BRIEF REVIEW Oral leukoplakia—to treat or not to treat P Holmstrup, E Dabelsteen Section of Periodontology, Microbiology and Community Dentistry, School of Dentistry, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark Various treatment modalities have been described for reducing or eliminating malignant development of oral leukoplakia, but no treatment has gained universal approval due to lack of randomized clinical studies. At present, it is uncertain whether we can do harm to the patients by treating or by not treating them. An essen- tial aspect is the observation of cancer development even after surgical removal of the clinical lesions. Inade- quate resection of the lesions or field cancerization may account for this phenomenon. Another challenge is whether surgical removal of the lesions in fact is associ- ated with a cancer promotional effect resulting in increased risk of cancer. Moreover, unidentified existing cancer in non-suspicious oral leukoplakias may for diag- nostic purposes imply that surgical removal is recom- mendable as well as serial section of all excised tissue. Intensive follow-up programmes for leukoplakias are important, independent of surgical intervention. Oral Diseases (2016) doi: 10.1111/odi.12443 Keywords: oral cancer; premalignant oral lesions; leukoplakia; malignant transformation; treatment; precancer; prognosis Treatment scenario The idea of identifying oral lesions with a precancerous nature 1 , that is, in the sense of pertaining to a pathologic process with an increased risk for future malignant devel- opment, of course, is to prevent frank malignancy to occur in the affected area. The most common oral lesion with a precancerous nat- ure is oral leukoplakia, and for decades, it has been dis- cussed how to treat these lesions. Various treatment modalities, such as systemic therapies and surgical removal, have been suggested. The systemic therapies tested so far include retinoids, extracts of green tea, inhibi- tors of cyclooxygenase-2 and of epidermal growth factor, and peroxisome proliferator-activated receptor-c agonists (William, 2012), but there is no generally approved stan- dard systemic therapy regimen so far (William, 2012). Local removal includes photodynamic therapy, laser ther- apy, cryotherapy and conventional removal by scalpel, but no treatment has so far gained universal approval, no treatment has so far been subjected to a randomized clini- cal trial (RCT), and no treatment has been shown to pre- vent recurrence or significantly reduce malignant development in long-term follow-up studies (Holmstrup, 2009; Balasundarum et al, 2014). It is well established that no treatment results in malignant development at an annual rate of 2–3% (van der Waal, 2014). The overall purpose of treatment therefore is to reduce this percentage. However, the situation for us to take responsibility for the welfare of our patients still is, as it has been so far: despite treatment, in some types of lesions cancers do occur, so the important question is whether we can do harm to our patients by not treating or by treating them? (Holmstrup, 2009). Lack of randomized clinical trials accounts for this persistent question, and while waiting for such studies to be reported, it is necessary to reflect on the existing scenarios. A crucial aspect to deal with is the identification of mucosal areas as target for therapy due to increased risk for future malignant development. So far, we have been focusing on clinical lesions, and previous studies have shown that increased risk for malignant progression of leukoplakias may depend on a number of characteristics of the lesion itself including size, site, and clinical type, that is, homogenous or non-homogenous, and presence or absence of degrees of epithelial dysplasia. Although the predictive value of epithelial dysplasia has been shown to increase by combining DNA ploidy analysis with dys- plasia grading (Sperandio et al, 2013), the significance for future development of cancer of some of these characteris- tics has been seriously questioned in the past (Holmstrup et al, 2006; Brouns et al, 2014; Fonseca-Silva et al, 2016). Recent advances in the understanding of the biology of processes related to malignant development have pointed to changes of the oral mucosa described as patches when Correspondence: Palle Holmstrup, Professor and Chairman, DDS, Ph.D., Dr.Odont., Odont.Dr. (h.c.), Section of Periodontology, Microbiology and Community Dentistry, School of Dentistry, Faculty of Health and Medi- cal Sciences, University of Copenhagen, 20 Norre Alle, DK-2200 Copen- hagen N, Denmark. Tel: +45 35326690, Fax: +45 3532 6722, E-mail: pah@sund.ku.dk Received 14 January 2016; accepted 14 January 2016 Oral Diseases (2016) doi:10.1111/odi.12443 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd All rights reserved www.wiley.com