Pre-Cancerous Skin Lesions

& Skin Cancer

Ian D.R. Landells, MD, FRCPCClinical Associate Professor

Memorial University of NewfoundlandMedical Director Dermatology

Nexus Clinical ResearchSt. John’s, NL

Canada

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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

Actinic Keratoses and NMSC

• AK is a pre-cancerous skin lesion1,2

• AKs may progress to squamous cell carcinoma

(SCC),

a type of NMSC3-5

– SCC can be in situ (Bowen’s disease) or invasive

– NMSC is the most common type of cancer6

• The other type of NMSC is basal cell carcinoma

(BCC)

1. Criscione VD, et al. Cancer. 2009;115(11):2523-30. 2. Lober BA, et al. South Med J. 2000;93:650-5.

3. Marks R, et al. Lancet. 1988;1:795-7. 4. Mittelbronn MA, et al. Int J Dermatol. 1998;37:677-81.

5. Dinehart SM, et al. Cancer. 1997;79:920-3. 6. Rogers HW, et al. Arch Dermatol. 2010;146(3):283-7.

Actinic Keratoses and NMSC

• AK lesions and SCC

are frequently

contiguous as they

share the same

genetic alterations

and morphology

Berman B, et al. J Fam Pract. 2006;55(5):suppl 1-8.

Feldman SR, et al. Cutis. 2011; 87:201-7.

SCC

AK© Diepgen TL, Yihune G, et al. Dermatology Online Atlas.

Natural History of AKs

• Natural course of AKs is unpredictable1-5

– Estimates of 40% to 80% of cutaneous SCCs

arise from, or near, AKs2-5

• AKs may persist, regress, or progress1,3

– 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):2523-30.

2. Feldman SR, et al. Cutis. 2011;87(4):201-7.

3. Marks R, et al. Lancet. 1988;1(8589):795-7.

4. Mittelbronn MA, et al. Int J Dermatol. 1998;37:677-81.

5. Dinehart SM, et al. Cancer. 1997;79:920-3.

What factors put patients at risk of AKs?

• What questions should you ask patients to determine AK risk

factors?

Male gender

… But is also seen in

individuals aged 20 to

50 years

Older age, especially

those age 50 years and

older

Fair skin

Red or

blond hair

Light-coloured eyes

Individual Susceptibility Factors for AK

Salasche SJ. J Am Acad Dermatol. 2000;42(1 Pt 2):4-7.

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;2:33034. 2. Sng J, et al. J Am Acad Dermatol. 2009;61(3):426-32.

3. Ahluwalia J, et al. J Drugs Dermatol. 2012;11(4):484-6. 4. Davis SA, et al. J Drugs Dermatol. 2012;11(4):466-73.

1 1 2-4

General Risk Factors for AKs

• High intensity or cumulative exposure to UV

radiation1-3

– 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 cancer4

1. Diepgen TL, et al. Br J Dermatol.2002;146(suppl 61):1-6.

2. Berman B, et al. J Fam Pract. 2006;55(5):suppl 1-8.

3. Hemminki K, et al. Arch Dermatol. 2003;139:885-9.

4. Feldman SR, et al. Cutis. 2011;87(4):201-7.

General Risk Factors for AKs

(cont’d)

• Clinical signs of photodamage, such as solar/senile

lentigines, facial telangiectasia, and solar elastosis of the

neck1

• Immunosuppression2

– 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 AKs2

– Strongest association in immunosuppressed patients, particularly

organ transplant recipients

1. Feldman SR, et al. Cutis. 2011;87(4):201-7.

2. Goldberg LH, et al. J Drugs Dermatol. 2010;9(9):1125-32.

Clinical Signs of Photodamage

Facial telangiectasia

Solar elastosis of the neck Solar/senile lentigines©

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Clinical Signs

of Actinic Keratoses

• Visible/detectable lesions are reddish to reddish brown, rough,

scaly spots (macules or papules) less than 1 cm in diameter1

• Non-visible, non-palpable lesions (subclinical lesions) occur up to

10 times more often than visible lesions, particularly in sun-

damaged skin2

• >80% of AKs are distributed in sun-exposed areas, including the

face, bald scalp, ears, neck, anterior chest, dorsal forearms, and

dorsal hands3,4

1. Ulrich M, et al. Dermatology. 2010;220(1):15-24.

2. Berman B, et al. Expert Opin Pharmacother. 2009;10(18):3015-31.

3. Salasche SJ. J Am Acad Dermatol. 2000;42(1 Pt 2):4-7.

4. Shoimer I, et al. Skin Therapy Lett. 2010;15(5):5-7.

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

Photo courtesy Ted Rosen, MD.

Which AK May Progress to Invasive SCC?

• Lesions can often be felt

more easily than seen1

• Red, rough, scaling spots2

• Adherent scale over a pink

macule or papule1

• Pinhead to 4–5 mm in

diameter1

• Distribution: solitary,

clustered, or disseminated1

• Generally asymptomatic1,2

1. Stulberg D, et al. Am Fam Physician. 2004;70(8):1481-8.

2. Canadian Dermatology Association. Actinic keratoses fact sheet. 2012.

© Danderm.

Clinical Signs

of Actinic Keratoses

Ask female patients to remove makeup that may be camouflaging red or brown spots

Examples of AKs

© DermNet NZ. © DermNet NZ.

Examples of AKs

© DermNet NZ.

© DermNet NZ.

© DermNet NZ.

The Differential Diagnosis of

AKs

BCC

Bowen’s disease (SCC in situ)

Invasive SCC

Duncan KO, et al. In: Wolff K, et al. Fitzpatrick's Dermatology in General Medicine: 7th ed. 2008:Chapter 113.

© Danderm.

© DermNet NZ.

© Danderm.

The Differential Diagnosis of

AKs

Keratoacanthoma

Lentigo maligna

Duncan KO, et al. In: Wolff K, et al. Fitzpatrick's Dermatology in General Medicine: 7th ed. 2008:Chapter 113.

Pigmented actinic keratosis

© Danderm.

© Interactive Medical Media LLC.

© Danderm.

The Differential Diagnosis of AKs

Solar lentigo

Verruca vulgaris

Seborrheic keratosis

Duncan KO, et al. In: Wolff K, et al. Fitzpatrick's Dermatology in General Medicine: 7th ed. 2008:Chapter 113.

© Danderm.

© DermNet NZ.

© DermNet NZ.

The Differential Diagnosis of AKs

Lichen planus

Discoid lupus erythematosus

Duncan KO, et al. In: Wolff K, et al. Fitzpatrick's Dermatology in General Medicine: 7th ed. 2008:Chapter 113.

© Danderm.

© DermAtlas.

What is the rationale for prompt

treatment of AKs?

Actinic Keratosis is a

Field Disease

• Field of cancerisation surrounds clinical AKs and

can be clinically invisible with multifocal,

paraneoplastic, subclinical changes1

• Histopathology of AK is found in surrounding

skin2

• Subclinical (non-palpable, non-visible) AK lesions

occur ~10 times more often than clinical AK

lesions in sun-damaged skin3

1. Vatve M, et al. Br J Dermatol. 2007;157(Suppl 2):21-4.

2. Berman B, et al. Exp Opin Pharmacother. 2009;10(18):3015-31.

3. Braakhuis BJM, et al. Cancer Res. 2003;63(8):1727-30.

25

Field Cancerization: A Key Concept Driving Treatment Choices for AK1,2

• 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”

1. Slaughter DP, et al. Cancer. 1953;6:963-968; 2. Quatresooz P, et al. Eur J Dermatol. 2008;18:6-10.

© iStockphoto.com/Alexander Soloviev

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 tumor1

• Mutations in key genes drive transition to SCC2-5,*

1. Perrett CM, et al. Br J Dermatol. 2007;156:320-328; 2. Park HR, et al. J Cutan Pathol. 2004;31:544-549; 3. Soufir N, et al. Oncogene. 1999;18:5477-5481;

4. Mortier L, et al. Cancer Lett. 2002;176:205-214; 5. Spencer JM, et al. Arch Dermatol. 1995;131:796-800.

p532 mutation

Initial loss of cell-cycle control

Additional mutations: p16, ras, others?2-5

Increasing loss of cell-cycle control

Activation of antiapoptotic pathways

Normal keratinocyte

Transformed keratinocyte

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

27

Field Cancerization Is a Direct Result of UV Radiation1,2

UV radiation interacts with foci at multiple stages of malignant transformation, facilitating tumor promotion and progression

1. Slaughter DP, et al. Cancer. 1953;6:963-968; 2. Quatresooz P, et al. Eur J Dermatol. 2008;18:6-10.

Image adapted courtesy Eggert Stockfleth, MD.

Photo courtesy Eggert Stockfleth, MD.

Field cancerization:lesions at different

stages of NMSC may be found next

to each other

28

Lesion-directed Treatments:

Physically Destructive Methods

• Place in therapy: scattered AKs, AKs limited in number, thick,

hyperkeratotic AKs, patients non-adherent to topical regimens1,2

• Cryotherapy with liquid nitrogen is most common method1,2

– Standard treatment for isolated AK lesions, especially small lesions

with well demarcated borders3

– Thin lesions may respond better than thick lesions3

– Freeze times determine response: 39% for <5 seconds, 83% for

>20 seconds at 3-month follow-up2,3

• Electrodesiccation

– Best applied to well demarcated, non-invasive tumours2

1. Shoimer I, et al. Skin Therapy Lett. 2010;15(5):5-7.

2. Han A, et al. J Drugs Dermatol. 2010;9(7):864-9.

3. Berman B, et al. J Fam Pract. 2006;55(5):suppl 1-8.

Lesion-directed Treatments:

Surgical Removal

• Shave excision or curettage ± electrodesiccation1-3

• Place in therapy: individual AKs, well demarcated,

non-invasive tumours; biopsy required to rule out

frank carcinoma; hypertrophic AKs refractory to other

treatments1,3

• May be followed by electrocautery to destroy

additional atypical cell layers and provide

hemostasis2

• No documented cure rates with these treatments2

1. Shoimer I, et al. Skin Therapy Lett. 2010;15(5):5-7.

2. de Berker D, et al. Br J Dermatol. 2007;156:222-30.

3. Berman B, et al. J Fam Pract. 2006;55(5):suppl 1-8.

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

treated1

• The ultimate goal of treatment is to clear the entire

actinically damaged field2

– Addressing both clinical and non-visible lesions may

significantly reduce recurrence rates of AKs2

• Early diagnosis and treatment of the field of actinic

damage decreases overall disease burden and helps

to prevent development of invasive SCC1,2

1. Martin G. J Clin Aesthet Dermatol. 2010;3(11):20-5.

2. Ulrich M, et al. Exp Opin Emerg Drugs. 2010;15(4):545-55.

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,

scalp)4

Once daily 3 consecutive days

Ingenol mebutate 0.05% (trunk,

extremities)4

Once daily 2 consecutive days

Aminolevulinic acid5 or methyl

aminolevulinate6 with PDT

(photodynamic therapy)

Agents applied a day5 or a few

hours6 before light treatment

15 to 26 treatment cycles

May be retreated 8+ weeks5 or

3+ months6 after initial treatment

1. EFUDEX® product monograph, 2004. 2. ZYCLARA® product monograph, 2013.

3. ALDARA® product monograph, 2013. 4. PICATO® product monograph, 2013.

5. Levulan Kerastick® product monograph, 2004. 6. METVIX™ product monograph, 2009.

Combination/Sequential

Therapy

• Cryotherapy or curettage to treat visible AKs +

topical treatment to treat underlying field

cancerisation:

– 5-fluorouracil (5-FU) 5% followed by cryotherapy1

– Cryotherapy followed by imiquimod 3.75%2

– Cryotherapy followed by ingenol mebutate 0.015% on face

or scalp3

1. Jorizzo J, et al. Arch Dermatol. 2004;140:813-6.

2. Jorizzo J, et al. J Drugs Dermatol. 2010;9:1101-8.

3. Swanson N, et al. 22nd EADV Congress. Abstract P532; IST13-1514.

Field-directed Treatments:

Local Skin Reactions

Treatment Local skin reactions

5-fluorouracil (5-FU) 5%1 • 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

Imiquimod 3.75%, 5%2,3* • 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

Ingenol mebutate 0.015%*, 0.05%4 • 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

Aminolevulinic acid or methyl

aminolevulinate with PDT5,6

• Erythema, edema, crusting

• Usually resolve in days to 1 week

1. EFUDEX® product monograph, 2004. 2. ZYCLARA® product monograph, 2013.

3. ALDARA® product monograph, 2013. 4. PICATO® product monograph, 2013.

5. Levulan Kerastick® product monograph, 2004. 6. METVIX™ product monograph, 2009.

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.

Examples of Local Skin

Reactions

This LSR comprises erythema,

vesiculation, and mild swelling.

This LSR comprises more pronounced

swelling and erythema.

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

aminolevulinate with PDT6,7

• Pain, stinging, and burning during light therapy

• 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, 2004. 2. Cheigh NH. In: DiPiro JT, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 2008:1584-5.

3. ZYCLARA® product monograph, 2013. 4. ALDARA® product monograph, 2013. 5. PICATO® product monograph, 2013.

6. Levulan Kerastick® product monograph, 2004. 7. METVIX™ product monograph, 2009.

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

40

Non-Melanoma Skin Cancers (NMSCs)

NMSCs constitute nearly half of all cancers in the United States1

• Estimated U.S. annual newly diagnosed cases in 2003: 900,000-1,200,000

• NMSCs may be divided into 2 main types: BCC and SCC1. McGovern TW, et al. Actinic keratoses and non-melanoma skin cancer. American Academy of Dermatology Web site.

http://www.aad.org/education/students/ak_nonmelanoma.htm. Accessed April 28, 2009.

About 75%-80% of NMSCs About 15% of NMSCs

Basal Cell Carcinoma (BCC) Invasive SCC

Photos courtesy Jason Smith, MD.

Non- Melanoma Skin Cancer

– Basal Cell Carcinoma (BCC)

– Bowen’s Disease (SCC in situ)

– Squamous Cell Carcinoma (SCC)

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

Basal Cell Carcinoma

• Nodular

• Ulcerating

• Superficial

• Pigmented

• Sclerosing

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

Keratoacanthoma

• Less aggressive variant of SCC

• Dome shaped nodule with central

keratotic plug

• Tx:

– Cryotherapy

– Excision and cautery if necessary

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:

Excision! By you or refer.

XRT

NB:

If Melanoma suspected, NO cautery – need

edges

Take darkest/most unusual area if biopsy

Malignant Melanoma

Malignant Melanoma features

Asymmetry

Border irregularity

Colour – variation or black

Diameter – usually >6mm

Evolution – change in colour, size, shape, itching, painful bleeding

Congenital Nevomelanocytic Nevus

• Present at birth

• Benign

• May be precursors to melanoma but uncommon

MM’s rarely have hair

If not sure…

• Punch BIOPSY!

– DONT use forceps!!!!

• Can crush specimen

• Pathology may come back inconclusive

For Excision of any papule or superficial nevus

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

For Excision of any papule or superficial nevus

Intradermal Local

Bend 30 g needle 45 degrees

Determine Depth

Insert needle at angle and run under lesion

coming out at far side

Cut Beneath Needle

Run 15 blade, angled up, under and along needle

Specimen

Remains on needle for easy transfer to formalin

Hemostasis

20% Aluminum Chloride

(Drysol)

Minimal Scar

Superficial wound heals with minimum scarring

Always Send Specimen

Use Separate containers for each specimen

Malignant Melanoma

• Rx

• Wide Excision

– MIS - 0.5 cm

– < 1.0 mm – 1.0 cm

– >1.0 – 2.0 cm & Sentinel Node Biopsy

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

And Now for Something

Completely Different

A few skin lesions often mistaken for

skin cancer

Dermatofibroma

“ I was bitten by a bug”....

Benign

Chondrodermatitis Nodularis Helicus

• Rapid developing

vascular lesion

• May follow minor

trauma

• Bleeds spontaneously

• Tx: surgical excision

and cautery

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