口腔扁平苔藓癌变的研究进展

0 引言 口腔扁平苔藓(OLP)是一种常见的口腔黏膜慢性炎性疾病,是细胞介导的自身免疫性疾病.女性好发,糜烂型较常见,精神压力、食物、牙科操作、全身性疾病和口腔卫生不良等因素均可以诱发或加重疾病的发展[1].     

放疗对口腔粘膜白斑和扁平苔癣的作用观察

目的　对伴有口腔粘膜慢性病变的 2 4例口腔鳞癌术后放疗病例进行观察 ,了解 6 0钴 (γ—射线 )对口腔粘膜白斑和扁平苔癣是否具有抑制发展和治疗作用。方法　选择上海市第九人民医院口腔颌面外科放疗室 1994年 3月到 1999年 3月间进行放疗的 2 4例伴有慢性口腔粘膜疾病的口腔鳞癌病例 ,分放疗、放疗后、康复期 3个阶段进行观察 (其中粘膜白斑 16例、扁平苔癣 8例 ) ,另选 2 4例口腔鳞癌病例作对照观察。结果　放疗阶段两组病例相比 ,观察组放射耐受性比对照组差 ,表现在口腔粘膜溃疡出现早持续时间长 ;放疗结束后两组相比 ,对照组口腔粘膜修复过程快 ,观察组内相比口腔粘膜白斑比扁平苔癣恢复快 (包括全身和口腔内粘膜反应 ) ;康复期内观察口腔粘膜白斑比扁平苔癣复发率高。结论　 6 0钴 (γ—射线 )对口腔粘膜白斑和扁平苔癣具有一定的抑制和减缓发展的作用。     

洋槐蜂蜜防治鼻咽癌患者放射性口腔粘膜炎的临床观察

目的 探讨洋槐蜂蜜对鼻咽癌患者放射性口腔粘膜炎的防治作用.方法 将72例根治性放射治疗的鼻咽癌患者随机分为两组,各36例,对照组给予常规口腔护理和健康宣教,研究组在常规护理基础上含服洋槐蜂蜜,10ml/次,3次/日,直至放疗结束后8周;按照NCI-CTCAE v3.0和文献报道的方法观察和评价两组患者急慢性放射性口腔粘膜炎情况.结果 ①两组患者基本临床特征匹配(均P ＞0.05);②72例患者均存在不同程度的急性口腔粘膜炎,与对照组相比,研究组重度口腔粘膜炎的发生率从41.67％下降至19.44％,P=0.0407;急性口腔粘膜炎出现时间从(20.78±6.06)天延迟至(23.14±6.21)天,P=0.107;③对照组和研究组慢性口腔粘膜炎的发生率分别为25.0％ (9/36)和11.1％(4/36),P=0.1255.结论 洋槐蜂蜜可减少鼻咽癌患者重度急性放射性口腔粘膜炎的发生,值得进一步探索.     

半乳糖凝集素-9和T细胞免疫球蛋白黏蛋白分子3在口腔扁平苔藓和口腔鳞状细胞癌组织中的表达及临床意义

目的探讨半乳糖凝集素-9(Galectin-9)和T细胞免疫球蛋白黏蛋白分子3(TIM3)在口腔扁平苔藓和口腔鳞状细胞癌组织中的表达及临床意义。方法收集42例口腔扁平苔藓组织、25例口腔鳞状细胞癌组织及30例正常口腔黏膜组织,采用免疫组织化学染色法检测3种组织中Galectin-9和TIM3的表达情况,分析Galectin-9和TIM3表达情况与口腔扁平苔藓和口腔鳞状细胞癌患者临床特征的关系,采用Pearson相关分析法分析口腔扁平苔藓及口腔鳞状细胞癌患者中Galectin-9和TIM3表达的相关性。结果口腔鳞状细胞癌组织中Galectin-9的阳性表达率低于口腔扁平苔藓组织和正常口腔黏膜组织,TIM3的阳性表达率高于正常口腔黏膜组织,差异均有统计学意义(P﹤0.05);口腔扁平苔藓组织中Galectin-9的阳性表达率低于正常口腔黏膜组织,TIM3的阳性表达率高于正常口腔黏膜组织,差异均有统计学意义(P﹤0.05)。糜烂型口腔扁平苔藓患者口腔扁平苔藓组织中Galectin-9的阳性表达率低于非糜烂型口腔扁平苔藓患者,TIM3的阳性表达率高于非糜烂型口腔扁平苔藓患者,差异均有统计学意义(P﹤0.05)。不同分化程度、淋巴结转移情况口腔鳞状细胞癌患者口腔鳞状细胞癌组织中Galectin-9的表达情况比较,差异均有统计学意义(P﹤0.05);不同分化程度口腔鳞状细胞癌患者口腔鳞状细胞癌组织中TIM3的表达情况比较,差异有统计学意义(P﹤0.05)。Pearson相关分析结果显示,口腔扁平苔藓和口腔鳞状细胞癌患者中Galectin-9和TIM3的表达均呈负相关(r=-0.415、-0.437,P﹤0.01)。结论Galectin-9和TIM3可能参与口腔扁平苔藓及口腔鳞状细胞癌的发生发展,并可能与口腔扁平苔藓的癌变有关。     

口腔鳞状细胞癌患者术后局部感染的危险因素

目的 探讨口腔鳞状细胞癌患者术后局部感染的危险因素.方法 收集275例口腔鳞状细胞癌患者的临床资料,统一制表并登记,统计病原学分析结果及一般资料,分析院内感染的危险因素.结果 90例口腔鳞状细胞癌术后局部感染患者中共分离出107株病原菌,主要为革兰阳性菌(59.81％),其中金黄色葡萄球菌(27.10％)较为常见;其次为革兰阴性菌(40.19％),其中铜绿假单胞菌(18.69％)较为常见.单因素分析结果显示,不同年龄、体重指数(BMI)、肿瘤部位、肿瘤直径、合并糖尿病情况、合并慢性阻塞性肺疾病情况、合并症数量、缺损修复方案、手术时间和输血情况的口腔鳞状细胞癌患者术后局部感染情况比较,差异均有统计学意义(P﹤0.05).多因素分析结果显示,年龄≥60岁、BMI﹤20 kg/m2、合并糖尿病、合并症数量﹥2个、缺损修复区域/游离皮瓣、手术时间﹥6 h均是口腔鳞状细胞癌患者术后局部感染的独立危险因素(P﹤0.05).结论 口腔鳞状细胞癌患者术后局部感染的危险因素较多,可通过充分术前评估尽可能地减少危险因素对口腔鳞状细胞癌患者造成的影响.     

口腔疣状癌MMP-2、TIMP-2的表达及意义

目的研究口腔疣状癌中MMP-2、TIMP-2的表达,探讨其在口腔疣状癌发生发展的作用和意义。方法取15例口腔疣状癌,10例正常口腔粘膜,20例口腔鳞癌(高、低分化鳞癌各10例),应用免疫组织化学S-P法检测上述标本中MMP-2、TIMP-2表达和分布。结果口腔疣状癌和口腔鳞癌中MMP-2、TIMP-2主要表达于癌细胞胞浆,正常口腔粘膜MMP-2、TIMP-2为阴性表达。口腔疣状癌MMP-2阳性表达率为26.7%(4/15),平均染色强度低于高分化鳞癌和低分化鳞癌组(P<0.05)。口腔疣状癌TIMP-2阳性表达率为73.3%(11/15),阳性表达率、平均染色强度高于口腔高分化鳞癌组和口腔低分化鳞癌组(P<0.05)。口腔疣状癌、口腔高分化鳞癌、口腔低分化鳞癌MMP-2、TIMP-2表达均高于正常口腔粘膜(P<0.05)。结论口腔疣状癌具有一定的侵袭和转移能力。但从MMP-2、TIMP-2表达水平来看,口腔疣状癌侵袭、转移能力弱于口腔高分化鳞癌和口腔低分化鳞癌。     

口腔鳞癌细胞增殖和细胞凋亡的相关性研究

目的:通过观察口腔鳞癌中细胞增殖和细胞凋亡之间的关系,探讨细胞凋亡在口腔鳞癌发生中的作用.方法:利用脱氧核糖核酸末端转移酶介导的dUTP缺口末端标记(TUNEL)技术及增殖细胞核抗原(PCNA)免疫组织化学染色,对69例(维族36例、汉族33例)口腔鳞癌中的凋亡细胞和增殖细胞进行原位观察和比较.结果:口腔鳞癌不同组织学分级比较,高分化口腔鳞癌与中低分化口腔鳞癌之间增殖指数及凋亡指数均有显著性差异(P<0.05),不同部位的口腔鳞癌其增殖指数无显著差异,而舌癌组凋亡指数低于唇癌组和牙龈癌组(P<0.05),增殖指数与凋亡指数在口腔鳞癌中呈负相关关系(r=-0.663,P<0.05).结论:口腔鳞癌癌变过程不仅存在活跃的细胞增殖,而且存在细胞凋亡之异常,细胞增殖和细胞凋亡平衡失调在舌癌发病中可能起重要作用.     

口腔鳞癌患者血清一氧化氮水平及其手术前后的变化

目的 :探讨口腔鳞癌患者血清一氧化氮水平及手术前后的变化和意义。方法 :采用化学比色法对 41例口腔鳞癌、31例口腔颈面部良性肿瘤及 2 0例健康人血清一氧化氮 (NO)和一氧化氮合成酶 (NOS)水平进行了检测。结果 :口腔鳞癌组血清NO和NOS水平显著高于良性病变组和健康对照组 (P <0 .0 5) ,口腔鳞癌组中NO和NOS水平在有颈淋巴结转移者显著高于无颈淋巴结转移者 (P <0 .0 5) ,病变切除手术后NO及NOS显著低于手术前 (P <0 .0 5)。结论 :NO和NOS与口腔鳞癌的发生、发展有密切关系 ,NO和NOS的检测对口腔鳞癌的病情判定和指导治疗有重要的意义     

整合素αvβ6和JunB在口腔鳞癌组织中的表达及其临床意义

目的:探讨整合素αvβ6、JunB在口腔鳞癌组织中的表达及其临床意义。方法:采用免疫组化方法检测120例口腔鳞癌及15例口腔正常黏膜组织中整合素αvβ6和JunB的表达情况,并分析两者表达与口腔鳞癌患者临床病理指标及预后的关系。结果:整合素αvβ6表达于口腔鳞癌组织的细胞质和胞膜,而JunB定位在口腔鳞癌组织和口腔正常黏膜组织的细胞核内。整合素αvβ6、JunB在口腔鳞癌组织中的表达强度显著高于口腔正常黏膜组织(P<0.01)。整合素αvβ6在口腔鳞癌组织中的表达与浸润深度(T分期)、组织分化程度、是否有淋巴结转移(N分期)密切相关(P<0.05),而JunB在口腔鳞癌组织中的表达与浸润深度、是否有淋巴结转移密切相关(P<0.05)。单因素生存分析表明,整合素αvβ6高表达患者的预后较低表达的患者差(P=0.021)。Cox回归多因素分析表明是否有淋巴结转移是影响患者预后的独立危险因素(P<0.05)。结论:整合素αvβ6和JunB在口腔鳞癌组织中表达增加,并与口腔鳞癌的浸润、转移密切相关;整合素αVβ6表达可作为判断口腔鳞癌患者预后判断的指标。     

基质金属蛋白酶MMP-9在口腔疣状癌中的表达及意义

目的　研究MMP-9在口腔疣状癌和鳞癌中的表达,探讨口腔疣状癌和鳞癌的不同生物行为的分子基础。方法　取 15例口腔疣状癌, 10例正常口腔粘膜, 20例口腔鳞癌(高、低分化鳞癌各 10例),应用免疫组织化学S-P法检测上述标本MMP-9表达和分布。结果　口腔疣状癌组织中MMP-9阳性表达率为 40% (6 /15),明显低于高分化鳞癌 70% (7 /10)和低分化鳞癌 80% ( 8 /10 ) (P<0. 05 );平均染色强度低于高分化鳞癌和低分化鳞癌(P<0. 05);口腔疣状癌、口腔高分化鳞癌、口腔低分化鳞癌组织中MMP-9表达均高于正常口腔粘膜组织(P<0. 05)。结论　MMP-9在口腔疣状癌的发生中起重要作用。MMP-9在口腔疣状癌、口腔高分化鳞癌、口腔低分化鳞癌的表达存在明显差异,说明口腔疣状癌是一种独立类型的恶性肿瘤。     

Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model

Oral squamous cell carcinoma (OSCC) is a lethal disease whose incidence is increasing. Epidemiologic studies demonstrate an association between periodontitis and oral cancer, and periodontal pathogens are implicated in the pathogenesis of numerous disorders, including rheumatoid arthritis, cardiovascular diseases, diabetes and gastrointestinal malignancies. Nevertheless, a causal role for periodontal pathogens in OSCC has not been shown, partly due to the lack of an appropriate animal model. Here, utilizing a newly-established murine model of periodontitis-associated oral tumorigenesis, we report that chronic bacterial infection promotes OSCC, and that augmented signaling along the IL-6-STAT3 axis underlies this effect. Our results indicate that periodontal pathogens P. gingivalis and F. nucleatum stimulate tumorigenesis via direct interaction with oral epithelial cells through Toll-like receptors. Furthermore, oral pathogens stimulate human OSCC proliferation and induce expression of key molecules implicated in tumorigenesis. To the best of our knowledge, these findings represent the first demonstration of a mechanistic role for oral bacteria in chemically induced OSCC tumorigenesis. These results are highly relevant for the design of effective prevention and treatment strategies for OSCC.     

Mutational analysis of PTEN/PIK3CA/AKT pathway in oral squamous cell carcinoma

The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma (AKT) viral oncogene pathway is involved in regulating the signaling of multiple biological processes such as apoptosis, metabolism, cell proliferation, and cell growth. Mutations in the genes associated with the PI3K/AKT pathway including PI3K, AKT, RAS and PTEN, are infrequently found within head and neck squamous cell carcinoma and more specifically are rarely reported in oral squamous cell carcinoma (OSCC) cases. We aimed to investigate the frequency of mutations in AKT1, PTEN, PIK3CA, and RAS (K-RAS, N-RAS, H-RAS) genes in 37 cases of oral squamous cell carcinoma (OSCC). Mutational analysis of PTEN, RAS, PIK3CA and AKT genes was performed using chip-based matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry and by direct sequencing. The only gene mutated in our series was the PIK3CA. Missense mutations of the PIK3CA gene were found in 4 of our cases (10.8%); no correlation has been found with oral location, stage and survival. The absence of mutations in AKT1, PTEN, and RAS genes in the present study is in accordance with previous studies confirming that these genes are rarely mutated in OSCC. Our data confirm that PIK3CA is important to OSCC tumorigenesis and can contribute to oncogene activation of the PIK3CA/AKT pathway in OSCC. The knowledge of the PIK3CA's involvement in OSCC is important because a specific kinase inhibitor could be considered as a future therapeutic option for OSCC patients with PIK3CA mutations.     

Anti-tumor activity of dehydroxymethylepoxyquinomicin against human oral squamous cell carcinoma cell lines in vitro and in vivo

Several reports have indicated that nuclear factor-kappa B (NF-κB) is constitutively activated in a variety of cancer cells including human oral squamous carcinoma cells, and play a key role in their growth and survival. Recent studies report that NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), inhibits proliferation and induces apoptosis in prostate cancer cell lines. However this anti-tumor effects are still unknown in end human oral squamous carcinoma cells. In the present study, we investigated the effects of DHMEQ on oral squamous carcinoma cell (OSCC) lines in vitro and in vivo. Human OSCC cell lines (HSC-3, SAS) were treated with DHMEQ and examined for cell viability by MTT assay, cell cycle distribution by flow-cytometry, apoptosis by TUNEL assay, and protein expression by western blotting, respectively. In vivo activities were also investigated in a mouse xenograft model. DHMEQ inhibited growth of two OSCC cell lines in a dose-dependent manner measured by MTT assay. A flow cytometric analysis demonstrated that treatment with DHMEQ induced accumulation in sub-G1 phase. TUNEL assay showed that DHMEQ induced DNA fragmentation. Protein expression by western blotting analysis revealed that DHMEQ induced nuclear down regulation of Survivin, cIAP-1, and cIAP-2. In nude mice, DHMEQ inhibited growth of OSCC without major toxic side effects. The present results demonstrated that administration of DHMEQ is suggested to be a novel anti-tumor approach to the treatment of OSCC.     

Nitrative and oxidative DNA damage in oral lichen planus in relation to human oral carcinogenesis

Oral lichen planus (OLP) is a chronic inflammatory disease, which has been clinically associated with development to oral cancer. A double immunofluorescence labeling study found that 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) accumulated in oral epithelium in OLP and oral squamous cell carcinoma (OSCC) biopsy specimens, whereas little or no immunoreactivity was observed in normal oral mucosa. Colocalization of 8-nitroguanine and inducible nitric oxide synthase (iNOS) was found in oral epithelium of OLP and OSCC. Immunoreactivity of 3-nitrotyrosine, which is formed by protein tyrosine nitration and is considered to be a biochemical marker for inflammation, was also observed in oral epithelial cells and colocalized with 8-nitroguanine. Accumulation of p53 was more strongly observed in oral epithelium in OSCC than OLP, whereas there was no p53 accumulation in normal oral mucosa. Our findings demonstrate that iNOS-dependent DNA damage in OLP may lead to p53 accumulation in not only OLP but also OSCC. We conclude that the formation of potentially mutagenic DNA lesions including 8-nitroguanine and 8-oxodG may contribute to the development of oral cancer from OLP.     

PLCE1在口腔鳞状细胞癌中的表达及其临床意义

目的:探讨磷脂酶Cε1（phospholipase C epsilon－1,PLCE1)在口腔鳞状细胞癌(OSCC)组织中的表达及其与临床病理特征和患者预后的关系。方法:应用免疫组织化学方法检测PLCE1在83例OSCC组织和20例正常口腔黏膜组织中的表达,并分析 PLCE1表达与OSCC临床病理特征的关系;采用Kaplan-Meier法进行生存分析,Cox 风险比例回归模型分析影响OSCC患者预后的独立因素。结果:PLCE1在OSCC组织与口腔正常黏膜组织中高表达率分别为53.01%和15.00%,差异有统计学意义（P=0.002）。PLCE1的表达与患者年龄、性别、吸烟无相关性,而与肿瘤分化程度、T分期、临床分期、N分期有密切关系。单变量分析显示临床分期、PLCE1、T分期、N分期是影响OSCC预后的因素,双变量分析显示PLCE1是其独立预后因素。结论:PLCE1过表达与OSCC的发生、发展密切相关,可作为判断OSCC恶性程度和不良预后的参考指标。     

Ki67, CD105, and α-SMA Expression Supports Biological Distinctness of Oral Squamous Cell Carcinoma Arising in the Background of Oral Submucous Fibrosis

Background: The clinicopathological distinctness of oral squamous cell carcinoma arising in the background of oral submucous fibrosis (OSCC-OSF) is well known; however, the molecular distinctness of this unique OSCC-OSF has not been investigated to date. With this in mind, we compared the expression of Ki67, CD105, and α-SMA between OSCC-OSF and oral squamous cell carcinoma (OSCC). Methods: Formalin-fixed paraffin-embedded tissues of 105 OSCC-OSF and 112 OSCC cases were subjected to immunohistochemistry for evaluation of Ki67, CD105, and α-SMA expression. Results: Ki67 (labeling index) LI, MVD and α-SMA expression were significantly higher in OSCC compared to OSCC-OSF. Ki67 LI and MVD was significantly higher in OSCC compared to OSCC-OSF in parameters such as well-differentiated, early TNM stage, non-metastatic, and more than 3-year survival. α-SMA expression was significantly higher in OSCC compared to OSCC-OSF in parameters such as moderate differentiation, metastatic lesions, and survival less than 3 years. Ki67 LI, MVD and α-SMA showed significant positive correlation with each other in OSCC and OSCC-OSF. Conclusion: Proliferation, neoangiogenesis and myofibroblast differentiation were significantly higher in the OSCC group compared to the OSCC-OSF group. This suggests the biological distinctness of OSCC-OSF, which could help the future development of targeted therapies.     

MMP-2、TIMP-2在口腔鳞状细胞癌中表达的临床病理研究

[目的]研究口腔鳞状细胞癌（OSCC）组织中基质金属蛋白酶-2（MMP-2），基质金属蛋白酶组织抑制因子-2（TIMP-2）的表达。[方法]采用免疫组化SP法检测60例OSCC、35例非典型增生、20例止常口腔黏膜中MMP-2、TIMP-2的表达情况。[结果]OSCC中MMP-2、TIMP-2的表达均高于非典划增生组（P〈0．05），在非典型增生组中表达高于正常口腔黏膜组（R＜0．05）。MMP-2的表达与肿瘤细胞分化程度、淋巴结转移密切相关（P〈0．05），与年龄、肿瘤大小、TNM分期无关（P〉0．05）。TIMP-2与肿瘤的淋巴结转移密切相关（P〈0．05），与年龄、肿瘤大小、肿瘤细胞分化程度、TNM分期无关（P〉0．05）。淋巴结转移组中MMP-2／TIMP-2比值显著高于无淋巴结转移组（P〈0．05）。[结论]MMP-2、TIMP-2是OSCC转移的重要生物学标志，MMP-／TIMP-2比值对评估淋巴结转移的潜能有重要意义。     

VacA基因与口腔鳞癌组织中VEGF表达的相关性分析

目的:检测口腔鳞状细胞癌组织中是否存在幽门螺杆菌毒力因子VacA基因以及与VEGF表达的相关性,探讨幽门螺杆菌与口腔鳞状细胞癌的关系。方法:采用聚合酶链反应检测40例口腔鳞状细胞癌组织和23例正常黏膜组织中VacA基因的阳性率,采用免疫组化染色检测VEGF的表达情况,并比较口腔鳞状细胞癌组织VacA基因阳性组和阴性组中VEGF表达的差异。结果:OSCC组织中VacA基因阳性率为25%,正常口腔黏膜VacA基因阳性率为0,两者差异有统计学意义(P=0.024)。VacA阳性组OSCC组织中VEGF的强阳性率高于VacA阴性组（P=0.018）,VacA阳性组中VEGF的平均光密度高于VacA阴性组（P=0.023）,差异均有统计学意义。结论:OSCC中存在VacA基因,并与VEGF的表达可能存在相关性,幽门螺杆菌是否通过VacA毒力因子调控VEGF的表达而影响OSCC的发生和发展,需要进一步研究。