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- Material and methods
- Author contributions
Oral leukoplakia is a potentially malignant disorder which means that in this morphologically altered tissue, squamous cell carcinoma is more likely to occur than in its apparently normal counterpart (Warnakulasuriya et al, 2007). The reported annual malignant transformation of oral leukoplakia into oral squamous cell carcinoma (OSCC) is approximately 1–2% (van der Waal, 2009). Several factors have been suggested to predict an increased risk of malignant transformation of oral leukoplakia, such as age, gender, tobacco habits, homogeneity and size of the lesion, oral subsite, degree of epithelial dysplasia, if present, loss of heterozygosity, survivin, matrix metalloproteinase 9 and DNA content (Schepman et al, 1998; Dietrich et al, 2004; Holmstrup et al, 2006; Fillies et al, 2007; Smith et al, 2009; van der Waal, 2009; Bremmer et al, 2011; Brouns et al, 2012b). The possible role of human papilloma virus infection with regard to malignant transformation of oral leukoplakia is yet unclear (Syrjanen et al, 2011; Feller and Lemmer, 2012). Management of oral leukoplakia consists of surgical excision, laser surgery, CO2 laser vaporisation and observation (Mehanna et al, 2009; Ribeiro et al, 2010).
The aim of the present retrospective study was to identify the factors that possibly predict malignant transformation in a well-defined cohort of patients with a long-term follow-up. All leukoplakias were staged according to a clinicopathological classification and staging system. Furthermore, a certainty factor has been used with which the diagnosis has been established.
- Top of page
- Material and methods
- Author contributions
In the present study, 144 patients with a histopathological diagnosis of oral leukoplakia and a minimum follow-up of 12 months were included. Moreover, a classification and staging system has been used (Tables 1 and 4) (van der Waal and Axell, 2002; van der Waal, 2009; Brouns et al, 2012c). There were 16 of 144 (11%) patients in whom a malignant transformation occurred during the follow-up, resulting in an annual malignant transformation rate of 2.6%. Ninety-five of 144 (66%) patients underwent any type of treatment at the initial stage or during follow-up, while in a previous study from our institute, only 87 of 166 (52%) underwent any type of active treatment (Schepman et al, 1998). In the latter study, the annual malignant transformation rate amounted 2.9% (Schepman et al, 1998). Apparently, active or passive management policy is not related to the risk of malignant transformation. This observation has also been made in various other studies (Schepman et al, 1998; Lodi et al, 2006; Arduino et al, 2009). It is actually unknown whether the width of the margin, either in surgical removal or CO2 laser vaporisation, would be of relevance in this respect. At present, no molecular markers are available to determine the optimal width of the margin.
The gender distribution of the entire patient group showed a female preponderance with a male/female ratio of approximately 1:2,3 (Figure 1). Of the patients with malignant transformation, the male/female ratio is even 1:3,7. In most long-term follow-up studies of oral leukoplakia, there is a preference for males in the entire patient group (Banoczy, 1977; Lumerman et al, 1995; Saito et al, 1999; Liu et al, 2011). However, other studies have shown that female gender was a higher risk of malignant transformation (Silverman et al, 1984; Schepman et al, 1998). Despite the high female preponderance in the present study, no statistically significant difference was found between gender and malignant transformation (P = 0.609).
A large size of the lesion (L3 ≥ 4 cm) showed to be the only significant predictor of malignant transformation (P = 0.034). This relationship has also been shown in another study (Holmstrup et al, 2006). As mentioned by Saito et al (Saito et al, 1999), widespread multiple leukoplakias have a higher potential for the development of cancer than the localised ones. These authors also mentioned that their multiple leukoplakias probably represented examples of proliferative verrucous leukoplakia. The latter term has been the subject of discussion related to its definition for several decades. Anyhow, every leukoplakia, how small and how benign histopathologically looking, may turn into malignancy and widespread multiple leukoplakias apparently carry a higher risk of malignant transformation than localised small ones.
Of the patients with a malignant transformation, eight carcinomas arose at the tongue and not one at the upper or lower alveolus and gingiva (Table 3). There was no statistically significant relation found between the oral subsite and malignant transformation (P = 0.144) and also not when the subsites were subdivided into high risk (floor of mouth and tongue) versus low risk (remaining oral subsites) (P = 0.408). We also did not identify ‘alveolar ridge keratosis’ as a separate entity, and we did not exclude cases of ‘frictional keratosis of the attached gingiva’ that did not disappear after changing the brushing habits (Chi et al, 2007; Natarajan and Woo, 2008; Mignogna et al, 2011).
Other reported predicting factors of malignant transformation such as age, the absence of tobacco habits, heterogeneity of the lesion, presence of C. albicans and presence and degree of epithelial dysplasia were not found in the present study (Schepman et al, 1998; Holmstrup et al, 2006; Liu et al, 2010; Bremmer et al, 2011; Warnakulasuriya et al, 2011; Ho et al, 2012).
In 11 patients, surgical excision was performed after an incisional biopsy. The advantage of additional surgical excision after an incisional biopsy is the availability of a surgical specimen for additional histopathological examination. It has been shown that the histopathological findings in an incisional biopsy from leukoplakia are not always representative of the entire lesion (Vedtofte et al, 1987; Holmstrup et al, 2007).
No reliable comparison can be made in our study between the treatment results of CO2 laser vaporisation and cold-knife surgery, because of different indications for both treatment modalities in the present study. In the literature, no randomised controlled trials are available to compare both treatment modalities with regard to the local recurrence rate and the risk of malignant transformation. For both treatment modalities, high recurrence rates have been reported in the literature (Vedtofte et al, 1987; Brouns et al, 2012a; Kuribayashi et al, 2012). The present study showed for both surgical excision and CO2 laser vaporisation treatment a recurrence rate of approximately 40% during a mean follow-up period of 48.8 months and 61.9 months, respectively.
The annual malignant transformation rate (2.6%) in this study may be difficult to compare with that of other studies, due to possible differences in study populations, different tobacco and alcohol habits, different diagnostic criteria used for oral leukoplakia and allied white lesions, different treatment strategies and perhaps also different follow-up policies. A size of ≥ 4 cm showed to be the only significant predicting factor of malignant transformation in oral leukoplakia. No other epidemiological, aetiological, clinical or histopathological parameters were shown to be of statistical significance. Although the efficacy of removal of oral leukoplakia with regard to the risk of malignant transformation is uncertain, such removal should be considered in each patient with such lesion, particularly also in the extensive ones.