Actinic Keratosis: New Solutions for The Primary Care Physician

Marcie Ulmer MD FRCPC FAAD

Clinical Instructor

Department of Dermatology & Skin Science

University of British Columbia

Actinic Keratosis: New Solutions for the Primary Care Physician

Faculty/Presenter Disclosure

• Faculty: Marcie Ulmer MD FRCPC FAAD

• Relationships with commercial interests:– Speakers Bureau/Honoraria: Valeant Canada, Leo

Pharma, Inc.

– Consulting Fees: Valeant Canada, Leo Pharma, Inc.

Actinic Keratosis: New Solutions for the Primary Care Physician

Disclosure of Commercial Support

• This program has received financial support from Leo Pharma, Inc. in the form of an educational grant

• This program has received in-kind support from Leo Pharma, Inc. in the form of logistical support

• Potential for conflict(s) of interest:– Dr. Marcie Ulmer has received funding from Leo Pharma, Inc. and

Valeant Canada whose products are being discussed in this program.

– Leo Pharma, Inc. and Valeant Canada benefit from the sale of products that will be discussed in this program: ingenol mebutate, 5-fluorouracil and Imiquimod.

Actinic Keratosis: New Solutions for the Primary Care Physician

Mitigating Potential Bias

• Information will be presented supporting multiple therapeutic options for the treatment of actinic keratoses

Actinic Keratosis: New Solutions for the Primary Care Physician

Case 1: Denise

Diagnosis and Treatment of Actinic Keratosis Lesions

Learning Objectives

After attending this session, participants will be able to:• Explain the link between actinic keratosis (AK) and

non-melanoma skin cancers (NMSC)• Identify the clinical signs and symptoms of actinic

keratosis lesions• Describe current treatment options for actinic keratosis

Patient Profile

• Female, age 63 years• Non-smoker• Spends time outdoors gardening, swimming, and golfing

in the summer, cross-country skiing in the winter• History of sunburn as both a child and adult• Conscientious about using sunscreen and wearing a hat

for past 10+ years

Prior Medical History

• History of AK lesions 12 months ago (2 on back of right hand, 2 on right forearm)– Treated successfully with cryosurgery by family physician

• History of basal cell carcinoma over past 15 years (3 on chest, 2 on back)– Excised/biopsied by dermatologist

Discussion Question

1. True or false: There is a link between actinic keratosis and non-melanoma skin cancer.A. True

B. False

Actinic Keratoses and Non-melanoma Skin Cancer

• AK is pre-cancerous skin lesion1,2

• Non-melanoma skin cancer (NMSC) includes squamous cell carcinoma (SCC) and basal cell carcinoma (BCC)– NMSC is the most common type of cancer3

– A history of NMSC increases the risk for malignant melanoma and other types of cancer, including colon, lung, and breast cancer4

1. Criscione VD, et al. Cancer. 2009;115(11):2523-30. 2. Lober BA, et al. South Med J. 2000;93:650-5.3. Rogers HW, et al. Arch Dermatol. 2010;146(3):283-7.4. Chen J, et al. J Natl Cancer Inst. 2008;100:1215-22.

Actinic Keratoses and NMSC

• AK lesions may progress to SCC1-3

– Progress less often to BCC4

• AK lesions and SCC are frequently contiguous as they share the same genetic alterations and morphology5,6

1. Marks R, et al. Lancet. 1988;1:795-7. 2. Mittelbronn MA, et al. Int J Dermatol. 1998;37:677-81. 3. Dinehart SM, et al. Cancer. 1997;79:920-3. 4. Criscione VD, et al. Cancer. 2009;115(11):2523-30.5. Berman B, et al. J Fam Pract. 2006;55(5):suppl 1-8. 6. Feldman SR, et al. Cutis. 2011; 87:201-7.

SCC

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

Natural History of AK Lesions

• Natural course of AK lesions is unpredictable1-5

– Estimates of 40 to 80% of cutaneous SCCs arise from, or near, an AK lesion2-5

• AK lesions 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.

Discussion Question

2. Which of the following is not a risk factor for development of actinic keratosis lesions?A. Male gender

B. Light-coloured eyes and hair

C. Cumulative exposure to UV radiation

D. Excessive/habitual alcohol consumption

E. Fair skin

F. Immunosuppression

G. All of the above are risk factors

General Risk Factors for AK

• High intensity or cumulative exposure to UV radiation1,2

• Use of tanning beds or sunlamps3

• Prior history of AKs or other skin cancer4

• Clinical signs of photodamage, such as solar/senile lentigines, facial telangiectasia, and actinic elastosis of the neck4

• Immunosuppression5

• Human papillomaviruses may play a role in etiology of AKs5

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):201-7.5. Goldberg LH, et al. J Drugs Dermatol. 2010;9(9):1125-32.

Male gender

… But 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

Denise’s Recent History

• 2 months ago, Denise returned to her physician because she found a “suspicious spot” on her forehead

• The lesion had the appearance of an AK lesion• The physician also noted a small rough patch next to

the more visible lesion that he concluded was also an AK lesion

Discussion Question

3. Which of the following is not a clinical sign or symptom of actinic keratosis lesions?A. Lesions are usually less than 1 cm in diameter

B. Lesions are generally found on sun-exposed areas of the body

C. Visible lesions are usually brown to dark brown

D. Lesions may be rough and/or scaly to the touch

Clinical Signs of Actinic Keratosis Lesions

• Visible/detectable lesions are reddish to reddish brown, rough, scaly patches less than 1 cm in diameter1

• Non-visible, non-palpable lesions occur up to 10 times more often than visible lesions, particularly in sun-damaged skin2

– >80% of all AK lesions are found on sun-exposed areas of the body3

When one AK is seen, assume that other,

perhaps non-visible, AK lesions exist4

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

Courtesy of Dr. Kirk Barber .

• Lesions can often be felt more easily than seen1

• Red, rough, scaling spots2

• White 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.

© DermNet NZ; dermnetnz.org.

Clinical Signs of Actinic Keratosis Lesions

Examples of AK Lesions

Photos: © DermNet NZ; dermnetnz.org.

Differential Diagnosis of AK Lesions

Keratoacanthoma

Lentigo maligna

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.Photos, top and bottom left, top and bottom right, © Danderm; www.danderm-pdv.is.kkh.dk. Photo, centre, © DermNet NZ; dermnetnz.org.

The Differential Diagnosis of AK Lesions

Lichen planus

Discoid lupus erythematosus

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. Photos: Top left, bottom right, © Danderm; www.danderm-pdv.is.kkh.dk. Top centre and right, © DermNet NZ; http://dermnetnz.org. Bottom left, © DermAtlas; www.DermAtlas.org.

Discussion Question

4. Which of the following factors should be considered when selecting treatment for actinic keratosis lesions?A. Number of lesions

B. Location of lesions

C. Potential for presence of subclinical (non-visible, non-palpable) lesions

D. All of the above

E. A and B only

Actinic Keratosis Is a Field Disease

• Field of cancerisation surrounds clinical AK lesions and is partially or completely clinically invisible – multifocal, paraneoplastic, subclinical changes1

• Histopathology of AKs 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.

Clinical lesions

Subclinical lesions

Is Field Treatment the Necessary Approach?

• It is impossible to know which AK lesions will progress to invasive SCC, so it is recommended that all AK lesions 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 AK2

• 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.

Discussion Question

5. Which of the following topical medications is not indicated for field-directed treatment of AK lesions?A. Imiquimod 3.75%

B. Tretinoin cream 0.025%

C. Ingenol mebutate 0.015%

D. 5-fluorouracil

E. B and C

Field-directed Topical Treatment Options

Treatment Dosing Duration of treatment

5-fluorouracil (5-FU)1 Twice daily Usual duration: 2-4 weeks

Imiquimod 3.75% (face, balding scalp)2

Up to 2 packets 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

Agents applied a day5 or a few hours6 before light treatment

15 to 26 treatment cyclesMay be retreated 8+ weeks5 or 3+ months6 after initial treatment

1. EFUDEX® product monograph, 2004. 2. ZYCLARA® product monograph, 2012.3. ALDARA® product monograph, 2012. 4. PICATO® product monograph, 2013.5. Levulan Kerastick® product monograph, 2004. 6. METVIX™ product monograph, 2009.

Efficacy of Field-directed Topical Therapies

Treatment

Complete clearance, % patients

Follow-up period

Patients with sustained

clearance, %Follow-up

period

5-FU 48–58%1-3 4 weeks 54%4 12 months

Imiquimod 3.75%* 36%5 8 weeks 41%6 12 months

Imiquimod 5%7* 45% 8 weeks 43% 12-18 months

Ingenol mebutate 0.015%*8 42% 57 days 46% 12 months

Ingenol mebutate 0.05%8 34% 57 days 50% 12 months

Photodynamic therapy (PDT)

47–82%9-11 1–3 months 40%9 12 months

1. Jorizzo J, et al. Cutis. 2002;70(6):335-9. 2. Weiss J, et al. Cutis. 2002;70(2 Suppl):22-9. 3. Tanghetti E, et al. J Drugs Dermatol. 2007;6(2):144-7. 4. Krawtchenko N, et al. Br J Dermatol. 2007;157(Suppl 2):34-40. 5. ZYCLARA® product monograph, 2012. 6. Hanke CW, et al. J Drugs Dermatol. 2011;10(2):165-70. 7. ALDARA® product monograph, 2012. 8. Lebwohl M, et al. New Engl J Med. 2012;366(11):1010-9. 9. Tschen EH, et al. Br J Dermatol. 2006;155(6):1262-9. 10. Piacquadio DJ, et al. Arch Dermatol. 2004;140(1):41-6. 11. Pariser DM, et al. J Am Acad Dermatol. 2003;48(2):227-32.

Between-study comparisons are not intended due to differences in patient demographics and other study parameters.*Indicated for face and scalp only.

Lesion-directed Treatment Options

• Physically destructive methods– Cryosurgery

– Laser ablation

• Surgical removal– Shave excision

– Curettage

– Electrodessication

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

Combination/Sequential Therapy

• Cryosurgery to treat visible AK lesions + topical treatment to treat underlying field cancerisation:– 5-FU followed by cryosurgery1

– Cryosurgery followed by 3.75% imiquimod2

1. Jorizzo J, et al. Arch Dermatol. 2004;140:813-6.2. Jorizzo J, et al. J Drugs Dermatol. 2010;9:1101-8.

Denise’s Recent Treatment

• Because of concerns about field cancerisation and Denise’s desire for a non-surgical treatment on her forehead, her physician prescribed ingenol mebutate 0.015%, once daily for 3 days

Treatment Follow-up

• Two months later, Denise returns for a follow-up appointment to check on clearance of forehead lesions

• At this appointment, she points out another “suspicious spot” located near the scar from removal of an earlier AK lesion on her right hand– Her physician diagnoses it as an AK lesion

Discussion Question

6. What treatment would you recommend for this new AK lesion on Denise’s hand?A. Cryosurgery ± 5-FU

B. 5-FU monotherapy

C. Imiquimod 5%

D. Ingenol mebutate 0.05%

E. Other

Summary

• Actinic keratoses are pre-cancerous skin lesions that may progress to SCC; progression is unpredictable

• Risk factors for development of AK lesions include:– Amount of cumulative/prolonged exposure to UV

– Fair skin

– Light-coloured hair/eyes

– Older age

– Male gender

• AK lesions may be visible or non-visible/non-palpable

• Effective treatment of AK lesions may help to prevent recurrence and/or progression to SCC

Case 2: Frank

Treating Actinic Keratosis Lesions and Counselling Patients

Learning Objectives

After attending this session, participants will be able to:• Describe the expected local skin reactions for various

topical, field-directed treatment options for actinic keratosis (AK)

• Identify other potential adverse effects of topical AK therapies

• Discuss key messages when counselling patients about the application of topical AK therapies and potential local skin reactions

Patient Profile

• Male, age 58 years• Non-smoker (quit 15 years ago)• Sedentary lifestyle; doesn’t participate in outdoor

activities or sports• History of sunburn as both a child and adult• Freckled skin on torso, arms, legs, face, and scalp• “Never” remembers to wear sunscreen unless his wife

reminds him

Frank’s Recent History

• During a routine physical, Frank’s family physician noticed reddish lesions on Frank’s scalp, some of which had white scaling

• Upon further examination, the physician noted 2 lesions that were palpable (rough to the touch, like grains of salt) but not readily visible, for a total of 7 lesions

Prior Medical History

• No prior history of non-melanoma skin cancer (squamous cell carcinoma and basal cell carcinoma) or AK lesions

• Family history of melanoma (father, age 72 years)

Frank’s Risk Factors for AK Lesions

• Sun-damaged skin as evidenced by number and distribution of lentigines

• Tans with difficulty, usually burns• History of sunburn• Male gender• Age (over 50 years)• Fair skin• Light-coloured eyes

Discussion Question

7. What is the recommended strategy for treatment of multiple AK lesions?A. Lesion-directed therapy (cryosurgery, shave excision,

curettage, etc.)

B. Field-directed topical therapy

C. Sequential/combination therapy (e.g., topical 5-FU followed by cryosurgery)

D. Any of the above

E. B or C only

AK Treatment Strategies

• Primary treatment decision point: is it a single AK lesion vs. multiple lesions?

• Single lesion:– Consider lesion-directed therapy

– If there is evidence of extensive photodamage, consider field-directed therapy to treat potential subclinical AK lesions

• Multiple lesions:– Consider sequential/combination therapy

– If there are a significant number of AK lesions in an area, consider field-directed therapy

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

Other Factors to Consider When Selecting Treatment

• Size of lesions1

• Typical vs. atypical lesions1

• Well defined vs. poorly defined lesions1

• Location of lesions1

• The potential for field cancerisation (non-visible lesions)2,3

• Patient’s desire to improve appearance of photoaged skin4

1. de Berker D, et al. Br J Dermatol. 2007;156:222-30.2. Martin G. Clin Aesthet Dermatol. 2010;3(11):20-5.3. Ulrich M, et al. Exp Opin Emerg Drugs. 2010;15(4):545-55.4. LEO Pharma. Market research data on file. 2011.

Discussion Question

8. What treatment would you recommend for the 7 AK lesions on Frank’s scalp?A. 5-FU monotherapy

B. Imiquimod 3.75%

C. Imiquimod 5%

D. Ingenol mebutate 0.015%

E. Ingenol mebutate 0.05%

F. Other

Field-directed Treatments: Local Skin Reactions

Treatment Local skin reactions

5-FU1 • Erythema, erosion, crusting, ulceration• Significant erythema, burning, erosion, crusting, and/or ulceration can occur

during treatment and may require treatment interruption

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

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

1. EFUDEX® product monograph, 2004. 2. ZYCLARA® product monograph, 2012. 3. ALDARA® product monograph, 2012. 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.

Additional Question

• How will you explain the time course of LSRs (topical agents) with your patients?

Examples of LSRs

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-FU1,2 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, photosensitivity

Flu-like symptoms, including malaise, fever, nausea, myalgias, 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

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.

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, 2012. 4. ALDARA® product monograph, 2012. 5. PICATO® product monograph, 2013.6. Levulan Kerastick® product monograph, 2004. 7. METVIX™ product monograph, 2009.

Frank’s Treatment

• Frank asked his physician if he could just “zap” off the lesions to get rid of them quickly

• Because of the number of AK lesions (7) and the potential for non-visible lesions, Frank’s physician prescribed 5-FU twice daily for 21 days

Setting Treatment Expectations

• It is important that your patients…– Understand the importance of field therapy

– Know all treatment options available

– Know the direct effects of treatment options

– Know that local skin reactions are a normal and expected part of topical therapy

– Understand the side effects associated with every option and how to manage them

– Recognize that new/additional AKs can recur after initial treatment

Counselling Tips for Topical AK Therapies

• Wash hands before and after applying treatment• Use care if applying the medication near the eyes,

nostrils, or mouth• Some local skin reactions may become visible and/or

cause discomfort

EFUDEX® product monograph, 2004. ZYCLARA® product monograph, 2012.ALDARA® product monograph, 2012. PICATO® product monograph, 2013.

Patient Counselling Tips: 5-FU

• Before applying, wash the area to be treated with soap and water and dry carefully1

• Apply a thin layer of medication only to the affected area1

• Apply with cotton-tipped applicator or suitable glove1

• Do not cover treated area with a bandage or other dressing1

• If the area being treated becomes painful with continued use, stop treatment for 1–3 days1

– An over-the-counter steroid may help to alleviate swelling and soreness2

• During treatment and for 1 to 2 months after treatment has ended, stay out of direct sunlight1

1. EFUDEX® product monograph, 2004.2. Cheigh NH. In: DiPiro JT, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 2008:1584-5.

Patient Counselling Tips: Imiquimod

• Apply a thin layer of medication only to the affected area

• Avoid washing or getting the area wet for 8 hours; after 8 hours, wash the area with mild soap and water

• Stop treatment and contact the office if:– You have a severe local skin reaction; wash off the medication with mild soap

and water

– Skin breaks down

– Sores develop during the first week of treatment

– You have any skin reactions that affect your daily activities or do not go away

– Your develop flu-like signs and symptoms, such as malaise, fever, nausea, muscle pain, and chills

• Non-visible lesions may become visible during treatment

• During treatment, avoid exposure to sunlight, a sunlamp, or a tanning bed

ZYCLARA® product monograph, 2012.ALDARA® product monograph, 2012.

Patient Counselling Tips: Ingenol Mebutate

• Apply gel gently with the fingertip to the treatment area

• Allow to dry for 15 minutes

• Avoid washing or touching the treated skin for 6 hours

• Avoid applying immediately after taking a shower or less than 2 hours before bedtime

• Do not cover the treated area with a bandage or other type of dressing

• If a local skin reaction does not improve, contact the office

• Put medication in a refrigerator (2°C to 8°C) as soon as possible after picking it up from the pharmacy and always store it in the fridge

PICATO® product monograph, 2013.

Discussion Question

9. How often would you follow-up with Frank after cessation of treatment?A. 8 weeks initially, then twice a year

B. 4-8 weeks initially, then twice a year

C. 8 weeks initially, then once a year

D. 2 weeks initially, then once a year

Summary

• When there is a significant number of AK lesions in one area, consider field-directed therapies to help ensure adequate treatment of both visible and non-visible lesions

• Set treatment expectations with patients, including potential for adverse effects/local skin reactions

• Follow-up/monitor patients for recurrence or malignant transformation