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Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with long-term follow-up
Journal of Cranio-Maxillo-Facial Surgery xxx (2015) 1e6
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Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with long-term follow-up Giacomo Del Corso a, *, Davide Bartolomeo Gissi a, Achille Tarsitano b, Enrico Costabile b, Claudio Marchetti b, Lucio Montebugnoli a, Maria Pia Foschini c a
Department of Biomedical and Neuromotor Sciences, Section of Oral Science, University of Bologna, Italy Department of Biomedical and Neuromotor Sciences, University of Bologna, Section of Maxillo-facial Surgery at Policlinico S. Orsola-Malpighi, Bologna, Italy c Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology at Bellaria Hospital, University of Bologna, Italy b
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 13 January 2015 Accepted 8 April 2015 Available online xxx
Objectives: The study makes a comparison between two surgical approaches for the treatment of oral leukoplakia (OL) in terms of recurrence in a well-defined cohort of patients with a long-term follow-up period. Methods: The cohort consisted of 77 OL patients divided into 2 groups. Group 1: 47 patients treated with laser evaporation using a Nd:YAG laser. Group 2: 30 patients treated with a CO2 laser for excision. Clinical and histological examinations were performed for the diagnosis of OL before treatment. We included OLs with or without dysplasia. The mean follow-up period was 60 ± 32.49 months. Results: Of the 77 patients, 22 (28.5%) showed recurrence during the follow-up period. No significant difference was found between the two treatments (c2 ¼ 2.6; p ¼ 0.2). However, CO2 laser excision resulted in better results than the Nd:YAG laser evaporation, considering the non-homogeneous OLs (c2 ¼ 3.9; p ¼ 0.04) and OLs with mild dysplasia (c2 ¼ 4.6; p ¼ 0.03). Discussion: The study makes a comparison between our results and articles from the literature, and suggests when each of the two surgical approaches is most appropriate. © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Keywords: Laser surgery Oral leukoplakia Laser excision Laser evaporation Nd:YAG laser CO2 laser
1. Introduction Oral squamous cell carcinoma (OSCC) is the most common tumour of the oral cavity with 5-year and 22-year survival rates of 30e45% and 6.3%, respectively, while locoregional recurrence after treatment occurs in almost 30% of cases (Lopez-Cedrun and Andres de Liano, 2015; Kreppel et al., 2013). Oral leukoplakia (OL) is considered a premalignant oral lesion, and its diagnosis is essentially made by excluding other known diseases. The prevalence of OL worldwide is ~2% (Petti, 2003), and it is more frequent in smokers than non-smokers. Its diagnosis is made by clinical features, and a biopsy is mandatory to exclude other diseases. OL is a white plaque, and is divided into homogeneous and non* Corresponding author. Department of Biomedical and Neuromotor Sciences, Via S Vitale 59, Bologna, Italy. E-mail address: [email protected] (G. Del Corso).
homogeneous types: the homogeneous type is a white plaque that is flat, thin, and uniform, whereas the non-homogeneous type can be irregularly flat, nodular, verrucous, and with a white and red colouration (van der Waal, 2010). With respect to nonhomogeneous OL, proliferative verrucous leukoplakia (PVL) can involve any site in the oral cavity and has a high risk of malignant transformation (van der Waal and Reichart, 2008). A histological examination must be performed to exclude other diseases, and in particular, to determine the presence of dysplasia (mild, moderate, or severe; low-grade intraepithelial lesion or high-grade intraepithelial lesion, according to the 2014 Ljubljana classification). Malignant transformation ranged from 0.13% to 17.55% (Lee et al., 2006; Reibel, 2003). Thus, not all OL cases transform into OSCC. A high risk of malignant transformation is correlated with the degree of histological dysplasia. Treatment modalities range from cessation of smoking to medication with retinoids, cryosurgery, or laser surgery. Laser
http://dx.doi.org/10.1016/j.jcms.2015.04.009 1010-5182/© 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Del Corso G, et al., Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with longterm follow-up, Journal of Cranio-Maxillo-Facial Surgery (2015), http://dx.doi.org/10.1016/j.jcms.2015.04.009
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G. Del Corso et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2015) 1e6
surgery was first performed in 1978 (Ben-Bassat et al., 1978). It presents some advantages, such as total removal of the lesion, minimal damage to surrounding tissues, and reduction of postoperative pain and oedema (van der Hem et al., 2005). Healing is typically very good because of the limited contraction of the tissues and minimal oral dysfunction (Ishii et al., 2003). CO2 and Nd:YAG lasers are mainly used to treat OL in two different modalities: evaporation and excision. Evaporation induces limited postoperative discomfort, and can be performed in different stages, especially in patients with wide lesions or multiple lesions. The main disadvantage of the evaporation technique, with respect to excision, is the impossibility of examining the whole lesion histologically. In addition, excision can lead to functional problems with very large lesions. The present study describes, for the first time, a comparison between the two different surgical approaches for the treatment of OLs: Nd:YAG laser evaporation versus CO2 laser excision. The longterm follow-up and the two different cohorts of patients validate this retrospective study. The objective was to assess whether there were significant differences in terms of recurrence between the two surgical treatments. 2. Materials and methods From 2004 to 2013, 77 OL cases were diagnosed at the Department of Oral Sciences of the University of Bologna, after which they were treated at the Maxillo-Facial Unit of the S. Orsola Hospital, Bologna, Italy. 2.1. Inclusion and exclusion criteria Only patients referred to the Department of Oral Sciences, University of Bologna, with a diagnosis of OL were included. The inclusion criteria were OLs with or without dysplasia and clear surgical margins on histological examination. Patients with preexisting OSCC, OLs with severe dysplasia (high-grade intraepithelial lesion, according to the 2014 Ljubljana classification), and patients with other white lesions not identifiable as OL were excluded. In addition, surgical specimens with positive dysplastic margins and OSCC found in the first surgical specimen were excluded. 2.2. Patient management All of the patients underwent histological examination for diagnosis. Specimens were taken with a biopsy punch to a depth of at least 5 mm, and a 3e5 mm margin of clinically normal mucosa was also included. All of the tissues were fixed in 10% formalin and paraffin wax-embedded by routine procedures. Serial sections were cut from each block, and stained with haematoxylin and eosin for histological evaluation. Histological examinations and immunohistochemical staining were performed blindly at the Section of Anatomic Pathology of the Department of Hematology and
Table 1 Age and sex distribution of patients treated with laser evaporation (Group 1) and laser excision (Group 2) respectively.
Group 1
Group 2
Men Women Total Men Women Total
Number
Age (year)
Mean (year)
19 28 47 19 11 30
34e78 42e80 34e80 34e79 26e80 26e80
55 60 58 65 57 62
Table 2 The sites of all the lesions. Site
Number
Percentage
Tongue Floor of the mouth Hard palate Buccal mucosa Upper or lower gingiva Total
18 5 8 25 21 77
23% 6.5% 10% 32.5% 28% 100%
Oncology, Bologna University, at Bellaria Hospital. All of the cases were examined by the same pathologist (MPF). Histological diagnoses were performed according to the WHO criteria. Age, gender distribution, site of the lesions, and grade of dysplasia at the biopsy are shown in Tables 1e3. The sites of OL were the tongue, floor of the mouth, hard palate, buccal mucosa, and upper and lower gingiva. Treatment consisted of the surgical excision of the OLs. Group 1 consisted of 47 OLs treated with laser evaporation with a Nd:YAG laser; Group 2 consisted of 30 OLs treated with CO2 laser excision. All of the treatments were performed under local anaesthesia, except some larger lesions where excision was performed under general anaesthesia. Laser treatment was performed at the Laser Centre of S. Orsola Hospital (Bologna, Italy) by the same surgeon, using a 1064 nm Nd:YAG laser (Model 6000, Laser Sonics, Cooper Laser Sonics) with a laser spot of 600 mm. The laser beam was set at 9 W for the lip, tongue, and marginal gingiva, and at 12 W for the remaining areas, and was administered in pulsed mode (0.3 s followed by a 0.1 s pause). Power density ranged from 3200 W/cm2 to 4200 W/cm2. The total energy irradiated and the time needed for complete ablation depended on the extent of the treated areas, varying from 3 to 10 min with a total maximum power of 300 J (Montebugnoli et al., 2012). A different laser was used for the excision: a CO2 laser (Deka Smart Office þ LCD) with a laser spot of 200 mm and a wavelength of 10.6 mm. The laser beam was set at 8e15 W, and used in pulse mode (0.5 s followed by a pause of 0.1 s) with a 20 Hz frequency. The time of excision depended on the extent of the lesion, ranging from 10 to 15 min. The laser was used in focused mode to obtain a precise cut at a distance of 1.5 cm from the oral mucosa. The excision of the lesions included 3e5 mm of normal mucosa surrounding the lesion. The depth of excision involved the mucosal and submucosal layers. The analysis endpoint was considered the appearance of recurrence. Recurrence was considered to be a leukoplakia arising in the same site as the first, within the borders of the treated area (Ben-Bassat et al., 1978). To evaluate the recurrence rate, we only included patients with a minimum follow-up of 6 months. Followup visits were scheduled 1 week after the treatment, and until healing was achieved with intervals of 3, 6, or 12 months,
Table 3 The grade of dysplasia (and Ljubljana 2014 classification) at the biopsy of patients treated with laser evaporation (Group 1) and laser excision (Group 2) respectively. Dysplasia Group 1 No dysplasia Mild Moderate Severe Total Group 2 No dysplasia Mild Moderate Severe Total
Lujbljana 2014 classification
Number Percentage
Low grade intraepithelial lesion 35 Low grade intraepithelial lesion 11 High grade intraepithelial lesion 1 High grade intraepithelial lesion 0 47 Low grade intraepithelial lesion 18 Low grade intraepithelial lesion 5 High grade intraepithelial lesion 7 High grade intraepithelial lesion 0 30
75% 23% 2% 0% 100% 60% 17% 23% 0% 100%
Please cite this article in press as: Del Corso G, et al., Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with longterm follow-up, Journal of Cranio-Maxillo-Facial Surgery (2015), http://dx.doi.org/10.1016/j.jcms.2015.04.009
G. Del Corso et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2015) 1e6
depending on the clinical and histological features. The follow-up period ranged from 6 to 112 months, with a median follow-up time of 60 ± 32.49 months. 2.3. Statistical analysis Patients' age, gender, smoking habits, site, clinical appearance, grade of dysplasia, and surgical treatment were analysed for their relationship with risk of recurrence during follow-up. Survival rate was estimated using the KaplaneMeier method. Statistical significance was evaluated using the log-rank test. Time was defined as the period between diagnosis and the target event or last followup. P values <0.05 were considered statistically significant in all analyses. 3. Results
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Table 5 The difference of the two treatment modalities in terms of malignant transformation.
Total OLs Malignant transformation Mean period (months) Mean age (years) Female patients Male patients Smokers Palate Buccal mucosa Tongue Gingiva No dysplasia at the biopsy Mild dysplasia at the biopsy Moderate dysplasia at the biopsy Homogeneous Non-homogeneous
Group 1
Group 2
47 3 39 55 2 1 3 / 1 2 / 1 2 / 1 2
30 0 / / / / / / / / / / / / / /
3.1. Descriptive analysis Of the 77 patients, 38 were males and 39 were females, aged 26e80 years (mean, 59.58 ± 12.57). In total, 21 OLs were on the upper or lower gingiva, 25 were on the buccal mucosa, 18 were on the tongue, 8 were on the hard palate, and 5 were on the floor of the mouth. Of the OLs, 55 appeared as white homogeneous lesions, whereas 23 were white or white/red non-homogeneous lesions. In their histology, 53 OLs showed squamous cell hyperplasia (simple hyperplasia, according to the Ljubljiana classification), characterised by increased basaleparabasal layers and acanthosis in the absence of architectural changes, 16 OLs showed mild dysplasia, and 8 OLs showed moderate dysplasia. Group 1 (47 OLs treated with laser evaporation with the Nd:YAG laser): 33 OLs appeared as homogeneous lesions, and 14 appeared as non-homogeneous lesions; 35 OLs showed an absence of dysplasia, 11 showed mild dysplasia, and 1 showed moderate dysplasia. Group 2 (30 patients treated with the CO2 laser): 21 OLs appeared as homogeneous lesions, and 9 appeared as nonhomogeneous lesions; 18 OLs showed an absence of dysplasia, 5 showed mild dysplasia, and 7 showed moderate dysplasia. In a mean follow-up period of 60 ± 32.49 months, 22 of 77 (28.5%) showed OL recurrence. In particular, 18 of 47 (38.2%) patients in Group 1 had recurrence at a mean period of 27 months after the first treatment, whereas 4 of 30 (13.3%) patients in Group 2 had recurrence at a mean period of 22.5 months after the first treatment. Of the total 77 patients, 3 (3.9%) evolved to OSCC during the follow-up period. All three had been treated with Nd:YAG laser
evaporation (6.4%). Tables 4 and 5 show the difference between treatments in terms of recurrence and malignant transformation. 3.2. Statistical analysis Results from the KaplaneMeier analysis showed that clinical appearance was the only variable that was significantly (c2 ¼ 18.15; p ¼ 0.01) related to recurrence during the follow-up period: 14 of 23 (60.9%) cases with non-homogeneous lesions were more likely to have recurrence than 8 of 54 (14.8%) cases with homogeneous lesions (Fig. 1). Regarding the two surgical treatments (Nd:YAG laser vs. CO2 laser excision), relative to recurrence, the difference was not significant (c2 ¼ 2.6; p ¼ 0.2). However, the type of treatment relative to recurrence in non-homogeneous lesions was significant (c2 ¼ 3.9; p ¼ 0.04): 12 of 14 (85.7%) cases in Group 1 were more likely to have recurrence in non-homogeneous lesions than 2 of 9 (22.2%) cases in Group 2 (Fig. 2). The type of treatment was also significantly related (c2 ¼ 4.6; p ¼ 0.03) to recurrence in lesions with mild dysplasia: 7 of 11 (63.6%) cases in Group 1 were more likely to have recurrence in lesions with mild dysplasia than 0 of 5 (0%) cases in Group 2 (Fig. 3). 4. Discussion Tables 6 and 7 report a literature review on the two treatment modalities. Recent retrospective articles that describe the use of a
Table 4 The difference of the two treatment modalities in terms of recurrence.
Total OLs Recurrence Mean period (months) Mean age (years) Female patients Male patients Smokers Palate Buccal mucosa Tongue Gingiva No dysplasia at the biopsy Mild dysplasia at the biopsy Moderate dysplasia at the biopsy Homogeneous Non-homogeneous
Group 1
Group 2
47 18 27 56 14 4 12 3 7 4 4 11 7 / 6 12
30 4 22.5 60 1 3 4 1 / 2 1 2 / 2 2 2
Fig. 1. KaplaneMeier analysis shows that non-homogeneous lesions are related to recurrence more than homogeneous lesions.
Please cite this article in press as: Del Corso G, et al., Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with longterm follow-up, Journal of Cranio-Maxillo-Facial Surgery (2015), http://dx.doi.org/10.1016/j.jcms.2015.04.009
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G. Del Corso et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2015) 1e6
4.2. Literature review about laser evaporation
Fig. 2. KaplaneMeier analysis shows that Nd:YAG laser treatment is more related to the recurrence in non-homogeneous lesions than CO2 laser excision.
Fig. 3. KaplaneMeier analysis shows that Nd:YAG laser treatment is more related to the recurrence in lesions with mild dysplasia than CO2 laser excision.
laser for evaporation or excision with a long follow-up period (>30 months) were selected. 4.1. Literature review about excision Regarding excision, Yang et al. (2011) treated 114 OLs using a CO2 laser with a recurrence rate of 17.5% and malignant transformation in 11.4% of cases. Smoking after surgical treatment, diffuse and nonhomogeneous OL, and high-grade dysplasia were correlated with recurrence. Unlike Yang's study, all cases of high-grade dysplasia or carcinomainsituwereexcludedinthepresentstudy.Viveketal.(2008) describedtheuseofaNd:YAGlaserin28OLswitharecurrencerateof7% and malignant transformation in 3.5% of the cases. Kuribayashi et al. (2012) reported 15.1% recurrence and 1.9% malignant transformation in53OLstreatedwithascalpel,andfoundnorelationshipbetweenthe severity of dysplasia and recurrence. We agree with their statement that surgical treatment is a preventative method against the developmentofOSCCif the resection margins arewide andfreeofepithelial abnormalities.
Regarding laser evaporation, seven articles were selected and ranked from the highest malignant transformation percentage to the lowest. Pedrosa et al. (2014) showed that 59 OLs treated with a CO2 laser had a recurrence rate of 12% and a malignant transformation of 25%. In particular, moderate and severe dysplasia were associated with disease-free survival of 25% at 6 months post-laser treatment, compared to 94% in patients with low-grade or no dysplasia. Brouns et al. (2013) revealed a high percentage of recurrence: 40% in 35 laser-evaporated OLs and malignant transformation in 14% of cases. The authors argued that the high recurrence rate was probably due to difficulty in determining whether the OL was a persistent lesion after laser treatment or recurrence. Chandu and Smith (2005) reported a recurrence rate of 28.9% and 7.3% malignant transformation in 73 OLs; however, they included severe dysplasia and carcinoma in situ. The highest sample of OLs was described by van der Hem et al. (2005), who reported a 9.9% recurrence rate and 1.1% malignant transformation in 282 OLs. They stated that early malignant transformation could be explained by an error in an initial biopsy that missed an area of malignancy. Three articles reported no malignant transformation: Tewari et al. (2007) used a Nd:YAG laser to evaporate 27 OLs with 2.8% recurrence; Deppe et al. (2012) treated 91 OLs with 30.7% recurrence over a very long follow-up period (75 months), and stated that the defocused laser beam at 15 W was more efficacious than other laser modalities; Gooris et al. (1999) evaporated 27 OLs with 14.8% recurrence, and only included patients treated for OSCC and in the lower lip area. The literature review on the excision of OL shows that reported recurrence rates ranged from 7% to 17.5%, with a mean value of 13.2%, and malignant transformation ranged from 1.9% to 11.4%, with a mean value of 5.6% in a follow-period of ~35 months. Moreover, laser evaporation showed a recurrence rate from 2.8% to 40%, with a mean rate of 19.9%, and malignant transformation revealed a mean value of 6.8% (range, 0e25%) in a follow-up period of ~60 months. The results of the present study have a long follow-up period compared to most articles in the literature. Moreover, the data reveal that the OLs in Group 2 showed a recurrence rate of 13.3% with no malignant transformation (0%). These results are similar to literature reports, particularly regarding the lack of malignant transformation. Excluding the article of Yang et al. (2011) that included OLs with high-grade dysplasia or carcinoma in situ, the data in the present article about excision are very similar to other articles (Vivek et al., 2008). However, in Group 1, OLs recurred in 38.2% of the cases and malignant transformation was seen in 6.4% of all cases. The present study showed a high percentage of recurrence, which was somewhat different from the literature; however, regarding malignant transformation, our data are similar to the mean value of previous reports. 4.3. Why do recurrence and malignant transformation occur? The results showed 28.5% recurrence in all OLs analysed during the follow-up period, similar to some previous reports (Brouns
Table 6 The recurrence rate and malignant transformation of OLs treated with excision described in the articles from the literature. Authors
Year
Laser type
Treatment
Number of OLs
Recurrence rate (%)
Malignant transformation (%)
Mean follow-up (months)
Yang et al. (2011) Vivek et al. (2008) Kuribayashi et al. (2012) Present article
2010 2007 2012 2014
CO2 Nd:YAG scalpel CO2
excision excision excision excision
114 28 53 30
17.5 7 15.1 13.3
11.4 3.5 1.9 0
40 ± 15 36 31 60 ± 32.49
Please cite this article in press as: Del Corso G, et al., Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with longterm follow-up, Journal of Cranio-Maxillo-Facial Surgery (2015), http://dx.doi.org/10.1016/j.jcms.2015.04.009
G. Del Corso et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2015) 1e6
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Table 7 The recurrence rate and malignant transformation of OLs treated with laser evaporation described in the articles from the literature. Authors
Year
Laser type
Treatment
Number of OLs
Recurrence rate (%)
Malignant transformation (%)
Mean follow-up (months)
Pedrosa et al. (2014) Brouns et al., 2014 Chandu and Smith (2005) van der Hem et al. (2005) Tewari et al. (2007) Deppe et al. (2012) Gooris et al. (1999) Present article
2014 2013 2004 2004 2007 2012 1998 2014
CO2 CO2 CO2 CO2 Nd:YAG CO2 CO2 Nd:YAG
evaporation evaporation evaporation evaporation evaporation evaporation evaporation evaporation
59 35 73 282 27 91 27 47
12 40 28.9 9.9 2.8 30.7 14.8 38.2
25 14 7.3 1.1 0 0 0 6.4
43.75 ± 23.4 61.9 47.2 ± 28.2 52 60 75 / 60 ± 32.49
et al., 2013; Chandu and Smith, 2005; Deppe et al., 2012). One possible explanation for recurrence and malignant transformation may be the concept of field cancerisation, where the field is the result of molecular changes affecting multiple cells (Ha and Califano, 2003). Patients with multiple OLs are at more risk of developing recurrence or a tumour due to field-change carcinogenesis. Such patients should avoid smoking and chewing betel quid, and need to be followed-up every 3 or 6 months (Yang et al., 2011). Independent from the type of treatment, a unique significant variable related to recurrence is the presence of a nonhomogeneous lesion (c2 ¼ 18.15; p ¼ 0.01). In particular, 14 of 23 (60.9%) of the non-homogeneous OLs showed recurrence. This is likely due, at least in part, to the long follow-up period in this study, and to the presence of 7 PVL among the 14 non-homogeneous OL recurrences. Indeed, PVL appears to resist all attempts at therapy and often recurs. Schoelch et al. (1999) in a similar study reported 83% recurrence in verrucous OLs treated with both CO2 and Nd:YAG lasers. Laser surgery has been performed for several years, and is a good choice for treating OLs. To the best of our knowledge, there is no reported study that has compared two different laser surgical modalities, evaporation and excision, for the treatment of OL. In 2015, Brouns et al. reported the rate of malignant transformation in 114 patients treated with surgical excision, CO2 evaporation, and observation, finding 11% of OLs transformed to OSCC. However, the authors stated that it was not possible to make a comparison between the two treatment methods due to different indications. They showed that the only significant factor associated with malignant transformation was a lesion size 4 cm. Holmstrup et al. (2006) reported the long-term outcome of oral premalignant lesions, including OL and erythroplakia, treated with scalpel excision and untreated. They stated that surgical intervention did not prevent malignant transformation. In fact, the development of OSCC in the treated lesions was more frequent than in the untreated lesions (13% vs. 4%). They argued that the two significant factors associated with prognostic value were the clinical aspects and the size of the lesion. The more important difference between excision and evaporation treatment is the likelihood of examining the whole lesion. It is well known that a histological diagnosis of an incisional biopsy, performed for diagnosis of OL, is a snapshot of the whole lesion, and sometimes can underestimate the true nature of the whole lesion. There is no evidence in the literature of whether the opportunity to histologically examine the whole excised leukoplakia could be significant in terms of recurrence or malignant transformation of OL. The present study showed an insignificant difference between Nd:YAG laser evaporation and CO2 laser excision in 77 OLs analysed (c2 ¼ 2.6; p ¼ 0.2). However, excision showed better results in terms of recurrence in non-homogeneous OLs (c2 ¼ 3.9; p ¼ 0.04) and OLs with mild dysplasia (c2 ¼ 4.6; p ¼ 0.03) (Yang et al., 2011; Schoelch et al., 1999; Yang et al., 2010). Moreover, regarding
malignant transformation, 3 of 77 OLs evolved into OSCC in a mean period of 39 months after the first treatment, and all three cases were in Group 1. The worse results of laser evaporation versus laser excision in non-homogeneous OLs and in OLs with dysplasia may be explained, other than by the field cancerisation concept, by the presence of positive surgical margins, a residual area of malignancy, genetic changes after the vaporisation treatment, or an underestimation of the true nature of the lesion. In fact, laser evaporation is only based on one or more small incisional biopsies, and clinicians are aware that an incisional biopsy can lead to an underdiagnosis of the whole lesion in a percentage of OLs. 5. Conclusions The present retrospective study describes for the first time a comparison between two laser surgical techniques for removing OLs, laser evaporation versus laser excision, in a cohort study, selected with restrictive inclusion and exclusion criteria and a long follow-up period. The data about the two treatment modalities showed that there were no significant differences between them. However CO2 laser excision appears to be the better choice for treating OLs with any grade of dysplasia and non-homogeneous type, in terms of recurrence. The present study also suggests use of the Nd:YAG laser for evaporation of OLs without dysplasia, homogeneous, and in wide anatomical sites where excision could cause discomfort to the patient. Randomised controlled trials (RCT) are needed to better establish the effectiveness of the different surgical methods to treat OLs. However, to date, no relevant RCT has been reported (Lodi et al., 2006). As others have stated, we recommend the surgical removal of potentially malignant disorders such as OL, particularly if clinical and histological features suggest any potential risk of evolution into OSCC. Regardless, even the surgical removal of the entire OL can still be associated with future recurrence and malignant development, so careful follow-up examinations after surgery are essential. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgements The English in this document has been checked by at least two professional editors, both native speakers of English. http://www. textcheck.com/certificate/1Azsbg. References Ben-Bassat M, Kaplan I, Shindel Y, Edlan A: The CO2 laser in surgery of the tongue. Br J Plast Surg 31(2): 155e156, 1978 Brouns ER, Baart JA, Karagozoglu KH, Aartman IH, Bloemena E, van der Waal I: Treatment results of CO2 laser vaporisation in a cohort of 35 patients with oral leukoplakia. Oral Dis 19(2): 212e216, 2013
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Brouns E, Baart J, Karagozoglu Kh, Aartman IH, Bloemena E, van der Waal I: Malignant transformation of oral leukoplakia in a well-defined cohort of 144 patients. Oral Dis 20(3): e19e24, 2014 Chandu A, Smith AC: The use of CO2 laser in the treatment of oral white patches: outcomes and factors affecting recurrence. Int J Oral Maxillofac Surg 34(4): 396e400, 2005 Deppe H, Mücke T, Hohlweg-Majert B, Hauck W, Wagenpfell S, Holzle F: Different CO2 laser vaporization protocols for the therapy of oral precancerous lesions and precancerous conditions: a 10-year follow-up. Lasers Med Sci 27(1): 59e63, 2012 Gooris PJ, Roodenburg JL, Vermey A, Nauta JM: Carbon dioxide laser evaporation of leukoplakia of the lower lip: a retrospective evaluation. Oral Oncol 35(5): 490e495, 1999 Ha PK, Califano JA: The molecular biology of mucosal field cancerization of the head and neck. Crit Rev Oral Biol Med 14(5): 363e369, 2003 Holmstrup P, Vedtofte P, Reibel J, Stoltze K: Long-term treatment outcome of oral premalignant lesions. Oral Oncol 42(5): 461e474, 2006 Ishii J, Fujita K, Komori T: Laser surgery as a treatment for oral leukoplakia. Oral Oncol 39(8): 759e769, 2003 € ller JE, et al: The role of Kreppel M, Dreiseidler T, Rothamel D, Eich HT, Drebber U, Zo clinical versus histopathological staging in patients with advanced oral squamous cell carcinoma treated with neoadjuvant radiochemotherapy followed by radical surgery. J Craniomaxillofac Surg 41(1): 22e27, 2013 Kuribayashi Y, Tsushima F, Sato M, Morita K, Omura K: Recurrence patterns of oral leukoplakia after curative surgical resection: important factors that predict the risk of recurrence and malignancy. J Oral Pathol Med 41(9), 2012 Lee JJ, Hung HC, Cheng SJ, Chen YJ, Chiang CP, Liu BY, et al: Carcinoma and dysplasia in oral leukoplakias in Taiwan: prevalence and risk factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 101(4): 472e480, 2006 Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A: Interventions for treating oral leukoplakia. Cochrane Database Syst Rev (4): CD001829, 2006 Lopez-Cedrun JL, Andres de Liano J: A 22 years survival and prognostic factors analysis in a homogeneous series of 64 patients with advanced cancer of the tongue and the floor of the mouth. J Craniomaxillofac Surg 43(3): 376e381, 2015 Apr pii: S1010-5182(15)00017-7
Montebugnoli L, Frini F, Gissi DB, Gabusi A, Cervellati F, Foschini MP, et al: Histological and immunohistochemical evaluation of new epithelium after removal of oral leukoplakia with Nd:YAG laser treatment. Lasers Med Sci 27(1), 2012 Pedrosa A, Santos A, Ferreira M, Araujo C, Barbosa R, Medeiros L: Is carbon dioxide laser vaporization a valuable tool in the management of oral leukoplakia? A survey at an oncology hospital. Lasers Med Sci, 2014 Petti S: Pooled estimate of world leukoplakia prevalence: a systematic review. Oral Oncol 39(8): 770e780, 2003 Reibel J: Prognosis of oral pre-malignant lesions: significance of clinical, histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med 14(1): 47e62, 2003 Schoelch ML, Sekandari N, Regezi JA, Silverman Jr S: Laser management of oral leukoplakias: a follow-up study of 70 patients. Laryngoscope 109(6): 949e953, 1999 Tewari M, Rai P, Singh GB, Kumar M, Shukla HS: Long-term follow-up results of Nd: YAG laser treatment of premalignant and malignant (Stage I) squamous cell carcinoma of the oral cavity. J Surg Oncol 95(4): 281e285, 2007 van der Hem PS, Nauta JM, van der Wal JE, Roodenburg JL: The results of CO2 laser surgery in patients with oral leukoplakia: a 25 year follow up. Oral Oncol 41(1): 31e37, 2005 van der Waal I: Potentially malignant disorders of the oral and oropharyngeal mucosa; present concepts of management. Oral Oncol 46(6): 423e425, 2010 van der Waal I, Reichart PA: Oral proliferative verrucous leukoplakia revisited. Oral Oncol 44(8): 719e721, 2008 Vivek V, Jayasree RS, Balan A, Sreelatha KT, Gupta AK: Three-year follow-up of oral leukoplakia after neodymium:yttrium aluminum garnet (Nd:YAG) laser surgery. Lasers Med Sci 23(4): 375e379, 2008 Yang SW, Tsai CN, Lee YS, Chen TA: Treatment outcome of dysplastic oral leukoplakia with carbon dioxide laser e emphasis on the factors affecting recurrence. J Oral Maxillofac Surg 69(6): e78e87, 2011 Yang SW, Wu CJ, Lee YS, Chen TA, Tsai CN: Postoperative recurrence as an associated factor of malignant transformation of oral dysplastic leukoplakia. ORL J Otorhinolaryngol Relat Spec 72(5), 2010
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Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with long-term follow-up Giacomo Del Corso a, *, Davide Bartolomeo Gissi a, Achille Tarsitano b, Enrico Costabile b, Claudio Marchetti b, Lucio Montebugnoli a, Maria Pia Foschini c a
Department of Biomedical and Neuromotor Sciences, Section of Oral Science, University of Bologna, Italy Department of Biomedical and Neuromotor Sciences, University of Bologna, Section of Maxillo-facial Surgery at Policlinico S. Orsola-Malpighi, Bologna, Italy c Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology at Bellaria Hospital, University of Bologna, Italy b
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 13 January 2015 Accepted 8 April 2015 Available online xxx
Objectives: The study makes a comparison between two surgical approaches for the treatment of oral leukoplakia (OL) in terms of recurrence in a well-defined cohort of patients with a long-term follow-up period. Methods: The cohort consisted of 77 OL patients divided into 2 groups. Group 1: 47 patients treated with laser evaporation using a Nd:YAG laser. Group 2: 30 patients treated with a CO2 laser for excision. Clinical and histological examinations were performed for the diagnosis of OL before treatment. We included OLs with or without dysplasia. The mean follow-up period was 60 ± 32.49 months. Results: Of the 77 patients, 22 (28.5%) showed recurrence during the follow-up period. No significant difference was found between the two treatments (c2 ¼ 2.6; p ¼ 0.2). However, CO2 laser excision resulted in better results than the Nd:YAG laser evaporation, considering the non-homogeneous OLs (c2 ¼ 3.9; p ¼ 0.04) and OLs with mild dysplasia (c2 ¼ 4.6; p ¼ 0.03). Discussion: The study makes a comparison between our results and articles from the literature, and suggests when each of the two surgical approaches is most appropriate. © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Keywords: Laser surgery Oral leukoplakia Laser excision Laser evaporation Nd:YAG laser CO2 laser
1. Introduction Oral squamous cell carcinoma (OSCC) is the most common tumour of the oral cavity with 5-year and 22-year survival rates of 30e45% and 6.3%, respectively, while locoregional recurrence after treatment occurs in almost 30% of cases (Lopez-Cedrun and Andres de Liano, 2015; Kreppel et al., 2013). Oral leukoplakia (OL) is considered a premalignant oral lesion, and its diagnosis is essentially made by excluding other known diseases. The prevalence of OL worldwide is ~2% (Petti, 2003), and it is more frequent in smokers than non-smokers. Its diagnosis is made by clinical features, and a biopsy is mandatory to exclude other diseases. OL is a white plaque, and is divided into homogeneous and non* Corresponding author. Department of Biomedical and Neuromotor Sciences, Via S Vitale 59, Bologna, Italy. E-mail address: [email protected] (G. Del Corso).
homogeneous types: the homogeneous type is a white plaque that is flat, thin, and uniform, whereas the non-homogeneous type can be irregularly flat, nodular, verrucous, and with a white and red colouration (van der Waal, 2010). With respect to nonhomogeneous OL, proliferative verrucous leukoplakia (PVL) can involve any site in the oral cavity and has a high risk of malignant transformation (van der Waal and Reichart, 2008). A histological examination must be performed to exclude other diseases, and in particular, to determine the presence of dysplasia (mild, moderate, or severe; low-grade intraepithelial lesion or high-grade intraepithelial lesion, according to the 2014 Ljubljana classification). Malignant transformation ranged from 0.13% to 17.55% (Lee et al., 2006; Reibel, 2003). Thus, not all OL cases transform into OSCC. A high risk of malignant transformation is correlated with the degree of histological dysplasia. Treatment modalities range from cessation of smoking to medication with retinoids, cryosurgery, or laser surgery. Laser
http://dx.doi.org/10.1016/j.jcms.2015.04.009 1010-5182/© 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Del Corso G, et al., Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with longterm follow-up, Journal of Cranio-Maxillo-Facial Surgery (2015), http://dx.doi.org/10.1016/j.jcms.2015.04.009
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surgery was first performed in 1978 (Ben-Bassat et al., 1978). It presents some advantages, such as total removal of the lesion, minimal damage to surrounding tissues, and reduction of postoperative pain and oedema (van der Hem et al., 2005). Healing is typically very good because of the limited contraction of the tissues and minimal oral dysfunction (Ishii et al., 2003). CO2 and Nd:YAG lasers are mainly used to treat OL in two different modalities: evaporation and excision. Evaporation induces limited postoperative discomfort, and can be performed in different stages, especially in patients with wide lesions or multiple lesions. The main disadvantage of the evaporation technique, with respect to excision, is the impossibility of examining the whole lesion histologically. In addition, excision can lead to functional problems with very large lesions. The present study describes, for the first time, a comparison between the two different surgical approaches for the treatment of OLs: Nd:YAG laser evaporation versus CO2 laser excision. The longterm follow-up and the two different cohorts of patients validate this retrospective study. The objective was to assess whether there were significant differences in terms of recurrence between the two surgical treatments. 2. Materials and methods From 2004 to 2013, 77 OL cases were diagnosed at the Department of Oral Sciences of the University of Bologna, after which they were treated at the Maxillo-Facial Unit of the S. Orsola Hospital, Bologna, Italy. 2.1. Inclusion and exclusion criteria Only patients referred to the Department of Oral Sciences, University of Bologna, with a diagnosis of OL were included. The inclusion criteria were OLs with or without dysplasia and clear surgical margins on histological examination. Patients with preexisting OSCC, OLs with severe dysplasia (high-grade intraepithelial lesion, according to the 2014 Ljubljana classification), and patients with other white lesions not identifiable as OL were excluded. In addition, surgical specimens with positive dysplastic margins and OSCC found in the first surgical specimen were excluded. 2.2. Patient management All of the patients underwent histological examination for diagnosis. Specimens were taken with a biopsy punch to a depth of at least 5 mm, and a 3e5 mm margin of clinically normal mucosa was also included. All of the tissues were fixed in 10% formalin and paraffin wax-embedded by routine procedures. Serial sections were cut from each block, and stained with haematoxylin and eosin for histological evaluation. Histological examinations and immunohistochemical staining were performed blindly at the Section of Anatomic Pathology of the Department of Hematology and
Table 1 Age and sex distribution of patients treated with laser evaporation (Group 1) and laser excision (Group 2) respectively.
Group 1
Group 2
Men Women Total Men Women Total
Number
Age (year)
Mean (year)
19 28 47 19 11 30
34e78 42e80 34e80 34e79 26e80 26e80
55 60 58 65 57 62
Table 2 The sites of all the lesions. Site
Number
Percentage
Tongue Floor of the mouth Hard palate Buccal mucosa Upper or lower gingiva Total
18 5 8 25 21 77
23% 6.5% 10% 32.5% 28% 100%
Oncology, Bologna University, at Bellaria Hospital. All of the cases were examined by the same pathologist (MPF). Histological diagnoses were performed according to the WHO criteria. Age, gender distribution, site of the lesions, and grade of dysplasia at the biopsy are shown in Tables 1e3. The sites of OL were the tongue, floor of the mouth, hard palate, buccal mucosa, and upper and lower gingiva. Treatment consisted of the surgical excision of the OLs. Group 1 consisted of 47 OLs treated with laser evaporation with a Nd:YAG laser; Group 2 consisted of 30 OLs treated with CO2 laser excision. All of the treatments were performed under local anaesthesia, except some larger lesions where excision was performed under general anaesthesia. Laser treatment was performed at the Laser Centre of S. Orsola Hospital (Bologna, Italy) by the same surgeon, using a 1064 nm Nd:YAG laser (Model 6000, Laser Sonics, Cooper Laser Sonics) with a laser spot of 600 mm. The laser beam was set at 9 W for the lip, tongue, and marginal gingiva, and at 12 W for the remaining areas, and was administered in pulsed mode (0.3 s followed by a 0.1 s pause). Power density ranged from 3200 W/cm2 to 4200 W/cm2. The total energy irradiated and the time needed for complete ablation depended on the extent of the treated areas, varying from 3 to 10 min with a total maximum power of 300 J (Montebugnoli et al., 2012). A different laser was used for the excision: a CO2 laser (Deka Smart Office þ LCD) with a laser spot of 200 mm and a wavelength of 10.6 mm. The laser beam was set at 8e15 W, and used in pulse mode (0.5 s followed by a pause of 0.1 s) with a 20 Hz frequency. The time of excision depended on the extent of the lesion, ranging from 10 to 15 min. The laser was used in focused mode to obtain a precise cut at a distance of 1.5 cm from the oral mucosa. The excision of the lesions included 3e5 mm of normal mucosa surrounding the lesion. The depth of excision involved the mucosal and submucosal layers. The analysis endpoint was considered the appearance of recurrence. Recurrence was considered to be a leukoplakia arising in the same site as the first, within the borders of the treated area (Ben-Bassat et al., 1978). To evaluate the recurrence rate, we only included patients with a minimum follow-up of 6 months. Followup visits were scheduled 1 week after the treatment, and until healing was achieved with intervals of 3, 6, or 12 months,
Table 3 The grade of dysplasia (and Ljubljana 2014 classification) at the biopsy of patients treated with laser evaporation (Group 1) and laser excision (Group 2) respectively. Dysplasia Group 1 No dysplasia Mild Moderate Severe Total Group 2 No dysplasia Mild Moderate Severe Total
Lujbljana 2014 classification
Number Percentage
Low grade intraepithelial lesion 35 Low grade intraepithelial lesion 11 High grade intraepithelial lesion 1 High grade intraepithelial lesion 0 47 Low grade intraepithelial lesion 18 Low grade intraepithelial lesion 5 High grade intraepithelial lesion 7 High grade intraepithelial lesion 0 30
75% 23% 2% 0% 100% 60% 17% 23% 0% 100%
Please cite this article in press as: Del Corso G, et al., Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with longterm follow-up, Journal of Cranio-Maxillo-Facial Surgery (2015), http://dx.doi.org/10.1016/j.jcms.2015.04.009
G. Del Corso et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2015) 1e6
depending on the clinical and histological features. The follow-up period ranged from 6 to 112 months, with a median follow-up time of 60 ± 32.49 months. 2.3. Statistical analysis Patients' age, gender, smoking habits, site, clinical appearance, grade of dysplasia, and surgical treatment were analysed for their relationship with risk of recurrence during follow-up. Survival rate was estimated using the KaplaneMeier method. Statistical significance was evaluated using the log-rank test. Time was defined as the period between diagnosis and the target event or last followup. P values <0.05 were considered statistically significant in all analyses. 3. Results
3
Table 5 The difference of the two treatment modalities in terms of malignant transformation.
Total OLs Malignant transformation Mean period (months) Mean age (years) Female patients Male patients Smokers Palate Buccal mucosa Tongue Gingiva No dysplasia at the biopsy Mild dysplasia at the biopsy Moderate dysplasia at the biopsy Homogeneous Non-homogeneous
Group 1
Group 2
47 3 39 55 2 1 3 / 1 2 / 1 2 / 1 2
30 0 / / / / / / / / / / / / / /
3.1. Descriptive analysis Of the 77 patients, 38 were males and 39 were females, aged 26e80 years (mean, 59.58 ± 12.57). In total, 21 OLs were on the upper or lower gingiva, 25 were on the buccal mucosa, 18 were on the tongue, 8 were on the hard palate, and 5 were on the floor of the mouth. Of the OLs, 55 appeared as white homogeneous lesions, whereas 23 were white or white/red non-homogeneous lesions. In their histology, 53 OLs showed squamous cell hyperplasia (simple hyperplasia, according to the Ljubljiana classification), characterised by increased basaleparabasal layers and acanthosis in the absence of architectural changes, 16 OLs showed mild dysplasia, and 8 OLs showed moderate dysplasia. Group 1 (47 OLs treated with laser evaporation with the Nd:YAG laser): 33 OLs appeared as homogeneous lesions, and 14 appeared as non-homogeneous lesions; 35 OLs showed an absence of dysplasia, 11 showed mild dysplasia, and 1 showed moderate dysplasia. Group 2 (30 patients treated with the CO2 laser): 21 OLs appeared as homogeneous lesions, and 9 appeared as nonhomogeneous lesions; 18 OLs showed an absence of dysplasia, 5 showed mild dysplasia, and 7 showed moderate dysplasia. In a mean follow-up period of 60 ± 32.49 months, 22 of 77 (28.5%) showed OL recurrence. In particular, 18 of 47 (38.2%) patients in Group 1 had recurrence at a mean period of 27 months after the first treatment, whereas 4 of 30 (13.3%) patients in Group 2 had recurrence at a mean period of 22.5 months after the first treatment. Of the total 77 patients, 3 (3.9%) evolved to OSCC during the follow-up period. All three had been treated with Nd:YAG laser
evaporation (6.4%). Tables 4 and 5 show the difference between treatments in terms of recurrence and malignant transformation. 3.2. Statistical analysis Results from the KaplaneMeier analysis showed that clinical appearance was the only variable that was significantly (c2 ¼ 18.15; p ¼ 0.01) related to recurrence during the follow-up period: 14 of 23 (60.9%) cases with non-homogeneous lesions were more likely to have recurrence than 8 of 54 (14.8%) cases with homogeneous lesions (Fig. 1). Regarding the two surgical treatments (Nd:YAG laser vs. CO2 laser excision), relative to recurrence, the difference was not significant (c2 ¼ 2.6; p ¼ 0.2). However, the type of treatment relative to recurrence in non-homogeneous lesions was significant (c2 ¼ 3.9; p ¼ 0.04): 12 of 14 (85.7%) cases in Group 1 were more likely to have recurrence in non-homogeneous lesions than 2 of 9 (22.2%) cases in Group 2 (Fig. 2). The type of treatment was also significantly related (c2 ¼ 4.6; p ¼ 0.03) to recurrence in lesions with mild dysplasia: 7 of 11 (63.6%) cases in Group 1 were more likely to have recurrence in lesions with mild dysplasia than 0 of 5 (0%) cases in Group 2 (Fig. 3). 4. Discussion Tables 6 and 7 report a literature review on the two treatment modalities. Recent retrospective articles that describe the use of a
Table 4 The difference of the two treatment modalities in terms of recurrence.
Total OLs Recurrence Mean period (months) Mean age (years) Female patients Male patients Smokers Palate Buccal mucosa Tongue Gingiva No dysplasia at the biopsy Mild dysplasia at the biopsy Moderate dysplasia at the biopsy Homogeneous Non-homogeneous
Group 1
Group 2
47 18 27 56 14 4 12 3 7 4 4 11 7 / 6 12
30 4 22.5 60 1 3 4 1 / 2 1 2 / 2 2 2
Fig. 1. KaplaneMeier analysis shows that non-homogeneous lesions are related to recurrence more than homogeneous lesions.
Please cite this article in press as: Del Corso G, et al., Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with longterm follow-up, Journal of Cranio-Maxillo-Facial Surgery (2015), http://dx.doi.org/10.1016/j.jcms.2015.04.009
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4.2. Literature review about laser evaporation
Fig. 2. KaplaneMeier analysis shows that Nd:YAG laser treatment is more related to the recurrence in non-homogeneous lesions than CO2 laser excision.
Fig. 3. KaplaneMeier analysis shows that Nd:YAG laser treatment is more related to the recurrence in lesions with mild dysplasia than CO2 laser excision.
laser for evaporation or excision with a long follow-up period (>30 months) were selected. 4.1. Literature review about excision Regarding excision, Yang et al. (2011) treated 114 OLs using a CO2 laser with a recurrence rate of 17.5% and malignant transformation in 11.4% of cases. Smoking after surgical treatment, diffuse and nonhomogeneous OL, and high-grade dysplasia were correlated with recurrence. Unlike Yang's study, all cases of high-grade dysplasia or carcinomainsituwereexcludedinthepresentstudy.Viveketal.(2008) describedtheuseofaNd:YAGlaserin28OLswitharecurrencerateof7% and malignant transformation in 3.5% of the cases. Kuribayashi et al. (2012) reported 15.1% recurrence and 1.9% malignant transformation in53OLstreatedwithascalpel,andfoundnorelationshipbetweenthe severity of dysplasia and recurrence. We agree with their statement that surgical treatment is a preventative method against the developmentofOSCCif the resection margins arewide andfreeofepithelial abnormalities.
Regarding laser evaporation, seven articles were selected and ranked from the highest malignant transformation percentage to the lowest. Pedrosa et al. (2014) showed that 59 OLs treated with a CO2 laser had a recurrence rate of 12% and a malignant transformation of 25%. In particular, moderate and severe dysplasia were associated with disease-free survival of 25% at 6 months post-laser treatment, compared to 94% in patients with low-grade or no dysplasia. Brouns et al. (2013) revealed a high percentage of recurrence: 40% in 35 laser-evaporated OLs and malignant transformation in 14% of cases. The authors argued that the high recurrence rate was probably due to difficulty in determining whether the OL was a persistent lesion after laser treatment or recurrence. Chandu and Smith (2005) reported a recurrence rate of 28.9% and 7.3% malignant transformation in 73 OLs; however, they included severe dysplasia and carcinoma in situ. The highest sample of OLs was described by van der Hem et al. (2005), who reported a 9.9% recurrence rate and 1.1% malignant transformation in 282 OLs. They stated that early malignant transformation could be explained by an error in an initial biopsy that missed an area of malignancy. Three articles reported no malignant transformation: Tewari et al. (2007) used a Nd:YAG laser to evaporate 27 OLs with 2.8% recurrence; Deppe et al. (2012) treated 91 OLs with 30.7% recurrence over a very long follow-up period (75 months), and stated that the defocused laser beam at 15 W was more efficacious than other laser modalities; Gooris et al. (1999) evaporated 27 OLs with 14.8% recurrence, and only included patients treated for OSCC and in the lower lip area. The literature review on the excision of OL shows that reported recurrence rates ranged from 7% to 17.5%, with a mean value of 13.2%, and malignant transformation ranged from 1.9% to 11.4%, with a mean value of 5.6% in a follow-period of ~35 months. Moreover, laser evaporation showed a recurrence rate from 2.8% to 40%, with a mean rate of 19.9%, and malignant transformation revealed a mean value of 6.8% (range, 0e25%) in a follow-up period of ~60 months. The results of the present study have a long follow-up period compared to most articles in the literature. Moreover, the data reveal that the OLs in Group 2 showed a recurrence rate of 13.3% with no malignant transformation (0%). These results are similar to literature reports, particularly regarding the lack of malignant transformation. Excluding the article of Yang et al. (2011) that included OLs with high-grade dysplasia or carcinoma in situ, the data in the present article about excision are very similar to other articles (Vivek et al., 2008). However, in Group 1, OLs recurred in 38.2% of the cases and malignant transformation was seen in 6.4% of all cases. The present study showed a high percentage of recurrence, which was somewhat different from the literature; however, regarding malignant transformation, our data are similar to the mean value of previous reports. 4.3. Why do recurrence and malignant transformation occur? The results showed 28.5% recurrence in all OLs analysed during the follow-up period, similar to some previous reports (Brouns
Table 6 The recurrence rate and malignant transformation of OLs treated with excision described in the articles from the literature. Authors
Year
Laser type
Treatment
Number of OLs
Recurrence rate (%)
Malignant transformation (%)
Mean follow-up (months)
Yang et al. (2011) Vivek et al. (2008) Kuribayashi et al. (2012) Present article
2010 2007 2012 2014
CO2 Nd:YAG scalpel CO2
excision excision excision excision
114 28 53 30
17.5 7 15.1 13.3
11.4 3.5 1.9 0
40 ± 15 36 31 60 ± 32.49
Please cite this article in press as: Del Corso G, et al., Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with longterm follow-up, Journal of Cranio-Maxillo-Facial Surgery (2015), http://dx.doi.org/10.1016/j.jcms.2015.04.009
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Table 7 The recurrence rate and malignant transformation of OLs treated with laser evaporation described in the articles from the literature. Authors
Year
Laser type
Treatment
Number of OLs
Recurrence rate (%)
Malignant transformation (%)
Mean follow-up (months)
Pedrosa et al. (2014) Brouns et al., 2014 Chandu and Smith (2005) van der Hem et al. (2005) Tewari et al. (2007) Deppe et al. (2012) Gooris et al. (1999) Present article
2014 2013 2004 2004 2007 2012 1998 2014
CO2 CO2 CO2 CO2 Nd:YAG CO2 CO2 Nd:YAG
evaporation evaporation evaporation evaporation evaporation evaporation evaporation evaporation
59 35 73 282 27 91 27 47
12 40 28.9 9.9 2.8 30.7 14.8 38.2
25 14 7.3 1.1 0 0 0 6.4
43.75 ± 23.4 61.9 47.2 ± 28.2 52 60 75 / 60 ± 32.49
et al., 2013; Chandu and Smith, 2005; Deppe et al., 2012). One possible explanation for recurrence and malignant transformation may be the concept of field cancerisation, where the field is the result of molecular changes affecting multiple cells (Ha and Califano, 2003). Patients with multiple OLs are at more risk of developing recurrence or a tumour due to field-change carcinogenesis. Such patients should avoid smoking and chewing betel quid, and need to be followed-up every 3 or 6 months (Yang et al., 2011). Independent from the type of treatment, a unique significant variable related to recurrence is the presence of a nonhomogeneous lesion (c2 ¼ 18.15; p ¼ 0.01). In particular, 14 of 23 (60.9%) of the non-homogeneous OLs showed recurrence. This is likely due, at least in part, to the long follow-up period in this study, and to the presence of 7 PVL among the 14 non-homogeneous OL recurrences. Indeed, PVL appears to resist all attempts at therapy and often recurs. Schoelch et al. (1999) in a similar study reported 83% recurrence in verrucous OLs treated with both CO2 and Nd:YAG lasers. Laser surgery has been performed for several years, and is a good choice for treating OLs. To the best of our knowledge, there is no reported study that has compared two different laser surgical modalities, evaporation and excision, for the treatment of OL. In 2015, Brouns et al. reported the rate of malignant transformation in 114 patients treated with surgical excision, CO2 evaporation, and observation, finding 11% of OLs transformed to OSCC. However, the authors stated that it was not possible to make a comparison between the two treatment methods due to different indications. They showed that the only significant factor associated with malignant transformation was a lesion size 4 cm. Holmstrup et al. (2006) reported the long-term outcome of oral premalignant lesions, including OL and erythroplakia, treated with scalpel excision and untreated. They stated that surgical intervention did not prevent malignant transformation. In fact, the development of OSCC in the treated lesions was more frequent than in the untreated lesions (13% vs. 4%). They argued that the two significant factors associated with prognostic value were the clinical aspects and the size of the lesion. The more important difference between excision and evaporation treatment is the likelihood of examining the whole lesion. It is well known that a histological diagnosis of an incisional biopsy, performed for diagnosis of OL, is a snapshot of the whole lesion, and sometimes can underestimate the true nature of the whole lesion. There is no evidence in the literature of whether the opportunity to histologically examine the whole excised leukoplakia could be significant in terms of recurrence or malignant transformation of OL. The present study showed an insignificant difference between Nd:YAG laser evaporation and CO2 laser excision in 77 OLs analysed (c2 ¼ 2.6; p ¼ 0.2). However, excision showed better results in terms of recurrence in non-homogeneous OLs (c2 ¼ 3.9; p ¼ 0.04) and OLs with mild dysplasia (c2 ¼ 4.6; p ¼ 0.03) (Yang et al., 2011; Schoelch et al., 1999; Yang et al., 2010). Moreover, regarding
malignant transformation, 3 of 77 OLs evolved into OSCC in a mean period of 39 months after the first treatment, and all three cases were in Group 1. The worse results of laser evaporation versus laser excision in non-homogeneous OLs and in OLs with dysplasia may be explained, other than by the field cancerisation concept, by the presence of positive surgical margins, a residual area of malignancy, genetic changes after the vaporisation treatment, or an underestimation of the true nature of the lesion. In fact, laser evaporation is only based on one or more small incisional biopsies, and clinicians are aware that an incisional biopsy can lead to an underdiagnosis of the whole lesion in a percentage of OLs. 5. Conclusions The present retrospective study describes for the first time a comparison between two laser surgical techniques for removing OLs, laser evaporation versus laser excision, in a cohort study, selected with restrictive inclusion and exclusion criteria and a long follow-up period. The data about the two treatment modalities showed that there were no significant differences between them. However CO2 laser excision appears to be the better choice for treating OLs with any grade of dysplasia and non-homogeneous type, in terms of recurrence. The present study also suggests use of the Nd:YAG laser for evaporation of OLs without dysplasia, homogeneous, and in wide anatomical sites where excision could cause discomfort to the patient. Randomised controlled trials (RCT) are needed to better establish the effectiveness of the different surgical methods to treat OLs. However, to date, no relevant RCT has been reported (Lodi et al., 2006). As others have stated, we recommend the surgical removal of potentially malignant disorders such as OL, particularly if clinical and histological features suggest any potential risk of evolution into OSCC. Regardless, even the surgical removal of the entire OL can still be associated with future recurrence and malignant development, so careful follow-up examinations after surgery are essential. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgements The English in this document has been checked by at least two professional editors, both native speakers of English. http://www. textcheck.com/certificate/1Azsbg. References Ben-Bassat M, Kaplan I, Shindel Y, Edlan A: The CO2 laser in surgery of the tongue. Br J Plast Surg 31(2): 155e156, 1978 Brouns ER, Baart JA, Karagozoglu KH, Aartman IH, Bloemena E, van der Waal I: Treatment results of CO2 laser vaporisation in a cohort of 35 patients with oral leukoplakia. Oral Dis 19(2): 212e216, 2013
Please cite this article in press as: Del Corso G, et al., Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with longterm follow-up, Journal of Cranio-Maxillo-Facial Surgery (2015), http://dx.doi.org/10.1016/j.jcms.2015.04.009
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Brouns E, Baart J, Karagozoglu Kh, Aartman IH, Bloemena E, van der Waal I: Malignant transformation of oral leukoplakia in a well-defined cohort of 144 patients. Oral Dis 20(3): e19e24, 2014 Chandu A, Smith AC: The use of CO2 laser in the treatment of oral white patches: outcomes and factors affecting recurrence. Int J Oral Maxillofac Surg 34(4): 396e400, 2005 Deppe H, Mücke T, Hohlweg-Majert B, Hauck W, Wagenpfell S, Holzle F: Different CO2 laser vaporization protocols for the therapy of oral precancerous lesions and precancerous conditions: a 10-year follow-up. Lasers Med Sci 27(1): 59e63, 2012 Gooris PJ, Roodenburg JL, Vermey A, Nauta JM: Carbon dioxide laser evaporation of leukoplakia of the lower lip: a retrospective evaluation. Oral Oncol 35(5): 490e495, 1999 Ha PK, Califano JA: The molecular biology of mucosal field cancerization of the head and neck. Crit Rev Oral Biol Med 14(5): 363e369, 2003 Holmstrup P, Vedtofte P, Reibel J, Stoltze K: Long-term treatment outcome of oral premalignant lesions. Oral Oncol 42(5): 461e474, 2006 Ishii J, Fujita K, Komori T: Laser surgery as a treatment for oral leukoplakia. Oral Oncol 39(8): 759e769, 2003 € ller JE, et al: The role of Kreppel M, Dreiseidler T, Rothamel D, Eich HT, Drebber U, Zo clinical versus histopathological staging in patients with advanced oral squamous cell carcinoma treated with neoadjuvant radiochemotherapy followed by radical surgery. J Craniomaxillofac Surg 41(1): 22e27, 2013 Kuribayashi Y, Tsushima F, Sato M, Morita K, Omura K: Recurrence patterns of oral leukoplakia after curative surgical resection: important factors that predict the risk of recurrence and malignancy. J Oral Pathol Med 41(9), 2012 Lee JJ, Hung HC, Cheng SJ, Chen YJ, Chiang CP, Liu BY, et al: Carcinoma and dysplasia in oral leukoplakias in Taiwan: prevalence and risk factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 101(4): 472e480, 2006 Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A: Interventions for treating oral leukoplakia. Cochrane Database Syst Rev (4): CD001829, 2006 Lopez-Cedrun JL, Andres de Liano J: A 22 years survival and prognostic factors analysis in a homogeneous series of 64 patients with advanced cancer of the tongue and the floor of the mouth. J Craniomaxillofac Surg 43(3): 376e381, 2015 Apr pii: S1010-5182(15)00017-7
Montebugnoli L, Frini F, Gissi DB, Gabusi A, Cervellati F, Foschini MP, et al: Histological and immunohistochemical evaluation of new epithelium after removal of oral leukoplakia with Nd:YAG laser treatment. Lasers Med Sci 27(1), 2012 Pedrosa A, Santos A, Ferreira M, Araujo C, Barbosa R, Medeiros L: Is carbon dioxide laser vaporization a valuable tool in the management of oral leukoplakia? A survey at an oncology hospital. Lasers Med Sci, 2014 Petti S: Pooled estimate of world leukoplakia prevalence: a systematic review. Oral Oncol 39(8): 770e780, 2003 Reibel J: Prognosis of oral pre-malignant lesions: significance of clinical, histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med 14(1): 47e62, 2003 Schoelch ML, Sekandari N, Regezi JA, Silverman Jr S: Laser management of oral leukoplakias: a follow-up study of 70 patients. Laryngoscope 109(6): 949e953, 1999 Tewari M, Rai P, Singh GB, Kumar M, Shukla HS: Long-term follow-up results of Nd: YAG laser treatment of premalignant and malignant (Stage I) squamous cell carcinoma of the oral cavity. J Surg Oncol 95(4): 281e285, 2007 van der Hem PS, Nauta JM, van der Wal JE, Roodenburg JL: The results of CO2 laser surgery in patients with oral leukoplakia: a 25 year follow up. Oral Oncol 41(1): 31e37, 2005 van der Waal I: Potentially malignant disorders of the oral and oropharyngeal mucosa; present concepts of management. Oral Oncol 46(6): 423e425, 2010 van der Waal I, Reichart PA: Oral proliferative verrucous leukoplakia revisited. Oral Oncol 44(8): 719e721, 2008 Vivek V, Jayasree RS, Balan A, Sreelatha KT, Gupta AK: Three-year follow-up of oral leukoplakia after neodymium:yttrium aluminum garnet (Nd:YAG) laser surgery. Lasers Med Sci 23(4): 375e379, 2008 Yang SW, Tsai CN, Lee YS, Chen TA: Treatment outcome of dysplastic oral leukoplakia with carbon dioxide laser e emphasis on the factors affecting recurrence. J Oral Maxillofac Surg 69(6): e78e87, 2011 Yang SW, Wu CJ, Lee YS, Chen TA, Tsai CN: Postoperative recurrence as an associated factor of malignant transformation of oral dysplastic leukoplakia. ORL J Otorhinolaryngol Relat Spec 72(5), 2010
Please cite this article in press as: Del Corso G, et al., Laser evaporation versus laser excision of oral leukoplakia: A retrospective study with longterm follow-up, Journal of Cranio-Maxillo-Facial Surgery (2015), http://dx.doi.org/10.1016/j.jcms.2015.04.009