National Medical Policy

National Medical Policy Subject: Policy Number: Benign Skin Lesion Removal NMP150 Effective Date: June 2004 Updated: August 2015 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate Medicaid Manuals for coverage guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link X National Coverage Determination (NCD) Treatment of Actinic Keratosis (250.4): Skin Lesion (Non-Melanoma) Removal (L33488) http://www.cms.gov/medicare-coveragedatabase/search/advanced-search.aspx X National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other None Actinic Keratosis; Cosmetic and Reconstructive Surgery; Skin Lesion (Non-Melanoma) Removal; Skin Lesion Removal (Excludes Actinic Keratosis and MOHS; Removal of Benign Skin Lesions: http://www.cms.gov/medicare-coveragedatabase/search/advanced-search.aspx Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located Benign Skin Lesion Removal Aug 15 1

outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Medical Policy Benign skin lesions include seborrheic keratoses, sebaceous (epidermoid) cysts, skin tags, milia (keratin-filled cysts), nevi (moles), acquired hyperkeratosis (keratoderma), papillomas, hemangiomas and viral warts. Health Net, Inc. considers removal of benign skin lesions as medically necessary, and not cosmetic, when any of the following is met and is clearly documented in the medical record, operative report or pathology report: 1. The lesion is symptomatic as documented by any of the following: Intense itching Burning Irritation Pain Tenderness Chronic, recurrent or persistent bleeding Physical evidence of inflammation (e.g., purulence, oozing, edema, erythema, etc.) 2. The lesion demonstrates a significant change in color or size 3. The lesion obstructs an orifice or clinically restricts vision. 4. There is clinical uncertainty as to the likely diagnosis, particularly where malignancy is a realistic consideration based on lesional appearance, change in appearance and/or non-response to conventional treatment* 5. The lesion is likely to turn malignant as documented by medical peerreviewed literature or medical textbooks 6. A prior biopsy suggests the possibility of lesional malignancy. 7. The lesion is in an anatomical region subjected to recurrent physical trauma that has in fact occurred and objective evidence of such injury or the potential for such injury is documented. 8. Wart removal is considered medically necessary when any of 1 through 7 above is met; in addition, wart destructions are considered medically necessary when any of the following is met: Lesion causes symptoms of such a severity that the patient s normal bodily functions/activities of daily living are impeded (e.g., palmar or plantar warts) Periocular warts associated with chronic recurrent conjunctivitis thought secondary to lesion virus shedding; Benign Skin Lesion Removal Aug 15 2

Warts showing evidence of spread from one body area to another, particularly in immunosuppressed patients. Lesions are condyloma acuminata or molluscum contagiosum. Cervical dysplasia or pregnancy associated with genital warts *Note: If the diagnosis is uncertain, biopsy or removal may be more prudent than destruction. Note: The decision to submit a specimen for pathological interpretation will be independent of the decision to remove or not remove the lesion. It is assumed, however, that the pathology description and tissue diagnosis will be part of the medical record if a specimen is submitted to pathology. Note: Should lesions be a concern but not be explicitly described in this policy, color photographs must be submitted with the request. Health Net, Inc. does not consider lesion removal medically necessary for any of the following: 1. Lesions in sensitive anatomic locations that are non-problematic do not qualify for removal coverage on the basis of location alone. 2. Rosacea 3. Vascular proliferative disorders Actinic Keratoses Health Net Inc, considers the destruction of correctly diagnosed actinic keratoses, also known as solar keratoses, medically necessary as they are considered to be premalignant lesions with a low but real possibility of malignant transformation. I. Health Net, Inc, considers any of the following treatment for actinic keratoses medically necessary: A. Liquid nitrogen cryotherapy Most common treatment, usually recommended for treatment of solitary lesions or small numbers of scattered lesions and/or thin, well-demarcated lesions May cause skin redness; blistering may occur B. Topical drug therapy (e.g. 5-fluorouracil, Imiquimod, Diclofenac, ingenol mebutate gel) Recommended for individuals with more than 15 actinic keratoses Anatomic location of the lesions impacts response time. AK s of the face respond the quickest, whereas lesions on the arms usually take the longest to respond. C. Any of the following treatment for multiple actinic keratoses is considered medically necessary when there is failure to adequately respond to topical 5- FU or cryosurgery: Laser skin resurfacing therapy Chemical peel Benign Skin Lesion Removal Aug 15 3

Dermabrasion II. Health Net, Inc. considers photodynamic therapy (PDT) with topical aminolevulinic acid (Levulan Kerastick) and exposure to blue light medically necessary for non-hyperkeratotic actinic keratoses of the face and scalp. Note: Lesions treated with Levulan Kerastick that have not completely resolved after 8 weeks may be treated a second time. However, in the absence of data that indicate efficacy for a third treatment, the medical necessity for a third treatment of the same lesion(s) is not established. III. Health Net, Inc. considers photodynamic therapy PDT with topical Metvixia, followed by exposure to a red light source medically necessary in immunocompetent patients in conjunction with lesion preparation (debridement using a sharp dermal curette) when other therapies are unacceptable or considered medically less appropriate. Note: Metvixia Cream has not been studied for more than one course which consists of two treatment sessions one week apart. Lesion response should be assessed 3 months after the last treatment session. IV. Electrodessication and curettage or full-thickness excision of actinic keratoses is rarely medically necessary. However, excisional biopsy of actinic keratoses may be considered medically necessary when the following criteria are met: 1. There is bleeding, induration, rapid growth or pain, which suggest progression to squamous cell carcinoma 2. The lesion does not respond to treatment V. An alternative approach to treating AKs is to observe the lesions over time and remove them only if they exhibit specific clinical features suggesting possible transformation to invasive squamous cell carcinoma (SCC). Note: Health Net, Inc. does not consider removal of skin lesions to improve appearance medically necessary. Removal of certain benign skin lesions that do not pose a threat to health or function are considered cosmetic, and as such, are not medically necessary. In the absence of any of the above indications, removal of seborrheic keratoses, sebaceous cysts, nevi (moles) or skin tags is considered cosmetic. Note: Excision of lesion with simple closure should be coded as excision only. A simple repair is used when the wound is superficial; e.g., involving primarily epidermis or dermis, or subcutaneous tissues without significant involvement of deeper structures, and requires simple one layer closure/suturing. Excision of lesions with intermediate or complex closure should be coded separately for benign lesions with a diameter greater than 0.5cm or the excision of a malignant lesion of any size. An intermediate repair includes the repair of wounds that require layered closure of one or more of the deeper layers of subcutaneous tissue and superficial (nonmuscle) fasciae, in addition to the skin (epidermal and dermal) closure. Complex repair includes the repair of wounds requiring more than layered closure including scar revision, debridement, (e.g., traumatic lacerations or avulsions, extensive Benign Skin Lesion Removal Aug 15 4

undermining, stents or retention sutures). Excision of lesion with adjacent tissue transfer should be coded as adjacent tissue transfer only. Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures will be replaced by ICD-10 code sets. Health Net National Medical Policies will now include the preliminary ICD-10 codes in preparation for this transition. Please note that these may not be the final versions of the codes and that will not be accepted for billing or payment purposes until the October 1, 2015 implementation date. ICD-9 078.0 Molluscum contagiosum 078.10 Viral warts, unspecified 078.11 Condyloma acuminatum 078.19 Other specified viral warts 135 Sarcoidosis (cutaneous) 210.0 Benign neoplasm of lip (specify type) 214.0 Lipoma of skin and subcutaneous tissue 214.1 215.0 Other benign neoplasm of connective and other soft tissue of head, face and neck 215.3 Other benign neoplasm of connective and other soft tissue of lower limb, including hip 216.0 Benign neoplasm of skin of lip 216.1 Benign neoplasm of eyelid, including canthus 216.2 Benign neoplasm of skin of ear and external auditory canal 216.3 Benign neoplasm of skin of other and unspecified parts of face 216.4 Benign neoplasm of skin of scalp and neck 216.5 Benign neoplasm of skin of trunk except scrotum 216.6 Benign neoplasm of skin of upper limb, including shoulder 216.7 Benign neoplasm of skin of lower limb, including hip 216.8 Benign neoplasm of skin of other specified sites 221.2 Benign neoplasm of vulva 222.1 Benign neoplasm of penis 222.4 Benign neoplasm of scrotum 228.01 Hemangioma of skin and subcutaneous tissue 235.1 Neoplasm of uncertain behavior of lip 238.2 Neoplasm of uncertain behavior of skin 239.2 Neoplasm of unspecified nature, skin 374.84 Sebaceous cyst of eyelid 380.00- Perichondritis of pinna (chondrodermatitis) 380.02 455.9 Residual hemorrhoidal skin tags 448.1 Nevus, nonneoplastic 528.5 Diseases of lip 682.0- Cellulitis and abscess Benign Skin Lesion Removal Aug 15 5

682.9 686.1 Pyogenic granuloma of skin and subcutaneous tissue 686.8 Other specified local infections of skin and subcutaneous tissue 690.10 Seborrheic dermatitis, unspecified 690.11 Seborrhea capitis 690.12 Seborrheic infantile dermatitis 690.18 Other seborrheic dermatitis 690.8 Other erythematosquamous dermatosis 691.8 Other atopic dermatitis and related conditions 692.70 Unspecified dermatitis due to sun 692.75 Disseminated superficial actinic porokeratosis (DSAP) 695.89 Other specified erythematous conditions 695.9 Unspecified erythematous conditions 698.9 Unspecified pruritus disorder 698.3 Prurigo nodularis 701.0 Circumscribed scleroderma 701.2 Acquired acanthosis nigricans 701.1 Keratoderma (acquired) symptomatic, painful and/or inflamed 701.4 Keloid 701.9 Skin tags 702.0 Actinic keratosis 702.11 Inflamed seborrheic keratosis 702.19 Other seborrheic keratosis 706.2 Sebaceous cyst 709.9 Unspecified disorder of skin and subcutaneous tissue 744.1 Accessory auricle 757.39 Other anomalies of the skin 782.0 Pain, paresthesia, burning of skin 959.8 Injury [trauma] of other specified site, skin ICD-10 Codes A63.0 Anogenital (venereal) warts B07.0-B07.9 Viral warts B08.1 Molluscum contagiosum D10.0 Benign neoplasm of lip D17.0-D17.9 Benign lipomatous neoplasm D18.01 Hemangioma of skin and subcutaneous tissue D21.0-D21.9 Other benign neoplasm of connective and other soft tissue D23.0-D23.9 Other benign neoplasm of skin D28.0 Benign neoplasm of vulva D29.0 Benign neoplasm of penis D29.4 Benign neoplasm of scrotum D37.01 Neoplasm of uncertain behavior of lip D48.5 Neoplasm of uncertain behavior of skin D49.2 Neoplasm of unspecified behavior of bone, soft tissue, and skin D86.3 Sarcoidosis of skin H02.821-H02.829 Cysts of eyelid H61.001-H61.009 Unspecified perichondritis of external ear I78.1 Nevus, non-neoplastic K12.2 Cellulitis and abscess of mouth K13.0 Diseases of lips K64.4 Residual hemorrhoidal skin tags Benign Skin Lesion Removal Aug 15 6

L08.89 Other specified local infections of the skin and subcutaneous tissue L11.0 Acquired keratosis follicularis L20.0-L20.9 Atopic dermatitis L21.0-L21.9 Seborrheic dermatitis L26 Exfoliative dermatitis L28.0 Lichen simplex chronicus L28.1 Prurigo nodularis L29.0-L29.9 Pruritus L30.3 Infective dermatitis L30.4 Erythema intertrigo L53.8 Other specified erythematous conditions L56.5 Disseminated superficial actinic porokeratosis (DSAP) L57.0 Actinic keratosis L57.8 Other skin changes due to chronic exposure to nonionizing radiation L72.3 Sebaceous cyst L82.0-L82.1 Seborrheic keratosis L83 Acanthosis nigricans L85.0 Acquired ichthyosis L85.1 Acquired keratosis [keratoderma] palmaris et plantaris L85.2 Keratosis punctata (palmaris et plantaris) L87.0 Keratosis follicularis et parafollicularis in cutem penetrans L87.2 Elastosis perforans serpiginosa L90.0 Lichen sclerosus et atrophicus L90.5 Scar conditions and fibrosis of skin L91.0-L91.9 Hypertrophic disorders of the skin L94.0 Localized scleroderma [morphea] L98.0 Pyogenic granuloma L98.9 Disorder of the skin and subcutaneous tissue, unspecified Q17.0 Accessory auricle Q28.8 Other specified congenital malformations of skin R20.0-R20.9 Disturbances of skin sensation CPT Codes 11200 Removal of skin tags, multiple fibrocutaneous tags, any area; up to and including 15 lesions 11201 each additional ten lesions (List separately in addition to code for primary procedure) 11300 Shaving of epidermal or dermal lesions, single lesion, trunk, arms or legs; lesion diameter 0.5 cm or less 11301 lesion diameter 0.6 to1.0 cm 11302 lesion diameter 1.1 to 2.0 cm 11303 lesion diameter over 2.0 cm 11305 Shaving of epidermal or dermal lesion, single lesion, scalp, neck, hands, genitalia; lesion diameter 0.5 cm 11306 lesion diameter 0.6 to 1.0 cm 11307 lesion diameter 1.1 to 2.0 cm 11308 lesion diameter over 2.0 cm 11310 Shaving of epidermal or dermal lesion, single lesion, face, ears, eyelids, nose, lips, mucous membrane; lesion diameter 0.5 cm or less 11311 lesion diameter 0.6 to 1.0 cm Benign Skin Lesion Removal Aug 15 7

11312 lesion diameter 1.1 to 2.0 cm 11313 lesion diameter over 2.0 cm 11400 Excision, benign lesion including margins, except skin tag (unless listed elsewhere), trunk, arms or legs; excised diameter 0.5 or less 11401 excised diameter 0.6 to 1.0 cm 11402 excised diameter 1.1 to 2.0 cm 11403 excised diameter 2.1 to 3.0 cm 11404 excised diameter 3.1 to 4.0 cm 11406 excised diameter over 4.0 cm 11420 Excision, benign lesion including margins, except skin tag (unless listed elsewhere), scalp, neck, hands, feet, genitalia; excised diameter 0.5 cm or less 11421 excised diameter 0.6 to 1.0 cm 11422 excised diameter 1.1 to 2.0 cm 11423 excised diameter 2.1 to 3.0 cm 11424 excised diameter 3.1 to 4.0 cm 11426 lesion diameter over 4.0 cm 11440 Excision, other benign lesion including margins(unless listed elsewhere), face, ears, eyelids, nose, lips, mucous membrane; excised diameter 0.5 cm or less 11441 excised diameter 0.6 to 1.0 cm 11442 excised diameter 1.1 to 2.0 cm 11443 excised diameter 2.1 to 3.0 cm 11444 excised diameter 3.1 to 4.0 cm 11446 excised diameter over 4.0 cm 12001-12007 Simple repair of superficial wounds of scalp, neck, axillae, external genitalia, trunk and or extremities (including hands and feet); 2.5cm or less - over 30cm 12011-12018 Superficial repair of superficial wounds of face, ears, eyelids, nose, lips and/or mucous membranes; 2.5cm or less - over 30cm 12031-12037 Repair, intermediate, wounds of scalp, axillae, trunk and/or extremities (excluding hands and feet); 2.5 cm or less to 30.0 cm 12041-12047 Repair, intermediate, wounds of neck, hands, feet and/or external genitalia; 2.5 cm or less -over 30 cm 12051-12057 Repair, intermediate, wounds of face, ears, eyelids, nose, lips and/or mucous membranes; 2.5 cm or less- over 30 cm. 13100 Repair, complex, trunk; 1.1 cm to 2.5 cm 13102 each additional 5 cm or less (List separately in addition to code for primary procedure) (Code deleted) 13120 Repair, complex, scalp, arms and/or legs:1.1.cm to 2.5 cm 13121 each additional 5 cm or less (List separately in addition to code for primary procedure) 13131 Repair, complex, forehead, cheek, chin, mouth, neck, axillae, genitalia, hands and/or feet; 1.1 cm to 2.5 cm 13132 2.6 cm to 7.5 cm 13133 each additional 5 cm or less (List separately in addition to code for primary procedure) 13150 Repair, complex, eyelids, nose, ears and/or lips; 1.0 cm or less (Code deleted in 2015) Benign Skin Lesion Removal Aug 15 8

13151 Repair, complex, eyelids, nose, ears and/or lips; 1.1 cm to 2.5cm 13152 2.6 cm to 7.5 cm 13153 each additional 5 cm or less 13160 Secondary closure of surgical wound or dehiscence, extensive or complicated 14000 Adjacent tissue transfer or rearrangement, trunk; defect 10 sq cm or less 14001 defect 10.1 sq cm to 30 sq cm 14020 Adjacent tissue transfer or rearrangement, scalp, arms and/or legs; defect 10 sq cm or less 14021 defect 10.1 sq cm to 30 sq cm 14040 Adjacent tissue transfer or rearrangement, forehead, cheeks, chin, mouth, neck, axillae, genitalia, hands and/or feet; defect 10 sq cm or less 14041 defect 10.1 sq cm to 30 sq cm 14060 Adjacent tissue transfer or rearrangement, eyelids nose, ears and/or lips; defect 10sq cm or less 10461 defect 10.1 sq cm to 30 sq cm 14301 Adjacent tissue transfer or rearrangement, any area; defect 30.1 sq cm to 60.0 sq cm 14302 Adjacent tissue transfer or rearrangement, each additional 30.0 sq cm. Or part thereof (List separately in addition to code for primary procedure) 17000 Destruction (e.g., laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement), premalignant lesions (e.g., actinic keratoses); first lesion 17003 second through 14 lesions, each (List separately in addition to code for first lesion) 17004 Destruction (e.g., laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement) premalignant lesions (e.g., actinic keratoses); 15 or more lesions 17110 Destruction (e.g., laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement), of benign lesions other than skin tags or cutaneous vascular proliferative lesions; up to 14 lesions 17111 15 or more lesions 96567 Photodynamic therapy by external application of light to destroy premalignant and/or malignant lesions of the skin and adjacent mucosa (e.g.lip) by activation of photosensitive drug(s), each phototherapy exposure session HCPCS Codes J3490 J7308 J9190 Unclassified drugs Aminolevulinic acid HCL for topical administration, 20%, single unit dosage form (354 mg) Injection, fluorouracil, 500 mg (Use this code for Adrucil) Scientific Rationale Update August 2014 Ianhez et al (2014) studied the effectiveness of two consecutive sessions of cryosurgery for actinic keratosis and investigated factors associated with its therapeutic success. The authors conducted a longitudinal study including 92 patients of both sexes, aged 50-75years with 5-50 actinic keratosis on the face and Benign Skin Lesion Removal Aug 15 9

forearms, who underwent cryosurgery and treatment with sunscreen SPF 30, at baseline and after 120days. The lesions were counted in duplicate by the same examiner before the start of treatment and after 120 (N=92) and 300days (N=33), represented by their medians and quartiles and compared using the generalized linear mixed effects model (negative binomial). Treatment behavior was investigated in relation to sex, age, education, skin type, smoking, sun exposure at work and the use of aspirin, anti-inflammatory and angiotensin-converting enzyme inhibitors. There was a significant reduction in the actinic keratosis count on the face and forearms (p<0.05). Our results confirmed the effectiveness of cryosurgery for actinic keratosis, with a 57% reduction in the number, and size of the lesions. Higher education levels (p=0.02) and less sun exposure at work (p=0.02) independently promoted a significant reduction in the actinic keratosis count. The authors concluded different population groups showed characteristic responses to the treatment, which may be explained by the degree of adherence to the use of photoprotection. In two sessions, cryosurgery with liquid nitrogen reduced the actinic keratosis count. Zane et al (2014) compared CO2 laser ablation with cryotherapy in the treatment of isolated AKs of the face and scalp in a single-centre, open-label, prospective, nonsponsored, randomized, controlled clinical trial. Patients with isolated ( 4) AKs of the face and scalp were randomized to receive CO2 laser ablation or cryotherapy. After 90 days, the overall complete remission (CR) rates of patients and lesions were assessed and correlated with thickness grade. Two hundred patients with a total number of 543 AKs were enrolled. The CR rates of lesions after 3 months were 78 2% with cryotherapy and 72 4% with CO2 laser ablation. Thicker lesions were significantly more responsive to cryotherapy (P = 0 034). Seventy-three patients (71 6%) had CR of all lesions 3 months after cryotherapy and 64 (65 3%) after laser ablation. At 12 months after treatment the number of patients with CR was reduced to 53 with cryotherapy and 14 with laser ablation. Investigators concluded the rate of patients and lesions with CR is similar after 3 months, but more patients remain in stable remission for 12 months after cryotherapy. Cryotherapy is more effective for thick lesions. The cosmetic outcome was good or excellent in almost all patients. Buinauskaite et al (2014) evaluated the efficacy and side effects of two different light doses when treating AKs with ALA-PDT on the face/scalp. Thirty-eight patients with two histologically confirmed AKs were enrolled in the within-patient comparison study. ALA-PDT was performed twice with two weeks interval for each AK. Patients were randomized to receive a light dose of 70 or 100J/cm2 as their first split face/scalp treatment. Follow-up examinations were carried out at months 3 and 6. Efficacy end point included clinical/histological AK clearance rate. No significant difference in therapeutic efficacy and adverse events of ALA-PDT was found between the two light doses at both follow-up visits. At months 3 and 6 after PDT the RATE of complete remission were respectively 100% and 92.1% for 70J/cm2, 92.1% and 84.2% for 100J/cm2. The adverse events of the treatment were rosacea 5/76 (6.58%), hyperpigmentation 4/76 (5.26%), hypopigmentation 4/76 (5.26%), transient milia 3/76 (3.95%). Investigators concluded the topical ALA-PDT with the red light dose of 70J/cm2 is an effective treatment for mild and moderate AKs on the face/scalp with expected adverse events of pigmentation changes, rosacea and transient milia. Scientific Rationale Update August 2013 Gupta and Paquet (2013) performed a network meta-analysis for eight treatments [5-aminolevulinic acid (ALA)-photodynamic therapy (PDT), cryotherapy (CRYO), 3% Benign Skin Lesion Removal Aug 15 10

diclofenac in 2.5% hyaluronic acid (DCF/HA), 0.5% or 5.0% 5-fluorouracil (5-FU), 5% imiquimod (IMI), 0.015-0.05% ingenol mebutate (IMB), methyl aminolevulinate (MAL-PDT), and placebo/vehicle (including placebo-pdt)] to determine their relative efficacies. As part of a prior Cochrane systematic review, different databases and grey literature were searched for randomized controlled trials up to April 2012. The inclusion criteria were parallel-group studies with non-immunosuppressed participants: 1) reporting "participant complete clearance" and 2) comparing at least two of the interventions. Thirty-two publications met the criteria and they included the following number of individual or pooled studies (n) and total number of participants (N) for the different interventions: 0.5% 5-FU (n=4, N=169), 5.0% 5-FU (n=2, N=44), ALA-PDT (n=6, N=739), CRYO (n=2, N=174), DCF/HA (n=5, N=299), IMI (n=14, N=1411), IMB (n=3, N=560), MAL-PDT (n=7, N=557), and placebo (n=32, N=2520). Network analyses using a random effects Bayesian model were carried out with the software ADDIS v1.16.1. The interventions were ranked as followed based on calculated probabilities and odd ratios: 5-FU > ALA-PDT ~ IMI ~ IMB ~ MAL-PDT > CRYO > DCF> placebo. This efficacy ranking was obtained based on the current available data on "participant complete clearance" from randomized controlled trials and the analysis model used. However, several other factors should also be considered when prescribing a treatment for AK. In 2012, ingenol mebutate gel (Picato gel) was approved by the FDA for the treatment of actinic keratosis (AK). Picato gel is an inducer of cell death indicated for the topical treatment of actinic keratosis. For the treatment of actinic keratosis on the face and scalp Picato gel, 0.015% should be applied to the affected area once daily for 3 consecutive days. For the treatment of actinic keratosis on the trunk and extremities Picato gel, 0.05% should be applied to the affected area once daily for 2 consecutive days. In phase III trials, ingenol mebutate gel applied topically once daily at 0.015% for 3 days or 0.05% for 2 days, respectively, significantly reduced head and non-head actinic keratosis lesions. Adverse events were mostly mild or moderate. Local skin responses elicited by the treatment, i.e., erythema, flaking/scaling and crusting, were transient, and resolved spontaneously without sequelae. Adherence to the therapy can be facilitated by the short duration of the treatment. In four phase III clinical studies of more than 1,000 patients with actinic keratosis, a significantly higher proportion of those treated with Picato gel (n=503) saw complete clearance of AKs in the field of treatment as compared to placebo (n=502). The most common adverse events (AEs) were local skin reactions (LSRs), including erythema, flaking/scaling, crusting and swelling. Lebwohl et al (2012) investigated the efficacy and safety of a new topical field therapy for actinic keratosis, ingenol mebutate gel (0.015% for face and scalp and 0.05% for trunk and extremities). In four multicenter, randomized, double-blind studies, investigators randomly assigned patients with actinic keratoses on the face or scalp or on the trunk or extremities to receive ingenol mebutate or placebo (vehicle), self-applied to a 25-cm(2) contiguous field once daily for 3 consecutive days for lesions on the face or scalp or for 2 consecutive days for the trunk or extremities. Complete clearance (primary outcome) was assessed at 57 days, and local reactions were quantitatively measured. In a pooled analysis of the two trials involving the face and scalp, the rate of complete clearance was higher with ingenol mebutate than with placebo (42.2% vs. 3.7%, P<0.001). Local reactions peaked at day 4, with a mean maximum composite score of 9.1 on the local-skin-response scale (which ranges from 0 to 4 for six types of reaction, yielding a composite score of 0 to 24, with higher numbers indicating more severe reactions), rapidly decreased by day 8, and continued to decrease, approaching baseline scores by day 29. In a Benign Skin Lesion Removal Aug 15 11

pooled analysis of the two trials involving the trunk and extremities, the rate of complete clearance was also higher with ingenol mebutate than with placebo (34.1% vs. 4.7%, P<0.001). Local skin reactions peaked between days 3 and 8 and declined rapidly, approaching baseline by day 29, with a mean maximum score of 6.8. Adverse events were generally mild to moderate in intensity and resolved without sequelae. Investigators concluded ingenol mebutate gel applied topically for 2 to 3 days is effective for field treatment of actinic keratoses. Scientific Rationale - Update September 2009 According to the American Academy of Dermatology, available treatment of actinic keratoses (AK) may include cryosurgery, topical chemotherapy (e.g., 5-fluoruracil), topical immunotherapy (e.g., imiquimod), topical non-steroidal anti-inflammatory drugs (e.g. sodium diclofenac gel), photodynamic therapy with exposure to red or blue light, chemical peels and laser therapy. Dermatologists may use one therapy or combine therapies. Photodynamic therapy (PDT) for the treatment of superficial nonhyperkeratotic AK lesions of the face and scalp involves application of a light-sensitive drug that is then activated by exposure to light of a specific wavelength. For PDT treatment of AKs, 5- aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) is applied to the lesion. Once absorbed by the lesion, ALA and MAL undergo conversion via the heme biosynthesis pathway to protoporphyrin IX (PpIX), which is an efficient photosensitizer and makes the treated tissue particularly susceptible to damage when exposed to a light source. One potential advantage of PDT, compared with peel and liquid nitrogen therapy, is its ability to be applied more selectively, thus sparing the surrounding skin from iatrogenic damage and reducing scarring. In addition, PDT can be used to treat multiple lesions simultaneously; and treatment can be repeated if necessary. PDT with Metvixia consists of the topical application of methyl aminolevulinate (MAL) (in contrast to ALA used in the Kerastick procedure) followed by exposure with a red light source (in contrast to the blue light source in the Kerastick procedure). According to its FDA approval, Metvixia is indicated for treatment of nonhyperkeratotic actinic keratoses of the face and scalp in immunocompetent patients when used in conjunction with lesion preparation (debridement using a sharp dermal curette) in the physician s office when other therapies are unacceptable or considered medically less appropriate. One Metvixia-PDT session consists of: lesion preparation, application of Metvixia Cream, application of occlusive dressing, occlusion for 3 hours, removal of excess cream with saline and positioning lamp and illumination with red light. During the time period between the application of Metvixia Cream and exposure to red light illumination, the treatment site will become photosensitive. The FDA approval of Metvixia cream plus illumination with the CureLight BroadBand was based on two clinical trials of 130 patients with non-hyperkeratotic actinic keratoses. Both trials were randomized, multicenter, and double-blinded with patients randomized to Metvixia -PDT and Vehicle-PDT study arms that required two treatment sessions (7 days apart). One study was conducted in the U.S. and patients were randomized 1:1 Metvixia to Vehicle and one study was conducted in Australia with patients randomized 4:1 Metvixia to Vehicle. In both studies treatment consisted of a multi-step process that was repeated after 7 days consisting of lesion preparation (debridement with sharp curette) to roughen the surface of the lesion, Metvixia or Vehicle Cream application to lesions with occlusion with an adhesive, Benign Skin Lesion Removal Aug 15 12

non-absorbent dressing, waiting at least 2.5 hours, but no more than 4 hours to allow for conversion of the methyl aminolevulinate, removal of cream with gauze and saline, and red light Dosimetry and Illumination with the CureLight BroadBand Model CureLight 01 (a red light of 570 to 670 nm wavelength). Study patients had previously untreated facial and scalp actinic keratoses (AKs) that were slightly palpable (better felt than seen). Hyperkeratotic actinic keratoses were excluded. In the U.S. study 100% of patients had 4 to 10 lesions at baseline whereas in the Australian study, 63% (70/111) of patients had less than 4 lesions at baseline, 31% (34/111) had 4 to 10 lesions, and 6% (7/111) had more than 10 lesions at baseline (a maximum of 6 treatment fields were allowed in this study). A Cleared AK lesion was defined as being not visible and not palpable as assessed 3 months after the second treatment session. Patients with all treated lesions cleared at 3 months were defined as Complete Responders. In the Australian study, 86% (76/88) of patients had 75% or more lesions clear and 81% (71/88) were complete responders at three-month follow-up. In the U.S. study 83% (35/42) of patients had 75% or more lesions clear, and 79% (33/42) were complete responders at three-month follow-up. Patients with 4 or more lesions had lower success rates than those with less than 4 lesions when treated with PDT and Metvixia. In the Austrailian study, 67% (18/27) of patients with 4-10 lesions were complete responders whereas 79% (33/42) with 4-10 lesions were complete responders in the U.S. study. The FDA indicated data beyond the three-month follow-up was not available. The FDA also noted that pretreatment debridement could be an essential component of the therapy and, therefore, is included in the labeling for Metvixia Szeimes et al (2009) investigated one hundred thirty-one patients with 4 to 10 nonpigmented, previously untreated thin or moderately thick AKs on the face or scalp in a multicenter, double-blind, randomized, placebo-controlled study. MAL or matching placebo cream was applied to the débrided lesion surface for 3 hours before illumination with noncoherent red light. Treatment was repeated 1 week later. Efficacy was evaluated in 57 patients with 418 lesions treated with MAL PDT and 58 with 414 lesions treated with placebo PDT. Sixteen patients were excluded as protocol violators (not randomized). The investigators reported that MAL PDT was superior to placebo PDT in lesion complete response rates (83.3% vs 28.7%) and patient complete response rates (all lesions showing complete response; 68.4% vs 6.9%). Pariser et al (2008) evaluated the efficacy of MAL PDT using red light-emitting diode light in a multicenter, double-blind, randomized study. A total of 49 patients with 363 AK lesions had 16.8% MAL cream applied under occlusion for 3 hours, and 47 patients with 360 AK lesions had vehicle cream similarly applied. The lesions were then illuminated with repeated treatment 1 week later. Complete lesion and patient (all lesions showing complete response) response rates were evaluated 3 months after last treatment. MAL PDT was superior to vehicle PDT with respect to lesion complete response (86.2% vs 52.2%) and patient complete response (59.2% vs 14.9%) Moloney and Collins (2007) compared the efficacy of 5-aminolaevlinic acid methylester (MAL) and 5-aminolaevulinic acid (ALA) PDT as treatment options for AK of the scalp. Sixteen male patients aged 59-87 years with extensive scalp AK were Benign Skin Lesion Removal Aug 15 13

randomized into a double-blind, split-scalp prospective study. Two treatment fields were defined (right and left frontoparietal scalp) and treated 2 weeks apart. These fields were randomized to receive either MAL or ALA as first or second treatment. MAL cream was applied for 3 h; 20% ALA cream was applied for 5 h. A blinded observer assessed efficacy comparing AK counts before and 1 month after treatment. Pain was assessed using a visual analogue scale at 3, 6, 12 and 16 min. Fifteen patients completed treatment to both fields. There was a mean reduction from baseline in AK counts with the use of ALA-PDT of 6.2 +/- 1.9 compared with 5.6 +/- 3.2 with MAL-PDT. All patients experienced pain which was of greater intensity in the ALA-treated side at all time points. Similarly, duration of discomfort postprocedure persisted for longer following treatment with ALA when compared with MAL-PDT. The authors concluded that both ALA-PDT and MAL-PDT result in a significant reduction in scalp AK with no significant difference in efficacy. They also noted that ALA-PDT is more painful than MAL-PDT in the treatment of extensive scalp AK. According to British Association of Dermatologists Therapy Guidelines and Audit on the management of actinic keratoses, Photodynamic therapy is effective in up to 91% of AKs in trials comparing it with cryotherapy, with consistently good cosmetic result. Per the British Association of Dermatologists Guidelines for topical photodynamic therapy: Topical application of the prodrugs 5-aminolaevulinic acid (ALA) and methyl aminolaevulinate (MAL) is effective in cutaneous photodynamic therapy (PDT) (Strength of Recommendation A, Quality of Evidence I). Currently, a range of light sources, doses and irradiances continues to be used in ALA-PDT, whereas in MAL-PDT the standard procedure now typically involves a light-emitting diode (LED) source. A range of continuous wave light sources is effective in topical PDT (Strength of recommendation A, Quality of evidence II-iii). Topical PDT is an effective therapy for thin and moderate thickness actinic keratoses (AK), with superiority to cryotherapy depending on protocol. Efficacy is relatively poorer for acral lesions, but PDT may still offer therapeutic benefit. Cosmetic outcome following PDT for AK is superior to cryotherapy (Strength of recommendation A, Quality of evidence I). Scientific Rationale - Update May 2006 Actinic keratoses (AKs) are rough, scaly, or warty, pre-cancerous skin lesions that occur primarily on sun-exposed skin surfaces. They are most common in older individuals with fair complexions, with a prevalence of >80% in fair skinned people over the age of 60. AKs appear as patches of hyperkeratosis with some surrounding erythema on sun-exposed areas of the head and neck, forearms and hands, and upper back. Treatment of AKs begins with prevention such as avoidance of sun exposure along with the use of sunscreens in an effort to reduce the development of AKs. Active treatment of AKs depends upon the size of the lesion and the number of lesions present. Some physicians choose to observe the lesions over time and remove them only if they exhibit specific clinical features suggesting possible transformation to invasive squamous cell carcinoma (SCC). Benign Skin Lesion Removal Aug 15 14

The available treatments for actinic keratoses can generally be divided into surgical and non-surgical methods. Surgical treatments used to treat one or a small number of dispersed individual lesions include excision, cryosurgery, curettage (either alone or combined with electrodesiccation), and laser surgery. Non-surgical treatments include topical chemotherapy (5-fluorouracil or masoprocol creams), chemexfoliation (also known as chemical peels), and dermabrasion. These methods are generally used in patients with multiple lesions and the involvement of extensive areas of skin. Under some circumstances, combinations of different treatment methods may be used. In 1999, Levulan Kerastick, a topical preparation of ALA, in conjunction with illumination with the BLU-U Blue Light Photodynamic Therapy Illuminator, received approval by the U.S. Food and Drug Administration (FDA) for the treatment of nonhyperkeratotic actinic keratoses of the face and scalp. The technique involves two steps starting with application of the ALA Topical Solution in the physician's office. The package insert recommends that the application should involve either face or scalp lesions, but not both simultaneously. The patient is told to return in 14 to 18 hours, at which point the lesion is exposed to blue light for 17 minutes. During this period, the patient experiences sensations of tingling, stinging, or burning of the treated lesions. Treated lesions that have not completely resolved after 8 weeks may be treated a second time. As summarized in the package insert, two similarly designed studies randomized 243 patients with 4 to 15 non-hyperkeratotic actinic keratoses to receive Levulan Kerastick plus blue light exposure or a vehicle solution plus blue light exposure. From 63% to 69% of patients in the active treatment group reported complete response at 8 weeks, compared to 13% to 14% in the placebo group. Patients who were not complete responders after 8 weeks had retreatment of the persistent lesions. Among these patients 43% showed a complete response after a second treatment, compared to only 4% in the placebo group. Scientific Rationale Initial The term "benign" refers to a condition, tumor, or growth that is not cancerous. This means that it does not spread to other parts of the body or invade and destroy nearby tissue. Benign tumors usually grow slowly. In general, a benign tumor or condition is not harmful. However, this is not always the case. If a benign tumor is big enough, its size and weight can press on nearby blood vessels, nerves, or organs, or otherwise cause problems. Benign skin lesions are common and are frequently removed at the patient s request to improve appearance. As such, excision of benign skin lesions that do not pose a threat to health or function are considered cosmetic. Seborrheic keratoses, also referred to as senile keratoses, are non-cancerous growths of the outer layer of skin. The origin is unknown. It commonly appears after age 40. The tumors appear as wart-like growths in a variety of colors. They may appear in large numbers on the surface of the body. They are usually painless and benign, but may become irritated and itch. They are usually brown, but can vary in color from beige to black, and vary in size from a fraction of an inch to more than an inch in diameter. They have the appearance of being glued or stuck on to skin. Seborrheic keratoses are most often found on the chest or back, although, they can also be found almost anywhere on the body. These become more common with age, and most elderly patients develop one or more of these lesions. Seborrheic keratoses can get irritated by clothing rubbing against them, and their removal may be Benign Skin Lesion Removal Aug 15 15

appropriate if they itch, get irritated, or bleed easily. Although seborrheic keratoses are noncancerous, they may be difficult to distinguish from skin cancer if they turn black. Diagnosis is based primarily on the appearance of the growths. A skin lesion biopsy may be used to confirm the diagnosis. Seborrheic keratoses may be removed by cryosurgery, curretage, or electrosurgery. Particular growths usually do not recur after removal, but people who are prone to this condition may develop more in the future. Moles (nevi) are very common growths on the skin and can appear anywhere on the skin. Melanocytes are spread evenly throughout the skin and produce the pigment that gives skin its natural color. When skin is exposed to the sun, melanocytes produce more pigment, causing the skin to tan, or darken in a cluster with tissue surrounding them. They are usually brown in color, but can be skin colored or pink, light tan to brown, or blue-black. Moles may be flat or raised and can be various sizes and shapes and no larger than a pencil eraser. Most appear during the first 20 years of a person's life, although some may not appear until later in life. Sun exposure increases the number of moles. The majority of moles are benign. However, moles that raise suspicion of malignancy are those that significantly change in size, shape or color, and those that bleed, itch, or become painful. Atypical moles (dysplastic nevi) have an increased risk of developing into melanoma. Atypical moles are larger than average (> 6 mm) and irregular in shape. They tend to have uneven color with dark brown centers and lighter, sometimes reddish, uneven borders or black dots at edge. The most common methods of removal include shaving and excision. A sebaceous (keratinous) cyst is a slow-growing, closed sac found just under the skin containing "pasty" or "cheesy" looking skin secretions. The sebaceous cyst is firm, globular, movable, and nontender. These cysts seldom cause discomfort unless the cyst ruptures or becomes infected. Ranging in size, sebaceous cysts are usually found on the scalp, face, ears, and genitals. They are formed when the release of sebum from the sebaceous glands in the skin is blocked. Unless they become infected and painful or large, sebaceous cysts do not require medical attention or treatment, and usually go away on their own. These cysts may occasionally become infected and form into painful abscesses. Infected cysts can be incised and drained, or the entire cyst may be surgically removed. Recurrence after excision is also not unusual. A skin tag (arochordon) is a small growth of tissue that is painless, soft, and moveable. It hangs from the surface of the skin on a thin piece of tissue called a stalk. The prevalence of skin tags increases with age. They appear most often in skin folds of the neck, armpits, trunk, beneath the breasts or in the genital region. They may become painful if thrombosed or if irritated. They may become irritated if they occur in an area where clothing or jewelry rubs against them. Skin tags may be removed by excision, cryosurgery, or electrosurgery. Warts (verruca vulgaris) are simply areas of skin that grow faster than normal due to the presence of the wart virus. Warts are skin-colored and feel rough to the touch. They are most common on the hands, feet and face but they can grow almost anywhere in the body. They are infectious and some people, especially children, are more susceptible than others. Flat warts are much smaller and are less rough than hand or foot warts. They tend to grow in great numbers - 20 to 100 at any one time. They can occur anywhere, but in children they are most common on the face. In adults they are most often found in the beard area in men and on the legs in women. Benign Skin Lesion Removal Aug 15 16

Skin irritation from shaving probably accounts for this. A plantar wart is simply a wart growing on the weight-bearing surface of the foot that grows inward rather than outwards because it is pressed on when a person walks. As warts are caused by a virus infection, the body will build up resistance over a period of time and eventually the body will cause the warts to disappear. This may take months or sometimes years but is the natural way the body deals with warts. If they are allowed to disappear in this way it is less likely that a person will get any further ones as one will then be immune to that virus. The first treatment to try on warts is removal with a salicylic acid liquid or pad. A bottle of wart medication like Occlusal-HP or Compound W, a roll of 1-inch surgical tape ('Micropore' or 'Blenderm' are good) and a pumice stone or emery board can be tried next. One needs to keep going down until just below the level of the surrounding skin to eradicate a wart completely. When the base of the wart looks exactly like normal skin (i.e. no black dots or 'graininess), medication can be stopped. Liquid nitrogen cryotherapy is what dermatologists use most often to cure warts. This method can cause pain, soreness and blistering and usually cures 50% of warts after one treatment. Frequent applications of liquid nitrogen are needed to cure more stubborn warts. Burning warts off with a CO2 Laser or electric needle is often effective, but scars may result. HCPCS Codes N/A Review History June 8, 2004 Medical Advisory Council, initial approval May 2006 Change in position on treatment of Actinic Keratoses March 2007 Code Update August 2008 CA reconstructive surgery law added to disclaimer September 2009 Added PDT with topical Metvixia, followed by exposure to a red light source as medically necessary for treatment of Actinic Keratoses, when criteria is met for commercial members. Added separate Medicare criteria. November 2009 Removed requirement of topical 5-FU or cryosurgery prior to photodynamic therapy with topical aminolevulinic acid (Levulan Kerastick) and exposure to blue light for non-hyperkeratotic actinic keratoses of the face and scalp. January 2011 Added Medicare LCD link. No revisions. September 2011 Update. Added Revised Medicare Table. No Revisions. August 2012 Update no revisions August 2013 Update added ingenol mebutate gel to list of topical therapies approved for treatment of Actinic keratoses. Code updates August 2014 Update no revisions August 2015 Update no revisions. Codes updated. This policy is based on the following evidence-based guidelines: 1. National Institute for Health and Clinical Excellence. Photodynamic Therapy for Non-Melanoma Skin Tumors (Including Premalignant and Primary Non- Metastatic Skin Lesions.) February 2006. 2. Morton CA, McKenna KE, Rhodes LE, British Association of Dermatologists Therapy Guidelines and Audit Subcommittee. Guidelines for topical photodynamic therapy: update. Br J Dermatol 2008 Dec; 159(6): 1245-66. Benign Skin Lesion Removal Aug 15 17

3. de Berker D, McGregor JM, Hughes BR, British Association of Dermatologists Therapy Guidelines and Audit. Guidelines for the management of actinic keratoses. Br J Dermatol 2007 Feb; 156(2): 222-30. 4. McIntyre W, Downs M, Bedwell S. Treatment Options for Actinic Keratoses. Am Fam Physician 2007;76:667-71, 672. Available at: http://www.aafp.org/afp/20070901/667.html References Update August 2015 1. Wat H, Wu DC, Rao J, et al. Application of intense pulsed light in the treatment of dermatologic disease: A systematic review. Dermatol Surg. 2014;40. 2. Wat H, Dytoc M. Off-label uses of topical vitamin D in dermatology: A systematic review. J Cutan Med Surg. 2014;18(2):91-108. References Update August 2014 1. Bettencourt MS. Use of ingenol mebutate gel for actinic keratosis in patients in a community dermatology practice. J Drugs Dermatol. 2014 Mar;13(3):269-73. 2. Buinauskaite E, Maciulaitis R, Buinauskiene J, Valiukeviciene S. Topical photodynamic therapy of actinic keratoses with 5-aminolevulinic acid: randomized controlled trial with six months follow-up. J Dermatolog Treat. 2014 Dec;25(6):519-22. 3. Dixon AJ, Anderson SJ, Mazzurco JD, Steinman HK. Novel photodynamic therapy does not prevent new skin cancers--randomized controlled trial. Dermatol Surg. 2014 Apr;40(4):412-9. 4. Ianhez M, Miot HA, Bagatin E..Liquid nitrogen for the treatment of actinic keratosis: A longitudinal assessment. Cryobiology. 2014 Jun 30. 5. Ko DY, Kim KH, Song KH. Comparative Study of Photodynamic Therapy with Topical Methyl Aminolevulinate versus 5-Aminolevulinic Acid for Facial Actinic Keratosis with Long-Term Follow-Up. Ann Dermatol. 2014 Jun;26(3):321-31. 6. Rubel DM, Spelman L, Murrell DF, et al. Daylight PDT with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional PDT in actinic keratosis treatment: a randomised controlled trial. Br J Dermatol. 2014 May 24. 7. Zane C, Facchinetti E, Rossi MT, et al. Cryotherapy is preferable to ablative CO2 laser for the treatment of isolated actinic keratoses of the face and scalp: a randomized clinical trial. Br J Dermatol. 2014 May;170(5):1114-21. doi: 10.1111/bjd.12847. References Update August 2013 1. Berman B. New developments in the treatment of actinic keratosis: focus on ingenol mebutate gel. Clin Cosmet Investig Dermatol. 2012;5:111-22 2. Buinauskaite E, Zalinkevicius R, Buinauskiene J, Valiukeviciene S. Pain during topical photodynamic therapy of actinic keratoses with 5-aminolevulinic acid and red light source: randomized controlled trial. Photodermatol Photoimmunol Photomed. 2013 Aug;29(4):173-81. 3. Dirschka T, Radny P, Dominicus R, et al. Long-term (6 and 12 months) followup of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis. Br J Dermatol. 2013 Apr;168(4):825-36. 4. Gholam P, Kroehl V, Enk AH. Dermatology Life Quality Index and Side Effects after Topical Photodynamic Therapy of Actinic Keratosis. Dermatology. 2013 Jun 18. Benign Skin Lesion Removal Aug 15 18

5. Gras J. Ingenol mebutate: a new option for actinic keratosis treatment. Drugs Today (Barc). 2013 Jan;49(1):15-22. 6. Gupta AK, Paquet M. Network meta-analysis of the outcome "participant complete clearance" in non-immunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol. 2013 Mar 29. 7. Ingraffea A. Benign skin neoplasms. Facial Plast Surg Clin North Am. 2013 Feb;21(1):21-32 8. Keating GM. Ingenol mebutate gel 0.015% and 0.05%: in actinic keratosis. 9. Drugs. 2012 Dec 24;72(18):2397-405. 10. Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012 Mar 15;366(11):1010-9. 11. Martin G, Swanson N. Clinical findings using ingenol mebutate gel to treat actinic keratoses. J Am Acad Dermatol. 2013 Jan;68(1 Suppl 1):S39-48 12. Rigel DS, Stein Gold LF. The importance of early diagnosis and treatment of actinic keratosis. J Am Acad Dermatol. 2013 Jan;68(1 Suppl 1):S20-7 13. Rosen RH, Gupta AK, Tyring SK. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response. J Am Acad Dermatol. 2012 Mar;66(3):486-93 14. Samrao A, Cockerell CJ. Pharmacotherapeutic Management of Actinic Keratosis: Focus on Newer Topical Agents. Am J Clin Dermatol. 2013 May 3 15. Siller G, Gebauer K, Welburn P, et al. PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, doubleblind, vehicle-controlled, multicentre, phase IIa study. Australas J Dermatol. 2009 Feb;50(1):16-22. 16. Stockfleth E. The paradigm shift in treating actinic keratosis: a comprehensive strategy. J Drugs Dermatol. 2012 Dec;11(12):1462-7. 17. Rosen RH, Gupta AK, Tyring SK. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response. J Am Acad Dermatol. 2012 Mar;66(3):486-93 18. U.S. FDA. FDA approved drug products. Picato. Jan 12. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=s earch.label_approvalhistory#apphist 19. Zimmerman EE, Crawford P. Cutaneous cryosurgery. Am Fam Physician. 2012 Dec 15;86(12):1118-24. References Update August 2012 1. Couch SM, Custer PL. Topical 5-fluorouracil for the treatment of periocular actinic keratosis and low-grade squamous malignancy. Ophthal Plast Reconstr Surg. 2012 May;28(3):181-3. 2. Dirschka T, Radny P, Dominicus R, et al. Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5- aminolaevulinate cream and placebo. Br J Dermatol. 2012 Jan;166(1):137-46. 3. Foley P, Merlin K, Cumming S, et al. A comparison of cryotherapy and imiquimod for treatment of actinic keratoses: lesion clearance, safety, and skin quality outcomes. J Drugs Dermatol. 2011 Dec;10(12):1432-8. 4. Galitzer BI. Effect of retinoid pretreatment on outcomes of patients treated by photodynamic therapy for actinic keratosis of the hand and forearm. J Drugs Dermatol. 2011 Oct;10(10):1124-32. 5. Hagele TJ, Levender MM, Davis SA, et al. Practice trends in the treatment of actinic keratosis in the United States: 0.5% fluorouracil and combination Benign Skin Lesion Removal Aug 15 19

cryotherapy plus fluorouracil are underused despite evidence of benefit. J Cutan Med Surg. 2012 Mar-Apr;16(2):107-14. 6. Hasson A, Navarrete-Dechent C, Nicklas C, de la Cruz C. Topical photodynamic therapy with methylaminolevulinate for the treatment of actinic keratosis and reduction of photodamage in organ transplant recipients: A case-series of 16 patients. Indian J Dermatol Venereol Leprol. 2012 Jul;78(4):448-53. 7. Serra-Guillén C, Nagore E, Hueso L, et al. A randomized pilot comparative study of topical methyl aminolevulinate photodynamic therapy versus imiquimod 5% versus sequential application of both therapies in immunocompetent patients with actinic keratosis: clinical and histologic outcomes. J Am Acad Dermatol. 2012 Apr;66(4):e131-7. 8. Wiegell SR, Heydenreich J, Fabricius S, Wulf HC. Continuous ultra-low-intensity artificial daylight is not as effective as red LED light in photodynamic therapy of multiple actinic keratoses. Photodermatol Photoimmunol Photomed. 2011 Dec;27(6):280-5. References Updated September 2011 1. Goldstein BG, Goldstein AO. Overview of benign lesions of the skin. UpToDate. September 2, 2010. 2. Kumaraswamy KL, Vidhya M. Human papilloma virus and oral infections: An update. J Cancer Res Ther. 2011 Apr-Jun;7(2):120-7. 3. Argenziano G, Zalaudek I, Hofmann-Wellenhof R, et al. Total body skin examination for skin cancer screening in patients with focused symptoms. J Am Acad Dermatol. 2011 Jul 12. [Epub ahead of print]. 4. Matteucci P, Pinder R, Magdum A, et al. Accuracy in skin lesion diagnosis and the exclusion of malignancy. J Plast Reconstr Aesthet Surg. 2011 Jul 6. References Updated September 2009 1. Annemans L, Caekelbergh K, Roelandts R et al. Real-life practice study of the clinical outcome and cost-effectiveness of photodynamic therapy using methyl aminolevulinate (MAL-PDT) in the management of actinic keratosis and basal cell carcinoma. Eur J Dermatol. 2008 Sep-Oct; 18(5): 539-46. 2. Braathen LR, Paredes BE, Saksela O, et al. Short incubation with methyl aminolevulinate for photodynamic therapy of actinic keratoses. J Eur Acad Dermatol Venereol. 2009 May; 23(5): 550-5. 3. Fernández-Guarino M, Harto A, Sánchez-Ronco M, et al. Retrospective, descriptive, observational study of treatment of multiple actinic keratoses with topical methyl aminolevulinate and red light: results in clinical practice and correlation with fluorescence imaging. Actas Dermosifiliogr. 2008 Dec; 99(10): 779-87. 4. Hayes Medical Technology Directory. Photodynamic Therapy for Actinic Keratoses. May 2004. Updated Oct. 2008. 5. Kasche A, Luderschmidt S, Ring J, Hein R. Photodynamic therapy induces less pain in patients treated with methyl aminolevulinate compared to aminolevulinic acid. J Drugs Dermatol. 2006 Apr; 5(4): 353-6. 6. Kaufmann R, Spelman L, Weightman W et al. Multicentre intraindividual randomized trial of topical methyl aminolaevulinate-photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities. Br J Dermatol. 2008 May; 158(5): 994-9 7. Lehmann P. Methyl aminolaevulinate-photodynamic therapy: a review of clinical trials in the treatment of actinic keratoses and nonmelanoma skin cancer. Br J Dermatol. 2007 May; 156(5): 793-801 Benign Skin Lesion Removal Aug 15 20

8. Moloney FJ, Collins P. Randomized, double-blind, prospective study to compare topical 5-aminolaevulinic acid methylester with topical 5-aminolaevulinic acid photodynamic therapy for extensive scalp actinic keratosis. Br J Dermatol. 2007 Jul; 157(1): 87-91 9. Morton C, Campbell S, Gupta G, et al. Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol 2006; 155:1029. 10. Morton, CA. Methyl aminolevulinate: actinic keratoses and Bowen's disease. Dermatol Clin 2007; 25:81Ortiz-Policarpio B, Lui H. Methyl aminolevulinate-pdt for actinic keratoses and superficial nonmelanoma skin cancers. Skin Therapy Lett. 2009 Jul-Aug; 14(6): 1-3. 11. Pariser D, Loss R, Jarratt M et al. Topical methyl-aminolevulinate photodynamic therapy using red light-emitting diode light for treatment of multiple actinic keratoses: A randomized, double-blind, placebo-controlled study. J Am Acad Dermatol. 2008 Oct; 59(4): 569-76. 12. Piacquadio DJ, Chen DM, Farber HF et al. Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3, multicenter trials. Arch Dermatol. 2004 Jan;140(1):41-6 13. Smith S, Piacquadio D, Morhenn V et al. 3: Short incubation PDT versus 5-FU in treating actinic keratoses. J Drugs Dermatol. 2003 Dec;2(6):629-35. 14. Smits T, Moor AC. New aspects in photodynamic therapy of actinic keratoses. 15. J Photochem Photobiol B. 2009 Jun 13 16. Szeimies RM, Matheson RT, Davis SA et al. Topical methyl aminolevulinate photodynamic therapy using red light-emitting diode light for multiple actinic keratoses: a randomized study. Dermatol Surg. 2009 Apr; 35(4): 586-92 17. Tarstedt M, Rosdahl I, Berne B et al. A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)-PDT in actinic keratosis of the face and scalp. Acta Derm Venereol. 2005; 85(5): 424-8. 18. Tschen EH, Wong DS, Pariser DM et al. Photodynamic therapy using aminolaevulinic acid for patients with nonhyperkeratotic actinic keratoses of the face and scalp: phase IV multicentre clinical trial with 12-month follow up. Br J Dermatol. 2006 Dec; 155(6): 1262-9. 19. Tschen EH, Wong DS, Pariser DM et al. 1: Photodynamic therapy using aminolaevulinic acid for patients with nonhyperkeratotic actinic keratoses of the face and scalp: phase IV multicentre clinical trial with 12-month follow up. Br J Dermatol. 2006 Dec;155(6):1262-9. 20. United States Food and Drug Administration. Metvixia. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=se arch.drugdetails 21. Wennberg AM, Stenquist B, Stockfleth E, et al. Photodynamic therapy with methyl aminolevulinate for prevention of new skin lesions in transplant recipients: a randomized study. Transplantation. 2008 Aug 15; 86(3): 423-9. 22. Centers for Medicare and Medicaid Services. NCD for Treatment of Actinic Keratosis (AKs). Nov. 2001 Available at: http://www.cms.hhs.gov/mcd/viewncd.asp?ncd_id=250.4&ncd_version=1&baske t=ncd%3a250%2e4%3a1%3atreatment+of+actinic+keratosis+%28aks%29 23. Centers for Medicare and Medicaid Services. LCD for Removal of Benign Skin Lesions. July 2009. References Updated May 2006 1. Babilas P, Karrer S, Sidoroff A, et al. Photodynamic therapy in dermatology--an update. Photodermatol Photoimmunol Photomed. 2005 Jun;21(3):142-9. Benign Skin Lesion Removal Aug 15 21

2. US. Food and Drug Administration. Levulan Kerastick. Accessed May 2006. 3. Hayes Alert - Technology Assessment Brief. Photodynamic Therapy for Acne Vulgaris.Volume VIII, Number 8 - August 2005. Accessed May 2006. Available at: http://www.hayesinc.com/subscribers/searcharticles.do 4. Garcia-Zuazaga J, Cooper KD, Baron ED. Photodynamic therapy in dermatology: current concepts in the treatment of skin cancer. Expert Rev Anticancer Ther. 2005 Oct;5(5):791-800 5. Gilaberte Y, Serra-Guillen C, De Las Heras ME, et al. Photodynamic therapy in dermatology. Actas Dermosifiliogr. 2006 Mar;97(2):83-102 6. Gold MH, Nestor MS. Current treatments of actinic keratosis. J Drugs Dermatol. 2006 Feb;5(2 Suppl):17-25. 7. Jeffes, EW, McCullough, JL, Weinstein, GD, et al. Photodynamic therapy of actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light. J Am Acad Dermatol 2001; 45:96. 8. Kasche A, Luderschmidt S, Ring J, Hein R. Photodynamic therapy induces less pain in patients treated with methyl aminolevulinate compared to aminolevulinic acid. J Drugs Dermatol. 2006 Apr;5(4):353-6. 9. Langan SM, Collins P. Randomized, double-blind, placebo-controlled prospective study of the efficacy of topical anaesthesia with a eutetic mixture of lignocaine 2.5% and prilocaine 2.5% for topical 5-aminolaevulinic acid-photodynamic therapy for extensive scalp actinic keratoses. Br J Dermatol. 2006 Jan;154(1):146-9. 10. Melnick S. Cystic acne improved by photodynamic therapy with short-contact 5- aminolevulinic acid and sequential combination of intense pulsed light and blue light activation. J Drugs Dermatol. 2005 Nov-Dec;4(6):742-5. 11. Radakovic-Fijan S, Blecha-Thalhammer U, Kittler H, et al. Efficacy of 3 different light doses in the treatment of actinic keratosis with 5-aminolevulinic acid photodynamic therapy: a randomized, observer-blinded, intrapatient, comparison study. J Am Acad Dermatol. 2005 Nov;53(5):823-7. 12. Sekula-Gibbs S, Uptmore D, Otillar L. Retinoids. J Am Acad Dermatol. 2004 Mar;50(3):405-15 13. Zakhary K, Ellis DA. Applications of aminolevulinic Acid-based photodynamic therapy in cosmetic facial plastic practices. Facial Plast Surg. 2005 May;21(2):110-6. References - Initial 1. Luba MC, M.D., Bangs SA. Common Benign Skin Tumors. Am Fam Physician 2003;67:729-38. 2. Andrews MD. Cryosurgery for common skin conditions. Am Fam Physician. 2004 May 15;69(10):2365-72. 3. Kelley LC, Hruza GJ. Benign skin tumors. Facial Plast Surg Clin North Am. 2003 May;11(2):243-51. 4. De Gannes GC, Ip JL, Martinka M, et al. Early Detection of Skin Cancer by Family Physicians: A Pilot Project. J Cutan Med Surg. 2004 Mar 25 5. Beers MH, Berkow R, eds. Disorders of hair follicles and sebaceous glands: Keratinous cyst. In: The Merck Manual of Diagnosis and Therapy. 17th ed. Sec. 10, Ch. 116. White House Station, NJ: Merck; 2002. 6. Berg P, Lindelof B. Congenital nevocytic nevi: Follow-up of a Swedish birth register sample regarding etiologic factors, discomfort, and removal rate. Pediatr Dermatol. 2002;19(4):293-297. 7. Bader RS, Scarborough DA. Surgical pearl: intralesional electrodesiccation of sebaceous hyperplasia. J Am Acad Dermatol 2000;42(1 Pt 1):127-8. Benign Skin Lesion Removal Aug 15 22

8. Christenson L, Patterson J, Davis D. Surgical pearl: use of the cutaneous punch for the removal of lipomas. J Am Acad Dermatol 2000;42:675-6. 9. Dinehart SM. Actinic keratoses: scientific evaluation and public health implications. Journal of the American Academy of Dermatology. 2000;42(1):25-8 10. Plunkett A, Merlin K, Gill D, Zuo Y, Jolley D, Marks R. The frequency of common nonmalignant skin conditions in adults in central Victoria, Australia. Int J Dermatol 1999;38:901-8. 11. Rosenthal TC, Kraybill W. Soft tissue sarcomas: integrating primary care recognition with tertiary care center treatment. Am Fam Physician 1999;60: 567-72. 12. Feldman SR, Fleischer AB, Williford PM, Jorizza JL. Clinical and laboratory studies; destructive procedures are the standard of care for treatment of actinic keratoses. Journal of the American Academy of Dermatology. 1999;40(1):43-7 13. Signorini M, Campiglio GL. Posttraumatic lipomas: where do they really come from? Plast Reconstr Surg 1998;101:699-705. 14. Pariser RJ. Benign neoplasms of the skin. Med Clin North Am 1998;82:1285-307. 15. Manstein CH, Frauenhoffer CJ, Besden JE. Keratoacanthoma: is it a real entity? Ann Plast Surg 1998;40:469-72. 16. Canas GC, Robson KJ, Arpey CJ. Persistent keratoacanthoma: challenges in management. Dermatol Surg 1998;24:1364-9. 17. Miller AM, Sahl WJ, Brown SA, Young SK, Quinlan CM, Patel PR, et al. The role of human papillomavirus in the development of pyogenic granulomas. Int J Dermatol 1997;36:673-6. 18. Requena L, Sangueza OP. Cutaneous vascular proliferation. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol 1997;37:887-919. 19. Callen JP, Bickers DR, Moy RL. From the academy; actinic keratoses. Journal of the American Academy of Dermatology. 1997;36(4):650-3 20. Drake LA et al. Academy guidelines: guidelines of care for photoaging/photodamage. Journal of the American Academy of Dermatology. 1996;35(3):462-464 21. de Berker DA, Taylor AE, Quinn AG, Simpson NB. Sebaceous hyperplasia in organ transplant recipients: shared aspects of hyperplastic and dysplastic processes? J Am Acad Dermatol 1996;35(5 Pt 1):696-9. 22. Weiss SW. Lipomatous tumors. Monogr Pathol 1996;38:207-39. 23. Schwartz RA. Keratoacanthoma. J Am Acad Dermatol 1994;30:1-19. 24. Rosian R, Goslen JB, Brodell RT. The treatment of benign sebaceous hyperplasia with the topical application of bichloracetic acid. J Dermatol Surg Oncol 1991;17:876-9. 25. Patrice SJ, Wiss K, Mulliken JB. Pyogenic granuloma (lobular capillary hemangioma): a clinicopathologic study of 178 cases. Pediatr Dermatol 1991;8:267-76. 26. Scott MA. Benign cutaneous neoplasms. Prim Care 1989;16:645-63. 27. Lanigan SW, Robinson TW. Cryotherapy for dermatofibromas. Clin Exp Dermatol 1987;12:121-3. 28. Rydholm A, Berg NO. Size, site and clinical incidence of lipoma. Factors in the differential diagnosis of lipoma and sarcoma. Acta Orthop Scand 1983;54:929-34. 29. Myhre-Jensen O. A consecutive 7-year series of 1331 benign soft tissue tumours. Clinicopathologic data. Comparison with sarcomas. Acta Orthop Scand 1981;52:287-93. 30. Taira JW, Hill TL, Everett MA. Lobular capillary hemangioma (pyogenic granuloma) with satellitosis. J Am Acad Dermatol 1992;27(2 Pt 2):297-300. Benign Skin Lesion Removal Aug 15 23

31. Gonzalez S, Vibhagool C, Falo LD Jr, Momtaz KT, Grevelink J, Gonzalez E. Treatment of pyogenic granulomas with the 585 nm pulsed dye laser. J Am Acad Dermatol 1996;35(3 Pt 1):428-31. 32. Crile G Jr. Thirteen shortcuts in office surgery. Surg Clin North Am 1975;55:1025-9. 33. Zuber TJ. Minimal excision technique for epidermoid (sebaceous) cysts. Am Fam Physician 2002; 65:1409-12. Important Notice General Purpose. Health Net's National Medical Policies (the "Policies") are developed to assist Health Net in administering plan benefits and determining whether a particular procedure, drug, service or supply is medically necessary. The Policies are based upon a review of the available clinical information including clinical outcome studies in the peer-reviewed published medical literature, regulatory status of the drug or device, evidence-based guidelines of governmental bodies, and evidence-based guidelines and positions of select national health professional organizations. Coverage determinations are made on a case-by-case basis and are subject to all of the terms, conditions, limitations, and exclusions of the member's contract, including medical necessity requirements. Health Net may use the Policies to determine whether under the facts and circumstances of a particular case, the proposed procedure, drug, service or supply is medically necessary. The conclusion that a procedure, drug, service or supply is medically necessary does not constitute coverage. The member's contract defines which procedure, drug, service or supply is covered, excluded, limited, or subject to dollar caps. The policy provides for clearly written, reasonable and current criteria that have been approved by Health Net s National Medical Advisory Council (MAC). The clinical criteria and medical policies provide guidelines for determining the medical necessity criteria for specific procedures, equipment, and services. In order to be eligible, all services must be medically necessary and otherwise defined in the member's benefits contract as described this "Important Notice" disclaimer. In all cases, final benefit determinations are based on the applicable contract language. To the extent there are any conflicts between medical policy guidelines and applicable contract language, the contract language prevails. Medical policy is not intended to override the policy that defines the member s benefits, nor is it intended to dictate to providers how to practice medicine. Policy Effective Date and Defined Terms. The date of posting is not the effective date of the Policy. The Policy is effective as of the date determined by Health Net. All policies are subject to applicable legal and regulatory mandates and requirements for prior notification. If there is a discrepancy between the policy effective date and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. * In some states, prior notice or posting on the website is required before a policy is deemed effective. For information regarding the effective dates of Policies, contact your provider representative. The Policies do not include definitions. All terms are defined by Health Net. For information regarding the definitions of terms used in the Policies, contact your provider representative. Policy Amendment without Notice. Health Net reserves the right to amend the Policies without notice to providers or Members. In some states, prior notice or website posting is required before an amendment is deemed effective. No Medical Advice. The Policies do not constitute medical advice. Health Net does not provide or recommend treatment to members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. No Authorization or Guarantee of Coverage. The Policies do not constitute authorization or guarantee of coverage of particular procedure, drug, service or supply. Members and providers should refer to the Member contract to determine if exclusions, limitations, and dollar caps apply to a particular procedure, drug, service or supply. Policy Limitation: Member s Contract Controls Coverage Determinations. Statutory Notice to Members: The materials provided to you are guidelines used by this plan to authorize, modify, or deny care for persons with similar illnesses or conditions. Specific care and treatment may vary depending on individual need and the benefits covered under your contract. The determination of coverage for a particular procedure, drug, service or supply is not based upon the Policies, but rather is subject to the facts of the individual clinical case, terms and conditions of the member s contract, and requirements of applicable laws and regulations. The contract language contains specific terms and conditions, including pre-existing conditions, limitations, exclusions, benefit maximums, eligibility, and Benign Skin Lesion Removal Aug 15 24

other relevant terms and conditions of coverage. In the event the Member s contract (also known as the benefit contract, coverage document, or evidence of coverage) conflicts with the Policies, the Member s contract shall govern. The Policies do not replace or amend the Member s contract. Policy Limitation: Legal and Regulatory Mandates and Requirements The determinations of coverage for a particular procedure, drug, service or supply is subject to applicable legal and regulatory mandates and requirements. If there is a discrepancy between the Policies and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. Reconstructive Surgery CA Health and Safety Code 1367.63 requires health care service plans to cover reconstructive surgery. Reconstructive surgery means surgery performed to correct or repair abnormal structures of the body caused by congenital defects, developmental abnormalities, trauma, infection, tumors, or disease to do either of the following: (1) To improve function or (2) To create a normal appearance, to the extent possible. Reconstructive surgery does not mean cosmetic surgery," which is surgery performed to alter or reshape normal structures of the body in order to improve appearance. Requests for reconstructive surgery may be denied, if the proposed procedure offers only a minimal improvement in the appearance of the enrollee, in accordance with the standard of care as practiced by physicians specializing in reconstructive surgery. Reconstructive Surgery after Mastectomy California Health and Safety Code 1367.6 requires treatment for breast cancer to cover prosthetic devices or reconstructive surgery to restore and achieve symmetry for the patient incident to a mastectomy. Coverage for prosthetic devices and reconstructive surgery shall be subject to the co-payment, or deductible and coinsurance conditions, that are applicable to the mastectomy and all other terms and conditions applicable to other benefits. "Mastectomy" means the removal of all or part of the breast for medically necessary reasons, as determined by a licensed physician and surgeon. Policy Limitations: Medicare and Medicaid Policies specifically developed to assist Health Net in administering Medicare or Medicaid plan benefits and determining coverage for a particular procedure, drug, service or supply for Medicare or Medicaid members shall not be construed to apply to any other Health Net plans and members. The Policies shall not be interpreted to limit the benefits afforded Medicare and Medicaid members by law and regulation. Benign Skin Lesion Removal Aug 15 25