口腔扁平苔藓发病及其恶变机理的探讨
摘要
目的
口腔扁平苔藓(oral lichen planus,OLP),是一种较常见的口腔粘膜慢性非特异性炎症,被认为是细胞介导的自身免疫性疾病,具有癌变潜在性,WHO将OLP确定为癌前状态。
口腔扁平苔藓的粘膜病损可累及口腔粘膜的任何部位,多发于颊部,其次为舌、龈、唇、腭、口底等处。临床常表现为复杂的联合病损,如丘疹样、斑块的、萎缩性、溃疡和大疱等,也可表现为角化样病变,如白斑。萎缩型病变和糜烂型病变,最有可能引起疼痛。
OLP主要的病理特征为:上皮过度角化、上皮下固有层淋巴细胞带状浸润及基底层细胞液化变性;同时具有上皮细胞凋亡增加、固有层炎性细胞凋亡减少。变性的基底细胞形成胶样小体或Civatte小体,表现为均匀嗜酸性粒细胞,超微结构表明,胶样小体为角质细胞的凋亡。
口腔扁平苔藓的发生涉及诸多因素,与局部慢性机械损伤、药物刺激、牙科材料、口腔内电流刺激以及精神紧张、全身性疾患和遗传因素等有关;还可能与某些细菌、病毒感染相关。以往研究提示,淋巴细胞介导的免疫反应、细胞因子的释放及角质细胞的凋亡异常,被认为是其发生发展的主要原因。迄今为止,口腔扁平苔藓的病因与发病机制尚不明确。
OLP于1869年被首次报道,一百多年来对于其发病率的调查结果,各地域存在较大差异。国内外资料流行病学资料显示:OLP是除复发性口疮外,最多见的口腔粘膜疾病。1981年我国“口腔白斑、扁平苔藓两病防治协作组”的调查资料显示,OLP患病率为0.51%。迄今为止,河北省各地区尚缺乏关于OLP的流行病学资料。
研究表明,OLP病变使口腔癌发生的危险性大大增加,是具有癌变潜能的口腔粘膜病损。OLP发生的相关因素有很多,其中Ki-67、Cox-2的过表达及p53基因的突变可能与其发生的密切相关因素。
Ki-67位于人的所有增殖细胞的核内,是细胞增殖活性的一种标志性抗原,也是判断良、恶性肿瘤组织生长状态的关键指标。Ki-67过度表达提示细胞增殖过度,与传统的增殖核抗原PCNA相比背景干扰小,是近两年得到应用的,更为准确可靠的检测细胞增殖状态的指标。
环氧合酶Cox-2(cyclooxygenase,Cox-2)又名前列腺素内过氧化物合成酶,是一种诱导型膜结合蛋白酶,位于细胞内质网和细胞核周围,Cox-2在多种因子(如内毒素、感染因子、生长因子等)的作用下表达上调,与细胞凋亡和肿瘤发生关系密切。
p53基因是重要的抑癌基因之一,可以启动细胞凋亡机制。大量研究表明:恶性肿瘤及癌前病变中野生型p53基因突变或失活而导致的功能异常,是肿瘤发生的重要原因。p53基因突变可能与口腔粘膜良性病损恶性变有关。研究显示,P53蛋白表达增高与OLP特征性病变及癌变相关,p53基因的突变可能引起OLP的发生与发展。
本课题第一部分:在河北省内,通过多阶段分层等容量随机抽样的方法,调查OLP在河北省的发病特征、人群和空间分布状况,并对上述诸多因素进行流行病学研究,为我国人群中OLP的诊断、治疗提供流行病学资料。本课题第二部分:收集五年期间在河北医科大学口腔医院就诊的OLP患者101例的临床病理资料,采用免疫组织化学方法,针对OLP的相关癌变因素:Ki-67和Cox-2,检测其在101例OLP患者病变中的表达,并以正常口腔粘膜和口腔鳞状细胞癌作为比较,探讨Ki-67、Cox-2表达与口腔OLP潜在恶性的关系。本课题第三部分:采用RT-PCR的方法,检测60例OLP患者病变及病变旁组织和相邻正常口腔粘膜中突变型p53基因的mRNA表达水平,并与口腔鳞状细胞癌比较,探讨OLP癌变潜在危险性和癌变机理,为OLP的早期诊断、治疗以及癌变的预防提供可靠依据。
材料与方法
1河北省口腔扁平苔藓的流行病学调查
根据“第三次全国口腔健康流行病学调查方案”,参照WHO《口腔健康调查基本方法》(第四版),采用多阶段分层等容量随机抽样的方法,通过样本估计总体。在河北省三市、三县,随机抽样共选取36个调查点,2个年龄组各调查742人,男女比为1:1,共调查1548人。OLP诊断标准:采用全国牙防组制定的《第三次全国口腔健康流行病学调查方案》中对OLP的诊断标准。全部调查资料使用SPSS10.0软件进行统计学分析。2口腔扁平苔藓中Ki-67、Cox-2表达与其潜在恶性的关系
收集口腔扁平苔藓101例,另取口腔癌手术标本10例,口腔正常颊粘膜标本10例作为对照。使用免疫组化(SP法)方法检测Ki-67、Cox-2蛋白的表达情况。采用SPSS10.0统计分析软件进行单因素方差分析。3口腔扁平苔藓中突变型p53基因mRNA表达的检测
60例口腔扁平苔藓和30例颊癌均经病理确诊,20例正常口腔颊粘膜来自外伤创面周围的组织,作为正常对照组标本。采用一步法RT-PCR检测突变型p53基因mRNA水平的表达。所有数据采用SPSS10.0软件进行统计学分析,采用χ2检验。
4口腔扁平苔藓及其邻近组织中突变型p53基因mRNA的表达30名患者经病理诊断确诊为口腔扁平苔藓。每名患者采集病变区、病变旁、正常组织区三个部位标本各一,共90个标本。病变旁组织与病变组织距离≥5mm,正常组织与病变旁组织距离≥1cm。所有标本的采集均在患者知情并同意的情况下进行。采用一步法RT-PCR检测突变型p53基因mRNA水平的表达。所有数据采用SPSS10.0软件进行统计学分析,采用χ2检验。
结果
1在本次流行病学调查中,河北省被调查人群中口腔扁平苔藓的患病率为0.82%,略高于我国“口腔白斑、扁平苔藓两病防治协作组”的调查结果,测算河北省口腔扁平苔藓患病率的95%可信区间为0.38%～1.26%。
2流行病学调查结果显示:河北省各种口腔粘膜病构成比差异有统计学意义,口腔扁平苔藓是目前口腔粘膜病中除复发性口疮外的最多见的口腔粘膜病。
3口腔扁平苔藓好发于颊部,其患病有随着年龄增加而增加的趋势,无城乡差异。
4临床病理资料分析
101例口腔扁平苔藓中,男性39例,女性62例,男:女之比为1:1.6,女性多于男性。就诊年龄最小者21岁,最长者78岁,平均年龄为48.8岁。发病部位最常见为颊部81例;其次为舌部11例;其它牙龈5例;唇部4例。
5口腔扁平苔藓的病理学改变
101例口腔扁平苔藓的组织病理学改变为,上皮增生和/或萎缩,基底细胞灶状或片状液化消失,上皮下淋巴细胞呈带状浸润。其中表现为上皮增生者48例;上皮萎缩者22例;上皮增生与萎缩同时出现者23例。15例伴有上皮下疱;19例伴上皮糜烂和溃疡。7例出现上皮轻度不典型增生;1例出现上皮癌变,OLP癌变率为0.9%(1/101),癌前病变发病率为6.9%(7/101)。口腔鳞状细胞的病理组织学表现为,异型性的肿瘤细胞呈多边形或圆形,排列成巢状,可见细胞间桥,肿瘤细胞有角化倾向,形成癌珠。
6 Ki-67在口腔扁平苔藓中的表达
10例正常口腔粘膜均表达Ki-67,阳性细胞散在于基底细胞中,其阳性细胞比例为15.2%。在101例口腔扁平苔藓中,93例表达Ki-67,阳性细胞位于增生上皮或萎缩上皮的基底细胞和基底旁细胞中,其阳性细胞比例为37.1%。扁平苔藓伴上皮轻度不典型增生的病例中,阳性细胞比例为47.0%;扁平苔藓伴上皮癌变的病例,其阳性细胞比例为61.0%。10例口腔鳞状细胞癌全部表达Ki-67,阳性细胞随着肿瘤异型性基底细胞和基底样细胞增多而明显增多,其阳性细胞比例为62.5%。统计学分析表明,扁平苔藓阳性率高于正常口腔粘膜,低于口腔鳞状细胞癌,差别均有显著性(P<0.05)。单纯扁平苔藓(36.1%)与扁平苔藓伴上皮轻度不典型增生(47.0%)之间差别无显著性(P>0.05);而与扁平苔藓伴上皮癌变(61.0%)之间差别有显著性(P<0.05)。
7 Cox-2在口腔扁平苔藓中的表达
10例正常粘膜均不表达Cox-2。101例扁平苔藓中36例表达Cox-2,阳性率为35.6%,病变表现为上皮棘层细胞、粒层细胞和表层细胞呈阳性表达,基底细胞呈阴性表达。扁平苔藓伴上皮轻度不典型增生的病变中,阳性的棘层细胞增多,并具有异型性。扁平苔藓伴上皮癌变的病变中,阳性的肿瘤细胞浸润至肿瘤间质。在阳性的36例口腔扁平苔藓中,组织病理学改变为上皮增生者16例阳性;上皮萎缩者9例阳性;上皮增生与萎缩相间者4例;上皮不典型增生阳性者6例;上皮癌变阳性者1例。10例口腔鳞状细胞癌中2例表达Cox-2,阳性率为20.0%。阳性的肿瘤细胞异型性明显,浸润性生长。Cox-2在正常口腔粘膜(0%)、扁平苔藓(35.6%)及口腔鳞状细胞癌(20.0%)三者之间差别有显著性(P<0.05);口腔粘膜与扁平苔藓之间以及口腔粘膜与口腔鳞状细胞癌之间差别均有显著性(P<0.05)。扁平苔藓(35.6%)及口腔鳞状细胞癌(20.0%)之间差别无显著性(P>0.05)。
8口腔扁平苔藓突变型p53基因mRNA水平表达的结果显示,60例口腔扁平苔藓中表达阳性者13例;阳性率为21.67%(13/60)。30例口腔颊癌中表达阳性者16例;阳性率为53.3%(16/30)。20例口腔正常粘膜p53基因mRNA表达阳性者1例;阳性率为5%(1/20)。口腔扁平苔藓组与口腔癌中p53基因mRNA阳性率比较,差异有显著性(P<0.017)。口腔扁平苔藓组与口腔正常粘膜组的p53基因mRNA阳性率比较,差异无显著性(P>0.05)。口腔颊癌与正常口腔粘膜p53基因mRNA阳性率比较,差异有显著性(P<0.017)。
9 RT-PCR检测突变型p53基因在扁平苔藓及其邻近组织中的表达,结果显示,30例口腔扁平苔藓患者中,每例包括扁平苔藓病变组织、病变旁组织及正常组织,共90个标本,其中p53基因mRNA表达均为阳性者3例;占全部患者的10%(3/30)。扁平苔藓病变旁组织为阳性,病变组织和正常组织为阴性者3例;占全部患者的10%(3/30)。扁平苔藓病变组织为阳性,病变旁组织及正常组织为阴性者1例;占全部患者的3.33%(1/30)。扁平苔藓病变和病变旁组织均为阳性,正常组织阴性者1例;占全部患者的3.33% (1/30)。
结论
1河北省被调查人群中OLP患病率为0.82%,河北省OLP患病率的95%可信区间为0.38%～1.26%。
2本研究流行病学调查结果显示:河北省各种口腔粘膜病构成比差异有统计学意义,OLP是口腔粘膜病中除复发性口疮外的最多见的口腔粘膜病。
3本研究临床病理分析显示:OLP癌变率为0.9%,癌前病变发病率为6.9%;说明OLP具有潜在癌变性。
4 Ki-67蛋白表达阳性率从正常口腔粘膜到OLP和口腔癌依次增加,三者之间差别有显著性(P<0.05),表明上皮细胞增殖能力的异常提高和细胞分化的异型,是OLP癌变的机理。
5 Ki-67在单纯OLP与OLP伴上皮轻度不典型增生之间,差异无显著性,在单纯OLP与OLP伴上皮癌变之间,差异有显著性(P<0.05);表明OLP上皮增生以及恶性转变,存在由量变到质变的飞跃过程。
6在OLP伴癌前病变的早期阶段,Cox-2已经明显增高,这对于癌的发生起到了催化和促进作用。
7 OLP与口腔癌中p53基因mRNA表达阳性率比较,差异有显著性(P <0.017);OLP与口腔正常粘膜的p53基因mRNA阳性率比较,差异无显著性(P>0.05)。口腔癌与正常口腔粘膜p53基因mRNA阳性率比较,差异有显著性(P<0.017)。
8 p53基因突变及癌变潜在性存在于OLP病变区及病变周围1cm范围内的正常口腔粘膜。
Objectives:
Oral lichen planus (OLP) is chronic nonspecific inflammation of oral mucosa, which is a T cell-mediated autoimmune disease with significant risk of malignant potential. OLP was identified as a precancerous condition by WHO. The prevalence rate reported of OLP varied from 0.14% to 3.17%, and the carcinogenesis rate was 0.14% to 3.17%. The common age affected was between 30 and 60 years old, and with women more frequently.
OLP could occur at any part of oral mucosa, but the first common site involved was buccal mucosa, second at tongue (mainly the dorsum), gingiva, labial mucosa, and vermilion of the lower lip. OLP lesions were usually complex and almost always had bilateral, symmetrical distribution. OLP showed small, raised, white, lacy lesions, papules, or plaques, and resembled keratotic diseases such as leukoplakia. Atrophic lesions and erosions were most likely to cause pain.
OLP is characterized histologically by dense subepithelial lymphocytic infiltrated and vaculation and liquefaction of epithelial basal cells. The number of intraepithelial lymphocytes is increased and basal cell liquefied and disappeared. At the same time with epithelial cell apoptosis increased, and along with the inherent reduction of inflammatory cells. The basal keratinocytes degenerated and formed colloid or Civatte bodies, which appeared as homogenous eosinophilic globule. The ultrastructure of colloid bodies suggested that they were apoptotic keratinocytes.
The incidence of OLP involved in many factors, such as local chronic mechanical damage, drug stimulation, dental materials, oral stimulation and tension, systemic diseases and genetic factors, and it may also be connected with some infection caused by bacteria or virus. A great deal of researches suggested that cell-mediated immune response, the release of cytokines and the abnormal apoptosis perhaps was main responsibility for OLP occurrence and development. So far, the mechanism of OLP incidence is not yet clear.
OLP was first reported in 1869, and the different country had the different reports about OLP incidence over recent 100 years. Epidemiological data of domestic and foreign showed that OLP was ranged at the first common disease of oral mucosa except the recurrent ulcer. In 1981, the survey data from“The two diseases of oral leukoplakia and lichen planus”Collaboration Organization showed that the prevalence rate of OLP in some Chinese regions was 0.51%. So far, there is no epidemical information of OLP in Hebei province.
Former researches showed that OLP had increased the malignant risk to oral squamous cell carcinoma, it was a potential cancerous oral mucosa lesion. A lot of factors were connected with the occurrence of OLP, the over- expression of Ki-67 and Cox-2 may be related closely to the development of OLP, as well as the mutation of p53 gene. The over-expression of Ki-67 implicated excessive cell proliferation, compared with the conventional proliferation of nuclear antigen PCNA, the background of Ki67 had small interference, and applied in nearly two years with more accurate and reliable to detect the cell proliferation.
Cox-2 (cyclooxygenase, Cox-2) is also known as prostaglandin endoperoxide synthase, induced-type membrane protein located at the cell nucleus and endoplasmic reticulum. The expression of Cox-2 could be increased induced by a variety of factors (such as: the toxic, infection factor, growth factor, etc.) and it has a close relationship with apoptosis and tumor carcinogenesis.
p53 gene is an important one of the tumor suppressor gene, can initiate apoptosis mechanism. A considerable research showed that: the mutation or inactivation wild-type p53 gene in malignant tumors and precancerous lesions resulted in dysfunction, is an important reason of carcinogenesis. Mutation of p53 gene may be related to the malignant transformation of the benign lesions of oral mucosa. Literatures reported that over-expression of P53 protein is connected with characteristic lesions and carcinogenesis of OLP. Mutation of p53 gene may relate to the incidence and development of OLP.
The part I of this subject: Epidemiological investigation by multistage, stratified, quota-sampling method was adopted to evaluate the prevalence, incidence features and space distribution of OLP in Hebei province, so that to find out the more efficient diagnosis and treatment methods for Hebei people involved OLP.
The part II of this subject: The clinical and pathological information of 101 patients with OLP were collected from the hospital of stomatology of Hebei Medical University. The expression of Ki-67 and Cox-2 were detected in 100 cases of OLP by immunochemistry, and compared with the normal oral mocusa and oral squamous cell carcinoma. The realationship of Ki-67, Cox-2 and potential carcinogenesis of OLP was discussed.
The part III of this subject: The mRNA expression of mutation p53 gene in 60 cases of OLP was detected by RT-PCR, the three samples from each patient were collected by following regions: OLP lesion,adjacent tissue and normal tissue. The mRNA expression of mutation p53 gene of OLP was compared with oral squamous cell carcinoma in order to reveal the potential carcinogenesis risk of OLP, and provided a reliable basis for the early diagnosis, treatment and prevention of OLP.
Methods
1 The epidemiological investigation of OLP in Hebei province Based on“The Third National Oral Health Investigation Criteria”, OLP was surveyed by using multistage, stratified, quota-sample methods estimated by the overall sample. Thirty-six regions were selected by random from three cities and three counties in Hebei province, the two age groups of 742 people were surveyed, the ratio of male and female was 1:1, a total of 1548 people were investigated. OLP diagnostic criteria: the diagnostic criteria of OLP according to the“Third national epidemiological survey of oral health programme”. All data was dealt statistically with SPSS 10.0.
2 The relationship between the potential carcinogenesis risk of OLP and the expression of Ki-67 and Cox-2
A total of 101 cases of OLP and 10 cases of oral cancer sample were enrolled. Additional 10 normal oral mocusa were used as the control. The expression of Ki-67 and Cox-2 were detected by immunochemistry (SP method). All data was dealt statistically with SPSS 10.0.by single-factor analysis of variance.
3 The detection of mRNA expression of mutant p53 gene in OLP Sixty cases of OLP and 30 cases of oral cancer were confirmed by pathology. Twenty cases of normal oral mucosa were collected from the tissue around injury wound acted as the control. The mRNA expresstion of mutant p53 gene was detected by one-step RT-PCR. All data was dealt statistically with SPSS 10.0.by usingχ2–test.
4 The detection of mRNA expression of p53 gene mutant in OLP and the adjacent tissues of the lesion
Thirty cases of OLP were confirmed by pathology. Three samples from the same patient were collected by the following three regions: OLP lesion,adjacent tissues and normal tissues, and 90 samples in total. The distance of the adjacent tissue far from OLP lesion was more than 0.5cm; the distance of the normal tissues far from OLP lesion was more than 1cm. All samples were obtained by patient agreement with the knowledge. The mRNA expression of mutant p53 gene was detected by one-step RT-PCR. All data was dealt statistically with SPSS 10.0.by usingχ2–test.
Result
1 The prevalence of oral lichen planus was 0.82% in the investigated people of Hebei province. The result was slightly higher than that of“The two diseases of oral leukoplakia and lichen planus”Collaboration Organization. It suggested that the prevalence rate of OLP of Hebei province was 95%, confidence interval was 0.38% to 1.26%.
2 This epidemiological investigation showed that the statistically significant difference of the proportions of all kinds of oral mucosa disease, at present OLP was ranged the first common disease of oral mucosa except the recurrent oral ulcer.
3 OLP was easy to happen on cheek, the illness had a tendency to increase with the age. There was no difference in rural areas and urban areas.
4 Clinic-pathological features: One hundred and one cases of OLP were enrolled in this study, including 39 males and 62 females, age ranged from 21 to 78, with an average age of 48.8. The ratio of male and female was 1:1.6, there were more women than men. The most common site for the onset in cheek was of 81 cases, followed by the tongue of 11 cases; 5 cases in other gingival, 4 cases in lip.
5 The pathological change of 101 cases of OLP: Epithelial hyperplasia and / or atrophy, basal cells were liquefied and disappeared, the band infiltrating lymphocytes were observed closely subepithelium. Epithelial hyperplasia was of 48 cases; epithelial atrophy of 22 cases; both epithelial hyperplasia and atrophy of 23 cases. Fifteen cases were with vesicle and 19 cases with epithelial erosion and ulcers. Mild epithelial dysplasia was involved in 7 cases and epithelial carcinogenesis in 1 case. The histopathology of oral squamous cell showed: the special-shaped tumor cells were of the polyhedral cells arranged nest, tended to keratosis with cancer beads.
6 The expression of Ki-67 in OLP: Ki-67 was expressed in all 10 normal oral mucosa. The positive cells scattered distributed in the basal cell, the ratio of positive cells was 15.2%. Ki-67 was expressed in 93 cases out of 101 cases of OLP which located in epithelial hyperplasia or atrophy epithelial cells in the basement and adjacent cells, the ratio of positive cells was 37.1%. OLP with epithelial dysplasia, the ratio of positive cells was 47.0%. OLP with squamous cell carcinoma, the ratio of positive cells was 61.0%. Ki-67 was expressed in all cases of oral squamous cell carcinoma, the positive cells increased markedly with the up-regulated atypical basal cells and basal-like cells, the ratio of positive cells was 62.5%. Statistical analysis showed that the positive rate of OLP was higher than that of normal oral mucosa, lower than that of the oral squamous cell carcinoma (P<0.05), there was significant difference. There was no significant difference between the OLP (36.1%) and OLP with epithelial dysplasia (47.0%) (P> 0.05); there was significant difference between the OLP and OLP with carcinoma.
7 The expression of Cox-2 in OLP: Cox-2 was not expressed in all 10 normal oral mucosa. Cox-2 was expressed in 36 cases out of 101 cases of OLP, the positive ratio was 35.6%, which both pathological changes showed Cox-2 over-expressed in the cytoplasm of stratum spinosum cells and stratum granulosum cells, basal cells submitted negative expression. OLP with epithelial dysplasia, the positive spinosum cells increased markedly with slight malignancy. OLP with carcinoma, the positive tumor cells infiltrated the mesenchyme. In the 36 cases of OLP positive, 16 cases were with the epithelial dysplasia, 9 cases with epithelial atrophy, 4 cases with both epithelial hyperplasia and atrophy, 6 cases with epithelial dysplasia, 1 case with epithelial carcinogenesis. Cox-2 was expressed in 2 out of 10 cases of carcinoma, which tumor cells grew infiltrated and showed obviously malignancy, the ratio of positive cells was 20.0%. There was significant difference among the normal (0%), OLP (36.1%) and OLP with epithelial dysplasia (47.0%) (P<0.05). There was no significant difference between OLP(35.6%)and oral squamous cell carcinoma(20.0%)(P>0.05).
8 The results of mRNA expression of mutant p53 gene of OLP showed:
There were 13 positive cases out of 60 cases of OLP, the positive rate was 21.67% (13/60). There were 16 positive cases out of 30 cases of oral cancer, the positive rate was 53.3% (16/30). There was 1 positive case out of 20 cases of oral normal mucosa, the positive rate was 5% (1/20). There were significant differences (P<0.017) between OLP and oral cancer in the positive rate of mutant p53 gene mRNA. There was no significant differences(P>0.05) between OLP and oral normal mucosa in the positive rate of mutant p53 gene mRNA. There were significant differences (P<0.017) between oral normal mucosa and oral cancer in the positive rate of mutant p53 gene mRNA.
9 The detection of mRNA expression of p53 gene mutant in OLP and the adjacent tissues, the results showed: In the total of 90 samples from 30 cases of OLP, including OLP lesions, adjacent tissue and normal tissue of each case, 3 cases the mRNA of mutant p53 gene in 9 samples were all positive, accounting for 10% of all patients (3/30). Three cases the mRNA of mutant p53 gene in adjacent tissue were positive, but negative in OLP lesion and normal tissue, accounting for 10% of all patients (3/30). One case the mRNA of mutant p53 gene in OLP lesion was positive, but negative in adjacent tissue and normal tissue, accounting for 3.33 % of all patients (1/30). One case the mRNA of mutant p53 gene in OLP lesion and adjacent tissue were positive, but negative in normal tissue, accounting for 3.33 % (1/30).
Conclusion
1 The prevalence of oral lichen planus was 0.82% among the investigated persons in Hebei province. The 95% confidence interval of the prevalence rate of OLP in Hebei province was 0.38% to 1.26%.
2 This investigation results showed that the significant difference of the proportions existed the all kinds of oral mucosa diseases, OLP was the first common disease in oral mucosa except the recurrent oral ulcer.
3 The clinical pathology analysis showed that: The carcinogenesis rate of OLP was 0.9%, the incidence of precancerous lesions was 6.9%, implicated that OLP has potential carcinogenesis.
4 The positive rate of Ki-67 expression increased from the normal oral mucosa to OLP and oral cancer in turn, the difference among the three groups was significant (P<0.05), The result suggested that the abnormal proliferation and atypical differentiation of epithelial cells were the mechanism of the carcinogenesis of OLP.
5 There was no significant difference between OLP and OLP with epithelial dysplasia (P>0.05); but there was significant difference between OLP and OLP with carcinoma (P<0.05). The result implicated that there was a leap process of quantitative change from epithelial hyperplasia and malignant transformation to squamous cell carcinoma.
6 The expression of Cox-2 showed significantly increased in the early stages of OLP with precancerous lesions, suggested that Cox-2 promoted and played a catalytic role in the carcinogenesis.
7 There were significant differences (P<0.017) between OLP and oral cancer in the positive rate of mutant p53 gene mRNA. There was no significant differences between OLP and oral normal mucosa in the positive rate of mutant p53 gene mRNA (P>0.05). There was significant differences (P<0.017) between oral normal mucosa and oral cancer in the positive rate of mutant p53 gene mRNA.
8 The potential mutation of p53 gene and carcinogenesis existed in the regions both OLP lesions and the normal oral mucosa within 1cm around OLP lesions .
口腔扁平苔藓(oral lichen planus,OLP),是一种较常见的口腔粘膜慢性非特异性炎症,被认为是细胞介导的自身免疫性疾病,具有癌变潜在性,WHO将OLP确定为癌前状态。
口腔扁平苔藓的粘膜病损可累及口腔粘膜的任何部位,多发于颊部,其次为舌、龈、唇、腭、口底等处。临床常表现为复杂的联合病损,如丘疹样、斑块的、萎缩性、溃疡和大疱等,也可表现为角化样病变,如白斑。萎缩型病变和糜烂型病变,最有可能引起疼痛。
OLP主要的病理特征为:上皮过度角化、上皮下固有层淋巴细胞带状浸润及基底层细胞液化变性;同时具有上皮细胞凋亡增加、固有层炎性细胞凋亡减少。变性的基底细胞形成胶样小体或Civatte小体,表现为均匀嗜酸性粒细胞,超微结构表明,胶样小体为角质细胞的凋亡。
口腔扁平苔藓的发生涉及诸多因素,与局部慢性机械损伤、药物刺激、牙科材料、口腔内电流刺激以及精神紧张、全身性疾患和遗传因素等有关;还可能与某些细菌、病毒感染相关。以往研究提示,淋巴细胞介导的免疫反应、细胞因子的释放及角质细胞的凋亡异常,被认为是其发生发展的主要原因。迄今为止,口腔扁平苔藓的病因与发病机制尚不明确。
OLP于1869年被首次报道,一百多年来对于其发病率的调查结果,各地域存在较大差异。国内外资料流行病学资料显示:OLP是除复发性口疮外,最多见的口腔粘膜疾病。1981年我国“口腔白斑、扁平苔藓两病防治协作组”的调查资料显示,OLP患病率为0.51%。迄今为止,河北省各地区尚缺乏关于OLP的流行病学资料。
研究表明,OLP病变使口腔癌发生的危险性大大增加,是具有癌变潜能的口腔粘膜病损。OLP发生的相关因素有很多,其中Ki-67、Cox-2的过表达及p53基因的突变可能与其发生的密切相关因素。
Ki-67位于人的所有增殖细胞的核内,是细胞增殖活性的一种标志性抗原,也是判断良、恶性肿瘤组织生长状态的关键指标。Ki-67过度表达提示细胞增殖过度,与传统的增殖核抗原PCNA相比背景干扰小,是近两年得到应用的,更为准确可靠的检测细胞增殖状态的指标。
环氧合酶Cox-2(cyclooxygenase,Cox-2)又名前列腺素内过氧化物合成酶,是一种诱导型膜结合蛋白酶,位于细胞内质网和细胞核周围,Cox-2在多种因子(如内毒素、感染因子、生长因子等)的作用下表达上调,与细胞凋亡和肿瘤发生关系密切。
p53基因是重要的抑癌基因之一,可以启动细胞凋亡机制。大量研究表明:恶性肿瘤及癌前病变中野生型p53基因突变或失活而导致的功能异常,是肿瘤发生的重要原因。p53基因突变可能与口腔粘膜良性病损恶性变有关。研究显示,P53蛋白表达增高与OLP特征性病变及癌变相关,p53基因的突变可能引起OLP的发生与发展。
本课题第一部分:在河北省内,通过多阶段分层等容量随机抽样的方法,调查OLP在河北省的发病特征、人群和空间分布状况,并对上述诸多因素进行流行病学研究,为我国人群中OLP的诊断、治疗提供流行病学资料。本课题第二部分:收集五年期间在河北医科大学口腔医院就诊的OLP患者101例的临床病理资料,采用免疫组织化学方法,针对OLP的相关癌变因素:Ki-67和Cox-2,检测其在101例OLP患者病变中的表达,并以正常口腔粘膜和口腔鳞状细胞癌作为比较,探讨Ki-67、Cox-2表达与口腔OLP潜在恶性的关系。本课题第三部分:采用RT-PCR的方法,检测60例OLP患者病变及病变旁组织和相邻正常口腔粘膜中突变型p53基因的mRNA表达水平,并与口腔鳞状细胞癌比较,探讨OLP癌变潜在危险性和癌变机理,为OLP的早期诊断、治疗以及癌变的预防提供可靠依据。
材料与方法
1河北省口腔扁平苔藓的流行病学调查
根据“第三次全国口腔健康流行病学调查方案”,参照WHO《口腔健康调查基本方法》(第四版),采用多阶段分层等容量随机抽样的方法,通过样本估计总体。在河北省三市、三县,随机抽样共选取36个调查点,2个年龄组各调查742人,男女比为1:1,共调查1548人。OLP诊断标准:采用全国牙防组制定的《第三次全国口腔健康流行病学调查方案》中对OLP的诊断标准。全部调查资料使用SPSS10.0软件进行统计学分析。2口腔扁平苔藓中Ki-67、Cox-2表达与其潜在恶性的关系
收集口腔扁平苔藓101例,另取口腔癌手术标本10例,口腔正常颊粘膜标本10例作为对照。使用免疫组化(SP法)方法检测Ki-67、Cox-2蛋白的表达情况。采用SPSS10.0统计分析软件进行单因素方差分析。3口腔扁平苔藓中突变型p53基因mRNA表达的检测
60例口腔扁平苔藓和30例颊癌均经病理确诊,20例正常口腔颊粘膜来自外伤创面周围的组织,作为正常对照组标本。采用一步法RT-PCR检测突变型p53基因mRNA水平的表达。所有数据采用SPSS10.0软件进行统计学分析,采用χ2检验。
4口腔扁平苔藓及其邻近组织中突变型p53基因mRNA的表达30名患者经病理诊断确诊为口腔扁平苔藓。每名患者采集病变区、病变旁、正常组织区三个部位标本各一,共90个标本。病变旁组织与病变组织距离≥5mm,正常组织与病变旁组织距离≥1cm。所有标本的采集均在患者知情并同意的情况下进行。采用一步法RT-PCR检测突变型p53基因mRNA水平的表达。所有数据采用SPSS10.0软件进行统计学分析,采用χ2检验。
结果
1在本次流行病学调查中,河北省被调查人群中口腔扁平苔藓的患病率为0.82%,略高于我国“口腔白斑、扁平苔藓两病防治协作组”的调查结果,测算河北省口腔扁平苔藓患病率的95%可信区间为0.38%～1.26%。
2流行病学调查结果显示:河北省各种口腔粘膜病构成比差异有统计学意义,口腔扁平苔藓是目前口腔粘膜病中除复发性口疮外的最多见的口腔粘膜病。
3口腔扁平苔藓好发于颊部,其患病有随着年龄增加而增加的趋势,无城乡差异。
4临床病理资料分析
101例口腔扁平苔藓中,男性39例,女性62例,男:女之比为1:1.6,女性多于男性。就诊年龄最小者21岁,最长者78岁,平均年龄为48.8岁。发病部位最常见为颊部81例;其次为舌部11例;其它牙龈5例;唇部4例。
5口腔扁平苔藓的病理学改变
101例口腔扁平苔藓的组织病理学改变为,上皮增生和/或萎缩,基底细胞灶状或片状液化消失,上皮下淋巴细胞呈带状浸润。其中表现为上皮增生者48例;上皮萎缩者22例;上皮增生与萎缩同时出现者23例。15例伴有上皮下疱;19例伴上皮糜烂和溃疡。7例出现上皮轻度不典型增生;1例出现上皮癌变,OLP癌变率为0.9%(1/101),癌前病变发病率为6.9%(7/101)。口腔鳞状细胞的病理组织学表现为,异型性的肿瘤细胞呈多边形或圆形,排列成巢状,可见细胞间桥,肿瘤细胞有角化倾向,形成癌珠。
6 Ki-67在口腔扁平苔藓中的表达
10例正常口腔粘膜均表达Ki-67,阳性细胞散在于基底细胞中,其阳性细胞比例为15.2%。在101例口腔扁平苔藓中,93例表达Ki-67,阳性细胞位于增生上皮或萎缩上皮的基底细胞和基底旁细胞中,其阳性细胞比例为37.1%。扁平苔藓伴上皮轻度不典型增生的病例中,阳性细胞比例为47.0%;扁平苔藓伴上皮癌变的病例,其阳性细胞比例为61.0%。10例口腔鳞状细胞癌全部表达Ki-67,阳性细胞随着肿瘤异型性基底细胞和基底样细胞增多而明显增多,其阳性细胞比例为62.5%。统计学分析表明,扁平苔藓阳性率高于正常口腔粘膜,低于口腔鳞状细胞癌,差别均有显著性(P<0.05)。单纯扁平苔藓(36.1%)与扁平苔藓伴上皮轻度不典型增生(47.0%)之间差别无显著性(P>0.05);而与扁平苔藓伴上皮癌变(61.0%)之间差别有显著性(P<0.05)。
7 Cox-2在口腔扁平苔藓中的表达
10例正常粘膜均不表达Cox-2。101例扁平苔藓中36例表达Cox-2,阳性率为35.6%,病变表现为上皮棘层细胞、粒层细胞和表层细胞呈阳性表达,基底细胞呈阴性表达。扁平苔藓伴上皮轻度不典型增生的病变中,阳性的棘层细胞增多,并具有异型性。扁平苔藓伴上皮癌变的病变中,阳性的肿瘤细胞浸润至肿瘤间质。在阳性的36例口腔扁平苔藓中,组织病理学改变为上皮增生者16例阳性;上皮萎缩者9例阳性;上皮增生与萎缩相间者4例;上皮不典型增生阳性者6例;上皮癌变阳性者1例。10例口腔鳞状细胞癌中2例表达Cox-2,阳性率为20.0%。阳性的肿瘤细胞异型性明显,浸润性生长。Cox-2在正常口腔粘膜(0%)、扁平苔藓(35.6%)及口腔鳞状细胞癌(20.0%)三者之间差别有显著性(P<0.05);口腔粘膜与扁平苔藓之间以及口腔粘膜与口腔鳞状细胞癌之间差别均有显著性(P<0.05)。扁平苔藓(35.6%)及口腔鳞状细胞癌(20.0%)之间差别无显著性(P>0.05)。
8口腔扁平苔藓突变型p53基因mRNA水平表达的结果显示,60例口腔扁平苔藓中表达阳性者13例;阳性率为21.67%(13/60)。30例口腔颊癌中表达阳性者16例;阳性率为53.3%(16/30)。20例口腔正常粘膜p53基因mRNA表达阳性者1例;阳性率为5%(1/20)。口腔扁平苔藓组与口腔癌中p53基因mRNA阳性率比较,差异有显著性(P<0.017)。口腔扁平苔藓组与口腔正常粘膜组的p53基因mRNA阳性率比较,差异无显著性(P>0.05)。口腔颊癌与正常口腔粘膜p53基因mRNA阳性率比较,差异有显著性(P<0.017)。
9 RT-PCR检测突变型p53基因在扁平苔藓及其邻近组织中的表达,结果显示,30例口腔扁平苔藓患者中,每例包括扁平苔藓病变组织、病变旁组织及正常组织,共90个标本,其中p53基因mRNA表达均为阳性者3例;占全部患者的10%(3/30)。扁平苔藓病变旁组织为阳性,病变组织和正常组织为阴性者3例;占全部患者的10%(3/30)。扁平苔藓病变组织为阳性,病变旁组织及正常组织为阴性者1例;占全部患者的3.33%(1/30)。扁平苔藓病变和病变旁组织均为阳性,正常组织阴性者1例;占全部患者的3.33% (1/30)。
结论
1河北省被调查人群中OLP患病率为0.82%,河北省OLP患病率的95%可信区间为0.38%～1.26%。
2本研究流行病学调查结果显示:河北省各种口腔粘膜病构成比差异有统计学意义,OLP是口腔粘膜病中除复发性口疮外的最多见的口腔粘膜病。
3本研究临床病理分析显示:OLP癌变率为0.9%,癌前病变发病率为6.9%;说明OLP具有潜在癌变性。
4 Ki-67蛋白表达阳性率从正常口腔粘膜到OLP和口腔癌依次增加,三者之间差别有显著性(P<0.05),表明上皮细胞增殖能力的异常提高和细胞分化的异型,是OLP癌变的机理。
5 Ki-67在单纯OLP与OLP伴上皮轻度不典型增生之间,差异无显著性,在单纯OLP与OLP伴上皮癌变之间,差异有显著性(P<0.05);表明OLP上皮增生以及恶性转变,存在由量变到质变的飞跃过程。
6在OLP伴癌前病变的早期阶段,Cox-2已经明显增高,这对于癌的发生起到了催化和促进作用。
7 OLP与口腔癌中p53基因mRNA表达阳性率比较,差异有显著性(P <0.017);OLP与口腔正常粘膜的p53基因mRNA阳性率比较,差异无显著性(P>0.05)。口腔癌与正常口腔粘膜p53基因mRNA阳性率比较,差异有显著性(P<0.017)。
8 p53基因突变及癌变潜在性存在于OLP病变区及病变周围1cm范围内的正常口腔粘膜。
Objectives:
Oral lichen planus (OLP) is chronic nonspecific inflammation of oral mucosa, which is a T cell-mediated autoimmune disease with significant risk of malignant potential. OLP was identified as a precancerous condition by WHO. The prevalence rate reported of OLP varied from 0.14% to 3.17%, and the carcinogenesis rate was 0.14% to 3.17%. The common age affected was between 30 and 60 years old, and with women more frequently.
OLP could occur at any part of oral mucosa, but the first common site involved was buccal mucosa, second at tongue (mainly the dorsum), gingiva, labial mucosa, and vermilion of the lower lip. OLP lesions were usually complex and almost always had bilateral, symmetrical distribution. OLP showed small, raised, white, lacy lesions, papules, or plaques, and resembled keratotic diseases such as leukoplakia. Atrophic lesions and erosions were most likely to cause pain.
OLP is characterized histologically by dense subepithelial lymphocytic infiltrated and vaculation and liquefaction of epithelial basal cells. The number of intraepithelial lymphocytes is increased and basal cell liquefied and disappeared. At the same time with epithelial cell apoptosis increased, and along with the inherent reduction of inflammatory cells. The basal keratinocytes degenerated and formed colloid or Civatte bodies, which appeared as homogenous eosinophilic globule. The ultrastructure of colloid bodies suggested that they were apoptotic keratinocytes.
The incidence of OLP involved in many factors, such as local chronic mechanical damage, drug stimulation, dental materials, oral stimulation and tension, systemic diseases and genetic factors, and it may also be connected with some infection caused by bacteria or virus. A great deal of researches suggested that cell-mediated immune response, the release of cytokines and the abnormal apoptosis perhaps was main responsibility for OLP occurrence and development. So far, the mechanism of OLP incidence is not yet clear.
OLP was first reported in 1869, and the different country had the different reports about OLP incidence over recent 100 years. Epidemiological data of domestic and foreign showed that OLP was ranged at the first common disease of oral mucosa except the recurrent ulcer. In 1981, the survey data from“The two diseases of oral leukoplakia and lichen planus”Collaboration Organization showed that the prevalence rate of OLP in some Chinese regions was 0.51%. So far, there is no epidemical information of OLP in Hebei province.
Former researches showed that OLP had increased the malignant risk to oral squamous cell carcinoma, it was a potential cancerous oral mucosa lesion. A lot of factors were connected with the occurrence of OLP, the over- expression of Ki-67 and Cox-2 may be related closely to the development of OLP, as well as the mutation of p53 gene. The over-expression of Ki-67 implicated excessive cell proliferation, compared with the conventional proliferation of nuclear antigen PCNA, the background of Ki67 had small interference, and applied in nearly two years with more accurate and reliable to detect the cell proliferation.
Cox-2 (cyclooxygenase, Cox-2) is also known as prostaglandin endoperoxide synthase, induced-type membrane protein located at the cell nucleus and endoplasmic reticulum. The expression of Cox-2 could be increased induced by a variety of factors (such as: the toxic, infection factor, growth factor, etc.) and it has a close relationship with apoptosis and tumor carcinogenesis.
p53 gene is an important one of the tumor suppressor gene, can initiate apoptosis mechanism. A considerable research showed that: the mutation or inactivation wild-type p53 gene in malignant tumors and precancerous lesions resulted in dysfunction, is an important reason of carcinogenesis. Mutation of p53 gene may be related to the malignant transformation of the benign lesions of oral mucosa. Literatures reported that over-expression of P53 protein is connected with characteristic lesions and carcinogenesis of OLP. Mutation of p53 gene may relate to the incidence and development of OLP.
The part I of this subject: Epidemiological investigation by multistage, stratified, quota-sampling method was adopted to evaluate the prevalence, incidence features and space distribution of OLP in Hebei province, so that to find out the more efficient diagnosis and treatment methods for Hebei people involved OLP.
The part II of this subject: The clinical and pathological information of 101 patients with OLP were collected from the hospital of stomatology of Hebei Medical University. The expression of Ki-67 and Cox-2 were detected in 100 cases of OLP by immunochemistry, and compared with the normal oral mocusa and oral squamous cell carcinoma. The realationship of Ki-67, Cox-2 and potential carcinogenesis of OLP was discussed.
The part III of this subject: The mRNA expression of mutation p53 gene in 60 cases of OLP was detected by RT-PCR, the three samples from each patient were collected by following regions: OLP lesion,adjacent tissue and normal tissue. The mRNA expression of mutation p53 gene of OLP was compared with oral squamous cell carcinoma in order to reveal the potential carcinogenesis risk of OLP, and provided a reliable basis for the early diagnosis, treatment and prevention of OLP.
Methods
1 The epidemiological investigation of OLP in Hebei province Based on“The Third National Oral Health Investigation Criteria”, OLP was surveyed by using multistage, stratified, quota-sample methods estimated by the overall sample. Thirty-six regions were selected by random from three cities and three counties in Hebei province, the two age groups of 742 people were surveyed, the ratio of male and female was 1:1, a total of 1548 people were investigated. OLP diagnostic criteria: the diagnostic criteria of OLP according to the“Third national epidemiological survey of oral health programme”. All data was dealt statistically with SPSS 10.0.
2 The relationship between the potential carcinogenesis risk of OLP and the expression of Ki-67 and Cox-2
A total of 101 cases of OLP and 10 cases of oral cancer sample were enrolled. Additional 10 normal oral mocusa were used as the control. The expression of Ki-67 and Cox-2 were detected by immunochemistry (SP method). All data was dealt statistically with SPSS 10.0.by single-factor analysis of variance.
3 The detection of mRNA expression of mutant p53 gene in OLP Sixty cases of OLP and 30 cases of oral cancer were confirmed by pathology. Twenty cases of normal oral mucosa were collected from the tissue around injury wound acted as the control. The mRNA expresstion of mutant p53 gene was detected by one-step RT-PCR. All data was dealt statistically with SPSS 10.0.by usingχ2–test.
4 The detection of mRNA expression of p53 gene mutant in OLP and the adjacent tissues of the lesion
Thirty cases of OLP were confirmed by pathology. Three samples from the same patient were collected by the following three regions: OLP lesion,adjacent tissues and normal tissues, and 90 samples in total. The distance of the adjacent tissue far from OLP lesion was more than 0.5cm; the distance of the normal tissues far from OLP lesion was more than 1cm. All samples were obtained by patient agreement with the knowledge. The mRNA expression of mutant p53 gene was detected by one-step RT-PCR. All data was dealt statistically with SPSS 10.0.by usingχ2–test.
Result
1 The prevalence of oral lichen planus was 0.82% in the investigated people of Hebei province. The result was slightly higher than that of“The two diseases of oral leukoplakia and lichen planus”Collaboration Organization. It suggested that the prevalence rate of OLP of Hebei province was 95%, confidence interval was 0.38% to 1.26%.
2 This epidemiological investigation showed that the statistically significant difference of the proportions of all kinds of oral mucosa disease, at present OLP was ranged the first common disease of oral mucosa except the recurrent oral ulcer.
3 OLP was easy to happen on cheek, the illness had a tendency to increase with the age. There was no difference in rural areas and urban areas.
4 Clinic-pathological features: One hundred and one cases of OLP were enrolled in this study, including 39 males and 62 females, age ranged from 21 to 78, with an average age of 48.8. The ratio of male and female was 1:1.6, there were more women than men. The most common site for the onset in cheek was of 81 cases, followed by the tongue of 11 cases; 5 cases in other gingival, 4 cases in lip.
5 The pathological change of 101 cases of OLP: Epithelial hyperplasia and / or atrophy, basal cells were liquefied and disappeared, the band infiltrating lymphocytes were observed closely subepithelium. Epithelial hyperplasia was of 48 cases; epithelial atrophy of 22 cases; both epithelial hyperplasia and atrophy of 23 cases. Fifteen cases were with vesicle and 19 cases with epithelial erosion and ulcers. Mild epithelial dysplasia was involved in 7 cases and epithelial carcinogenesis in 1 case. The histopathology of oral squamous cell showed: the special-shaped tumor cells were of the polyhedral cells arranged nest, tended to keratosis with cancer beads.
6 The expression of Ki-67 in OLP: Ki-67 was expressed in all 10 normal oral mucosa. The positive cells scattered distributed in the basal cell, the ratio of positive cells was 15.2%. Ki-67 was expressed in 93 cases out of 101 cases of OLP which located in epithelial hyperplasia or atrophy epithelial cells in the basement and adjacent cells, the ratio of positive cells was 37.1%. OLP with epithelial dysplasia, the ratio of positive cells was 47.0%. OLP with squamous cell carcinoma, the ratio of positive cells was 61.0%. Ki-67 was expressed in all cases of oral squamous cell carcinoma, the positive cells increased markedly with the up-regulated atypical basal cells and basal-like cells, the ratio of positive cells was 62.5%. Statistical analysis showed that the positive rate of OLP was higher than that of normal oral mucosa, lower than that of the oral squamous cell carcinoma (P<0.05), there was significant difference. There was no significant difference between the OLP (36.1%) and OLP with epithelial dysplasia (47.0%) (P> 0.05); there was significant difference between the OLP and OLP with carcinoma.
7 The expression of Cox-2 in OLP: Cox-2 was not expressed in all 10 normal oral mucosa. Cox-2 was expressed in 36 cases out of 101 cases of OLP, the positive ratio was 35.6%, which both pathological changes showed Cox-2 over-expressed in the cytoplasm of stratum spinosum cells and stratum granulosum cells, basal cells submitted negative expression. OLP with epithelial dysplasia, the positive spinosum cells increased markedly with slight malignancy. OLP with carcinoma, the positive tumor cells infiltrated the mesenchyme. In the 36 cases of OLP positive, 16 cases were with the epithelial dysplasia, 9 cases with epithelial atrophy, 4 cases with both epithelial hyperplasia and atrophy, 6 cases with epithelial dysplasia, 1 case with epithelial carcinogenesis. Cox-2 was expressed in 2 out of 10 cases of carcinoma, which tumor cells grew infiltrated and showed obviously malignancy, the ratio of positive cells was 20.0%. There was significant difference among the normal (0%), OLP (36.1%) and OLP with epithelial dysplasia (47.0%) (P<0.05). There was no significant difference between OLP(35.6%)and oral squamous cell carcinoma(20.0%)(P>0.05).
8 The results of mRNA expression of mutant p53 gene of OLP showed:
There were 13 positive cases out of 60 cases of OLP, the positive rate was 21.67% (13/60). There were 16 positive cases out of 30 cases of oral cancer, the positive rate was 53.3% (16/30). There was 1 positive case out of 20 cases of oral normal mucosa, the positive rate was 5% (1/20). There were significant differences (P<0.017) between OLP and oral cancer in the positive rate of mutant p53 gene mRNA. There was no significant differences(P>0.05) between OLP and oral normal mucosa in the positive rate of mutant p53 gene mRNA. There were significant differences (P<0.017) between oral normal mucosa and oral cancer in the positive rate of mutant p53 gene mRNA.
9 The detection of mRNA expression of p53 gene mutant in OLP and the adjacent tissues, the results showed: In the total of 90 samples from 30 cases of OLP, including OLP lesions, adjacent tissue and normal tissue of each case, 3 cases the mRNA of mutant p53 gene in 9 samples were all positive, accounting for 10% of all patients (3/30). Three cases the mRNA of mutant p53 gene in adjacent tissue were positive, but negative in OLP lesion and normal tissue, accounting for 10% of all patients (3/30). One case the mRNA of mutant p53 gene in OLP lesion was positive, but negative in adjacent tissue and normal tissue, accounting for 3.33 % of all patients (1/30). One case the mRNA of mutant p53 gene in OLP lesion and adjacent tissue were positive, but negative in normal tissue, accounting for 3.33 % (1/30).
Conclusion
1 The prevalence of oral lichen planus was 0.82% among the investigated persons in Hebei province. The 95% confidence interval of the prevalence rate of OLP in Hebei province was 0.38% to 1.26%.
2 This investigation results showed that the significant difference of the proportions existed the all kinds of oral mucosa diseases, OLP was the first common disease in oral mucosa except the recurrent oral ulcer.
3 The clinical pathology analysis showed that: The carcinogenesis rate of OLP was 0.9%, the incidence of precancerous lesions was 6.9%, implicated that OLP has potential carcinogenesis.
4 The positive rate of Ki-67 expression increased from the normal oral mucosa to OLP and oral cancer in turn, the difference among the three groups was significant (P<0.05), The result suggested that the abnormal proliferation and atypical differentiation of epithelial cells were the mechanism of the carcinogenesis of OLP.
5 There was no significant difference between OLP and OLP with epithelial dysplasia (P>0.05); but there was significant difference between OLP and OLP with carcinoma (P<0.05). The result implicated that there was a leap process of quantitative change from epithelial hyperplasia and malignant transformation to squamous cell carcinoma.
6 The expression of Cox-2 showed significantly increased in the early stages of OLP with precancerous lesions, suggested that Cox-2 promoted and played a catalytic role in the carcinogenesis.
7 There were significant differences (P<0.017) between OLP and oral cancer in the positive rate of mutant p53 gene mRNA. There was no significant differences between OLP and oral normal mucosa in the positive rate of mutant p53 gene mRNA (P>0.05). There was significant differences (P<0.017) between oral normal mucosa and oral cancer in the positive rate of mutant p53 gene mRNA.
8 The potential mutation of p53 gene and carcinogenesis existed in the regions both OLP lesions and the normal oral mucosa within 1cm around OLP lesions .
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