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Research Letter |

Fluorouracil and Other Predictors of Morpheaform Basal Cell Carcinoma Among High-Risk Patients: The Veterans Affairs Topical Tretinoin Chemoprevention Trial FREE

Michael Y. Xiong, BA1,2; Kaveri Korgavkar, BS1,2; John J. DiGiovanna, MD3; Martin A. Weinstock, MD, PhD1,2,4,5 ; for the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial Group
[+] Author Affiliations
1Dermatoepidemiology Unit, VA Medical Center, Providence, Rhode Island
2Department of Dermatology, Warren Alpert Medical School of Brown University, Providence, Rhode Island
3DNA Repair Section, Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
4Department of Dermatology, Rhode Island Hospital, Providence
5Department of Epidemiology, Brown University, Providence, Rhode Island
JAMA Dermatol. 2014;150(3):332-334. doi:10.1001/jamadermatol.2013.5619.
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Published online

Although basal cell carcinoma (BCC) overall is less aggressive than other forms of skin cancer, the morpheaform subtype is particularly concerning because of its benign appearance and aggressive subclinical spread. We sought to evaluate risk factors for its development on the face or ears in a high-risk population of veterans with at least 2 prior keratinocyte carcinomas in the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial.

The VATTC Trial included 1131 high-risk veterans followed up for 2 to 6 years, as described elsewhere.1 We determined risk factors for time to first morpheaform BCC (mBCC) within the entire study population via Cox regression (measured by hazard rate ratio [HRR]) and also compared the risk of developing mBCC relative to that of developing nonmorpheaform BCC (nmBCC) via logistic regression (measured by odds ratios [ORs]). All variables with P values <.15 in the univariate models were included in the multivariate backward stepwise regression models. The study was approved by multiple ethics and oversight committees; informed consent was obtained for this study.

Participants had a mean age of 72 years, were followed up for a mean of 3.6 years, and had a mean of 3.6 keratinocyte carcinomas during the 5 years before enrollment. An mBCC developed in 50 participants (10% of those in whom any BCC developed). The 1-, 3-, and 5-year cumulative risks of mBCC were 1.2%, 4.1%, and 5.4%.

In univariate Cox regression, the most important risk factor for mBCC was the number of BCCs in the 5 years before enrollment (HRR, 7.06; P < .001). Other significant predictors included a history of ever using fluorouracil, sun sensitivity, and the number of actinic keratoses at baseline. The Long Beach, California, center was also a positive predictor for mBCC (HRR, 3.53; P = .01). In the multivariate Cox model (Table 1), the number of BCCs in the 5 years before enrollment and a history of ever using fluorouracil were the only 2 predictors of mBCC when study site was not considered. When study site was included, these 2 variables were retained, and the Oklahoma City, Oklahoma, center became a significant predictor.

Univariate logistic regression revealed that the most important risk factor for mBCC vs nmBCC was a history of ever using fluorouracil (OR, 2.49; P = .004). Other significant predictors included the number of BCCs in the 5 years before enrollment and sun sensitivity, but not the number of actinic keratoses at baseline. When study site was considered, the Long Beach center was associated with increased risk of mBCCs vs nmBCCs. In the multivariate logistic regression model (Table 1), a history of ever using fluorouracil was the strongest independent predictor for mBCC vs nmBCCs when study site was not considered (OR,  2.48; P = .009); the number of BCCs in the prior 5 years was marginally significant (P = .050). When study site was included, the Long Beach center was a significant predictor, and the number of BCCs in the prior 5 years was not.

Among patients in whom at least 2 BCCs developed during the study and whose first BCC was morpheaform, the odds were nearly 12 times greater that the second BCC would also be morpheaform compared with patients whose first BCC was nonmorpheaform (Table 2) (P = .002).

Table Graphic Jump LocationTable 2.  Distribution of First and Second Postenrollment BCCs

Patients with a history of treatment with fluorouracil had a higher risk of developing mBCC, even though fluorouracil use was not associated with increased risk of BCC overall in this study.1 Fluorouracil treatment may eliminate some superficial BCCs but leave mBCCs intact, which might explain why fluorouracil was associated with mBCCs but not BCCs overall; it has been shown to be up to 90% effective for superficial BCC.2 On the other hand, surgery is currently the only recommended treatment for mBCC3; less aggressive treatments are not as effective.4

Fluorouracil may also have destroyed cancer cells at the surface while deeper pockets remained viable and later proliferated, resulting in mBCCs. Some studies suggested that mBCCs tend to occur on areas of previous nmBCCs.5,6

Strengths of this study include a large sample size of veterans from 6 locations with a mean follow-up duration of 3.6 years. Patients were examined semiannually by board-certified dermatologists. End points were verified by electronic medical records for completeness and by central dermatopathology reviews for diagnosis, which have been shown to be reliable.7

Limitations include a study population of primarily elderly men with at least 2 prior keratinocyte carcinomas, which may limit the generalizability of our results. Index event bias may shift results toward the null. We cannot eliminate possible recall bias, although it was minimized because predictors, such as prior BCCs and baseline actinic keratoses, were identified through medical record review and dermatological examination. Prospective ascertainment of variables also minimizes recall bias.

The findings of our study underscore key risk factors for mBCC in a high-risk population. Fluorouracil treatment was associated with increased risk of mBCC in the entire study population and also the subpopulation in whom any BCC developed during the study. The possibility that fluorouracil treatment may predispose to development of mBCC warrants further investigation.

Corresponding Author: Martin A. Weinstock, MD, PhD, Dermatoepidemiology Unit, VA Medical Center, Mail Code 111D, 830 Chalkstone Ave, Providence, RI 02908 (maw@brown.edu).

Accepted for Publication: May 23, 2013.

Published Online: November 20, 2013. doi:10.1001/jamadermatol.2013.5619.

Author Contributions: Dr Weinstock had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Xiong, DiGiovanna, Weinstock.

Acquisition of data: Xiong, Weinstock.

Analysis of data: All authors.

Drafting of the manuscript: Xiong, Korgavkar, Weinstock.

Critical revision of manuscript for important intellectual content: All authors.

Statistical analysis: Xiong, Weinstock.

Obtained funding: Weinstock.

Administrative, technical, or material support: DiGiovanna, Weinstock.

Study supervision: Weinstock.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by the VA Cooperative Studies Program (CSP) (grant CSP 402), Office of Research and Development, Department of Veterans Affairs (VA).

Role of the Sponsor: Because this was a VA CSP trial, the VA necessarily played a role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; and the preparation, review, and approval of the manuscript,

Group Information: Key personnel for the VATTC Trial Group Study Chair’s Office: Martin A. Weinstock, MD, PhD (chair), and Kimberly Marcolivio, MEd (Providence VA Medical Center [VAMC], Rhode Island). Executive Committee: Martin A. Weinstock (Providence), Stephen Bingham, PhD (Perry Point, Maryland), John J. DiGiovanna, MD (Providence), Russell Hall, MD (Durham, North Carolina), Mark Naylor, MD (Oklahoma City), J. Richard Taylor, MD (Miami, Florida), Julia Vertrees, PharmD (Albuquerque, New Mexico), and Clifton White, MD (Portland, Oregon). Clinical Centers: Durham VAMC, Durham: Russell Hall and Deborah Hannah; Hines VA Hospital, Chicago, Illinois: David Eilers, Tehming Liang, Nadia Sakla, and Ann Kreuger; Long Beach VAMC, Long Beach, California: Gary Cole, Edward Jeffes, and Terri Labrador; Miami VAMC, Miami, Florida: J. Richard Taylor, Robert Kirsner, Jonette E. Kerri, Anna G. Falabella, and Margarita Givens; Oklahoma City VAMC, Oklahoma City: Mark Naylor, Mary Beth Benson, and Lisa Perry; and Phoenix VAMC, Phoenix, Arizona: James Kalivas, Catherine Yanni, Selma Targovnik, Janet Austin, and Susan Collier. Cooperative Studies Program Coordinating Center, Perry Point: 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 Coordinating Center, Albuquerque: Mike Sather, Erica Copeland, Carol Fye, William Gagne, Patricia Grimes de Naranjo, Chad Messick, and Julia Vertrees. Dermatopathologists: Michael Piepkorn (Bellevue, Washington) and Clifton White (Portland). Data and Safety Monitoring Board: Robert Lew (Boston, Massachusetts), Irwin Braverman (New Haven, Connecticut), Bernard Cole (Lebanon, New Hampshire), Richard Kalish (Stony Brook, New York), David McLean (Vancouver, British Columbia, Canada), and Bruce Harris Thiers (Charleston, South Carolina).

Dyer  RK, Weinstock  MA, Cohen  TS, Rizzo  AE, Bingham  SF; VATTC Trial Group.  Predictors of basal cell carcinoma in high-risk patients in the VATTC (VA Topical Tretinoin Chemoprevention) trial. J Invest Dermatol. 2012;132(11):2544-2551.
PubMed   |  Link to Article
Love  WE, Bernhard  JD, Bordeaux  JS.  Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review. Arch Dermatol. 2009;145(12):1431-1438.
PubMed   |  Link to Article
Neville  JA, Welch  E, Leffell  DJ.  Management of nonmelanoma skin cancer in 2007. Nat Clin Pract Oncol. 2007;4(8):462-469.
PubMed   |  Link to Article
Blixt  E, Nelsen  D, Stratman  E.  Recurrence rates of aggressive histologic types of basal cell carcinoma after treatment with electrodesiccation and curettage alone. Dermatol Surg. 2013;39(5):719-725.
PubMed   |  Link to Article
Teo  WL, Wong  CH, Song  C.  Morpheaform facial basal cell carcinoma: a 16-year experience in an Asian center. Int J Dermatol. 2012;51(11):1396-1398.
PubMed   |  Link to Article
Burdon-Jones  D, Thomas  PW.  One-fifth of basal cell carcinomas have a morphoeic or partly morphoeic histology: implications for treatment. Australas J Dermatol. 2006;47(2):102-105.
PubMed   |  Link to Article
Jagdeo  J, Weinstock  MA, Piepkorn  M, Bingham  SF; Department of Veteran Affairs Topical Tretinoin Chemoprevention Trial Group.  Reliability of the histopathologic diagnosis of keratinocyte carcinomas. J Am Acad Dermatol. 2007;57(2):279-284.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 2.  Distribution of First and Second Postenrollment BCCs

References

Dyer  RK, Weinstock  MA, Cohen  TS, Rizzo  AE, Bingham  SF; VATTC Trial Group.  Predictors of basal cell carcinoma in high-risk patients in the VATTC (VA Topical Tretinoin Chemoprevention) trial. J Invest Dermatol. 2012;132(11):2544-2551.
PubMed   |  Link to Article
Love  WE, Bernhard  JD, Bordeaux  JS.  Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review. Arch Dermatol. 2009;145(12):1431-1438.
PubMed   |  Link to Article
Neville  JA, Welch  E, Leffell  DJ.  Management of nonmelanoma skin cancer in 2007. Nat Clin Pract Oncol. 2007;4(8):462-469.
PubMed   |  Link to Article
Blixt  E, Nelsen  D, Stratman  E.  Recurrence rates of aggressive histologic types of basal cell carcinoma after treatment with electrodesiccation and curettage alone. Dermatol Surg. 2013;39(5):719-725.
PubMed   |  Link to Article
Teo  WL, Wong  CH, Song  C.  Morpheaform facial basal cell carcinoma: a 16-year experience in an Asian center. Int J Dermatol. 2012;51(11):1396-1398.
PubMed   |  Link to Article
Burdon-Jones  D, Thomas  PW.  One-fifth of basal cell carcinomas have a morphoeic or partly morphoeic histology: implications for treatment. Australas J Dermatol. 2006;47(2):102-105.
PubMed   |  Link to Article
Jagdeo  J, Weinstock  MA, Piepkorn  M, Bingham  SF; Department of Veteran Affairs Topical Tretinoin Chemoprevention Trial Group.  Reliability of the histopathologic diagnosis of keratinocyte carcinomas. J Am Acad Dermatol. 2007;57(2):279-284.
PubMed   |  Link to Article

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