Outline Cancers and Common Spots • Common lesions • Skin cancers – Non‐ melanoma Lindy P. Fox, MD – Melanoma

Associate Professor Director, Hospital Consultation Service Department of Dermatology University of California, San Francisco [email protected]

I have no conflicts of interest to disclose 1

Common Skin Lesions Seborrheic Keratoses • Seborrheic keratosis • BENIGN • Dermatofibroma • Appear beginning at age 40, earlier in • sunny regions • Sebaceous hyperplasia • Stuck-on morphology (above the skin) • Greasy/waxy/warty texture, horn cysts • Face, under breasts, trunk • 0.1 to 2.0 cm in diameter • Treatment: Reassure, cryotherapy

1 Dermatofibroma Cherry • Firm, 3‐7 mm slightly rough surfaced, slightly elevated papules • Very Common • Overlying hyperpigmentation • Increases with age (senile angioma) • Firm to palpation; Dimple sign • F>M (?hormonal) • Often at sites of minimal trauma • 1‐5 mm bright dome‐shaped papule – Bug bite, ingrown hair, etc • Not easily compressible • Treatment : Reassure, cryotherapy, removal • Often recur after removal • Association: None • Association: Multiple (>15) of sudden onset may • Complications: None rarely signal T cell dysregulation (Lupus, HIV)

Pyogenic Granuloma Sebaceous Hyperplasia

• Friable, 5‐10 mm papule • Common, benign • Occurs after trauma • Single or multiple pink to yellow papules on the face, • Children and adults often with and central dell • Biopsy: Excess granulation tissue • May mimic BCC • Treatment: Surgical removal (curette), • Multiple associated with calcineurin inhibitors electrodessication of base • When associated with sebaceous adenoma or • Complication: Rarely may recur and form satellites sebaceous carcinoma, rule‐out Muir Torre (Lynch) syndromes • Treatment‐ low dose isotretinoin, electrodessication, laser, shave removal, PDT, cryotherapy

2 Nonmelanoma Skin Cancer Actinic Keratosis (NMSC) • In-situ dysplasia from ultraviolet exposure. • Actinic Keratosis • Sign of sufficient sun injury to develop NMSC. • Basal Cell Carcinoma • Precancerous (low rate <1%) • Squamous Cell Carcinoma • Prevented by sun screen use, even in adults.

• Caused primarily by ultraviolet radiation • SCC and Actinic Keratoses – P53 tumor suppression gene mutated by UV •BCC – PTCH gene

Actinic Keratoses- Treatment Actinic Keratosis • Liquid nitrogen (single freeze‐thaw cycle) • Diagnosis ‐ Clinical • Topical treatment • 5‐fluorouracil (0.5‐5%) (Efudex) inspection • 5% qd or BID for 2‐4 weeks • Red, scaly patch < 6mm. • Imiquimod 5% cream (Aldara) • TIW x 4 weeks, with repeated cycles PRN • Tender to touch. • BIW or TIW x 16 weeks • QW x 24 weeks • Sandpaper consistency. • Diclofenac (Solareze) • Location ‐ Scalp, face, dorsal • BID x 60‐90 days • Long term treatment (>120 days), moderately effective, side hands, lower legs (women) effects • Picato (ingenol mebutate); 0.015%, 0.05% • When very thick, suspect • Face/scalp‐ 0.015% QD x 3d hypertrophic AK or SCC • Trunk/extrem‐ 0.05% QD x 2d • Photodynamic therapy

3 AKs treated with 5-fluorouracil Actinic Keratoses‐ Treatment

• Always biopsy if an AK is not responding to appropriate therapy – r/o SCC, superficial BCC

http://www.crutchfielddermatology.com

Basal Cell Carcinoma Basal Cell Carcinoma‐ Clinical Subtypes

• Most common of all cancers • Nodular (classic) – > 1,000,000 diagnosed annually in USA • Superficial – Lifetime risk for Caucasians: up to 50% • Pigmented • Intermittent intense sun exposure and • Morpheaform (scar‐like) overexposure (sunburns) • Locally aggressive, very rarely • Clinical subtypes have different biologic metastasize behavior • Histologic subtypes also influence behavior

4 Basal Cell Carcinoma‐ Superficial Basal Cell Carcinoma‐ Pigmented

• Clinically pink, slightly scaly, slightly shiny • May be entirely pigmented or there may patch be specks of pigment within what • Looks like an actinic keratosis otherwise looks like a nodular or • May be treated with imiquimod, ED+C superficial BCC • Melanoma is on the differential!!

Basal Cell Carcinoma‐ Treatment Basal Cell Carcinoma‐ Morpheaform Location, Size, and Subtype Guide Therapy • Clinically scar-like • Superficial • Imiquimod • Difficult to determine clinically where • Electrodesiccation and curettage (ED+C) lesion begins and ends • Nodular or pigmented • Treat with excision (have pathologist • ED+C check margins) or Mohs micrographic • Excision (4mm margins) surgery • Mohs micrographic surgery –DO NOT ED+C • Radiation‐ comorbidities, tumor size and location • Morpheaform, infiltrative, micronodular • Excision (4mm margins) • Mohs micrographic surgery

5 Topical Treatment of Skin Cancer Topical Treatment of Skin Cancer

• Nonsurgical approaches for managing some • Imiquimod 5% cream can effectively treat skin cancers are available superficial BCC’s and SCC in situ • Patient selection is the key • Treatment regimen is 5X per week for 6-10 • Topical treatments work for superficial weeks depending on the host reaction cancers (not invasive ones) • Efficacy is relatively high (75%-85%) • Superficial BCC, SCC in situ • Scarring may be reduced compared to surgery • Long courses of treatment (months) may be required • Biopsy to confirm diagnosis before treating

Basal Cell Carcinoma‐ Treatment Mohs micrographic surgery Squamous Cell Carcinoma

• Recurrent or incompletely excised tumors • Presents as red plaque, ulceration, or • Aggressive histologic subtype (infiltrative, wart like lesion morpheaform, micronodular) • Risk factors: • Poorly defined clinical margins – Fair skin • High risk location (face, ears, eyes) – Inability to tan • Large (>1.0 cm face, >2.0 cm trunk, extrem) – Chronic sun exposure • Tissue sparing location (face, hands, genitalia) • Special situations: – Organ transplant • Immunosuppressed patients recipients • Tumors in previously irradiated skin or scar • Tumors arising in setting of genetic diseases

6 Keratoacanthoma Squamous Cell Carcinoma Treatment • SCC in situ – 5FU, imiquimod, liquid nitrogen, electrodesiccation and curettage • Invasive SCC – Excision with 4 mm margins – Mohs micrographic surgery

• Rapidly growing (1month) • Dome-shaped nodule with central core of keratin • May spontaneously regress, but treat as an SCC

Squamous Cell Carcinoma‐ Treatment Mohs micrographic surgery Skin Cancers on the Lower Legs • Recurrent or incompletely excised tumors • BCC and SCC in situ is common on the • Aggressive histologic subtype (perivascular, perineural) lower legs, especially in women • Poorly defined clinical margins • They presents as a fixed, red, scaly • High risk location (face, ears, eyes) patch(es) • Large (>1.0 cm face, >2.0 cm trunk, extrem) • It looks very much like a spot of eczema • Tissue sparing location (face, hands, genitalia) • Think of skin cancer when red patches on • Immunosuppressed patients the lower legs don’t clear with • Tumors in previously irradiated skin or scar moisturizing. • Tumors arising in setting of genetic diseases

7 Case • Skin Biopsy = Squamous • 64 year old man with Cell Carcinoma psoriasis, , s/p • Chronic phototherapy and renal transplant immunosuppressive • 3 months of ulceration of treatments have led to skin medial aspect of left lower cancer leg, thought to be due to • If leg ulcer doesn’t heal with venous insufficiency appropriate treatment—refer • 3 months of topical treatment or biopsy fails to improve ulceration

Question: Which of the following is FALSE Question: Which of the following is FALSE about skin cancer in organ transplant about skin cancer in organ transplant recipients recipients 1. Basal cell cancers are more common 1. Basal cell cancers are more common than squamous cell cancers than squamous cell cancers 2. Voriconazole use is associated with 2. Voriconazole use is associated with skin cancer in transplant patients skin cancer in transplant patients 3. The skin cancers are more 3. The skin cancers are more aggressive aggressive 4. The skin cancers are potentially fatal 4. The skin cancers are potentially fatal 5. Skin cancers are the most common 5. Skin cancers are the most common type of malignancy in this group type of malignancy in this group

8 Skin Cancer in Organ Transplant Skin Cancer in Organ Transplant Recipients Recipients • Skin cancer is the most common malignancy in • Biologic behavior much more aggressive than in sold organ transplant patients the general population • Incidence increases with survival time post • SCC transplant • Presents at a younger age • Ongoing debate as to whether one or another • Presents 3‐5 years after transplantation immunosuppressive is more associated with skin • High frequency of local recurrence in first 6 mo after cancer risk excision (13.4%) • 90% are nonmelanoma skin cancer: SCC>BCC • 7% LN metastasis during second year after excision – Squamous cell carcinoma (SCC) • Grow rapidly • 65 X the incidence in the general population • Aggressive histologic growth pattern – Basal cell carcinoma • 10 X the incidence in the general population Derm Surg 2004. 30: 642-50

Skin Cancer in Organ Transplant Skin Cancer in Organ Transplant Recipients Recipients • Risk Factors – Increased age • To reduce skin cancer risk in transplants: – Increased exposure to UV radiation – Reduce total immunosuppressive dose to minimum – Increased amount of immunosuppression required (SCC) – Absolute sun protection – Fair skin (Fitzpatrick skin types I, II, III) – Oral acitretin (25 mg daily) may reduce rate of SCC – Personal history of AK, NMSC, melanoma development – Heart > kidney > liver transplants – Switch from voriconazole to another antifungal – HPV infection • Please refer your organ transplant patients to a dermatologist for regular skin checks – Voriconazole

9 Acquired Nevi (Moles) Atypical Moles • Almost universal • In areas of sun exposure • Not in sun exposed sites • Change throughout life, appearing at preschool • Larger than 6 mm in diameter age, growing during young adulthood, and • Greater than 50 involuting in old age • 5mm in diameter or less (size of pencil eraser) • Size (>6mm), number (more than 50) and pattern (not in sun exposed sites) predicts melanoma

Question: The most important prognostic Question: The most important prognostic indicator in melanoma is: indicator in melanoma is: 1. Duration of lesion before diagnosis 1. Duration of lesion before diagnosis 2. Depth of lesion 2. Depth of lesion 3. Presence of ulceration 3. Presence of ulceration 4. Size of radial growth phase 4. Size of radial growth phase 5. Location of lesion 5. Location of lesion

10 Malignant Melanoma Lifetime Risk of Invasive Melanoma in US • Most frequent cause of death from skin cancer • Frequently occurs in young adults – #1 cause of cancer death in women age 30-35 • Intermittent, intense sun exposure (sunburns) • Certain genetic mutations explain melanoma in non sun-exposed sites

Dermatol Clin. 2012 Jul;30(3):363-8

Malignant Melanoma Malignant Melanoma

• Current lifetime risk of melanoma in US • 85% are cured by early diagnosis. This – 1.94% males, 1.30% females has been increased from 65% 30 years • Current lifetime risk of dying of melanoma in US ago by educating MD’s and patients. – 0.35% males, 0.20% females • 2/3 of melanomas diagnosed bet 1988-99 <1mm in • Advanced lesions are virtually always fatal depth (thin) • The goal of all physicians is to recognize • Proportion of thick melanomas (≥ 2mm) stayed the same (14.4-15.5%) melanomas EARLY when curable. • KEY- know who is at risk and what to look for and diagnose early

J Am Acad Dermatol. 2007 Oct;57(4):555-72 Ann Int Med. 2009; 150: 188-93

11 Diagnosis of Melanoma Risk factors for melanoma

• The prognosis is DEPENDENT on the depth of lesion (Breslow’s classification) and lymph node M oles - atypical status M oles - typical > 50 • Melanoma of < 1mm in thickness is low risk R ed hair and freckling • Sentinel lymph node biopsy is recommended for melanoma > 1mm (controversial) I nability to tan – skin types 1 and 2 • If melanoma is on the differential, complete S evere childhood sunburns excision or full thickness incisional biopsy is K indred - first degree relatives with indicated melanoma; genetic mutations: CDKN2A, CDK4, others

Melanoma and Sunscreen Use Malignant Melanoma

• Sunscreen use does decrease the risk of melanoma • Asymmetry – 1621 patients • Border • Regular sunscreen vs. “discretionary sunscreen” • Color use •Diameter • 11 melanomas in sunscreen group vs 22 in • Evolution discretionary group • Fewer invasive melanomas in sunscreen group

Green et al. J Clin Oncol 2011.

12 Malignant Melanoma Malignant Melanoma

• Asymmetry – Two halves of lesion not • Asymmetry the same • Border – Irregular, notched, vague • Border • Color • Color •Diameter •Diameter • Evolution • Evolution

Malignant Melanoma Malignant Melanoma

• Asymmetry • Asymmetry • Border • Border • Color - Variations in color: red, white • Color and blue • Diameter - Approximately 6mm (pencil •Diameter eraser) • Evolution • Evolution

13 Amelanotic Melanoma Malignant Melanoma • Form of melanoma that lacks pigment • Asymmetry • Must THINK about it in order to make the • Border diagnosis • Color •Diameter • Evolution - Changing

Reports in literature supporting treatment of LM with imiquimod Melanoma and Imiquimod

• Lentigo maligna (LM) = in situ melanoma in sun exposed areas • Lentigo maligna melanoma (LMM)- when LM becomes invasive melanoma

CONTROVERSIAL, more studies needed, I don’t recommend

14 NEW Systemic Therapies for the Treatment of Advanced Skin Cancer Melanoma and Pregnancy •BCC – Vismodegib (Erivedge) • In pregnant patients • Hedgehog signaling pathway inhibitor • Biopsy suspicious lesions • Metastatic, relapsed, inoperable, ornot amenable to radiation • Localized melanoma does not change prognosis • Melanoma • Treatment with wide local excision is safe • BRAF inhibitors (V600E mutation) • SLN mapping/ biopsy controversial in pregnancy • Vemurafenib (Zelboraf); Dabrafenib (Tafinlar); trametinib (Mekinist); • Pregnancy before or after melanoma does not cobimetinib (Cotellic) change prognosis – Monoclonal Ab to CTLA4 • Ipilimumab (Yervoy) • No absolute contraindication to OCPs or HRT in – Monoclonal Ab to PD-1 patient with history of melanoma with no • Pembrolizumab (Keytruda); Nivolumab (Opdivo) reasonable alternative – MEK inhibitor Clin Dermatol. 2009 Jan-Feb;27(1):116-21 • Trametinib (Mekinist)

Why Sunscreens?

• Prevention of skin cancer • Prevention of photosensitivity (UVA) Sunscreens 101 – Medications – Diseases: e.g. lupus erythematosus • Prevention of skin aging

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15 UV-B and UV-A Sunscreen 101 UVB (290‐320nm) UVA (320‐400nm) • SPF refers ONLY to UVB blockage • Burning rays of the • Tanning rays sun • Aging rays • There is no standardized measure of UVA • Filtered by the ozone – a complete UVA blockade (yet) layer blocker = anti-aging • Water resistant cream • Most carcinogenic • Maintain SPF after 40 minutes of immersion in • Primary target of • Cause of medication water sunscreens related photosensitivity (e.g. • Water proof HCTZ) • Maintain SPF after 80 minutes of immersion in • SPF refers only to • Harder to block water UVB blockade

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New Sunscreen Labeling Chemical vs Physical Sunscreens (Summer 2012) • Broad spectrum = blocks UVA and UVB • Chemical sunscreens have UV absorbing chemicals • SPF= UVB blockade – Benzophenone, Parsol 1789, Mexoryl, etc • For sunscreen to say can prevent skin cancer – Chemical UVA blockers are photo‐unstable (degrade) AND sunburn, must • Stabilizers are now common (e.g. Helioplex) 1. be broad spectrum • 2. SPF ≥ 15 Physical sunscreens scatter or block UV rays – Zinc and titanium are physical blockers • Water resistant for 40 min or 80 min – More photostable – No more “water proof”, “sweat proof” – Block UVA well – Suggests that always need to re‐apply every 2h – Inelegant (white film)

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16 What Sunscreen Should I Buy? How to Apply Sunscreen

• SPF must be double digits (preferably≥30) • Put it on every morning before leaving the house • Broad spectrum (UVA AND UVB protection) – at least 20 min before sun exposure • UVA blockade does not parallel SPF on the label • For heavy sun exposure: reapply 20 minutes • Best UVA protection in US: after exposure begins •TiO2, ZnO, Mexoryl, or Parsol 1789 with Helioplex • Reapply every 2 hours or after swimming/sweating/towel-drying • Examples: • Apply liberally – Neutrogena Ultrasheer SPF 85 (Parsol 1789 with helioplex) – 1oz application= shot glass = covers the body – Anthelios XL 50+ (Mexoryl) (now approved in US as SPF 40) – Vanicream 50+ (Zinc and titanium)

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Sunscreen Myths

• The American Academy of Dermatology recommends that an • Antioxidants in sunscreens adequate amount of vitamin D should be obtained from a healthy diet that includes foods naturally rich in vitamin D, foods/beverages – Vit E, Vit C, tea extract, etc fortified with vitamin D, and/or vitamin D supplements. Vitamin D – No SPF value, prob no beneficial effect should not be obtained from unprotected exposure to ultraviolet (UV) radiation. • Nanoparticles in sunscreens (e.g. zinc and titanium) • Unprotected UV exposure to the sun or indoor tanning devices is a – Coated when in sunscreen, do not penetrate known risk factor for the development of skin cancer. intact skin, remain on surface of the skin • There is no scientifically validated, safe threshold level of UV exposure from the sun or indoor tanning devices that allows for – No evidence of any consequences when used on maximal vitamin D synthesis without increasing skin cancer risk. • To protect against skin cancer, a comprehensive photoprotective intact skin, not sufficient data when there is regimen, including the regular use and proper use of a broad- barrier dysfunction spectrum sunscreen, is recommended

68 Taken from: American Academy of Dermatology website, 1/25/11

17 Vitamin D Summary • Typical sunscreen use does not affect Vit D levels • Look at the skin during routine exams • Strict use will lead to low Vit D levels • If you suspect invasive melanoma, try to • Supplement those at risk for osteoporosis who perform an excisional biopsy, if not obey stringent sun-protections practices saucerization OK • E.g. organ transplant patients • UVA and UVB exposure are implicated in skin disease – Broad spectrum sunscreens required to block both • Dermatologists do not recommend UV exposure as vitamin D supplementation

The FOX family

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