Expression of vascular endothelial growth factor in salivary gland carcinomas and its relation to p53, Ki-67 and prognosis

BACKGROUND: Vascular endothelial growth factor (VEGF) has been demonstrated to play an important role in tumor angiogenesis and to influence prognosis in many cancers. But, its significance in salivary gland carcinomas has not been elucidated. The authors investigated the association between VEGF expression and clinicopathological factors, p53, and Ki-67 to verify its validity as a prognostic factor. METHODS: Surgical specimens from 45 patients with salivary gland carcinoma were examined for VEGF, p53, and Ki-67 expression by immunohistochemical staining. The results were compared with the clinicopathological factors and the relationships were correlated. RESULTS: VEGF expression was low in 14 cases, moderate in 15 cases, and high in 16 cases. It was significantly correlated with a variety of clinicopathological factors such as TNM stage, perineural and vascular invasion, and recurrence. VEGF showed significant association with the expression of p53 but not with that of Ki-67. Univariate analysis showed that age, gender, lymph node metastasis, vascular invasion, p53, Ki-67, and VEGF expression correlate with prognosis. Multivariate analysis demonstrated that VEGF is an independent prognostic factor for patients with salivary gland carcinomas. CONCLUSIONS: The results of this study suggest that VEGF expression is correlated with p53 expression and that it may have prognostic value in salivary gland carcinomas.     

PCNA, Ki-67 and p53 expressions in submandibular salivary gland tumours

Salivary gland tumours are uncommon with a broad heterogeneity. The most common benign tumour is the pleomorphic adenoma, whereas mucoepidermoid carcinoma and adenoid cystic carcinoma predominate among the malignancies. Most salivary gland tumours occur in the parotid, and consequently clinical and biological data are normally derived from this site. This work describes the expressions of PCNA, Ki-67 and p53 in 15 pleomorphic adenomas, 15 mucoepidermoid carcinomas and 15 adenoid cystic carcinomas of the submandibular gland. Our results showed that all pleomorphic adenomas were negative for p53 and Ki-67 with 66.6% being positive for PCNA. Conversely, p53 was positive in 53% of the mucoepidermoid carcinomas and in 20% of the adenoid cystic carcinomas. Ki-67 was expressed in 47.7% of the mucoepidermoid carcinomas and 40% of the adenoid cystic carcinomas. All malignant tumours were positive for PCNA. These results indicate that the proliferative rate analysed with PCNA and Ki-67 and the expression of p53 in pleomorphic adenoma and adenoid cystic carcinoma of the submandibular gland were similar to those described in the parotid and minor salivary glands. However, mucoepidermoid carcinomas showed higher expression of these markers than those of other salivary glands. This work is the first describing the expression of these immunohistochemical markers exclusively in submandibular salivary gland tumours.     

Prognostic role of p21WAF1 expression in areca quid chewing and smoking-associated oral squamous cell carcinoma in Taiwan.

BACKGROUND: Alterations in p21WAF1 protein expression have been observed in a wide variety of human cancers by immunohistochemistry, and both decreased and increased levels of p21WAF1 protein expression have been shown to correlate with poor prognosis. METHOD: To examine the relation between p21WAF1 protein expression and prognosis in oral squamous cell carcinomas (SCCs), we performed an immunohistochemical study with antip21WAF1 antibody on 43 oral SCCs. Immunostaining results were then correlated with p53 protein levels, clinicopathological parameters of the tumors and overall patient survival. RESULTS: Of the 43 patients, 31 (72%) had tumors with positive p21WAF1 nuclear staining and 27 (63%) had tumors with p53 nuclear staining. There was no significant correlation between p21WAF1 and p53 protein expressions and both mutant p53-containing oral SCCs overexpressed p21WAF1 protein. In addition, no significant correlation was found between the p21WAF1 expression and the patients' age, sex, oral habit, cancer location, or primary tumor TNM status at the time of initial presentation. The Kaplan-Meier analysis showed a significant correlation between p21WAF1 protein overexpression and poor patient overall survival (P = 0.049). When p53 and p21WAF1 were evaluated together, the 5-year overall survival was lowest in p53(+)-p21WAF1(+) patients and highest in p53(-)-p21WAF1(-) patients (P = 0.057). CONCLUSION: Combined evaluation of p21WAF1 and p53 expressions may be useful in estimating the prognosis of patients with oral SCCs in Taiwan.     

The myoepithelial cell differentiation of mucoepidermoid carcinoma in a collagen gel-based coculture model

BACKGROUND: Mucoepidermoid carcinomas (MECs) are the most common malignant tumor of the salivary glands; however, the histogenesis of MECs has been still controversial. This study was undertaken to investigate the histogenesis of MECs by the examination of their collagen gel-based coculture tissue and transplanted tumors. METHODS: Two cell lines from a primary and a metastatic MECs were established and characterized by the mutational analysis of the p53 gene and in vivo tumorigenicity in athymic nude mice. Collagen gel-based organotypic cocultures were performed, and the ultrastructural and immunohistochemical findings were examined. RESULTS: Two cell lines demonstrated p53 point mutation at the same codon. A metastatic cell line of MEC showed in vivo tumorigenicity. Transplanted tumors and the collagen gel-based culture tissues showed poorly differentiated squamous cell carcinomas devoid of mucous cell differentiation; however, they disclosed the differentiation of myoepithelial cells. CONCLUSIONS: MECs appear to be centered on the squamous cell differentiation, and the specific differentiation of myoepithelial or mucous cells seems to be modulated by the property of microenvironment.     

Cytoplasmic expression of p53 protein and its morphological features in salivary gland lesions

An immunohistochemical study of p53 protein was carried out on 45 salivary gland lesions using a monoclonal antibody, Bp53–12, raised to the intracellular domain of the p53 protein. p53 protein expression was found in 34.4% of 32 salivary gland carcinomas. Nuclear p53 expression was detected in tumor cells but not in non-neoplastic cells, except in one salivary duct carcinoma. The perinuclear cytoplasm of luminal duct cells was specifically positive for the antibody used here. Cytoplasmic p53 expression was observed mostly in non-neoplastic cells. There was a tendency for the Cytoplasmic staining of p53 protein to be observed in the normal cells adjacent to p53-positive carcinomas, but none of the normal cells were positive in the tissues surrounding p53-negative carcinomas. Cytoplasmic expression of p53 protein in salivary gland tissues seems to be correlated with tumorigenesis.     

Expression of C-X-C motif chemokine receptors 4 and 7 in salivary gland neoplasms

ObjectivesChemokine receptors have been shown to overexpress in several cancer types. Binding of chemokines to their cognate chemokine receptors on tumor cells can promote tumor growth, angiogenesis and metastasis. The purposes of this study was to examine the expression of chemokine receptors, CXCR4 and CXCR7, in salivary gland neoplasms and its association with pathologic characteristics.DesignSixty-two cases of salivary gland neoplasms, including 25 mucoepidermoid carcinomas (MEC), 18 adenoid cystic carcinomas (ACC), 14 pleomorphic adenomas (PA) and 5 polymorphous low-grade adenocarcinoma (PLGA) were investigated for CXCR4 and CXCR7 expression immunohistochemically. The immunoreactivity was categorized as low expression or high expression group, based on whether the positive staining was below or higher than 50% of the neoplastic cells, respectively.ResultsThe majority of MECs, ACCs and PLGAs showed high CXCR4 and CXCR7 expression, whereas most PAs showed high CXCR4 but low CXCR7 expression. The levels of CXCR4 and CXCR7 expression were significantly correlated. In MECs, the expression of both chemokine receptors was localized to squamous cells, intermediate cells and glandular epithelial cells, whereas mucous cells and clear cells were negative. In ACCs and PAs, their immunoreactivity was more intense in ductal cells than myoepithelial cells. Most neoplastic myoepithelial cells in PAs did not express CXCR7, while those in ACCs showed strong CXCR7 expression. The increased CXCR4 expression was significantly associated with advanced pathologic grade of MECs (P = 0.03).ConclusionOverexpression of CXCR4 and CXCR7 is common in the 4 salivary gland neoplasms investigated. CXCR4 may play a role in the progression of MECs.     

环氧化酶2、X染色体连锁凋亡抑制蛋白在唾液腺恶性肿瘤中的表达及意义

目的: 检测环氧化酶2(Cox-2)与X染色体连锁凋亡抑制蛋白(XIAP)在唾液腺腺样囊性癌(ACC)与黏液表皮样癌(MEC)中的表达,探讨两者在唾液腺恶性肿瘤发生、发展中的作用及相关性。方法:采用免疫组织化学SP法检测95例唾液腺恶性肿瘤(包括50例ACC、45例MEC)、10例多形性腺瘤及10例正常唾液腺组织中Cox-2和XIAP的表达情况,使用SPSS17.0软件包对数据进行统计学处理。结果:Cox-2、XIAP在唾液腺恶性肿瘤中高表达,在多形性腺瘤和正常唾液腺组织中不表达或低表达。Cox-2、XIAP的表达与唾液腺恶性肿瘤组织临床分期和远处转移呈正相关(P<0.05),而与肿瘤部位无相关性(P>0.05)。结论:Cox-2和XIAP在唾液腺恶性肿瘤中高表达,可能在唾液腺恶性肿瘤发生、发展过程中具有重要作用。     

Maspin蛋白在唾液腺黏液表皮样癌中的表达及意义

目的：检测乳腺丝氨酸蛋白酶抑制剂（marray serine proteinase inhibitor，Maspin）在唾液腺黏液表皮样癌中的表达．及其与唾液腺黏液表皮样癌患者临床病理特征之间的关系。方法：应用免疫组织化学方法，分别对58例唾液腺黏液表皮样癌的癌组织及其癌旁正常腺体组织标本行Maspin蛋白含量的半定量测定，与各临床病理指标进行统计学分析，采用SPSS13．0统计学软件进行非参数检验。结果：Maspin蛋白在唾液腺黏液表皮样癌的癌组织中的表达显著高于癌旁正常腺体组织（P〈0．001），唾液腺黏液表皮样癌组织中Maspin蛋白的表达与淋巴结转移（P=0．020）、术后转移（P=0．008）呈负相关，与总体生存状况呈正相关（P=0．028）。结论：Maspin蛋白的检测在唾液腺黏液表皮样癌患者中可能具有较好的预后判断价值。     

P53 and Ki-67 antigen expression in small oral biopsy specimens of salivary gland tumors

OBJECTIVE: To investigate the possibility that various salivary gland tumors that look histologically similar could express p53 oncoprotein and Ki-67 proliferation antigen differentially and possibly aid in distinguishing benign from malignant lesions.Study Design: Intraoral paraffin-embedded biopsy specimens of salivary gland tumors were used. Thirty-eight pleomorphic adenomas, 17 adenoid cystic carcinomas, 23 monomorphic adenomas, and 17 polymorphous low-grade adenocarcinomas were stained with p53 and Ki-67 antibodies by using an immunoperoxidase detection system. Each case was evaluated in terms of staining intensity and percentage of cells staining. RESULTS: Ki-67 and p53 antigens are expressed in generally low levels in the histologically well-differentiated salivary tumors that were studied here, both benign and malignant. Only 1 solid-type adenoid cystic carcinoma showed a high percentage of cells expressing p53. CONCLUSIONS: The histologically well-differentiated salivary tumors studied do not show differential expression of p53 and Ki-67, in spite of their differing courses of biologic behavior. These antibodies should not be relied on to distinguish benign from malignant lesions of the salivary glands; however, they might be markers for those lesions that are dedifferentiating histologically and, therefore, might be displaying more aggressive behavior.     

基质金属蛋白酶及其组织抑制剂表达失衡与涎腺恶性肿瘤浸润生长的关系

目的　探讨基质金属蛋白酶2、9(MMP-2、9),膜型基质金属蛋白酶1(MT1-MMP)及基质金属蛋白酶组织抑 制剂1、2(TIMP-1、2)与涎腺恶性肿瘤浸润生长的关系。方法　应用免疫组化SP法和明胶酶谱法检测28例涎腺良 性肿瘤、26例涎腺恶性肿瘤中MMP-2、9,MT1-MMP及TIMP-1、2的表达及细胞定位,分析其中酶原与活性酶的含量 比例。结果　涎腺恶性肿瘤中MMP-2、9的表达强于良性肿瘤(P<0·05),TIMP-1、2的表达低于良性肿瘤 (P<0·05)。MMP-2、MT1-MMP、TIMP-2的表达有相关性。MMP-9酶原及活性MMP-9在恶性肿瘤中的表达均高于良 性肿瘤(P<0·05)。结论　MMP-2、9在涎腺恶性肿瘤浸润性生长中扮演了重要角色。涎腺恶性肿瘤中,TIMP-1、2 抑制作用的降低导致了MMP-2、9合成、激活的增多,令MMP-2、9与其天然组织抑制剂TIMP-1、2之间的平衡失调, 从而基底膜加速降解。     

Expression and mutations of p53 in salivary gland tumours

A series of 219 salivary gland tumours (103 carcinomas and 116 benign tumours) were analysed for p53 protein expression using immunohistochemistry, and for mutations in p53 gene using non-radioactive single strand conformation polymorphism (SSCP). p53 expression was present in 36% (42/116) of the benign tumours and in 54% (56/103) of the carcinomas. The highest prevalence of p53 expression was found in adenoid cystic carcinomas (69%). followed by mucoepidermoid carcinomas (67%). Of the benign tumours, pleomorphic adenomas showed the highest prevalence of p53 positivity (41%). In malignant tumours, expression of p53 bore no correlation to local recurrence, metastatic disease or survival of the patients. Exons 5 through 9 were analysed and four mutations were found in 20 cases of p53-immunopositive tumours and two in 20 p53-negative tumours. Each of the exons 5.6 and 8/9 had two mutations, whereas no mutations were detected in exon 7.     

Genetic analysis of DNA microsatellite loci in salivary gland tumours: comparison with immunohistochemical detection of hMSH2 and p53 proteins

To investigate genetic alterations in salivary gland tumours, microsatellite instability at eight representative loci and loss of heterozygosity (LOH) on chromosome 17 were analysed by polymerase chain reaction amplification. The results were compared with immunohistochemical expression of the hMSH2 and p53 proteins. Microsatellite instability and expression loss of hMSH2 protein were not recognized in the salivary gland tumours, suggesting a low frequency of abnormalities of the mismatch repair system. LOH associated with the p53 gene was detected in approximately one-half of pleomorphic adenomas and salivary carcinomas, which often showed strong p53 immunoreactivity. These features suggest that the p53 gene plays an important role in malignant transformation of salivary gland tumours. The genetic characteristics of pleomorphic adenomas might reflect a low-grade potential for malignant progression.     

MDM2 expression in areca quid chewing-associated oral squamous cell carcinomas in Taiwan

MDM2 (murine double minute gene 2) overexpression has been implicated in the pathogenesis of human tumors via inhibition of the p53 tumor suppressor protein. To investigate the potential involvement of MDM2 overexpression in the pathogenesis of oral squamous cell carcinomas (SCCs) in Taiwan, we examined the expression of MDM2 protein and its relationship to p53 protein levels in 52 oral SCCs using antibodies to MDM2 and p53. Of the 52 patients, 36 (69 %) had tumors with positive MDM2 nuclear staining and 32 (61%) had tumors with p53 nuclear staining. Co-expression of MDM2 protein and p53 was detected in 25 (48%) cases; and 9 (17%) tumors showed neither MDM2 protein nor p53 staining. A significant correlation was observed between MDM2 protein and p53 expression in 38 cases with an areca quid (AQ) chewing habit (P=0.032). No significant correlation was found between the degree of MDM2 protein staining and the patients' ages, sex, cancer location, clinical staging, primary tumor TNM status or histological differentiation of SCC at the time of initial presentation. Kaplan-Meier analysis showed that either MDM2 protein expression or co-expression of p53 and MDM2 protein did not relate significantly to patient overall survival. Nevertheless, the high prevalence of MDM2 protein overexpression found in this study suggest that MDM2 may also participate in the carcinogenesis of AQ chewing-associated oral SCCs in Taiwan.     

Vascular endothelial growth factor and thymidine phosphorylase expression in salivary gland tumors with distinct metastatic behavior

J Oral Pathol Med (2010) 40 : 456–459 Background: Metastasis of salivary gland tumors has a negative impact on survival. Angiogenesis and its factors are potential markers for predicting metastasis in different malignant tumors, but this is not the case for salivary gland tumors. Methods: Salivary gland tumors of distinct biologic behavior were analyzed according to the semiquantitative immunoexpression of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). Results: Vascular endothelial growth factor expression was predominantly weak in benign tumors. Weak TP expression was observed in 100% cases of benign tumors and in 74.3% of primary malignant tumors. High VEGF and TP expression levels were significantly associated with primary malignant tumors but not with primary non‐metastasizing and primary metastasizing malignant tumors or with subtypes of malignant tumors. Conclusions: Vascular endothelial growth factor and TP expression levels discriminate benign and malignant tumors but cannot predict metastasis from non‐metastasizing tumors.     

Immunohistochemical expression of MMP-9 and VEGF in squamous cell carcinoma of the tongue

Squamous cell carcinomas (SCCs) account for approximately 95% of all oral malignant neoplasms and for about 38% of all malignant head and neck tumors, especially affecting the tongue and lips. The aim of this study was to evaluate the immunohistochemical expression of MMP-9 and VEGF in oral SCC according to the occurrence of metastasis. Eighteen cases of tongue SCC without metastases and 17 cases of tongue SCC with metastases were subjected to immunohistochemical methods. High immunohistochemical expression of MMP-9 and VEGF by neoplastic cells and stroma was observed in tongue SCCs at the invasion front. Metastatic tumors tended to express higher levels of MMP-9 and VEGF than non-metastatic tumors, but the difference was not significant (P > 0.05). Spearman's correlation test showed no significant correlation between VEGF-immunopositive vessels and metastasis (P > 0.05). The present results demonstrate the importance of the expression of MMP-9 and VEGF for the development of SCC of the tongue. However, no significant association was observed between the overexpression of MMP-9 or VEGF and the presence of metastases.     

Osteopontin expression in salivary gland carcinomas

J Oral Pathol Med (2010) 40 : 451–455 Background: In several cancer types, osteopontin (OPN) expression has been correlated with tumor progression and prognosis. Two earlier studies have examined OPN expression in salivary gland carcinomas with contradictory results. Methods: One hundred and seventy‐five patients with a primary salivary gland carcinoma diagnosed from January 1, 1990 to December 31, 2005 were identified in the local pathology register, Odense University Hospital. Criteria as documented by Allred et al. were used to assess OPN immunostaining that was performed on surgical specimens. Results: Osteopontin was expressed in all salivary gland carcinomas. Adenoid cystic carcinomas had the highest mean sum score (7.3) and a significantly higher proportion of carcinomas with high OPN sum score than both mucoepidermoid carcinoma and acinic cell carcinoma. Correlation of OPN expression with known prognostic factors in salivary gland carcinomas was insignificant. Conclusions: Salivary gland carcinomas express OPN. The expression does not correlate with known prognostic factors.     

癌基因c-myc抑癌基因p53在涎腺肿瘤中的表达

方法：本文采用免疫组化（ＳＰ）法，研究了３０例涎腺肿瘤。目的：观察ｃ－ｍｙｃ癌基因和ｐ５３抑癌基因在涎腺肿瘤中的表达。结果：多形性腺瘤中，ｃ－ｍｙｃ和ｐ５３阳性率分别为５０．０％和２５．０％，均分别低于恶性肿瘤的阳性率７５％和５０．８％，两组比较均有高度显著性差异（Ｐ＜０．０１）。结论：ｃ－ｍｙｃ抑癌基因ｐ５３表达与涎腺上皮细胞增殖速度加快和突变有关，ｐ５３阳性率升高，虽与细胞恶变关系密切，但仅为判断细胞分化程度的一个参考指标。     

p21Waf1/Cip1与Skp2在涎腺肿瘤中的表达及意义

目的:研究p21 Waf1/Cip1与Skp2在涎腺良、恶性肿瘤中的表达及临床意义。方法:应用免疫组织化学SABC法检测10例正常涎腺组织、20例涎腺良性肿瘤、33例涎腺恶性肿瘤组织中p21 Waf1/Cip1和Skp2蛋白的表达情况,分析它们表达之间的相关性。结果:p21 Waf1/Cip1在涎腺正常组织以及涎腺良、恶性肿瘤的表达率依次降低,各组之间存在显著性差异(x2=11.113,P=0.006)。Skp2在涎腺恶性肿瘤中的阳性表达率(75.76%)明显高于良性肿瘤组织(35.00%),差异有显著性意义(x2=19.128,P=0.001)。p21 Waf1/Cip1与Skp2在涎腺良性肿瘤中的表达呈负相关,但相关性不明显(r=-0.390,P=0.089);它们在涎腺恶性肿瘤中的表达呈显著性负相关(r=-0.467,P=0.006)。结论:p21Waf1/Cip1低表达以及Skp2高表达与涎腺肿瘤的发生、发展密切相关。Skp2可能通过下调p21 Waf1/Cip1蛋白的表达而参与涎腺肿瘤的形成过程。     

抑癌基因PTEN、p27及Ki-67在涎腺粘液表皮样癌中的表达

目的　检测抑癌基因PTEN、p2 7及Ki 6 7在涎腺粘液表皮样癌中的表达 ,并探讨其意义。方法　采用免疫组织化学SP法对 31例涎腺粘液表皮样癌的PTEN、p2 7和Ki 6 7表达进行检测 ,并作统计学分析。结果　PTEN、p2 7表达在高分化组粘液表皮样癌的阳性率分别为 88 89%、94 4 4 % ,低分化组分别为 5 3 85 %、4 6 15 % ;Ki 6 7增殖指数在高、低分化组间分别为 (5 18± 2 97) %、(10 38± 3 6 5 ) % ,三者在高低分化组间均有统计学差异 (P <0 0 5 ) ;PTEN和p2 7的表达呈正相关 (rs=0 4 4 5 ,P <0 0 5 ) ,p2 7和Ki 6 7的表达呈负相关 (rs=- 0 4 2 3,P <0 0 5 )。结论　涎腺粘液表皮样癌中 ,PTEN、p2 7和Ki 6 7的表达水平与其组织分化程度有关