Potentially malignant oval lesions in northern ireland: a 20-year population-based perspective of malignant transformation

Transcription

1 Potentially malignant oval lesions in northern ireland: a 20-year population-based perspective of malignant transformation Cowan, G., Gregg, T. A., Napier, S. S., McKenna, S. M., & Kee, F. (2001). Potentially malignant oval lesions in northern ireland: a 20-year population-based perspective of malignant transformation., 7, Published in: Queen's University Belfast - Research Portal: Link to publication record in Queen's University Belfast Research Portal General rights Copyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The Research Portal is Queen's institutional repository that provides access to Queen's research output. Every effort has been made to ensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content in the Research Portal that you believe breaches copyright or violates any law, please contact openaccess@qub.ac.uk. Download date:15. Feb. 2017

2 Clinical Oral Medicine (2001) 7, Munksgaard All rights reserved X/01 Potentially malignant oral lesions in Northern Ireland: a 20-year population-based perspective of malignant transformation CG Cowan 1, TA Gregg 1, SS Napier 1, SM McKenna 2, F Kee 3 1 School of Dentistry, The Queen s University Belfast and the Royal Group of Hospitals; 2 Orthodontic Department, Liverpool University Dental Hospital; 3 Department of Epidemiology and Public Health The Queen s University Belfast, Northern Ireland This retrospective laboratory-based study investigates the potential for malignant transformation of oral mucosal lesions in a population of 1.6 million. Over the 20-year period there were 745 patients diagnosed with primary intra-oral squamous cell carcinoma (OSCC), 165 patients with dysplasia and 1182 patients with nondysplastic lesions (epithelial hyperplasia, hyperkeratosis epithelial atrophy, lichen planus and lupus erythematosus). Malignant transformation occurred in 15% of dysplasias and in 1% of non-dysplastic lesions at average intervals after diagnosis of 48 and 65 months respectively. Only 6% of patients with OSCC had a preinvasive lesion biopsied. These data suggest that white lesions are only rarely the pre-invasive phase of OSCC. It is possible therefore that early changes are red, small or even microscopic with carcinoma developing without a clinically observable phase. More effective management strategies will require the development of tissue markers to enhance early detection. (2001) 7, Keywords: oral leukoplakia; malignant transformation; oral squamous cell carcinoma; epidemiology Introduction The development of improved management strategies for primary intra-oral squamous cell oral carcinoma (OSCC), in common with other malignancies, is dependent on a clear understanding of the pathogenesis. This is recognised by the UK Working Group on Oral Cancer and Precancer (Speight et al, 1993) wherein it recommends further research into the natural history of oral cancer and precancer. Correspondence: CG Cowan, Division of Oral Surgery, Oral Medicine & Oral Pathology, School of Dentistry, Royal Group of Hospitals, Grosvenor Road, Belfast BT12 6BP, Northern Ireland. Tel: ext. 3672, Fax: Received 5 August 1999; accepted 12 May 2000 It is generally accepted, particularly where epithelial cancers are concerned, that frank malignancy may be preceded by an identifiable but as yet non-invasive precursor lesion. These areas of altered mucosa, described according to their clinical appearances as leukoplakia or erythroplasia, may be seen adjacent to OSCC at first presentation, or may predate the appearance of the tumour by months or years, leading to the assumption that they represent the precursors of OSCC. There are many studies reporting the malignant potential of these lesions from both developing and developed countries (Mehta et al, 1969; Banoczy and Sugar, 1972; Silverman et al, 1976; Kramer et al, 1978; Gupta et al, 1980; Silverman et al, 1984; Lind, 1987; Bouquot et al, 1988; Hogewind et al, 1989; Lummerman et al, 1995; Schepman et al, 1998). Indeed it has been suggested that the vast majority of OSCC in India arise from preexisting leukoplakias (Gupta, 1989). Although OSCC may arise in lesions without dysplasia (Silverman et al, 1984; Schepman et al, 1998), the presence of dysplasia in oral leukoplakia is regarded as being particularly sinister in that it is these lesions which show the greatest likelihood for malignant transformation (Silverman et al, 1976; Lind, 1987; Lummerman et al, 1995), especially those with moderate or severe dysplasia (Mincer et al, 1972; Banoczy and Csiba, 1976; Lind, 1987; Schepman et al, 1998). A previous study in Northern Ireland (Gregg et al, 1992), reported that in terms of relative frequency the incidence of dysplasia was low when compared to that of established invasive carcinoma: over a 15-year period, nearly four times as many carcinomas were detected as dysplastic lesions. This contrasts sharply with carcinomas of the cervix and the large bowel where the frequencies of severe dysplasia (CIN III) and adenomatous polyps respectively far out-weigh invasive tumours (Cancer Research Campaign Fact-sheet, 1990; Winawer et al, 1991). Whereas the increased detection of CIN III lesions of the cervix could be attributed at least in part to screening, it is not the case for bowel cancer were there is no such programme. The apparent low frequency of dysplasia compared with OSCC (Gregg et al, 1992) could have several explanations. As the study was based on laboratory records it may be

3 that patients do not attend while lesions are still in the preinvasive phase or clinicians may fail to recognise and/or biopsy them. In addition, because of histological heterogeneity, a biopsy sample may not include the dysplastic area. Furthermore, it is well known that the detection of dysplasia is subjective (Pindborg et al, 1985; Abbey et al, 1995), and therefore there could be under-diagnosis of dysplasia. Alternatively, some cases of OSCC may have a short-lived, or even lack a clinically detectable, pre-invasive phase. The aim of this study was to improve our understanding of the pathogenesis of OSCC by investigating the relative frequency and transformation of potentially malignant lesions in a population. Methods The study was based on histopathology records abstracted from all laboratories that receive oral biopsy specimens in Northern Ireland for the 20-year period 1975 to Data sets were established for dysplastic lesions and OSCC. In recognition of the problems with reproducibility of histological grading of dysplasia (Pindborg et al, 1985; Abbey et al, 1995) the dysplastic group was not further sub-divided. To assess the malignant potential of other epithelial oral lesions and to address the possible under-diagnosis of dysplasia that could arise in relation to tissue selection or its histological interpretation, a third group was established. This group, referred to as non-dysplastic, included all epithelial lesions that for clinical reasons must have been considered sufficiently worrying in terms of their malignant potential to merit biopsy but were subsequently diagnosed as histologically innocent (ie, chronic mucosal lesions diagnosed as epithelial hyperplasia, hyperkeratosis and epithelial atrophy). Potentially malignant conditions such as lichen planus and lupus erythematosus were also included in this group. All other lesions were excluded. The data sets were constructed by linking individual patients to their biopsies by reference to name, age, gender, date of birth and when necessary clinical records. This allowed study of the biopsy history of each patient. Patients with multiple biopsies could therefore be common to more than one group depending on the histological diagnosis for each biopsy. However, those with an initial diagnosis of OSCC were confined to the carcinoma group notwithstanding the results of subsequent mucosal biopsies. For ease of analysis, when more than one diagnosis was given for lesions within the non-dysplastic group, eg, hyperkeratosis and atrophy, sub-classification was based on the first diagnosis listed, as this tended to represent the predominant microscopic alteration. Clinical records and histological sections were reviewed for all patients who had more than one diagnostic biopsy irrespective of the original diagnosis. This provided a review of the clinical and histological diagnoses and confirmed which patients had lesions that had undergone malignant transformation. A total of 136 patients clinical records and histological slides were reviewed. Six were reclassified in terms of histological diagnosis. The numbers of patients in each group and those progressing between the groups were determined and analysed according to age, gender and interval period. Age standardisation was perfor- Table 1 Composition of groups Group Males Females Unknown Average Total gender age a Non-dysplastic Dysplastic Carcinoma a Average age in years (first diagnosis) Table 2 Non-dysplastic group by diagnosis. Cases with more than one diagnosis are grouped according to the first diagnosis listed Non-dysplastic Males Females Unknown Total gender Hyperkeratosis Epithelial hyperplasia Epithelial atrophy Lichen planus a Lupus erythematosus Total a Includes lichenoid reaction med by usual methods using the World Standard population (Muir et al, 1987). Results Northern Ireland has a population of 1.6 million, 64% aged between 15 and 64 years and 13% 65 and over. Thirty-five percent of males and 30% of females smoke tobacco. Trends show more young people, particularly females, are taking up smoking. Seventy-five percent of males and 63% of females consume alcohol. Thirty-three percent of males and 10% of females exceed recommended limits of 21 and 14 units per week, and it appears that Northern Irish men and women are drinking more heavily and frequently than previously (Health and Social Wellbeing Survey, ). Over the 20-year period there were 745 patients who had an initial diagnosis of OSCC, 165 patients with dysplasia and 1182 patients with epithelial lesions classified as nondysplastic (Tables 1 and 2). Trends over the 20-year period (Figure 1) show a significant increase in frequency in the Figure 1 Frequency of the groups by year of diagnosis over the 20- year period 19

4 20 Table 3 Age-standardised incidence per population Non dysplastic group Males (n = 63) (n = 68) (n = 124) (n = 257) Rate Confidence Limits ( ) ( ) ( ) ( ) Females (n = 80) (n = 87) (n = 153) (n = 312) Rate Confidence Limits ( ) ( ) ( ) ( ) non-dysplastic group in the latter half of the period. Comparing the two 10-year periods ( and ), there was little difference in the proportion of patients with dysplastic lesions that progressed to carcinoma (9% and 8% respectively). Similarly, there was no increase in the proportion progressing to carcinoma for the non-dysplastic group (both 0.9%), despite the large increase in the number of patients biopsied (data not shown). Age-standardised incidence rates per show an increase for males and females in the non-dysplastic group (Table 3). As previously reported (Cowan et al, 1992; Gregg et al, 1992) equivalent rates for dysplasia were males 0.6 and females 0.4, and for OSCC, males 3.1 and females 1.2 per population. There was no significant change in incidence of dysplasia or OSCC in females but a small but significant increase in OSCC incidence in males. Forty-six patients categorised initially in dysplastic or non-dysplastic groups subsequently progressed to other groups (Table 4). Five of these progressed from the nondysplastic group to dysplasia and were not subjected to further analysis. The remaining 41 patients, 24 (14%) with dysplasia and 17 (1%) from the non-dysplastic group, had a subsequent diagnosis of OSCC (Table 5). The tumour developed at the site of the initial lesion for 29 patients, 20 from the dysplastic group and nine from the non-dysplastic group. For seven patients (9, 13, 27, 28, 31, 32 and 33), the records suggested the same site but the information was not considered specific. The general sites were the same, eg, tongue or palate but the details were not precise (Table 5). In three cases (3, 16 and 29) the tumour arose at a different site from the recorded pre-existing mucosal lesion. Table 4 Numbers of patients that progressed (n = 46) Group Progressed Progressed Progressed to to carcinoma to dysplasia dysplasia and then to but not to carcinoma carcinoma Non-dysplastic (total = 1182) Dysplastic 24 NR NR (total = 165) Regarding interval time, review of the clinical records and histological sections strongly suggested that 10 patients from the dysplastic group (6, 7, 11, 12, 13, 14, 21, 22, 23 and 24) and six from the non-dysplastic group (26, 27, 31, 32, 36 and 38), had an infiltrating neoplasm adjacent to the site of biopsy at the time of presentation. It was felt that these patients could not be included in the analysis of interval time as they were examples of inaccurate selection of tissue at biopsy. Interval time was assessed for the remaining patients, 14 from the dysplastic group and 11 patients from the nondysplastic group. All had intervals of 12 months or more, on average 47.8 months for the dysplastic group (range months) and 64.5 months for the non-dysplastic lesions (range months). Five patients from the nondysplastic group progressed to the dysplastic group and subsequently developed OSCC (37 41). Only 6% of the OSCC group had a biopsied pre-invasive lesion. Patients, in either dysplastic or non-dysplastic group, who later progressed to OSCC were older than those who did not, average age 63.8 years (range years) and 54.3 years (range years) respectively. Analysis of the gender showed a ratio of 1:2.5, males to females compared to equal proportions in the patients that did not develop OSCC). Discussion Studies such as this can present difficulties in interpretation of the results. These problems relate to the definition of potentially malignant lesions and the abstraction of representative data. In relation to sample selection Northern Ireland is particularly well suited to population studies as it provides an ethnically homogeneous population, at least in health care terms, and very few of its people seek care outside the province. The source of the material is also of great significance, ie, whether the studies are clinical or histologically based. Each has its limitations in terms of case selection. Although our study derives from biopsy data, it differs from other studies in that the sample includes all epithelial alterations ( non-dysplasia group) and provides a clinico-pathological correlation for those cases with multiple biopsies. This design, as well as including all biopsied cases of leukoplakia and erythroplasia, minimises clinical case selection bias, reduces errors that could arise from tissue selected for biopsy and negates the under-diagnosis of dysplasia that could arise from histological interpretation. Clearly all cases of leukoplakia are not biopsied and Bouquot (1986) reported that even in cancer screening clinics only 25% of leukoplakias were biopsied. Our data however, shows increasing numbers of biopsies (Figure 1) from 1985 onwards suggesting a change in clinical practice in terms of the use of biopsy as an investigation. It is also significant that there was no resultant increase in the numbers of dysplastic lesions or cases progressing to carcinoma. Overall 3% of the epithelial lesions (dysplasia and nondysplasia) progressed to carcinoma. This proportion is low compared with other studies (Silverman et al, 1984; Bouquot et al, 1999) but probably reflects the size and composition of the non-dysplastic group. This contained a much

5 Table 5 Patients who progressed to carcinoma 21 Pt no. Gender Age Site(s) of lesion(s) Site 1st Histol. dx Site 1st Interval Comment biopsy SCC 1 F 82 RIBM-RtLA-RtUL RtBM Dysplasia RtLA 13 Metachronous intraoral SCC 3 2 F 80 LtLT LtLT Dysplasia LtLT 31 3 F 55 RtBM, LtBM LtBM Dysplasia RtLA 30 Separate lesions 4 F 63 RtLT RtLT Dysplasia RtLT 83 5 M 61 RtBM-RtUA-HP; FOM-VT- RtLT Dysplasia RtLT 60 Extensive mucosal RtDT; LtBM abnormality 6 F 67 FOM-LtRMP-LtPF-LtTO FOM Dysplasia FOM 3 7 F 69 RtLT; LtLT LtLT Dysplasia LtLT 6 Synchronous SCC RtLT 8 F 67 RtLT RtLT Dysplasia RtLT 72 9 M 80 RtHP Palate Dysplasia RtHP 19 Precise sites not specified 10 M 68 LtLT LtLT Dysplasia LtLT M 47 FOM FOM Dysplasia FOM 1 12 M 52 FOM FOM Dysplasia FOM 1 13 M 74 Palate Palate Dysplasia Palate 1 Precise sites not specified 14 M 47 FOM FOM Dysplasia FOM 1 15 F 64 RtBM-RtU&LA-RtUL RtBM Dysplasia RtRMP F 70 RtBC-RtBM-RtU&LA-RtU& RtBM Dysplasia LtVT 128 Separate lesions LL; LtBM 17 M 27 LtLT LtLT Dysplasia LtLT F 53 FOM-Rt&LtLA-LtRMP FOM Dysplasia LtLA F 46 LtLT LtLT Dysplasia LtLT F 78 FOM-VT-Rt&LtLT RtLT Dysplasia RtLT 12 Extensive mucosal abnormality 21 M 66 FOM FOM Dysplasia FOM 6 22 F 65 LtHP-LtUA LtUA Dysplasia LtHP 1 23 M 47 FOM/VT FOM Dysplasia FOM 1 24 M 40 FOM-VT FOM Dysplasia FOM 1 25 F 58 RtBC-RtBM-RtU&LA- RtBM Hyperplasia RtBM 31 RtRMP 26 F 71 RtHP-RtUA RtHP Hyperplasia HP 2 27 F 37 RtLT Tongue Hyperplasia Tongue 1 Precise sites not specified 28 M 45 Tongue Tongue Hyperplasia Tongue 16 Precise sites not specified 29 F 30 Rt&LtUA-HP RtHP Keratosis RtRMP F 59 FOM/VT FOM Hyperplasia FOM F 60 LtLT Tongue Hyperplasia Tongue 2 Precise sites not specified 32 F 87 Tongue Tongue Hyperplasia Tongue 2 Precise sites not specified 33 F 65 Upper alveolus Gum Hyperplasia RtUA 14 Precise sites not specified 34 F 74 RtBC-RtBM-RtLA-RtRMP; RtBM Hyperplasia RtLA 156 Extensive mucosal LtBM abnormality 35 M 49 HP;Rt&LtBM;Rt&LtLT-VT LtLT Keratosis RtHP 70 Extensive mucosal abnormality 36 M 74 LtLT LtLT Hyperplasia LtLT 6 37 F 61 RtBM-RtUA-RtHP RtUA Hyperplasia RtBM 82 Progressed to dysplasia 38 M 49 FOM FOM Keratosis FOM 4 Progressed to dysplasia 39 M 73 RtRMP-RtPF-RtSP RtPF Keratosis RtPF 35 Progressed to dysplasia 40 F 56 LtBC-LtBM-LtU&LA- LtBC Hyperplasia LtBM 107 Progressed to dysplasia LtRMP;HP-SP, LtLT;RtBM 41 F 67 RtBM RtBM Keratosis RtBM 35 Progressed to dysplasia Gender: M, male; F, female Age: Age in years at initial diagnosis Site(s) of lesion(s): Rt, right; Lt, left; BC, buccal commissure; BM, buccal mucosa; LL, lower lip; UL, upper lip; LT, lateral border of tongue; VT, ventral tongue; DT, dorsal tongue; FOM, floor of mouth; LA, lower alveolus; UA, upper alveolus; RMP, retromolar pad; HP, hard palate; SP, soft palate; PF, anterior pillar of fauces; TO, palatine tonsil. Sites separated by hyphen (-) indicate contiguous involvement by one lesion. Sites separated by semicolon (;) indicate apparently separate lesions. Sites within inverted commas (.. ) indicate unspecified sites Hist. dx: Primary histological diagnosis of initial biopsy specimen Site 1st SCC: Site of origin of first intra-oral squamous cell carcinoma Interval: Time in months between initial diagnosis and subsequent histological diagnosis of carcinoma Comment: Additional features

6 22 wider range of lesions including lichen planus and therefore would not be easily compared with studies based on the clinical diagnosis of leukoplakia. If the dysplastic group alone is considered the figure is 14%. To minimise this distortion it may be of more value to look at the cases known to have progressed to carcinoma as a proportion of the OSCC group. This shows that 6% of OSCC patients had a previously biopsied epithelial lesion that progressed to carcinoma. In this study a total of 41 patients progressed to OSCC. This figure is probably an over-estimate as in some cases the tumour was known not to have developed at the site of a pre-existing mucosal abnormality. It is also noteworthy that in a number of cases where clinical and histological findings suggested that there was already an adjacent invasive tumour, there was a short interval time of less than 12 months, often only 1 or 2 months. Interestingly other studies (Pindborg et al, 1968; Silverman et al, 1984; Lind, 1987; Schepman et al, 1998) found that a significant number of leukoplakias developed tumours in the first year of follow-up. It is also of note that 3% of leukoplakias might already be carcinoma at the time of biopsy (Waldron and Shafer, 1975). These cases could reflect unrepresentative tissue sampling, perhaps longstanding lesions in the final phase of malignant transformation. In any event, even the most optimistic interpretation of our data shows that a clinically detectable lesion rarely precedes OSCC. The vast majority could be considered as arising de novo, ie, arising from otherwise clinically normal mucosa. Notwithstanding this conclusion it is evident that a significant percentage of the dysplastic lesions (14%) progressed to cancer and represent a true pre-cancerous lesion in these cases. Whereas it is accepted that dysplasia is considered a critical factor in determining malignant potential it is also known that progression to cancer is not inevitable. In fact some lesions will regress spontaneously (Banoczy and Sugar, 1972; Mincer et al, 1972; Gupta et al, 1980). The matter is further complicated in that lesions that are not dysplastic may become malignant (Silverman et al, 1984; Schepman et al, 1998). We have tried to address this issue by including the non-dysplastic group and by following the biopsy history of individual patients over the 20-year period. Our data shows that only a small minority of patients who had a chronic intra-oral mucosal abnormality biopsied had a histological diagnosis of dysplasia (12.2%). Comparative population-based studies in the literature are few, but other workers in developed nations have highlighted the relative rarity of intra-oral dysplastic lesions. Waldron and Shafer (1975) reviewed 3256 biopsies of leukoplakias, over a 13-year period, and found that only 17% were dysplastic. Bouquot and Gorlin (1986) found an equal proportion of invasive carcinoma and carcinoma-in situ (12%) in 176 leukoplakias which were biopsied as part of a volunteer screening programme in the USA. In contrast, Bouquot et al (1988), in a retrospective laboratory-based study of oral and oropharyngeal cancers in the USA reported leukoplakia or erythroplakia associated with 25 of 61 intra-oral carcinomas (41%). Schepman et al (1999) suggest that almost 50% of oral concerns were associated with or preceded by a leukoplakia. These relatively large proportions could to some degree reflect observation of reactive epithelial change at the tumour margin in contrast to establishing the lesion of origin of the OSCC. As this study is based on biopsy results other interpretations of the low incidence of dysplastic lesions are possible. The failure of patients to attend or clinicians to detect would be the most likely explanations. In Northern Ireland the proportion of the adult population registered with a dentist is approximately 55% (Watters P, personal communication) a figure that compares favourably with other populations. Also a previous study (Cowan et al, 1995) reported that in Northern Ireland 94% of primary care dentists routinely examine the oral cavity for cancer and pre-cancerous lesions. Whereas only 12% of practitioners would undertake biopsies, suspicious lesions were referred without delay, more than 80% within 1 month and the remainder within 6 months of presentation. This study shows an increasing awareness of OSCC and potentially malignant lesions, as evidenced by a dramatic increase in the numbers of patients with epithelial lesions biopsied. This has not been matched by a corresponding rise in the numbers of patients with dysplasia. These findings suggest that the failure of patients to attend or clinicians to detect would not account for the low relative frequency of dysplasia. Alternatively, it is possible that an area of dysplasia was missed at biopsy: lesions may not be histologically homogenous and the dysplastic area may not be included in the sample. Our data does indicate that some biopsies may not be representative of the worst areas of the lesions. Furthermore as previously stated the histological interpretation of dysplasia is subjective and relatively unreliable (Pindborg et al, 1985; Abbey et al, 1995). However, by following the non-dysplastic group over the same period, we have shown that there is no significant under-diagnosis of dysplasia either through sample selection or through histological interpretation. Only 17 of the 1182 patients (less than 1.5%) progressed to carcinoma and on review none was considered to show changes of dysplasia. Evidently this is not the full explanation for the perceived low incidence of dysplasia. It is also noteworthy that the proportion of non-dysplastic lesions progressing to OSCC is much the same in the latter half of the study when there had been a large increase in the number of patients biopsied. It is clear from the histological diagnoses that the vast majority of the dysplastic and non-dysplastic lesions in this study would have been mostly white or speckled in clinical appearance. If these mucosal lesions have such a low risk of malignant change and if dysplasia is apparently so rare, what is the origin of the vast majority of oral squamous cell carcinomas? It is possible that the pre-invasive lesion is red rather than white, a contention supported by Mashberg et al (1973). They reported that nearly 96% of 158 asymptomatic OSCC had an erythroplasia component and suggested that a red lesion was the earliest visible sign of an asymptomatic oral squamous cell carcinoma. A high occurrence of dysplasia in erythroplasia was found by Shafer and Waldron (1975). In their report of 65 biopsies taken from 58 patients with erythroplasia, 91% demonstrated either invasive carci-

7 noma, carcinoma-in situ or severe dysplasia with the remainder showing moderate or mild dysplasia. This is in contrast with their study of leukoplakia (Waldron and Shafer, 1975) which showed only 17% were dysplastic. Perhaps of more significance is the difference in the sample sizes between the two studies, 3526 leukoplakias compared with 65 erythroplasias, emphasising the rarity of erythroplasia as a clinical diagnosis. Furthermore detection would be even less likely if these lesions were small or even microscopic. This would certainly account for the low relative frequency of dysplasia. In this study, cases with proven progression had an average interval to transformation of 48 months for dysplastic lesions and 65 months for non-dysplastic lesions, similar to other work (Banoczy and Sugar, 1972; Silverman et al, 1984; Lummerman et al, 1995; Schepman et al, 1998). These patients differ from the majority who did not progress in that they are older and have a female gender bias. This observation is difficult to interpret, as numbers are small but it is accepted that there is a preponderance of females in older age groups. Furthermore in Northern Ireland females in the 65 and over age group attend the dentist more frequently than males, 41% compared with 35% (Cullen J, personal communication). It could be speculated that these factors account, to some degree, for this gender/age bias. These observations and the suggestion that OSCC arising from pre-existing lesions tend to behave less aggressively than those presenting with an invasive tumour (Shibuya et al, 1986; Bouquot et al, 1988) could indicate that there is more than one pathway for the development of OSCC. Perhaps the vast majority of OSCC arise de novo from clinically normal mucosa (small red areas) while a lesser number develop more slowly from white lesions. Resolution of these questions is fundamental to our understanding of the natural history of OSCC and this in turn is the basis of any attempt to reduce the burden of the disease. The development of tissue markers to enhance the detection of patients and lesions with a high potential for malignant change is therefore paramount. References Abbey LM, Kaugers GE, Gunsolley JC et al (1995). Intra-examiner and inter-examiner reliability in the diagnosis of oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 80: Banoczy J, Csiba A (1976). Occurrence of epithelial dysplasia in oral leukoplakia. Oral Surg Oral Med Oral Pathol 42: Banoczy J, Sugar L (1972). Longitudinal studies in oral leukoplakias. J Oral Pathol 1: Bouquot JE, Gorlin RJ (1986). Leukoplakia, lichen planus, and other oral keratoses in 23,616 white Americans over the age of 35 years. Oral Surg Oral Med Oral Pathol 61: Bouquot JE, Weiland LH, Kurland LT (1988). Leukoplakia and carcinoma in situ synchronously associated with invasive oraloropharyngeal carcinoma in Rochester, Minn, Oral Surg Oral Med Oral Pathol 65: Bouquot JE (1986). Common oral lesions found in a large mass screening. J Am Dent Assoc 112: Bouquot J, Kurland L, Weiland L (1999). Leukoplakia of the head and neck: characteristics of 568 lesions with 6,720 person years follow-up. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88: 202 (abstract). Cancer Research Campaign (1990). Cervical Cancer Screening Factsheet Cowan CG, Gregg TA, Kee F (1992). Trends in the incidence of intra-oral carcinoma in Northern Ireland, Br Dent J 173: Cowan CG, Gregg TA, Kee F (1995). Prevention and detection of oral cancer: the views of primary care dentists in Northern Ireland. Br Dent J 179: Gregg TA, Cowan CG, Kee F (1992). Trends in the relative frequency of histologically epithelial dysplasia and intra-oral carcinoma in Northern Ireland, Br Dent J 173: Gupta PC, Mehta FS, Daftary DK et al (1980). Incidence rates of oral cancers and natural history of oral precancerous lesions in a ten-year follow up study of Indian villagers. Community Dent Oral Epidemiol 8: Gupta PC (1989). Leukoplakia and the incidence of oral cancer. J Oral Pathol Med 18: 17. Health and Social Wellbeing Survey ( ). Preliminary Report DHSS (NI). Hogewind WC, van der Kwast WAM, van der Waal I (1989). Oral leukoplakia, with emphasis on malignant transformation. J Craniomaxillofac Surg 17: Kramer IRH, El-Labban N, Lee KW (1978). The clinical features and risk of malignant transformation in sublingual keratosis. Br Dent J 144: Lind PO (1987). Malignant transformation in oral leukoplakia. Scand J Dent Res 95: Lummerman H, Freedman P, Kerpel S (1995). Oral epithelial dysplasia and the development of invasive squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 79: Mashberg A, Morrissey JB, Garfinkel L (1973). A study of the appearance of early asymptomatic oral squamous cell carcinoma. Cancer 32: Mehta FS, Pindborg JJ, Gupta PC et al (1969). Epidemiologic and histologic study of oral cancer and leukoplakia among 50,915 villagers in India. Cancer 24: Mincer HH, Coleman SA, Hopkins KP (1972). Observations on the clinical characteristics of oral lesions showing histological epithelial dysplasia. Oral Surg Oral Med Oral Pathol 33: Muir C, Waterhouse T, Mack J et al (eds) (1987). Cancer Incidence in Five Continents. Vol V, IARC Scientific Publication 88, Lyon. Pindborg JJ, Renstrup G, Jolst O, Roed-Peterson B (1968). Studies in oral leukoplakia: a preliminary report on the period prevalence of malignant transformation in leukoplakia based on follow-up study of 248 patients. J Am Dent Assoc 76: Pindborg JJ, Reibel J, Holmstrup P (1985). Subjectivity in evaluating oral epithelial dysplasia, carcinoma-in-situ and initial carcinoma. J Oral Pathol 14: Schepman KP, van der Meij EH, Smeele LE et al (1998). Malignant transformation of oral leukoplakia: a follow-up study of a hospital-based population of 166 patients with oral leukoplakia from The Netherlands. Oral Oncol 34: Schepman KP, van der Meij EH, Smeele LE, van der Waal I (1999). Concomitant leukoplakia in patients with oral squamous cell carcinoma. Oral Dis 5: Shafer WG, Waldron CA (1975). Erythroplakia of the oral cavity. Cancer 36: Shibuya H, Amagasa T, Seto K-I et al (1986). Leukoplakia-associated multiple carcinomas in patients with tongue carcinoma. Cancer 57: Silverman S, Bhargava K, Mani NJ et al (1976). Malignant trans- 23

8 24 formation and natural history of oral leukoplakia in 57,518 industrial workers of Gujarat, India. Cancer 38: Silverman S, Gorsky M, Lozada F (1984). Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer 53: Speight PM, Downer MC, Zakrzewska J (eds) (1993). Screening for oral cancer and precancer. Report of a UK Working Group. Conclusions and recommendations. Community Dent Health 10 (Suppl 1): Waldron C, Shafer W (1975). Leukoplakia revisited: a clinicopathological study of 3,256 oral leukoplakias. Cancer 36: Winawer SJ, Schotenfield D, Flehinger BJ (1991). Colorectal cancer screening. J Natl Cancer Inst 83: