Pre-Cancerous Skin Lesions & Skin Cancer

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1 Pre-Cancerous Skin Lesions & Skin Cancer Ian D.R. Landells, MD, FRCPC Clinical Associate Professor Memorial University of Newfoundland Medical Director Dermatology Nexus Clinical Research St. John s, NL Canada

2 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

3 Learning Objectives After attending this session, participants will be able to: Explain the link between actinic keratoses (AKs) and non-melanoma skin cancers (NMSCs) Describe current treatment options for Aks, Discuss the features of squamous cell carcinoma Discuss the features of basal cell carcinoma Discuss the features of dysplastic nevi and melanoma

4 Actinic Keratoses and NMSC AK is a pre-cancerous skin lesion 1,2 AKs may progress to squamous cell carcinoma (SCC), a type of NMSC 3-5 SCC can be in situ (Bowen s disease) or invasive NMSC is the most common type of cancer 6 The other type of NMSC is basal cell carcinoma (BCC) 1. Criscione VD, et al. Cancer. 2009;115(11): Lober BA, et al. South Med J. 2000;93: Marks R, et al. Lancet. 1988;1: Mittelbronn MA, et al. Int J Dermatol. 1998;37: Dinehart SM, et al. Cancer. 1997;79: Rogers HW, et al. Arch Dermatol. 2010;146(3):283-7.

5 Actinic Keratoses and NMSC AK lesions and SCC are frequently contiguous as they share the same genetic alterations and morphology SCC AK Diepgen TL, Yihune G, et al. Dermatology Online Atlas. Berman B, et al. J Fam Pract. 2006;55(5):suppl 1-8. Feldman SR, et al. Cutis. 2011; 87:201-7.

6 Natural History of AKs Natural course of AKs is unpredictable 1-5 Estimates of 40% to 80% of cutaneous SCCs arise from, or near, AKs 2-5 AKs may persist, regress, or progress 1,3 Some lesions that regress will recur, from 32% within 1 year to 92% within 5 years Progression identified as hypertrophic AK, SCC in situ (Bowen s disease), and/or invasive SCC 1. Criscione VD, et al. Cancer. 2009;115(11): Feldman SR, et al. Cutis. 2011;87(4): Marks R, et al. Lancet. 1988;1(8589): Mittelbronn MA, et al. Int J Dermatol. 1998;37: Dinehart SM, et al. Cancer. 1997;79:920-3.

7 What factors put patients at risk of AKs? What questions should you ask patients to determine AK risk factors?

seen in individuals aged 20 to 50 years Individual

8 Male gender Red or blond hair Light-coloured eyes Fair skin Older age, especially those age 50 years and older But is also seen in individuals aged 20 to 50 years Individual Susceptibility Factors for AK Salasche SJ. J Am Acad Dermatol. 2000;42(1 Pt 2):4-7.

Individual Susceptibility Factors for AK 1 1 2-4 Classification Response to UV rays Skin colour I Never tans, always burns White II Tans with difficulty, usually burns White III Average tanning,

9 Individual Susceptibility Factors for AK Classification Response to UV rays Skin colour I Never tans, always burns White II Tans with difficulty, usually burns White III Average tanning, sometimes burns White IV Easily tans, rarely burns Moderate brown V Very easy to tan, very rarely burns Hispanic, Latin, African, Asian, Indian VI Never burns Black 1. Fitzpatrick TB. J Med Esthet. 1975;2: Sng J, et al. J Am Acad Dermatol. 2009;61(3): Ahluwalia J, et al. J Drugs Dermatol. 2012;11(4): Davis SA, et al. J Drugs Dermatol. 2012;11(4):

10 General Risk Factors for AKs High intensity or cumulative exposure to UV radiation 1-3 Sunburns easily, history of severe or blistering sunburn Use of tanning beds or sunlamps Sun vacations, lived in sunny location, snowbirds Outdoor occupation Outdoor hobbies, e.g., golf, skiing, sailing Light therapy or phototherapy for treatment of skin conditions, e.g., psoriasis Prior history of AKs or other skin cancer 4 1. Diepgen TL, et al. Br J Dermatol.2002;146(suppl 61): Berman B, et al. J Fam Pract. 2006;55(5):suppl Hemminki K, et al. Arch Dermatol. 2003;139: Feldman SR, et al. Cutis. 2011;87(4):201-7.

11 General Risk Factors for AKs (cont d) Clinical signs of photodamage, such as solar/senile lentigines, facial telangiectasia, and solar elastosis of the neck 1 Immunosuppression 2 Organ transplantation Immunosuppressive drugs, e.g., abatacept, azathioprine, basiliximab, ciclosporin, glucocorticoids, infliximab, mycophenolate mofetil, tacrolimus HIV Human papillomaviruses may play a role in the etiology of AKs 2 Strongest association in immunosuppressed patients, particularly organ transplant recipients 1. Feldman SR, et al. Cutis. 2011;87(4): Goldberg LH, et al. J Drugs Dermatol. 2010;9(9):

12 Danderm Diepgen TL, Yihune G, et al. Dermatology Online Atlas. Danderm Clinical Signs of Photodamage Solar elastosis of the neck Solar/senile lentigines Facial telangiectasia

13 Clinical Signs of Actinic Keratoses Visible/detectable lesions are reddish to reddish brown, rough, scaly spots (macules or papules) less than 1 cm in diameter 1 Non-visible, non-palpable lesions (subclinical lesions) occur up to 10 times more often than visible lesions, particularly in sundamaged skin 2 >80% of AKs are distributed in sun-exposed areas, including the face, bald scalp, ears, neck, anterior chest, dorsal forearms, and dorsal hands 3,4 1. Ulrich M, et al. Dermatology. 2010;220(1): Berman B, et al. Expert Opin Pharmacother. 2009;10(18): Salasche SJ. J Am Acad Dermatol. 2000;42(1 Pt 2): Shoimer I, et al. Skin Therapy Lett. 2010;15(5):5-7.

14 Clinical Signs of Actinic Keratoses When one AK is observed, you can assume that other non-visible AKs exist Berman B, et al. J Fam Pract. 2006;55(5):suppl 1-8. Photo courtesy of Dr. Kirk Barber.

15 15 Which AK May Progress to Invasive SCC? Photo courtesy Ted Rosen, MD.

Clinical Signs of Actinic Keratoses Lesions can often be felt more easily than seen 1 Red, rough, scaling spots 2 Adherent scale over a pink macule or papule 1 Pinhead to 4 5 mm in diameter 1

16 Clinical Signs of Actinic Keratoses Lesions can often be felt more easily than seen 1 Red, rough, scaling spots 2 Adherent scale over a pink macule or papule 1 Pinhead to 4 5 mm in diameter 1 Distribution: solitary, clustered, or disseminated 1 Generally asymptomatic 1,2 Danderm. Ask female patients to remove makeup that may be camouflaging red or brown spots 1. Stulberg D, et al. Am Fam Physician. 2004;70(8): Canadian Dermatology Association. Actinic keratoses fact sheet

17 Examples of AKs DermNet NZ. DermNet NZ.

18 Examples of AKs DermNet NZ. DermNet NZ. DermNet NZ.

19 The Differential Diagnosis of AKs Bowen s disease (SCC in situ) Danderm. BCC DermNet NZ. Invasive SCC Danderm. Duncan KO, et al. In: Wolff K, et al. Fitzpatrick's Dermatology in General Medicine: 7 th ed. 2008:Chapter 113.

The Differential Diagnosis of AKs Danderm.

20 The Differential Diagnosis of AKs Danderm. Keratoacanthoma Lentigo maligna Danderm. Interactive Medical Media LLC. Pigmented actinic keratosis Duncan KO, et al. In: Wolff K, et al. Fitzpatrick's Dermatology in General Medicine: 7 th ed. 2008:Chapter 113.

21 The Differential Diagnosis of AKs Solar lentigo Danderm. Seborrheic keratosis DermNet NZ. Verruca vulgaris DermNet NZ. Duncan KO, et al. In: Wolff K, et al. Fitzpatrick's Dermatology in General Medicine: 7 th ed. 2008:Chapter 113.

22 The Differential Diagnosis of AKs Lichen planus DermAtlas. Discoid lupus erythematosus Danderm. Duncan KO, et al. In: Wolff K, et al. Fitzpatrick's Dermatology in General Medicine: 7 th ed. 2008:Chapter 113.

23 What is the rationale for prompt treatment of AKs?

24 Actinic Keratosis is a Field Disease Field of cancerisation surrounds clinical AKs and can be clinically invisible with multifocal, paraneoplastic, subclinical changes 1 Histopathology of AK is found in surrounding skin 2 Subclinical (non-palpable, non-visible) AK lesions occur ~10 times more often than clinical AK lesions in sun-damaged skin 3 1. Vatve M, et al. Br J Dermatol. 2007;157(Suppl 2): Berman B, et al. Exp Opin Pharmacother. 2009;10(18): Braakhuis BJM, et al. Cancer Res. 2003;63(8):

25 Field Cancerization: A Key Concept Driving Treatment Choices for AK 1,2 In addition to visible AKs, the surrounding area ( field ) of sun-damaged skin may contain subclinical AKs This results from

25 25 Field Cancerization: A Key Concept Driving Treatment Choices for AK 1,2 In addition to visible AKs, the surrounding area ( field ) of sun-damaged skin may contain subclinical AKs This results from UV-induced damage over an extended area, termed field cancerization Therefore, an AK lesion is the tip of the iceberg istockphoto.com/alexander Soloviev 1. Slaughter DP, et al. Cancer. 1953;6: ; 2. Quatresooz P, et al. Eur J Dermatol. 2008;18:6-10.

26 AK to Invasive SCC Transition Is Likely Driven by Multiple Mutations Initial lesion from first mutation to attenuation of cell-cycle

2-5, * * Order of events may vary, but p53 alteration is usually first.

2-5 Transformed keratinocyte Initial loss of cell-cycle control Increasing loss of cell-cycle control Activation of antiapoptotic

26 26 AK to Invasive SCC Transition Is Likely Driven by Multiple Mutations Initial lesion from first mutation to attenuation of cell-cycle control In UV-damaged skin, immunosuppression facilitates growth and spread of tumor 1 Mutations in key genes drive transition to SCC 2-5, * * Order of events may vary, but p53 alteration is usually first. Normal keratinocyte p53 2 mutation Additional mutations: p16, ras, others? 2-5 Transformed keratinocyte Initial loss of cell-cycle control Increasing loss of cell-cycle control Activation of antiapoptotic pathways 1. Perrett CM, et al. Br J Dermatol. 2007;156: ; 2. Park HR, et al. J Cutan Pathol. 2004;31: ; 3. Soufir N, et al. Oncogene. 1999;18: ; 4. Mortier L, et al. Cancer Lett. 2002;176: ; 5. Spencer JM, et al. Arch Dermatol. 1995;131:

27 Field Cancerization Is a Direct Result of UV Radiation 1,2 UV radiation interacts with foci at multiple stages of malignant transformation, facilitating tumor

27 27 Field Cancerization Is a Direct Result of UV Radiation 1,2 UV radiation interacts with foci at multiple stages of malignant transformation, facilitating tumor promotion and progression Image adapted courtesy Eggert Stockfleth, MD. 1. Slaughter DP, et al. Cancer. 1953;6: ; 2. Quatresooz P, et al. Eur J Dermatol. 2008;18:6-10.

28 28 Field cancerization: lesions at different stages of NMSC may be found next to each other Photo courtesy Eggert Stockfleth, MD.

29 Lesion-directed Treatments: Physically Destructive Methods Place in therapy: scattered AKs, AKs limited in number, thick, hyperkeratotic AKs, patients non-adherent to topical regimens 1,2 Cryotherapy with liquid nitrogen is most common method 1,2 Standard treatment for isolated AK lesions, especially small lesions with well demarcated borders 3 Thin lesions may respond better than thick lesions 3 Freeze times determine response: 39% for <5 seconds, 83% for >20 seconds at 3-month follow-up 2,3 Electrodesiccation Best applied to well demarcated, non-invasive tumours 2 1. Shoimer I, et al. Skin Therapy Lett. 2010;15(5): Han A, et al. J Drugs Dermatol. 2010;9(7): Berman B, et al. J Fam Pract. 2006;55(5):suppl 1-8.

30 Lesion-directed Treatments: Surgical Removal Shave excision or curettage ± electrodesiccation 1-3 Place in therapy: individual AKs, well demarcated, non-invasive tumours; biopsy required to rule out frank carcinoma; hypertrophic AKs refractory to other treatments 1,3 May be followed by electrocautery to destroy additional atypical cell layers and provide hemostasis 2 No documented cure rates with these treatments 2 1. Shoimer I, et al. Skin Therapy Lett. 2010;15(5): de Berker D, et al. Br J Dermatol. 2007;156: Berman B, et al. J Fam Pract. 2006;55(5):suppl 1-8.

31 Is Field Therapy the Necessary Approach? It is impossible to know which AKs will progress to invasive SCC, so it is recommended that all AKs be treated 1 The ultimate goal of treatment is to clear the entire actinically damaged field 2 Addressing both clinical and non-visible lesions may significantly reduce recurrence rates of AKs 2 Early diagnosis and treatment of the field of actinic damage decreases overall disease burden and helps to prevent development of invasive SCC 1,2 1. Martin G. J Clin Aesthet Dermatol. 2010;3(11): Ulrich M, et al. Exp Opin Emerg Drugs. 2010;15(4):

32 Field-directed Topical Therapy Options Treatment Dosing Duration of treatment 5-fluorouracil (5-FU) 5% 1 Twice daily Usual duration: 2-4 weeks Imiquimod 3.75% (face, balding scalp) 2 Up to 2 packets or 2 full actuations of the pump once daily 6 weeks (2 treatment cycles of 2 weeks, separated by a 2-week no-treatment period) Imiquimod 5% (face, balding scalp) 3 Twice weekly 16 weeks Ingenol mebutate 0.015% (face, Once daily 3 consecutive days scalp) 4 Ingenol mebutate 0.05% (trunk, Once daily 2 consecutive days extremities) 4 Aminolevulinic acid 5 or methyl aminolevulinate 6 with PDT (photodynamic therapy) Agents applied a day 5 or a few hours 6 before light treatment 1 5 to 2 6 treatment cycles May be retreated 8+ weeks 5 or 3+ months 6 after initial treatment 1. EFUDEX product monograph, ZYCLARA product monograph, ALDARA product monograph, PICATO product monograph, Levulan Kerastick product monograph, METVIX product monograph, 2009.

33 Combination/Sequential Therapy Cryotherapy or curettage to treat visible AKs + topical treatment to treat underlying field cancerisation: 5-fluorouracil (5-FU) 5% followed by cryotherapy 1 Cryotherapy followed by imiquimod 3.75% 2 Cryotherapy followed by ingenol mebutate 0.015% on face or scalp 3 1. Jorizzo J, et al. Arch Dermatol. 2004;140: Jorizzo J, et al. J Drugs Dermatol. 2010;9: Swanson N, et al. 22nd EADV Congress. Abstract P532; IST

34 Field-directed Treatments: Local Skin Reactions Treatment 5-fluorouracil (5-FU) 5% 1 Imiquimod 3.75%, 5% 2,3 * Ingenol mebutate 0.015%*, 0.05% 4 Aminolevulinic acid or methyl aminolevulinate with PDT 5,6 Local skin reactions Erythema, erosion, crusting, ulceration Significant erythema, burning, erosion, crusting, and/or ulceration can occur during treatment and may require treatment interruption Usually resolve within 2 to 4 weeks Erythema, flaking/scaling/dryness, scabbing/crusting Intense local skin reactions including erythema, scabbing/crusting, and erosion/ulceration can occur after a few applications, and may require treatment interruption Usually resolve within 1 to 2 weeks of discontinuation Erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation Typically occur within 1 day of treatment initiation and peak in intensity up to 1 week following completion of treatment Usually resolve within 2 weeks on face and scalp and within 4 weeks on trunk and extremities Erythema, edema, crusting Usually resolve in days to 1 week Between-study comparisons are not intended due to differences in patient demographics and other study parameters. *Indicated for face and scalp only. PDT, photodynamic therapy. 1. EFUDEX product monograph, ZYCLARA product monograph, ALDARA product monograph, PICATO product monograph, Levulan Kerastick product monograph, METVIX product monograph, 2009.

35 Examples of Local Skin Reactions This LSR comprises erythema, vesiculation, and mild swelling. This LSR comprises more pronounced swelling and erythema.

36 Field-directed Treatments: Other Adverse Events Treatment Other adverse events 5-fluorouracil (5-FU) 5% 1,2 Application site pain, pruritus, burning, dermatitis, soreness, tenderness, hyperpigmentation, scarring Insomnia, stomatitis, suppuration, scaling, swelling, irritability, medicinal taste, photosensitivity, and lacrimation Laboratory abnormalities (leukocytosis, thrombocytopenia, toxic granulation, eosinophilia) Imiquimod 3.75%, 5% 3,4 * Target site pain, tenderness, bleeding, itching, stinging, burning, tingling, irritation, and induration Flu-like symptoms, including fatigue, fever, nausea, myalgias, arthralgias, and chills Exacerbation of inflammatory skin conditions Ingenol mebutate 0.015%*, 0.05% 5 Administration site pruritus, irritation, pain, infection Periorbital pain Headache Eyelid edema Aminolevulinic acid or methyl Pain, stinging, and burning during light therapy aminolevulinate with PDT 6,7 Application site itching, photosensitivity Between-study comparisons are not intended due to differences in patient demographics and other study parameters. *Indicated for face and scalp only. PDT, photodynamic therapy. 1. EFUDEX product monograph, Cheigh NH. In: DiPiro JT, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 2008: ZYCLARA product monograph, ALDARA product monograph, PICATO product monograph, Levulan Kerastick product monograph, METVIX product monograph, 2009.

37 Summary AKs are pre-cancerous skin lesions that may progress to SCC; progression is unpredictable Risk factors for development of AKs include: Amount of cumulative/prolonged exposure to UV Fair skin Light-coloured hair/eyes Older age Immunosuppression AKs may be visible or non-visible/non-palpable Effective treatment of AKs may help to prevent recurrence and/or progression to SCC

38 Non-Melanoma Skin Cancers (NMSCs) Basal Cell Carcinoma (BCC) About 75%-80% of NMSCs Invasive SCC About 15% of NMSCs Photos courtesy Jason Smith, MD. NMSCs constitute nearly half of all cancers in the United States 1 Estimated U.S. annual newly diagnosed cases in 2003: 900,000-1,200,000 NMSCs may be divided into 2 main types: BCC and SCC 1. McGovern TW, et al. Actinic keratoses and non-melanoma skin cancer. American Academy of Dermatology Web site. Accessed April 28,

39 Non- Melanoma Skin Cancer Basal Cell Carcinoma (BCC) Bowen s Disease (SCC in situ) Squamous Cell Carcinoma (SCC)

40 Skin Cancers Basal Cell Ca Most common cancer in humans 80% of skin ca Tumour of Basal cells Nodular, ulcerating, pigmented, sclerosing and superficial types Locally invasive/slow growing Squamous Cell Ca Malignant 15 % of skin ca Tumour of keratinocytes Arises from epidermis Low rate of distant metastases Nodes Malignant Melanoma Tumour of melanocytes 5% of skin ca Commonly back and legs A,B,C,D,E s Assoc dysplastic nevus MIS (melanoma in situ) Metastasize Skin, nodes, liver, lungs, brain

41 Basal Cell Carcinoma Nodular Ulcerating Superficial Pigmented Sclerosing

43 SCC In Situ - Bowen Disease Large sharply demarcated plaque Erythematous Scaly May simulate a psoriatic lesion +/- hyperkeratosis w/ crusts Rx Cryotherapy 5-FU, Imiquimod, Ingenol mebutate Electrodessication

44 Keratoacanthoma Less aggressive variant of SCC Dome shaped nodule with central keratotic plug Tx: Cryotherapy Excision and cautery if necessary

45 Rx Skin CA If small: Bx to confirm type If BCC or Bowen s: Aldara 5x per week x 6 wks LN2- but not if pigmented Otherwise: NB: Excision! By you or refer. XRT If Melanoma suspected, NO cautery need edges Take darkest/most unusual area if biopsy

46 Malignant Melanoma

47 Malignant Melanoma features Asymmetry Border irregularity Colour variation or black Diameter usually >6mm Evolution change in colour, size, shape, itching, painful bleeding

48 Congenital Nevomelanocytic Nevus Present at birth Benign May be precursors to melanoma but uncommon MM s rarely have hair

49 If not sure Punch BIOPSY! DONT use forceps!!!! Can crush specimen Pathology may come back inconclusive

50 For Excision of any papule or superficial nevus

53 Equipment 30 gauge needle with local 15 blade Drysol solution Cotton tipped applicator Band-aid DONT use forceps!!!! Can crush specimen Pathology may come back inconclusive

54 For Excision of any papule or superficial nevus

55 Intradermal Local Bend 30 g needle 45 degrees

56 Determine Depth Insert needle at angle and run under lesion coming out at far side

57 Cut Beneath Needle Run 15 blade, angled up, under and along needle

59 Specimen Remains on needle for easy transfer to formalin

60 Hemostasis 20% Aluminum Chloride (Drysol)

61 Minimal Scar Superficial wound heals with minimum scarring

62 Always Send Specimen Use Separate containers for each specimen

63 Malignant Melanoma Rx Wide Excision MIS cm < 1.0 mm 1.0 cm > cm & Sentinel Node Biopsy

64 Stage III Melanoma That Cannot Be Removed By Surgery, Stage IV Melanoma, and Recurrent Melanoma Immunotherapy Ipilimumab, pembrozilumab, nivolumab, IL-2 Targeted Therapy Vemurafenib, debrafenib, trametinib, cobimetinib Injections into tumor Oncolytic virus therapy Chemotherapy Palliative surgery or radiation

65 And Now for Something Completely Different A few skin lesions often mistaken for skin cancer

66 Dermatofibroma I was bitten by a bug... Benign

67 Chondrodermatitis Nodularis Helicus

68 Rapid developing vascular lesion May follow minor trauma Bleeds spontaneously Tx: surgical excision and cautery

69 Summary BCC 80% Almost never spread SCC 15% May metastasize to nodes Melanoma 5% Potentially lethal Early detection critical A B C D E All related to UV radiation exposure Please protect yourself!! Sunscreen, Hat, Shirt, Shade, Sunglasses

Clinical characteristics

Skin Cancer Fernando Vega, MD Seattle Healing Arts Clinical characteristics Precancerous lesions Common skin cancers ACTINIC KERATOSIS Precancerous skin lesions Actinic keratoses Dysplastic melanocytic