黑色素瘤抗原基因-A在头颈部肿瘤中的研究进展

黑色素瘤抗原基因(MAGE)-A是黑色素瘤抗原基因家族中的成员,其表达产物是一种肿瘤相关抗原,其编码的抗原肽仅在肿瘤组织、睾丸及胎盘组织表达,与人白细胞抗原-Ⅰ类分子结合后被细胞毒性T淋巴细胞识别,从而特异性杀伤肿瘤细胞。本文对MAGE-A在头颈部肿瘤中的研究现状作一综述。     

头颈部黏膜恶性黑色素瘤的临床分期

恶性黑色素瘤属于易复发和高转移率的恶性肿瘤。与头颈部鳞状细胞癌具有统一独立的肿瘤淋巴结转移(TNM)分期不同,头颈部黏膜恶性黑色素瘤的临床分期一直沿用皮肤恶性黑色素瘤的TNM分期。但头颈部黏膜在组织学结构上与皮肤有着显著的差异,所以头颈黏膜恶性黑色素瘤应该具有一套独立的分期体系,以利于临床上进行诊治和判断预后。下面就口腔、鼻腔和副鼻窦黏膜恶性黑色素瘤分期的研究进展作一综述。     

病人源性头颈部黏膜恶性黑色素瘤细胞模型的构建及鉴定

目的：构建及鉴定头颈部黏膜恶性黑色素瘤（mucosal melanoma of head and neck, HNMM）病人源性肿瘤细胞（patient derived tumor cell, PDC）模型。方法：通过肿瘤组织块原代培养、分离肿瘤细胞,利用免疫荧光染色鉴定分离的肿瘤细胞;以PDC皮下成瘤,通过组织切片染色和免疫组织化学染色对比病人原发灶和PDC成瘤组织的细胞学形态。结果：头颈黏膜恶性黑色素瘤患者移植瘤组织块分离出的细胞细胞膜和细胞质HMB-45和Melan-A免疫荧光染色呈阳性。PDC可以在裸鼠皮下成瘤,成瘤组织与患者组织细胞形态一致。结论：头颈部黏膜恶性黑色素瘤构建的PDC模型能够反映患者的组织学特征,PDC模型能够为头颈部黏膜恶性黑色素瘤的研究提供可靠的模型。     

An update on the current management of head and neck mucosal melanoma

Primary mucosal melanomas of the head and neck are rare and aggressive tumours that arise in the nasal cavity, paranasal sinuses and more rarely in the oral cavity. The current treatment options include radical surgical resection with adjuvant external beam radiotherapy being offered in high‐risk patients. Although the latter can improve regional control, it does not reduce overall survival. Elective neck dissection is recommended for nodular oral mucosal melanoma, but its role in the clinically node negative neck is controversial. Systemic therapies including the use of tyrosine kinase inhibitors for tumours with c‐KIT mutations are suitable for patients with advanced loco‐regional and/or metastatic disease, but current results are variable. Patients with head and neck mucosal melanoma have a poor prognosis due to the high incidence of metastatic disease. This review assesses the latest evidence in the diagnosis and management of primary oral and head and neck mucosal melanoma including details of systemic therapies.     

3种铸造合金全冠戴用后Ki67和P53蛋白在牙龈组织中的表达

目的研究3种常用铸造合金全冠戴用后Ki67、P53蛋白在牙龈组织中的表达,探讨3种常用牙科铸造合金的生物学性能。方法对犬分别行58%金合金、不含铍的镍铬合金、含铍的镍铬合金铸造全冠修复,建立实验动物模型。应用免疫组化Envision二步法检测戴冠前、戴冠后2周,1、2及3个月时Ki67、P53蛋白在牙龈组织中的表达。结果含铍的镍铬合金与不含铍的镍铬合金铸造全冠戴用后,Ki67、P53蛋白在牙龈组织的表达逐渐升高,戴冠1个月后达到最高,随后逐渐降低;而58%金合金全冠戴用后,Ki67、P53蛋白的阳性表达率与空白对照组无统计学差异,随时间延长也无明显改变。结论镍铬合金全冠戴用后,牙龈组织中Ki67、P53蛋白表达明显,而58%金合金全冠戴用后表达不明显。3种铸造合金材料均未造成长时期的牙龈上皮异常增殖。     

Immunohistochemical study of syndecan-1 down-regulation and the expression of p53 protein or Ki-67 antigen in oral leukoplakia with or without epithelial dysplasia

BACKGROUND: Leukoplakia is an oral pre-cancerous lesion that sometimes develops into squamous cell carcinoma. Therefore, leukoplakia with epithelial dysplasia is useful for studying carcinogenesis at the cellular level. The purpose of this study was to evaluate a potential association between the loss of syndecan-1 expression and the expression of p53 protein and Ki-67 antigen, and to identify reliable markers for predicting malignant changes in oral leukoplakia with epithelial dysplasia. METHODS: Changes in the expression of syndecan-1, p53, and Ki-67 were examined immunohistochemically in 43 cases of oral leukoplakia with or without epithelial dysplasia. The subjects were categorized as: none, 13 cases; mild dysplasia, 5 cases; moderate dysplasia, 17 cases; and severe dysplasia, 8 cases. The expression of these molecules in normal oral epithelia (22 cases) was also investigated. RESULTS: Strong syndecan-1 expression was observed on the surface of keratinocytes in normal epithelium. Immunopositivity was lost gradually as the extent of epithelial dysplasia increased. In normal epithelium, p53 and Ki-67 appeared mainly in the basal cell layer, while they were more widely distributed in leukoplakia. Specifically, significant changes were observed in the labeling index of p53 and Ki-67 in leukoplakia as epithelial dysplasia progressed from mild to moderate or severe. CONCLUSION: Our results reveal that overexpression of p53 protein and Ki-67 antigen, and down-regulation of syndecan-1 expression in the lower part of the epithelium, are associated with dysplastic changes. Therefore, the down-regulation of syndecan-1 expression may be the most important reliable marker for dysplastic changes.     

不同材料暂时冠戴用后牙龈组织中Ki67、P53蛋白的表达

目的:研究4种常用暂时冠戴用后Ki67、P53蛋白在牙龈组织中的表达,探讨4种暂时冠材料的生物学效应。方法:给犬进行自凝塑料、热凝塑料、DMG-TEMP复合树脂和松风SWIFT-TEMP树脂暂时冠修复,建立实验动物模型。应用免疫组化Envision二步法检测戴冠前、戴冠后1周、2周及1月时Ki67、P53蛋白在牙龈组织中的表达,并观察HE切片。结果:自凝塑料暂时冠和热凝塑料暂时冠戴用后,牙龈组织中Ki67、P53蛋白的阳性表达率逐渐升高,戴冠1周后达到最高,随后逐渐降低;而DMG-TEMP树脂暂时冠和SWIFT-TEMP树脂暂时冠戴用后,Ki67、P53的阳性表达率与空白对照组无统计学差异,随时间延长亦无明显改变。结论:自凝塑料暂时冠和热凝塑料暂时冠戴用后,牙龈组织中Ki67、P53蛋白表达明显,而DMG-TEMP和SWIFT-TEMP树脂暂时冠戴用后表达不明显。4种材料暂时冠并未造成长时期的牙龈上皮细胞异常增殖。     

Survival of oral mucosal melanoma according to treatment,tumour resection margin,and metastases

Because of the poor prognosis and of oral mucosal melanoma, and patients’ short survival, large, randomised, clinical studies are difficult. We have investigated its demographic characteristics and analysed the effect of treatment, resection margins, and metastases on survival. We recorded age, sex, site of primary tumour, and types of treatment, survival, and metastases in 74 patients treated at the Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital. Survival was analysed based on bony invasion, depth of invasion, and resection margins, and we found that it varied depending on the primary site (p = 0.002), and declined with liver (p = 0.001) or brain (p = 0.033) metastases. The two-year survival according to the primary site was as follows: palate 85% (n = 32), anterior maxillary gingiva 53% (n = 13), mandible 58% (n = 13), and posterior maxillary gingival 74% (n = 10) and buccal mucosa 50% (n = 4). The two-year survival was 34% (n = 8) in patients with liver metastases and 23% (n = 7) in patients with brain metastases. In cases of bony invasion (p = 0.005), depth of invasion (p = 0.042), unclear resection margin (p = 0.023), or higher T stages (p = 0.009), the survival declined considerably. Neck dissection did not affect survival (p = 0.343). Survival of the patients given chemotherapy was significantly lower (p = 0.013) and the two-year survival was 54.0%. The patients given radiotherapy showed no significant difference in survival compared with those not given radiotherapy (p = 0.107). In conclusion, primary site, bony invasion, resection margins, depth of invasion and systemic metastases were critical to predict prognosis and selection of treatment of oral mucosal melanoma.     

Immunohistochemical detection of Ki‐67 is not associated with tumor‐infiltrating macrophages and cyclooxygenase‐2 in oral squamous cell carcinoma

J Oral Pathol Med (2010) 39 : 565–570 Background: An inflammatory component consisting of cells and chemical mediators may influence the proliferation and dissemination of the oral squamous cell carcinoma (OSCC). In the present study, we evaluated the possible relationship between Ki‐67, tumor‐associated macrophages (TAMs), and COX‐2 in OSCCs. In addition, the immunodetection of these proteins was associated with different histological grades of malignancy, including invasive and in situ tumors. Methods: Twenty‐seven OSCC cases were examined by light microscopy using criteria adopted WHO, and immunohistochemistry for Ki‐67, CD68, and COX‐2 using EnVision System in invasive and in situ lesions. Immunohistochemical detection of these proteins was assessed and scored for COX‐2, and results were compared with their histological grades of malignancy. Results: A correlation between Ki‐67, COX‐2, and CD68 was not found. Histological grade of malignancy (HDM) was associated with the Ki‐67 immunostaining (P = 0.00), but this was not observed regarding both CD68 (P = 0.51) and COX‐2 (P = 0.89). Furthermore, there was a COX‐2 overexpression in 62.96% of the sample, and a high density of TAMs in both OSCCs and in situ carcinomas. Conclusions: Imunolabeling for Ki‐67 was directly correlated with less‐differentiated tumors, suggesting that this marker may contribute to understand the biological behavior of OSCC, and help to distinguish risk groups of OSCC. Furthermore, the lack of correlation between Ki‐67, COX‐2, and CD68 indicates that the latter two markers may play a pivotal role in oral carcinogenesis. However, further studies are needed to clarify their contribution for cell proliferation and tumor differentiation.     

Head and neck squamous cell carcinoma in non‐smoking and non‐drinking patients with multiple tumors: etiologic significance of p53 and Ki‐67 in non‐tumorous epithelium

Background: Non‐smoking and non‐drinking patients with head and neck squamous cell carcinoma have different clinical characteristics than their smoking and drinking counterparts. They are predominantly older female patients with oral cavity tumors, however, both groups show the same percentage of second primary tumors. Expression of tumor suppressor gene p53 and proliferation marker Ki‐67 in mucosal epithelial cells was analyzed to study whether biomarker expression is associated with a history of smoking and drinking and with single and multiple tumors. Methods: Non‐smoking and non‐drinking patients with multiple (n = 18) and single tumors (n = 15), smoking and drinking patients with multiple (n = 15) and single tumors (n = 14) were selected. For all groups, p53 and Ki‐67 expression patterns in non‐tumorous (tumor‐adjacent) mucosa including positivity of dispersed single cells and clusters for p53 and for suprabasal expression of Ki‐67 were immunohistochemically analyzed and compared. Results: p53 expression was significantly higher in users of tobacco and alcohol than in non‐users. Ki‐67 expression was not affected by tobacco and alcohol usage. Both Ki‐67 and p53 were similarly expressed in the groups with single and multiple tumors and hence not significantly related to the number of tumors. Conclusions: Non‐smoking and non‐drinking patients with squamous cell carcinoma have the same risk for developing multiple tumors as their smoking and drinking counterparts. As this occurs without an increased expression of p53 or Ki‐67, the significance of these proteins as biomarkers indicating pre‐malignant mucosal alterations is doubtful. Further research is needed to clarify this predisposition for developing multiple head and neck cancer.     

牙齿发育中神经生长因子及其受体表达的免疫组化研究

目的 探讨神经生长因子在牙齿发育中的作用。方法 制备人牙齿发育各阶段标本,进行神经生长因子及其受体的免疫组化研究,结果;两者在牙齿发育中有各自的时空表达,结论神经生长因子不仅参与牙齿神经支配的建立,而且调控细胞的增殖分化和牙胚的发育。     

Primary head and neck mucosal melanoma: Predictors of survival and a case series on sentinel node biopsy

IntroductionHead and neck mucosal melanoma (HNMM) is a rare tumor with a poor outcome. The objective of this study was to assess outcome and prognostic factors for a cohort of patients treated in a head and neck cancer center. In addition, a case series on sentinel lymph node biopsy (SLNB) was included to evaluate it as a method for staging the node-negative neck.MethodsA retrospective study design was chosen, and 50 patients who were treated from 1973 to 2015 in our institution for primary HNMM were included. The Kaplan–Meier method was used to estimate survival rates. Uni- and multivariate analyses were used to study the influence of possible risk factors on the patients' outcome. These risk factors included patient demographics, tumor characteristics, and treatment modalities.ResultsAll patients were treated surgically and 50% received adjuvant treatment. The median disease specific survival (DSS) was 38 months, with a 5-year survival rate of 44%. Positive surgical margin (p = 0.004) and distant failure (p = 0.005) were associated with a worse DSS. The median disease-free survival (DFS) was 27 months, with a 5-year disease-free rate of 12%. Only tumor depth >5 mm (p = 0.002) was associated with a worse DFS. Five clinically node-negative patients received SLNB and only the two SLN-positive individuals suffered from distant failure. Radiotherapy, chemotherapy, and AJCC/UICC stage had no influence on any outcome measure.ConclusionsPositive surgical margin and distant failure are the only independent prognostic factors for DSS. Tumor depth can predict distant failure. SLNB may be a valuable staging tool for the node-negative neck.