口腔黏膜癌前病变癌变过程中染色体17p13.3区杂合性丢失的研究

目的　了解口腔黏膜良性增生、异常增生、鳞形细胞癌D17S6 95 (17p13.3)位点杂合性丢失 (lossofheterozygosity ,LOH)情况 ,为新的肿瘤抑制基因定位提供依据。方法　应用聚合酶链反应 (PCR) -聚丙烯酰胺尿素凝胶电泳 (PAUGE) -DNA银染方法 ,以D17S6 95位点微卫星多态标记为遗传标记 ,检测 2 9例口腔癌前病变及鳞癌组织的LOH。结果　 19例提供信息的病例中 ,1例良性增生、2例异常增生、1例鳞癌出现LOH。结论　 17p13.3区D17S6 95位点可能是口腔鳞癌发生的早期事件 ,提示该区域可能存在与口腔鳞癌发生发展密切相关的肿瘤抑制基因。     

Oral squamous cell carcinoma arising in a patient with Werner syndrome

Werner syndrome (WS) is an autosomal recessive disorder characterized by physical signs and symptoms, including premature aging and scleroderma-like skin changes. The gene responsible for WS is the WRN gene. A significant proportion of WS-related malignant tumours are non-epithelial types, and the incidence of oral squamous cell carcinoma (SCC) is rare. A case of oral SCC of the lower alveolus and gingiva arising in a 63-year-old woman with WS is reported here. Biopsy confirmed moderately differentiated SCC. Surgical resection was performed and there was no recurrence or metastasis at the 3-year follow-up. Mutation analysis using next-generation sequencing, detected no mutations in the genes encoding the molecules strongly involved in the development of oral SCC, such as TP53 or PIK3CA. No obvious mutations were detected. Based on the results of the study, the results of mutation analysis suggest that this case might be genetically different from the common mechanisms of SCC in the oral cavity.     

Cytoplasmic HMGB1 and HMGB1-Beclin1 complex are increased in radioresistant oral squamous cell carcinoma

Cytoplasmic high mobility group box 1 (HMGB1) is an autophagy regulator, and autophagy is important in the radioresistance of various solid cancers. We evaluated the degree of autophagy and cytoplasmic HMGB1 in radioresistant oral squamous cell carcinoma (SCC) by culturing the SCC15 and quasiliquid layer 1 (QLL1) SCC cell lines that originate from cancer of the oral tongue and a metastatic lymph node, respectively, and then delivered radiation to induce radioresistance to cells. We then compared the degree of autophagy between non-irradiated control and radioresistant cancer cells using a western blot assay. We also compared the total and cytoplasmic concentrations of HMGB1 between the non-irradiated control and radioresistant cancer cells by western blot assay, and extracellular concentrations of HMGB1 with an enzyme-linked immunosorbent assay (ELISA). Formation of an HMGB1-Beclin1 complex was evaluated by immunofluorescence and co-immunoprecipitation assays. Autophagy increased in the radioresistant SCC15 cells (compared with non-irradiated control SCC15 cells) but not in the radioresistant QLL1 cells. The total amount of HMGB1 expression within cells did not differ; however, the degree of cytoplasmic HMGB1 expression was higher in radioresistant SCC15 cells than in non-irradiated control SCC15 cells. The HMGB1-Beclin1 complex, which is a main regulator of autophagy, was also increased in radioresistant SCC15 cells compared with non-irradiated control SCC15 cells. Autophagy flux and cytoplasmic HMGB1-Beclin1 increased after the acquisition of radioresistance in oral SCC.     

A rare presentation of multiple primary squamous cell carcinoma of the tongue in a patient with recurrent hepatitis C infection

Hepatitis C virus (HCV) infection has been implicated as a risk factor for development of oral squamous cell carcinoma (SCC). Multiple primary sites of oral SCC associated with HCV infection occurs infrequently. This case report describes a rare presentation of multiple primary SCCs of the tongue in a patient with recurrent HCV cirrhosis status post liver transplant that required interdisciplinary medical and surgical management. It is important for oral health care providers to understand the local and systemic implications of HCV infection and perform routine clinical examinations to monitor for development of oral lesions and associated complications.     

Clinical relevance of thymidylate synthase (TS) activity for S-1-based chemotherapy in squamous cell carcinoma of the oral cavity

S-1 is a newly developed oral fluoropyrimidine derivative that is now widely used as a chemotherapeutic agent in the treatment of oral squamous cell carcinoma (SCC). Thymidylate synthase (TS) is the rate-limiting enzyme in the de novo DNA biosynthetic pathway, and improves clinical response to chemotherapy with fluoropyrimidines. We have retrospectively evaluated the predictive value of thymidylate synthase activity in 75 patients with oral SCC with an enzyme-linked immunosorbent assay (ELISA). Mean (SD) activity (pmol/mg) in the specimens was 0.078 (0.080) (median 0.059). The median value was taken as the cut-off value based on which the patients were divided into high and low activity groups. Both the clinical and histopathological responses to chemotherapy and radiochemotherapy were higher in the group with low TS activity. The group with low TS activity also differed significantly in their clinical response to S-1-based chemotherapy (p < 0.05). However, there was no significant difference in cause-specific survival. Measurement of TS activity may aid in predicting the clinical response to chemotherapy including S-1 for oral SCC.     

Mandibular SCC in a 10 year old child--a clinical rarity

Oral squamous cell carcinoma (SCC) represents 90%-95% of all malignant neoplasms of the oral cavity and is regarded as an adult disease. It is uncommon in adults under 45 years of age and exceptionally rare in children. We present a case of a 10-year-old boy with advanced mandibular alveolar SCC with no established risk factors and discuss its immediate and long-term management.     

Reduced expression of CD9 in oral squamous cell carcinoma: CD9 expression inversely related to high prevalence of lymph node metastasis

Because CD9 is implicated in cell growth, cell adhesion and cell motility, altered CD9 expression might be involved in cancer invasion and metastasis. We have studied the immunolocalization of CD9 in oral squamous cell carcinoma (SCC). Sections prepared from paraffin-embedded specimens from patients with SCC of the oral cavity were stained with a monoclonal anti-CD9 antibody by means of the streptoavidin biotin method. Significant reduction or complete loss of CD9 expression was observed in cancer cells at the periphery of the cancer nests in the advancing front of invading tumor. Among 78 cases of oral SCCs examined, 46 (59.0%) cases were completely negative for CD9 expression. Loss of CD9 expression in cancer tissue strongly correlated with a high incidence of cervical lymph node metastasis and poorer prognosis (P=0.001). Thus a close examination of CD9 in SCC tissue would be useful for the prognosis of patients with oral carcinoma.     

Regulatory T cells in oral squamous cell carcinoma

Regulatory T cells (Tregs) play a critical role in modulating and maintaining immune homeostasis and tolerance. They accumulate in many types of tumors and play a critical role in tumor evasion of immune surveillance. Oral cancer is characterized by an increase in the number of infiltrating Tregs; however, the significance of this increase on the prognosis of oral cancer is controversial. This review focuses on the function of Tregs in oral squamous cell carcinoma and its implications on prognosis. We also discuss potential therapeutic strategies aimed at Tregs modification in oral SCC.     

Expression of p53 protein correlates with decreased survival in patients with areca quid chewing and smoking-associated oral squamous cell carcinomas in Taiwan

Expression of p53 protein was examined in oral squamous cell carcinoma (SCC) from patients who were areca quid (AQ) chewers and/or tobacco smokers, using anti-p53 antibodies with an immunoperoxidase technique. Positive p53 stain was observed in 47 of 81 (58%) cases of oral SCC. p53 overexpression was found to higher in patients without AQ chewing and smoking habits than in patients with these two habits (80% vs 52%, P=0.076). No significant correlation was found between p53 expression and the patients' age, sex, cancer location, clinical staging, primary tumor TNM status, or histological differentiation of SCC. The Kaplan-Meier analysis showed that the prognosis for patients with p53-negative tumors was significantly better than that for patients with p53-positive tumors (P<0.05). A significant correlation was also observed between positive lymph node status and poor prognosis (P<0.05). These results suggest that p53 may serve as an adjuvant marker of poor survival in patients with oral SCCs in Taiwan.     

IκB kinase α: an independent prognostic factor that promotes the migration and invasion of oral squamous cell carcinoma

IκB kinase α (IKKα) is associated with tumourigenesis, metastasis, and poor prognosis. However, its expression and function in oral squamous cell carcinoma (SCC) remain unknown. The aim of this study was to elucidate the clinicopathological associations and functions of IKKα in oral squamous cell carcinoma (SCC). We made an immunohistochemical analysis of IKKα in 94 tissue microarrays of specimens of oral SCC. We also examined IKKα expression in the patients’ samples by quantitative real-time polymerase chain reaction (qRT-PCR), as well as the migration, invasion, and matrix metalloproteinase (MMP) activity of the cells under IKKα knockdown treatment. In oral SCC, immunostaining for IKKα was found in 60 of the 94 patients, and it correlated with lymph node status and poor prognosis. Univariate and multivariate analysis using Cox’s proportional hazards model identified that IKKα expression was an independent predictor of distant- disease-free survival (p < 0.05) and overall survival in oral SCC (p < 0.05). Knocking down IKKα suppressed cell migration and invasion in oral SCC cells. Our results indicate that IKKα has an important role in promoting oral SCC, and it may be a useful biomarker and therapeutic target for diagnosis and treatment.     

Oral and oropharyngeal cancer in the West of Scotland—long-term outcome data of a prospective audit 1999-2001

We prospectively studied patients from the west of Scotland who presented with a primary cancer of the oral cavity or oropharynx over a period of 24 months from November 1999, and report long-term outcomes and prognostic factors. A total of 481 patients had squamous cell carcinoma (SCC), 5-year disease-specific survival (DSS) was 50%, and overall survival (OS) was 35%. One hundred were not suitable for treatment with curative intent, and factors other than stage were important in this decision. Of those treated with curative intent, 249 had SCC of the oral cavity (5-year DSS 67%; OS 42%), and 132 had SCC of the oropharynx (5-year DSS 62%; OS 42%). Multivariate analysis showed that pathological nodal stage (p = 0.051, 95% CI 0.998-1.955), and perineural invasion (p = 0.001, 95% CI 0.186-0.666) were prognostic indicators. Improved results using intensive treatment protocols that have been seen in trials are not likely to translate directly into a general population of patients with head and neck cancer. Algorithms that allow several pathological prognostic indicators to be incorporated into decisions about adjuvant treatment should be used.     

Clinicopathological and immunohistochemical features of oral spindle cell carcinoma

J Oral Pathol Med (2010) 39 : 335–341 Background: Oral spindle cell carcinoma (SpCC) is a rare variant of oral squamous cell carcinoma (SCC). The aims of this study were to compare the clinicopathologic and immunohistochemical features of oral SpCC with conventional oral SCC. Methods: Five cases of oral SpCC and 10 cases of oral SCC (five well‐differentiated and five poorly differentiated) were evaluated through conventional hematoxylin and eosin staining and immunohistochemical reactions to cytokeratins (CK), vimentin, desmin, smooth muscle actin, muscle‐specific actin, S‐100 protein, epithelial membrane antigen (EMA), p53, and ki‐67. Results: Oral SpCC showed predilection for males on their sixth decade of life, presenting clinically as painful infiltrative ulcers or ulcerated exophytic polypoid masses, preferably located on the alveolar mucosa. Mesenchymal markers were expressed in the spindle cell but not in the carcinomatous component of SpCC, and it was negative in all SCC. CKs AE1/AE3, 6, 14, and EMA were positive on both carcinomatous and spindle cell components of most SpCCs. These tumors also presented higher p53 and ki‐67 expression and no CK 1 expression in contrast to well‐differentiated SCC. Conclusion: Oral SpCC presented a different clinical profile than conventional SCC and histopathologic features and p53 and ki‐67 expression closer to poorly differentiated SCC. Besides mesenchymal markers, CK AE1/AE3, 6, 14, and EMA expression on spindle cells may be useful as an adjunct on microscopical differential diagnosis of SpCC.     

E-cadherin and β-catenin expression in well-differentiated and moderately-differentiated oral squamous cell carcinoma: relations with clinical variables

The aim of this study was to establish the expression and localisation of E-cadherin and β-catenin in oral squamous cell carcinomas (SCC) so that we could correlate the findings with prognostically-relevant clinicopathological variables. E-cadherin and β-catenin expression in normal oral mucosa and in oral squamous cell carcinomas were examined immunohistochemically, and their association with clinicopathological factors and prognosis were then analysed in 69 patients who had been operated on for oral SCC. E-cadherin expression was found in all 69 cases: in 11 cases (16%) it was weak; in 21 (30%) moderate, and in 37 (54%) high. β-Catenin expression was found in 64 cases (93%): in 18 cases (26%) cell-membrane expression was weak; in 26 (38%) it was moderate; in 19 (28%) it was high, and in one case (1%) there was cytoplasmic staining. No nuclear staining was detected. E-cadherin was significantly associated with histological grade (p = 0.002) and alcohol consumption (p = 0.05), and β-catenin was significantly associated with nodal stage (p = 0.02), TNM stage (p = 0.009), and E-cadherin expression (p = 0.01). However, none of them were independent prognostic factors in the disease-specific survival analysis. E-cadherin is closely linked to β-catenin expression in oral SCC and to tumour differentiation. Alcohol consumption could increase the aggressiveness of SCC, leading to reduced expression of E-cadherin. β-catenin could be an early marker for the identification of occult metastases in patients with oral SCC.     

Anatomical surgical planning for oral and oropharyngeal primary carcinoma combined with adjuvant treatment where indicated is associated with improved local control

We aimed to find out whether surgical tactics that lead to a reduction in tumour-involved surgical margins also improve local control. We retrospectively reviewed a consecutive case series (n = 162) of previously untreated patients who had operations for squamous cell carcinoma (SCC) of the oral cavity or oropharynx. Extensive use was made of computed tomographic multiplanar imaging to plan primary resections. Nine patients (6%) had tumour at the resection margin. Local control at 36 months was 96%, disease-specific survival (DSS) was 86%, and overall survival (OS) was 77%. Carefully planned primary operation for SCC of the oral cavity and oropharynx to minimise tumour-involved margins combined with conventional adjuvant treatment where indicated, is associated with a high probability of local control and disease-specific survival.     

Highly sensitive detection of HPV-DNA in paraffin sections of human oral carcinomas

BACKGROUND: Although human papillomavirus (HPV) infection has been shown to be a significant carcinogen in cervical squamous cell carcinoma (SCC), its significance in oral SCC remains unclear. METHODS: We developed highly sensitive detection methods for HPV to elucidate the prevalence and localization of HPV in paraffin sections from human oral SCC using modified in situ polymerase chain reaction (PCR) and in situ hybridization AT tailing (ISH-AT). Analyses revealed a high prevalence of several HPV types (HPV-16, -18, -22, -38 and -70) under optimal conditions. The ISH-AT method can be used as an alternative to in situ PCR. RESULTS: Various staining patterns were observed in the 20 cases examined, and HPV-positive cells were localized within the surface epithelium as well as in neoplastic cells. We demonstrated that HPV-DNA could be detected in paraffin sections using either the method of in situ PCR or ISH, providing an appropriate primer and probe are used. CONCLUSION: These results suggest that HPV infection could be one of several risk factors being involved in oral SCC.     

Immunocytochemical localization of fibroblast growth factor-1 (FGF-1) and FGF-2 in oral squamous cell carcinoma (SCC)

The localization of fibroblast growth factor-1 (FGF-1) and FGF-2 in human oral squamous cell carcinoma (SCC) was examined by immunohistochemical techniques using anli-FGF-1 and anti-FGF-2 monoclonal antibodies. Immunofluorescence staining of two oral SCC cell lines revealed that growing cancel-cells were intensely positive for both FGF-1 and FGF-2, but confluent cells showed a faint immunostaining. In addition, two molecular mass species of FGF-1(16 and 18 kDa) and one of FGF-2 (18 kDa) were identified by Western blot in cell extracts derived from growing SCC cells, but not from confluent SCC cells. The growing cell extracts significantly stimulated the proliferation of human umbilical vein endothelial cells. Immunoperoxidase staining of 13 oral SCC cases showed that both well-differentiated and poorly-differentiated cancer cells were positive for FGF-1 and FGF-2 with high frequency and intensity as compared to normal oral epithelium. These results indicate that SCC cells express high levels of endogenous FGF-1 and FGF-2, and suggest that these growth factors may contribute to cancer cell growth.     

唾液SA、CEA测定在口腔鳞状细胞癌诊断中的意义

目的　通过对唾液中癌胚抗原 (CEA)和唾液酸 (SA)含量的测定和分析 ,探讨唾液中CEA和SA含量在口腔颌面部鳞状细胞癌诊断中的意义。方法　分别采用ELLISA法酶法 ,检测了 2 2例口腔鳞状细胞癌患者、2 2例口腔良性肿瘤患者、4 0例正常人唾液中的CEA和SA含量。结果　经过对测定数据进行统计学处理 ,SA含量在正常人组与良性肿瘤组对比 ,P >0 .0 5 ;正常人与鳞状细胞癌组对比 ,P <0 .0 1。良性肿瘤与鳞状细胞癌组对比 ,P >0 .0 5 ;CEA含量在正常人组与良性肿瘤和鳞状细胞癌组对比 ,P <0 .0 1,而鳞状细胞癌和良性组对比P >0 .0 5。结论　联合检测口腔颌面部鳞状细胞癌唾液CEA和SA含量明显高于正常人和良性肿瘤患者 ,口腔科临床开展唾液CEA和SA的测定 ,对诊断颌面部鳞状细胞癌具有一定的辅助作用     

Expression of cyclin D1 is correlated with poor prognosis in patients with areaca quid chewing-related oral squamous cell carcinomas in Tiwan

Abnormal expression of cell cycle regulatory proteins, particularly cyclin D1, has been implicated in the pathogenesis of several types of cancer. We have examined the expression of cyclin D1 in histological sections of oral squamous cell carcinomas (SCCs) using anti-cyclin D1 antibodies with an immunoperoxidase technique. Cyclin D1 nuclear staining was observed in 73 of 88 (83%) cases of oral SCC. In 54 of these 73 (74%) cases, positive cyclin D1 staining was also found in the normal appearing epithelium immediately adjacent to the cyclin D1-positive SCCs. No significant correlation was found between the expression of cyclin D1 and the patients' age, sex, oral habits, cancer location and STNM status. The Kaplan-Meier analysis showed that patients with tumors containing more than 10% cyclin D1-positive cells had significantly shorter overall survival than those with tumors containing less than 10% cyclin D1-positive cells or with cyclin D1-negative tumors (P<0.05). Patients with positive lymph node status also had significantly shorter overall survival (P<0.01). These results indicate that cyclin D1 may play an important role in the genesis of oral SCC and may serve as an adjuvant marker of worse prognosis in patients with oral SCCs in Taiwan.     

Role of angiogenic and non-angiogenic mechanisms in oral squamous cell carcinoma: correlation with histologic differentiation and tumor progression

BACKGROUND: Angiogenesis has been demonstrated to associate with various measures of tumor aggressiveness in many human malignancies. However, studies of tumor angiogenesis in oral squamous cell carcinoma (SCC) are still unclear. Recent studies indicate non-angiogenesis mechanism (tumor-lined vessel) may exist in certain tumors. Therefore, we investigate microvessel density (MVD) and tumor-lined vessel in oral SCC. METHODS: Peritumoral and intratumoral MVD were measured by immunohistochemical staining. Tumor-lined vessels were identified by double staining. Statistical analysis of peritumoral and intratumoral MVD and presence of tumor-lined vessels with clinicopathologic parameters was performed. RESULTS: The results showed peritumoral MVD increased with disease progression and further increases of intratumoral MVD was detected by CD31 and CD34. Non-angiogenesis, tumor-lined vessel, presented in oral SCC and correlated significantly with tumor size, stage, and histologic differentiation. CONCLUSION: Our results suggest at the initiation of oral SCC, increasing vascularity is observed at the periphery of the tumor. As the tumor continues to grow, further increases of intratumoral vascularity and the presence of tumor-lined vessels are associated with cancer progression.