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A retrospective analysis of clinical features of oral malignant and potentially malignant disorders with and without oral epithelial dysplasia
Vol. 116 No. 6 December 2013
A retrospective analysis of clinical features of oral malignant and potentially malignant disorders with and without oral epithelial dysplasia Fatima Dost, BOralH, MPhil,a,b Kim-Anh Lê Cao, PhD, MSc,c Pauline J. Ford, BDSc (Hons), BDentSt, PhD, GCHEd,b and Camile S. Farah, BDSc, MDSc, PhD, FRACDS (OralMed)a,b The University of Queensland, Herston, Brisbane, and St Lucia, Australia
Objective. Clinical identification of underlying histopathology of oral mucosal lesions (OMLs) remains difficult. The study aims to identify clinical indicators of underlying histopathology of oral malignant and potentially malignant disorders. Study Design. All clinical patient records of an oral medicine and pathology clinic over a 12-year period were manually searched. Cases of OMLs with a histopathologic diagnosis of dysplasia (n ¼ 124) and malignancy (n ¼ 27) and a sample of nondysplastic OMLs (n ¼ 109) were analyzed using both univariate and multivariate analysis and odds ratios for an association with clinical characteristics. Results. A nonhomogeneous clinical appearance was strongly associated with underlying dysplasia in both univariate and multivariate analysis (P < .001; odds ratio, 4.4). For lesions with homogeneous appearance, dysplasia was associated with lesion location (P ¼ .005; odds ratio, 2.6) and smoking history (P ¼ .04). Conclusions. These findings suggest that a nonhomogeneous mucosal lesion is a significant independent indicator for underlying oral epithelial dysplasia, with location, size, and color as additional contributing factors. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:725-733)
Oral and oropharyngeal cancers combined are the sixth most common cancers worldwide, with an estimated prevalence of over 500 000 and an annual incidence of 275 000.1 Globally, approximately 90% of cancers of the upper aerodigestive tract, including the oral cavity, are squamous cell carcinoma (SCC), a malignancy that has a high tendency to metastasize to regional lymph nodes and occurs primarily in older individuals.1-3 Risk factors for oral SCC include tobacco exposure and excessive alcohol consumption, and for cancers of the lip, excessive ultraviolet light exposure.3 Mortality rates for oral SCC remain high, despite advances in oncology therapy, with 5-year survival rates at approximately 50% for late stage tumors, whereas survival rates have been reported as low as 15% for some parts of the oral cavity.1 Tumor stage at diagnosis is the greatest factor in determining prognosis, with early stages having better survival outcomes.4,5 There is therefore a need for early diagnosis of oral SCCs, ideally at the premalignant or potentially malignant stage. Oral epithelial dysplasia (OED) is a histopathologic diagnosis that describes this precancerous stage, and it is characterized by a range of cellular and morphologic tissue This work was supported by a grant from Cancer Australia held by author C.S.F. a The University of Queensland, Centre for Clinical Research, Herston. b The University of Queensland, School of Dentistry, Brisbane. c The University of Queensland, Queensland Facility for Advanced Bioinformatics, St Lucia. Received for publication May 9, 2013; returned for revision Aug 5, 2013; accepted for publication Aug 7, 2013. Ó 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.08.005
changes which are similar to those of SCC but are restricted to epithelial cells only and remain noninvasive.3 Histopathologic assessment for the presence of OED is considered the current gold standard for predicting malignant transformation of oral potentially malignant disorders (OPMDs).6-8 OED may manifest in a wide range of clinical presentations. Generally, mucosal lesions that exhibit redness or are of an irregular surface texture (nonhomogeneous) are at a greater risk of harboring dysplastic cells.9 This clinical appearance often guides the decision to undertake surgical intervention over the course of follow-up, with the “wait and watch” approach watching for these clinical changes. Although various other factors may contribute to the decision to surgically intervene, including smoking history, patient gender, lesion size, and age, the clinical appearance is often the primary factor. Although these clinical features may estimate the rate of dysplasia occurring within OPMDs, there is no way of meaningfully differentiating OPMDs into dysplastic and nondysplastic based on clinical
Statement of Clinical Relevance This study provides new data on the clinical characteristics of oral potentially malignant disorders presenting with underlying oral epithelial dysplasia, including nonhomogeneity, surface texture, and lesion extension. We also provide a proposal for the routine identification and management of oral potentially malignant disorders at initial presentation. 725
ORAL MEDICINE 726 Dost et al.
examination alone, because dysplasia may manifest clinically in any number of presentations.10-13 Of significance are homogeneous leukoplakias, which, although displaying a low rate of OED, are considered the most common OPMDs, suggesting a clinically significant rate of malignant transformation, despite their supposed benign or low-risk nature.9 The aim of this study was therefore to retrospectively identify whether any clinical factors are associated with oral malignant and potentially malignant histopathology. It is hypothesized that lesions that present with underlying OED or malignancy are more likely to have a clinically nonhomogeneous appearance.
MATERIALS AND METHODS A retrospective audit of the clinical records of an oral medicine and pathology specialist referral practice in Brisbane, Australia, was undertaken. The single-site practice receives referrals from general and specialist dentists as well as medical practitioners for oral lesions that are clinically suspicious for malignancy or premalignancy and may warrant biopsy.14 The clinic is serviced by a single oral medicine and pathology specialist (C.S.F.) who undertook all clinical examinations, chart entries, photographic records, clinical descriptions, provisional diagnoses, and biopsy procedures found in this study. Clinical records were retrospectively manually searched for patients with a histopathologic diagnosis of interest: no dysplasia, dysplasia, oral lichen planus (OLP), or malignancy. The no dysplasia group included diagnoses of hyperkeratosis, hyperplasia, chronic hyperplastic candidiasis, or atypia. All cases of dysplasia and malignancy were included for analysis. Cases of no dysplasia and OLP were identified based on the histopathologic diagnosis as determined in previous studies of OPMDs by the authors.15-17 For each case, information regarding patient demographics (gender, age), exposure to risk factors (tobacco, alcohol, mouthrinse), and lesion characteristics (anatomic location, color, surface texture, size and extension, pain) was obtained. Lesions were categorized according to site as being of the external lip, labial mucosa, tongue, floor of the mouth, gingiva and alveolus, palate, and buccal mucosa. Clinical diagnosis was categorized into 4 groups described previously as homogeneous, nonhomogeneous, lichenoid, and other lesions.16 Homogeneous lesions are those that are consistent in appearance and texture across the entire surface of the lesion, whereas nonhomogeneous lesions are those that are uneven in color, composition, or texture from one area to another. Histopathologic diagnosis was based on biopsy results reported at the time of initial biopsy by a single external pathologist with training in head and neck pathology and was categorized
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as no dysplasia, dysplasia, OLP, or malignancy based on conventional histopathologic guidelines.3,18 Dysplasia was further classified into mild, moderate, and severe/ carcinoma in situ based on conventional guidelines.3,19 Extensive OPMDs that varied in clinical appearance or that extended over multiple oral sites underwent multiple biopsy sampling. Tobacco, alcohol, and mouthrinse use were all selfreported by the patient. For tobacco, patients were categorized as current users, past users, or never users, and pack-years were calculated.20 Regular alcohol consumption and mouthrinse use were subjectively reported by the patient as either exposed or unexposed. Statistical analysis was undertaken using the R software (version 2.15.0; multicontributor freeware, www.r-project.org) and IBM SPSS (version 20.0; IBM, Armonk, NY, USA). Descriptive analysis was performed for all relevant variables. Outcomes of interest were the histopathologic diagnosis and, for those with a diagnosis of OED, the grade of dysplasia. Univariate analysis (Fisher exact test) and multivariate analysis (multinomial logistic regression) were performed to determine whether any patient or clinical factors were associated with the outcome variables. Associations between behavioral factors and clinical features were also investigated. A P value of <.05 was considered significant. Odds ratios (ORs) were also calculated. This study was conducted according to Human Ethics Guidelines approved by The University of Queensland (2007001478) and the Royal Brisbane and Women’s Hospital (HREC/10/QRBW/336).
RESULTS A total of 216 patients were included in the study, from which 260 biopsies were included for analysis. Biopsies were undertaken over the course of 12 years, between March 2000 and September 2012. Patient features are described in Table I. The mean age at diagnosis was 57.9 years (standard deviation [SD], 13.0). Approximately half the population reported a history of smoking, at a mean level of exposure of 28.0 pack-years (SD, 21.2; interquartile range, 12.537.8). Table II presents the features of the 260 biopsies undertaken. Fisher exact test found a significant association for histopathologic diagnosis with gender, lifetime tobacco exposure, regular alcohol consumption, lesion extension, color, size, and clinical diagnosis. Malignancy was approximately equal between genders, but dysplasia was more likely to be diagnosed among men. Lifetime exposure to tobacco and regular alcohol consumption were significantly associated with dysplasia on histopathology, but these 2 risk habits were also significantly associated with the male gender
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ORIGINAL ARTICLE Dost et al. 727
Table I. Characteristics of patients presenting for assessment of clinically suspicious oral mucosal lesions Variable
Male, n (%) Female, n (%) Total, n (%)
Total 105 (51.4) Tobacco use (n ¼ 216) Never 41 (40.6) Ever 64 (55.6) Current 43 (59.7) Past 21 (48.8) Betel 1 (50.0) Alcohol use (n ¼ 216) Yes 66 (57.9) No 39 (38.2) Mouthrinse use (n ¼ 98) Yes 10 (55.6) No 34 (42.5)
111 (48.6) 60 51 29 22 1
(59.4) (44.3) (40.3) (51.2) (50.0)
216 (100.0) 101 115 72 43 2
(100.0) (100.0) (100.0) (100.0) (100.0)
48 (42.1) 63 (61.8)
114 (100.0) 102 (100.0)
8 (44.4) 46 (57.5)
18 (100.0) 80 (100.0)
(P ¼ .02 and P < .01, respectively). A greater proportion of mouthrinse users had dysplasia on histopathology, but this did not reach statistical significance. Multisite lesions were more likely among patients who reported a history of smoking (P ¼ .002). Clinical diagnosis was the variable most associated with histopathologic diagnosis within the univariate analysis. This association remained significant when OLP and malignancy were excluded as outcome variables, owing to their high call rate (P < .001). Furthermore, exclusion of OLP and malignancy resulted in attenuation of several variables; only surface texture and color, factors that contribute to the final clinical diagnosis, remained significant (P < .001 and P ¼ .05, respectively). On multinomial logistic regression, lesion extension, smoking history, surface texture, and clinical diagnosis remained significant independent factors for histopathology. Further analysis using a backward feature selection approach in the multinomial model indicated that both the clinical diagnosis and location variables significantly contributed to histopathologic diagnosis. Based on these findings, an adjusted multinomial model was applied to these variables. Compared with a homogeneous lesion with no dysplasia, all other lesion categories were more likely to present with dysplasia; this risk of dysplasia was increased by 4.2 times for a nonhomogeneous lesion and 3.1 times for a lichenoid lesion. This was also true for occurrence of malignancy, which was significantly less likely to present in homogeneous lesions. In relation to dysplasia grading, an association was not found between any patient or clinical variables and the grade of dysplasia on histopathology through univariate analysis (Table III). Multivariate analysis found a significant relationship for dysplasia grading with smoking status, when divided into current, past, and never exposed (P ¼ .04).
Further analysis of homogeneous lesions only found that the presence of underlying OED was significantly associated with the location of the lesion (P ¼ .005) and smoking history (P ¼ .04). Of significance, OED was more likely to occur on the tongue and floor of the mouth, whereas a homogeneous lesion of the gingiva was unlikely to be dysplastic. The odds ratio of dysplasia or malignancy occurring in the tongue or floor of the mouth compared with other anatomic sites was 2.6 (Figure 1). Nineteen patients underwent multiple biopsy sampling owing to the presence of large lesions extending onto multiple sites or owing to irregularity in lesion consistency. Biopsy site selection was based on specialist clinical judgment as to the area that was deemed most severe. The majority of these patients (n ¼ 14, 73.7%) reported a history of tobacco exposure (Table IV).
DISCUSSION The usefulness of clinical appearance as an indicator for tissue dysplasia has previously been reported in the literature, with those lesions exhibiting redness or a nonhomogeneous texture more likely to be dysplastic.9,21,22 Homogeneous leukoplakias, those that exhibit a predominantly white appearance, tend to be problematic in relation to management. Rates of OED and malignant transformation for leukoplakia vary significantly between studies and geographic settings. Furthermore, the diagnosis of oral leukoplakia has been revised and modified over several decades, making comparisons across studies difficult.23 The annual global malignant transformation rate of oral leukoplakia has been estimated to be less than 2%, and less than 0.03% of oral SCCs may be attributed to a precursor leukoplakia.24 Given the dynamic nature of oral leukoplakia, with reference to the fact that these lesions may regress or further develop depending on both local and systemic conditions, close monitoring for the development of OED or malignancy is necessary.25-28 A nonhomogeneous clinical appearance was strongly associated with OED and therefore indicative of significant adverse tissue changes, although this has not been consistently noted.10-13 This study found that clinical factors relating to OPMD, including lesion extension, surface texture, clinical diagnosis, and, to a lesser extent, tobacco exposure, were consistently associated with histopathology in both univariate and multivariate analyses. Given that clinical appearance was reliably associated with histopathology, this is the primary factor that clinicians should use when assessing the need for surgical biopsy at initial presentation. This concept is clearly supported by the current study, in which a nonhomogeneous appearance was highly
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Table II. Summary of histopathologic diagnosis against selected patient and clinical variables Histopathologic diagnosis, n (%) P*
Variable
No dysplasia
Dysplasia
Oral lichen planus
Malignancy
Total
Total Gender Male Female Age at diagnosis <45 years >45 years Tobacco use Yes No Alcohol use Yes No Mouthrinse use (n ¼ 112) Yes No Location Buccal mucosa Tongue Gingiva External lip Floor of the mouth Palate Labial mucosa Lesion extension Single site Multiple site Lesion color White White and red Surface texture Uniform Irregulary Ulcer Growthz Pain Yes No Lesion size (n ¼ 219) <200 mm2 200 mm2 Clinical diagnosis Homogeneous Nonhomogeneous Lichenoid Other
73 (100.0)
124 (100.0)
36 (100.0)
27 (100.0)
260 (100.0)
40 (54.8) 33 (45.2)
69 (55.6) 55 (44.4)
7 (19.4) 29 (80.6)
14 (51.9) 13 (48.1)
130 (50.0) 130 (50.0)
9.7 104
17 (23.3) 56 (76.7)
16 (12.9) 108 (87.1)
6 (16.7) 30 (83.3)
3 (11.1) 24 (88.9)
42 (15.8) 218 (81)
.263
42 (57.5) 31 (42.5)
80 (64.5) 44 (35.5)
14 (38.9) 22 (61.1)
14 (51.9) 13 (48.1)
150 (57.7) 110 (42.3)
.048
34 (46.6) 39 (53.4)
75 (60.5) 49 (39.5)
16 (44.4) 20 (55.6)
20 (74.1) 7 (25.9)
145 (55.8) 115 (44.2)
.027
8 (17.0) 39 (83.0)
10 (31.3) 22 (68.8)
2 (7.4) 25 (92.6)
2 (33.3) 4 (66.7)
22 (19.6) 90 (80.4)
.079
20 18 18 5 8 3 1
41 42 12 13 11 4 1
(33.1) (33.9) (9.7) (10.5) (8.9) (3.2) (0.8)
18 (50.0) 7 (19.4) 6 (16.7) 2 (5.6) 3 (8.3) 0 0
0 9 (33.3) 8 (29.6) 3 (11.1) 5 (18.5) 2 (7.4) 0
79 76 44 23 27 9 2
42 (57.5) 31 (42.5)
53 (42.7) 71 (57.3)
7 (19.4) 29 (80.6)
15 (55.6) 12 (44.4)
117 (45.0) 143 (55.0)
59 (80.8) 14 (19.2)
81 (65.3) 43 (34.7)
16 (44.4) 20 (55.6)
7 (25.9) 20 (74.0)
163 (62.7) 97 (37.3)
42 18 5 8
35 55 56 8
(28.2) (44.6) (45.2) (6.5)
15 (41.7) 14 (38.9) 7 (9.4) 0
1 (3.7) 4 (14.8) 14 (51.9) 8 (29.6)
12 (16.4) 61 (83.6)
27 (21.8) 97 (78.2)
10 (27.8) 26 (72.2)
10 (37.0) 17 (63.0)
59 (22.7) 201 (77.3)
41 (80.4) 10 (19.6)
79 (69.3) 35 (30.7)
17 (58.6) 12 (41.4)
9 (36.0) 16 (64.0)
146 (66.7) 73 (33.3)
38 17 9 9
32 63 25 4
0 8 (22.2) 28 (77.7) 0
1 (3.7) 22 (81.5) 1 (3.7) 3 (11.1)
71 110 63 16
(27.4) (24.7) (24.7) (6.8) (11.0) (4.1) (1.4)
(57.5) (24.7) (6.8) (11.0)
93 91 82 24
(31.2) (29.2) (16.9) (8.8) (10.4) (3.5) (0.8) .001 1.2 106
(35.8) (35.0) (31.5) (9.2) .146
.001
(52.1) (23.3) (12.3) (12.3)
(25.8) (50.8) (20.2) (3.2)
(27.3) (42.3) (24.2) (6.2)
3.0 1019
*Fisher exact test; test not undertaken for location and surface texture, owing to low cell count. Includes speckled, corrugated, and, for oral lichen planus, erosive lesions. z Includes nodules, exophytic masses, and lumps. y
associated with underlying OED at initial biopsy using standardized clinical descriptors and category assignments (P < 3.0 1019; OR, 4.4). This is further supported by the finding that lesion surface texture was strongly associated with presence of OED (P ¼ .01). Furthermore, because clinical appearance is employed to assess further tissue changes during long-term surveillance of OPMD, this remains the only feature
that can reliably be used to assess the need for additional surgical intervention. A large number of homogeneous lesions in this study presented with OED, and discerning the histopathology of these lesions is much more difficult. For these lesions, anatomic site and, to a lesser extent, smoking history were associated with histopathology. A significant association exists between tobacco exposure and
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ORIGINAL ARTICLE Dost et al. 729
Table III. Summary of dysplasia grading against selected patient and clinical variables Dysplasia grade, n (%) Variable
Mild dysplasia
Moderate dysplasia
Severe dysplasia/carcinoma in situ
Total
Total Tobacco use Yes No Alcohol use Yes No Gender Male Female Location Buccal mucosa Tongue Gingiva External lip Floor of the mouth Palate Labial mucosa Lesion extension Single site Multiple site Mouthrinse usey Yes No
75
19
17
124
40 (63.5) 28 (70.0)
10 (15.9) 8 (20.0)
13 (20.6) 4 (10.0)
63 (100.0) 40 (100.0)
.443
41 (67.2) 26 (63.4)
12 (19.7) 6 (14.6)
8 (13.1) 9 (22.0)
61 (100.0) 41 (100.0)
.390
42 (70.0) 33 (64.7)
9 (15.1) 10 (19.6)
9 (15.0) 8 (15.7)
60 (100.0) 51 (100.0)
.811
26 (72.2) 24 (64.9) 5 (50.0) 11 (84.6) 5 (45.5) 4 (100.0) 0
7 (19.4) 6 (16.2) 1 (10.0) 1 (7.7) 4 (36.4) 0 0
3 (8.3) 7 (18.9) 4 (40.0) 1 (7.7) 2 (18.2) 0 0
36 (100.0) 37 (100.0) 10 (100.0) 13 (100.0) 11 (100.0) 4 (100.0) 0
.294
35 (46.7) 40 (53.3)
9 (47.4) 10 (52.6)
6 (35.3) 11 (64.7)
50 (45.0) 61 (55.0)
.685
7 (70.0) 17 (81.0)
2 (20.0) 3 (14.3)
1 (10.0) 1 (4.8)
10 (100.0) 21 (100.0)
.668
P*
*Fisher exact test. y Reported for n ¼ 31 cases.
leukoplakia development, with an increased risk of up to 6 times in smokers compared with nonsmokers.29,30 In relation to the development of OED, tobacco exposure and level of tobacco exposure have been significantly associated with dysplastic tissue changes.29,30 A recent review, however, challenges the currently accepted notion of a cause-and-effect relationship between smoking and development of OPMDs, in particular leukoplakia. Arduino et al.24 argue that the landmark studies were conducted without appropriate statistical analysis and that more recent studies fail to adjust for confounding factors, such as alcohol exposure, which has a synergistic effect with tobacco.24,31-33 In the current study, a history of smoking was also associated with multisite lesion extension, which suggests that the effects of smoking tobacco may be seen throughout the mucosa. This often reduces the clinical suspicion of OED, because the changes are viewed as reactive and, owing to their widespread nature, unlikely to be dysplastic. This is not supported by data in the current study, because homogeneous lesions that presented in patients with a history of smoking were associated with OED. It would therefore seem reasonable to undertake biopsy on homogeneous lesions that present in patients with a history of smoking, although biopsy site selection remains an
important consideration in multisite lesions, because a single biopsy may be unrepresentative of the entire mucosa. In this study, biopsies of homogeneous lesions that presented on the tongue and floor of the mouth were significantly more likely to be dysplastic, which is consistent with previous studies.12,34 These sites, particularly the floor of the mouth, are associated with more severe dysplastic changes compared with the remaining mucosa, although this was not noted in the present study. Therefore, biopsy site selection among smokers with extensive leukoplakic changes should be focused on the floor of the mouth and tongue to determine the most advanced histopathologic changes. Another subset of oral mucosal lesions that present a challenge are oral lichenoid conditions, particularly lichenoid dysplasia and OLP. In this study, OLP was identified in 37 biopsies, which were mostly identified as lichenoid on clinical examination, although a number were described as nonhomogeneous. Lichenoid dysplasia has been proposed to describe lesions that on histopathology are primarily dysplastic in nature but exhibit some features of OLP.35,36 In this study, 20% (25/124) of OED cases exhibited lichenoid features. OLP requires symptomatic management and regular surveillance for changes indicative of
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Fig. 1. Schematic representation of selected oral potentially malignant disorder characteristics that may predict histopathology.
either OED or malignant transformation. Change to a nonhomogeneous presentation is generally considered the best indicator of adverse OPMD progression, and hence clinical appearance remains an important factor. Although there is conflicting evidence to support the role of alcohol in the development of OED and OPMD,21,25,37-41 in the current study, self-reporting of alcohol exposure was associated with histopathologic outcome. Over half of the OPMDs presenting with dysplasia occurred in patients who reported regular alcohol consumption. There is also an argument that the use of high-alcohol mouthrinses (>15% ethanol) may also contribute to the risk of developing oral cancer.41 In this study, the alcohol content of mouthrinse was not known, but given that alcohol-free mouthrinses were commercially unavailable in Australia before 2010, it may be expected that all patients who used mouthrinse were using an alcohol-containing mouthrinse, with the market leader being Listerine (Johnson & Johnson Pacific Pty Ltd), whose rinses range from 8% to 26% ethanol by volume.41 Although the significant details for duration and frequency of use are not available, these data provide some insight into mouthrinse use patterns of patients presenting with OPMDs, given that there was a higher proportion of patients who
were mouthrinse users presenting with dysplasia on histopathology. The readers should recognize the inherent limitations of this retrospective study design, as well as the missing data regarding mouthrinse use, information regarding alcohol exposure, and complete clinical information. Furthermore, some subjectivity is expected in the interpretation and categorization of clinical features, emphasizing the importance of detailed record keeping including digital photographs.
CONCLUSIONS The clinical appearance (color and homogeneity) of a mucosal lesion is a significant factor in the management of OED and OPMD and therefore guides the decision to undertake surgical biopsy. The present study substantiates that a nonhomogeneous mucosal lesion is a strongly significant independent indicator for underlying OED. Based on the present findings, it may be concluded that once a mucosal lesion has been designated as nonhomogeneous, biopsy should be undertaken to confirm the presence of underlying OED. The corollary may also be true: that designation of a clinical lesion as nonhomogeneous is not meaningful in terms of a final diagnosis, and perhaps such lesions should be designated clinically as potentially dysplastic
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ORIGINAL ARTICLE Dost et al. 731
Table IV. Selected patient and specimen characteristics of cases undergoing multiple biopsy sampling within 6 months Patient No.
Gender
Location of lesion
1
F
Right anterior and posterior mandibular alveolar ridge extending onto the buccal mucosal and soft palate
2
M
Right lateral tongue
3
M
Bilateral lower lip
4
M
Bilateral lower lip
5
F
Right buccal mucosa extending to the buccal sulcus
6
M
Left lateral tongue
7
F
Bilateral floor of the mouth extending into the right gingiva
8
F
Bilateral tongue
9
F
Left buccal mucosa
10
F
11
F
Right buccal mucosa Right posterior lateral tongue Right lateral tongue
12
M
Right posterior alveolar ridge extending to the retromolar pad
13
M
Left dorsal and ventral tongue
Right lateral tongue extending to the ventral tongue 14
F
15
M
16
M
17
M
18
F
19
M
Bilateral floor of the mouth Left buccal mucosa Bilateral floor of the mouth Left lower alveolus extending into floor of the mouth and posterior palate
Right alveolar ridge extending into the buccal sulcus Left buccal mucosa Right alveolar ridge extending into the buccal sulcus Lower lip Upper lip Bilateral buccal mucosa extending to the maxillary vestibule Bilateral buccal mucosa
Biopsy location
Clinical diagnosis
Diagnosis
Anterior gingiva
Nonhomogeneous
Malignancy
Posterior gingiva Right lateral tongue Right lateral tongue Left lower lip Right lower lip Right lower lip Left lower lip Right buccal mucosa
Nonhomogeneous Nonhomogeneous Homogeneous Nonhomogeneous Nonhomogeneous Other Other Homogeneous
Malignancy Dysplasia, NOS Dysplasia, mild Dysplasia, mild Malignancy No dysplasia Malignancy Dysplasia, mild
Right buccal sulcus Left anterior lateral tongue Left posterior lateral tongue Left anterior floor of the mouth Right posterior floor of the mouth Right gingiva, tooth 45-47 region Left anterior lateral tongue Left posterior lateral tongue Right lateral tongue Left buccal mucosa Left buccal mucosa Right buccal mucosa Right posterior lateral tongue Right posterior lateral tongue Right anterior lateral tongue Right retromolar pad
Nonhomogeneous Nonhomogeneous Nonhomogeneous Nonhomogeneous
Dysplasia, Dysplasia, Dysplasia, Dysplasia,
Nonhomogeneous
Dysplasia, moderate
Nonhomogeneous
Malignancy
Homogeneous Homogeneous Homogeneous Lichenoid Lichenoid Homogeneous Homogeneous Homogeneous Homogeneous Nonhomogeneous
Dysplasia, Dysplasia, Dysplasia, OLP OLP Dysplasia, Dysplasia, Dysplasia, Dysplasia, Dysplasia,
mild moderate mild moderate moderate
Right posterior gingiva Left posterior dorsal tongue Left anterior ventral tongue Left anterior dorsal tongue Right posterior lateral tongue
Nonhomogeneous Nonhomogeneous Homogeneous Nonhomogeneous Homogeneous
Dysplasia, Dysplasia, Dysplasia, Dysplasia, Dysplasia,
severe NOS severe severe NOS
Right anterior ventral tongue Left floor of the mouth Left buccal mucosa Right floor of the mouth Left alveolus
Homogeneous Nonhomogeneous Homogeneous Homogeneous Nonhomogeneous
Dysplasia, severe Dysplasia, moderate Dysplasia, severe Dysplasia, severe Malignancy
Left palate Right lateral tongue Right alveolar gingiva
Nonhomogeneous Nonhomogeneous Nonhomogeneous
Malignancy Malignancy Malignancy
Left buccal mucosa Right buccal mucosa
Nonhomogeneous Nonhomogeneous
Dysplasia, mild Dysplasia, mild
Lower lip Upper lip Right anterior buccal mucosa
Nonhomogeneous Nonhomogeneous Nonhomogeneous
Dysplasia, mild Dysplasia, mild No dysplasia
Right posterior buccal mucosa Left buccal mucosa Right buccal mucosa
Nonhomogeneous Homogeneous Nonhomogeneous
No dysplasia Dysplasia, mild Dysplasia, mild
F, female; M, male; NOS, not otherwise specified; OLP, oral lichen planus.
mild moderate moderate moderate
mild mild NOS
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lesions from the outset and excised accordingly. For homogeneous leukoplakia, which presents a more challenging clinical scenario, lesions presenting on the tongue and floor of the mouth, particularly among patients with a history of tobacco exposure, should be regarded as highly suspicious for OED. REFERENCES 1. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45:309-316. 2. Sugerman PB, Savage NW. Oral cancer in Australia: 1983-1996. Aust Dent J. 2002;47:45-56. 3. Barnes L, Eveson JW, Reichart P, Sidransky D, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Head and Neck Tumours. Lyon, France: IARC Press; 2005. 4. Sciubba JJ. Oral cancer: the importance of early diagnosis and treatment. Am J Clin Dermatol. 2001;2:239-251. 5. Gomez I, Seoane J, Varela-Centelles P, Diz P, Takkouche B. Is diagnostic delay related to advanced-stage oral cancer? A metaanalysis. Eur J Oral Sci. 2009;117:541-546. 6. McCullough MJ, Prasad G, Farah CS. Oral mucosal malignancy and potentially malignant lesions: an update on the epidemiology, risk factors, diagnosis and management. Aust Dent J. 2010;55(suppl 1):61-65. 7. Speight PM. Update on oral epithelial dysplasia and progression to cancer. Head Neck Pathol. 2007;1:61-66. 8. Warnakulasuriya S, Reibel J, Bouquot J, Dabelsteen E. Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement. J Oral Pathol Med. 2008;37:127-133. 9. Van Der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa: terminology, classification and present concepts of management. Oral Oncol. 2009;45:317-323. 10. Brouns E, Baart J, Karagozoglu K, Aartman I, Bloemena E, van der Waal I. Malignant transformation of oral leukoplakia in a welldefined cohort of 144 patients [e-pub]. Oral Dis; 2013 Mar 6. 11. Arduino PG, Surace A, Carbone M, et al. Outcome of oral dysplasia: a retrospective hospital-based study of 207 patients with a long follow-up. J Oral Pathol Med. 2009;38:540-544. 12. Jaber MA, Porter SR, Speight P, Eveson JW, Scully C. Oral epithelial dysplasia: clinical characteristics of western European residents. Oral Oncol. 2003;39:589-596. 13. Pereira J, Carvalho Mde V, Henriques AC, de Queiroz Camara TH, Miguel MC, Freitas Rde A. Epidemiology and correlation of the clinicopathological features in oral epithelial dysplasia: analysis of 173 cases. Ann Diagn Pathol. 2011;15:98-102. 14. Farah CS, Simanovic B, Savage NW. Scope of practice, referral patterns and lesion occurrence of an oral medicine service in Australia. Oral Dis. 2008;14:367-375. 15. Farah CS, McCullough MJ. A pilot case control study on the efficacy of acetic acid wash and chemiluminescent illumination (ViziLite) in the visualisation of oral mucosal white lesions. Oral Oncol. 2007;43:820-824. 16. Farah CS, McIntosh L, Georgiou A, McCullough MJ. Efficacy of tissue autofluorescence imaging (VELScope) in the visualization of oral mucosal lesions. Head Neck. 2012;34:856-862. 17. McIntosh L, McCullough MJ, Farah CS. The assessment of diffused light illumination and acetic acid rinse (Microlux/DL) in the visualisation of oral mucosal lesions. Oral Oncol. 2009;45: e227-e231. 18. Eisenberg E. Oral lichen planus: a benign lesion. J Maxillofac Surg. 2000;58:1278-1285.
OOOO December 2013 19. Pindborg JJ, Reichart P, Smith CJ, Van Der Waal I. World Health Organization: Histological Typing of Cancer and Precancer of the Oral Mucosa. Berlin, Germany: Springer-Verlag; 1997. 20. Grossi SG, Zambon JJ, Ho AW, et al. Assessment of risk for periodontal disease, I: risk indicators for attachment loss. J Periodontol. 1994;65:260-267. 21. Hashibe M, Mathew B, Kuruvilla B, et al. Chewing tobacco, alcohol, and the risk of erythroplakia. Cancer Epidem Biomar. 2000;9:639-645. 22. Schepman KP, van der Meij EH, Smeele LE, van der Waal I. 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. 1998;34: 270-275. 23. Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med. 2007;36:575-580. 24. Arduino P, Bagan J, El-Naggar A, Carrozzo M. Urban legends series: oral leukoplakia. Oral Dis. 2013;19(7):642-659. 25. Macigo FG, Mwaniki DL, Guthua SW. The association between oral leukoplakia and use of tobacco, alcohol and khat based on relative risks assessment in Kenya. Eur J Oral Sci. 1995;103: 268-273. 26. Roed-Petersen B. Effect on oral leukoplakia of reducing or ceasing tobacco smoking. Acta Derm-Venereol. 1982;62:164-167. 27. Pindborg JJ, Roed-Peterson B, Renstrup G. Role of smoking in floor of the mouth leukoplakias. J Oral Pathol. 1972;1:22-29. 28. Silverman S Jr, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer. 1984;53:563-568. 29. Lim K, Moles DR, Downer MC, Speight PM. Opportunistic screening for oral cancer and precancer in general dental practice: results of a demonstration study. Brit Dent J. 2003;194:497-502. discussion 493. 30. Baric JM, Alman JE, Feldman RS, Chauncey HH. Influence of cigarette, pipe, and cigar smoking, removable partial dentures, and age on oral leukoplakia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1982;54:424-429. 31. Ogden GR, Wight AJ. Aetiology of oral cancer: alcohol. Brit J Oral Max Surg. 1998;36:247-251. 32. Zygogianni AG, Kyrgias G, Karakitsos P, et al. Oral squamous cell cancer: early detection and the role of alcohol and smoking. Head Neck Oncol. 2011;3:2. 33. Znaor A, Brennan P, Gajalakshmi V, et al. Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. Int J Cancer. 2003;105:681-686. 34. Zhang L, Cheung KJ Jr, Lam WL, et al. Increased genetic damage in oral leukoplakia from high risk sites: potential impact on staging and clinical management. Cancer. 2001;91: 2148-2155. 35. Krutchkoff DJ, Eisenberg E. Lichenoid dysplasia: a distinct histopathologic entity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1985;60:308-315. 36. Eisenberg E, Krutchkoff DJ. Lichenoid lesions of oral mucosa. Diagnostic criteria and their importance in the alleged relationship to oral cancer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1992;73:699-704. 37. Shiu MN, Chen TH, Chang SH, Hahn LJ. Risk factors for leukoplakia and malignant transformation to oral carcinoma: a leukoplakia cohort in Taiwan. Brit J Cancer. 2000;82:18711874. 38. Dietrich T, Reichart PA, Scheifele C. Clinical risk factors of oral leukoplakia in a representative sample of the US population. Oral Oncol. 2004;40:158-163.
OOOO Volume 116, Number 6 39. Lee CH, Ko YC, Huang HL, et al. The precancer risk of betel quid chewing, tobacco use and alcohol consumption in oral leukoplakia and oral submucous fibrosis in southern Taiwan. Brit J Cancer. 2003;88:366-372. 40. García-Pola Vallejo MJ, Martínez Díaz-Canel AI, García Martín JM, González García M. Risk factors for oral soft tissue lesions in an adult Spanish population. Community Dent Oral. 2002;30:277-285. 41. McCullough MJ, Farah CS. The role of alcohol in oral carcinogenesis with particular reference to alcohol-containing mouthwashes. Aust Dent J. 2008;53:302-305.
ORIGINAL ARTICLE Dost et al. 733 Reprint requests: Camile S. Farah, BDSc, MDSc, PhD, FRACDS (OralMed) University of Queensland UQ Centre for Clinical Research Building 71/918 Royal Brisbane & Women’s Hospital Campus Herston, QLD 4029 Australia [email protected]
A retrospective analysis of clinical features of oral malignant and potentially malignant disorders with and without oral epithelial dysplasia Fatima Dost, BOralH, MPhil,a,b Kim-Anh Lê Cao, PhD, MSc,c Pauline J. Ford, BDSc (Hons), BDentSt, PhD, GCHEd,b and Camile S. Farah, BDSc, MDSc, PhD, FRACDS (OralMed)a,b The University of Queensland, Herston, Brisbane, and St Lucia, Australia
Objective. Clinical identification of underlying histopathology of oral mucosal lesions (OMLs) remains difficult. The study aims to identify clinical indicators of underlying histopathology of oral malignant and potentially malignant disorders. Study Design. All clinical patient records of an oral medicine and pathology clinic over a 12-year period were manually searched. Cases of OMLs with a histopathologic diagnosis of dysplasia (n ¼ 124) and malignancy (n ¼ 27) and a sample of nondysplastic OMLs (n ¼ 109) were analyzed using both univariate and multivariate analysis and odds ratios for an association with clinical characteristics. Results. A nonhomogeneous clinical appearance was strongly associated with underlying dysplasia in both univariate and multivariate analysis (P < .001; odds ratio, 4.4). For lesions with homogeneous appearance, dysplasia was associated with lesion location (P ¼ .005; odds ratio, 2.6) and smoking history (P ¼ .04). Conclusions. These findings suggest that a nonhomogeneous mucosal lesion is a significant independent indicator for underlying oral epithelial dysplasia, with location, size, and color as additional contributing factors. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:725-733)
Oral and oropharyngeal cancers combined are the sixth most common cancers worldwide, with an estimated prevalence of over 500 000 and an annual incidence of 275 000.1 Globally, approximately 90% of cancers of the upper aerodigestive tract, including the oral cavity, are squamous cell carcinoma (SCC), a malignancy that has a high tendency to metastasize to regional lymph nodes and occurs primarily in older individuals.1-3 Risk factors for oral SCC include tobacco exposure and excessive alcohol consumption, and for cancers of the lip, excessive ultraviolet light exposure.3 Mortality rates for oral SCC remain high, despite advances in oncology therapy, with 5-year survival rates at approximately 50% for late stage tumors, whereas survival rates have been reported as low as 15% for some parts of the oral cavity.1 Tumor stage at diagnosis is the greatest factor in determining prognosis, with early stages having better survival outcomes.4,5 There is therefore a need for early diagnosis of oral SCCs, ideally at the premalignant or potentially malignant stage. Oral epithelial dysplasia (OED) is a histopathologic diagnosis that describes this precancerous stage, and it is characterized by a range of cellular and morphologic tissue This work was supported by a grant from Cancer Australia held by author C.S.F. a The University of Queensland, Centre for Clinical Research, Herston. b The University of Queensland, School of Dentistry, Brisbane. c The University of Queensland, Queensland Facility for Advanced Bioinformatics, St Lucia. Received for publication May 9, 2013; returned for revision Aug 5, 2013; accepted for publication Aug 7, 2013. Ó 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.08.005
changes which are similar to those of SCC but are restricted to epithelial cells only and remain noninvasive.3 Histopathologic assessment for the presence of OED is considered the current gold standard for predicting malignant transformation of oral potentially malignant disorders (OPMDs).6-8 OED may manifest in a wide range of clinical presentations. Generally, mucosal lesions that exhibit redness or are of an irregular surface texture (nonhomogeneous) are at a greater risk of harboring dysplastic cells.9 This clinical appearance often guides the decision to undertake surgical intervention over the course of follow-up, with the “wait and watch” approach watching for these clinical changes. Although various other factors may contribute to the decision to surgically intervene, including smoking history, patient gender, lesion size, and age, the clinical appearance is often the primary factor. Although these clinical features may estimate the rate of dysplasia occurring within OPMDs, there is no way of meaningfully differentiating OPMDs into dysplastic and nondysplastic based on clinical
Statement of Clinical Relevance This study provides new data on the clinical characteristics of oral potentially malignant disorders presenting with underlying oral epithelial dysplasia, including nonhomogeneity, surface texture, and lesion extension. We also provide a proposal for the routine identification and management of oral potentially malignant disorders at initial presentation. 725
ORAL MEDICINE 726 Dost et al.
examination alone, because dysplasia may manifest clinically in any number of presentations.10-13 Of significance are homogeneous leukoplakias, which, although displaying a low rate of OED, are considered the most common OPMDs, suggesting a clinically significant rate of malignant transformation, despite their supposed benign or low-risk nature.9 The aim of this study was therefore to retrospectively identify whether any clinical factors are associated with oral malignant and potentially malignant histopathology. It is hypothesized that lesions that present with underlying OED or malignancy are more likely to have a clinically nonhomogeneous appearance.
MATERIALS AND METHODS A retrospective audit of the clinical records of an oral medicine and pathology specialist referral practice in Brisbane, Australia, was undertaken. The single-site practice receives referrals from general and specialist dentists as well as medical practitioners for oral lesions that are clinically suspicious for malignancy or premalignancy and may warrant biopsy.14 The clinic is serviced by a single oral medicine and pathology specialist (C.S.F.) who undertook all clinical examinations, chart entries, photographic records, clinical descriptions, provisional diagnoses, and biopsy procedures found in this study. Clinical records were retrospectively manually searched for patients with a histopathologic diagnosis of interest: no dysplasia, dysplasia, oral lichen planus (OLP), or malignancy. The no dysplasia group included diagnoses of hyperkeratosis, hyperplasia, chronic hyperplastic candidiasis, or atypia. All cases of dysplasia and malignancy were included for analysis. Cases of no dysplasia and OLP were identified based on the histopathologic diagnosis as determined in previous studies of OPMDs by the authors.15-17 For each case, information regarding patient demographics (gender, age), exposure to risk factors (tobacco, alcohol, mouthrinse), and lesion characteristics (anatomic location, color, surface texture, size and extension, pain) was obtained. Lesions were categorized according to site as being of the external lip, labial mucosa, tongue, floor of the mouth, gingiva and alveolus, palate, and buccal mucosa. Clinical diagnosis was categorized into 4 groups described previously as homogeneous, nonhomogeneous, lichenoid, and other lesions.16 Homogeneous lesions are those that are consistent in appearance and texture across the entire surface of the lesion, whereas nonhomogeneous lesions are those that are uneven in color, composition, or texture from one area to another. Histopathologic diagnosis was based on biopsy results reported at the time of initial biopsy by a single external pathologist with training in head and neck pathology and was categorized
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as no dysplasia, dysplasia, OLP, or malignancy based on conventional histopathologic guidelines.3,18 Dysplasia was further classified into mild, moderate, and severe/ carcinoma in situ based on conventional guidelines.3,19 Extensive OPMDs that varied in clinical appearance or that extended over multiple oral sites underwent multiple biopsy sampling. Tobacco, alcohol, and mouthrinse use were all selfreported by the patient. For tobacco, patients were categorized as current users, past users, or never users, and pack-years were calculated.20 Regular alcohol consumption and mouthrinse use were subjectively reported by the patient as either exposed or unexposed. Statistical analysis was undertaken using the R software (version 2.15.0; multicontributor freeware, www.r-project.org) and IBM SPSS (version 20.0; IBM, Armonk, NY, USA). Descriptive analysis was performed for all relevant variables. Outcomes of interest were the histopathologic diagnosis and, for those with a diagnosis of OED, the grade of dysplasia. Univariate analysis (Fisher exact test) and multivariate analysis (multinomial logistic regression) were performed to determine whether any patient or clinical factors were associated with the outcome variables. Associations between behavioral factors and clinical features were also investigated. A P value of <.05 was considered significant. Odds ratios (ORs) were also calculated. This study was conducted according to Human Ethics Guidelines approved by The University of Queensland (2007001478) and the Royal Brisbane and Women’s Hospital (HREC/10/QRBW/336).
RESULTS A total of 216 patients were included in the study, from which 260 biopsies were included for analysis. Biopsies were undertaken over the course of 12 years, between March 2000 and September 2012. Patient features are described in Table I. The mean age at diagnosis was 57.9 years (standard deviation [SD], 13.0). Approximately half the population reported a history of smoking, at a mean level of exposure of 28.0 pack-years (SD, 21.2; interquartile range, 12.537.8). Table II presents the features of the 260 biopsies undertaken. Fisher exact test found a significant association for histopathologic diagnosis with gender, lifetime tobacco exposure, regular alcohol consumption, lesion extension, color, size, and clinical diagnosis. Malignancy was approximately equal between genders, but dysplasia was more likely to be diagnosed among men. Lifetime exposure to tobacco and regular alcohol consumption were significantly associated with dysplasia on histopathology, but these 2 risk habits were also significantly associated with the male gender
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ORIGINAL ARTICLE Dost et al. 727
Table I. Characteristics of patients presenting for assessment of clinically suspicious oral mucosal lesions Variable
Male, n (%) Female, n (%) Total, n (%)
Total 105 (51.4) Tobacco use (n ¼ 216) Never 41 (40.6) Ever 64 (55.6) Current 43 (59.7) Past 21 (48.8) Betel 1 (50.0) Alcohol use (n ¼ 216) Yes 66 (57.9) No 39 (38.2) Mouthrinse use (n ¼ 98) Yes 10 (55.6) No 34 (42.5)
111 (48.6) 60 51 29 22 1
(59.4) (44.3) (40.3) (51.2) (50.0)
216 (100.0) 101 115 72 43 2
(100.0) (100.0) (100.0) (100.0) (100.0)
48 (42.1) 63 (61.8)
114 (100.0) 102 (100.0)
8 (44.4) 46 (57.5)
18 (100.0) 80 (100.0)
(P ¼ .02 and P < .01, respectively). A greater proportion of mouthrinse users had dysplasia on histopathology, but this did not reach statistical significance. Multisite lesions were more likely among patients who reported a history of smoking (P ¼ .002). Clinical diagnosis was the variable most associated with histopathologic diagnosis within the univariate analysis. This association remained significant when OLP and malignancy were excluded as outcome variables, owing to their high call rate (P < .001). Furthermore, exclusion of OLP and malignancy resulted in attenuation of several variables; only surface texture and color, factors that contribute to the final clinical diagnosis, remained significant (P < .001 and P ¼ .05, respectively). On multinomial logistic regression, lesion extension, smoking history, surface texture, and clinical diagnosis remained significant independent factors for histopathology. Further analysis using a backward feature selection approach in the multinomial model indicated that both the clinical diagnosis and location variables significantly contributed to histopathologic diagnosis. Based on these findings, an adjusted multinomial model was applied to these variables. Compared with a homogeneous lesion with no dysplasia, all other lesion categories were more likely to present with dysplasia; this risk of dysplasia was increased by 4.2 times for a nonhomogeneous lesion and 3.1 times for a lichenoid lesion. This was also true for occurrence of malignancy, which was significantly less likely to present in homogeneous lesions. In relation to dysplasia grading, an association was not found between any patient or clinical variables and the grade of dysplasia on histopathology through univariate analysis (Table III). Multivariate analysis found a significant relationship for dysplasia grading with smoking status, when divided into current, past, and never exposed (P ¼ .04).
Further analysis of homogeneous lesions only found that the presence of underlying OED was significantly associated with the location of the lesion (P ¼ .005) and smoking history (P ¼ .04). Of significance, OED was more likely to occur on the tongue and floor of the mouth, whereas a homogeneous lesion of the gingiva was unlikely to be dysplastic. The odds ratio of dysplasia or malignancy occurring in the tongue or floor of the mouth compared with other anatomic sites was 2.6 (Figure 1). Nineteen patients underwent multiple biopsy sampling owing to the presence of large lesions extending onto multiple sites or owing to irregularity in lesion consistency. Biopsy site selection was based on specialist clinical judgment as to the area that was deemed most severe. The majority of these patients (n ¼ 14, 73.7%) reported a history of tobacco exposure (Table IV).
DISCUSSION The usefulness of clinical appearance as an indicator for tissue dysplasia has previously been reported in the literature, with those lesions exhibiting redness or a nonhomogeneous texture more likely to be dysplastic.9,21,22 Homogeneous leukoplakias, those that exhibit a predominantly white appearance, tend to be problematic in relation to management. Rates of OED and malignant transformation for leukoplakia vary significantly between studies and geographic settings. Furthermore, the diagnosis of oral leukoplakia has been revised and modified over several decades, making comparisons across studies difficult.23 The annual global malignant transformation rate of oral leukoplakia has been estimated to be less than 2%, and less than 0.03% of oral SCCs may be attributed to a precursor leukoplakia.24 Given the dynamic nature of oral leukoplakia, with reference to the fact that these lesions may regress or further develop depending on both local and systemic conditions, close monitoring for the development of OED or malignancy is necessary.25-28 A nonhomogeneous clinical appearance was strongly associated with OED and therefore indicative of significant adverse tissue changes, although this has not been consistently noted.10-13 This study found that clinical factors relating to OPMD, including lesion extension, surface texture, clinical diagnosis, and, to a lesser extent, tobacco exposure, were consistently associated with histopathology in both univariate and multivariate analyses. Given that clinical appearance was reliably associated with histopathology, this is the primary factor that clinicians should use when assessing the need for surgical biopsy at initial presentation. This concept is clearly supported by the current study, in which a nonhomogeneous appearance was highly
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Table II. Summary of histopathologic diagnosis against selected patient and clinical variables Histopathologic diagnosis, n (%) P*
Variable
No dysplasia
Dysplasia
Oral lichen planus
Malignancy
Total
Total Gender Male Female Age at diagnosis <45 years >45 years Tobacco use Yes No Alcohol use Yes No Mouthrinse use (n ¼ 112) Yes No Location Buccal mucosa Tongue Gingiva External lip Floor of the mouth Palate Labial mucosa Lesion extension Single site Multiple site Lesion color White White and red Surface texture Uniform Irregulary Ulcer Growthz Pain Yes No Lesion size (n ¼ 219) <200 mm2 200 mm2 Clinical diagnosis Homogeneous Nonhomogeneous Lichenoid Other
73 (100.0)
124 (100.0)
36 (100.0)
27 (100.0)
260 (100.0)
40 (54.8) 33 (45.2)
69 (55.6) 55 (44.4)
7 (19.4) 29 (80.6)
14 (51.9) 13 (48.1)
130 (50.0) 130 (50.0)
9.7 104
17 (23.3) 56 (76.7)
16 (12.9) 108 (87.1)
6 (16.7) 30 (83.3)
3 (11.1) 24 (88.9)
42 (15.8) 218 (81)
.263
42 (57.5) 31 (42.5)
80 (64.5) 44 (35.5)
14 (38.9) 22 (61.1)
14 (51.9) 13 (48.1)
150 (57.7) 110 (42.3)
.048
34 (46.6) 39 (53.4)
75 (60.5) 49 (39.5)
16 (44.4) 20 (55.6)
20 (74.1) 7 (25.9)
145 (55.8) 115 (44.2)
.027
8 (17.0) 39 (83.0)
10 (31.3) 22 (68.8)
2 (7.4) 25 (92.6)
2 (33.3) 4 (66.7)
22 (19.6) 90 (80.4)
.079
20 18 18 5 8 3 1
41 42 12 13 11 4 1
(33.1) (33.9) (9.7) (10.5) (8.9) (3.2) (0.8)
18 (50.0) 7 (19.4) 6 (16.7) 2 (5.6) 3 (8.3) 0 0
0 9 (33.3) 8 (29.6) 3 (11.1) 5 (18.5) 2 (7.4) 0
79 76 44 23 27 9 2
42 (57.5) 31 (42.5)
53 (42.7) 71 (57.3)
7 (19.4) 29 (80.6)
15 (55.6) 12 (44.4)
117 (45.0) 143 (55.0)
59 (80.8) 14 (19.2)
81 (65.3) 43 (34.7)
16 (44.4) 20 (55.6)
7 (25.9) 20 (74.0)
163 (62.7) 97 (37.3)
42 18 5 8
35 55 56 8
(28.2) (44.6) (45.2) (6.5)
15 (41.7) 14 (38.9) 7 (9.4) 0
1 (3.7) 4 (14.8) 14 (51.9) 8 (29.6)
12 (16.4) 61 (83.6)
27 (21.8) 97 (78.2)
10 (27.8) 26 (72.2)
10 (37.0) 17 (63.0)
59 (22.7) 201 (77.3)
41 (80.4) 10 (19.6)
79 (69.3) 35 (30.7)
17 (58.6) 12 (41.4)
9 (36.0) 16 (64.0)
146 (66.7) 73 (33.3)
38 17 9 9
32 63 25 4
0 8 (22.2) 28 (77.7) 0
1 (3.7) 22 (81.5) 1 (3.7) 3 (11.1)
71 110 63 16
(27.4) (24.7) (24.7) (6.8) (11.0) (4.1) (1.4)
(57.5) (24.7) (6.8) (11.0)
93 91 82 24
(31.2) (29.2) (16.9) (8.8) (10.4) (3.5) (0.8) .001 1.2 106
(35.8) (35.0) (31.5) (9.2) .146
.001
(52.1) (23.3) (12.3) (12.3)
(25.8) (50.8) (20.2) (3.2)
(27.3) (42.3) (24.2) (6.2)
3.0 1019
*Fisher exact test; test not undertaken for location and surface texture, owing to low cell count. Includes speckled, corrugated, and, for oral lichen planus, erosive lesions. z Includes nodules, exophytic masses, and lumps. y
associated with underlying OED at initial biopsy using standardized clinical descriptors and category assignments (P < 3.0 1019; OR, 4.4). This is further supported by the finding that lesion surface texture was strongly associated with presence of OED (P ¼ .01). Furthermore, because clinical appearance is employed to assess further tissue changes during long-term surveillance of OPMD, this remains the only feature
that can reliably be used to assess the need for additional surgical intervention. A large number of homogeneous lesions in this study presented with OED, and discerning the histopathology of these lesions is much more difficult. For these lesions, anatomic site and, to a lesser extent, smoking history were associated with histopathology. A significant association exists between tobacco exposure and
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ORIGINAL ARTICLE Dost et al. 729
Table III. Summary of dysplasia grading against selected patient and clinical variables Dysplasia grade, n (%) Variable
Mild dysplasia
Moderate dysplasia
Severe dysplasia/carcinoma in situ
Total
Total Tobacco use Yes No Alcohol use Yes No Gender Male Female Location Buccal mucosa Tongue Gingiva External lip Floor of the mouth Palate Labial mucosa Lesion extension Single site Multiple site Mouthrinse usey Yes No
75
19
17
124
40 (63.5) 28 (70.0)
10 (15.9) 8 (20.0)
13 (20.6) 4 (10.0)
63 (100.0) 40 (100.0)
.443
41 (67.2) 26 (63.4)
12 (19.7) 6 (14.6)
8 (13.1) 9 (22.0)
61 (100.0) 41 (100.0)
.390
42 (70.0) 33 (64.7)
9 (15.1) 10 (19.6)
9 (15.0) 8 (15.7)
60 (100.0) 51 (100.0)
.811
26 (72.2) 24 (64.9) 5 (50.0) 11 (84.6) 5 (45.5) 4 (100.0) 0
7 (19.4) 6 (16.2) 1 (10.0) 1 (7.7) 4 (36.4) 0 0
3 (8.3) 7 (18.9) 4 (40.0) 1 (7.7) 2 (18.2) 0 0
36 (100.0) 37 (100.0) 10 (100.0) 13 (100.0) 11 (100.0) 4 (100.0) 0
.294
35 (46.7) 40 (53.3)
9 (47.4) 10 (52.6)
6 (35.3) 11 (64.7)
50 (45.0) 61 (55.0)
.685
7 (70.0) 17 (81.0)
2 (20.0) 3 (14.3)
1 (10.0) 1 (4.8)
10 (100.0) 21 (100.0)
.668
P*
*Fisher exact test. y Reported for n ¼ 31 cases.
leukoplakia development, with an increased risk of up to 6 times in smokers compared with nonsmokers.29,30 In relation to the development of OED, tobacco exposure and level of tobacco exposure have been significantly associated with dysplastic tissue changes.29,30 A recent review, however, challenges the currently accepted notion of a cause-and-effect relationship between smoking and development of OPMDs, in particular leukoplakia. Arduino et al.24 argue that the landmark studies were conducted without appropriate statistical analysis and that more recent studies fail to adjust for confounding factors, such as alcohol exposure, which has a synergistic effect with tobacco.24,31-33 In the current study, a history of smoking was also associated with multisite lesion extension, which suggests that the effects of smoking tobacco may be seen throughout the mucosa. This often reduces the clinical suspicion of OED, because the changes are viewed as reactive and, owing to their widespread nature, unlikely to be dysplastic. This is not supported by data in the current study, because homogeneous lesions that presented in patients with a history of smoking were associated with OED. It would therefore seem reasonable to undertake biopsy on homogeneous lesions that present in patients with a history of smoking, although biopsy site selection remains an
important consideration in multisite lesions, because a single biopsy may be unrepresentative of the entire mucosa. In this study, biopsies of homogeneous lesions that presented on the tongue and floor of the mouth were significantly more likely to be dysplastic, which is consistent with previous studies.12,34 These sites, particularly the floor of the mouth, are associated with more severe dysplastic changes compared with the remaining mucosa, although this was not noted in the present study. Therefore, biopsy site selection among smokers with extensive leukoplakic changes should be focused on the floor of the mouth and tongue to determine the most advanced histopathologic changes. Another subset of oral mucosal lesions that present a challenge are oral lichenoid conditions, particularly lichenoid dysplasia and OLP. In this study, OLP was identified in 37 biopsies, which were mostly identified as lichenoid on clinical examination, although a number were described as nonhomogeneous. Lichenoid dysplasia has been proposed to describe lesions that on histopathology are primarily dysplastic in nature but exhibit some features of OLP.35,36 In this study, 20% (25/124) of OED cases exhibited lichenoid features. OLP requires symptomatic management and regular surveillance for changes indicative of
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Fig. 1. Schematic representation of selected oral potentially malignant disorder characteristics that may predict histopathology.
either OED or malignant transformation. Change to a nonhomogeneous presentation is generally considered the best indicator of adverse OPMD progression, and hence clinical appearance remains an important factor. Although there is conflicting evidence to support the role of alcohol in the development of OED and OPMD,21,25,37-41 in the current study, self-reporting of alcohol exposure was associated with histopathologic outcome. Over half of the OPMDs presenting with dysplasia occurred in patients who reported regular alcohol consumption. There is also an argument that the use of high-alcohol mouthrinses (>15% ethanol) may also contribute to the risk of developing oral cancer.41 In this study, the alcohol content of mouthrinse was not known, but given that alcohol-free mouthrinses were commercially unavailable in Australia before 2010, it may be expected that all patients who used mouthrinse were using an alcohol-containing mouthrinse, with the market leader being Listerine (Johnson & Johnson Pacific Pty Ltd), whose rinses range from 8% to 26% ethanol by volume.41 Although the significant details for duration and frequency of use are not available, these data provide some insight into mouthrinse use patterns of patients presenting with OPMDs, given that there was a higher proportion of patients who
were mouthrinse users presenting with dysplasia on histopathology. The readers should recognize the inherent limitations of this retrospective study design, as well as the missing data regarding mouthrinse use, information regarding alcohol exposure, and complete clinical information. Furthermore, some subjectivity is expected in the interpretation and categorization of clinical features, emphasizing the importance of detailed record keeping including digital photographs.
CONCLUSIONS The clinical appearance (color and homogeneity) of a mucosal lesion is a significant factor in the management of OED and OPMD and therefore guides the decision to undertake surgical biopsy. The present study substantiates that a nonhomogeneous mucosal lesion is a strongly significant independent indicator for underlying OED. Based on the present findings, it may be concluded that once a mucosal lesion has been designated as nonhomogeneous, biopsy should be undertaken to confirm the presence of underlying OED. The corollary may also be true: that designation of a clinical lesion as nonhomogeneous is not meaningful in terms of a final diagnosis, and perhaps such lesions should be designated clinically as potentially dysplastic
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ORIGINAL ARTICLE Dost et al. 731
Table IV. Selected patient and specimen characteristics of cases undergoing multiple biopsy sampling within 6 months Patient No.
Gender
Location of lesion
1
F
Right anterior and posterior mandibular alveolar ridge extending onto the buccal mucosal and soft palate
2
M
Right lateral tongue
3
M
Bilateral lower lip
4
M
Bilateral lower lip
5
F
Right buccal mucosa extending to the buccal sulcus
6
M
Left lateral tongue
7
F
Bilateral floor of the mouth extending into the right gingiva
8
F
Bilateral tongue
9
F
Left buccal mucosa
10
F
11
F
Right buccal mucosa Right posterior lateral tongue Right lateral tongue
12
M
Right posterior alveolar ridge extending to the retromolar pad
13
M
Left dorsal and ventral tongue
Right lateral tongue extending to the ventral tongue 14
F
15
M
16
M
17
M
18
F
19
M
Bilateral floor of the mouth Left buccal mucosa Bilateral floor of the mouth Left lower alveolus extending into floor of the mouth and posterior palate
Right alveolar ridge extending into the buccal sulcus Left buccal mucosa Right alveolar ridge extending into the buccal sulcus Lower lip Upper lip Bilateral buccal mucosa extending to the maxillary vestibule Bilateral buccal mucosa
Biopsy location
Clinical diagnosis
Diagnosis
Anterior gingiva
Nonhomogeneous
Malignancy
Posterior gingiva Right lateral tongue Right lateral tongue Left lower lip Right lower lip Right lower lip Left lower lip Right buccal mucosa
Nonhomogeneous Nonhomogeneous Homogeneous Nonhomogeneous Nonhomogeneous Other Other Homogeneous
Malignancy Dysplasia, NOS Dysplasia, mild Dysplasia, mild Malignancy No dysplasia Malignancy Dysplasia, mild
Right buccal sulcus Left anterior lateral tongue Left posterior lateral tongue Left anterior floor of the mouth Right posterior floor of the mouth Right gingiva, tooth 45-47 region Left anterior lateral tongue Left posterior lateral tongue Right lateral tongue Left buccal mucosa Left buccal mucosa Right buccal mucosa Right posterior lateral tongue Right posterior lateral tongue Right anterior lateral tongue Right retromolar pad
Nonhomogeneous Nonhomogeneous Nonhomogeneous Nonhomogeneous
Dysplasia, Dysplasia, Dysplasia, Dysplasia,
Nonhomogeneous
Dysplasia, moderate
Nonhomogeneous
Malignancy
Homogeneous Homogeneous Homogeneous Lichenoid Lichenoid Homogeneous Homogeneous Homogeneous Homogeneous Nonhomogeneous
Dysplasia, Dysplasia, Dysplasia, OLP OLP Dysplasia, Dysplasia, Dysplasia, Dysplasia, Dysplasia,
mild moderate mild moderate moderate
Right posterior gingiva Left posterior dorsal tongue Left anterior ventral tongue Left anterior dorsal tongue Right posterior lateral tongue
Nonhomogeneous Nonhomogeneous Homogeneous Nonhomogeneous Homogeneous
Dysplasia, Dysplasia, Dysplasia, Dysplasia, Dysplasia,
severe NOS severe severe NOS
Right anterior ventral tongue Left floor of the mouth Left buccal mucosa Right floor of the mouth Left alveolus
Homogeneous Nonhomogeneous Homogeneous Homogeneous Nonhomogeneous
Dysplasia, severe Dysplasia, moderate Dysplasia, severe Dysplasia, severe Malignancy
Left palate Right lateral tongue Right alveolar gingiva
Nonhomogeneous Nonhomogeneous Nonhomogeneous
Malignancy Malignancy Malignancy
Left buccal mucosa Right buccal mucosa
Nonhomogeneous Nonhomogeneous
Dysplasia, mild Dysplasia, mild
Lower lip Upper lip Right anterior buccal mucosa
Nonhomogeneous Nonhomogeneous Nonhomogeneous
Dysplasia, mild Dysplasia, mild No dysplasia
Right posterior buccal mucosa Left buccal mucosa Right buccal mucosa
Nonhomogeneous Homogeneous Nonhomogeneous
No dysplasia Dysplasia, mild Dysplasia, mild
F, female; M, male; NOS, not otherwise specified; OLP, oral lichen planus.
mild moderate moderate moderate
mild mild NOS
ORAL MEDICINE 732 Dost et al.
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ORIGINAL ARTICLE Dost et al. 733 Reprint requests: Camile S. Farah, BDSc, MDSc, PhD, FRACDS (OralMed) University of Queensland UQ Centre for Clinical Research Building 71/918 Royal Brisbane & Women’s Hospital Campus Herston, QLD 4029 Australia [email protected]