Vol. 117 No. 4 April 2014
Histologic lichenoid features in oral dysplasia and squamous cell carcinoma Sarah G. Fitzpatrick, DDS,a Kord S. Honda, MD,b Abdus Sattar, PhD,c and Stanley A. Hirsch, DDS, MSa Case Western Reserve University, Cleveland, OH, USA
Objective. This study describes the occurrence of histopathologic characteristics of oral lichenoid mucositis in epithelial dysplasia and squamous cell carcinoma. Study Design. This retrospective review examined 352 histologic specimens of group 1 (mild to moderate dysplasia), group 2 (severe dysplasia or carcinoma in situ), and group 3 (squamous cell carcinoma) for correlation between 5 histologic characteristics frequently found in oral lichen planus and grade, age, gender, and oral subsite. Results. In this sample, 29% of all cases exhibited 3 or more lichenoid features. Lichenoid features were significantly more frequent in group 1 over group 2 lesions for cases meeting a minimum lichenoid threshold (P ¼ .001). No statistically significant patterns were noted for age or gender. The buccal mucosa was significantly overrepresented (P ¼ .039) and the floor of the mouth was significantly underrepresented (P ¼ .049) in regard to lichenoid feature frequency. Conclusions. This study confirms the frequent correlation of lichenoid characteristics in oral premalignant and malignant lesions. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:511-520)
The relationship between oral lichen planus (OLP) and oral lichenoid lesions (OLL), lesions with histologic lichenoid features often associated with medication or local agents or material not fulfilling clinical patterns of OLP, and oral squamous cell carcinoma (SCCA) has long been controversial. For the sake of brevity, both OLP and OLL together are referred to in this article under the nonspecific term oral lichenoid mucositis (OLM). Isolated case reports and observational studies have linked OLM to a variable yet generally low rate of malignant transformation; however, much inconsistency has been present in the criteria used for the diagnosis of the original cases of OLM, and many of the cases reported have been argued to have insufficient evidence to support the initial diagnosis.1 In 1985, the term “lichenoid dysplasia” was introduced to differentiate cases of oral dysplasia exhibiting lichenoid characteristics from OLP.2 Considerable clinical and histologic overlap has been found between OLM and certain premalignant lesions of the oral cavity, especially an entity termed proliferative verrucous leukoplakia, raising the question of whether the Presented as an oral abstract at the 67th Annual Meeting of the American Academy of Oral and Maxillofacial Pathology, Portland, Oregon, June 2013. a Department of Oral and Maxillofacial Medicine and Diagnostic Sciences, School of Dental Medicine, Case Western Reserve University. b Department of Dermatology, School of Medicine, Case Western Reserve University. c Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University. Received for publication Sep 13, 2013; returned for revision Dec 28, 2013; accepted for publication Dec 31, 2013. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.12.413
cases of OLM that purportedly transform to SCCA in fact represent undetected premalignant lesions with a nonspecific inflammatory response that mimics OLM.3 Diagnostic criteria for OLP were developed by the World Health Organization in 1978 and outlined clinical and histologic features of the disease.4 These guidelines were modified in 2003 to exclude cases of epithelial dysplasia and attempt to further clarify the clinical and histopathologic differences between OLP and OLL.5 Within these guidelines, the histopathologic criteria for both entities include features such as a welldefined band-like inflammatory infiltrate (BLI) in the superficial lamina propria consisting mainly of lymphocytes, liquefactive degeneration of the basal cell layer (DBL), variable hyperkeratosis or atrophy of the epithelium, and the presence of Civatte bodies (dyskeratotic keratinocytes) in the lower epithelium, although the 2003 modified guidelines limit the histopathologic criteria to BLI and DBL only.4 Clinically, OLP differs from OLL in that the former generally presents as bilateral and symmetric lesions.5 Other features that have long been described include sawtooth rete ridges (SRRs) and interface stomatitis.3 Some of these features are fundamentally nonspecific response mechanisms to epithelium altered by an immune reaction.6 In particular,
Statement of Clinical Relevance Lichenoid features may be common and nonspecific in premalignant and malignant oral lesions, possibly leading to misdiagnosis. Lichenoid criteria are subjective, is difficult to standardize, and application between pathologists is inconsistent, potentially contributing to inconsistencies in diagnosis. 511
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Table I. Interrater reliability measures Test character
OMP-OMP k
OMP1-DP k
OMP2-DP k
Intraclass correlation coefficient
Grade Threshold focal included Threshold focal excluded BLI focal included BLI focal excluded SRR focal included SRR focal excluded IS focal included IS focal excluded CB focal included CB focal excluded DBL focal included DBL focal excluded
0.672 0.430 0.465 0.532 0.614 0.179 0.146 0.474 0.456 0.127 0.066 0.262 0.273
0.481 0.283 0.281 0.123 0.213 0.153 0.394 0.359 0.346 0.043 0.030 0.458 0.388
0.510 0.205 0.277 0.183 0.199 0.423 0.146 0.270 0.441 0.108 0.108 0.329 0.352
0.719 0.381 0.394 0.339 0.408 0.296 0.269 0.422 0.449 0.160 0.141 0.397 0.366
Focal included: cases included if characteristics at least focally present. Focal excluded: cases with characteristics only focally present were excluded. k ¼ interrater reliability between 2 panel members. Intraclass correlation coefficient: with 95% CI between all 3 panel members. Interrater reliability13: > 0, poor agreement. 0.0-0.20, slight agreement. 0.21-0.40, fair agreement. 0.41-0.60, moderate agreement. 0.61-0.80, substantial agreement. 0.81-1.00, almost perfect agreement. BLI, band-like infiltrate; SRR, sawtooth rete ridges; IS, interface stomatitis; CB, Civatte bodies; DBL, degeneration of basal layer; OMP, oral and maxillofacial pathologist; DP, dermatopathologist.
a prominent band-like inflammatory response subjacent to the epithelium has been reported as a striking (and potentially misleading) feature associated with OLM that may lead pathologists to overlook atypia or dysplasia of the epithelium.6 A predominantly T celledominant lymphocyte response is a feature shared by both OLM and the inflammatory response associated with oral SCCA, which can contribute to confusion in diagnosis and therefore has significant clinical implication.7,8 OLM has a female predilection, most commonly occurring in middle aged and older patients, and favors the tongue, buccal mucosa, and gingiva.9 Both the dorsal and lateral tongue are commonly affected.9 Oral SCCA, conversely, is more common in males, with a similar pattern of age distribution, and commonly involves the lateral and ventral tongue (uncommonly the dorsal aspect), floor of the mouth (FOM), and gingiva.10-12 The purpose of this study was to evaluate the frequency of histologic features of OLM in cases of biopsy-proven dysplasia and SCCA of the oral cavity; to evaluate the parameters of gender, age, subsite, and grade of dysplasia/malignancy; and to determine if there is an association between a lichenoid response and premalignant and malignant lesions of the oral cavity.
MATERIALS AND METHODS With institutional review board approval, a retrospective record review was performed of the archives of 2
biopsy services housed at the Case Western Reserve University School of Dental Medicine: an in-house institutional biopsy service and a private practice oral pathology biopsy service. The records were searched from January 1, 1990, through July 1, 2012, for the following diagnoses found in oral cavity biopsies: “squamous cell carcinoma,” “carcinoma in situ,” and “dysplasia.” The original biopsy slides were then pulled and reviewed for inclusion criteria. Cases were excluded for the following reasons: insufficient tissue for review (including small biopsies, fragmented biopsies, lack of sufficient connective tissue, or poor orientation of the tissue), extension of SCCA completely through the connective tissue leaving no remaining epithelialeconnective tissue interface, or evidence of a metastatic SCCA or primary intraosseous SCCA either through clinical history or suggested by lack of involvement of the overlying mucosa. To limit potential confounding factors, cases with large ulcerations or abundant fungal colonization in cases diagnosed as mild dysplasia were excluded. In addition, verrucous carcinoma, papillary SCCA, adenosquamous carcinoma, spindle cell carcinoma and lesions clinically compatible with proliferative verrucous leukoplakia and verrucous hyperplasia were excluded. Cases from the lips, tonsillar fauces, and base of tongue were excluded as well. Lesions from the soft palate were included. If more than one biopsy was found for the same patient in
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Fig. 1. Band-like inflammatory infiltrate. A, Group 1 (mild dysplasia) (hematoxylin-eosin, original magnification 2). B, Group 2 (carcinoma in situ) (hematoxylin-eosin, original magnification 4). C, Group 3 (well differentiated squamous cell carcinoma) (hematoxylin-eosin, original magnification 2).
Fig. 2. Sawtooth rete ridge formation. A, Group 1 (mild dysplasia) (hematoxylin-eosin, original magnification 4). B, Group 3 (moderately differentiated squamous cell carcinoma invading in small islands) (hematoxylin-eosin, original magnification 4).
Fig. 3. Interface stomatitis. A, Group 1 (mild dysplasia) (hematoxylin-eosin, original magnification 10). B, Group 2 (severe dysplasia) (hematoxylin-eosin, original magnification 10). C, Group 3 (moderately differentiated squamous cell carcinoma) (hematoxylin-eosin, original magnification 10).
the same location, the earliest biopsy was included and subsequent biopsies were excluded to minimize any confounding by postbiopsy healing-related inflammation and to avoid counting the same lesion more than once. Data from the original biopsy report were recorded for gender, age, subsite location, and grade/diagnosis. Mild dysplasia was defined as dysplastic features limited to the basal third of the epithelium; moderate, as those extending to the middle third; and severe, as those extending to the upper third of the epithelium. Carcinoma in situ was defined as dysplastic changes
extending throughout the entire epithelium. Diagnoses were categorized into 3 groups: group 1 (mild to moderate dysplasia), group 2 (severe dysplasia or carcinoma in situ, including cases with areas suspicious but not certain for microinvasion), and group 3 (frank invasive SCCA). The final selected cases were assigned case numbers for review. After calibration to apply standardized criteria, 2 board-certified oral and maxillofacial pathologists (S.A.H. and S.G.F.) and one board-certified dermatopathologist (K.S.H.) then evaluated each case independently for the presence or absence of the 5 lichenoid features: (1) BLI
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Fig. 4. Civatte body formation. A, Group 1 (mild dysplasia) (hematoxylin-eosin, original magnification 10). B, Group 2 (severe dysplasia) (hematoxylin-eosin, original magnification 10). C, Group 3 (well differentiated squamous cell carcinoma) (hematoxylin-eosin, original magnification 10).
Fig. 5. Degeneration of the basal layer. A, Group 1 (mild dysplasia) (hematoxylin-eosin, original magnification 10). B, Group 2 (severe dysplasia) (hematoxylin-eosin, original magnification 40).
Fig. 6. Frequency of individual lichenoid characteristics in 352 total cases. (BLI, band-like infiltrate; SRR, sawtooth rete ridges; IS, interface stomatitis; CB, Civatte bodies; DBL, degeneration of basal layer.) With focal: cases included if characteristics at least focally present. Without focal: cases with characteristics only focally present were excluded.
immediately subjacent to the epithelium; (2) SRR formation; (3) interface stomatitis, or the infiltration of the basal layer of epithelium by lymphocytes; (4) formation of Civatte (colloid) bodies (CB); and (5) DBL. If the characteristics were seen only focally, this was recorded separately. The panel of pathologists also categorized the grade of the lesions, as described earlier. Nine cases were dropped from the study owing to poor agreement as
to grade. The final number of cases included in the study was 352. The responses were tabulated into 2 subgroups: characteristics including focally present features and characteristics excluding focally present features. An interrater reliability analysis using the intraclass correlation coefficient was performed between all 3 panel members for consistency in assigning grade level and
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Table II. Overall percentages of cases meeting threshold of 9 of 15 or greater lichenoid features Group
Including focal (%)
Excluding focal (%)
Overall cases Group 1 dysplasia (n ¼ 108) Group 2 dysplasia (n ¼ 132) Group 3 SCCA (n ¼ 112) Male (n ¼ 199) Female (n ¼ 153) 60 y (n ¼ 192) Tongue, L or V (n ¼ 166) Floor of mouth (n ¼ 73) Gingiva (n ¼ 36) Buccal mucosa (n ¼ 25) Multiple/other (n ¼ 52)
29 39 16 34 27 31 29 29 29 33 16 25 56 23
21 28 11 28 19 25 29 20 21 22 11 22 44 23
Focal included: cases included if characteristics at least focally present. Focal excluded: cases with characteristics only focally present were excluded. Group 1 dysplasia: mild to moderate dysplasia. Group 2 dysplasia: severe dysplasia or carcinoma in situ. Group 3 SCCA: invasive squamous cell carcinoma. Multiple/other: 23 multiple sites; 10 vestibule; 7 palate; 4 tongue NOS; 4 retromolar pad; 2 dorsal tongue; 1 lower lip; 1 no location given. L, lateral; V, ventral; NOS, not otherwise specified.
for each individual lichenoid characteristic. The k statistic was also performed on each to evaluate consistency among pairs of raters and to evaluate for patterns. A descriptive/qualitative summary was performed for both groups of the overall data in regard to positive responses in each individual characteristic group, total positive responses, and a designated measure of threshold designating a single case as having overall lichenoid characteristics. Each case had a maximum possible total number of positive responses of 15 (5 characteristics 3 pathologists). The threshold for a case to be considered positive overall for lichenoid characteristics was a score of 9 or above out of a total possible 15 for each case, comparable with each pathologist finding at least 3 of the 5 characteristics present. The overall total number of positive lichenoid features for each case was evaluated by simple regression for grade, gender, age, and subsite. The number of cases that scored above the threshold for lichenoid characteristics was evaluated by logistic regression in the context of the subgroups grade, gender, age, and subsite also using logistical regression. For the purposes of this study, statistical significance was set at P .05. Statistical calculations were performed using IBM SPSS Statistics (version 20; IBM) and Stata (version 11.2; StataCorp LP).
RESULTS The results of the interrater reliability tests are summarized in Table I. The intraclass correlation coefficient
for the assignment of lesion grade was found to be 0.719, indicating strong/substantial agreement.13 The intraclass correlation coefficient ranged between fair and moderate agreements for assessment of the presence of individual lichenoid characteristics with the exception of the presence of Civatte bodies, which showed only slight/poor agreement. For cases reaching a threshold of at least 3 of 5 lichenoid characteristics, the intraclass correlation coefficient again indicated fair agreement. Within some parameters there was a greater agreement between the 2 oral and maxillofacial pathologists (OMPs) than between either OMP and the dermatopathologist, specifically evaluation of which cases met the threshold for lichenoid features, presence of BLI, and presence of interface stomatitis. In other parameters, agreement level was not dependent on evaluator background; these included SRR formation, Civatte body formation, and DBL. Histomicrograph examples of the lichenoid features in the study cases are shown in Figures 1 to 5. The frequency of individual lichenoid features is presented in Figure 6. The most commonly noted lichenoid features within all groups were, in descending order, BLI (74% positive responses with focal responses included; 60% without focal responses); IS (68% of positive responses with focal; 56% without); DBL and CB (respectively, 32%/26% and 30%/30%); and (with the lowest frequency) SRR formation (13%/10%). Table II shows the percentages of cases meeting the threshold of 9 of 15 or greater lichenoid features. Nearly a third of all of the overall cases reached the threshold if focal characteristics were included. Cases reaching the threshold level were broken down by parameter. Less than half of the group 2 dysplasia cases met the threshold, as compared with the other groups, which were comparable with the total. Age and gender showed similar percentages reaching the threshold as the overall group. For subsite, less than half of the FOM cases met the threshold, and nearly 2 times the BM cases reached the threshold as the overall group. Tables III and IV describe the simple regression analysis for the total number of lichenoid characteristics for each case and the logistic regression analysis of the cases reaching lichenoid characteristic threshold described earlier, both in terms of focal responses included and excluded. In terms of grade, group 2 dysplasia was significantly less likely to exhibit a lichenoid response than the other categories. This pattern persisted even if group 3 SCCA cases were excluded, with the exception of focally excluded total responses, a point that is explored further in the discussion section. There were no statistically significant patterns in regard to age (median subtracted age) or gender. The subsite analysis with focal responses included showed a significantly increased lichenoid characteristic rate on the BM measured by
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Table III. Simple regression analysis of total lichenoid responses Parameter
Coefficient
Standard error
Including focal presentation of features Grade: all cases (compared with group 1 dysplasia) Total group 2 dysplasia 0.975 0.422 Total group 3 SCCA 0.197 0.439 Grade with group 3 SCCA cases dropped (compared with group 1 dysplasia) Total group 2 dysplasia 0.966 0.430 Age: all cases (median subtracted age) Total 0.007 0.013 Gender: all cases (female compared with male) Total 0.028 0.351 Site: all cases (compared with T) Total FOM 0.768 0.456 Total G 0.749 0.608 Total BM 1.463 0.608 Total M/O 0.344 0.513 Excluding focal presentation of features Grade: all cases (compared with group 1 dysplasia) Total group 2 dysplasia 0.711 0.441 Total group 3 SCCA 0.497 0.459 Grade with group 3 SCCA cases dropped (compared with group 1 dysplasia) Total group 2 dysplasia 0.666 0.439 Age: all cases (median subtracted age) Total 0.010 0.013 Gender: all cases (female compared with male) Total 0.112 0.367 Site: all cases (compared with T) Total FOM 0.495 0.477 Total G 0.463 0.636 Total BM 1.785 0.717 Total M/O 0.105 0.536
Z
P
95% CI
2.31 0.45
0.022* 0.654
1.806 to 0.143 0.668 to 1.062
2.25
0.025*
1.813 to 0.120
0.60
0.552
0.018 to 0.032
0.08
0.937
0.719 to 0.663
1.68 1.23 2.13 0.67
0.093 0.219 0.034* 0.503
1.665 to 0.129 1.946 to 0.448 0.112 to 2.814 1.354 to 0.666
1.61 1.08
0.108 0.280
1.579 to 0.158 0.406 to 1.401
1.52
0.131
1.531 to 0.120
0.76
0.448
0.016 to 0.036
0.30
0.761
0.834 to 0.611
1.04 0.73 2.49 0.20
0.300 0.467 0.013* 0.845
1.432 to 0.443 1.713 to 0.787 0.374 to 3.196 1.160 to 0.950
Group 1 dysplasia: mild to moderate dysplasia. Group 2 dysplasia: severe dysplasia or carcinoma in situ. Group 3 SCCA: invasive squamous cell carcinoma. Focal included: cases included if characteristics at least focally present. Focal excluded: cases with characteristics only focally present were excluded. T, lateral and ventral tongue; FOM, floor of mouth; G, gingiva; BM, buccal mucosa; M/O, multiple sites involved or other sites. *Significant (P < .05).
total and threshold cases, and in addition it showed a significantly decreased lichenoid characteristic rate on the FOM when measured by total responses. When focal responses were excluded, only the significant association for the buccal mucosa site remained. Of interest was that, owing to the relatively high propensity of OLM to involve the dorsal tongue, the 2 cases on the dorsal tongue both failed to meet the threshold criteria for overall lichenoid characteristics, either with focal features included or excluded.
DISCUSSION Interrater reliability The most significant limitation of this study is the lack of strong agreement between raters in the identification of lichenoid characteristics in dysplastic and SCCA lesions. This is likely a result of subjectivity and difficulty in accurately evaluating and quantifying the features constituting a lichenoid response. It mirrors the
longstanding problem of standardization of diagnostic criteria, which has been a critical point in the controversy regarding the malignant transformation of OLM. The determination of whether a characteristic is focal or generalized may also lead to inconsistency. The differences noted between the OMP responses and the dermatopathology responses, although the reviews were not conducted by a large number of reviewers, suggest the possibility that the background of the pathologist might influence the interpretation of a lichenoid response in dysplastic lesions. Lichenoid feature frequency Little has been written concerning the frequency of individual (single) lichenoid characteristics in dysplastic lesions, although Krutchkoff and Eisenberg argued that the presence of liquefactive DBL was rarely noted in lichenoid dysplasia and may serve to differentiate such lesions from nondysplastic lichenoid
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Table IV. Logistic regression analysis of cases meeting threshold for lichenoid characteristics Parameter
Odds ratio
Standard error
Including focal presentation of features Grade: all cases (compared with group 1 dysplasia) Threshold group 2 dysplasia 0.358 0.112 Threshold group 3 SCCA 0.865 0.253 Grade with group 3 SCCA cases dropped (compared with group 1 dysplasia) Threshold group 2 dysplasia 0.363 0.115 Age: all cases (median subtracted age) Threshold 0.999 0.009 Gender: all cases (female compared with male) Threshold 1.062 0.267 Site: all cases (compared with T) Threshold FOM 0.487 0.178 Threshold G 0.650 0.285 Threshold BM 2.512 1.119 Threshold M/O 0.757 0.281 Excluding focal presentation of features Grade: all cases (compared with group 1 dysplasia) Threshold group 2 dysplasia 0.336 0.122 Threshold group 3 SCCA 0.979 0.308 Grade with group 3 SCCA cases dropped (compared with group 1 dysplasia) Threshold group 2 dysplasia 0.346 0.126 Age: all cases (median subtracted age) Threshold 0.998 0.010 Gender: all cases (female compared with male) Threshold 1.401 0.387 Site: all cases (compared with T) Threshold FOM 0.548 0.235 Threshold G 0.981 0.458 Threshold BM 2.647 1.206 Threshold M/O 1.249 0.492
Z
P
95% CI
3.28 0.05
0.001* 0.620
0.193 to 0.661 0.487 to 1.536
3.21
0.001*
0.195 to 0.674
0.08
0.938
0.982 to 1.017
0.24
0.810
0.649 to 1.740
1.97 0.98 2.07 0.75
0.049* 0.327 0.039* 0.453
0.238 0.275 1.050 0.365
2.99 0.07
0.003* 0.947
0.165 to 0.686 0.529 to 1.814
2.90
0.004*
0.169 to 0.708
0.20
0.841
0.978 to 1.018
1.22
0.223
0.814 to 2.407
0.161 0.968 0.033* 0.573
0.236 0.393 1.084 0.577
1.40 0.04 2.14 0.56
to to to to
to to to to
0.996 1.537 6.016 1.568
1.272 2.448 6.463 2.702
Group 1 dysplasia: mild to moderate dysplasia. Group 2 dysplasia: severe dysplasia or carcinoma in situ. Group 3 SCCA: invasive squamous cell carcinoma. Focal included: cases included if characteristics at least focally present. Focal excluded: cases with characteristics only focally present were excluded. T, lateral and ventral tongue; FOM, floor of mouth; G, gingiva; BM, buccal mucosa; M/O, multiple sites involved or other sites. *Significant (P < .05).
mucositis; nonetheless, they warned that this was not always the case and that the presence of atypical features should overrule any lichenoid feature that might be coincident.2 The most common lichenoid feature noted in this study was BLI. This is arguably one of the most recognizable lichenoid features, but it is also a relatively nonspecific feature seen in response to many forms of antigenic challenge to the epithelium.6 The findings of this study support the idea that, although BLI is easily recognizable, it may be a nonspecific and unreliable lichenoid feature arising in dysplastic or carcinomatous lesions of the oral cavity. Interface stomatitis was also a frequent feature that may be similarly nonspecific and unreliable. Civatte body formation can be particularly difficult to assess consistently in dysplastic or SCCA cases, owing to the similarity of CB formation and dyskeratotic keratinocytes in group 2 dysplasia or group 3 SCCA. The difference between these 2 entities may be mainly
contextual in nature; therefore, this might contribute to inconsistency in diagnosis of “lichenoid dysplasia” lesions and increase the chance of overlooking atypia or dysplasia in a premalignant lesion with prominent lichenoid features.
Grade A bimodal pattern of the lichenoid features observed in this study, with higher rates in group 1 dysplasia and group 3 SCCA and a lower rate in group 2 dysplasia, was unexpected. It was postulated that the lichenoid characteristics would be lost with progression toward SCCA. An anticipated difficulty within the SCCA group was the ability to accurately assess lichenoid characteristics when the basal layer was extensively destroyed by tumor and not amenable for reliable evaluation. This was not a problem for superficial or minimally invasive, cohesive SCCA, but it emerged (as expected) as a difficulty with the more extensively invasive and
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could be argued that females would be disproportionately represented in this study in cases exhibiting the greater number of lichenoid characteristics. However, this was not the case. Despite the gender prevalence favoring SCCA in males, a female predominance has been reported in cases of SCCA in patients with a history of OLM.14,15
Fig. 7. A band-like inflammatory infiltrate in the superficial lamina propria on the right side of the specimen corresponding to overlying low-grade dysplasia of the oral epithelium. The left side of the specimen exhibits no dysplasia and also lacks the band-like inflammatory infiltrate (hematoxylin-eosin, original magnification 2).
higher-grade carcinomas. For these cases, the lesions were evaluated in areas of intact epithelium immediately adjacent to the areas of invasion. All cases classified as groups 1 or 2 dysplasia showed no evidence of invasion in any other areas of the slides. Although not consistent, the epithelium adjacent to the carcinoma sometimes exhibited dysplasia and thus introduced a confounder. In addressing this, if the SCCA group is entirely discounted from the assessment of frequency of lichenoid characteristics across grade levels, which is also shown in Tables III and IV, the significant patterns remain comparable, showing a decrease in lichenoid features from group 1 dysplasia to group 2 dysplasia. Whether there is truly an increase in lichenoid features in SCCA from high-grade dysplasia is doubtful, owing to the assessment difficulties outlined earlier, but it appears clear that before the point of invasive SCCA, lichenoid features decreased as dysplasia increased from low grade to high grade in this study. In addition, the groups in this study were not differentiated by keratinizing or nonkeratinizing; therefore, patterns of lichenoid expression between these groups were not identified. Gender and age No statistically significant patterns for age or gender were noted in regard to lichenoid characteristics. Although both OLM and SCCA are more common in older patients, OLM most often affects females, whereas SCCA most often affects males.9,10 If the majority of the cases of dysplasia or SCCA resulted from a true malignant transformation of OLM, rather than a nonspecific lichenoid-mimicking inflammatory reaction, then it
Subsite Two findings of this study are of distinct interest. First is the predominance of lichenoid features on the buccal mucosa, a location frequently associated with OLP/OLM but infrequently with SCCA. The next most commonly affected area in this study is the lateral tongue, a location common to both OLM and SCCA. Also interesting was the underrepresentation of the FOM cases with lichenoid features. It is striking how rarely the FOM is associated with OLM yet shows a higher frequency of SCCA. As with gender difference, it could be argued that if transformation occurred mainly from preexisting OLP to SCCA, the sites most affected by OLP would also be most represented in dysplasia or SCCA with lichenoid features. Unlike gender, in regard to this subcategory, this expectation is supported in this study. Aside from classic OLP, localized or systemic allergic responses consistent with OLL have been reported to have oral subsite predilections that favor sites also common to OLP, specifically the buccal mucosa, tongue, and gingiva.16,17 Other immune-related conditions that manifest with a lichenoid response in the oral cavity include graft-vs-host-disease (GVHD) and chronic ulcerative stomatitis (CUS). Like OLP, CUS has been reported most commonly to involve the tongue, followed by the buccal mucosa and gingiva.18 Oral GVHD has also been found in similar locations, involving the buccal and labial mucosa and tongue most commonly.19 This study found that a higher rate of involvement of the buccal mucosa was correlated with lichenoid-appearing dysplastic or carcinomatous lesions over other intraoral sites and is consistent with the pattern of buccal mucosa site predilection also seen in many forms of other oral lichenoid response lesions outside the category of true OLP.
Clinical correlation A currently favored explanation for transformation of OLP into SCCA is that the epithelium overlying the inflammatory infiltrate in OLM is affected by the release of cytokines associated with oxidative stress, which, in turn, activate transcription factors in epithelial cells with premalignant potential.20-22 A variety of
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scenarios may lead to a clinical and histologic presentation of OLM, including local or systemic allergy (OLL), GVHD, immune-related disease including OLP and CUS, and dysplastic oral lesions. One point not yet determined is if the proposed mechanism for transformation could be applied to all etiologies of OLM or whether it applies only to classic OLP. In the case of dysplastic oral lesions eliciting a lichenoid response, if this model is applicable, it would seem that the lichenoid response in an already premalignant lesion could exacerbate and accelerate the progression to malignancy. If the inflammatory infiltrate acts as a trigger for transformation to malignancy, the high level of observation of the BLI in low-grade dysplasia, highgrade dysplasia, and SCCA cases in this study is of particular interest. Should this mechanism be responsible for malignant transformation of OLP/OLM cases, then it might follow that the lichenoid response be perpetuated as the level of dysplasia increases. The loss of lichenoid features in this study as the grade progressed from low-grade to high-grade dysplasia argues that for the majority of these cases, the lichenoid response is a nonspecific inflammatory response associated with the dysplastic epithelium within a certain window in malignant development. Figure 7 illustrates a case of low-grade dysplasia in which a prominent BLI corresponds only to the area where the dysplasia is present. This was a frequently observed phenomenon in this study, although it was not measured formally as a parameter, owing to the lack of “normal” surrounding epithelium in many of the cases.
CONCLUSIONS There are several possibilities for the purported association between OLM and SCCA: (1) all cases of malignancy in patients with a history of OLM may be the direct result of malignant transformation of the OLM lesion only; (2) all cases of malignancy in OLM may be the direct result of a nonspecific lichenoid inflammatory response in undetected atypia or dysplasia; (3) although a small number of OLM lesions may possibly progress to malignancy, a much larger number of cases of dysplasia and SCCA show lichenoid features as a nonspecific inflammatory response; or (4) a patient may develop both conditions independently. This study found a high frequency of certain individual lichenoid characteristics such as BLI in premalignant and malignant lesions, and it found associations with parameters such as location, which may argue for the lichenoid response signifying a nonspecific inflammatory reaction in many cases. The practical application of these data is to highlight the frequency of these lichenoid features in situations where they likely do not signify any relationship with OLM. Pathologists should carefully examine lichenoid
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lesions for atypia or dysplasia and avoid being distracted by lichenoid appearing features that may lead to misdiagnosis. The higher frequency of lichenoid characteristics in low-grade dysplasia over high-grade dysplasia may also contribute to the misdiagnosis of early dysplastic lesions, in which atypia or mild dysplasia may be overlooked or attributed to ulcerated components. Finally, the difficulties posed by the subjective nature and difficulty in standardization in the application of criteria for evaluating lichenoid responses in oral lesions with or without dysplasia is a significant challenge for the proper identification of lesions with a potential for malignant progression.
REFERENCES 1. Krutchkoff DJ, Cutler L, Laskowski S. Oral lichen planus: the evidence regarding potential malignant transformation. J Oral Pathol. 1978;7:1-7. 2. Krutchkoff DJ, Eisenberg E. Lichenoid dysplasia: a distinct histopathologic entity. Oral Surg Oral Med Oral Pathol. 1985;60: 308-315. 3. Muller S. Oral manifestations of dermatologic disease: a focus on lichenoid lesions. Head Neck Pathol. 2011;5:36-40. 4. Rad M, Hashemipoor MA, Mojtahedi A, et al. Correlation between clinical and histopathologic diagnoses of oral lichen planus based on modified WHO diagnostic criteria. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107:796-800. 5. van der Meij EH, van der Waal I. Lack of clinicopathologic correlation in the diagnosis of oral lichen planus based on the presently available diagnostic criteria and suggestions for modifications. J Oral Pathol Med. 2003;32:507-512. 6. 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. 1992;73:699-704. 7. Mattsson T, Sundqvist KG, Heimdahl A, Dahllof G, Ljungman P, Ringden O. A comparative immunological analysis of the oral mucosa in chronic graft-versus-host disease and oral lichen planus. Arch Oral Biol. 1992;37:539-547. 8. Neuchrist C, Grasl M, Scheiner O, Lassmann H, Ehrenberger K, Kraft D. Squamous cell carcinoma: infiltrating monocyte/macrophage subpopulations express functional mature phenotype. Br J Cancer. 1990;62:748-753. 9. Eisen D. The clinical manifestations and treatment of oral lichen planus. Dermatol Clin. 2003;21:79-89. 10. National Cancer Institute. Surveillance Epidemiology and End Results: SEER Stat Fact Sheets: Oral Cavity and Pharynx. Available at: http://seer.cancer.gov/statfacts/html/oralcav.html. Accessed February 12, 2013. 11. Rodu B, Cole P. Oral cavity and pharynx-throat cancer in the United States, 1973-2003. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;104:653-658. 12. Goldenberg D, Ardekian L, Rachmiel A, Peled M, Joachims HZ, Laufer D. Carcinoma of the dorsum of the tongue. Head Neck. 2000;22:190-194. 13. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159-174. 14. Mattsson U, Jontell M, Holmstrup P. Oral lichen planus and malignant transformation: is a recall of patients justified? Crit Rev Oral Biol Med. 2002;13:390-396. 15. Gonzalez-Moles MA, Scully C, Gil-Montoya JA. Oral lichen planus: controversies surrounding malignant transformation. Oral Dis. 2008;14:229-243.
ORAL AND MAXILLOFACIAL PATHOLOGY 520 Fitzpatrick et al. 16. Hirota SK, Moreno RA, dos Santos CH, Seo J, Migliari DA. Analysis of a possible association between oral lichen planus and drug intake: a controlled study. Med Oral Patol Oral Cir Bucal. 2011;16:e750-e756. 17. Lartitegui-Sebastian MJ, Martinez-Revilla B, Saiz-Garcia C, Eguizabal-Saracho S, Aguirre-Urizar JM. Oral lichenoid lesions associated with amalgam restorations: a prospective pilot study addressing the adult population of the Basque Country. Med Oral Patol Oral Cir Bucal. 2012;17:e545e549. 18. Solomon LW. Chronic ulcerative stomatitis. Oral Dis. 2008;14: 383-389. 19. Treister NS, Cook EF Jr, Antin J, Lee SJ, Soiffer R, Woo SB. Clinical evaluation of oral chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2008;14:110-115. 20. Georgakopoulou EA, Achtari MD, Achtaris M, Foukas PG, Kotsinas A. Oral lichen planus as a preneoplastic inflammatory model. J Biomed Biotech. 2012;2012:759626.
OOOO April 2014 21. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883-899. 22. Rhodus NL, Cheng B, Myers S, Miller L, Ho V, Ondrey F. The feasibility of monitoring NF-kappaB associated cytokines: TNFalpha, IL-1alpha, IL-6, and IL-8 in whole saliva for the malignant transformation of oral lichen planus. Mol Carcinog. 2005;44:77-82. Reprint requests: Sarah G. Fitzpatrick Department of Oral and Maxillofacial Medicine and Diagnostic Sciences School of Dental Medicine Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 USA sarah.fi[email protected]; sfi[email protected]fl.edu
Histologic lichenoid features in oral dysplasia and squamous cell carcinoma Sarah G. Fitzpatrick, DDS,a Kord S. Honda, MD,b Abdus Sattar, PhD,c and Stanley A. Hirsch, DDS, MSa Case Western Reserve University, Cleveland, OH, USA
Objective. This study describes the occurrence of histopathologic characteristics of oral lichenoid mucositis in epithelial dysplasia and squamous cell carcinoma. Study Design. This retrospective review examined 352 histologic specimens of group 1 (mild to moderate dysplasia), group 2 (severe dysplasia or carcinoma in situ), and group 3 (squamous cell carcinoma) for correlation between 5 histologic characteristics frequently found in oral lichen planus and grade, age, gender, and oral subsite. Results. In this sample, 29% of all cases exhibited 3 or more lichenoid features. Lichenoid features were significantly more frequent in group 1 over group 2 lesions for cases meeting a minimum lichenoid threshold (P ¼ .001). No statistically significant patterns were noted for age or gender. The buccal mucosa was significantly overrepresented (P ¼ .039) and the floor of the mouth was significantly underrepresented (P ¼ .049) in regard to lichenoid feature frequency. Conclusions. This study confirms the frequent correlation of lichenoid characteristics in oral premalignant and malignant lesions. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:511-520)
The relationship between oral lichen planus (OLP) and oral lichenoid lesions (OLL), lesions with histologic lichenoid features often associated with medication or local agents or material not fulfilling clinical patterns of OLP, and oral squamous cell carcinoma (SCCA) has long been controversial. For the sake of brevity, both OLP and OLL together are referred to in this article under the nonspecific term oral lichenoid mucositis (OLM). Isolated case reports and observational studies have linked OLM to a variable yet generally low rate of malignant transformation; however, much inconsistency has been present in the criteria used for the diagnosis of the original cases of OLM, and many of the cases reported have been argued to have insufficient evidence to support the initial diagnosis.1 In 1985, the term “lichenoid dysplasia” was introduced to differentiate cases of oral dysplasia exhibiting lichenoid characteristics from OLP.2 Considerable clinical and histologic overlap has been found between OLM and certain premalignant lesions of the oral cavity, especially an entity termed proliferative verrucous leukoplakia, raising the question of whether the Presented as an oral abstract at the 67th Annual Meeting of the American Academy of Oral and Maxillofacial Pathology, Portland, Oregon, June 2013. a Department of Oral and Maxillofacial Medicine and Diagnostic Sciences, School of Dental Medicine, Case Western Reserve University. b Department of Dermatology, School of Medicine, Case Western Reserve University. c Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University. Received for publication Sep 13, 2013; returned for revision Dec 28, 2013; accepted for publication Dec 31, 2013. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.12.413
cases of OLM that purportedly transform to SCCA in fact represent undetected premalignant lesions with a nonspecific inflammatory response that mimics OLM.3 Diagnostic criteria for OLP were developed by the World Health Organization in 1978 and outlined clinical and histologic features of the disease.4 These guidelines were modified in 2003 to exclude cases of epithelial dysplasia and attempt to further clarify the clinical and histopathologic differences between OLP and OLL.5 Within these guidelines, the histopathologic criteria for both entities include features such as a welldefined band-like inflammatory infiltrate (BLI) in the superficial lamina propria consisting mainly of lymphocytes, liquefactive degeneration of the basal cell layer (DBL), variable hyperkeratosis or atrophy of the epithelium, and the presence of Civatte bodies (dyskeratotic keratinocytes) in the lower epithelium, although the 2003 modified guidelines limit the histopathologic criteria to BLI and DBL only.4 Clinically, OLP differs from OLL in that the former generally presents as bilateral and symmetric lesions.5 Other features that have long been described include sawtooth rete ridges (SRRs) and interface stomatitis.3 Some of these features are fundamentally nonspecific response mechanisms to epithelium altered by an immune reaction.6 In particular,
Statement of Clinical Relevance Lichenoid features may be common and nonspecific in premalignant and malignant oral lesions, possibly leading to misdiagnosis. Lichenoid criteria are subjective, is difficult to standardize, and application between pathologists is inconsistent, potentially contributing to inconsistencies in diagnosis. 511
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Table I. Interrater reliability measures Test character
OMP-OMP k
OMP1-DP k
OMP2-DP k
Intraclass correlation coefficient
Grade Threshold focal included Threshold focal excluded BLI focal included BLI focal excluded SRR focal included SRR focal excluded IS focal included IS focal excluded CB focal included CB focal excluded DBL focal included DBL focal excluded
0.672 0.430 0.465 0.532 0.614 0.179 0.146 0.474 0.456 0.127 0.066 0.262 0.273
0.481 0.283 0.281 0.123 0.213 0.153 0.394 0.359 0.346 0.043 0.030 0.458 0.388
0.510 0.205 0.277 0.183 0.199 0.423 0.146 0.270 0.441 0.108 0.108 0.329 0.352
0.719 0.381 0.394 0.339 0.408 0.296 0.269 0.422 0.449 0.160 0.141 0.397 0.366
Focal included: cases included if characteristics at least focally present. Focal excluded: cases with characteristics only focally present were excluded. k ¼ interrater reliability between 2 panel members. Intraclass correlation coefficient: with 95% CI between all 3 panel members. Interrater reliability13: > 0, poor agreement. 0.0-0.20, slight agreement. 0.21-0.40, fair agreement. 0.41-0.60, moderate agreement. 0.61-0.80, substantial agreement. 0.81-1.00, almost perfect agreement. BLI, band-like infiltrate; SRR, sawtooth rete ridges; IS, interface stomatitis; CB, Civatte bodies; DBL, degeneration of basal layer; OMP, oral and maxillofacial pathologist; DP, dermatopathologist.
a prominent band-like inflammatory response subjacent to the epithelium has been reported as a striking (and potentially misleading) feature associated with OLM that may lead pathologists to overlook atypia or dysplasia of the epithelium.6 A predominantly T celledominant lymphocyte response is a feature shared by both OLM and the inflammatory response associated with oral SCCA, which can contribute to confusion in diagnosis and therefore has significant clinical implication.7,8 OLM has a female predilection, most commonly occurring in middle aged and older patients, and favors the tongue, buccal mucosa, and gingiva.9 Both the dorsal and lateral tongue are commonly affected.9 Oral SCCA, conversely, is more common in males, with a similar pattern of age distribution, and commonly involves the lateral and ventral tongue (uncommonly the dorsal aspect), floor of the mouth (FOM), and gingiva.10-12 The purpose of this study was to evaluate the frequency of histologic features of OLM in cases of biopsy-proven dysplasia and SCCA of the oral cavity; to evaluate the parameters of gender, age, subsite, and grade of dysplasia/malignancy; and to determine if there is an association between a lichenoid response and premalignant and malignant lesions of the oral cavity.
MATERIALS AND METHODS With institutional review board approval, a retrospective record review was performed of the archives of 2
biopsy services housed at the Case Western Reserve University School of Dental Medicine: an in-house institutional biopsy service and a private practice oral pathology biopsy service. The records were searched from January 1, 1990, through July 1, 2012, for the following diagnoses found in oral cavity biopsies: “squamous cell carcinoma,” “carcinoma in situ,” and “dysplasia.” The original biopsy slides were then pulled and reviewed for inclusion criteria. Cases were excluded for the following reasons: insufficient tissue for review (including small biopsies, fragmented biopsies, lack of sufficient connective tissue, or poor orientation of the tissue), extension of SCCA completely through the connective tissue leaving no remaining epithelialeconnective tissue interface, or evidence of a metastatic SCCA or primary intraosseous SCCA either through clinical history or suggested by lack of involvement of the overlying mucosa. To limit potential confounding factors, cases with large ulcerations or abundant fungal colonization in cases diagnosed as mild dysplasia were excluded. In addition, verrucous carcinoma, papillary SCCA, adenosquamous carcinoma, spindle cell carcinoma and lesions clinically compatible with proliferative verrucous leukoplakia and verrucous hyperplasia were excluded. Cases from the lips, tonsillar fauces, and base of tongue were excluded as well. Lesions from the soft palate were included. If more than one biopsy was found for the same patient in
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Fig. 1. Band-like inflammatory infiltrate. A, Group 1 (mild dysplasia) (hematoxylin-eosin, original magnification 2). B, Group 2 (carcinoma in situ) (hematoxylin-eosin, original magnification 4). C, Group 3 (well differentiated squamous cell carcinoma) (hematoxylin-eosin, original magnification 2).
Fig. 2. Sawtooth rete ridge formation. A, Group 1 (mild dysplasia) (hematoxylin-eosin, original magnification 4). B, Group 3 (moderately differentiated squamous cell carcinoma invading in small islands) (hematoxylin-eosin, original magnification 4).
Fig. 3. Interface stomatitis. A, Group 1 (mild dysplasia) (hematoxylin-eosin, original magnification 10). B, Group 2 (severe dysplasia) (hematoxylin-eosin, original magnification 10). C, Group 3 (moderately differentiated squamous cell carcinoma) (hematoxylin-eosin, original magnification 10).
the same location, the earliest biopsy was included and subsequent biopsies were excluded to minimize any confounding by postbiopsy healing-related inflammation and to avoid counting the same lesion more than once. Data from the original biopsy report were recorded for gender, age, subsite location, and grade/diagnosis. Mild dysplasia was defined as dysplastic features limited to the basal third of the epithelium; moderate, as those extending to the middle third; and severe, as those extending to the upper third of the epithelium. Carcinoma in situ was defined as dysplastic changes
extending throughout the entire epithelium. Diagnoses were categorized into 3 groups: group 1 (mild to moderate dysplasia), group 2 (severe dysplasia or carcinoma in situ, including cases with areas suspicious but not certain for microinvasion), and group 3 (frank invasive SCCA). The final selected cases were assigned case numbers for review. After calibration to apply standardized criteria, 2 board-certified oral and maxillofacial pathologists (S.A.H. and S.G.F.) and one board-certified dermatopathologist (K.S.H.) then evaluated each case independently for the presence or absence of the 5 lichenoid features: (1) BLI
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Fig. 4. Civatte body formation. A, Group 1 (mild dysplasia) (hematoxylin-eosin, original magnification 10). B, Group 2 (severe dysplasia) (hematoxylin-eosin, original magnification 10). C, Group 3 (well differentiated squamous cell carcinoma) (hematoxylin-eosin, original magnification 10).
Fig. 5. Degeneration of the basal layer. A, Group 1 (mild dysplasia) (hematoxylin-eosin, original magnification 10). B, Group 2 (severe dysplasia) (hematoxylin-eosin, original magnification 40).
Fig. 6. Frequency of individual lichenoid characteristics in 352 total cases. (BLI, band-like infiltrate; SRR, sawtooth rete ridges; IS, interface stomatitis; CB, Civatte bodies; DBL, degeneration of basal layer.) With focal: cases included if characteristics at least focally present. Without focal: cases with characteristics only focally present were excluded.
immediately subjacent to the epithelium; (2) SRR formation; (3) interface stomatitis, or the infiltration of the basal layer of epithelium by lymphocytes; (4) formation of Civatte (colloid) bodies (CB); and (5) DBL. If the characteristics were seen only focally, this was recorded separately. The panel of pathologists also categorized the grade of the lesions, as described earlier. Nine cases were dropped from the study owing to poor agreement as
to grade. The final number of cases included in the study was 352. The responses were tabulated into 2 subgroups: characteristics including focally present features and characteristics excluding focally present features. An interrater reliability analysis using the intraclass correlation coefficient was performed between all 3 panel members for consistency in assigning grade level and
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Table II. Overall percentages of cases meeting threshold of 9 of 15 or greater lichenoid features Group
Including focal (%)
Excluding focal (%)
Overall cases Group 1 dysplasia (n ¼ 108) Group 2 dysplasia (n ¼ 132) Group 3 SCCA (n ¼ 112) Male (n ¼ 199) Female (n ¼ 153) 60 y (n ¼ 192) Tongue, L or V (n ¼ 166) Floor of mouth (n ¼ 73) Gingiva (n ¼ 36) Buccal mucosa (n ¼ 25) Multiple/other (n ¼ 52)
29 39 16 34 27 31 29 29 29 33 16 25 56 23
21 28 11 28 19 25 29 20 21 22 11 22 44 23
Focal included: cases included if characteristics at least focally present. Focal excluded: cases with characteristics only focally present were excluded. Group 1 dysplasia: mild to moderate dysplasia. Group 2 dysplasia: severe dysplasia or carcinoma in situ. Group 3 SCCA: invasive squamous cell carcinoma. Multiple/other: 23 multiple sites; 10 vestibule; 7 palate; 4 tongue NOS; 4 retromolar pad; 2 dorsal tongue; 1 lower lip; 1 no location given. L, lateral; V, ventral; NOS, not otherwise specified.
for each individual lichenoid characteristic. The k statistic was also performed on each to evaluate consistency among pairs of raters and to evaluate for patterns. A descriptive/qualitative summary was performed for both groups of the overall data in regard to positive responses in each individual characteristic group, total positive responses, and a designated measure of threshold designating a single case as having overall lichenoid characteristics. Each case had a maximum possible total number of positive responses of 15 (5 characteristics 3 pathologists). The threshold for a case to be considered positive overall for lichenoid characteristics was a score of 9 or above out of a total possible 15 for each case, comparable with each pathologist finding at least 3 of the 5 characteristics present. The overall total number of positive lichenoid features for each case was evaluated by simple regression for grade, gender, age, and subsite. The number of cases that scored above the threshold for lichenoid characteristics was evaluated by logistic regression in the context of the subgroups grade, gender, age, and subsite also using logistical regression. For the purposes of this study, statistical significance was set at P .05. Statistical calculations were performed using IBM SPSS Statistics (version 20; IBM) and Stata (version 11.2; StataCorp LP).
RESULTS The results of the interrater reliability tests are summarized in Table I. The intraclass correlation coefficient
for the assignment of lesion grade was found to be 0.719, indicating strong/substantial agreement.13 The intraclass correlation coefficient ranged between fair and moderate agreements for assessment of the presence of individual lichenoid characteristics with the exception of the presence of Civatte bodies, which showed only slight/poor agreement. For cases reaching a threshold of at least 3 of 5 lichenoid characteristics, the intraclass correlation coefficient again indicated fair agreement. Within some parameters there was a greater agreement between the 2 oral and maxillofacial pathologists (OMPs) than between either OMP and the dermatopathologist, specifically evaluation of which cases met the threshold for lichenoid features, presence of BLI, and presence of interface stomatitis. In other parameters, agreement level was not dependent on evaluator background; these included SRR formation, Civatte body formation, and DBL. Histomicrograph examples of the lichenoid features in the study cases are shown in Figures 1 to 5. The frequency of individual lichenoid features is presented in Figure 6. The most commonly noted lichenoid features within all groups were, in descending order, BLI (74% positive responses with focal responses included; 60% without focal responses); IS (68% of positive responses with focal; 56% without); DBL and CB (respectively, 32%/26% and 30%/30%); and (with the lowest frequency) SRR formation (13%/10%). Table II shows the percentages of cases meeting the threshold of 9 of 15 or greater lichenoid features. Nearly a third of all of the overall cases reached the threshold if focal characteristics were included. Cases reaching the threshold level were broken down by parameter. Less than half of the group 2 dysplasia cases met the threshold, as compared with the other groups, which were comparable with the total. Age and gender showed similar percentages reaching the threshold as the overall group. For subsite, less than half of the FOM cases met the threshold, and nearly 2 times the BM cases reached the threshold as the overall group. Tables III and IV describe the simple regression analysis for the total number of lichenoid characteristics for each case and the logistic regression analysis of the cases reaching lichenoid characteristic threshold described earlier, both in terms of focal responses included and excluded. In terms of grade, group 2 dysplasia was significantly less likely to exhibit a lichenoid response than the other categories. This pattern persisted even if group 3 SCCA cases were excluded, with the exception of focally excluded total responses, a point that is explored further in the discussion section. There were no statistically significant patterns in regard to age (median subtracted age) or gender. The subsite analysis with focal responses included showed a significantly increased lichenoid characteristic rate on the BM measured by
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Table III. Simple regression analysis of total lichenoid responses Parameter
Coefficient
Standard error
Including focal presentation of features Grade: all cases (compared with group 1 dysplasia) Total group 2 dysplasia 0.975 0.422 Total group 3 SCCA 0.197 0.439 Grade with group 3 SCCA cases dropped (compared with group 1 dysplasia) Total group 2 dysplasia 0.966 0.430 Age: all cases (median subtracted age) Total 0.007 0.013 Gender: all cases (female compared with male) Total 0.028 0.351 Site: all cases (compared with T) Total FOM 0.768 0.456 Total G 0.749 0.608 Total BM 1.463 0.608 Total M/O 0.344 0.513 Excluding focal presentation of features Grade: all cases (compared with group 1 dysplasia) Total group 2 dysplasia 0.711 0.441 Total group 3 SCCA 0.497 0.459 Grade with group 3 SCCA cases dropped (compared with group 1 dysplasia) Total group 2 dysplasia 0.666 0.439 Age: all cases (median subtracted age) Total 0.010 0.013 Gender: all cases (female compared with male) Total 0.112 0.367 Site: all cases (compared with T) Total FOM 0.495 0.477 Total G 0.463 0.636 Total BM 1.785 0.717 Total M/O 0.105 0.536
Z
P
95% CI
2.31 0.45
0.022* 0.654
1.806 to 0.143 0.668 to 1.062
2.25
0.025*
1.813 to 0.120
0.60
0.552
0.018 to 0.032
0.08
0.937
0.719 to 0.663
1.68 1.23 2.13 0.67
0.093 0.219 0.034* 0.503
1.665 to 0.129 1.946 to 0.448 0.112 to 2.814 1.354 to 0.666
1.61 1.08
0.108 0.280
1.579 to 0.158 0.406 to 1.401
1.52
0.131
1.531 to 0.120
0.76
0.448
0.016 to 0.036
0.30
0.761
0.834 to 0.611
1.04 0.73 2.49 0.20
0.300 0.467 0.013* 0.845
1.432 to 0.443 1.713 to 0.787 0.374 to 3.196 1.160 to 0.950
Group 1 dysplasia: mild to moderate dysplasia. Group 2 dysplasia: severe dysplasia or carcinoma in situ. Group 3 SCCA: invasive squamous cell carcinoma. Focal included: cases included if characteristics at least focally present. Focal excluded: cases with characteristics only focally present were excluded. T, lateral and ventral tongue; FOM, floor of mouth; G, gingiva; BM, buccal mucosa; M/O, multiple sites involved or other sites. *Significant (P < .05).
total and threshold cases, and in addition it showed a significantly decreased lichenoid characteristic rate on the FOM when measured by total responses. When focal responses were excluded, only the significant association for the buccal mucosa site remained. Of interest was that, owing to the relatively high propensity of OLM to involve the dorsal tongue, the 2 cases on the dorsal tongue both failed to meet the threshold criteria for overall lichenoid characteristics, either with focal features included or excluded.
DISCUSSION Interrater reliability The most significant limitation of this study is the lack of strong agreement between raters in the identification of lichenoid characteristics in dysplastic and SCCA lesions. This is likely a result of subjectivity and difficulty in accurately evaluating and quantifying the features constituting a lichenoid response. It mirrors the
longstanding problem of standardization of diagnostic criteria, which has been a critical point in the controversy regarding the malignant transformation of OLM. The determination of whether a characteristic is focal or generalized may also lead to inconsistency. The differences noted between the OMP responses and the dermatopathology responses, although the reviews were not conducted by a large number of reviewers, suggest the possibility that the background of the pathologist might influence the interpretation of a lichenoid response in dysplastic lesions. Lichenoid feature frequency Little has been written concerning the frequency of individual (single) lichenoid characteristics in dysplastic lesions, although Krutchkoff and Eisenberg argued that the presence of liquefactive DBL was rarely noted in lichenoid dysplasia and may serve to differentiate such lesions from nondysplastic lichenoid
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Table IV. Logistic regression analysis of cases meeting threshold for lichenoid characteristics Parameter
Odds ratio
Standard error
Including focal presentation of features Grade: all cases (compared with group 1 dysplasia) Threshold group 2 dysplasia 0.358 0.112 Threshold group 3 SCCA 0.865 0.253 Grade with group 3 SCCA cases dropped (compared with group 1 dysplasia) Threshold group 2 dysplasia 0.363 0.115 Age: all cases (median subtracted age) Threshold 0.999 0.009 Gender: all cases (female compared with male) Threshold 1.062 0.267 Site: all cases (compared with T) Threshold FOM 0.487 0.178 Threshold G 0.650 0.285 Threshold BM 2.512 1.119 Threshold M/O 0.757 0.281 Excluding focal presentation of features Grade: all cases (compared with group 1 dysplasia) Threshold group 2 dysplasia 0.336 0.122 Threshold group 3 SCCA 0.979 0.308 Grade with group 3 SCCA cases dropped (compared with group 1 dysplasia) Threshold group 2 dysplasia 0.346 0.126 Age: all cases (median subtracted age) Threshold 0.998 0.010 Gender: all cases (female compared with male) Threshold 1.401 0.387 Site: all cases (compared with T) Threshold FOM 0.548 0.235 Threshold G 0.981 0.458 Threshold BM 2.647 1.206 Threshold M/O 1.249 0.492
Z
P
95% CI
3.28 0.05
0.001* 0.620
0.193 to 0.661 0.487 to 1.536
3.21
0.001*
0.195 to 0.674
0.08
0.938
0.982 to 1.017
0.24
0.810
0.649 to 1.740
1.97 0.98 2.07 0.75
0.049* 0.327 0.039* 0.453
0.238 0.275 1.050 0.365
2.99 0.07
0.003* 0.947
0.165 to 0.686 0.529 to 1.814
2.90
0.004*
0.169 to 0.708
0.20
0.841
0.978 to 1.018
1.22
0.223
0.814 to 2.407
0.161 0.968 0.033* 0.573
0.236 0.393 1.084 0.577
1.40 0.04 2.14 0.56
to to to to
to to to to
0.996 1.537 6.016 1.568
1.272 2.448 6.463 2.702
Group 1 dysplasia: mild to moderate dysplasia. Group 2 dysplasia: severe dysplasia or carcinoma in situ. Group 3 SCCA: invasive squamous cell carcinoma. Focal included: cases included if characteristics at least focally present. Focal excluded: cases with characteristics only focally present were excluded. T, lateral and ventral tongue; FOM, floor of mouth; G, gingiva; BM, buccal mucosa; M/O, multiple sites involved or other sites. *Significant (P < .05).
mucositis; nonetheless, they warned that this was not always the case and that the presence of atypical features should overrule any lichenoid feature that might be coincident.2 The most common lichenoid feature noted in this study was BLI. This is arguably one of the most recognizable lichenoid features, but it is also a relatively nonspecific feature seen in response to many forms of antigenic challenge to the epithelium.6 The findings of this study support the idea that, although BLI is easily recognizable, it may be a nonspecific and unreliable lichenoid feature arising in dysplastic or carcinomatous lesions of the oral cavity. Interface stomatitis was also a frequent feature that may be similarly nonspecific and unreliable. Civatte body formation can be particularly difficult to assess consistently in dysplastic or SCCA cases, owing to the similarity of CB formation and dyskeratotic keratinocytes in group 2 dysplasia or group 3 SCCA. The difference between these 2 entities may be mainly
contextual in nature; therefore, this might contribute to inconsistency in diagnosis of “lichenoid dysplasia” lesions and increase the chance of overlooking atypia or dysplasia in a premalignant lesion with prominent lichenoid features.
Grade A bimodal pattern of the lichenoid features observed in this study, with higher rates in group 1 dysplasia and group 3 SCCA and a lower rate in group 2 dysplasia, was unexpected. It was postulated that the lichenoid characteristics would be lost with progression toward SCCA. An anticipated difficulty within the SCCA group was the ability to accurately assess lichenoid characteristics when the basal layer was extensively destroyed by tumor and not amenable for reliable evaluation. This was not a problem for superficial or minimally invasive, cohesive SCCA, but it emerged (as expected) as a difficulty with the more extensively invasive and
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could be argued that females would be disproportionately represented in this study in cases exhibiting the greater number of lichenoid characteristics. However, this was not the case. Despite the gender prevalence favoring SCCA in males, a female predominance has been reported in cases of SCCA in patients with a history of OLM.14,15
Fig. 7. A band-like inflammatory infiltrate in the superficial lamina propria on the right side of the specimen corresponding to overlying low-grade dysplasia of the oral epithelium. The left side of the specimen exhibits no dysplasia and also lacks the band-like inflammatory infiltrate (hematoxylin-eosin, original magnification 2).
higher-grade carcinomas. For these cases, the lesions were evaluated in areas of intact epithelium immediately adjacent to the areas of invasion. All cases classified as groups 1 or 2 dysplasia showed no evidence of invasion in any other areas of the slides. Although not consistent, the epithelium adjacent to the carcinoma sometimes exhibited dysplasia and thus introduced a confounder. In addressing this, if the SCCA group is entirely discounted from the assessment of frequency of lichenoid characteristics across grade levels, which is also shown in Tables III and IV, the significant patterns remain comparable, showing a decrease in lichenoid features from group 1 dysplasia to group 2 dysplasia. Whether there is truly an increase in lichenoid features in SCCA from high-grade dysplasia is doubtful, owing to the assessment difficulties outlined earlier, but it appears clear that before the point of invasive SCCA, lichenoid features decreased as dysplasia increased from low grade to high grade in this study. In addition, the groups in this study were not differentiated by keratinizing or nonkeratinizing; therefore, patterns of lichenoid expression between these groups were not identified. Gender and age No statistically significant patterns for age or gender were noted in regard to lichenoid characteristics. Although both OLM and SCCA are more common in older patients, OLM most often affects females, whereas SCCA most often affects males.9,10 If the majority of the cases of dysplasia or SCCA resulted from a true malignant transformation of OLM, rather than a nonspecific lichenoid-mimicking inflammatory reaction, then it
Subsite Two findings of this study are of distinct interest. First is the predominance of lichenoid features on the buccal mucosa, a location frequently associated with OLP/OLM but infrequently with SCCA. The next most commonly affected area in this study is the lateral tongue, a location common to both OLM and SCCA. Also interesting was the underrepresentation of the FOM cases with lichenoid features. It is striking how rarely the FOM is associated with OLM yet shows a higher frequency of SCCA. As with gender difference, it could be argued that if transformation occurred mainly from preexisting OLP to SCCA, the sites most affected by OLP would also be most represented in dysplasia or SCCA with lichenoid features. Unlike gender, in regard to this subcategory, this expectation is supported in this study. Aside from classic OLP, localized or systemic allergic responses consistent with OLL have been reported to have oral subsite predilections that favor sites also common to OLP, specifically the buccal mucosa, tongue, and gingiva.16,17 Other immune-related conditions that manifest with a lichenoid response in the oral cavity include graft-vs-host-disease (GVHD) and chronic ulcerative stomatitis (CUS). Like OLP, CUS has been reported most commonly to involve the tongue, followed by the buccal mucosa and gingiva.18 Oral GVHD has also been found in similar locations, involving the buccal and labial mucosa and tongue most commonly.19 This study found that a higher rate of involvement of the buccal mucosa was correlated with lichenoid-appearing dysplastic or carcinomatous lesions over other intraoral sites and is consistent with the pattern of buccal mucosa site predilection also seen in many forms of other oral lichenoid response lesions outside the category of true OLP.
Clinical correlation A currently favored explanation for transformation of OLP into SCCA is that the epithelium overlying the inflammatory infiltrate in OLM is affected by the release of cytokines associated with oxidative stress, which, in turn, activate transcription factors in epithelial cells with premalignant potential.20-22 A variety of
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scenarios may lead to a clinical and histologic presentation of OLM, including local or systemic allergy (OLL), GVHD, immune-related disease including OLP and CUS, and dysplastic oral lesions. One point not yet determined is if the proposed mechanism for transformation could be applied to all etiologies of OLM or whether it applies only to classic OLP. In the case of dysplastic oral lesions eliciting a lichenoid response, if this model is applicable, it would seem that the lichenoid response in an already premalignant lesion could exacerbate and accelerate the progression to malignancy. If the inflammatory infiltrate acts as a trigger for transformation to malignancy, the high level of observation of the BLI in low-grade dysplasia, highgrade dysplasia, and SCCA cases in this study is of particular interest. Should this mechanism be responsible for malignant transformation of OLP/OLM cases, then it might follow that the lichenoid response be perpetuated as the level of dysplasia increases. The loss of lichenoid features in this study as the grade progressed from low-grade to high-grade dysplasia argues that for the majority of these cases, the lichenoid response is a nonspecific inflammatory response associated with the dysplastic epithelium within a certain window in malignant development. Figure 7 illustrates a case of low-grade dysplasia in which a prominent BLI corresponds only to the area where the dysplasia is present. This was a frequently observed phenomenon in this study, although it was not measured formally as a parameter, owing to the lack of “normal” surrounding epithelium in many of the cases.
CONCLUSIONS There are several possibilities for the purported association between OLM and SCCA: (1) all cases of malignancy in patients with a history of OLM may be the direct result of malignant transformation of the OLM lesion only; (2) all cases of malignancy in OLM may be the direct result of a nonspecific lichenoid inflammatory response in undetected atypia or dysplasia; (3) although a small number of OLM lesions may possibly progress to malignancy, a much larger number of cases of dysplasia and SCCA show lichenoid features as a nonspecific inflammatory response; or (4) a patient may develop both conditions independently. This study found a high frequency of certain individual lichenoid characteristics such as BLI in premalignant and malignant lesions, and it found associations with parameters such as location, which may argue for the lichenoid response signifying a nonspecific inflammatory reaction in many cases. The practical application of these data is to highlight the frequency of these lichenoid features in situations where they likely do not signify any relationship with OLM. Pathologists should carefully examine lichenoid
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lesions for atypia or dysplasia and avoid being distracted by lichenoid appearing features that may lead to misdiagnosis. The higher frequency of lichenoid characteristics in low-grade dysplasia over high-grade dysplasia may also contribute to the misdiagnosis of early dysplastic lesions, in which atypia or mild dysplasia may be overlooked or attributed to ulcerated components. Finally, the difficulties posed by the subjective nature and difficulty in standardization in the application of criteria for evaluating lichenoid responses in oral lesions with or without dysplasia is a significant challenge for the proper identification of lesions with a potential for malignant progression.
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OOOO April 2014 21. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883-899. 22. Rhodus NL, Cheng B, Myers S, Miller L, Ho V, Ondrey F. The feasibility of monitoring NF-kappaB associated cytokines: TNFalpha, IL-1alpha, IL-6, and IL-8 in whole saliva for the malignant transformation of oral lichen planus. Mol Carcinog. 2005;44:77-82. Reprint requests: Sarah G. Fitzpatrick Department of Oral and Maxillofacial Medicine and Diagnostic Sciences School of Dental Medicine Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 USA sarah.fi[email protected]; sfi[email protected]fl.edu
