Oral Diseases (2014) 20, e19–e24 doi:10.1111/odi.12095
© 2013 John Wiley & Sons A/S
All rights reserved
www.wiley.com
ORIGINAL ARTICLE
Malignant transformation of oral leukoplakia in a
well-defined cohort of 144 patients
EREA Brouns1, JA Baart1, KH Karagozoglu1, IHA Aartman2, E Bloemena1,3, I van der Waal1
1
Department of Oral and Maxillofacial Surgery and Oral Pathology, VU University Medical Center (VUmc)/Academic Centre for
Dentistry Amsterdam (ACTA), Amsterdam; 2Department of Social Dentistry and Behavioural Sciences, Academic Centre for Dentistry
Amsterdam (ACTA), Amsterdam; 3Department of Pathology, VU University Medical Center (VUmc), Amsterdam The Netherlands
OBJECTIVES: Oral leukoplakia is a potentially malignant disorder of the oral mucosa. The aim of this 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.
MATERIAL AND METHODS: The group consisted of
144 patients. The size, presence and degree of epithelial
dysplasia were incorporated into a clinicopathological
classification and staging system. Initial management
consisted of surgical excision, CO2 laser vaporisation or
observation only. The mean follow-up period was
51.2 months (s.d. = 39.33, range 12–179 months).
RESULTS: In 16 of 144 patients (11%), malignant transformation occurred between 20 and 94 months (mean
57.0 months) after the first visit, the annual malignant
transformation rate being approximately 2.6%. A large
size of the lesion ( 4 cm) showed to be the only statistically significant predictor of malignant transformation (P = 0.034).
CONCLUSION: 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 of statistical significance.
Oral Diseases (2014) 20, e19–e24
Keywords: potentially malignant oral disorder; oral leukoplakia;
malignant transformation; oral epithelial dysplasia; oral cancer
Introduction
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.
Material and methods
Correspondence: Prof. Isa€ac van der Waal, Department of Oral and
Maxillofacial Surgery and Oral Pathology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Tel:
+31 20 4444039, Fax: +31 20 4444046, E-mail: [email protected]
Received 28 November 2012; revised 26 February 2013; accepted 26
February 2013
Patients
For the purpose of this retrospective study, 144 consecutive patients were included who were referred to the
Department of Oral and Maxillofacial Surgery and Oral
Pathology at VU Medical Center/ACTA, Amsterdam, the
Netherlands, between 1997 and 2012 and in whom a
definitive clinicopathological diagnosis of oral leukoplakia
was established. In case of possible aetiological factors, a
Malignant transformation of oral leukoplakia
EREA Brouns et al
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Table 1 Certainty (C) factor of a diagnosis of oral leukoplakia
C1 Evidence from a single visit, applying inspection and palpation as the
only diagnosis means (provisional clinical diagnosis), including a
clinical picture of the lesion.
C2 Evidence obtained by a negative result of elimination of suspected
aetiological factors, for example, mechanical irritation, during a followup period of 6 weeks (definitive clinical diagnosis)
C3 As C2, but complemented by pretreatment incisional biopsy in which,
histopathologically, no definable lesion is observed (histopathologically
supported diagnosis)
C4 Evidence following surgery and pathological examination of the
resected specimen
Table 2 Distribution of tobacco and alcohol habits among 144 patients
with oral leukoplakia
Total n = 144
Variable
Tobacco habits
User
70
Non-user
64
Unknown
10
Alcohol consumption
User
68
Non-user
26
Unknown
50
Malignant transformation n = 16
7
8
1
8
3
5
Table 3 Site distribution of 144 patients with oral leukoplakia
Oral subsite
Tongue
(dorsal and lateral surfaces)
Floor of mouth
Lower lip
Hard palate
Cheek mucosa
Upper alveolus and gingiva
Lower alveolus and gingiva
Multiple sites
Figure 1 Distribution of gender and age in 144 patients with oral leukoplakia
period of maximum 3 months was allowed to evaluate the
results of elimination of these factors. As a result, only
patients with a diagnostic certainty factor 3 and 4 have
been included (Table 1) (van der Waal and Axell, 2002;
Brouns et al, 2012c). The follow-up period lasted at least
12 months. Patients who developed a malignancy within a
period of 12 months after the biopsy (n = 2) have been
excluded beforehand. In these two patients, the initial
biopsy may not have been representative.
The group of 144 patients consisted of 44 men and 100
women, with a mean age of 58.7 years (s.d. = 14.11,
range 26–98 years) (Figure 1). The use of tobacco and
alcohol was registered in a simplified manner as being
user, non-user or unknown (Table 2).
In this study, the definition of leukoplakia, as proposed
by the WHO in 2005, has been used: ‘A predominantly
white plaque of questionable risk having excluded (other)
known diseases or disorders that carry no increased risk
for cancer’(Warnakulasuriya et al, 2007). Clinically, a distinction was made between homogeneous (flat, thin or
wrinkled, uniform white in colour) and non-homogeneous
Oral Diseases
Total n = 144
Malignant
transformation n = 16
43
8
25
3
10
9
13
18
23
1
1
2
2
2
(white or white-and-red, either speckled, nodular or verrucous) leukoplakia (Warnakulasuriya et al, 2007). There
were 65 patients with a homogeneous leukoplakia and 79
with a non-homogeneous type. Although many patients
had multiple or widespread leukoplakias, not a single one
fully qualified to be characterised as proliferative verrucous leukoplakia as being described in the literature (Hansen et al, 1985; Cerero-Lapiedra et al, 2010).
The location of leukoplakia was specified according to
eight subsites: (i) tongue, (ii) floor of mouth (FOM), (iii)
lower lip, (iv) hard palate, (v) buccal mucosa, (vi) upper
alveolus and gingiva, (vii) lower alveolus and gingiva,
and (viii) multiple sites (Table 3). In all patients, clinical
pictures of the oral leukoplakia were taken at the first visit
and in most cases also during follow-up, particularly in
case of recurrence or malignant transformation. The clinical picture taken at the first visit was used for this study.
The size, presence and degree of epithelial dysplasia were
incorporated into the OL-classification and OL-staging
system (Table 4) (van der Waal, 2009). There were 95
incisional and 49 excisional biopsies. In eleven patients,
there was an additional excision specimen available for
histopathological grading. In five of the eleven patients,
the final histopathological examination resulted in a different P-classification; the highest pathological score was
used in these cases. All histological sections were revised
by the same pathologists (EB/IW); in a limited number of
cases that were graded differently, a consensus was
arrived (Table 5). In 53 patients, PAS-D sections were
available for assessment of the presence of Candida albicans. In 14 of 53 (26%) sections, Candida albicans was
present.
Malignant transformation of oral leukoplakia
EREA Brouns et al
Table 4 Classification and staging system for oral leukoplakias (OL-system)
L (size of the leukoplakia)
Size of single or multiple leukoplakias together < 2 cm
L1
Size of single or multiple leukoplakias together 2–4 cm
L2
Size of single or multiple leukoplakias together > 4 cm
L3
Size not specified
Lx
P (pathology)
No epithelial dysplasia (includes ‘no or
P0
perhaps mild epithelial dysplasia’)
Mild or moderate epithelial dysplasia
P1
Severe epithelial dysplasia
P2
Absence or presence of epithelial dysplasia
Px
not specified in the pathology report
OL-staging system
Stage 1
L1P0
Stage 2
L2P0
Stage 3
L3P0 or L1L2P1
Stage 4
L3P1 or any L P2
General rules of the OL-staging system: (i) If there is doubt concerning
the correct L category to which a particular case should be allotted, then
the lower (i.e. less advanced) category should be chosen. This will also
be reflected in the stage grouping; (ii) in case of multiple biopsies of single leukoplakia or biopsies taken from multiple leukoplakias, the highest
pathological score of the various biopsies should be used; (iii) carcinoma
in situ has been excluded from this classification; (iv) for reporting purposes, the oral subsite according to the ICD-DA should be mentioned
(World Health Organisation, International Classification of Diseases.
Tenth Revision. Application to Dentistry and Stomatology, ICD-DA,
Geneva, 1992).
Table 5 Size, histopathology and stage in 144 patients with a definitive
clinicopathological diagnosis of oral leukoplakia
Variable
Size
L1
L2
L3
Dysplasia
P0
P1
P2
OL-staging system
Stage 1
Stage 2
Stage 3
Stage 4
Total n = 144
Malignant
transformation n = 16
67
42
35
4
4
8
88
40
16
8
6
2
39
29
51
25
1
3
7
5
Management and treatment
The initial treatment was performed within 6 months after
the first visit to the clinic. In 71 of 144 patients (49.3%),
initial treatment consisted of surgical excision (n = 49) or
CO2 laser vaporisation (n = 22). CO2 laser vaporisation
was mainly used in non-dysplastic leukoplakias and leukoplakias at sites that were less amenable for surgical excision, such as floor of the mouth and mucobuccal folds. In
most cases, a margin of a few millimetres clinically normal-looking mucosa was observed. In 73 of 144 (50.7%)
patients, initial management consisted of observation. The
treatment modalities during follow-up of these patients
consisted of surgical excision (n = 11) and CO2 laser
vaporisation (n = 13). Forty-nine patients never underwent
any type of treatment.
The follow-up period ranged from 12 to 179 months
with a mean of 51.2 months (s.d. = 39.33). Follow-up visits were scheduled at 3- or 6-month intervals. The followup period started at the first visit of the patient to the
clinic. It ended in case of lost to follow-up, death, development of OSCC at the site of the leukoplakia or
elsewhere in the oral cavity or in the head and neck region.
The design of this study adheres to the code for proper
secondary use of human tissue of the Dutch Federation of
Biomedical Scientific Societies (http://www.federa.org)
(Oosterhuis et al, 2003).
e21
Statistical analysis
Minimum, maximum and mean values of continuous variables were calculated. Statistically significant relations
were tested with the chi-square test. The results were
statistically significant if the P-value was < 0.05. The limited number of patients did not allow to perform a multivariate analysis. For malignant transformation, a survival
curve was plotted according to the Kaplan–Meier method.
For all statistical analyses, SPSS 17.0 for Windows (SPSS
Inc, Chicago, IL, USA) was used.
Results
Malignant transformation
In 16 of 144 (11%) patients, four men and twelve women,
malignant transformation occurred during follow-up
(Figure 2). There was no statistically significant relation
between malignant transformation and gender (P = 0.609).
The age of these sixteen patients ranged from 26 to
81 years (s.d. = 14.11, mean 58.2 years). The age of the
patients with malignant transformation was categorised
into 60 years and older (n = 10) and < 60 years (n = 6);
age was not related to malignant transformation
Figure 2 Kaplan–Meier analysis of malignant transformation in oral leukoplakia (n = 144)
Oral Diseases
Malignant transformation of oral leukoplakia
EREA Brouns et al
e22
(P = 0.593). Five patients had tobacco habits, and six
patients had regular use of alcohol. Also, tobacco habits
and regular alcohol use were not associated with malignant transformation (P = 0.894 and P = 0.953, respectively). Malignant transformation occurred between 20 and
94 months (mean 57.0 months) after the first visit, the
annual malignant transformation rate being approximately
2.6%.
Four oral leukoplakias were homogeneous and 12 nonhomogeneous. No statistically significant relation was
found between the clinical appearance and malignant
transformation (P = 0.086). The oral leukoplakias were
located at the tongue (n = 8), FOM (n = 1), lower lip
(n = 1), hard palate (n = 2), buccal mucosa (n = 2) and
multiple sites (n = 2). No statistically significant relation
was found between the oral subsite and malignant transformation (P = 0.144), even when the subsites were subdivided into high risk (floor of mouth and tongue) versus
low risk (remaining oral subsites) (P = 0.408). All carcinomas arose at the same subsite of the oral leukoplakia.
Four oral leukoplakias were L1 in size, four were L2
and eight lesions were L3. A large size of the lesion (L3
4 cm in largest diameter) showed to be a predictor for
malignant transformation (P = 0.034).
The initial biopsy showed no dysplasia (P0) in 10
patients, while in two patients mild/moderate dysplasia
(P1) and in two other cases severe epithelial dysplasia (P2)
were observed. No statistically significant relation was
found between the presence and degree of epithelial dysplasia and malignant transformation (P = 0.604); this was
also true when using a binary system, that is, no dysplasia
(P0) and presence of dysplasia (P1 and P2) (P = 0.334).
The patients were also staged according to the OL-classification and OL-staging system: Stage 1 (n = 1), Stage 2
(n = 3), Stage 3 (n = 7) and Stage 4 (n = 5). Stage was
not a statistically significant factor (P = 0.187). Of the 16
patients with a malignant transformation, PAS-D sections
were available in eight cases of which four were positive
for Candida albicans (P = 0.101).
Management and treatment
The initial treatment of the 16 patients with a malignant
transformation consisted of surgical excision (n = 3), CO2
laser vaporisation (n = 3) and observation (n = 10). Treatment during follow-up of the patients with initial observation consisted of surgical excision (n = 2) and CO2 laser
vaporisation treatment (n = 2). Six patients (37.5%) never
underwent any type of active treatment.
Of the 60 patients who underwent surgical excision as
the initial treatment (n = 49) or during follow-up
(n = 11), 25 (42%) patients had a recurrence in a mean
follow-up period of 48.8 months. There was no statistically significant relation between recurrence after surgical
excision and malignant transformation (P = 0.134). Of the
35 patients who underwent CO2 laser vaporisation as the
initial treatment (n = 22) or during follow-up (n = 13), 14
(40%) patients had a recurrence in a mean follow-up
period of 61.9 months (Brouns et al, 2012a). There was
no statistically significant relation between recurrence after
CO2 laser vaporisation and malignant transformation
(P = 0.324) (Brouns et al, 2012a).
Oral Diseases
Patients who underwent active treatment (surgical excision or CO2 laser vaporisation) (n = 95) did not have a
statistically significant lower risk of malignant transformation than patients managed by only observation (n = 49)
(P = 0.756).
Discussion
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
Malignant transformation of oral leukoplakia
EREA Brouns et al
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.
Author contributions
The study design came from Dr. I. van der Waal. Drs. J. A. Baart and K. H. Karagozoglu treated a large number of the patients.
Dr. E.R.E.A. Brouns analysed all data and wrote the manuscript.
The statistical analysis was carried out by Mrs. I.H.A. Aartman
and Dr. E. R. E. A. Brouns. Drs. E. Bloemena and I. van der
Waal revised the histopathological slides.
e23
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