Actinic Keratoses Natural History and Risk of Malignant Transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial Vincent D. Criscione, AB1,2, Martin A. Weinstock, MD, PhD1,2,3, Mark F. Naylor, MD4, Claudia Luque, MD1, Melody J. Eide, MD, MPH5, and Stephen F. Bingham, PhD6, for the Department of Veteran Affairs Topical Tretinoin Chemoprevention Trial Group BACKGROUND: Actinic keratoses (AKs) are established as direct precursors of squamous cell carcinoma (SCC), but there is significant controversy regarding the rate at which AKs progress to SCC. The authors of this report studied a high-risk population to estimate the risk of progression of AK to SCC and to basal cell carcinoma (BCC) and the risk of spontaneous regression of untreated AKs. METHODS: Data were obtained from participants in the Department of Veterans Affairs Topical Tretinoin Chemoprevention Trial. Partici- pants were examined every 6 months for up to 6 years. At each examination, the locations on the face and ears of clinically diagnosed AKs and lesions scheduled for biopsy were marked, and high-resolution digital photographs were taken. These photographs were used later to map and track the presence, absence, or biopsy of each AK across visits. RESULTS: In total, 7784 AKs were identified on the face and ears of 169 participants. The risk of progression of AK to primary SCC (invasive or in situ) was 0.60% at 1 year and 2.57% at 4 years. Approximately 65% of all primary SCCs and 36% of all primary BCCs diagnosed in the study cohort arose in lesions that previously were diagnosed clinically as AKs. The majority of AKs (55%) that were followed clinically were not present at the 1-year follow-up, and the majority (70%) were not present at the 5-year follow-up. CONCLUSIONS: In the current study, the authors quantified the malignant potential of clinically diagnosed AKs for both SCC and BCC, although many did not persist, and the results Received: September 25, 2008 Revised: November 14, 2008 Accepted: November 20, 2008 Published online: April 20, 2009, Published 2009 by the American Cancer Society* DOI: 10.1002/cncr.24284, www.interscience.wiley.com Corresponding author: Martin A. Weinstock, MD, PhD, Dermatoepidemiology Unit-111D, VA Medical Center, 830 Chalkstone Avenue, Providence, RI 02908-4799 Fax: (401) 457-3332 maw@brown.edu 1Dermatoepidemiology Unit, Veterans Affairs Medical Center, Providence, Rhode Island 2Departments of Dermatology and Community Health, Brown University, Providence, Rhode Island 3Department of Dermatology, Rhode Island Hospital, Providence, Rhode Island 4Department of Derma- tology, Veterans Affairs Medical Center, Oklahoma City, Oklahoma 5Department of Dermatology, Henry Ford Hospital, Detroit, Michigan 6Veterans Affairs Cooperative Studies Coordinating Center, Perry Point, Maryland We thank Kimberly Marcolivio, national project coordinator, and Lisa Perry, Oklahoma City data coordinator, for their outstanding work. Key personnel of the Department of Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial include the following: Study Chairman���s Office: Martin A. Weinstock (Chair) and Kimberly Marcolivio (Providence, RI). Executive Committee: Martin Weinstock (Providence, RI), Stephen Bing- ham (Perry Point, Md), John DiGiovanna (Providence, RI), Russell Hall (Durham, NC), Mark Naylor (Oklahoma City, Okla), J. Richard Taylor (Miami, Fla), Julia Vertrees (Albuquerque, NM), and Clifton White (Portland, Ore). Clinical Centers: Durham, NC (Russell Hall and Deborah Hannah) Chicago, Ill (Hines) (David Eilers, Tehming Liang, Nadia Sakla, and Ann Kreuger) Long Beach, Calif (Gary Cole, Edward Jeffes, and Terri Labrador) Miami, Fla (J. Richard Taylor, Robert Kirsner, Jonette E. Kerri, Anna G. Falabela, and Margarita Givens) Oklahoma City, Okla (Mark Naylor, Mary Beth Benson, and Lisa Perry) and Phoenix, Ariz (James Kalivas, Catherine Yanni, Selma Targovnik, Janet Austin, and Susan Collier). Cooperative Studies Program Coordinating Center (Perry Point, Md): Joseph F. Collins, Stephen Bingham, Beverly Calvert, Philip Connor, Colleen Crigler, Dawn Davis, Pat Grubb, Judy Kelly, Gail Kirk, Karen Lawson, Linda Linzy, Lorrine Palmer, and Maxine Rhoads. Cooperative Studies Program Clinical Research Pharmacy Coor- dinating Center (Albuquerque, NM): Mike Sather, Erica Copeland, Carol Fye, William Gagne, Patricia Grimes de Naranjo, Chad Messick, and Julia Ver- trees. Dermatopathologists: Michael Piepkorn (Bellevue, Wash) and Clifton White (Portland, Ore). Data and Safety Monitoring Board: Robert Lew (Boston, Mass), Irwin Braverman (New Haven, Conn), Bernard Cole (Lebanon, NH), Richard Kalish (Stony Brook, NY), David McLean (Vancouver, BC, Canada), and Bruce Thiers (Charleston, SC). *This article is US Government work and, as such, is in the public domain in the United States of America. Cancer June 1, 2009 2523 Original Article

suggested that AKs may play a greater role in the overall burden of keratinocyte carcinomas than previ- ously documented. Cancer 2009 115:2523���30. Published 2009 by the American Cancer Society.* KEY WORDS: actinic keratoses, squamous cell carcinoma, basal cell carcinoma, nonmelanoma skin cancer, epidemiology. Actinic keratoses (AKs) are dysplastic keratinocytic lesions confined to the epidermis that are caused by ultra- violet (UV) radiation.1 They are 1 of the most common conditions treated by dermatologists,2 with an estimated prevalence of 39.5 million in the US in 2004 and annual costs totaling $1.04 billion.3 Although the most common reason for treatment is prevention of malignancy, lesions also are treated for cosmetic purposes and to provide relief from symptoms, such as tenderness or itch. It is generally accepted that these lesions can be direct precursors of squamous cell carcinoma (SCC), but there has been a pau- city of investigations into the frequency of malignant transformation thus, there is significant controversy over the rate at which AKs progress to SCC. Annual rates of transformation ranging from 0.025% to 20% have been reported,4 yet we are aware of only 1 study that directly quantifies this risk using primary data.5 That study was conducted in a general population sample, and the maxi- mum follow-up of individual lesions was 1 year. The dearth of direct study of this phenomenon is remarkable. For the current investigation, we used prospectively collected data from 1 center of a randomized, multicenter trial in a high-risk population with up to 6 years of follow- up, including photography and dermatologist examina- tion, to estimate the risk of progression of AKs to kerati- nocyte carcinomas (KCs) and to assess the natural history of AKs. MATERIALS AND METHODS Data were collected from the participants at 1 of the 6 sites of the Department of Veterans Affairs (VA) Topical Treti- noin Chemoprevention (VATTC) trial, a randomized, multicenter trial of topical tretinoin 0.1% for the preven- tion of KCs of the face and ears. Additional details of that study are described elsewhere.6,7 Although quantifying the times to onset of new basal cell carcinoma (BCC) or SCC were the primary focus of the trial, understanding the natural history of AKs was a secondary objective and, for this purpose, a subprotocol was implemented for the 182 participants at 1 site (the Oklahoma City VA Medical Center). All participants had been diagnosed with 2 KCs in the 5 years before enrollment in the study and hence represent a high-risk population. The study derma- tologist (an experienced clinician who had been practicing clinical dermatology actively for 14 years) examined all participants at approximately 6-month intervals. There was no specific treatment of AKs (other than biopsy if they became bothersome or clinically suspect for KC) dur- ing the trial, although all participants were offered free sunscreen and encouraged to use it. Participants were queried at each visit regarding biopsies and dermatologic treatments that took place outside of the Oklahoma VA Medical Center. Participants did not report any biopsies and only reported 38 treatments outside of the VA (7.1% of all treatments) during the trial. During each examina- tion, a standardized set of 3 high-resolution digital photo- graphs of the face and ears was taken. Then, all AKs were identified by clinical criteria and were marked in red on the patient���s face or ears. Lesions that were suspected car- cinoma were scheduled for biopsy and marked in black. The photographs then were repeated to document these markings for later analysis. The investigators did not refer to images from previous visits during subsequent visits. After completion of the trial, the photographs were used to evaluate the presence, absence, or biopsy designation of each distinct face/ears lesion at each study visit. All lesions that were biopsied from the face or ears were evaluated by a local pathologist and by 1 of 2 central reference dermatopathologists who were blinded to the original diagnosis. The interobserver reliability of these diagnoses is documented elsewhere.8 The diagnosis made by the central reference dermatopathologists was used for study purposes. Only biopsies of lesions that once had been photographed and marked as AKs were included in our analyses of AK prognosis. AKs that were not located on the face or ears were excluded from all data considered in this study. Original Article 2524 Cancer June 1, 2009