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Oral leukoplakia, with emphasis on malignant transformation
128
J. Cranio-Max.-Fac. Surg. 17 (1989)
J. Cranio-Max.-Fac. Surg. 17 (1989) 128-133 © Georg Thieme Verlag Stuttgart • New York
Oral Leukoplakia, with Emphasis on Malignant Transformation A Follow-Up Study of 46 Patients Willern F. C. Hogewind, Willem A.M. van der Kwast, Isaac van der Waal Dept. of Oral Surgery (Head: Prof. Dr. W. A. M. van der Kwast, D.M.D.) Oral Pathology (Head: Prof. Dr. I. van der Waal, D.M.D.), Teaching Hospital, Free University/ACTA, Amsterdam, The Netherlands. Submitted 2 2 . 2 . 8 8 ; accepted 5 . 7 . 8 8
Introduction Leukoplakia is a clinical descriptive term; its use carries no implications with respect to the histological findings. It has recently been defined as "a whitish patch or plaque that cannot be characterized clinically or pathologically as any other disease and which is not associated with any physical or chemical causative agent except the use of tobacco" (Axkll et al., 1984).
Present concept of oral leukoplakia Oral leukoplakia is a precancerous lesion. The reported rate of malignant transformation is approximately 5 % in an average period of 5 years (Pindborg, 1980). Since the premalignant potential may be related to aetiology, it is thought important to describe aetiological factors (Ax~ll et al., 1984). Thus, lesions that are of unknown aetiology are listed as idiopathic or cryptogenic leukoplakias. Whitish patches or plaques associated with and thought to be the result of the use of tobacco are listed as tobacco-associated leukoplakias, while whitish patches or plaques for which a local cause other than the use of tobacco can be identified are listed according to the known cause and are not termed leukoplakias (AxSll et al., 1984). Examples are frictional lesions, lesions associated with dental restorations and lesions associated with cheek-biting. Only in the case of a residual lesion after treatment, which means that the lesion has become independent of the causes which probably induced it, is the term leukoplakia maintained. The prevalence of oral leukoplakia shows marked geographic differences, ranging from 0 : 4 ~ to 17 : 0 % (Bouquot and Gorlin, 1986). These geographic differences can probably be explained to a large extent by differences in tobacco habits and by the use of different criteria. Leukoplakia seems to be most prevalent in men, with a majority found in the age group of 40-70years (WaIdron and Sharer, 1975; AxbIl, 1987). The most frequently affected oral sites are the buccal mucosa and the labial commissures, and to a lesser extent the lower lip, the alveolar ridge, the tongue, the floor of the mouth and the palate.
Summary A review of oral leukoplakia, based on data from the literature and experience with 84 patients is presented. The leukoplakic lesions of 3 patients developed malignant transformation within an average period of 5 years. All three patients were elderly women with idiopathic leukoplakia, in two cases of the homogeneous and in one case of the non-homogeneous type. The initial biopsy of the former two patients showed only hyperorthokeratosis without epithelial dysplasia. In the first biopsy of the third patient epithelial dysplasia was recorded. One of the patients finally died of widespread metastases. The other two have been treated surgically and are still alive. Key words Oral pathology - Oral leukoplakia - Follow-up Malignant transformation
Leukoplakia may present itself in a localized or diffuse and sometimes even multifocal fashion. Leukoplakia affecting the floor of the mouth or the ventral surface of the tongue is also called sublingual keratosis (Kramer, 1978; Roch-Berry, 1981). Based on the clinical appearance of leukoplakia, a distinction is usually made between a homogeneous type and a non-homogeneous type. Homogeneous leukoplakia is described as a uniformly whitish lesion with a smooth or corrugated surface. The non-homogeneous leukoplakias include: 1. erythroleukoplakia or erosive leukoplakia: a whitish lesion that includes red areas; 2. nodular leukoplakia: a lesion with slightly raised, rounded, red and/or whitish excrescences that may be described as granules or nodules; and 3. verrucous leukoplakia: an exophytic lesion with irregular sharp or blunt projections (AxSll et al., 1984). Both erythroleukoplakia and the nodular type of leukoplakia are also referred to as speckled leukoplakia or speckled erythroplakia, and are, in most instances, associated with candidal infection (AxSll et al., 1984). The histological aspects of oral leukoplakia can vary from hyperkeratosis without epithelial dysplasia to epithelial dysplasia, carcinoma-in-situ and even squamous cell carcinoma (Figs. 1-3). It is recommended that a histological report should always include a statement on the presence of epithelial dysplasia and an assessment of its severity. Various cellular changes that may occur in epithelial dysplasia are described (Pindborg, 1980). Of these, particularly basal cell hyperplasia and disturbed epithelial maturation might have ominous prognostic significance (Wright and Shear, 1985). Based on the histopathologist's interpretation of the presence, degree and significance of dysplastic features, epithelial dysplasia is divided into three categories: mild, moderate and severe (WHO Collaborating Reference Centre for Oral Precancerous Lesions, 1978). Nevertheless, it has not proved possible to devise a scheme for grading dysplasia that gives consistent and reproducible results (Pindborg et al., 1985). Therapy is primarily directed to the elimination of possible causative factors. Biopsy is considered depending on the
Oral Leukoplakia, with Emphasis on Malignant Transformation
Fig.1
Hyperkeratosis without signs of epithelial dysplasia. (HE x 100),
J. Cranio-Max.-Fac.Surg. 17 (1989)
129
Fig.2 Epithelial dysplasia. (HE x 100).
malignant transformation in leukoplakia has been reported (Roed-Petersen, 1971 ; B[znOczy, 1982). Of all these factors, the grade of epithelial dysplasia seems to be the most important indicator of a malignant potential (Burkhardt, 1985). In this contribution a retrospective survey is presented, consisting of a study of 84 patients with oral leukoplakia, who attended the department of Oral and Maxillofacial Surgery at the Free University Hospital, Amsterdam, from 1969 till 1984. In particular, the rate of malignant transformation has been studied. Materials and Methods
Fig.3 Carcinoma-in-situ. (HExlO0).
results of those initial measures. Possible further treatment largely depends on the histopathological findings of such a biopsy and may consist of surgical excision (Scbwenzer, 1968; Vedtofte et al., 1987), cryosurgery (Bekke and Baart, 1979; Gongloff and Gage, 1983), or CO2-1asersurgery (Roodenburg, 1985; Horch et al., 1986). Other treatments, such as the administration of high doses of vitamin A or its derivates (Shklar, 1986) and the topical application of bleomycin (Hammersley et al., 1985), are still in an experimental stage. Both in the treated and untreated patient follow-up examination is mandatory. Certain features of leukoplakia seem to indicate an increased risk of malignant transformation. These are: pain associated with the leukoplakic lesion (Silverman et al., 1984), the absence of smoking habits (Einborn and Wersdll, 1967; Silverman et al., 1984), long duration of the leukoplakia (Silverman et al., 1984), location in the floor of the mouth and/or on the tongue (Kramer, 1978; Roch-Berry, 1981), the clinical non-homogeneous type (Sharer and Waldron, 1975; Mashberg, 1980; Silverman et al., 1984), the presence of epithelial dysplasia and the history of a previous oral cancer. (Moertel and Foss, 1958). Besides, a so far unexplained female preponderance of
The 84patients with oral leukoplakia involved in this study were selected retrospectively from the files of the department of Oral and Maxillofacial Surgery at the Free University Hospital, Amsterdam from 1969 until 1984. Leukoplakia was defined, as mentioned earlier in this study, as "a whitish patch or plaque that cannot be characterized clinically or pathologically as any other disease and which is not associated with any physical or chemical causative agent except the use of tobacco" (Ax~ll et al., 1984). A tobacco user was defined as any person who smoked at least 5 cigarettes a day or the equivalent in cigars, pipes or any other tobacco products. None of the patients had been treated for their leukoplakia before. Cases of leukoplakia associated with squamous cell carcinoma were excluded from this study. Age, sex, reason for referral, smoking habits, duration of the lesion, site and clinical appearance were recorded (Tables 1-6). The presence or absence of symptoms could not be retrieved reliably. The sites were specified according to anatomical distribution as recommended by the UICC (Hermanek and Sobin, 1987). In all patients, biopsies were taken either at the first visit or during follow-up, partly for academic reasons. In the case of non-homogeneous leukoplakia, a biopsy was usually taken at the first visit (Table 7). In the interpretation of epithelial dysplasia, use was made of the 12 criteria as listed by the WHO Collaborating Reference Centre for Oral Precancerous Lesions (WHO Collaborating Reference Centre for Oral Precancerous Lesions, 1978). The possible presence and degree of dysplasia has in all but three pa-
13 0
J. Cranio-Max.-Fac. Surg. 17 (1989)
W.F.C. Hogewind et al.
Table1 plakia
Age and sex distribution of 84 patients with oral leuko-
age (years)
m
f
0-15 16-30 31-45 46-60 >60
5 12 13 20
1 5 11 17
total
50 (59.5 %)
34 (40.5 %)
Table 2
homogeneous non-homogeneous not specified
31 45 8
Table8 Distribution of aetiological factors in 84 patients with oral leukoplakia. tobacco habits no tobacco habits tobacco habits not specified
Duration of oral leukoplakia in 84patients.
1-4 weeks 1-6 months > V2year not specified
Table 5 to site.
41 9 34
homogeneous
Distribution of 84 patients with oral leukoplakia according
buccal mucosa tongue commissure palate lower alveolar ridge floor of the mouth upper alveolar ridge lower lip (vermilion border) pharynx combinations not specified
hyper (ortho/para) keratosis without dysplasia dysplasia, slight dysplasia, moderate dysplasia, severe dysplasia, not graded not specified or no biopsy taken total
Table 8 4 11 13 56
12 10 6 4 4 3 3 3 2 35 2
dents been recorded as mild, moderate or severe. The histological sections of the three cases with unspecified dysplasia were not available for review. In the case with epithelial dysplasia present treatment by cryosurgery or coldknife surgery was instituted. Follow-up visits were scheduled at 3 - 6 months intervals. Thirty-eight patients were lost to follow-up or erroneously dismissed within one year. The follow-up period for the remaining group of 46 patients varied from 1 to 8 years, with an average of 2 ~ years.
11 22 51
Table7 Relationship between clinical type and histological changes in 46 patients with oral leukoplakia.
Reasons of referral in 84 patients with oral leukoplakia.
white lesion incidental finding not specified
Table4
Table6 Classification of oral leukoplakia in 84 patients according to clinical type.
nonhomogeneous
not total specified
4
2
16
22
1 -
1 3 3 -
1 1 3
2 3 5 3
5
4
2
11
10
13
23
46
Data of the 3 patients with malignant transformation.
sex age reason for referral tobacco habits location
clinical appearance epithelial dysplasia observation period (years)
1
2
3
f 79 leukoplakia and pain none lateral border of the tongue with extem sion into the floor of the mouth homogeneous
f 73 leukoplakia and pain none lateral border of the tongue with extension into the floor of the mouth non-homogeneous
f 79 leukoplakia and pain none lateral border of the tongue with extension into the floor of the mouth homogeneous
none
slightmoderate
none
7
2~
3
Results Three of the remaining 46 patients, all elderly, non-smoking women, subsequently developed squamous cell carcinoma. Two were referred because of leukoplakia with associated discomfort, the third because of discomfort only. In all three patients, the leukoplakic lesions were situated on the lateral border of the tongue and in the floor of the mouth. Two were of a homogeneous and one of a nonhomogeneous type (Figs. 4 a - 6 a). The biopsies of the homogeneous leukoplakias, taken at the first visit, showed no
Oral Leukoplakia, with Emphasis on Malignant Transformation
J. Cranio-Max.-Fac. Surg. 17 (1989)
131
Fig.4a
Homogeneous leukoplakia on lateral border of the tongue in patient 1. (see Table 9
Fig.4 b Same patient as in Fig.4a, after 7years.
Fig.5a Non-homogeneous leukoplakia on lateral border of the tongue in patient 2. (see Table 9).
Fig.5b
Fig. 6 a Homogeneous leukoplakia on lateral border of the tongue in patient 3. (see Table 9).
Fig. 6 b Same patient as in Fig, 6 a, after 3 years.
distinct signs of epithelial dysplasia, while the biopsy of the non-homogeneous leukoplakia showed slight to moderate epithelial dysplasia. Review of the initial biopsies of the three patients did not change the original interpretation. In all three patients a wait-and-see policy was followed: in two of them, because of the homogeneous, clinically not suspicious lesions and the absence of epithelial dysplasia. Because of the widespread character of the leukoplakia and the poor general condition of the patient, a wait-and-see policy was adopted in the third patient as well, in spite of the presence of epithelial dysplasia. The carcinomas developed within 21/2 to 7 years after the initial attendance (Figs. 4 b-6 b). Further data on these 3 patients are summarised in Table 8. All three patients were subjected to surgical treatment. In two patients treatment consisted of wide local excision. In the third patient a radical neck dissection was carried out at the same time, because of a clinically suspicious lymph
node. Nevertheless, this patient died of widespread metastases. The other two are still alive, apparently without turnout, 5 years after treatment of their malignancy.
Same patient as in Fig. 5 a, after 2Y2years.
Discussion and Conclusions
Our study has revealed a malignant transformation rate in oral leukoplakias of 3.6 percent during a mean follow-up period of 8 years. This percentage is in accordance with previous studies, showing a frequency of carcinomatous changes in oral leukoplakia that varies between 1.4 and 6percent during an observation period of 1 to 30 years (Pindborg, 1980; B~n6czy, 1982). In view of the retrospective nature of the present study, our findings should be interpreted carefully. On the one hand the total number of patients with leukoplakia who attended the department of Oral Surgery might have largely been under-reported, which would result in a lower rate of malignant transfor-
132
J. Cranio-Max.-Fac. Surg. 17 (1989)
Table9 Age distribution of 65,000 patients, referred to the department of Oral Surgery at the Free University Hospital, Amsterdam, during the period June 1968- June 1981, in a random sample of 2,000 patients (Allard, 1982). age
males
females
0-15 16-30 31-45 46-60 > 60
3.07* 24.73 10.32 5.25 2.19
3.12 33.86 9.09 5.24 3.06
total
45.6
54.4
= Figures represent percentages
mation. On the other hand the present series of leukoplakias may erroneously comprise a number of lesions that belong to the category of "other diagnosable lesions", which would result in a higher rate of malignant transformation. Besides, the patients presented in this study form part of a selected population. Furthermore, the information collected from the files was rather incomplete. Another point of concern is the relatively large number of 38 patients who were lost to follow-up. To the best of our knowledge no malignant transformation has taken place in those patients. Our total leukoplakia group comprised more men than women, while the sex distribution of the population of the out-patients of the Department of Oral Surgery actually showed a slight female preponderance (Table 9). The male preponderance in our group is of statistical significance (p < 0.05) and corresponds to that of several other studies (Waldron and Shafer, 1975; Pindborg, 1980; Ax~ll, 1987). In view of this sex distribution, the occurrence of malignant transformation in all three cases in women, points to female prevalence of malignant transformation in leukoplakia, as has been reported by others as well (Roed-Petersen, 1971; B~n6czy, 1982). Most patients were older than 45 years, which is in accordance with previous investigations showing a peak incidence above the age of 50 years (Roed-P etersen, 1971 ; Waldron and Sharer, 1975; Axkll, 1987). The average age of the three patients with carcinoma developing from leukoplakia was 77 years at the time of diagnosis of malignancy. This age was higher than the average age of 51years (range 23-82years) of the leukoplakia group as a whole and points to a certain latency period, which elapses between the onset of leukoplakia and the diagnosis of carcinoma (Einhorn and Wersdll, 1967; B[~n6czy, 1982). Of the 34women and 50 men with oral leukoplakia 12 (35 %) and 29 (58 %) respectively were smokers. This is a smaller percentage than commonly reported among patients with leukoplakic lesions. From these figures one may conclude that the role of smoking as the most important factor in the aetiology of leukoplakia is somewhat debatable (Axkll et al., 1984). The three women whose leukoplakia showed malignant transformation all belonged to the group of non-smokers. This increased risk of development of carcinoma in patients with oral leukoplakia who have never smoked is consistent with previous reports (Einhorn and WersMl, 1967; Roed-Petersen, 1971; B~n6czy, 1982; Silverman et al., 1984).
W.F.C. Hogewind et al. The most frequent sites of oral leukoplakia are the buccal mucosa and the commissures, as demonstrated in a Hungarian study of 670 cases of oral leukoplakia, in which the tongue was only affected in a small percentage of cases (B~nOczy, 1977). In the present material there is not only a preference for the buccal mucosa and the commissures, but also for the tongue. When considering the site-distribution in the three women who developed carcinoma it is striking that in all three patients the cancer was situated on the lateral border of the tongue and in the floor of the mouth. This preference for the tongue is in accordance with other studies (Waldron and Shafer, 1975; Kramer, 1978; Roch-Berry, 1981). Of the 46patients who have been followed for more than one year, eight had moderate or severe dysplasia (Table 7). Most of these patients were treated by surgical excision. During the period of observation no recurrences were observed. It should be realized, however, that the average follow-up period of 21/2years is rather a short one in this respect. The results, therefore, do not permit one to state that treatment of dysplastic epithelial tissue does indeed prevent the future development of a squamous cell carcinoma. In one patient with homogeneous leukoplakia the initial biopsy showed distinct features of epithelial dysplasia (Table 7), which finding illustrates that one cannot assess reliably the histopathological nature of leukoplakia on clinical grounds alone. For the same reason the clinical use of the term "sublingual keratosis" can be questioned. From the fact that the initial biopsies of two of the three patients who developed a carcinoma showed no epithelial dysplasia, one may conclude that carcinomatous transformation may take place even in non-dysplastic epithelium (Pindborg, 1980). However, one should realise that subjectivity plays a role in the histological diagnosis of dysplasia (Pindborg et al., 1985) and that one actually might have been dealing with some degree of epithelial dysplasia in these two cases. Besides, it is possible that the biopsies were not representative. The period in which a carcinoma developed varied from 2 ~ to 7 years and this emphasizes the importance of longterm follw-up, even in the case of apparently clinically and histopathologically innocuous leukoplakias.
References
Allard, R. H. B.: Non-odontogenic cysts of the oral regions. Thesis. Free University Amsterdam, The Netherlands 1982 Ax~ll, T., P. Holmstrup, I. R. H. Kramer, J. J. Pindborg, M. Shear: International seminar on oral [eukoplakia and associated lesions related to tobacco habits. Comm. Dent. Oral Epidemiol. 12 (1984) 145 Ax~ll, T.: Occurrence of leukoplakia and some other oral white lesions among 20,333 adult Swedish people. Comm. Dent. Oral Epidemiol. 15 (1987) 46 BilnOczy, J.: Follow-up studies in oral leukoplakia. J. Max.-Fac.Surg. 5 (1977) 69 Ban6czy, J.: Oral leukoplakia. Martinus Nijhoff, The Hague 1982 Bekke, J. P. H., J. A. Baart" Six years experience with cryosurgery in the oral cavity. Int. J. Oral Surg. 8 (1979) 251 Bouquot, J. E., R.J. Gorlin"Leukoplakia, lichen planus and other oral keratoses in 23, 616 white Americans over the age of 35 years. Oral Surg. 61 (1986) 373 Burkhardt, A." Advanced methods in the evaluation of premalignant lesions and carcinomas of the oral mucosa. J. Oral Pathol. 14 (1985) 751
Oral Leukoplakia, with Emphasis on Malignant Transformation
J. Cranio-Max.-Fac. Surg. 17 (1989)
133
Einhorn, J., J. Wersiill: Incidence of oral carcinoma in patients with
Schwenzer, N.: Konservative und operative Behandlung der Leuko-
leukoplakia of the oral mucosa. Cancer 20 (1967) 2189 Gongloff, R.K., A.A. Gage: Cryosurgical treatment of oral lesions: report of cases. J. A. D. A. 106 (1983) 47 Hammersley, N., M.M. Ferguson, J.S. Rennie: Topical bleomycin in the treatment of oral leukoplakia: a pilot study. Br. J. Oral Maxillofac. Surg. 23 (1985) 251 Hermanek, P., L.H. Sobin (Eds.): TNM-classification of malignant tumors, 4th ed. International Union Against Cancer. Springer Verlag, Berlin 1987 Horch, H.-H., K.L. Gerlach, H.-E. Schaefer: CO2 laser surgery of oral premalignant lesions. Int. J. Oral Maxillofac. Surg. 15 (1986) 19 Kramer, L R. H., N. EI-Labhan, K. W. Lee: The clinical features and risk of malignant transformation in sublingual keratosis. Brit. Dent. J. 144 (1978) 171 Mashberg, A.: Clinical features of oral malignancy in relation to prognosis. In: Mackenzie, Dabelsteen, Squier (Eds.): Oral Premalignancy. University of Iowa Press, Iowa City 1980 Moertel, C.G., E.L. Foss: Multicentric carcinomas of the oral cavity. Surg. Gynecol. Obstet. 106 (1958) 652 Pindhorg, J. J.: Oral cancer and precancer. Wright, Bristol 1980 Pindhorg, J. J., J. Reihel, P. Holmstrop: Subjectivity in evaluating oral epithelial dysplasia, carcinoma in situ and initial carcinoma. J. Oral Pathol. 14 (1985) 698 Roch-Berry, C. S. B.: Malignant changes in glossal leukoplakia. Clin. Radiol. 32 (1981) 693 Roed-Petersen, B.: Cancer development in oral leukoplakia. Follow-up of 331 patients. J. Dent. Res. 50 (1971) 711 Roodenburg, J.L.N.: CO2-1aser chirurgie van leukoplakie van het mondslijmvlies. Thesis. University Groningen, The Netherlands 1985
plakie der Mundh6he. In: Arnal et al.: Die Therapie des Mundh6hlenkarzinoms. Fortschr. Kiefer-Gesichtschir. 13 (1968) 140 Sharer, W.G., C.A. Waldron: Erythroplakia of the oral cavity. Cancer 36 (1975) 1021 Shklar, G.: Oral leukoplakia. N. Engl. J. Med. 315 (1986) 1544 Silverman, S., M. Gorsky, F. Lozada: Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer 53 (1984) 563 Vedtofte, P., P. Holmstrup, E. Hj6rting-Hansen, J. J. Pindhorg: Surgical treatment of premalignant lesions of the oral mucosa. Int. J. Oral Maxillofac. Surg. 16 (1987) 656 Waldron, C.A., W.G. Sharer: Leukoplakia revisited. A clinicopathologic study of 3256 oral leukoplakias. Cancer 36 (1975) 1386 WHO: Collaborating Reference Centre for Oral Precancerous Lesions. Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg. 46 (1978) 517 Wright, A., M. Shear: Epithelial dysplasia immediately adjacent to oral squamous carcinomas. J. Oral Pathol. 14 (1985) 559
W. F.C. Hogewind, D.M.D. Department of Oral Surgery Free University Hospital Postbus 7057 I007 MB Amsterdam The Netherlands
J. Cranio-Max.-Fac. Surg. 17 (1989)
J. Cranio-Max.-Fac. Surg. 17 (1989) 128-133 © Georg Thieme Verlag Stuttgart • New York
Oral Leukoplakia, with Emphasis on Malignant Transformation A Follow-Up Study of 46 Patients Willern F. C. Hogewind, Willem A.M. van der Kwast, Isaac van der Waal Dept. of Oral Surgery (Head: Prof. Dr. W. A. M. van der Kwast, D.M.D.) Oral Pathology (Head: Prof. Dr. I. van der Waal, D.M.D.), Teaching Hospital, Free University/ACTA, Amsterdam, The Netherlands. Submitted 2 2 . 2 . 8 8 ; accepted 5 . 7 . 8 8
Introduction Leukoplakia is a clinical descriptive term; its use carries no implications with respect to the histological findings. It has recently been defined as "a whitish patch or plaque that cannot be characterized clinically or pathologically as any other disease and which is not associated with any physical or chemical causative agent except the use of tobacco" (Axkll et al., 1984).
Present concept of oral leukoplakia Oral leukoplakia is a precancerous lesion. The reported rate of malignant transformation is approximately 5 % in an average period of 5 years (Pindborg, 1980). Since the premalignant potential may be related to aetiology, it is thought important to describe aetiological factors (Ax~ll et al., 1984). Thus, lesions that are of unknown aetiology are listed as idiopathic or cryptogenic leukoplakias. Whitish patches or plaques associated with and thought to be the result of the use of tobacco are listed as tobacco-associated leukoplakias, while whitish patches or plaques for which a local cause other than the use of tobacco can be identified are listed according to the known cause and are not termed leukoplakias (AxSll et al., 1984). Examples are frictional lesions, lesions associated with dental restorations and lesions associated with cheek-biting. Only in the case of a residual lesion after treatment, which means that the lesion has become independent of the causes which probably induced it, is the term leukoplakia maintained. The prevalence of oral leukoplakia shows marked geographic differences, ranging from 0 : 4 ~ to 17 : 0 % (Bouquot and Gorlin, 1986). These geographic differences can probably be explained to a large extent by differences in tobacco habits and by the use of different criteria. Leukoplakia seems to be most prevalent in men, with a majority found in the age group of 40-70years (WaIdron and Sharer, 1975; AxbIl, 1987). The most frequently affected oral sites are the buccal mucosa and the labial commissures, and to a lesser extent the lower lip, the alveolar ridge, the tongue, the floor of the mouth and the palate.
Summary A review of oral leukoplakia, based on data from the literature and experience with 84 patients is presented. The leukoplakic lesions of 3 patients developed malignant transformation within an average period of 5 years. All three patients were elderly women with idiopathic leukoplakia, in two cases of the homogeneous and in one case of the non-homogeneous type. The initial biopsy of the former two patients showed only hyperorthokeratosis without epithelial dysplasia. In the first biopsy of the third patient epithelial dysplasia was recorded. One of the patients finally died of widespread metastases. The other two have been treated surgically and are still alive. Key words Oral pathology - Oral leukoplakia - Follow-up Malignant transformation
Leukoplakia may present itself in a localized or diffuse and sometimes even multifocal fashion. Leukoplakia affecting the floor of the mouth or the ventral surface of the tongue is also called sublingual keratosis (Kramer, 1978; Roch-Berry, 1981). Based on the clinical appearance of leukoplakia, a distinction is usually made between a homogeneous type and a non-homogeneous type. Homogeneous leukoplakia is described as a uniformly whitish lesion with a smooth or corrugated surface. The non-homogeneous leukoplakias include: 1. erythroleukoplakia or erosive leukoplakia: a whitish lesion that includes red areas; 2. nodular leukoplakia: a lesion with slightly raised, rounded, red and/or whitish excrescences that may be described as granules or nodules; and 3. verrucous leukoplakia: an exophytic lesion with irregular sharp or blunt projections (AxSll et al., 1984). Both erythroleukoplakia and the nodular type of leukoplakia are also referred to as speckled leukoplakia or speckled erythroplakia, and are, in most instances, associated with candidal infection (AxSll et al., 1984). The histological aspects of oral leukoplakia can vary from hyperkeratosis without epithelial dysplasia to epithelial dysplasia, carcinoma-in-situ and even squamous cell carcinoma (Figs. 1-3). It is recommended that a histological report should always include a statement on the presence of epithelial dysplasia and an assessment of its severity. Various cellular changes that may occur in epithelial dysplasia are described (Pindborg, 1980). Of these, particularly basal cell hyperplasia and disturbed epithelial maturation might have ominous prognostic significance (Wright and Shear, 1985). Based on the histopathologist's interpretation of the presence, degree and significance of dysplastic features, epithelial dysplasia is divided into three categories: mild, moderate and severe (WHO Collaborating Reference Centre for Oral Precancerous Lesions, 1978). Nevertheless, it has not proved possible to devise a scheme for grading dysplasia that gives consistent and reproducible results (Pindborg et al., 1985). Therapy is primarily directed to the elimination of possible causative factors. Biopsy is considered depending on the
Oral Leukoplakia, with Emphasis on Malignant Transformation
Fig.1
Hyperkeratosis without signs of epithelial dysplasia. (HE x 100),
J. Cranio-Max.-Fac.Surg. 17 (1989)
129
Fig.2 Epithelial dysplasia. (HE x 100).
malignant transformation in leukoplakia has been reported (Roed-Petersen, 1971 ; B[znOczy, 1982). Of all these factors, the grade of epithelial dysplasia seems to be the most important indicator of a malignant potential (Burkhardt, 1985). In this contribution a retrospective survey is presented, consisting of a study of 84 patients with oral leukoplakia, who attended the department of Oral and Maxillofacial Surgery at the Free University Hospital, Amsterdam, from 1969 till 1984. In particular, the rate of malignant transformation has been studied. Materials and Methods
Fig.3 Carcinoma-in-situ. (HExlO0).
results of those initial measures. Possible further treatment largely depends on the histopathological findings of such a biopsy and may consist of surgical excision (Scbwenzer, 1968; Vedtofte et al., 1987), cryosurgery (Bekke and Baart, 1979; Gongloff and Gage, 1983), or CO2-1asersurgery (Roodenburg, 1985; Horch et al., 1986). Other treatments, such as the administration of high doses of vitamin A or its derivates (Shklar, 1986) and the topical application of bleomycin (Hammersley et al., 1985), are still in an experimental stage. Both in the treated and untreated patient follow-up examination is mandatory. Certain features of leukoplakia seem to indicate an increased risk of malignant transformation. These are: pain associated with the leukoplakic lesion (Silverman et al., 1984), the absence of smoking habits (Einborn and Wersdll, 1967; Silverman et al., 1984), long duration of the leukoplakia (Silverman et al., 1984), location in the floor of the mouth and/or on the tongue (Kramer, 1978; Roch-Berry, 1981), the clinical non-homogeneous type (Sharer and Waldron, 1975; Mashberg, 1980; Silverman et al., 1984), the presence of epithelial dysplasia and the history of a previous oral cancer. (Moertel and Foss, 1958). Besides, a so far unexplained female preponderance of
The 84patients with oral leukoplakia involved in this study were selected retrospectively from the files of the department of Oral and Maxillofacial Surgery at the Free University Hospital, Amsterdam from 1969 until 1984. Leukoplakia was defined, as mentioned earlier in this study, as "a whitish patch or plaque that cannot be characterized clinically or pathologically as any other disease and which is not associated with any physical or chemical causative agent except the use of tobacco" (Ax~ll et al., 1984). A tobacco user was defined as any person who smoked at least 5 cigarettes a day or the equivalent in cigars, pipes or any other tobacco products. None of the patients had been treated for their leukoplakia before. Cases of leukoplakia associated with squamous cell carcinoma were excluded from this study. Age, sex, reason for referral, smoking habits, duration of the lesion, site and clinical appearance were recorded (Tables 1-6). The presence or absence of symptoms could not be retrieved reliably. The sites were specified according to anatomical distribution as recommended by the UICC (Hermanek and Sobin, 1987). In all patients, biopsies were taken either at the first visit or during follow-up, partly for academic reasons. In the case of non-homogeneous leukoplakia, a biopsy was usually taken at the first visit (Table 7). In the interpretation of epithelial dysplasia, use was made of the 12 criteria as listed by the WHO Collaborating Reference Centre for Oral Precancerous Lesions (WHO Collaborating Reference Centre for Oral Precancerous Lesions, 1978). The possible presence and degree of dysplasia has in all but three pa-
13 0
J. Cranio-Max.-Fac. Surg. 17 (1989)
W.F.C. Hogewind et al.
Table1 plakia
Age and sex distribution of 84 patients with oral leuko-
age (years)
m
f
0-15 16-30 31-45 46-60 >60
5 12 13 20
1 5 11 17
total
50 (59.5 %)
34 (40.5 %)
Table 2
homogeneous non-homogeneous not specified
31 45 8
Table8 Distribution of aetiological factors in 84 patients with oral leukoplakia. tobacco habits no tobacco habits tobacco habits not specified
Duration of oral leukoplakia in 84patients.
1-4 weeks 1-6 months > V2year not specified
Table 5 to site.
41 9 34
homogeneous
Distribution of 84 patients with oral leukoplakia according
buccal mucosa tongue commissure palate lower alveolar ridge floor of the mouth upper alveolar ridge lower lip (vermilion border) pharynx combinations not specified
hyper (ortho/para) keratosis without dysplasia dysplasia, slight dysplasia, moderate dysplasia, severe dysplasia, not graded not specified or no biopsy taken total
Table 8 4 11 13 56
12 10 6 4 4 3 3 3 2 35 2
dents been recorded as mild, moderate or severe. The histological sections of the three cases with unspecified dysplasia were not available for review. In the case with epithelial dysplasia present treatment by cryosurgery or coldknife surgery was instituted. Follow-up visits were scheduled at 3 - 6 months intervals. Thirty-eight patients were lost to follow-up or erroneously dismissed within one year. The follow-up period for the remaining group of 46 patients varied from 1 to 8 years, with an average of 2 ~ years.
11 22 51
Table7 Relationship between clinical type and histological changes in 46 patients with oral leukoplakia.
Reasons of referral in 84 patients with oral leukoplakia.
white lesion incidental finding not specified
Table4
Table6 Classification of oral leukoplakia in 84 patients according to clinical type.
nonhomogeneous
not total specified
4
2
16
22
1 -
1 3 3 -
1 1 3
2 3 5 3
5
4
2
11
10
13
23
46
Data of the 3 patients with malignant transformation.
sex age reason for referral tobacco habits location
clinical appearance epithelial dysplasia observation period (years)
1
2
3
f 79 leukoplakia and pain none lateral border of the tongue with extem sion into the floor of the mouth homogeneous
f 73 leukoplakia and pain none lateral border of the tongue with extension into the floor of the mouth non-homogeneous
f 79 leukoplakia and pain none lateral border of the tongue with extension into the floor of the mouth homogeneous
none
slightmoderate
none
7
2~
3
Results Three of the remaining 46 patients, all elderly, non-smoking women, subsequently developed squamous cell carcinoma. Two were referred because of leukoplakia with associated discomfort, the third because of discomfort only. In all three patients, the leukoplakic lesions were situated on the lateral border of the tongue and in the floor of the mouth. Two were of a homogeneous and one of a nonhomogeneous type (Figs. 4 a - 6 a). The biopsies of the homogeneous leukoplakias, taken at the first visit, showed no
Oral Leukoplakia, with Emphasis on Malignant Transformation
J. Cranio-Max.-Fac. Surg. 17 (1989)
131
Fig.4a
Homogeneous leukoplakia on lateral border of the tongue in patient 1. (see Table 9
Fig.4 b Same patient as in Fig.4a, after 7years.
Fig.5a Non-homogeneous leukoplakia on lateral border of the tongue in patient 2. (see Table 9).
Fig.5b
Fig. 6 a Homogeneous leukoplakia on lateral border of the tongue in patient 3. (see Table 9).
Fig. 6 b Same patient as in Fig, 6 a, after 3 years.
distinct signs of epithelial dysplasia, while the biopsy of the non-homogeneous leukoplakia showed slight to moderate epithelial dysplasia. Review of the initial biopsies of the three patients did not change the original interpretation. In all three patients a wait-and-see policy was followed: in two of them, because of the homogeneous, clinically not suspicious lesions and the absence of epithelial dysplasia. Because of the widespread character of the leukoplakia and the poor general condition of the patient, a wait-and-see policy was adopted in the third patient as well, in spite of the presence of epithelial dysplasia. The carcinomas developed within 21/2 to 7 years after the initial attendance (Figs. 4 b-6 b). Further data on these 3 patients are summarised in Table 8. All three patients were subjected to surgical treatment. In two patients treatment consisted of wide local excision. In the third patient a radical neck dissection was carried out at the same time, because of a clinically suspicious lymph
node. Nevertheless, this patient died of widespread metastases. The other two are still alive, apparently without turnout, 5 years after treatment of their malignancy.
Same patient as in Fig. 5 a, after 2Y2years.
Discussion and Conclusions
Our study has revealed a malignant transformation rate in oral leukoplakias of 3.6 percent during a mean follow-up period of 8 years. This percentage is in accordance with previous studies, showing a frequency of carcinomatous changes in oral leukoplakia that varies between 1.4 and 6percent during an observation period of 1 to 30 years (Pindborg, 1980; B~n6czy, 1982). In view of the retrospective nature of the present study, our findings should be interpreted carefully. On the one hand the total number of patients with leukoplakia who attended the department of Oral Surgery might have largely been under-reported, which would result in a lower rate of malignant transfor-
132
J. Cranio-Max.-Fac. Surg. 17 (1989)
Table9 Age distribution of 65,000 patients, referred to the department of Oral Surgery at the Free University Hospital, Amsterdam, during the period June 1968- June 1981, in a random sample of 2,000 patients (Allard, 1982). age
males
females
0-15 16-30 31-45 46-60 > 60
3.07* 24.73 10.32 5.25 2.19
3.12 33.86 9.09 5.24 3.06
total
45.6
54.4
= Figures represent percentages
mation. On the other hand the present series of leukoplakias may erroneously comprise a number of lesions that belong to the category of "other diagnosable lesions", which would result in a higher rate of malignant transformation. Besides, the patients presented in this study form part of a selected population. Furthermore, the information collected from the files was rather incomplete. Another point of concern is the relatively large number of 38 patients who were lost to follow-up. To the best of our knowledge no malignant transformation has taken place in those patients. Our total leukoplakia group comprised more men than women, while the sex distribution of the population of the out-patients of the Department of Oral Surgery actually showed a slight female preponderance (Table 9). The male preponderance in our group is of statistical significance (p < 0.05) and corresponds to that of several other studies (Waldron and Shafer, 1975; Pindborg, 1980; Ax~ll, 1987). In view of this sex distribution, the occurrence of malignant transformation in all three cases in women, points to female prevalence of malignant transformation in leukoplakia, as has been reported by others as well (Roed-Petersen, 1971; B~n6czy, 1982). Most patients were older than 45 years, which is in accordance with previous investigations showing a peak incidence above the age of 50 years (Roed-P etersen, 1971 ; Waldron and Sharer, 1975; Axkll, 1987). The average age of the three patients with carcinoma developing from leukoplakia was 77 years at the time of diagnosis of malignancy. This age was higher than the average age of 51years (range 23-82years) of the leukoplakia group as a whole and points to a certain latency period, which elapses between the onset of leukoplakia and the diagnosis of carcinoma (Einhorn and Wersdll, 1967; B[~n6czy, 1982). Of the 34women and 50 men with oral leukoplakia 12 (35 %) and 29 (58 %) respectively were smokers. This is a smaller percentage than commonly reported among patients with leukoplakic lesions. From these figures one may conclude that the role of smoking as the most important factor in the aetiology of leukoplakia is somewhat debatable (Axkll et al., 1984). The three women whose leukoplakia showed malignant transformation all belonged to the group of non-smokers. This increased risk of development of carcinoma in patients with oral leukoplakia who have never smoked is consistent with previous reports (Einhorn and WersMl, 1967; Roed-Petersen, 1971; B~n6czy, 1982; Silverman et al., 1984).
W.F.C. Hogewind et al. The most frequent sites of oral leukoplakia are the buccal mucosa and the commissures, as demonstrated in a Hungarian study of 670 cases of oral leukoplakia, in which the tongue was only affected in a small percentage of cases (B~nOczy, 1977). In the present material there is not only a preference for the buccal mucosa and the commissures, but also for the tongue. When considering the site-distribution in the three women who developed carcinoma it is striking that in all three patients the cancer was situated on the lateral border of the tongue and in the floor of the mouth. This preference for the tongue is in accordance with other studies (Waldron and Shafer, 1975; Kramer, 1978; Roch-Berry, 1981). Of the 46patients who have been followed for more than one year, eight had moderate or severe dysplasia (Table 7). Most of these patients were treated by surgical excision. During the period of observation no recurrences were observed. It should be realized, however, that the average follow-up period of 21/2years is rather a short one in this respect. The results, therefore, do not permit one to state that treatment of dysplastic epithelial tissue does indeed prevent the future development of a squamous cell carcinoma. In one patient with homogeneous leukoplakia the initial biopsy showed distinct features of epithelial dysplasia (Table 7), which finding illustrates that one cannot assess reliably the histopathological nature of leukoplakia on clinical grounds alone. For the same reason the clinical use of the term "sublingual keratosis" can be questioned. From the fact that the initial biopsies of two of the three patients who developed a carcinoma showed no epithelial dysplasia, one may conclude that carcinomatous transformation may take place even in non-dysplastic epithelium (Pindborg, 1980). However, one should realise that subjectivity plays a role in the histological diagnosis of dysplasia (Pindborg et al., 1985) and that one actually might have been dealing with some degree of epithelial dysplasia in these two cases. Besides, it is possible that the biopsies were not representative. The period in which a carcinoma developed varied from 2 ~ to 7 years and this emphasizes the importance of longterm follw-up, even in the case of apparently clinically and histopathologically innocuous leukoplakias.
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W. F.C. Hogewind, D.M.D. Department of Oral Surgery Free University Hospital Postbus 7057 I007 MB Amsterdam The Netherlands