Oral Oncology Vol. 33, No. 5, pp.

291 301, 1997

Pergamon PII: S0964-1955 (97)00002-X

~' 1997 Elsevier Science Ltd. All rights reserved Printed in Great Britain 1368-8375/97 $17.00 + 0.00

Reviews Oral Leukoplakia: a C l i n i c o p a t h o l o g i c a l Review

I. van der Waal, K. P. S c he pm an , E. H. van der Meij and L. E. Smeele
Department o f O r a l & M a x i l l o f a c i a l S u r g e r y / P a t h o l o g y , U n i v e r s i t y H o s p i t a l Vrije U n i v e r s i t e i t / A C T A , Amsterdam, The Netherlands

L e u k o p l a k i a is t h e m o s t c o m m o n p r e m a l i g n a n t o r p o t e n t i a l l y m a l i g n a n t l e s i o n o f t h e o r a l m u c o s a . I t s e e m s p r e f e r a b l e to u s e t h e t e r m l e u k o p l a k i a as a c l i n i c a l t e r m o n l y . W h e n a b i o p s y is t a k e n , t h e term leukoplakia should be replaced by the diagnosis obtained histologically. The annual percentage of malignant t r a n s f o r m a t i o n v a r i e s in d i f f e r e n t p a r t s o f t h e w o r l d , p r o b a b l y a s a r e s u l t o f d i f f e r e n c e s in t o b a c c o a n d d i e t a r y h a b i t s . A l t h o u g h e p i t h e l i a l d y s p l a s i a is a n i m p o r t a n t p r e d i c t i v e f a c t o r o f m a l i g n a n t t r a n s f o r m a t i o n , i t s h o u l d b e r e a l i z e d t h a t n o t a l l d y s p l a s t i c l e s i o n s will b e c o m e m a l i g n a n t . O n t h e o t h e r h a n d n o n - d y s p l a s t i c l e s i o n s m a y b e c o m e m a l i g n a n t as w e l l . I n s o m e p a r t s o f t h e world the tongue and the floor of the mouth can be considered t o b e h i g h - r i s k sites w i t h r e g a r d t o m a l i g n a n t t r a n s f o r m a t i o n o f l e u k o p l a k i a , w h i l e t h i s d o e s n o t h a v e t o b e t h e c a s e in o t h e r p a r t s o f the world. The cessation of tobacco habits, being the most common known aetiological factor of oral l e u k o p l a k i a , h a s b e e n s h o w n t o b e a n e f f e c t i v e m e a s u r e w i t h r e g a r d to t h e i n c i d e n c e o f l e u k o p l a k i a a n d , t h e r e b y , t h e i n c i d e n c e o f o r a l c a n c e r as w e l l . S c r e e n i n g f o r o r a l p r e c a n c e r m a y b e i n d i c a t e d in i n d i v i d u a l s a t r i s k . (c, 1997 E l s e v i e r S c i e n c e L t d Key words: oral leukoplakia, precancerous lesion, epithelial dysplasia
Oral Oncology, Vol. 33, N o . 5, p p . 2 9 1 - 3 0 1 ,
1997

INTRODUCTION T h e present review of oral leukoplakia is largely based on personal experience both with the clinical and histopathological aspects, and on the literature about this subject during the last 30 years, without an attempt at complete coverage. Owing to the influence that tobacco habits and dietary products may have on the oral mucosa, it should be realized that lesions of the oral mucosa, including leukopakia, may show geographical and ethical differences, both with regard to the clinicopathological appearances and the biological behaviour.

m a d e when a lesion at clinical examination cannot be clearly diagnosed as any other disease of the oral mucosa with a white appearance; a definitive diagnosis of oral leukoplakia is made as a result of the identification, and if possible elimination, of suspected aetiological factors and, in the case of persistent lesions, histopathological examination [1]. W h e n the whiteness is not very distinct, the term preleukoplakia is sometimes used, not to be confused with leukoedema. Histopathological examination of a clinically diagnosed leukoplakia serves two purposes: (1) to exclude any other, definable, lesion, e.g. lichen planus; and (2) to establish the degree of epithelial dysplasia, if present. In the presence of carcinoma in situ or invasive carcinoma the clinical diagnosis of leukoplakia is replaced by the diagnosis obtained histologically [2, 3]. It seems preferable to follow the same concept in case of other histological findings, particularly with regard to the presence or absence of epithelial dysplasia. As a result, one may then recognize a (white) non-dysplastic or dysplastic lesion. In that way, the term leukoplakia remains a clinical term only and its use thus carries no implications with regard to the histological findings, which is in accordance with previous r e c o m m e n d a t i o n s [2, 3].

DEFINITION A N D TERMINOLOGY
Leukoplakia
Oral leukoplakia has recently been redefined as " a predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion; some oral leukoplakias will transform into cancer" [1]. In that report, a distinction was m a d e between a provisional diagnosis of oral leukoplakia and a definitive one. A provisional diagnosis is Correspondence to I. van der Waal. Received 8 Nov. 1996; provisionally accepted 14 Nov. 1996; revised manuscript received 11 Dec. 1996.

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I. v a n d e r Waal et al.

Definable white lesions I n the various definitions of oral leukoplakia reference is m a d e to " o t h e r diseases" or " d e f i n a b l e l e s i o n s " [1-3]. In daily practice the clinical a n d histopathological features o f white oral lesions are n o t always characteristic; a n u m b e r o f cases c a n n o t b e classified with certainty as a " d e f i n a b l e lesion". A few of the white lesions listed in T a b l e 1 deserve f u r t h e r a t t e n t i o n with regard to definition a n d terminology. Hype~olastic candidiasis versus Candida-associated leukoplakia. T h e r e is n o c o n s e n s u s in the literature w h e t h e r or n o t to recognize a hyperplastic s u b t y p e o f candidiasis. W h e n dealing with a hyperplastic epithelial lesion in w h i c h the p r e s e n c e of Candida albicans is d e m o n s t r a t e d , s o m e a u t h o r s prefer to refer to s u c h lesions as C a n d i d a - a s s o c i a t e d leukoplakias while others prefer the t e r m hyperplastic candidiasis [4]. In t h e a b s e n c e of clinical r e s p o n s e to antifungal t r e a t m e n t , it seem preferable to c o n s i d e r such lesion a leukoplakia. Hairy leukoplakia ("Greenspan lesions"). T h e t e r m " h a i r y l e u k o p l a k i a " is u n f o r t u n a t e for several reasons. First of all, hairy leukoplakia is a definable lesion [5, 6]. F u r t h e r m o r e , the lesion is n o t a p r e m a l i g n a n t one. T h e r e f o r e , the use of the t e r m hairy leukoplakia s h o u l d b e a b a n d o n e d . As a n alternative, the t e r m " G r e e n s p a n lesion" has b e e n suggested [7]. Tobacco-induced white lesions. Smoker's palate ( " l e u k o k e r a t o s i s n i c o t i n a p a l a t i " ) , palatal keratosis in reverse smokers, a n d s n u f f d i p p e r s ' lesions are clearly related to t o b a c c o use and, therefore, are usually listed as " t o b a c c o - i n d u c e d l e s i o n s " [1, 2]. T h e s e lesions are b e i n g r e g a r d e d as " d e f i n a b l e l e s i o n s " a n d are traditionally n o t described as leukoplakia [8]. Nevertheless, some of these lesions m a y t r a n s f o r m into cancer. A p p a r e n t l y , this is n o t the case for s m o k e r ' s palate, while it is for palatal lesions in reverse smokers. T h e possible p r e m a l i g n a n t n a t u r e of s n u f f d e p e n d s o n the type of s n u f f a n d possibility also o n o t h e r factors, s u c h as various ingredients t h a t m a y have b e e n a d d e d to the snuff [9 11].

Tobacco-associated leukoplakia; idiopathic leukoplakia. W i t h regard to white lesions o t h e r t h a n the t o b a c c o - i n d u c e d white lesions m e n t i o n e d previously, the aetiological role of t o b a c c o in p a t i e n t s w h o s m o k e cigarettes, cigars or pipes is less obvious [12, 13]. T h e r e f o r e , preference has b e e n given to t h e t e r m " t o b a c c o - a s s o c i a t e d leukoplakia" (leukoplakia in smokers) above the t e r m " t o b a c c o - i n d u c e d white l e s i o n " [2]. As a result, o n e also recognizes n o n - t o b a c c o associated leukoplakia (leukoplakia in n o n - s m o k e r s ) , often referred to as idiopathic leukoplakia. W h e t h e r this s u b t y p i n g is of any clinical relevance, is still to b e d e t e r m i n e d . F u r t h e r m o r e , the issue b e c o m e s even m o r e c o m p l e x in cases of m i x e d habits of t o b a c c o chewing a n d smoking.

Premalignant, precancerous or potentially malignant lesion Oral leukoplakia is r e g a r d e d to b e a p r e m a l i g n a n t or, s y n o n y m o u s l y , a potentially m a l i g n a n t or p r e c a n c e r o u s lesion. A p r e c a n c e r o u s lesion has b e e n defined as a m o r p h o logically altered tissue in w h i c h c a n c e r is m o r e likely to o c c u r t h a n in its apparently n o r m a l c o u n t e r p a r t [14]. H o w e v e r , n o o d d ratios have b e e n m e n t i o n e d in the literature t h a t w o u l d define " m o r e likely to o c c u r " . I n two studies from India, r a t h e r low a n n u a l m a l i g n a n t t r a n s f o r m a t i o n rates of oral leukoplakia have b e e n reported, 0.3% [15] a n d a 0 . 0 6 % [16], respectively. In reports from W e s t e r n countries, usually b a s e d o n hospital material, s o m e w h a t h i g h e r figures have b e e n m e n t i o n e d [17-25]. As stressed by G u p t a et al. [15, 26], one m u s t take into a c c o u n t , w h e n s t u d y i n g p e r c e n t a g e s of m a l i g n a n t t r a n s f o r m ation rates of oral leukoplakia: (1) the l e n g t h of o b s e r v a t i o n period; (2) the type of study p o p u l a t i o n ; a n d (3) the t h e r a peutic a p p r o a c h . O n the basis of the lowest r e p o r t e d a n n u a l m a l i g n a n t t r a n s f o r m a t i o n rate of oral leukoplakia, it can be calculated t h a t patients with oral leukoplakia carry a 5-fold higher risk of developing oral c a n c e r t h a n controls [16]. W h e t h e r this increased risk is sufficiently h i g h to m e e t criteria of " m o r e likely to o c c u r " , as m e n t i o n e d in the definition of a p r e c a n cerous lesion, r e m a i n s an o p e n question.

Table 1. The most common definable white or predominantly white lesions of the oral mucosa and their main diagnostic criten'a
Lesion Candidiasis, pseudomembranous* Discoid lupus erythematosus Frictional lesion Hairy leukoplakia ("Greenspan lesion") Lesion associated with dental restoration (incl. "galvanic lesion") Leukoedema Lichen planus, reticular and plaque type Linea alba Morsicatio (habitual chewing or biting of the cheeks, tongue, lips) Papilloma and allied lesions Syphilis, secondary ("mucous patches") Tobacco-induced lesions Smoker's palate Palatal lesions in reverse smoking Snuff dippers' lesion White sponge nevus Main diagnostic criteria Clinical aspect (pseudomembranes, often symmetrical pattern) History of skin lesion; clinical appearance (incl. bilateral pattern); histopathology Presence of mechanical irritation (e.g. habit of vigorous toothbrushing) Clinical aspect (incl. bilateral localisation on the tongue); histopathology (incl. EBV) Clinical aspect (relation to dental restoration) Clinical aspect (incl. symmetrical pattern) Clinical aspect (often symmetrical pattern); histopathology Clinical aspect (incl. location on line of occlusion in cheek mucosa) History of habitual biting or chewing; clinical aspect Clinical aspect; histopathology Clinical aspect; demonstration of T. pallidum; serology Clinical aspect; Clinical aspect; Clinical aspect; Family history; history of smoking history of reverse smoking site where snuff is placed Clinical aspect (often symmetrical pattern)

*There is no consensus in the literature whether or not to recognize a hyperplastic subtype of oral candidiasis

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Incidence and prevalence

In a 10 year prospective study in India in large r a n d o m samples, carried out in several geographic areas with various kinds of tobacco usage, the annual age-adjusted incidence rates of leukoplakia per 1000 population per year varied from 1.1 to 2.4 a m o n g m e n and from 0.2 to 1.3 a m o n g w o m e n ; the prevalence varied from 0.2 to 4.9% [15]. In an adult Swedish population a 3.6% prevalence rate was recorded [27].

Age and gender

T h e onset of leukoplakia usually takes place after the age of 30 years, resulting in a peak incidence above the age of 50 years, as shown in a large sample of leukoplakia with a data resource based on surgical pathology reports [28]. T h e gender distribution in most studies varies, ranging from a strong male p r e d o m i n a n c e in different parts in India, to almost 1:1 in the Western world. AETIOLOGY T h e possible role of tobacco has been previously mentioned. W h e t h e r the use of alcohol by itself is an independent aetiological factor in the d e v e l o p m e n t of oral leukoplakia, is still questionable [29-33]. T h e role of C. albicans as a possible aetiological factor in leukoplakia and its possible role in malignant transformation is still unclear [34 37]. In recent years, the possible contributory role of viral agents in the pathogenesis of oral leukoplakia has also been discussed, particularly with regard to exophytic, verrucous leukoplakia [38, 39]. In a study from India, serum vitamin levels of vitamin A, B12, C, beta carotene and folate acid were significantly decreased in patients with oral leukoplakia c o m p a r e d to controls, whereas serum vitamin E was not [40]. Fresh fruits and vegetables may have a protective effect in the primary prevention of oral cancer and precancer. Relatively little is yet known with regard to possible genetic factors in the d e v e l o p m e n t of oral leukoplakia [41]. CLINICAL ASPECTS Leukoplakias may occur either as a single, localised change of the oral mucosa or as diffuse, often multiple, lesions. T h e site distribution shows world-wide differences, that are partly related to gender and tobacco habits [15, 16, 18, 42]. In fact, any oral site may be affected. In general, two clinical variants of leukoplakia are being recognized, the h o m o g e n e o u s and the n o n - h o m o g e n e o u s type. Transitions or changes a m o n g the different clinical variants of oral leukoplakia may occur [43, 44]. H o m o g e n e o u s leukoplakia has been defined as a predominantly white lesion of uniform flat, thin appearance that may exhibit shallow cracks and has a smooth, wrinkled or corrugated surface with a constant texture throughout [1]. It should be emphasised that the adjective " h o m o g e n e o u s " not only applies to the h o m o g e n e o u s whitish colour of the lesion, but above all, to a flat, thin, and rather smooth surface. It does not apply to verrucous, papillary or exophytic lesions that otherwise may have a h o m o g e n e o u s colour or texture. T h o s e lesions are considered n o n - h o m o g e n e o u s leukoplakias. N o n - h o m o g e n e o u s leukoplakia has been defined as a predominantly white or white-and-red lesion ("erythroleu-

koplakia") that may be irregularly flat, nodular or exophytic. T h e nodular lesions are characterized by white patches or nodules on a erythematous base [45], while the exophytic lesions have irregular blunt or sharp projections [1]. T h e adjective " n o n - h o m o g e n e o u s " is applicable both to the aspect of colour, i.e. a mixture of white and red changes ("erythroleukoplakia") and to the aspect of texture, i.e. exophytic, papillary or verrucous. With regard to the latter lesions, no reproducible clinical criteria can be provided to distinguish (proliferative) verrucous leukoplakia from the clinical aspect of verrucous hyperplasia or verrucous carcin o m a [46, 47]. Furthermore, a diagnosis of proliferative verrucous leukoplakia can only be m a d e retrospectively after new lesions have developed [48]. T h e h o m o g e n e o u s type is usually otherwise asymptomatic, whereas the n o n - h o m o g e n e o u s (mixed white and red) leukoplakias are often associated with mild complaints of localised pain or discomfort. In the presence of redness or palpable induration, malignacy may already be present. DIAGNOSTIC PROCEDURES

Elimination of possible cause(s)

W h e n faced with a patient with a white lesion of the oral mucosa, the clinician will first try to rule out any of the definable white lesions listed in Table 1 before accepting a definitive clinical diagnosis of leukplakia. F o r instance, in the case of a n o n - h o m o g e n e o u s white and red lesion, the result of antifungal treatment may be awaited for a period of 2 - 4 weeks. A 2 - 4 week interval to observe the possible regression or disappearance of a white lesion after elimination of possible causative factors, including smoking habits, seems a fully acceptable period of time for the general practitioner before taking a biopsy or before referring the patient to a specialist for further advice. It is well recognized that the time to regress may in some cases be m u c h longer than the 2 - 4 weeks m e n t i o n e d previously. O n the other hand, it may be hazardous to just observe a whitish lesion longer than such a period without having taken a biopsy.

The biopsy
In h o m o g e n e o u s leukoplakia the value of histological examination might to some extent be questioned. T h e occurrence of epithelial dysplasia is rather low in this clinical subtype, as is the risk of future malignant transformation. However, even the experienced clinician will occasionally be surprised by the histopathological findings of a clinically innocent looking h o m o g e n e o u s leukoplakia. Therefore, the taking of a biopsy in h o m o g e n e o u s leukoplakia should be the standard rule. It usually suffices to take just one biopsy or to perform a conservative excisional biopsy, if that is feasible. If treatment consists of CO2-1aser evaporation it is mandatory to have a biopsy taken prior to such treatment. In n o n - h o m o g e n e o u s leukoplakias, that are usually symptomatic, epithelial dysplasia or even carcinoma in situ or early squamous cell carcinoma is rather c o m m o n . T h e biopsy should be taken at the site of symptoms, if present, and/or at a site of redness or induration. Biopsies of exophytic, verrucous or papillary lesions should be taken deep enough to include a sufficient a m o u n t of underlying connective tissue, and preferably from the margins. T h e problem in such lesions is not so m u c h the histological evaluation of the presence of epithelial dysplasia--which is usually not the case but of the possible invasive nature of the lesion.

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I. van der Waal et al. gress to squamous cell carcinoma. It is beyond the scope of this paper to discuss in detail the histopathological aspects of verrucous carcinoma, verrucous hyperplasia and papillary squamous cell carcinoma and the difficulty one may have to distinguish these entities from each other, if possible at all. F o r instance, some consider verrucous hyperplasia an early stage of verrucous carcinoma [57, 58], while others do make a distinction between verrucous hyperplasia and verrucous carcinoma, but notice that these entities may coexist [47]. Therefore, a note should be added to the histopathological report that some of the exophytic, verrucous or papillomatous lesions, in spite of the absence of epithelial dysplasia, may in time progress to squamous cell carcinoma and that long-term follow-up should be considered. At times, it may be difficult to arrive at or to exclude one of the definable lesions m e n t i o n e d in Table 1. T h e final diagnosis of a white lesion of the oral rnucosa can often only be m a d e through a close dialogue between the clinician and the pathologist. Even then, cases may remain unsettled.

T h e biopsy specimen can be placed in a regular fixative m e d i u m . In order to allow proper orientation of the often small mucosal biopsy, stretching the tissue on a piece of cardboard in the direction in which the slides have to be cut, is very helpful. T h e fresh biopsy specimen will stick to the cardboard by itself, which then should be placed upside down in a jar with the formalin. A written clinical history and description of the lesion and its oral subsite should a c c o m p a n y the specimen to the laboratory, together with information about possible (tobacco) habits. Diagnostic methods other than histological examination, such as the use of toluidine blue staining or Lugol's iodine, and exfoliative cytology are of limited value when dealing with leukoplakia [49 52]. HISTOPATHOLOGICAL ASPECTS T h e histopathological aspects of leukoplakia may vary from atrophy of the epithelium to hyperplasia with or without hyperkeratosis. Epithelial dysplasia, if present, may range from mild to severe. In some instances, carcinoma in situ and even squamous cell carcinoma are encountered histologically. T h e various cellular changes that may occur in epithelial dysplasia are listed in Table 2. Some authors consider a change in the microvascularisation and/or an increase in the n u m b e r of subepithelial lymphocytes, plasmacells, Langerhans' cells and interepithelial cells, and the presence of Candida organisms additional indicators of dysplasia. T h e clinical significance of h u m a n papillomavirus-associated epithelial dysplasia, so-called koilocytic dysplasia, remains to be investigated [53]. Dysplastic epithelium may show features that to some extent resemble those of lichen planus; some authors refer to such an event as "lichenoid dysplasia" [54]. In the presence of the use of tobacco, the often so-called chevron type of keratinisation is observed [55, 56]. Exocytosis of inflammatory cells in the epithelium is u n c o m mon. In the presence of C. albicans the formation of microabcesses may be observed in the superficial layers of the epithelium. White or whitish lesions that clinically and/or histopathologically have an exophytic, verrucous or papillomatous architecture and in which no distinct signs of epithelial dysplasia are present at the light microscopic level, may pro-

Grading of epithelial dysplasia

Based on the histopathologist's interpretation of the presence of dysplastic features, epithelial dysplasia is usually divided into three categories: mild, moderate and severe. It has been observed that the degree of epithelial dysplasia correlates with the age of the patient [59]. Until now, it has not been possible to devise a scheme for grading epithelial dysplasia that gives consistent and reproducible results [60 63], the main reason being the subjectivity of the assessment of the components of epithelial dysplasia as listed in Table 2. T h e r e may be, indeed, a strong interobserver discrepancy between pathologists in the evaluation of the presence and the degree of epithelial dysplasia [62, 63]. Nevertheless, it is r e c o m m e n d e d that the histological report of a leukoplakia should include a statem e n t on the absence or presence of epithelial dysplasia and an assessment of its severity [2]. T o some extent, the practical value of the grading of epithelial dysplasia is questionable. Although leukoplakias with m o d e r a t e or severe epithelial dysplasia show a greater disposition for malignant transformation than in the absence of dysplastic features, carcinomatous transformation may also take place in non-dysplastic leukoplakias [19, 46, 64 66].

Other examination techniques

In a review of advanced methods in the evaluation of premalignant lesions of the oral mucosa, it was concluded that the assessment of the biological potential of precancerous lesions still mainly relies on light microscopic histologic examination [64]. Nevertheless, there are many recent publications on promising new biological risk markers [41, 6 7 100].

Table 2. Commonly used histopathological features of epithelial dysplasia. After Kramer et al. [3]
1. Loss of polarity of the basal cells 2. Presence of more than one layer of cells having a basaloid appearance 3. Increased nuclear-cytoplasmic ratio 4. Drop-shaped rete processes 5. Irregular epithelial stratification 6. Increased number of mitotic figures (a few abnormal mitoses may be present) 7. Presence of mitotic figures in the superficial half of the epithelium 8. Cellular pleomorphism 9. Nuclear hyperchromatism 10. Enlarged nucleoli 11. Reduction of cellular cohesion 12. Keratinisation of single cells or cell groups in the prickle layer

MALIGNANT TRANSFORMATION Certain features have been reported to be associated with an increased risk of malignant transformation. These are, in arbitrary order: (1) gender, particularly w o m e n seem to be at risk; (2) long duration of the leukoplakia; (3) leukoplakia in non-smokers (idiopathic leukoplakia); (4) location in the floor of the m o u t h or/and on the tongue; (5) n o n - h o m o geneous type; (6) presence of C. albicans; and (7) presence of epithelial dysplasia.

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Table 3

MANAGEMENT OF ORAL LEUKOPLAKIA (PROVISIONAL CLINICAL DIAGNOSIS)

I
E L I M I N A T I O N OF P O S S I B L E C A U S E ( S )
(2-4 WEEKS

I
NO P O S S I B L E C A U S E ( S ) (DEFINITIVECLINICALDIAGNOSIS) OBSERVATION)

I
GOOD RESPONSE

I
NO R E S P O N S E (DEFINITIVECLINICALDIAGNOSIS) )

I
BIOPSY

DEFINABLE LESION

I
NO D E F I N A B L E L E S I O N DYSPLASIA NO D Y S P L A S I A

DEFINABLE LESION MANAGEMENT ACCORDINGLY

MANAGEMENT ACCORDINGLY

TREATMENT/OBSERVATION FOLLOW-UP

MANAGEMENT O f t h e a b o v e - m e n t i o n e d factors, the p r e s e n c e of epithelial d y s p l a s i a - - m o r e or less correlating with a clinical n o n h o m o g e n e o u s , erythroleukoplakic s u b t y p e - - s e e m s to b e the m o s t i m p o r t a n t i n d i c a t o r of m a l i g n a n t potential. It is generally a c c e p t e d t h a t dysplastic lesions carry a 5-fold greater risk t h a n n o n - d y s p l a s t i c ones. Nevertheless, it s h o u l d be recognized t h a t in a n I n d i a n s t u d y in a m e a n follow-up observation p e r i o d of 7 years, s o m e 6 0 % of the dysplastic lesions r e m a i n e d clinically u n c h a n g e d or even s h o w e d c o m plete regression [15]. I n fact, only s o m e 7% of the dysplastic lesions p r o g r e s s e d to c a n c e r in a m e a n o b s e r v a t i o n p e r i o d of 7 years. O t h e r s h a v e r e p o r t e d similar findings [101]. As has b e e n m e n t i o n e d previously, c a r c i n o m a t o u s t r a n s f o r m a t i o n m a y also take place in n o n - d y s p l a s t i c lesions. A l t h o u g h the p r e s e n c e of C. albicans has b e e n i n d i c a t e d as a risk factor [35, 36], it is r e m a r k a b l e t h a t this m i c r o o r g a n i s m seems to b e particularly p r e s e n t in leukoplakias at t h e c o m m i s s u r e s a n d at the d o r s u m of the tongue. T h e s e sites are r a t h e r rare for s q u a m o u s cell c a r c i n o m a s to o c c u r a n d at the same t i m e are c o m m o n sites for leukoplakia. In several studies o n m a l i g n a n t t r a n s f o r m a t i o n , p a r t i c u larly f r o m the W e s t e r n world, the b o r d e r s of the t o n g u e a n d the floor of the m o u t h have b e e n m e n t i o n e d as so-called high-risk sites. A good example is a r e p o r t o n sublingual keratosis in w h i c h a h i g h m a l i g n a n t t r a n s f o r m a t i o n rate of h o m o g e n e o u s leukoplakia of the floor of the m o u t h was discussed, initially s h o w i n g only hyperkeratosis w i t h o u t epithelial dysplasia [102]. H o w e v e r , in o t h e r parts of the world, subsites o t h e r t h a n the b o r d e r s of the t o n g u e a n d the floor of the m o u t h m a y b e c o n s i d e r e d high-risk sites [15, 16]. It is b e y o n d the scope of this treatise to discuss in d e p t h the q u e s t i o n of w h a t p e r c e n t a g e of oral s q u a m o u s cell carcin o m a s arises f r o m pre-existing lesions, particularly from leukoplakia. Figures f r o m J a p a n a n d the W e s t e r n w o r l d range f r o m 17 [103] to a p p r o x i m a t e l y 3 5 % [104], respectively.
General considerations

As has b e e n discussed previously, m a n a g e m e n t of white oral lesions is primarily directed towards the e l i m i n a t i o n of possible causative factors, e.g. friction, C. albicans, t h u s ruling o u t o t h e r definable lesions ( T a b l e 3). In persisting lesions or in the a b s e n c e of possible causative factors, a biopsy s h o u l d be t a k e n to exclude, histologically, the presence of a definable lesion a n d to establish the degree of epithelial dysplasia, if present, or even the p r e s e n c e of carcin o m a or c a r c i n o m a in situ. It is a n ethical q u e s t i o n w h e t h e r or n o t it w o u l d b e justified in case of persisting t o b a c c o h a b i t s to delay active treatm e n t of oral leukoplakia, w i t h o u t histological evidence of malignancy, as long as the p a t i e n t has n o t given u p those habits. I n the case of mild or a b s e n t epithelial dysplasia, the decision w h e t h e r or n o t to treat m a y be influenced b y the oral subsite. I n the p r e s e n c e of m o d e r a t e or severe epithelial dysplasia, active t r e a t m e n t is usually instituted. S o m e a u t h o r s r e c o m m e n d t r e a t m e n t of each oral leukoplakia, irrespective of t h e degree of epithelial dysplasia or the absence of epithelial dysplasia a n d irrespective of the oral subsite [22]. O n the o t h e r h a n d , o n e m i g h t c o n s i d e r limiting t r e a t m e n t to those cases with distinct signs of malignancy. It has b e e n suggested t h a t m u c o s a l c a r c i n o m a s associated with leukoplakia provide a b e t t e r prognosis t h a t " d e novo " c a r c i n o m a s [104]. Nevertheless, some of these p a t i e n t s will die of their cancer. It r e m a i n s a n o p e n q u e s t i o n w h e t h e r early, active t r e a t m e n t of t h e leukoplakia in s u c h cases w o u l d truly have p r e v e n t e d the o c c u r r e n c e of cancer, a n d w h e t h e r or n o t the m o r b i d i t y of r o u t i n e t r e a t m e n t of all patients with oral leukoplakia o u t w e i g h the d e a t h of a limited n u m b e r of patients. T h e r e are instances w h e r e active t r e a t m e n t of oral leukoplakia c a n hardly b e instituted. T h i s is especially true in extensive leukoplakia t h a t involves m o r e or less the entire

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I. van der Waal et al. necessitating reduction of the dose or temporary abstinence of the drug [115]. Adverse reactions comprise cheilitis, facial erythema, dryness and peeling of the skin, conjunctivitis, photophobia and hypertriglyceridemia. Betacarotene and vitamin E are considerably less toxic than 13cis-retinoid acid [116]. T h e patterns of response and relapse in several studies in which anti-oxident nutrients have been used are quite similar, showing partial and complete remission in 40 60% of the cases [117 123]. T h e topical application of bleomycine is still in an experimental phase [124-127]. T h e same holds true with regard to the systemic use of alpha-tocopherol [128, 129]. Synthetic retinoid N-(4-hydroxyphenyl)-retinamide (4H P R ) in a dosage of 200 m g daily, applied topically, may be effective in the prevention of recurrence of leukoplakia after surgical excision [130, 131]. T h e major drawback for most current agents is the recurrence of lesions when treatment is discontinued [132]. FOLLOW-UP T h e risk of malignant transformation is not completely eliminated by any of the above described treatment modalities. Spreading and malignant transformation of the lesion may take place in spite of treatment, while the n u m b e r of lesions prevented from malignant development is unknown [104]. S o m e verrucous leukoplakias have a strong tendency to recur after conservative surgical excision, being referred to as the previously discussed proliferative verrucous leukoplakia. O n the other hand, some leukoplakias may in time regress or disappear in patients who had no specific treatm e n t and no alteration in habit [12, 13, 15, 16, 19]. N o strict guidelines can be given with regard to duration and frequently of follow-up examinations. In general, long term follow-up examination is advised at 6 - 1 2 m o n t h intervals in patients who have not or not successfully been treated for their leukoplakia [133, 134]. Patients who, after treatment, remain disease free for 3 years need perhaps no longer be followed-up. PREVENTION AND SCREENING T o assess the feasibility of primary prevention of oral cancer, two cohorts were studied in base-line surveys and then followed-up annually for 10 years in the Ernakulam district of Kerala state. T h e intervention cohort consisted of 12,212 tobacco users aged 15 years and over, who were exposed to a concentrated program of education against tobacco use. T h e control cohort was a n o n - c o n c u r r e n t cohort of 6075 tobacco users studied using similar methods, but with a minimal a m o u n t of advice against tobacco use. T h e stoppage of tobacco use increased and the incidence rate of leukoplakia decreased significantly and substantially in the intervention cohort compared to the control cohort. T h e decrease in the incidence of leukoplakia was indicative of the decrease in the risk of oral cancer since the two were intimately related. This study demonstrated the feasibility of primary prevention of oral precancer and cancer [135, 136]. Therefore, primary health care workers are encouraged to carefully search the m o u t h for signs of malignancies and possible precursor lesions, and to encourage a healthy life style, particularly with regard to the abstinence of tobacco habits [137]. Screening is based on the assumption that early diagnosis of precursor lesions (leukoplakia) or small invasive lesions

oral mucosa. Also patient factors may hinder o p t i m u m treatment. Older age in itself does not seem to be a good delineator to decide whether or not to treat a leukoplakia that would otherwise require treatment. In oral leukoplakia in young patients perhaps, a more active treatment strategy is required because of the longer life expectancy.

Treatment modalities
Apart from the surgical excision, various treatment m o d alities are available, such as cryosurgery, CO2-1aser surgery, retinoids and other drugs, and, recently photodynamic therapy [105 108]. T h e latter treatment modality will not be taken into account here because of its rather recent application with regard to oral leukoplakia, not allowing comm e n t on long-term results. Surgical excision. Traditionally, the recommended treatment for oral leukoplakia, with or without epithelial dysplasia, has been surgical excision. Recurrent rates vary from 20 to 35% [109]. Recurrences are often located adjacent to the previous excised lesion, particularly in cases of lesions in the floor of the mouth. Difficulties in determining the proper margin of the lesion and dysplastic epithelium extending into salivary ducts after the surgical excision of the lesion are possible explanations for the comparatively high recurrence rate in these cases [109111]. Cryosurgery. T h e effects of therapeutic freezing u p o n oral lesions have been studied since the early 1960 s. T h e results of treatment vary. Apart from the advantage as an easily applicable outpatient technique, the most important disadvantages are the lack of visual control over the extent in depth of the cryosurgical treatment, the unavailability of an intact specimen for additional histopathological examination and the often occurring pain and edematous swelling in the first two postoperative weeks. With the present availability of CO2-1aser surgery, there is hardly any place anymore for cryosurgery in the treatment of oral leukoplakia. CO2-laser surgery. CO2-1aser surgery can be used to treat leukoplakia either by excision of the lesion and part of the underlying tissue, or by evaporation of the surface epithelium. In the latter case, a biopsy should be taken first. W h e n the added benefits of magnification and precise b e a m control provided by a microscope are considered, CO2-1aser excision permits the possibility of obtaining the entire lesion for histological examination, although the quality of the surgical margins may be slightly jeopardised by CO2-1aser excision. W h e n c o m p a r e d with cold knife excision, the CO2-1aser has certain advantages, especially w h e n large areas of the epithelium are involved. Morbidity is reduced because of the physical properties of laser energy, healing by secondary intention and epithelial regeneration. This minimises w o u n d contraction and impairment of functions due to scar formation. T h e recurrence rates vary from 9 to 22% [112, 113]. In a retrospective evaluation of 167 consecutive patients with oral leukoplakias, there were 69 unfavourable events within 5 years: 31 recurrences, 27 new lesions, 5 carcinomas and 6 other neoplasms elsewhere [112].

Vitamin A, retinoids, beta-carotene, vitamin E, bleomycin, alpha-tocopherol. It has been shown that oral leukoplakia can
be successfully treated with vitamin A [114]. Disadvantage of vitamin A acid and its derivates is its toxicity,

Oral Leukoplakia

297

Table 4. LSCP-classification and staging system for oral leukoplakia [139]

1st symbol: L = extent of the lesion Lo = no evidence of lesion L1 = lesion < 2 cm L2 = lesion 2 - 4 cm L3 = lesion >_ 4 cm Lx = not specified 2nd symbol: S = site of lesion S~ = all oral sites, except for the floor of the m o u t h and tongue $2 = floor of the m o u t h and/or tongue Sx = not specified 3rd symbol: C = clinical aspect C1 = h o m o g e n e o u s Cz = n o n - h o m o g e n e o u s Cx -- not specified 4th symbol: P = histopathological features of biopsy, if taken P1 = no dysplasia Pz = mild dysplasia P~ = moderate dysplasia P4 = severe dysplasia P~ = not specified Staging is only performed in leukoplakias that have been examined histopathologically Stage 1 Stage 2 any L, $1, C~, P h or P2 any L, $1, C2, Pt, or P2 any L, $2, C~, P~, or P2 Stage 3 any L, 82, C2, Pl, or P2 Stage 4 any L, any S, any C, P3, or P4 General rules of the L S C P system (1) If there is a doubt concerning the correct L, S, C, or P category to which a particular case should be alloted, then the lower (i.e. less advanced) category should be chosen. This will also be reflected in the stage grouping. (2) In the case of multiple simulataneous leukoplakias, the lesion with the highest L and/or the highest S category should be classified and the multiplicity of the n u m b e r of leukoplakias should be indicated in parentheses, e.g. t2(m). (3) In the case of different clinical types of leukoplakias the highest score of the various leukoplakias should be used. (4) In the case of multiple biopsies of a single leukoplakia or biopsies taken from multiple leukoplakias the higher pathological score of the various biopsies should be used. (5) For reporting purposes the oral subsite according to the I C S - D A should be m e n t i o n e d (World Health Organization, International Classification of Diseases, T e n t h Revision. Application to Dentistry and Stomatology, I C D - D A , Geneva, 1992).

will a l l o w effective t r e a t m e n t to b e i n s t i t u t e d e a r l y a n d will reduce the overall morbidity and mortality. Screening prog r a m m e s for oral c a n c e r a n d p r e c a n c e r m a y b e i n d i c a t e d in i n d i v i d u a l s at risk, s u c h as p r e d e t e r m i n e d a g e a n d risk h a b i t s ( t o b a c c o a n d / o r a l c o h o l u s e r s ) , or c e r t a i n g e o g r a p h i c a r e a s w i t h a h i g h i n c i d e n c e o f oral c a n c e r a n d p r e c a n c e r [138].

A m e r i c a a n d E u r o p e , b u t n o t so o r d i f f e r e n t in o t h e r p a r t s , e.g. I n d i a ,

CLASSIFICATION AND STAGING SYSTEM

I n o r d e r to p r o m o t e u n i f o r m r e p o r t i n g o f v a r i o u s a s p e c t s o f l e u k o p l a k i a , t h e r e is a n e e d for a c l a s s i f i c a t i o n a n d s t a g i n g s y s t e m in w h i c h t h e site, t h e clinical s u b t y p e a n d t h e h i s t o p a t h o l o g i c a l f e a t u r e s a r e t a k e n i n t o a c c o u n t . A p r o p o s a l for s u c h c l a s s i f i c a t i o n a n d s t a g i n g s y s t e m h a s b e e n p r e s e n t e d in T a b l e 4 [139]. T h e s t a g i n g s y s t e m ( S t a g e s I - I V ) h a s n o t y e t b e e n p r o v e n to b e o f v a l u e w i t h r e g a r d to t h e m a n a g e m e n t of the patient. A somewhat debatable item that has been i n c l u d e d in t h e s t a g i n g s y s t e m is t h e a s s u m p t i o n t h a t t h e r e are, i n d e e d , h i g h - r i s k sites ( t o n g u e a n d floor o f t h e m o u t h ) ; t h i s m a y b e t r u e in c e r t a i n p a r t s o f t h e w o r l d , e.g. N o r t h

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