人乳头瘤状病毒在头颈部鳞状细胞癌中的研究进展

高危型人乳头瘤状病毒是宫颈癌的主要致病因素,近年来研究发现人乳头瘤状病毒感染与头颈部鳞状细胞癌的发生也存在密切关系。本文对人乳头瘤状病毒相关性头颈部鳞状细胞癌的流行病学、致癌机制、诊断方法、治疗及预后等方面的研究进展作一综述。     

Human papillomavirus DNA types in squamous cell carcinomas of the head and neck.

Previous studies have found variable evidence suggestive of a role for human papillomavirus (HPV) in squamous cell carcinoma of the head and neck. In this study 49 cases of primary verrucous or squamous cell carcinoma from patients referred to a regional medical center were examined initially by Southern blot hybridization to detect HPV types 2, 6, 11, 13, 16, 18, and 32. Approximately 60% of carcinomas from certain head and neck sites, particularly the floor of the mouth, tongue, pharynx, piriform sinus, and larynx, were positive for episomal viral DNA of HPV-6, -11, -16, or -18. HPV DNA was found in some multiple tumors from separate sites of the same patient. Integration of viral DNA into the host cell chromosome was likely in a minority of the positive carcinomas, and no novel HPV DNA types were indicated by the hybridization analyses. Subsequently, DNA remaining from 30 of the carcinomas was examined by a more sensitive polymerase chain reaction amplification assay for DNA of HPV-6, -11, -16, and -18. Twenty-seven of the samples were positive for one or more HPV DNA types, with all positive carcinoma samples containing oncogenic HPV-16 or -18 DNAs. Almost all the patients examined were of the middle to older age group with a history of tobacco use. Although HPV infection of oral mucosa may be a frequent occurrence, a possible role for HPVs in the multifactorial etiology of head and neck carcinogenesis merits further epidemiologic investigation.     

CCND1 amplification and cyclin D1 immunohistochemical expression in head and neck squamous cell carcinomas

Objectives

Gene products, which show a significant association to cell proliferation and cell cycle control, are of high scientific interest, because genes as well as gene products could be possible targets for a specific therapeutic approach and eventually be prognostic markers.

Materials and methods

Cyclin D1 expression and amplification as well as the Ki-67 expression status were examined in a two tissue microarray analysis for head and neck squamous cell carcinoma (HNSCC) including 546 patients. A tumour site-specific analysis and a survival analysis of 222 oral squamous cell carcinoma (OSCC) patients were performed. Cyclin D1 amplification status was examined with fluorescence in situ hybridisation analysis, while cyclin D1 expression and Ki-67 expression status were examined with IHC.

Results

Amplification of the CCND1 gene and immunohistochemical expression of cyclin D1 and Ki-67 were examined in 546 tumours of the head and neck region in two tissue microarrays. CCND1 amplification was significantly more frequent in pharyngeal carcinomas (63 %) than in laryngeal (37 %) and oral (25 %) carcinomas. Among the 222 cases of OSCCs, both CCND1 amplification and cyclin D1 expression were significantly associated with overall survival of the patients (p?=?0.0127 and p?=?0.0004, respectively). Ki-67 expression was significantly associated with cyclin D1 expression and with amplification of the CCND1 gene (p?=?0.0002 and p?=?0.0015, respectively) but not with patient overall survival.

Conclusion

Our results suggest the prognostic value of CCND1 amplification and cyclin D1 expression for patients with OSCC and highlight the genetic differences in HNSCC of different subanatomic localisation.

Clinical relevance

Cyclin D1 expression and CCND1 amplification seem to have a prognostic value for OSCC. Further studies of HNSCC should always consider subanatomic genetic differences.     

人乳头瘤病毒相关头颈部鳞状细胞癌侵袭转移的分子机制

人乳头瘤病毒（HPV）是头颈部鳞状细胞癌（HNSCC）的主要致病因素之一,HPV感染与HNSCC的侵袭转移存在密切关系。本文对HPV相关性头颈部鳞状细胞癌基因变异、HPV致癌蛋白E6、E7通过众多复杂细胞元件相互作用的特异性致癌机制进行了阐述,并进一步讨论了HPV阳性HNSCC侵袭转移相关的分子机制,包括非编码RNAs、肿瘤细胞的能量代谢紊乱、肿瘤细胞微环境、肿瘤干细胞、肿瘤血管生成及淋巴管生成的研究进展。     

First hints for a correlation between amplification of the Int-2 gene and infection with human papillomavirus in head and neck squamous cell carcinomas

Infection with human papillomavirus (HPV) and alterations in certain genes have frequently been proposed as mechanisms in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Here, we investigated 47 HNSCC for the presence of HPV and, by fluorescence in situ hybridisation, for amplification of Int-2 and Hst-1 in the search for a possible correlation. The highest frequency of HPV infection was found in hypopharyngeal carcinomas, while amplification of Int-2 or Hst-1 was distributed more equally among the different localisations. Amplification of Int-2 was detectable (7 of 9 cases) in 78% of the HPV-positive carcinomas, whereas no virus infection could be found in the five cases with amplified Hst-1 only. In spite of the rather low number of infected tumour samples, our results suggest a correlation between HPV infection and amplification of Int-2.     

Prognostic value of lymph node involvement in oral squamous cell carcinoma

Clinical Oral Investigations - Different parameters have been identified in patients with oral squamous cell carcinomas (OSCC) that have a serious impact on survival, including residual tumour and...     

Multiple cytogenetic aberrations in squamous cell carcinomas of the head and neck

Chromosomal abnormalities in short term cultures have been investigated in 10 squamous cell carcinomas of the head and neck. Of these tumours, three demonstrated clonal chromosomal abnormalities, two showed random abnormalities and 5 patients' tumours had normal karyotypes. The 5 patients with aberrant karyotypes were all from previously treated tumours, of these, 4 patients had received radiotherapy and 1 surgery. On analysis of the three clonal tumours, two were found to be polyclonal, each with five separate clones. 116 breakpoints were demonstrated from the clonal data of these tumours, and all of the chromosomes were involved, apart from number 18. In this study we found three or more breakpoints at sites 1p36, 9q32 and 11q23. 1 of the patients investigated showed a clonal abnormality involving a breakpoint at the 11q13 site, with a further 2 patients having breakpoints at 1p22-sites previously reported to have marked clustering of cytogenetic abnormalities in oral cancer patients. Only further studies will demonstrate whether the breakpoints found are of clinical significance.     

Frequent microsatellite alterations of chromosome locus 4q13.1 in oral squamous cell carcinomas

BACKGROUND: Studies have revealed that losses of chromosome 4q24-25 regions are frequent in cancers including head and neck squamous cell carcinoma. Our previous comparative genomic hybridization analysis showed extensive losses of chromosome arm 4q in oral squamous cell carcinoma (OSCC). METHODS: To be more precise in mapping the potential regions of allelic losses and to understand the microsatellite instability (MSI) on 4q involving in oral pathogenesis, we performed allelotypings using eight polymorphic markers. Microsatellite analyses were first performed on 100 randomly selected controls to confirm the high informative rates of markers. Twenty OSCC tissues were microdissected from surgical specimens for microsatellite alterations (MA) analysis. RESULTS: MA was observed in 95% OSCC cases. The most eminently altered locus was 4q13.1 (75%), followed by 4q22.2 and 4q32.1 (55%). Allelic losses also occurred most frequently on these loci. Thirty-five percent cases had MA spanning 4q13.1 to 4q21.1. MSI occurred in 35% OSCC, at a lesser extent compared with allelic losses. The most common locus for MSI was 4q21.2 (20%). In addition, 4q MSI was significantly associated with the lymph node metastasis of OSCC (P = 0.01). So far, most tumor suppressor genes on 4q have not been specified. CONCLUSION: Our results were additive to previous findings and proposed novel scenario of suppressor loci located at 4q13.1-21.1 whose inactivation could be important for progression of OSCC.     

头颈部鳞癌抑癌基因nm23-H1的表达、DNA倍体与淋巴结转移的关系

目的 :研究头颈部鳞状细胞癌 (HNSCC)nm2 3 H1基因的表达、DNA含量与淋巴结转移的关系。方法 :选择 3 0例未经治疗的HNSCC患者术后新鲜肿瘤标本 ,应用免疫组化ABC技术和流式细胞术 (FCM )检测瘤细胞nm 2 3 -H1基因表达、异倍体 (aneuploid)和S期细胞比例 (S phasefraction ,SPF) ,探索这 3个参数与淋巴结转移之间的关系。结果 :nm 2 3 H1的阳性率为 60 % ,异倍体检出率为 66.7%。nm 2 3 H1表达、DNA倍体和SPF与淋巴结转移有关 (均为P <0 .0 1)。nm 2 3 H1表达与DNA倍体无关 (P >0 .0 5 ) ,nm 2 3 H1表达与SPF有关 (P <0 .0 5 )。结论 :对nm2 3 H1表达、DNA倍体和SPF的检测可预测HNSCC淋巴结转移趋势和预后 ,是指导临床治疗有意义的一项生物学指标     

Cannabinoid receptor-2 immunoreactivity is associated with survival in squamous cell carcinoma of the head and neck

The prediction of progression of individual tumours, prognosis, and survival in squamous cell carcinoma (SCC) of the head and neck is difficult. Cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptor expression is related to survival in several types of cancer, and the aim of this study was to find out whether the expression of CB1 and CB2 receptors is associated with survival in primary SCC of the head and neck. We made immunohistochemical analyses of the cannabinoid receptors on tissue arrays from 240 patients with the disease. Receptor immunoreactivity was classified as none, weak, moderate, or strong staining. Overall survival and disease-specific survival were plotted using Kaplan–Meier survival curves. A multivariate Cox proportional hazard model was created with all the relevant clinical and pathological features. Strong immunoreactivity of the CB2 receptor was significantly associated with reduced disease-specific survival (p = 0.007). Cox-proportional hazard ratio (HR) showed that CB2 receptor immunoreactivity contributed to the prediction of survival (HR 3.6, 95% CI 1.5–8.7, p = 0.004). Depth of invasion (HR 2.2, 95% CI 1.2–4.2, p = 0.01) and vascular invasion (HR 2.5, 95% CI 1.4–4.5, p = 0.001) were also associated with survival.     

口腔鳞状细胞癌淋巴结转移相关因素的单因素分析

目的 通过分析常用的临床、病理指标与口腔鳞状细胞癌颈淋巴结转移的关系,探讨其在预测口腔鳞癌颈淋巴结转移中的价值,为临床提供预测转移的有效指标.方法 选择100例口腔鳞癌患者,记录年龄、性别、发病部位、病程、T分期、N分期等临床指标;选择肿瘤细胞浸润深度、浸润方式、病理分级、淋巴细胞浸润程度、肿瘤的粘附力、基底膜的连续性、肿瘤血管生成、肿瘤增殖等病理指标,进行统计学分析,观察这些指标与淋巴结转移的相关性.结果 单因素分析结果显示,T分期、浸润深度、平均血管密度、VEGF、PCNA和E-CD染色阳性细胞率具有统计学意义.结论 T分期、肿瘤浸润深度、E-CD、PCNA和VEGF的表达程度、肿瘤血管平均密度是与口腔鳞癌淋巴结转移相关的危险因素,可作为术前预测的指标.     

Low expression of MSH2 DNA repair protein is associated with poor prognosis in head and neck squamous cell carcinoma

Objective

This study aimed to investigate the expression of the MSH2 DNA repair protein in head and neck squamous cell carcinoma (HNSCC) in order to analyze its association with clinicopathologic factors and overall survival of patients.

Material and Methods

Clinical data and primary lesions of HNSSC were collected from 55 patients who underwent surgical resection with postoperative radiotherapy in Montes Claros, state of Minas Gerais, Brazil, between 2000 and 2008. Immunohistochemical reactions were performed to analyze MSH2 protein expression.

Results

Bivariate analysis showed no significant correlation or association between MSH2 expression and clinicopathologic parameters by Mann-Whitney and Kruskal-Wallis tests. Patients with locoregional metastatic disease (OR=4.949, p<0.001) and lower MSH2 immunohistochemical expressions (OR=2.943, p=0.032) presented poorer survival for HNSCC by Cox regression models.

Conclusions

Our data demonstrated that lower MSH2 expression might contribute to a higher clinic aggressiveness of HNSCC by promoting an unfavorable outcome.     

Apoptosis-associated markers and clinical outcome in human oral squamous cell carcinomas

Background:  Apoptosis is a genetically regulated cell death involved in the deletion of cells in normal or malignant tissues. Proteins of the Bcl-2 family play a key role in the control of apoptosis and carry out both pro-apoptotic and anti-apoptotic functions. The present study evaluated the prognostic value of Bcl-2 and Bax expression at the invasive front of oral squamous cell carcinoma (OSCC), taking clinicopathological findings into account.
Methods:  Fifty-six specimens of OSCC were randomly selected, and Bcl-2 and Bax expression was evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded pre-treated specimens at the invasive front of OSCC. Clinicopathological data were gathered and patient survival was analysed.
Results:  No significant relationship was found between Bcl-2 or Bax expression and clinical variables. Patients with Bcl-2 expression had a worse prognosis than those without Bcl-2 expression, but the difference did not reach statistical significance. Patients with Bax expression had a significantly better prognosis than those without Bax expression ( P  <   0.05). In univariate analyses, T category, mode of cancer invasion and Bax expression showed significant correlations. Multivariate analysis revealed that the mode of cancer invasion and Bax expression were significant and independent variables. Bax expression was found to be the strongest independent prognostic parameter. Patients with negative Bcl-2 expression and positive Bax expression had a significantly better prognosis ( P  <   0.005).
Conclusion:  We suggest that Bax expression at the invasive front of OSCC is a significant predictor of prognosis and that it is therefore important to investigate the expression of Bcl-2 and Bax in this disease.     

Amplification of the PPFIA1 gene region on 11q13 in oral squamous cell carcinomas (OSCC)

IntroductionAnalyzing chromosomal amplifications delivers valuable information for identification of oncogenes. For carcinomas of the oral cavity only few genes have been identified in amplified regions. The aim of this study was to search genes in amplified regions as possible biomarkers and targets for novel therapies.Material and methodsDNA from 10 carcinomas of the floor of the oral cavity was examined using a 500K Array GeneChip (Affymetrix 6.0) to detect chromosomal losses, gains or amplifications. Suspicious alterations were validated on tissue microarrays using fluorescence in situ hybridization (FISH) with respective probes.ResultsFISH-validation on tissue arrays confirmed PPFIA1 amplifications as one of the most frequent events (32.6%). High (10–20 signals) and low (<10 signals) amplification of PPFIA1 was found in 10.9% (5/46) and 21.7% (10/46) tumours, respectively. Fine mapping with overlapping FISH probes showed co-amplification of PPFIA1 and the Cyclin D1 gene which are approximately 600 kb apart from each other, likely in the same amplicon.DiscussionPPFIA1 was frequently co-amplified with the Cyclin D1 gene in oral carcinomas and could present a biomarker as well as a novel target for specific gene therapy. Further studies are necessary to investigate the role of PPFIA1 in development and pathogenesis of oral carcinomas.     

头颈部鳞状细胞癌干细胞的研究进展

肿瘤干细胞假说认为,只有一小部分细胞可维持肿瘤的生长,这一小部分细胞被称为“肿瘤干细胞”,其他的大部分细胞只有有限的或根本没有生长潜能。在头颈部鳞状细胞癌在内的多种肿瘤中已经初步鉴定和分离出了肿瘤干细胞。本文就CD44阳性细胞、醛脱氢酶阳性细胞、侧群细胞和八聚体4／nanog／CD133阳性细胞等与头颈部鳞状细胞癌干细胞相关的研究现状作一综述。