Received Date : 28-Nov-2012

Accepted Article Revised Date : 26-Feb-2013

Accepted Date : 26-Feb-2013

Article type : Original Manuscript

Revised manuscript (26 February 2013)

Malignant transformation of oral leukoplakia in a well defined cohort of 144 patients

Running title: Malignant transformation of oral leukoplakia

E.R.E.A. Brouns1, J.A. Baart1,

K.H Karagozoglu1, I.H.A. Aartman2, E. Bloemena1,3, I. van der Waal1

E.R.E.A. Brouns: [email protected]

J.A. Baart: [email protected]
K.H. Karagozoglu: [email protected]
I.H.A. Aartman: [email protected]
E. Bloemena: [email protected]
I. van der Waal: [email protected]

1
VU University Medical Center (VUmc)/Academic Centre for Dentistry Amsterdam
(ACTA), Department of Oral and Maxillofacial Surgery and Oral Pathology, P.O. Box 7057,
1007 MB Amsterdam, The Netherlands

2
Academic Centre for Dentistry Amsterdam (ACTA), Department of Social Dentistry and
Behavioural Sciences, P.O. Box 7822, 1008 AA Amsterdam, The Netherlands

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/odi.12095

© 2013 John Wiley & Sons A/S

 3
VU University Medical Center (VUmc), Department of Pathology, P.O. Box 7057, 1007
MB Amsterdam, The Netherlands
Accepted Article
Corresponding author:
Professor I. 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
Phone : +31-20-4444039
Fax : +31-20-4444046
E-mail : [email protected]

Date of submission: November 28, 2012

Date of resubmission: February 26, 2013

Abstract

OBJECTIVES: Oral leukoplakia is a potentially malignant disorder of the oral mucosa. 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: The group consisted of 144 patients. The size, presence

and degree of epithelial dysplasia were incorporated in 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 (SD= 39.33, range 12-179

months).

© 2013 John Wiley & Sons A/S

 RESULTS: In 16/144 patients (11%) malignant transformation occurred between 20 and 94
Accepted Article 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, etiological, clinical

or histopathological parameters were of statistical significance.

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 (Bremmer et al. 2011; Brouns et al.

2012b; Dietrich et al. 2004; Fillies et al. 2007; Holmstrup et al. 2006; Schepman et al. 1998;

Smith et al. 2009; van der Waal 2009). The possible role of human papilloma virus infection

with regard to malignant transformation of oral leukoplakia is at yet unclear (Feller and

Lemmer 2012; Syrjanen et al. 2011). Management of oral leukoplakia consists of surgical

excision, laser surgery, CO2 laser vaporisation and observation (Mehanna et al. 2009; Ribeiro

et al. 2010).

© 2013 John Wiley & Sons A/S

 The aim of the present retrospective study was to identify the factors that possibly
Accepted Article 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

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 etiological factors, a period of maximum three 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) (Brouns et al. 2012c; van der Waal and Axell

2002). 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 (SD= 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, Johnson, &

© 2013 John Wiley & Sons A/S

 van der Waal 2007). Clinically, a distinction was made between homogenous (flat, thin or
Accepted Article wrinkled, uniform white in colour) and non-homogeneous (white or white-and-red, either

speckled, nodular or verrucous) leukoplakia (Warnakulasuriya, Johnson, & van der Waal

2007). There were 65 patients with a homogenous leukoplakia and 79 with a non-

homogeneous type. Although many patients had multiple or widespread leukoplakias, not a

single one fully qualified to be characterized as proliferative verrucous leukoplakia as being

described in the literature (Cerero-Lapiedra et al. 2010; Hansen et al. 1985).

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 in the OL-classification and 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 14/53 (26%) sections,

Candida albicans was present.

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 Management and treatment
Accepted Article The initial treatment was performed within six months after the first visit to the clinic. In

71/144 (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 millimeters clinically normal

looking mucosa was observed. In 73/144 (50.7%) of the 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

(SD= 39.33). Follow-up visits were scheduled at 3 or 6 months intervals. The follow-up

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

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).

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 less than 0.05. The limited number of patients did not allow to

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 perform a multivariate analysis. For malignant transformation, a survival curve was plotted
Accepted Article 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 16/144 (11%) patients, four men and twelve women, malignant transformation occurred

during follow-up (Figure 2). There was no statistical significant relation between malignant

transformation and gender (p = 0.609). The age of these sixteen patients ranged from 26-81

years (SD= 14.11, mean 58.2-years). The age of the patients with malignant transformation

was categorized into 60 years and older (n = 10) and less than 60 years (n = 6); age was not

related to malignant transformation (p = 0.593). Five patients had tobacco habits and six

patients regular used 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 non-homogeneous. 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.

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 Four oral leukoplakias were L1 in size, four were L2 and eight lesions were L3. A large
Accepted Article 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) was

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, i.e. no dysplasia (P0) and presence of dysplasia (P1 and P2) (p = 0.334). The

patients were also staged according to the OL-classification and 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

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 laser vaporisation as the initial treatment (n = 22) or during follow-up (n = 13), 14 (40%)
Accepted Article 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).

Patients who underwent active treatment (surgical excision or CO2 laser vaporization)

(n = 95) did not have a statistically significant lower risk for 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 (Table 1 and 4) (Brouns et al. 2012c; van der Waal & Axell 2002; van

der Waal 2009). There were 16/144 (11%) patients in whom a malignant transformation

occurred during the follow-up, resulting in an annual malignant transformation rate of 2.6%.

Ninety-five out 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 87/166 (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 (Arduino et al. 2009; Lodi et al. 2006; Schepman

et al. 1998). 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 are available to determine the optimal width of the margin.

© 2013 John Wiley & Sons A/S

 The gender distribution of the entire patient group showed a female preponderance with a
Accepted Article 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;

Liu et al. 2011; Lumerman et al. 1995; Saito et al. 1999). However, other studies have shown

that female gender was a higher risk for malignant transformation (Schepman et al. 1998;

Silverman et al. 1984). Despite of 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 localized 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 localized, 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)

© 2013 John Wiley & Sons A/S

 versus low-risk (remaining oral subsites) (p = 0.408). We also did not identify “alveolar ridge
Accepted Article 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;

Mignogna et al. 2011; Natarajan and Woo 2008).

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 (Bremmer et al. 2011; Ho et al.

2012; Holmstrup et al. 2006; Liu et al. 2010; Schepman et al. 1998; Warnakulasuriya et al.

2011).

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 (Holmstrup et al. 2007; Vedtofte et al. 1987).

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 randomized 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 (Brouns et al. 2012a; Kuribayashi et al. 2012; Vedtofte et al. 1987).

The present study showed for both surgical excision and CO2 laser vaporisation treatment a

recurrence rate of approximately 40% during a mean follow-up periodof 48.8 months and

61.9 months, respectively.

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 The annual malignant transformation rate (2.6%) in this study may be difficult to compare
Accepted Article 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, etiological, 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.

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 Dietrich T, Reichart, PA, Scheifele, C (2004). Clinical risk factors of oral leukoplakia in a
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Accepted Article
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 Ribeiro AS, Salles PR, da Silva TA, Mesquita RA (2010). A review of the nonsurgical
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Accepted Article
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Table 1 Certainty (C)-factor of a diagnosis of oral leukoplakia14,15

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 etiologic factors, e.g.

mechanical irritation, during a follow-up 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 pathologically examination of the resected specimen

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 Table 2 Distribution of tobacco and alcohol habits among 144 patients with oral leukoplakia
Accepted Article
Total Malignant transformation
n = 144 n = 16
Variable

Tobacco habits User 70 7

Non user 64 8
Unknown 10 1

Alcohol consumption User 68 8

Non user 26 3
Unknown 50 5

Table 3 Site distribution of 144 patients with oral leukoplakia

Total Malignant transformation

n = 144 n = 16
Oral subsite

Tongue (dorsal and lateral surfaces) 43 8

Floor of mouth 25 1
Lower lip 3 1
Hard palate 10 2
Cheek mucosa 9 2
Upper alveolus and gingiva 13
Lower alveolus and gingiva 18
Multiple sites 23 2

Table 4 Classification and staging system for oral leukoplakias (OL-system)2,15

L (size of the leukoplakia)

L1 Size of single or multiple leukoplakias together <2 cm
L2 Size of single or multiple leukoplakias together 2-4 cm
L3 Size of single or multiple leukoplakias together >4 cm
Lx Size not specified

P (pathology)
P0 No epithelial dysplasia (includes “no or perhaps mild epithelial dysplasia”)
P1 Mild or moderate epithelial dysplasia
P2 Severe epithelial dysplasia
Px Absence or presence of epithelial dysplasia not specified in the pathology report

OL-staging system
Stage 1 L1P0

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 Stage 2 L2P0
Stage 3 L3P0 or L1L2P1
Accepted Article Stage 4 L3P1 or any L P2

General rules of the OL-staging system

1. If there is doubt concerning the correct L category to which a particular case should be
allotted, than the lower (i.e. less advanced) category should be chosen. This will also be
reflected in the stage grouping.
2. 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.
3. Carcinoma in situ has been excluded from this classification.
4. 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.

Total Malignant transformation

n = 144 n =16
Variable

Size L1 67 4
L2 42 4
L3 35 8

Dysplasia P0 88 8
P1 40 6
P2 16 2

OL-staging system Stage 1 39 1

Stage 2 29 3
Stage 3 51 7
Stage 4 25 5

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Accepted Article
Figure 1 Distribution of gender and age in 144 patients with oral leukoplakia

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Accepted Article
Figure 2 Kaplan-Meier analysis of malignant transformation in oral leukoplakia (n = 144)

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