Oral lichen planus: progress in understanding its malignant potential and the implications for clinical management

Oral lichen planus (OLP) is an inflammatory lesion that has malignant potential, but few cases of OLP progress to malignancy. A diagnosis of OLP should be confirmed on the basis of historical, clinical, and histologic data. The presence of dysplasia in an OLP-like lesion increases the risk of malignant transformation, mandating management and close follow-up. A molecular assessment of OLP may provide the best evidence of malignant risk and will likely become available for clinical use. In addition, exfoliated cells may be examined for loss of heterozygosity and may become a valuable clinical tool for patient follow-up. The treatment of OLP should include elimination of tissue irritants and recurring exposure to oral carcinogens. If OLP is symptomatic, appropriate treatment with immunosuppressive medications, particularly corticosteroids, should be undertaken. For lesions with dysplastic changes, management may include attention directed to the inflammatory change and follow-up biopsies to assess residual histologic changes that may represent dysplasia. Dysplastic OLP may be best treated as other oral dysplastic conditions; thus, regular, more frequent follow-up is required.     

Oral lichen planus: Malignant potential and diagnosis

Oral lichen planus (OLP) is one of the most common diseases of the oral mucosa. Clinically, it has specific and clearly identifiable features; bilateral symmetric presentation showing a lace-like network of fine white lines (known as Wickham's striae) is an essential element of OLP even if the lesion exhibits a mainly atrophic and erosive pattern. There are various lesions that resemble OLP clinically and histologically. These lesions are widely referred to as lichenoid reactions or lichenoid lesions (OLLs). OLLs include contact hypersensitivity to dental materials, drug-induced lichenoid lesions, lichenoid reactions in chronic graft-versus-host disease, and other lesions that resemble OLP. The risk of malignant transformation of OLP is the subject of ongoing debate in the literature. Some authors have suggested that only OLLs, but not OLP, are of a premalignant nature and thus, should be categorized as “other dysplastic conditions.” Contrary to this suggestion, many cases of oral squamous cell carcinoma (OSCC) developing in patients with OLP presenting with no epithelial dysplasia have been reported. In addition, it has been reported that multiple events including multifocal dysplasia and/or OSCC subsequently occurred in some patients with OLP, suggesting possible field cancerization in OLP. In this paper, differential diagnosis between OLP and OLLs and their malignant potential are reviewed.     

Oral lichenoid dysplasia: a clinicopathologic analysis

Three women had a diagnosis of oral lichen planus (OLP), which was made on the basis of clinical and histologic features. All three had persistent burning pain associated with large mucosal lesions. Changes in the color (red, red and white, white), configuration, and severity of the lesions were unpredictable and did not correlate well with topical corticosteroid therapy. Only one patient used tobacco (cigarettes)--this patient had recurrent oral candidiasis and was receiving multiple medications. One of the two nonsmokers was a denture wearer with a single episode of candidiasis. After 63, 32, and 56 (mean 50) months, carcinoma developed in all three. In retrospect, the initial biopsy specimens of two patients exhibited lichenoid dysplasia, whereas that of the third showed only lichenoid mucositis. Although speckled erythroplakia was the earliest clinical sign of a classic, nonregressing premalignant lesion, it already signaled the presence of invasive carcinoma. Some early epithelial dysplasias appear to have a robust inflammatory/immunologic response to the antigenically (but as yet not histologically) altered dysplastic epithelium and a high probability of at least temporary resolution. Mucosal erythema of obscure origin displaying spontaneous, usually temporary, partial to complete regression may be common to both purely inflammatory conditions like lichen planus and early epithelial dysplasia. We contend that some, if not most, cases of apparent malignant transformation of OLP likely represent red and white lesions that were dysplastic from their inception but that mimic OLP both clinically and histologically.     

CD146 expression in oral lichen planus and oral cancer

Clinical Oral Investigations - To examine the CD146/METCAM expression on keratinocytes in normal oral mucosa (NOM), oral lichen planus (OLP), oral epithelial dysplasia (OED), and oral squamous cell...     

口腔粘膜扁平苔藓危险因素的Logistic回归分析

目的 :探讨引起口腔粘膜扁平苔藓的危险因素。方法 :对口腔粘膜扁平苔藓危险因素作出相关性的分析。应用Logistic回归分析方法研究口腔粘膜扁平苔藓与发病因素之间的数量关系。结果 :年龄、性别、胃炎、焦虑是口腔粘膜扁平苔藓发病的危险因素。口腔粘膜扁平苔藓的发病情况用Logistic回归分析计算结果的总判别率为95 %。结论 :年龄、性别、胃炎、焦虑是导致口腔扁平苔藓的危险因素。     

MAGE-A antigens in lesions of the oral mucosa

Oral squamous cell carcinoma develops continuously out of predamaged oral mucosa. For the physician and pathologist, difficulties arise in distinguishing precancerous from cancerous lesions. MAGE-A antigens are tumor antigens that are found solely in malignant transformed cells. These antigens might be useful in distinguishing precancerous from cancerous lesions. The aim of this study was to verify this assumption by comparing MAGE-A expression in benign, precancerous, and cancerous lesions of the oral mucosa. Retrospectively, biopsies of different oral lesions were randomly selected. The lesions that were included are 64 benign oral lesions (25 traumatic lesions (oral ulcers), 13 dental follicles, and 26 epulis), 26 oral lichen planus, 123 epithelial precursor lesions (32 epithelial hyperplasia found in leukoplakias, 24 epithelial dysplasia found in leukoplakias, 26 erythroplasia with oral epithelial dysplasia, and 41 carcinomas in situ in erythroleukoplakias). The lesions were immunohistochemically stained with the poly-MAGE-A antibody 57B, and the results were compared. Biopsies of oral lichen planus, oral ulcers, dental follicles, epulis, and leukoplakia without dysplasia showed no positive staining for MAGE-A antigens. Leukoplakia with dysplasia, dysplasia, and carcinomata in situ displayed positive staining in 33%, 65%, and 56% of the cases, respectively. MAGE-A antigens were not detectable via immunohistochemistry in benign lesions of the oral mucosa. The staining rate of dysplastic precancerous lesions or malignant lesions ranged from 33% to 65%. The MAGE-A antigens might facilitate better differentiation between precancerous and cancerous lesions of the oral mucosa.     

DNA ploidy in oral lichen planus,determined by image cytometry

J Oral Pathol Med (2010) 39 : 206–211 Background: The objective of this study was to use image cytometry to determine the degree and frequency of DNA ploidy in biopsies of reticular and atrophic‐erosive oral lichen planus and to analyze 14 karyometric measurements of the nuclei of epithelial cells from each specimen. Methods: A total of 40 slides were analyzed, each of them representing one biopsy of one oral lichen planus (OLP) lesion from each one of the 40 patients (cases) studied. Specimens were embedded in paraffin and comprised 20 slides of reticular oral lichen planus (group R) and 20 slides of atrophic‐erosive oral lichen planus (group AE). Results: Group R, the reticular lichen samples, had 18 diploid cases and two aneuploid cases. Group AE, the atrophic‐erosive lichen samples, had 10 diploid cases, one tetraploid case, and nine aneuploid cases. Of the 14 karyometric measurements of the nuclei of OLP epithelial cells analyzed, the group R mean values for mean density and minimum density were significantly greater than the group AE mean values, and mean roundness in group AE was significantly greater than in group R (t‐test: P < 0.05). Conclusions: The most common degree of DNA ploidy in OLP lesions was diploidy. Comparing the two groups (chi‐square test of association P = 0.021) demonstrated that diploidy was associated with the reticular clinical form of OLP, while aneuploidy was associated with the atrophic‐erosive clinical form of oral lichen planus.     

Pathogenesis of oral lichen planus – a review

J Oral Pathol Med (2010) 39 : 729–734 Oral lichen planus (OLP) is a T‐cell‐mediated chronic inflammatory oral mucosal disease of unknown etiology. OLP presents as white striations, white papules, white plaques, erythema, erosions, or blisters affecting predominantly the buccal mucosa, tongue and gingiva. Both antigen‐specific and non‐specific mechanisms are hypothesized to be involved in the pathogenesis of oral lichen planus (OLP). Antigen‐specific mechanisms in OLP include antigen presentation by basal keratinocytes and antigen‐specific keratinocyte killing by CD8⁺ cytotoxic T cells. Non‐specific mechanisms include mast cell degranulation and matrix metalloproteinase activation in OLP lesions. These mechanisms may combine to cause T cell accumulation in the superficial lamina propria, basement membrane disruption, intra‐epithelial T cell migration and keratinocyte apoptosis in OLP. The various hypotheses proposed for pathogenesis of oral lichen planus are discussed in this review.     

Differential expression of stem cell-like proteins in normal,hyperplastic and dysplastic oral epithelium

Objective

The identification of stem cells (SC) remains challenging. In the human oral mucosal epithelium, these cells are believed to be in the basal layer (stem cell niche), but their exact location is unclear. The aim of this study was to examine the dysplastic oral epithelium for these SC-like proteins in order to assess their diagnostic value as biomarkers complementing the histological grading of dysplasia.

Material and Methods

Thirty oral epithelial dysplasia (OED), 25 oral lichen planus (OLP), 10 oral hyperkeratosis and 5 normal oral epithelium (OE) were immunohistochemically examined for four SC markers [integrin β1, neuron-glial-2 (NG2), notch 1 (N1) and keratin 15 (K15)].

Results

Three of four SC markers were heterogeneously detected in all samples. K15 overexpression in the lower two-thirds of severe OED suggests an expanded SC niche. Integrin β1 distribution pattern was not measurably different between OEDs and control. NG2 was almost negative to absent in all samples examined. N1 expression was weak and highly variable in normal and dysplastic epithelium, making it an unreliable epithelial stem cell marker.

Conclusions

Present findings suggest that these markers were unable to identify individual epithelial stem cells. Instead, subpopulations of cells, most probably stem cells and transit amplifying cells with stem cell-like properties were identified in the dysplastic oral epithelium. The characteristic expressions of K15 might be of diagnostic value for oral dysplasia and should be investigated further.     

Malignant development of lichen planus-affected oral mucosa

The present report describes malignant development in oral lichen planus (OLP) among 611 patients (409 F, 202 M) followed for periods from 1–26 years (mean: 7.5). During follow-up, 9 patients (1.5%), 8 women (1.9%) and 1 man (0.5%) developed oral squamous cell carcinomas (SCC) in areas of lichen planus lesions. The age of the patients at diagnosis of carcinoma ranged from 56–79 years (mean: 70.4) and the length of follow-up before malignant development ranged from 4.9–24 years (mean: 10.1). The estimated number expected to develop oral cancer in a sample of the general Danish population of similar size, age distribution and follow-up was 0.18 (0.11 F, 0.07 M) i.e., OLP cases showed a 50-fold increase (F = 70- M = 14-fold). The observed number of cancer cases was significantly higher than the estimated number (p < 0.00001). Therefore, oral lichen planus fulfils the WHO criterion of a premalignant condition.     

Malignant transformation in 1458 patients with potentially malignant oral mucosal disorders: a follow-up study based in a Taiwanese hospital

BACKGROUND: It is generally accepted that the development of cancer in the oral mucosa is preceded by an identifiable non-invasive precursor lesion. The aim of this follow-up study was to estimate the rate and the time to transformation in a group of patients from southern Taiwan with potentially malignant oral epithelial lesions. METHODS: The follow-up time is defined as the duration between the onset of the initial diagnosis and the occurrence of confirmed oral cancer. A total of 1458 patients with histological diagnoses of various pre-malignant oral lesions were followed up between 1991 and 2001. The average age at initial diagnosis was 47.5 years. The histological diagnoses were divided into six categories: epithelial dysplasia with hyperkeratosis/epithelial hyperplasia (8.85%); epithelial dysplasia with submucous fibrosis (2.54%); submucous fibrosis (27.57%); hyperkeratosis/epithelial hyperplasia (29.01%); lichen planus (9.80%) and verrucous hyperplasia (22.22%). RESULTS: Within the cohort of 1458 patients, 44 patients progressed to oral cancer in the same site as the initial lesions with an overall transformation rate of 3.02% and a mean follow-up time of 42.64 months. Eight of the 166 patients with dysplastic lesions and 15 of 423 patients with hyperkeratosis/epithelial hyperplasia progressed to malignancy. The other patients with malignant transformation originated from various pre-cancerous oral lesions and conditions (submucous fibrosis, eight of 402; lichen planus, three of 143; verrucous hyperplasia, 10 of 324). CONCLUSION: These results indicate that patients with pre-malignant oral lesions need long-term follow up.     

COX-2、VEGF在口腔扁平苔藓、口腔白斑及口腔鳞状细胞癌中的表达

目的研究环氧合酶(COX)-2、血管内皮生长因子(VEGF)在口腔扁平苔藓(OLP)、口腔白斑(OLK)及口腔鳞状细胞癌(OSCC)组织中的表达及分布,探讨其在OLP、OLK癌变机制中的作用。方法采用免疫组化法检测33例OLP患者(单纯扁平苔藓19例,伴异常增生14例)、35例OLK患者(单纯增生14例、伴异常增生21例)、31例OSCC患者及10例正常对照者口腔黏膜组织(NOM)中COX-2、VEGF的分布和表达。应用统计分析软件SPSS 13.0对结果进行统计分析。结果COX-2、VEGF在正常口腔黏膜组织无表达或低表达;在单纯扁平苔藓组均为26.32%过表达;在扁平苔藓异常增生组分别为71.43%、64.29%过表达;在白斑单纯增生组过表达情况均为21.42%;在白斑异常增生组分别为80.95%、71.43%过表达;在口腔鳞状细胞癌组分别为93.55%、90.32%过表达;COX-2、VEGF在扁平苔藓异常增生组的表达明显高于单纯扁平苔藓组(P<0.05),低于OSCC组(P<0.05),与白斑异常增生组无明显差异(P>0.05)。COX-2的表达与VEGF表达呈明显正相关(r=0.595,P<0.01)。结论COX-2、VEGF在NOM、OLP及OLK伴异常增生、OSCC的表达逐渐增高,表明COX-2及VEGF与OLP、OLK的异常增生及癌变有关。     

Expression of TGF-beta1, Smad7 and cell apoptosis in epithelium of oral lichen planus

OBJECTIVE: To examine the expression of TGF-beta1, Smad7 and cell apoptosis in oral lichen planus (OLP) and to evaluate the possible pathogenesis of oral lichen planus. METHODS: Immunohistochemical technique was used to study the expression of TGF-beta1 and Smad7 in the epithelia cells of 17 OLP cases and 7 normal oral mucosa (NOM). TUNEL was used for detecting the cell apoptosis in 17 OLP cases and 7 NOM. RESULTS: TGF-beta1 was moderately positive in the epithelia cells of OLP. All the epithelia cells in OLP showed strong cytoplasmic staining. The expression of TGF-beta1 and Smad7 were significantly increased in OLP compared with that in NOM (P < 0.05). Cell apoptotic index (AI) was remarkably increased in epithelia cells in OLP cases, and the cell apoptosis was localized in basal and suprabasal epithelial layers. There was a positive correlation between TGF-beta1 expression and cell apoptosis in the epithelia of OLP (r = 0.69, P <0.05). CONCLUSIONS: High expression of TGF-beta1 and Smad7 in the epithelia of OLP suggests that TGF-beta1-Smad7 signal pathway was disturbed in oral lichen planus. The imbalance of TGF-beta1-Smad7 pathway may contribute to the mechanisms of cell apoptosis of epithelial cells in OLP.     

Squamous cell carcinoma arising in an oral lichenoid lesion

BACKGROUND: Oral lichen planus, or OLP, is a chronic inflammatory mucocutaneous disease that frequently involves the oral mucosa. Lichenoid dysplasia, or LD, refers to lesions that could be mistaken clinically for OLP but have histologic features of dysplasia and a true malignant predisposition. Published case reports of OLP conversion to squamous cell carcinoma, or SCC, have created a great deal of controversy about the true nature of OLP, highlighting the need to verify its clinical diagnosis histologically. CASE DESCRIPTION: The authors document the development of SCC in a 58-year-old woman with an oral lesion diagnosed clinically as OLP and described histologically as having lichenoid features with dysplastic changes. The time from the initial diagnosis of oral lichenoid lesions to the patient's return visit to the medical center with clinically evident cancer was three years and eight months. The SCC developed in the labial mucobuccal fold and left mandibular edentulous ridge, which had undergone multiple biopsy procedures. CLINICAL IMPLICATIONS: This case does not provide answers to the ongoing controversy about the innate propensity of OLP to become malignant. However, in view of both the common occurrence of OLP and unresolved issues regarding its premalignant potential, this case report illustrates the need for histologic confirmation and close follow-up of patients with clinical lesions that have lichenoid features.     

Telomerase activity in oral lichen planus

The purpose of this study was to determine the expression of telomerase in refractory oral lichen planus. Using a polymerase chain reaction-based telomerase activity assay, we investigated telomerase activity in 20 oral lichen planus specimens (erosive 9, atrophic 11). Telomerase activity was detected in 14 cases (erosive 7, atrophic 7). Furthermore, 13 cases of lichen planus with mild dysplasia proved telomerase-positive in eight specimens and six of seven cases devoid of dysplasia were also positive in the telomerase assay. The data indicate that, in general, telomerase activity might be frequently detectable in OLP. The data also suggest that telomerase activity might not be particularly associated with the premalignant phenotype in OLP.     

Oral lichen planus: controversies surrounding malignant transformation

Studies of the malignant potential of oral lichen planus (OLP) have been hampered by inconsistencies in the diagnostic criteria used for OLP, the criteria adopted to identify a true case of malignant transformation in OLP, the risk factors for malignant transformation and the optimum management of patients to ensure the early diagnosis of transformation. Consensus remains elusive, and leading workers in this field have recently published conflicting reports on the malignant potential of OLP and on the important question of the advisability of excluding patients with epithelial dysplasia or a tobacco habit from studies on this issue. The present review outlines these debates and proposes a possible a molecular basis for the malignant transformation in this disease.     

Evaluation on Malignant Transformation of Oral Lichen Planus

目的：口腔扁平苔藓（oral lichen planus,OLP)是否属于癌前病变，至今仍存在较大的争论。本文的目的在于评估OLP的癌变性质。方法：报告1995－2002年之间9例OLP的癌变病例。结果：5例OLP患者同时或继发为口腔鳞状细胞癌，1例为疣状癌，3例为上皮异常增生。其中7例发生在原OLP存在的部位，1例发生在其它部位，1例在同一部位同时存在OLP和鳞状细胞癌。OLP的癌变常发生在糜烂型和萎缩型，发生于颊粘膜，舌或牙龈。根据所制定的OLP的诊断及癌变标准，4例OLP患者发生了癌变。结论：OLP具有一定的癌变潜力，对OLP患者应每年随访2－4次，尤其是对发生在颊粘膜，舌或牙龈的糜烂型和萎缩型的患者。     

表皮生长因子受体在口腔扁平苔藓组织中的表达

目的探讨口腔扁平苔藓(OLP)癌变及发病机制。方法采用免疫组化法检测10例正常口腔黏膜,16例扁平苔藓,10例扁平苔藓伴不典型增生,14例口腔鳞癌上皮组织中表皮生长因子受体(EGFR)的表达水平。结果OLP伴不典型增生组织中EGFR的表达高于正常黏膜(P<0.05)。口腔鳞癌中EGFR的表达高于正常黏膜及OLP(P<0.01)。结论EGFR的过表达在OLP的发生、发展过程中可能起着重要的作用。     

口腔癌前病变细胞凋亡状况及Bcl-2、Bax表达的研究

目的 :通过对口腔白斑、扁平苔藓病变发展及癌变过程中细胞凋亡状况和凋亡相关蛋白表达水平的研究 ,探讨口腔白斑、扁平苔藓的癌变机理及病变机制。方法 :采用原位末端转移酶标记法及免疫组化法 ,观察分析 10例正常口腔黏膜上皮 ,18例扁平苔藓 ,2 3例白斑 ,2 2例口腔鳞癌上皮组织中细胞凋亡状况及凋亡相关蛋白Bcl- 2、Bax的表达水平。结果 :上皮 (轻 ,中 ,重 )不典型增生 ,鳞癌及糜烂型扁平苔藓的凋亡指数均高于正常 (P <0 .0 1)。Bcl- 2在白斑、扁平苔藓上皮细胞层无异常表达 ,但在扁平苔藓固有层淋巴细胞浸润处过度表达 ,在鳞癌组织中显高表达 (P <0 .0 1)。Bax在上皮单纯增生、轻、中度不典型增生和鳞癌及糜烂型扁平苔藓组织中显过度表达 (P <0 .0 5 )。结论 :白斑、扁平苔藓的病变发展及癌变过程中 ,上皮细胞凋亡状况发生了改变 ,Bax参与了白斑癌变的早期事件。扁平苔藓的发病机制与Bcl- 2、Bax在特定部位的过度表达有关