leukopaia review oral oncology 1997

Pergamon

PII: S0964-1955 (97)00002-X

Oral Oncology Vol. 33, No. 5, pp. 291 301, 1997 ~' 1997 Elsevier Science Ltd. All rights reserved

Printed in Great Britain 1368-8375/97 $17.00 + 0.00

Reviews

Oral Leukoplakia: a Cl inicopathological Review

I. van der Waal, K. P. Schepman, E. H. van der Meij and L. E. Smeele

D e p a r t m e n t 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 Vr i je U n i v e r s i t e i t / A C T A ,

A m s t e r d a m , T h e N e t h e r l a n d s

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 or 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 the ora 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 the t e r m l e u k o p l a k i a as a c l in i ca 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

t e r m l e u k o p l a k i a s h o u l d b e r e p l a c e d b y t h e d i a g n o s i s o b t a i n e d h i s t o l o g i c a l l y . T h e a n n u a l p e r c e n t a g e 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 var i e s in d i f f erent par t s o f the 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 hab 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 an 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 wi l l 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 par t s o f the w o r l d t h e t o n g u e a n d the f l o o r o f t h e m o u t h c a n b e c o n s i d e r e d t o b e h i g h - r i s k s i tes 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 th 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 par t s o f

t h e w o r l d . T h e c e s s a t i o n o f t o b a c c o hab i t s , b e i n g the m o s t c o m m o n k n o w n a e t i o l o g i c a l f ac tor o f ora l 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 an e f f ec t ive m e a s u r e w i t h r e g a r d to the 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 ora l c a n c e r as we l l . S c r e e n i n g for ora 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

K e y w o r d s : ora l l e u k o p l a k i a , p r e c a n c e r o u s l e s i o n , e p i t h e l i a l d y s p l a s i a

Oral Oncology, Vol. 33 , N o . 5, pp . 2 9 1 - 3 0 1 , 1997

I N T R O D U C T I O N 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 a t tempt at complete coverage. Owing to the influence that tobacco habits and dietary pro- ducts 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.

DEFINITION AND 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 t ransform into cancer" [1]. In that report, a dis- t inction was made 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.

made when a lesion at clinical examinat ion 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 elim-

ination, of suspected aetiological factors and, in the case of

persistent lesions, histopathological examinat ion [1]. When

the whiteness is not very distinct, the term preleukoplakia is

sometimes used, not to be confused with leukoedema.

Histopathological examinat ion 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 histo-

logically [2, 3]. It seems preferable to follow the same con-

cept 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 accord-

ance with previous recommendat ions [2, 3].

291

292 I. van der Waal et al.

Definable white lesions In the var ious defini t ions of oral leukoplakia reference is

m a d e to " o t h e r d iseases" or "def inab le les ions" [1-3] . In daily pract ice the clinical and h is topathologica l features of whi te oral lesions are no t always character is t ic ; a n u m b e r of cases c a n n o t be classified with cer ta inty as a "def inab le les ion" .

A few of the whi te lesions listed in Tab le 1 deserve fur ther a t t en t ion wi th regard to def ini t ion and terminology.

Hype~olastic candidiasis versus Candida-associated leukoplakia. T h e r e is no consensus in the l i terature whe the r or no t to recognize a hyperplas t ic subtype of candidiasis. W h e n deal ing wi th a hyperplas t ic epithelial lesion in which

the presence of Candida albicans is demons t r a t ed , some authors prefer to refer to such lesions as Cand ida-assoc ia ted leukoplakias while o thers prefer the t e rm hyperplas t ic candidiasis [4]. In the absence of clinical response to ant i fungal t r ea tmen t , it seem preferable to cons ider such lesion a leukoplakia.

Hairy leukoplakia ("Greenspan lesions"). T h e t e rm "ha i ry

leukoplakia" is un fo r tuna t e for several reasons. Firs t of all, hairy leukoplakia is a def inable lesion [5, 6]. F u r t h e r m o r e ,

the lesion is no t a p r ema l ignan t one. Therefore , the use of the t e rm hairy leukoplakia should be a b a n d o n e d . As an

al ternat ive, the t e rm " G r e e n s p a n les ion" has been suggested [7].

Tobacco-induced white lesions. Smoker ' s palate (" leukokera tos is n icot ina pa la t i " ) , palatal keratosis in reverse smokers , and snuff d ippers ' lesions are clearly related to tobacco use and, therefore, are usually l isted as " t o b a c c o - i n d u c e d les ions" [1, 2]. These lesions are be ing

regarded as "def inab le les ions" and are t radi t ional ly no t descr ibed as leukoplakia [8]. Never theless , some of these lesions may t r ans fo rm into cancer. Apparent ly , this is no t the case for smoker ' s palate, while it is for palatal lesions in reverse smokers. T h e possible p r ema l ignan t na tu re of snuf f depends on the type of snuf f and possibili ty also on o ther factors, such as various ingredients tha t may have been

added to the snuff [9 11].

Tobacco-associated leukoplakia; idiopathic leukoplakia. With regard to whi te lesions o ther t han the tobacco- induced whi te lesions m e n t i o n e d previously, the aetiological role of tobacco in pa t ien ts who smoke cigarettes, cigars or pipes is less obvious [12, 13]. Therefore , preference has been given to the t e rm " tobacco-assoc ia ted leukoplakia" (leukoplakia in smokers) above the t e rm " t o b a c c o - i n d u c e d white les ion" [2]. As a result, one also recognizes non - tobacco associated leukoplakia (leukoplakia in non-smokers ) , of ten referred to as id iopathic leukoplakia. W h e t h e r this subtyping is of any clinical relevance, is still to be de te rmined . Fu r the rmore , the issue becomes even more complex in cases of mixed habi ts of tobacco chewing and smoking.

Premalignant, precancerous or potentially malignant lesion Oral leukoplakia is regarded to be a p rema l ignan t or,

synonymously , a potent ia l ly ma l ignan t or p recancerous lesion. A p recance rous lesion has been defined as a m o r p h o - logically al tered tissue in which cancer is more likely to occur t h a n in its apparent ly no rma l coun te rpar t [14]. However , no odd ratios have b e e n m e n t i o n e d in the literature tha t would define " m o r e likely to occur" .

In two studies f rom India , r a ther low annua l ma l ignan t t r ans fo rmat ion rates of oral leukoplakia have been repor ted, 0 .3% [15] and a 0 .06% [16], respectively. In reports f rom Wes te rn countr ies , usually based on hospi ta l material , some- wha t h igher 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 mus t take into account , w h e n s tudying percentages of ma l ignan t t rans form- a t ion rates of oral leukoplakia: (1) the length of observat ion period; (2) the type of s tudy popula t ion ; and (3) the thera- peut ic approach .

O n the basis of the lowest repor ted annua l ma l ignan t t r ans fo rma t ion rate of oral leukoplakia, it can be calculated tha t pat ients wi th oral leukoplakia carry a 5-fold h igher risk of developing oral cancer t han controls [16]. W h e t h e r this increased risk is sufficiently h igh to mee t criteria of " m o r e likely to occur" , as m e n t i o n e d in the defini t ion of a precancerous lesion, remains an open quest ion.

Table 1. The most common definable white or predominantly white lesions of the oral mucosa and their main diagnostic criten'a

Lesion Main diagnostic criteria

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

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 Clinical Clinical History Clinical Clinical

aspect (incl. symmetrical pattern) aspect (often symmetrical pattern); histopathology aspect (incl. location on line of occlusion in cheek mucosa) of habitual biting or chewing; clinical aspect aspect; histopathology aspect; demonstration of T. pallidum; serology

Clinical aspect; history of smoking Clinical aspect; history of reverse smoking Clinical aspect; site where snuff is placed Family history; Clinical aspect (often symmetrical pattern)

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

Oral Leukoplakia 293

E P I D E M I O L O G Y Incidence and prevalence

In a 10 year prospective study in India in large random samples, carried out in several geographic areas with various kinds of tobacco usage, the annual age-adjusted incidence rates of leukoplakia per 1000 populat ion per year varied from 1.1 to 2.4 among men and from 0.2 to 1.3 among women; the prevalence varied from 0.2 to 4.9% [15]. In an adult Swedish populat ion 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].

The gender distribution in most studies varies, ranging from a strong male predominance in different parts in India, to almost 1:1 in the Western world.

koplakia") that may be irregularly flat, nodular or exophytic. The 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]. The 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 carcinoma [46, 47]. Fur thermore , a diagnosis of proliferative verrucous leukoplakia can only be made retrospectively after new lesions have developed [48].

T h e homogeneous type is usually otherwise asympto- matic, whereas the non-homogeneous (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.

A E T I O L O G Y The possible role of tobacco has been previously men-

tioned. Whether the use of alcohol by itself is an indepen- dent aetiological factor in the development of oral leukoplakia, is still quest ionable [29-33].

T h e role of C. albicans as a possible aetiological factor in leukoplakia and its possible role in malignant t ransformation is still unclear [34 37]. In recent years, the possible con- tr ibutory 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 compared to controls, whereas serum vitamin E was not [40]. Fresh fruits and vegetables may have a protective effect in the primary prevent ion of oral cancer and precancer.

Relatively little is yet known with regard to possible gen- etic factors in the development of oral leukoplakia [41].

C L I N I C A L A S P E C T S 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 homogeneous and the non-homogeneous type. Transi t ions or changes among the different clinical variants of oral leukoplakia may occur [43, 44].

Homogeneous 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 homogeneous 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 homogeneous colour or texture. Those lesions are considered non-homogeneous leukoplakias.

Non-homogeneous leukoplakia has been defined as a predominant ly white or white-and-red lesion ("erythroleu-

D I A G N O S T I C P R O C E D U R E S Elimination of possible cause(s)

When 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. For instance, in the case of a non-homogeneous white and red lesion, the result of antifungal t reatment 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 t ime for the general prac- ti t ioner before taking a biopsy or before referring the patient to a specialist for further advice. It is well recognized that the t ime to regress may in some cases be much longer than the 2 -4 weeks ment ioned previously. On 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 homogeneous leukoplakia the value of histological

examinat ion might to some extent be questioned. The 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 homogeneous leukoplakia. Therefore, the taking of a biopsy in homogeneous leukoplakia should be the standard rule. It usually suffices to take just one biopsy or to perform a conservative excisional biopsy, if that is feas- ible. If t reatment consists of CO2-1aser evaporation it is mandatory to have a biopsy taken prior to such treatment.

In non-homogeneous leukoplakias, that are usually symp- tomatic, epithelial dysplasia or even carcinoma in situ or early squamous cell carcinoma is rather common. The 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 amount of underlying connec- tive tissue, and preferably from the margins. The problem in such lesions is not so much the histological evaluation of the presence of epithelial dysplas ia--which is usually not the case but of the possible invasive nature of the lesion.


T h e biopsy specimen can be placed in a regular fixative medium. 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. The 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 accompany the specimen to the lab- oratory, 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 l imited value when dealing with leukoplakia [49 52].

H I S T O P A T H O L O G I C A L A S P E C T S The 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.

The 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 number of subepithelial lymphocytes, plasmacells, Langerhans ' cells and interepithelial cells, and the presence of Candida organisms additional indicators of dysplasia. The clinical significance of human papillomavirus-associated epithelial dysplasia, so-called koilocytic dysplasia, remains to be investigated [53]. Dysplastic epi thel ium may show features that to some extent resemble those of lichen planus; some authors refer to such an event as " l ichenoid dysplasia" [54].

In the presence of the use of tobacco, the often so-called chevron type of keratinisation is observed [55, 56]. Exocytosis of inf lammatory cells in the epi thel ium is uncom- mon. In the presence of C. albicans the formation of micro- abcesses may be observed in the superficial layers of the epithelium.

White or whitish lesions that clinically and/or histopathologically have an exophytic, verrucous or papil lomatous architecture and in which no distinct signs of epithelial dysplasia are present at the light microscopic level, may pro-

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

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. For 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 papil- lomatous lesions, in spite of the absence of epithelial dysplasia, may in t ime 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 ment ioned in Table 1. The final diagnosis of a white lesion of the oral rnucosa can often only be made through a close dialogue between the clinician and the pathologist. Even then, cases may remain unsettled.

Grading of epithelial dysplasia Based on the histopathologist 's interpretation of the pre-

sence 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 cor- relates with the age of the patient [59].

Unti l 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. There 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 ecommended that the histological report of a leukoplakia should include a state- ment on the absence or presence of epithelial dysplasia and an assessment of its severity [2].

To some extent, the practical value of the grading of epithelial dysplasia is questionable. Al though leukoplakias with modera te or severe epithelial dysplasia show a greater dispo- sition for malignant t ransformation 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 pre-

malignant 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 examinat ion [64]. Nevertheless, there are many recent pub- lications on promising new biological risk markers [41, 67 - 100].

M A L I G N A N T T R A N S F O R M A T I O N Certain features have been reported to be associated with

an increased risk of malignant transformation. These are, in arbitrary order: (1) gender, particularly women seem to be at risk; (2) long durat ion of the leukoplakia; (3) leukoplakia in non-smokers (idiopathic leukoplakia); (4) location in the floor of the mou th or/and on the tongue; (5) non-homogeneous type; (6) presence of C. albicans; and (7) presence of epithelial dysplasia.


Table 3

M A N A G E M E N T OF O R A L L E U K O P L A K I A (PROVISIONAL CLINICAL DIAGNOSIS)

I E L I M I N A T I O N OF P O S S I B L E CAUSE(S)

(2-4 WEEKS OBSERVATION)

I

I I GOOD RESPONSE NO RESPONSE

(DEFINITIVE CLINICAL DIAGNOSIS)

DEF INABLE LESION

• M A N A G E M E N T

A C C O R D I N G L Y

I NO P O S S I B L E CAUSE(S)

(DEFINITIVE CLINICAL DIAGNOSIS)

I ) B I O P S Y

I

I D E F I N A B L E LESION

• M A N A G E M E N T

A C C O R D I N G L Y

I NO D E F I N A B L E LESION

• D Y S P L A S I A

• NO D Y S P L A S I A

• TREATMENT/OBSERVATION • FOLLOW-UP

O f the a b o v e - m e n t i o n e d factors, the presence of epithelial d y s p l a s i a - - m o r e or less corre la t ing wi th 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 be the mos t i m p o r t a n t ind ica tor of ma l ignan t potent ia l . I t is gener- ally accepted tha t dysplastic lesions carry a 5-fold greater risk t han non-dysplas t ic ones. Never theless , it shou ld be recognized tha t in an Ind ian s tudy in a m e a n fol low-up observat ion per iod of 7 years, some 60% of the dysplastic lesions r ema ined clinically u n c h a n g e d or even showed complete regress ion [15]. In fact, only some 7% of the dysplastic lesions progressed to cancer in a m e a n observa t ion per iod of 7 years. O the r s have repor ted similar f indings [101]. As has b e e n m e n t i o n e d previously, ca rc inomatous t r ans fo rma t ion may also take place in non-dysplas t ic lesions.

A l though the p resence of C. albicans has been indica ted as a risk factor [35, 36], it is r emarkab le tha t this microor - gan i sm seems to be par t icular ly p resen t in leukoplakias at the commissures and at the d o r s u m of the tongue. These sites are r a the r rare for s q u a m o u s cell ca rc inomas to occur and at the same t ime are c o m m o n sites for leukoplakia.

In several s tudies on ma l ignan t t r ans format ion , par t icu- larly f rom the Wes t e rn world, the borders of the tongue and the floor of the m o u t h have been m e n t i o n e d as so-called high-r isk sites. A good example is a repor t on subl ingual keratosis in which a h igh ma l ignan t t r ans fo rma t ion 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 showing only hyperkeratos is w i thou t epithelial dysplasia [102]. However , in o ther par ts of the world, subsi tes o the r t h a n the borders of the tongue and the floor of the m o u t h may be cons idered high-r isk sites [15, 16].

I t is b e y o n d the scope of this treatise to discuss in d e p t h the ques t ion of wha t pe rcen tage of oral s q u a m o u s cell carci- n o m a s arises f rom pre-exis t ing lesions, par t icular ly f rom leukoplakia. Figures f rom Japan and the Wes t e r n wor ld range f rom 17 [103] to approx imate ly 35% [104], respectively.

M A N A G E M E N T

General considerations

As has been discussed previously, m a n a g e m e n t of whi te oral lesions is pr imari ly d i rected towards the e l iminat ion of possible causative factors, e.g. friction, C. albicans, thus rul- ing ou t o ther def inable lesions (Tab le 3). In pers is t ing lesions or in the absence of possible causative factors, a b iopsy should be taken to exclude, histologically, the presence of a definable lesion and to es tabl ish the degree of epithelial dysplasia, if present , or even the presence of carci- n o m a or ca rc inoma in situ.

I t is an ethical ques t ion whe the r or no t it would be justi- fied in case of persis t ing tobacco habi t s to delay active t reat- m e n t of oral leukoplakia, w i thou t histological evidence of mal ignancy, as long as the pa t ien t has no t given up those habi ts .

In the case of mi ld or absen t epithelial dysplasia, the de- cision whe the r or no t to t reat may be inf luenced by the oral subsite. In the presence of mode ra t e or severe epithelial dysplasia, active t r e a t m e n t is usually inst i tuted. Some authors r e c o m m e n d t r e a t m e n t of each oral leukoplakia, irrespective of the degree of epithelial dysplasia or the absence of epithelial dysplasia and irrespective of the oral subsi te [22]. O n the o ther hand , one migh t cons ider l imit ing t r e a t m e n t to those cases wi th dis t inct signs of mal ignancy. It has been suggested tha t mucosa l ca rc inomas associated with leukoplakia provide a be t t e r prognosis tha t "de novo " carc inomas [104]. Never theless , some of these pa t ien ts will die of thei r cancer. I t r emains an open ques t ion whe the r early, active t r e a t m e n t of the leukoplakia in such cases would truly have p reven ted the occur rence of cancer, and whe the r or no t the morb id i ty of rou t ine t r e a t m e n t of all pa t ients with oral leukoplakia outweigh the dea th of a l imi ted n u m b e r of pat ients .

T h e r e are ins tances where active t r e a t m e n t of oral leukoplakia can hardly be inst i tuted. Th i s is especially t rue in extensive leukoplakia tha t involves more or less the ent ire


oral mucosa. Also patient factors may hinder op t imum 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 t reatment strategy is required because of the longer life expectancy.

Treatment modalities Apart f rom the surgical excision, various t reatment mod-

alities are available, such as cryosurgery, CO2-1aser surgery, retinoids and other drugs, and, recently photodynamic therapy [105 108]. T h e latter t reatment modali ty will not be taken into account here because of its rather recent application with regard to oral leukoplakia, not allowing com- ment on long-term results.

Surgical excision. Traditionally, the r ecommended t reatment 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 [109- 111].

Cryosurgery. The effects of therapeutic freezing upon oral lesions have been studied since the early 1960 s. The results of t reatment 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 t reatment, 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 avail- ability of CO2-1aser surgery, there is hardly any place anymore for cryosurgery in the t reatment 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.

When the added benefits of magnification and precise beam control provided by a microscope are considered, CO2-1aser excision permits the possibility of obtaining the entire lesion for histological examination, although the qual- ity of the surgical margins may be slightly jeopardised by CO2-1aser excision. When compared with cold knife excision, the CO2-1aser has certain advantages, especially when large areas of the epi thel ium are involved. Morbidi ty is reduced because of the physical properties of laser energy, healing by secondary intention and epithelial regeneration. This minimises wound contract ion and impairment of func- tions due to scar formation.

The 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 vi tamin A acid and its derivates is its toxicity,

necessitating reduct ion 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. Beta- carotene and vi tamin E are considerably less toxic than 13- cis-retinoid acid [116]. The 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].

The topical application of bleomycine is still in an exper- imental phase [124-127]. The same holds true with regard to the systemic use of alpha-tocopherol [128, 129]. Synthetic retinoid N-(4-hydroxyphenyl)-ret inamide (4- HPR) in a dosage of 200 mg daily, applied topically, may be effective in the prevent ion of recurrence of leukoplakia after surgical excision [130, 131].

The major drawback for most current agents is the recurrence of lesions when t reatment is discontinued [132].

F O L L O W - U P The risk of malignant transformation is not completely

eliminated by any of the above described t reatment modalities. Spreading and malignant transformation of the lesion may take place in spite of treatment, while the number of lesions prevented from malignant development is unknown [104]. Some verrucous leukoplakias have a strong tendency to recur after conservative surgical excision, being referred to as the previously discussed proliferative verrucous leukoplakia. On the other hand, some leukoplakias may in t ime regress or disappear in patients who had no specific treatment and no alteration in habit [12, 13, 15, 16, 19].

No strict guidelines can be given with regard to duration and frequently of follow-up examinations. In general, long term follow-up examinat ion is advised at 6-12 month inter- vals in patients who have not or not successfully been treated for their leukoplakia [133, 134]. Patients who, after t reatment, remain disease free for 3 years need perhaps no longer be followed-up.

P R E V E N T I O N A N D S C R E E N I N G To assess the feasibility of primary prevent ion of oral can-

cer, two cohorts were studied in base-line surveys and then followed-up annually for 10 years in the Ernakulam district of Kerala state. The intervention cohort consisted of 12,212 tobacco users aged 15 years and over, who were exposed to a concentrated program of educat ion against tobacco use. The control cohort was a non-concurrent cohort of 6075 tobacco users studied using similar methods, but with a minimal amount of advice against tobacco use. The stop- page of tobacco use increased and the incidence rate of leukoplakia decreased significantly and substantially in the intervention cohort compared to the control cohort. The 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 demonstra ted the feasibility of primary prevent ion of oral precancer and cancer [135, 136]. Therefore, primary health care workers are encouraged to carefully search the mou th 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

Ora l L e u k o p l a k i a

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

297

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 = homogeneous Cz = non-homogeneous 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 any L, $1, C~, P h or P2 Stage 2 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 s imulataneous 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 ICS-DA should be ment ioned (World Heal th Organization, International

Classification of Diseases, T en t h Revision. Application to Dentis try and Stomatology, ICD-DA, Geneva, 1992).

will a l low effect ive t r e a t m e n t to be i n s t i t u t e d ear ly a n d will

r e d u c e t h e overa l l m o r b i d i t y a n d mor t a l i t y . S c r e e n i n g p r o -

g 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 be i n d i c a t e d in

i n d i v i d u a l s at r isk, s u c h as p r e d e t e r m i n e d age a n d r isk

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 ea 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] .

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 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 eukop l ak i a , t h e r e is a n e e d for a c l a s s i f i ca t ion 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 s i te , t h e c l in ical 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 re t a k e n in to a c c o u n t . A p r o p o s a l for

s u c h c la s s i f i ca t ion 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 tages I - I V ) h a s n o t ye t

b e e n p r o v e n to be o f va l ue w i t h r e g a r d to t h e m a n a g e m e n t o f t he pa t i en t . A s o m e w h a t d e b a t a b l e i t e m t h a t h a s b e e n

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 s i tes ( t o n g u e a n d f loor o f t h e m o u t h ) ;

t h i s m a y be t r u e in ce r t a in p a r t s o f t he wor l d , e .g. N o r t h

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 ren t in o t h e r pa r t s ,

e.g. Ind ia ,

1. Ax~ll, T. , Pindborg, J. J,, Smith, C. J., Waal van der, I. and an International Collaborative Group on Oral White Lesions, Oral white lesions with special reference to precancerous and tobacco-related lesions: conclusions of an international sym- pos ium held in Uppsala, Sweden, May 18 21, 1994. Jourmd o/ Oral Pathoh~L:v and Medicine, 1996, 25, 49 54.

2. Axd11, T. , Holmst rup , P., Kramer, I, R. H., Pindborg, J. J. Shear, M., International seminar on oral leukoplakia and associated lesions related to tobacco habits. Community Dental and Oral EpMemiolo.ey, 1984, 12, 145-154.

3. K.ramer, I. R. H., Lucas, R. B., Pindborg, J. J., Sobin, L. H. W H O Collaborating Centre for Oral Precancerous Lesions, Definition of leukopakia and related lesions: an aid to studies on oral precancer. Oral Surgery. Oral Medicim', Oral Pathology, 1978, 46~ 518-539.

4. Hogewind, W. F. C. and Waal van der, I., Leukoplakia of the labial commissure . Brilish JourJTal q/ Oral Ma.villqfilcial Surgeo', 1988, 26, 133 140.

5. Greenspan, D., Greenspan, J. S., Conant , M., Petersen, V., Silverman, S. Jr and Souza de, Y., Oral "hairy" leucoplakia in

298 I. van de r Waa l et al.

male homosexuals: evidence of association with both papilloma virus and a herpes group virus. Lancet, 1984, 13, 831 834.

6. EC Clearinghouse on oral problems related to HIV infection and W H O Collaborating Centre on oral manifestations of the immunodeflciency virus. Classification and diagnostic criteria for oral lesions in HIV infection. Journal of Oral Pathology and Medicine, 1993, 22, 289 291.

7. Waal van der, I., Letter to the Editor. Greenspan lesion is a better term than oral "hairy" leukoplakia. Journal of Oral Pathology and Medicine, 1996, 25, 144.

8. Mehta F. S. and Hammer J. E. Tobacco-related oral mucosal lesions and conditions in India, A guide for dental students, dentists, and physicians. Basic Dental Research Unit, Tata Institute of Fundamental Research, Bombay, 1993.

9. Idris, A. M., Warnakulasuriya, K. A. A. S., Ibrahim, Y. E., Nielsen, R., Cooper, D. and Johnson, N. W., Toombak-associated oral mucosal lesions in Sudanese show a low prevalence of epithelial dysplasia. Journal ~[ Oral Pathology and MedichTe, 1996, 25, 239 244.

10. Larsson, A, Ax611, T. and Andersson, G., Reversibility of snuff dipper's lesion in Swedish moist snuff users: a clinical and histological follow-up study. Journal (71" Oral Pathology and Medicine, 1991, 20, 258-264.

11. Kaugars, G. E., Riley, W. T., Brandt, R. B., Burns, J. C. and Svirsky, J. A., The prevalence of oral lesions in smokeless tobacco users and an evaluation of risk factors. Cancer, 1992, 70, 2579-2595.

12. Gupta, P. C., A study of dose-response relationship between tobacco habits and oral leukoplakia. British Journal ~1' Cancer, 1984, 50, 527-531.

13. Roed-Petersen, B., Effect on oral leukoplakia of reducing or increasing tobacco smoking. Aela Dermatolvener, 1981, 62, 164-167.

14. World Health Organization. Report from a meeting of investi- gators on the histological definition of precancerous lesions, 1973. CAN/731, Geneva.

15. Gupta, P. C., Mehta, F. S., Daftary, D. K., et aL, Incidence rates of oral cancer and natural history of oral precancerous lesions in a 10-year follow-up study of Indian villagers. Community Dental and Oral Epidemiology, 1980, 8, 287-333.

16. Silverman, S., Bhargava, K., Mani, N. J., Smith, L. W. and Malaowalla, A. M., Malignant transformation and natural history of oral leukoplakia in 57,518 industrial workers of Gujarat, India. Cancer, 1976, 38, 1790 1795.

17. Pindborg, J. J,, Renstrup, G., Jost, O. and Roed-Petersen, B., Studies in oral leukoplakia: a preliminary report on the period of prevalence of malignant transformation in leukoplakia based on a follow-up study of 248 patients. JADA, 1968, 76, 767 771.

18. Ban6czy, J. and Sug~ir, L., Longitudinal studies in oral leukoplakias. Journal ~I' Oral Pathology, 1972, 1 ,265 272.

19. Silverman, S., Gorsky, M. and Lozada, F., Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer, 1984~ 53, 563 568.

20. Lind, P. O., Malignant transformation in oral leukoplakia. Seandinavian Journal of Den tal Research, 1987, 95, 449-455.

21. Tischendorf, L. and Giehler, U., Studien zur Dignitfit der Leukoplakie yon Mundschleimhaut und Lippen. Deutsche Zeitschr([? Jh'r Mund-. Ki~/br-, und Gesichtschirurgie, 1990, 14, 301-305.

22. Dunsche, A., Kreusch, Th and Sauer, M., Die Leukoplakie der Mundschle imhaut- -e ine retrospektive Studie an 161 Patienten. Deutseh Zah,drztliehe Zeitschr([?, 1992, 47, 869- 871.

23. Frerich, B., Bschorer, R., Gehrke, G., G/irtner, H. V. and Schwenzer, N., Maligne Transformation oraler Leukoplakien. Line retrospektieve klinishche und zellproliferationskinetische Studie. Dtseh Zahndrztl Z, 1992, 47, 836-839.

24. Gundlach, K. K. H., Wieviele Plattenepithelkarzinome der Mundh6hle sind aus Leukoplakien entstanden? Deutsche Zeitsehr([? [h)" Mund-, Kiq/~'r-, und Gesichtschirugie, 1992, 16, 109-111.

25. Ax~ll, T., Occurrence of leukoplakia and some other white lesions among 20,333 adult Swedish people. Community Dental and Oral Epidemialogy, 1987, 15, 46 51.

26. Gupta, P. C., Leukoplakia and incidence of oral cancer. Journal of Oral Pathology and Medicine, 1989, 18, 17.

27. Ax~ll, T., A prevalence study of oral mucosal lesions in an adult Swedish population. Odontologist Revy, 1976, 27(suppl. 36), 1976.

28. Waldron, C. A. and Shafer, W. G., Leukoplakia revisited. A clinicopathologic study of 3256 oral leukoplakias. Cancer, 1975, 36, 1386-1392.

29. Gupta, P. C., Epidemiologic study of the association between alcohol habits and oral leukoplakia. Community Dental and Oral Epidemiology, 1984, 12, 47 50.

30. Evstifeeva, T. V. and Zaridze, D. G., Nass use, cigarette smoking, alcohol consumption and risk of oral and oesopha- geal precancer. Oral Oncology, European Journal o[" Cancer, 1992, 28B, 29-35.

31. Kulasegaram, R., Downer, M. C., Jullien, J. A,, Zakrzewska, J. M. and Speight, P. M., Case-control study of oral dysplasia and risk habits among patients of a dental hospital. Oral Oneology, European Journal ~I' Cancer, 1995, 31B, 227-231.

32. Blot, W. J., Winn, D. M. and Fraumeni, J. F., Oral cancer and mouthwash. Journal o[" the National Cancer Institute, 1983, 70, 251-253.

33. Kabat, G. C., Hubert, J. R. and Wynder, E. L., Risk factors for oral cancer in women. Cancer Research, 1989, 49, 2803 2806.

34. Kramer, I. R. H., Precancerous conditions of the oral mucosa. A computer-aided study. Annals ~1' the Royal College c~[' Surgeons, Enghmd, 1969, 45, 340 356.

35. Krogh, P., Hald, B. and Holmstrup, P., Possible mycological etiology of oral mucosal cancer: catalytic potential of infecting Candida albicans and other yeasts in production of N-nitroso- benzylmethylamine. Carcinogenesis, 1987, 8, 1543 1548.

36. Field, E. A., Field, J. K. and Martin, M. V., Does Candida have a role in oral epithelial neoplasia? Journal o1" Medical and Veterina O, ,~vcology, 1989, 27, 277-294.

37. Hornstein, O. P. and Gr~t3el, R., Hfiufigkeit und prognostische Bedeutung der Candida-Besiedelung oraler Leukoplakien. Deutsche Zeitschr(/~ j~ir Mund-, Kie~,r-, und Gesichtschirurgie, 1992, 16, 112 116.

38. Miller, C. S. and White, D. K., Human papillomavirus expression in oral mucosa, premalignant conditions, and squamous cell carcinoma. A retrospective review of the literature. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology Endod, 1996, 82, 57-68.

39. Palefsky, J. M., Silverman, S., Abdel-Salaam, M., Daniels, T. E. and Greenspan, J. S., Association between proliferative verrucous leukoplakia and infection with human papillomavirus type 16. Journal ~[' Oral Pathology and MeclicbTe, 1995, 24, 193-197.

40. Ramaswamy, G., Rao, V. R., Kumaraswamy, S. V. and Anantha, N., Serum vitamin's status in oral leucoplakias--a preliminary study. Oral Oncology, European Journal c~/' Cancer, 1996, 32B, 120-122.

41. Johnson~ N. W., Ranasinghe, A. W. and Warnakulasuriya, K. A. A. S., Potentially malignant lesions and conditions of the mouth and oropharynx: natural history--cellular and molecu- lar markers of risk. European Journal of Cancer Prevention, 1993, 2(suppl. 2), 31-51.

42. Baric, J. M., Alman, J. E., Feldman, R. S. and Chauncey, H. H., Influence of cigarette, pipe, and cigar smoking, removable partial dentures, and age on oral leukoplakia. Oral Surgery, Oral Medich~e, Oral Pathology, 1982, 54, 424 429.

43. Bfindczy, J. and Sugfir, L., Progressive and regressive changes in Hungarian oral leukoplakias in the course of longitudinal studies. Communit.~ Dental and Oral Epidemiology, 1975, 3, 194-197.

44. Sciubba, J. J., Oral leukoplakia. Critical Review ~[" Oral Biology and Medicine, 1995, 6, 147-160.

45. Gupta, P. C., Bhonsle, R. B., Murti, P. R., Daftary, D. L., Mehta, F. S. and Pindborg, J. J., An epidemiologic assessment of cancer risk in oral precancerous lesions in India with special reference to nodular leukoplakia. Cancer, 1989, 63, 2247 2252.

46. Hansen, L. S., Olson, J. A. and Silverman, S., Proliferative verrucous leukoplakia. Oral Surge13', Oral Medicine, Oral Pathology, 1985, 60, 285 298.


47. Shear, M. and Pindborg, J. J., Verrucous hyperplasia of the oral mucosa. Cancer, 1980, 46, 1855 1862.

48. Zakrzewska, J. M., Lopes, V., Speight, P. M. and Hopper, C., Proliferative verrucous leukoplakia. A report of ten cases. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology Endod, 1996, 82, 396 401.

49. Miller, R. L., Simms, B. W. and Gould, A. R., Toluidine blue staining for detecting of oral premalignant lesions and carcinomas. Journal ~?fOral Pathology, 1988, 17, 73 78.

50. Epstein, J. B., Scully, C. and Spinelli, J. J., Toluidine blue and Lugol's iodine application in the assessment of oral malignant disease and lesions at risk of malignancy. Journal of Oral Pathology and Medieine, 1992, 21, 160 163.

51. Barrellier, P., Babin, E., Louis, M. Y. and Meunier-Guttin, A., Utilisation du bleu de toluidine dans le diagnostic des l~sions nroplasiques de la cavit6 buccale. Revue de Stomatologie et Chirurgie Ma.villo[aciale, 1993, 94, 51-54.

52. Warnakulasuriya, K. A. A. S. and Johnson, N. W., Sensitivity and specificity of OraScan (R) toluidine blue mouthrinse in the detection of oral cancer and precancer. Journal of Oral Patholog3' and Medicine, 1996, 25, 97 103.

53. Fornatora, M., Cale, Jones A., Kerpel, S. and Freedman, P., Human papillomavirus-associated oral epithelial dysplasia (koilocytic dysplasia). An entity of unknown biologic potential. Oral Surge13', Oral Medicine, Oral Pathology. Oral Radiology Endod, 1996, 82, 47-56.

54. Krutchkoff, D. J. and Eisenberg, E., Lichenoid dysplasia: a distinct histopathologic entity. Oral Sargerl,, Oral Medicine, Oral Pathology, 1985, 60~ 308 315.

55. Pindborg, J. J., Reibel, J., Roed-Petersen, B. and Mehta, F. S., Tobacco-induced changes in oral leukoplakic epithelium. Cancer, 1980, 45, 2330 2336.

56. Daniels, T. E., Hansen, L. S., Greenspan, J. S., et aL, Histopathology of smokeless tobacco lesions in professional baseball players. Association with different types of tobacco. Oral Surget3'. Oral Medicine. Oral Pathology, 1992, 73, 720- 725.

57. Murrah, V. A. and Batsakis, J. G., Proliferative verrucous leukoplakia and verrucous hyperplasia. Annals ~/' Otology RhhTology and La/3'ngology, 1994, 103, 660-663.

58. Slootweg, P. J. and Mtiller, H., Verrucous hyperplasia or verrucous carcinoma. An analysis of 27 patients. Journal qf Maxilh{[acial Surgeo', 1983, 11, 13-19.

59. Vesper, M., Schmelzle, R., Ritter-Kr6hn, R. and Gfinzl, H-J., Vergleichende Untersuchung histologisch gesicherter Leukoplakien im Cavum oris. Deutsche Zahndrztliche Zeitsehr(]?, 1992, 47, 867-869.

60. Pindborg, J. J., Reibel, J. and Holmstrup, P., Subjectivity in evaluating oral epithelial dysplasia, carcinoma in situ and in- itial carcinoma. Journal ~?f Oral Pathology, 1985, 14, 698- 708.

61. Karabalut, A., Reibel, J., Therkildsen, M. H., Praetorius, F., Neilsen, H. W. and Dabelsteen, E., Observer variability in the histologic assessment of oral premalignant lesions. Journal t?/' Oral Pathology and Medicine, 1995, 24, 198-200.

62. Lumerman, H., Freedman, P. and Kerpel, S., Oral epithelial dysplasia and the development of invasive squamous cell carcinoma. Oral SurgeJ3", Oral Medichw, Oral Pathology, Oral Radioh)g) Endod, 1995, 79~ 321-329.

63. Abbey, L. M., Kaugars, G. E., Gunsolley, J. C., et al., Intraexaminer and interexaminer reliability in the diagnosis of oral epithelal dysplasia. Oral Surgeo,, Oral Medicine, Oral Pathology, Oral Radiology Endod, 1995, 80, 188-191.

64. Burkhardt, A., Advanced methods in the evaluation of premalignant lesions and carcinomas of the oral mucosa. Journal (~]" Oral Pathology, 1985, 14, 751 778.

65. Waldron, C. A. and Shafter, W. G., Leukoplakia revisted. A clinicoplathologic study of 3256 oral leukoplakias. Cancer, 1975, 36, 1386-1392.

66. Crissman, J. D. and Zarbo, R. J., Dysplasia, in situ carcinoma, and progression to invasive squamous cell carcinoma of the upper aerodigestive tract. American Journal o/" Surgel3' and Pathology, 1989, 13(suppl), 5 16,

67. Su, L., Morgan, P. R. and Lane, E. B., Keratin 14 and 19 expression in normal, dysplastic and malignant oral epithelia. A study using in situ hybridization and immunohistochemistry. Journal ~/' Oral Pathology and Medicine, 1996, 25, 293 301.

68. Kannan, R., Bijur, G. N., Mallery, S. R., et al., Transforming growth factor-alpha overexpression in proliferative verrucous leukoplakia and oral squamous cell carcinoma. An immunohistochemical study. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology Endod, 1996, 82, 69 74.

69. Johnson, N. W., Warnakulasuriya, S. and Tavassoli, M., Hereditary and enviromental risk factors; clinical and labora- tory risk markers for head and neck, especially oral, cancer and precancer. European Journal qf Cancer Prevention, 1996, 5, 5-17.

70. Johnson N. E. (ed.). Risk Markers for Oral Diseases, Vol. 2. Oral Cancer: Detection of Patients and Lesions at Risk. Cambridge University Press, Cambridge, 1991.

71. Abdel-Salam, M., Mayall, B. H., Chew, K., Silverman, S. Greenspan, J. S., Which oral white lesions will become malignant? An image cytometric study. Oral Surgery Oral Medicine Oral Pathology, 1990, 69, 345-350.

72. Mao, L., Lee, J. S., Fan, Y. H., et al., Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment. Nature Medieine, 1996, 2, 682-685.

73. Heyden, A., Huitfeld, H. S., Koppang, H. S., Thrane, P. S., Bryne, M. and Brandtzaeg, P., Cytokeratins as epithelial differentiation markers in premalignant and malignant oral lesions. Journal Of Oral Pathology and Medicine, 1992, 21, 7-11,

74. Kinoshita, Y., Inoue, S., Honma, Y. and Shimura, K., Diagnostic significance of nuclear DNA content and nuclear area in oral hyperplasia, dysplasia, and carcinoma. Journal ~/ Oral Maxillq/iwial Surgery, 1992, 50~ 728-733.

75. Eversole, L. R. and Sapp, J. P., c-myc oncoprotein expression in oral precancerous and early cancerous lesions. Oral Ontology, European Journal o/'Caneer, 1993, 28B, 131 135.

76. Kahn, M. A., Mincer, H. H., Dockter, M. E. and Hermann- Petrin, J. M., Comparing flow cytometric analysis and nucleolar organizer region enumeration in archival oral premalignant lesions. Journal ~?f Oral Pathology and Medieilw, 1993, 22, 257 262.

77. Scully, C. and Burkhardt, A., Tissue markers of potentially malignant human oral epithelial lesions. Journal ~[' Oral Pathology atut Medicine, 1993, 22, 246 256.

78. Steinbeck, R. G., Moege, J., Heselmeyer, I4,. M., et aL, DNA content and PCNA immunoreactivity in oral precancerous and cancerous lesions. Oral Oncology, European Journal ~/' Cancer, 1993, 29B, 279-284.

79. Warnakulasuriya, K. A. A. S. and Johnson, N. W., Nucleolar organiser region (NOR) distribution as a diagnostic marker in oral keratosis, dysplasia and squamous cell carcinoma. Journal of Oral Pathology and Medicine, 1993, 22, 77-81.

80. Z611er, J., Flentje, M., Sinn, P. and Born, I. A., "Nukleolar Organizer Region" und "Ki-67" als zellkinetische parameter f/Jr oral dysplasien und plattenepithelkarzinome. Deutsche Zeitschr(/?./~ir Mund-, Kiq/~)r-, und Gesichtsehirurgie, 1993, 17, 185-190.

81. Saiton, K., Yamashita, T., Notani, K-I., et aL, Flow cytometric analysis of nuclear DNA content in oral leukoplakia: relation to clinicopathologic findings. International Journal ~/' Oral Maxilh?facial Surgeo', 1995, 24, 44 47.

82. Robinson, P. A., Markham, A. F., Schalkwijk, J. and High, A. S., Increased elafin expression in cystic, dysplastic and neoplastic oral tissues. Journal of Oral Pathology and Medicine, 1996, 25, 135-139.

83. Velden van der, L-A., Schaafsma, H. E., Manni, J. J., Ramaekers, F. C. S. and Kuijpers, W., Cytokeratin expression in normal and (pre)malignant head and neck epithelia: an overview. Head and Neck, 1993, 15, 133-146.

84. Shirasuma, K., Hayashido, Y., Sugiyama, M., Yoshioka, H. Matsuya, T., Immuno-histochemical localization of epidermal growth factor (EGF) and EGF receptor in human oral mucosa and its malignancy. Virehows Archly A. Pathologische Anatomie, 1991, 418, 349-353.

85. High, A. S., Robinson, P. A. and Klein, C. E., Increased expression of a 38kd cell-surface glycoprotein MH99 (KS 1/4) in oral mucosal dysplasia. Journal ~/ Oral Pathology and Medic'hw, 1996, 25, 10-13.

86. Bryne, M., Reibel, J., Mandel, U. and Dabelsteen, E., Expression of mucin type carbohydrates may supplement his-


tologic diagnosis in oral premalignant lesions. Journal of Oral Pathology and Medicine, 1991, 20, 120-125.

87. Coltrera, M. D., Zarbo, R. J., Sakr, W. A. and Gown, A. M., Markers for dysplasia of the upper aerodigestive tract. Suprabasal expression of PCNA, p53, and CK19 in alcohol- fixed, embedded tissue. American Journal o[ Pathoh)gy, 1992, 141,817-825.

88. Schliephake, H., Eckardt, A., Gaida-Martin, C. and Pytlik, C., PCNA/Cyclin-Antik6rper als Proliferationsmarker bei Mundschleimhauterkrankungen. Deutsche Zahndrztliche Zeitsehrft, 1992, 47, 845-848.

89. Tsuji, T., Shrestha, P., Yamada, K., et al., Proliferating cell nuclear antigen in malignant and pre-malignant lesions of epithelial origin in the oral cavity and the skin: an immunohistochemical study. Virehows Archiv A. Pathologische Anatomie, 1992, 420, 377 383.

90, Huang, W. Y-F., Coltrera, M., Schubert, M., Morton, T. and Truelove, E., Histopathological evaluation of proliferating cell nuclear antigen (PC10) in oral epithelial hyperplasia and premalignant lesions. Oral Surge13', Oral Medicine, Oral Pathology, 1994, 78, 748-754.

91. Girod, S. C., Kruger, G. and Pape, H-D., p53 and Ki 67 expression in preneoplastic and neoplastic lesions of the oral mucosa. International Journal ~/" Oral Maxilhffdcial Surgery, 1993, 22, 285 288.

92. Nishioka, H., Hiasa, Y., Hayashi, I., Kitahori, Y., Konishi, N. Sugimara, M., Immunohistochemical detection of p53 oncoprotein in human oral squamous cell carcinomas and leukoplakias: comparison with proliferating cell nuclear antigen staining and correlation with clinicopathological findings. Oncologr, 1993, 50, 426 429.

93. Girod, S. C., Fischer, U., Knfifermann, R., Krfimer, Ch and Krfiger, G. R. F., p53-Mutationen bei Leukoplakien, Lichen planus und Karzinomen der Mundschleimhaut. Deutsche Zeitschr(/~./~'r Mund-, Ki~!/er-, und Gesichtsehirurgie, 1994, 18, 250-253.

94. Regezi, J. A., Zarbo, R. J., Regev, E., Pisanty, S., Silverman, S. and Gazit, D., p53 protein expression in sequential biopsies of oral dysplasia and in situ carcinomas. Journal q[ Oral Pathology and Medicine, 1995, 24, 18 22.

95. Matsuda, H., Konishi, N., Hiasa, Y., et aL, Alterations of pl6/CDKN2, p53 and ras genes in oral squamous cell cacino- mas and premalignant lesions. Journal (?[" Oral Pathology and Medichle, 1996, 25, 232 238.

96. Kusama, K., Okutsu, S., Takeda, A., et aL, p53 gene alterations and p53 protein in oral epithelial dysplasia and squamous cell carcinoma. Journal o[" Pathoh)gy, 1996, 178, 415 421.

97. Sugerman, P. B., Savage, N. W., Xu, L. J., Walsh, L. J. and Seymour, G. J., Heat shock protein expression in oral epithelial dysplasia and squamous cell carcinoma. Oral Oncology, European Journal qf Cancer, 1995, 31B, 63-67.

98. Pillai, K. R., Kannan, S., Koshy, P., et aL, Scanning electron microscopy of different types of oral leukoplakia: comparison with normal and malignant oral mucosa. Oral Ontology, European Journal of Cancer, 1994, 30B, 400-404.

99. Neilsen, H., Norrild, B., Vedtofte, P., Praetorius, F., Reibel, J. and Holmstrup, P., Human papillomavirus in oral premalignant lesions. Oral Ontology. European Journal of Cancer, 1996, 32B, 264-270.

100. Kahn, M. A., Dockter, M. E. and Hermann-Petrin, J. M., Proliferative verrucous leukoplakia. Four cases with flow cytometric analysis. Oral Surger)', Oral Medic&e, Oral Pathology, 1994, 78, 469 475.

101. Pindborg, J. J., Daftary, D. K. and Mehta, F. S., A follow-up study of sixty-one oral dysplastic precancerous lesions in Indian villagers. Oral Surgery. Oral Medichle, Oral Pathology, 1977, 43, 383 390.

102. Kramer, I. R. H., E1-Labban, N. and Lee, K. W., The clinical features and risk of malignant transformation in snblingual keratosis. British Dental Jotn'nal, 1978, 144, 171-180.

103. Shibuya, H., Amagasa, T., Seto, K-I., Ishibashi, K., Horiuchi, J-I. and Suzuki, S., Leukoplakia-associated multiple carcinomas in patients with tongue carcinoma. Cancer, 1986, 57, 843-846.

104. Bouquot, J. E., Weiland, L. H. and Kurland, L. T., Leukoplakia and carcinoma in situ synchronously associated

with oral/oropharyngeal carcinoma in Rochester, Minn., 1935-1984. Oral Surgery, Oral Medicine. Oral Pathology, 1988, 65, 199-207.

105. Grant, W. E., Hopper, C., Speight, P. M., Macrobert, A. J. Bown, S. G., Photodynamic therapy of malignant and premalignant lesions in patient with 'field cancerization' of the oral cavity. Journal o[" Laryngology and Otology, 1993, 107, 1140- 1145.

106. Gregory, G. F., Hopper, C., Fan, K., Grant, W. E., Bown, S. G. and Speight, P. M., Photodynamic therapy and lip vermi- lion dysplasia: a pilot study. Oral Oncoh)gy, European Journal of Cancer, 1995, 31B, 346-347.

107. Fan, K. F. M., Hopper, C., Speight, P. M., Buonaccorsi, G,, MacRobert, A. J. and Bown, S. G., Photodynamic therapy using 5-aminolevulinic acid for premalignant and malignant lesion of the oral cavity. Cancer, 1996, 78, 1374 1383.

108. Nauta, J. M., Van Leengoed, H. L. L. M., Star, W. N., Roodenburg, J. L. N., Witjes, M. J. H. and Vermey, A,, Photodynamic therapy of oral cancer. A review of basic mech- anism and clinical applications. European Journal Of Oral Science, 1996, 104, 69-81.

109. Vedtofte, P., Holmstrup, P., Hjorting-Hansen, E. and Pindborg, J. J., Surgical treatment of premalignant lesions of the oral mucosa. International Journal qf Oral MaxilloJaeial Smigery, 1987, 16, 656-664.

110. Chiesa, F., Boracchi, P., Tradati, N., et aL, Risk of preneoplastic and neoplastic events in operated oral leukoplakias. Oral Oncolog), European Journal of Cancer, 1993, 29B, 23- 28.

111. Browne, R. M. and Potts, A. J. C., Dysplasia in salivary gland ducts in sublingual leukoplakia and erythroplakia. Oral Surgeo,, Oral Medicine, Oral Pathology, 1986, 62, 44 49.

112. Chiesa, F., Tradati, N., Sala, L., et aL, Follow-up of oral leukoplakia after carbon dioxide laser surgery. Archives Otolao,ngolog) Head Neck Surgery, 1990, 116, 177 180.

113. Roodenburg, J. L. N., Panders, A. K. and Vermey, A., Carbon dioxide laser surgery of oral leukoplakia. Oral Surgery, Oral Medicine, Oral Pathology, 1991, 71,670 674.

114. Stich, H. F., Hornby, A. P., Mathew, B., Sankaranarayanan, R. and Nair, M. K., Response of oral leukoplakia to the ad- ministration of vitamin A. Cancer Letters, 1988, 40, 93-101.

115. Girod, S. C. and Pfahl, M., Retinoid actions and implications for prevention and therapy of oral cancer. International Journal of Oral Maxillqlacia/ SurgetT, 1996, 25, 69 73.

116. Toma, S., Mangiante, P. E., Margarino, G., Nicolo, G. and Palumbo, R., Progressive 13-cis-retinoid acid dosage in the treatment of oral leukoplakia. Oral Ontology, European Journal of Cancer, 1992, 281], 121-123.

117. Lippman, S. M., Batsakis, J. G., Toth, B. B., et aL, Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. New Enghmd Journal Of Medicine, 1993, 328, 15-20.

118. Stich, H. F., Mathew, B., Sankaranarayanan, R. and Nair, M. K., Remission of precancerous lesions in the oral cavity of tobacco chewers and maintenance of the protective effect of 13-carotene or vitamin A ~ 3. American Journal Of Clinical Nutrition, 1991, 53, 298S 304S.

119. Krishnaswamy, K., Prasad, M. P. R., Krishna, T. P., Annapurna, V. V. and Reddy, G. A., A case study of nutrient intervention of oral precancerous lesions in India. Oral Oncology, European Journal of Cancer, 1995, 31B, 41-48.

120. Kaugers, G. E., Silverman, S., Lovas, J. G. L., et aL, A clinical trial of antioxidant supplement in the treatment of oral leukoplakia. Oral Surgery, Oral Medicine, Oral Pathologl,, 1994, 78, 462 468.

121. Kaugers, G. E., Silverman, S., Lovas, J. G. L., Thompson, J. S., Bandt, R. B. and Singh, V. N., Use of antioxidant sup- plements in the treatment of human oral leukoplakia. Oral Surget3,. Oral Medicine. Oral Pathology, Oral Radiolog~v Endod, 1996, 81, 5-14.

122. Garewal, H. A., Meyskens, F. L., Killen, D., et aL, Response of oral leukoplakia to beta-carotene. Journal qf Clinical Oncologv, 1990, 8, 1715-1720.

123. Garewal, H., Chemoprevention of oral cancer: beta-carotene and vitamin E in leukoplakia. European Journal qf Cancer Prevention, 1994, 3, 101 107.


124. Hammersley, N., Fergnson, M. M. and Rennie, J. S., Topical bleomycin in the treatment of oral leukoplakia: a pilot study. British Journal of Oral Maxillojacial Surgery, 1985, 23, 251- 258.

125. Wong, F., Epstein, J. and Millner, A., Treatment of oral leukoplakia with topical bleomycin. A pilot study. Cancer, 1989, 64, 361-365.

126. Epstein, J. B., Wong, F. L., Millner, A. and Le, N. D., Topical bleomycin treatment of oral leukoplakia: a ran- domized double-blind clinical trial. Head and Neck, 1994, 16, 539-544.

127. Malmstr6m, M., Hietanen, J., Sane, J. and Sysmfilfiinen, M., Topical treatment of oral leukoplakia with bleomycin. British Journal q]' Oral Maxill~faeial Surgeo,, 1988, 26, 491-498.

128. Benner, S. E., Winn, R. J., Lippman, S. M., et aL, Regression of oral leukoplakia with alpha-tocopherol: a community clinical oncology program chemoprevention study. Journal of National Cancer hTstitute, 1993, 85, 44-47.

129. Benner, S. E., Wargovich, M. J., Lippman, S. M., et aL, Reduction in oral mucosa micronuclei frequency following alpha-tocopherol treatment of oral leukoplakia. Cancer Epidemiology, Biomarkers & Prevention, 1994, 3, 73 76.

130. Chiesa, F., Tradati, N., Marazza, M., et al., Prevention of local relapse and new localisations of oral leukoplakias with the synthetic retiniod fenretinide (4-HPR). Preliminary results. Oral Oncology, European Journal o/ Cancer, 1992, 28B, 97-102.

131. Tradati, N., Chiesa, F., Rossi, N., et aL, Successful topical treatment of oral lichen planus and leukoplakia with fenretinide (4-HPR). Cancer Letters, 1994, 76, 109-111.

132. Scully, C., Oral precancer: preventive and medical approaches to management. Oral Oncology, European Journal of Caneer, 1995, 31B, 16-26.

133. Bouquot, J. E. and Whitaker, S. B., Oral leukoplakia--ration- ale for diagnosis and prognosis of its clinical subtypes or "phases". Quintessence International, 1994, 25, 133-140.

134. Marley, J. J., Cowan, C. G., Lamey, P-J., Linden, G. J., Johnson, N. W. and Warnakulasuriya, K. A. A. S., Management of potentially malignant oral mucosal lesions by consultant UK oral and maxillofacial surgeons. British Journal o/' Oral Maxill(?/'aeial Surgery, 1996, 34, 28 36.

135. Gupta, P. C., Mehta, F. S., Pindborg, J. J., et al., Intervention study for primary prevention of oral cancer among 36000 Indian tobacco users. Lancet, 1986, May 31, 1235-1241.

136. Gupta, P. C., Mehta, F. S., Pindborg, J. J., et al., Primary prevention trial of oral cancer in India: a 10-year follow-up study. Journal of Oral Pathology and Medicine, 1992, 21,433 439.

137. Tomar, S. L., Husten, C. G. and Manley, M. W., Do dentists and physicians advise tobacco users to quit? Journal ~?[' the American Dental Assoeiation, 1996, 127, 259 265.

138. Speight, P. M., Downer, M. C. and Zakrzewska, J. Jr (eds), Screening for oral cancer and precancer. Report of a UK Working Groups. Community Dental Health, 1993, 10(suppl. 1), 1-89.

139. Schepman, K. P. and Waal van der, I., A proposal for a classification and staging system for oral leukoplakia: a preliminary study. Oral Oneology, European Journal ~?/' Cancer, 1995, 31B, 396-398.

leukopaia review oral oncology 1997

Documents