Before OR After: Is There a Connection Between the Use of Adjunctive Nonmelanoma Skin Cancer Treatments and Subsequent Invasive Tumors?

May 2015 | Volume 14 | Issue 5 | Editorials | 450 | Copyright © May 2015

Emily Stamell Ruiz MD,a Joel L. Cohen MD,b,c
and Adam Friedman MDd

aDepartment of Der matology, Brigham & Women’s Hospital, Boston, MA
bAboutSkin Dermatology and Der mSurgery, Englewood, CO
cDepartment of Der matology, University of Colorado, Denver, CO
dDivision of Der matology, Department of Medicine, and Department of
Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY

fluorouracil cream), Fluoroplex® (1% fluorouracil cream), and Carac® (0.5% fluorouracil cream). Topical fluorouracil is FDA-approved for the treatment of AKs (Efudex, Carac, and Fluoroplex) and superficial BCCs (Efudex). Sustained clearance at 12 months ranges from 33%12 to 81.1%.9 Although not FDA-approved for the treatment of squamous cell carcinoma in situ, 5% fluoruracil cream has been shown to be efficacious.13,14 However, despite approval since the 1970’s, the Veterans Affairs Topical Tretinoin Chemoprevention trial noted that prior treatment with topical fluorouracil was associated with a higher risk of development of morpheaform BCCs. These authors concede that fluorouracil may have destroyed superficial cancer cells while leaving deeper pockets untouched. However, they open the door to a causal relationship between therapy and these tumors by stating that “fluorouracil treatment may predispose to development of morpheaform BCC.”3
As presented above, these 3 recent reports suggest that the topical therapies may be associated with future development of histologically more aggressive BCCs. However, it is important to recognize that each modality is only indicated for the treatment of superficial neoplastic tumors. More aggressive tumor subtypes may be deeper than clinically apparent, making treatment beyond reach. This concept was clearly illustrated in a case series by Sambandan and Goldman5 in which they presented 8 patients initially treated for AKs who failed to improve with destructive modalities. Upon biopsy the lesions were noted to have underlying BCCs. Although there is a possibility that the BCC developed in response to the destructive modality, it is more likely that the tumor was always present but not clinically apparent.
In this context, it is important to recognize that the findings of histologically aggressive tumors in these 3 studies may be due to their lack of response to the PDT, imiquimod, or fluoruracil, and not to the therapy itself. Furthermore, the 3 studies provide weak evidence supporting their causal relationship in causing aggressive skin cancers. These therapeutics play an important role in the treatment of NMSC, but they do have their limitations. In addition to thorough clinical examinations, other imaging modalities such as high-frequency ultrasound may be useful in identifying deeper tumors.15 Close clinical follow up after topical field therapy is prudent in order to not miss deeper, aggressive tumors.


Dr. Cohen has served as a consultant for Valeant and DUSA.


  1. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146(3):283-287.
  2. Fiechter S, Skaria A, Nievergelt H, Anex R, Borradori L, Parmentier L. Facial basal cell carcinomas recurring after photodynamic therapy: a retrospective analysis of histological subtypes. Dermatology. 2012;224(4):346-351.
  3. Xiong MY, Korgavkar K, Digiovanna JJ, Weinstock MA; Veterans Affairs Topical Tretinoin Chemoprevention Trial Group. Fluorouracil and other predictors of morpheaform basal cell carcinoma among high-risk patients: the Veterans Affairs Topical Tretinoin Chemoprevention Trial. JAMA Dermatol. 2014;150(3):332-334.
  4. Skaria AM. Facial basal cell carcinomas recurring after imiquimod therapy. Dermatology. 2013;226(1):13-14.
  5. Sambandan PG, Goldman GD. Infiltrative basal cell carcinomas presenting as actinic keratosis: implications for clinical practice. Dermatol Surg. 2008;34(1):9-13.
  6. De Rosa FS, Bentley MV. Photodynamic therapy of skin cancers: sensitizers, clinical studies and future directives. Pharm Res. 2000;17(12):1447-1455.
  7. Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology,2005. J Am Acad Dermatol. 2007;56(1):125-143.
  8. 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;26(3):321-331.
  9. Lecluse LL, Spuls PI. Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial: a critical appraisal. Br J Dermatol. 2015;172(1):8-10.
  10. Desai T, Chen CL, Desai A, Kirby W. Basic pharmacology of topical imiquimod, 5-fluorouracil, and diclofenac for the dermatologic surgeon. Dermatol Surg. 2012;38(1):97-103.
  11. Stockfleth E, Christophers E, Benninghoff B, Sterry W. Low incidence of new actinic keratoses after topical 5% imiquimod cream treatment: a long-term follow-up study. Arch Dermatol. 2004;140(12):1542.
  12. Krawtchenko N, Roewert-Huber J, Ulrich M, Mann I, Sterry W, Stockfleth E. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007;157(suppl 2):s34-s40.
  13. Welch ML, Grabski WJ, McCollough ML, et al. 5-fluorouracil iontophoretic therapy for Bowen’s disease. J Am Acad Dermatol. 1997;36(6 pt 1):956-958.
  14. McGillis ST, Fein H. Topical treatment strategies for non-melanoma skin cancer and precursor lesions. Semin Cutan Med Surg. 2004;23(3):174-183.
  15. Desai TD, Desai AD, Horowitz DC, Kartono F, Wahl T. The use of high-frequency ultrasound in the evaluation of superficial and nodular basal cell carcinomas. Dermatol Surg. 2007;33(10):1220-1227.