 03 What If virtually percentage all melanomas of melanomas developed evolve on from melanocytic existing nevi, mole? excision of all nevi would reduce the melanoma risk to zero Reference Pre-existing existing Nevi and Melanoma No. of cases Histologic types Percent of associations Stolz et al. 1989 150 22 % Stadler & Garbe 1991 581 23 % Friedman et al 1983 557 23.3 % Kopf et al. 1987 679 all types 26 % for < 1.5 mm, 20-30% 15 % for 1.5-3 mm Rhodes et al. 1983 234 27.4 % Clark et al. 1984 241 30.7 % Sagebiel 1993 1954 SSM/NM 57.6 % 8

DERMATOSCOPY INCREASES SENSITIVITY AND SPECIFICITY Clinical Dermoscopy Examination 31! 10 x Courtesy Claus Garbe,MD and Jurgen Bauer, MD Eberhard-Karls-University Tuebingen, Germany Nevus Nevus March 2001 October 2001 Courtesy Claus Garbe,MD and Jurgen Bauer, MD Eberhard-Karls-University Tuebingen, Germany 9

How High does mole mole count count is a marker relate to of melanoma? risk Melanoma risk and number of common melanocytic nevi. Mole Counts and Melanoma Bauer & Garbe: Pigment Cell Res. 2003 Atypical Moles Clark s nevi or dysplastic nevi Potential pre-cursors of melanoma Markers of increased melanoma risk Melanoma risk and number of atypical melanocytic nevi. 1 dysplastic nevus doubles risk of melanoma 2 Fried-Egg Reverse Fried-Egg Bauer & Garbe: Pigment Cell Res. 2003 10

Atypical Mole Syndrome AMS >100 common nevi At least one > 8mm At least one that is clinically atypical FH not required, but if (+) then even higher risk of melanoma *RR No PH/FH 2-92 PH, no FH 8-127 1 family member w/mm 33-444 2 family member w/mm 85-1269 The Clark Model of Melanoma Progression CDKN2A (9p21) Increases susceptability to Pancreatic Cancer Ph p16 CDK4 p14 ARF MDM2 Retinoblastoma p53 degradation P16 mutations are found in 30-50% cases of familial melanoma; 10-15% of multiple primary melanomas Uncontrolled growth Miller & Mihm: MELANOMA; NEJM 2006 11

FAMMM Melanoma in 1 or more first- or second- degree relatives Many (often >50) melanocytic nevi, at least 1 clinically atypical Histologic confirmation of dysplasia Chances of finding CDKN2A (p16 mutation) 2 affected 1 st degree < 5% 3+ 20-40% 6+ >60% Multiple primary 10-15% When to offer testing CDKN2A Penetrance is highly variable Offering testing is premature Likelihood of finding mutation is low Doesn t change clinical management Families at Increased Risk of MM Familial Melanoma (FAMMM) XP 10,000 fold increased risk Werner Syndrome Retinoblastoma 50-100 fold increased risk Li-Fraumeni 12

Persons with atypical moles are not at equal risk 100% incidence Melanoma Risk What is the risk of a mole transforming into melanoma over a lifetime? Atypical moles (+) FH (+) PH (+) PH and FH FAMMM RR 2-92 RR 85-1269 Risk of Transformation into Melanoma Moles and Melanoma Tsao et al.: Arch Dermatol., 2003 Annual transformation rates of a single MN ranged from a minimum of 1:200000 in patients <40yo to a maximum of 1:33000 in > 60yo Lifetime risk for transformation of any melanocytic nevus in a 20yo Caucasians: 1:3000 in men, 1:10,000 in women Bauer et al.: Arch Dermatol., 2004 Lifetime risk in German population: < 1:2000 for MN, < 1:60 for DN Screen and risk stratify Low rate of transformation into melanoma Atypical nevi and large number of nevi are risk factors for melanoma Avoid prophylactic excisions of large number of nevi Sagebiel (personal communication) 1:150,000 (MN) 1:2000 (DN) 13

1993 SURGERY, Slingluff and Seigler (DUKE) 7899 patients with melanoma, 3.6% (283) with multiple (2-9) 1 year risk 2% 5 year risk 3.4% 10 year risk 5.3% Will I get another melanoma? 1999 Ann Surg Onc, Elashoff and Morton (City of Hope) 3300 patients with stage I and II, 3.4% developed mutiple melanomas 5 year risk 2.8% 10 year risk 3.6% Bimodal risk: 15-39; 60-79 Did not report on thickness of the 2 nd primary 2003 Cancer, Goggins and Tsao (HARVARD) SEER data base 61,245 patients with melanoma 1 year risk 1% 5 year risk 2.1% 10 year risk 3.2% No comment on thickness of 2 nd primary melanoma Cumulative 10 year risk of a second primary is 3-5% Majority of this risk occurs within the first 5 years Multiple Primary Melanomas History of 2 melanomas 3 rd 30% at 5 years Dysplastic Nevi FH Mutations (p16, tumor suppressor) The magnitude of risk depends on presence of nevi and other risk factors Early Diagnosis of Melanoma Asymmetry Border irregular Color variegated Diameter Patel and Coit, JAMA 2005 http://www.cs.wright.edu/people/faculty/agoshtas/skinseg.zip 14

Nodular melanoma Make up 15% of all types of melanoma Frequently lack classic ABCDs Account for thicker melanomas Account for majority of mortality from melanoma ABCD - E EVOLUTION www.dermis.net Abbasi et al. Early Diagnosis of Cutaneous Melanoma. Revisiting the ABCD Criteria. JAMA 2004 Surgical Management and Sentinel Lymph Node Biopsy in Cutaneous Melanoma Diagnostic Biopsy in Primary Melanoma Goals Rule out lesions with potentially similar features seborrheic keratosis pigmented basal cell cancer solar lentigines atypical nevi Determine depth and level of invasion Identify other prognostic features of the 1º lesion Narrow excisional biopsy (2-3 mm) Am J Clin Dermatol. 2002;3:401-426. 426. Cancer Principles & Practice of Oncology,, 6th ed. 2001:2012-2069. 2069. Guidelines of Care for Primary Cutaneous Melanoma. American Academy of Dermatology. 2001:1-11. 11. 15

Surgical Excision for Localized Cutaneous Melanoma: Recommended Margins Melanoma Thickness 1 1 mm 1.01 2.00 mm 2.01 4.00 mm >4 mm Margin * 1 cm 1 2 cm 2 cm 2 cm Sentinel Lymph Node (SLN) Mapping and Biopsy Lymphatic metastases from tumor spread first through afferent channels SLN is first node along those channels *Maximal achievable with 1 closure Where anatomically feasible NCCN Practice Guidelines: Melanoma. Ann Surg. 1999;230:453 465 465. Sentinel Lymph Node and Melanoma : MSLT-1 trial 2006 CLND when clinically palpable Observation Primary Melanoma (1269) WLE (all pts) SLNBx Nodes tested at time of WLE OBS SLNBx 5yr- OS 86.6% 87.1% 5yr- DFS 72% 78% (+) (-) (+) (-) CLND CLND Morton et al: Sentinel Node Biopsy or Nodal Observation in Melanoma. NEJM 2006 ; 355(13);1307-17 16

Subgroup analysis of (+) nodal disease OBS SLNBx 5yr-OS 52% 72% Mean # nodes 3.3 1.3 Not clear that all (+) sentinel nodes, if not removed, will progress to palpable nodal recurrence What information and benefit do we get from the SLNBx procedure in melanoma Prognostic information- those with nodal disease do worse compared to node (-) patients Allows patient selection for additional treatment (such as interferon) In patients with nodal disease, a complete dissection: Decreases bulky tumor recurrence Offers significant disease free survival Appears to offer overall survival advantage Sentinel node positivity by depth of melanoma < 1mm nearly 0% 1-2.9mm 16-17% 17% 3-3.9mm3.9mm 50% 4-4.94.9 40% Kashani-Sabet et al. Prediction of Sentinel Lymph Node Micrometastasis by Histological Features in Primary Cutaneous Malignant Melanoma. Arch Derm 1998 17

UCSF Melanoma Center Indications for SLN Biopsy Melanomas > 1 mm thick Melanomas of unknown primary Melanomas < 1 mm thick Clark level IV or V/ Ulceration (T1b) Vascular invasion/ microsatellites Extensive regression Ultraviolet Radiation Genetic changes Impairs cutaneous immune function Induces formation of DNA-damaging reactive oxygen species Melanin is main defense against UV radiation Variation in pigmentation associated with variations in susceptibility to melanoma Nature of exposure is important Tanning and melanoma risk 1,000,000 people use tanning beds every day in the US! 50,000 tanning facilities nationwide 28 million users of tanning facilities UV Emitting Devices (Pre 1980) (Post 1980) SUNLAMPS TANNING BEDS Cyr WH (1999) Cdrh evaluation of UV-emitting sunlamp products. In: Proceedings of the CDC and prevention conference. San Diego, CA Higher UVB Shown to increase melanoma risk Higher UVA Lag-time to melanoma development Clough-Gorr et al. Exposure to sunlamps, tanning beds and melanoma risk. Cancer Causes Control 2008 18

Who are the tanners? x More likely to tan outdoors Less likely to use sun protection Less knowledgeable about skin cancer risk More influenced by social factors More concerned about weight More likely to smoke More likely to binge drink More likely to use recreational drugs More likely to have parents who tan Ibrahim and Brown. Tanning and Cutaneous Malignancy. Brit J Derm April 2008 NO SUCH THING AS A PRE-VACATION or PRE-SUMMER TAN 19

Vitamin D {Debate} UVB 7-dehydrocholesterol Numerous roles in critical cellular processes UV is a documented human carcinogen Risks outweigh benefits Tanning industry is a multi-billion dollar business Frequently cited study advocating tanning for Vit D production UV foundation, supports the tanning industry 25-hydroxy D3 Vit D3 DIET 1,25-hydrox D3 Vitamin D Incidental sun exposure of face and hands 3x/week is sufficient to achieve normal serum levels of Vitamin D Daily intake of 2 8-oz glasses of fortified milk or OJ One MVI Wolpowitz and Gilchrest. The Vitamin D question: how much do you need and how should you get it. JAAD 2006. 20

Treatment of Metastatic Melanoma with Autologous CD4+ T cells against NY-ESO-1 Yee et al., June 19, 2008 NEJM 52yo wm with recurrent melanoma and pulmonary, left iliac and inguinal metastases. Unresponsive to high dose IL-2 Expanded CD4+ T cells specific for a melanoma antigen (NY-ESO-1) Several billion CD4+ T cells formed and infused After infusion, malaise, lymphopenia PET Scans Obtained before T-Cell Infusion and 2 Months after Infusion Immunotherapy with antigen specific T-cells can eliminate tumor cells that express the corresponding antigen The clone appears to also stimulate the immune system to attack tumor cells that don t express this antigen Hunder N et al. N Engl J Med 2008;358:2698-2703 Tumors regressed and pt alive at 2 years Until recently, means of isolating and expanding antitumor CD4+ T cells in numbers sufficient for cellular therapy has not been feasible 21

The art of medicine consists in amusing the patient while nature cures the disease Other Neoplasms of the Skin Voltaire - French author, humanist, rationalist, & satirist (1694-1778) The differential diagnosis includes 1. Melanoma 2. Merkel cell carcinoma 3. Squamous cell carcinoma 4. Cutaneous metastasis 5. All of the above 0% 0% 0% 0% 0% M e l a n o m a M e r k e l c e l l c a r c i n o m a S q u a m o u s c e l l c a r c i n o m a C u t a n e o u s m e t a s t a s i s A l l o f t h e a b o v e :10 22

Merkel Cell Carcinoma Rare and aggressive neuroendocrine carcinoma Account for < 1% all skin tumors SEER data 1986-2001 identified 1124 cases > 70yo 50% H and N M = F UV plays role Higher mortality than melanoma (25% at 3 years) Significant local recurrence, regional, distant metastasis Disparate recurrence and survival data Therapy differs from other cutaneous malignancies Optimal treatment remains controversial Rate per 100,000 Epidemiology: MCC 1986 SEER-9 data 2001 Rate of increase: 8% per year 1986-2001 (P<0.05) Hodgson NC. J Surg Oncol 2005;89:1-4. Epidemiology Organ transplantation HIV infected population Hematologic malignancy 10 fold risk 8 fold risk Post radiation therapy In association with other cutaneous malignancies Polyomavirus Clinical Presentation Red/violaceous non-tender nodule Rapid growth Sun exposed anatomic location Rarely may ulcerate Cyst on biopsy ddx Hodgson NC. J Surg Oncol 2005;89:1-4. Colebunders R et al. HIV Medicine 2004;4:452-454. Engles et al. Lancet 2002;359:497-498. Ziprin P et al. BR J Dermatol 2000;142:525-528. An KP, Ratner D. J Am Acad Dermatol 2001;45(2):309-312. Penn I, First MR. Transplantation 1999;68(11):1717-21. Ngyuen BD, McCullough AE. Radiographics 2002;22:367-376. Poulsen M. Lancet Oncol 2004;5:593-599. 23

Survival: Stage at Presentation 86% 75% Localized Relative Survival 32% 25% Regional Metastatic Time in Years MCC is cause of death in 35%, within first 3 years of diagnosis Agelli M, Clegg LX. J Am Acad Dermatol 2003;49:832-41). Pfeifer T, Weinberg H, Brady MS. J Am Acad Dermatol 1997;37:650-1. 70 yo woman presented with a scar-like lesion, no antecedent trauma Question 1. Merkel cell carcinoma 2. Basal cell carcinoma 3. Metastatic tumor 4. Squamous cell carcinoma 5. Trauma 0% 0% 0% 0% 0% Helm, T. Metastatic Carcinoma to Skin. Emedicine Jan 2007 M e r k e l c e l l c a r c i n o m a B a s a l c e l l c a r c i n o m a M e t a s t a t i c t u m o r S q u a m o u s c e l l c a r c i n o m a T r a u m a :10 24

Cutaneous Metastasis Occur in ~ 5% of patient with malignancy 55yo wm 10 years s/p renal transplant, presents with this: WOMEN MEN Breast 69% Lung 24% Colon 9% Colon 19% Melanoma 5% Melanoma 13% Ovaries 4% Oral cavity 12% Lung 4% Diagnosis Post-transplant transplant skin cancer 1. Merkel cell 2. Melanoma 3. Basal Cell 4. Squamous Cell 5. Seborrheic keratosis M e r k e l c e l l 0% 0% 0% 0% 0% M e l a n o m a B a s a l C e l l S q u a m o u s C e l l :10 S e b o r r h e i c k e r a t o s i s Nearly 30,000 organ transplantations annually Majority being kidney transplants NMSC most common 65 fold increased risk SCC 20 fold increased risk SCC lip 10 fold increased risk BCC 3-4 fold increased risk of melanoma Following 20 years of transplantation, 40-50% will get at least 1 NMSC 25

Organ Transplant Recipient Organ Transplant Recipient Photo courtesy of Isaac Neuhaus, MD 26

Diagnosis Leukemia cutis 1. Seborrheic keratosis 2. B cell cutaneous lymphoma 3. Leukemia cutis 4. Basal cell 5. Melanoma S e b o r r h e i c k e r a t o s i s B c e l l c u t a n e o u s l y m p h o m a 0% 0% 0% 0% 0% L e u k e m i a c u t i s B a s a l c e l l M e l a n o m a :10 Infiltration of neoplastic leukocytes into the epidermis, dermis, or subcutis Clinically identifiable cutaneous lesions Usually have concomitant systemic leukemia Pathogenesis not well defined Skin tropism may be due to chemokine receptors and adhesion molecules 78yo presents with dry flaky skin that is diffuse and associated with weight loss and malaise 1. Xerosis 2. Psoriasis 3. Sezary syndrome 4. Drug eruption 5. Adult onset Adult onset atopic dermatitis 0% 0% 0% 0% 0% X e r o s i s P s o r i a s i s S e z a r y s y n d r o m e D r u g e r u p t i o n A d u l t o n s e t a t o p i c d e r m... :10 27

Erythrodermic CTCL Sezary Syndrome QUESTIONS Leukemic phase of cutaneous T cell lymphoma (Mycosis fungoides) CTCL is considered a type of NHL Older patient Red, burning, scaly skin Weight loss, lymphadenopathy, malaise What percent of newly diagnosed melanomas are thin and can be managed with surgery alone? 1. 10% 2. 25% 3. 50% 4. 65% What is the 10-year cumulative risk of a 2 nd melanoma? 1. less than 1% 2. 1-2% 3. 3-5% 4. 20% 5. 50% 0% 0% 0% 0% 0% 1 0 % 0% 0% 0% 0% 2 5 % 5 0 % :10 6 5 % l e s s t h a n 1 % 1-2 % 3-5 % 2 0 % 5 0 % :10 28

Having one atypical mole increases your lifetime risk of melanoma by: 1. 1x 2. 2x 3. 3x 4. 10x 5. 100x 0% 0% 0% 0% 0% What percent of melanomas arise from a pre-existing existing mole? 1. 100% 2. 80% 3. 50% 4. 30% 5. 5% 0% 0% 0% 0% 0% 1 x 2 x 3 x 1 0 x 1 0 0 x :10 1 0 0 % 8 0 % 5 0 % 3 0 % 5 % :10 The projected lifetime risk of melanoma in the United States by 2010 The average wait time to see a dermatologist for a changing mole is 1. 1/1500 2. 1/150 3. 1/100 4. 1/50 5. 1/25 0% 0% 0% 0% 0% 1. 2.6 mos 2. 2.6 weeks 3. 26 days 4. 1 year 0% 0% 0% 0% 1 / 1 5 0 0 1 / 1 5 0 1 / 1 0 0 1 / 5 0 :10 1 / 2 5 2. 6 m o s 2. 6 w e e k s 2 6 d a y s :10 1 y e a r 29

The average wait time to see a dermatologist for Botox is 1. 8 mos 2. 8 weeks 3. 8 days 4. 8 minutes 5. 8 seconds 0% 0% 0% 0% 0% 8 m o s 8 w e e k s 8 d a y s 8 m i n u t e s :10 8 s e c o n d s 30