Cortactin, fascin, and survivin expression associated with clinicopathological parameters in esophageal squamous cell carcinoma

Cortactin, fascin, and survivin have been documented in several human cancers and play important roles in tumor progression. We collected 57 surgical specimens, including esophageal squamous cell carcinomas (SqCC; 7 well-differentiated, 15 moderately differentiated, and 24 poorly differentiated), 3 dysplasias, and 8 normal esophageal tissues. Tissue microarrays were constructed and the immunostaining scores for cortactin, fascin, and survivin were assessed. In 46 SqCC specimens, we examined the relationship between the expression of three biomarkers and tumor differentiation or clinical parameters. Higher immunostaining scores for cortactin, fascin, and survivin correlated positively with tumor differentiation of esophageal SqCC. Univariate survival analysis showed significantly worse prognosis in patients with high scores of cortactin (≥290), fascin (≥245), and survivin (score ≥ 175), poor differentiation, T4 stage, positive for lymph node metastasis, and positive for distant metastasis. In multivariate survival analysis, high scores of survivin (≥175) and poor differentiation were independent risk factors for worse prognosis. Our results demonstrated that higher expression of survivin may be related to tumor progression and it is an independent risk factor for poor survival time of esophageal SqCC. Survivin may be a good biomarker to be applied in clinic to predict the prognosis of esophageal SqCC.     

High expression of PDGFA predicts poor prognosis of esophageal squamous cell carcinoma

Platelet-derived growth factor A (PDGFA), the most known member of PDGF family, plays a crucial role in occurrence and progression of different tumors. However, PDGFA expression and its clinical significance in esophageal squamous cell carcinoma (ESCC) are not clear. The present study aimed to assess the expression and prognostic value of PDGFA in ESCC.The Gene Expression Omnibus databases ({"type":"entrez-geo","attrs":{"text":"GSE53625","term_id":"53625"}}GSE53625, {"type":"entrez-geo","attrs":{"text":"GSE23400","term_id":"23400"}}GSE23400, and {"type":"entrez-geo","attrs":{"text":"GSE67269","term_id":"67269"}}GSE67269) and fresh clinical samples were employed for detecting PDGFA messenger RNA expression in ESCC. The associations of PDGFA expression with clinicopathological characteristics were evaluated by chi-square test. Kaplan–Meier analysis and Cox proportional hazard regression model were performed to determine the prognostic value of PDGFA in ESCC patients. PDGFA-related signaling pathways were defined by gene set enrichment analysis based on Gene Expression Omnibus databases.The PDGFA messenger RNA expression was upregulated in ESCC tissues compared with paired adjacent noncancerous tissues (P < .05) and was positively correlated with T stage (P < .05). Kaplan–Meier survival analysis suggested that ESCC patients with high PDGFA expression were associated with poorer overall survival compared to those with low PDGFA expression (P < .05), especially in advanced T stage (P < .05). Cox analyses showed that high expression of PDGFA was an independent predictor for poor prognosis in ESCC patients. Gene set enrichment analysis identified 3 signaling pathways (extracellular matrix receptor interaction, focal adhesion, and glycosaminoglycan biosynthesis chondroitin sulfate) that were enriched in PDGFA high expression phenotype (all P < .01).PDGFA may serve as an oncogene in ESCC and represent an independent molecular biomarker for prognosis of ESCC patients.     

Prognostic significance of PTEN expression in esophageal squamous cell carcinoma from Linzhou City, a high incidence area of northern China

Decreased expression of tumor suppressor gene PTEN has been reported to be a poor prognostic indicator in a variety of human malignant tumors. The purpose of this study was to clarify the roles of PTEN in esophageal squamous cell carcinoma (ESCC) and the prognostic significance of PTEN protein expression. Sixty-four patients from a high incidence area of northern China who underwent esophagectomy for ESCC between January 1998 and December 1999 enrolled in this study. PTEN expression was assessed by immunohistochemistry in 64 primary cancers and 64 paired normal esophageal epithelium tissues. The positive rate and staining grade of PTEN protein expression was lower in the esophageal cancers than in paired adjacent normal esophageal epithelium (P < 0.001). PTEN expression correlated with tumor differentiation (P = 0.001), tumor infiltration depth (P = 0.015) and pTNM staging (P = 0.048). The 5-year survival rate in patients with PTEN positive expression was 82% compared to 39% in patients with PTEN negative expression (P = 0.0019). Our results show that the expression of PTEN is decreased in ESCC compared to normal esophageal epithelium. Therefore, PTEN may play an important role in carcinogenesis and the progression of ESCC in a high incidence area of northern China, and PTEN could serve as an important factor to predict clinical outcome and prognosis.     

Nuclear BAG-1 expression is a biomarker of poor prognosis in esophageal squamous cell carcinoma

Apoptosis is one of the critical biological factors that correlate with the biological behavior of malignant tumors including cancer progression and clinical outcome. The present study was performed to clarify the clinical implications of BAG-1, a bcl-2 binding protein in esophageal squamous cell carcinoma (ESCC). Seventy-one cases with ESCC were investigated. Immunohistochemical study of BAG-1 was performed on resected specimens. The expression pattern of BAG-1 in nuclei and/or cytoplasm was analyzed and correlated with TNM classification, vessel invasion, survival period after surgery. BAG-1 expression in the nuclei was related to the depth of tumor invasion (P = 0.0381) but not to any other clinicopathologic parameters. The cytoplasmic staining pattern of BAG-1 exhibited no correlation with clinicopathologic parameters. Univariate analysis (P < 0.05), but not multivariate analysis, revealed significantly poor prognosis for ESCC cases exhibiting positive nucleic staining for BAG-1. Our data suggests that BAG-1 expression in the nuclei of ESCC plays an important role in tumor development and may be useful for predicting the prognosis after surgery.     

食管鳞癌组织中STAT3蛋白的表达及临床意义

目的 探讨食管鳞癌组织和癌旁正常黏膜组织中信号转导子和转录激活子3（STAT3）的表达及与食管鳞癌发生发展的关系.方法 应用免疫组化SP法检测122例食管鳞癌及其癌旁正常黏膜组织中STAT3蛋白的表达.结果 食管鳞癌组织中STAT3蛋白表达阳性率为89.3%,明显高于癌旁正常黏膜组织的77%（P＜0.05）.Ⅰ级、Ⅱ级、Ⅲ级食管鳞癌组织中STAT3蛋白的阳性率分别为73.7%、89.5%和100%,Ⅲ级中STAT3蛋白的阳性率显著高于Ⅰ级（P＜0.05）.浸润至深层（深肌层和外膜）的食管鳞癌组织中STAT3蛋白阳性表达率为92.8%,明显高于浸润至浅层（黏膜和浅肌层）食管鳞癌组织的76%（P＜0.05）.STAT3的表达与淋巴结转移无关（P＞0.05）.结论 STAT3蛋白过度表达与食管鳞癌的发生发展及恶性演进有关,STAT3有望成为评估食管癌预后的一个新标志物.     

Prognostic value of the stem cell markers CD133 and ABCG2 expression in esophageal squamous cell carcinoma

In the light of increasing evidence supporting cancer stem cells (CSCs) theory, the expression of two stem cell markers, CD133 and adenosine triphosphate-binding cassette superfamily G member 2 (ABCG2), in esophageal squamous cell carcinoma (ESCC) was investigated, and their prognostic values were evaluated. Paraffin-embedded tissue sections of 110 ESCC patients were investigated using Immunohistochemistry. The association of CD133 and ABCG2 expression with clinicopathologic characteristics was analyzed by χ(2) test. Survival analysis was carried out using Kaplan-Meier method and Cox proportional hazards model. CD133 and ABCG2 expression were detected in 27.3% and 15.5% of ESCC patients, respectively. The presence of CD133-positive cancer cells was associated with tumor cell differentiation (P= 0.008) but not significantly related to the survival of ESCC patients (P= 0.085). ABCG2 expression was not associated with clinicopathologic characteristics but was a significant prognostic factor for adverse overall survival of ESCC patients (P= 0.005). The median overall survival time for ESCC patients with and without ABCG2 expression were 21.8 and >49.3 months, respectively. A combined analysis of CD133 and ABCG2 expression did not show that ESCC patients with coexpression of these two markers had a worse prognosis than those with only ABCG2 expression (P= 0.934). Moreover, ABCG2 expression was revealed to be an independent prognostic factor along with tumor node metastasis stage in multivariate analysis (hazard ratio of ABCG2, 3.38; 95% confidence interval, 1.61～7.09; P= 0.001). By survival analysis based on tumor node metastasis stage of ESCC, the association between ABCG2 expression and the patients' prognosis was found significant in the group of relatively early stage (P= 0.005) and marginally significant in the group of relatively late stage (P= 0.058). This is the first time to report the presence of CD133-positive cancer cells in ESCC but not supporting its prognostic value and validity as a CSC marker for ESCC. ABCG2 expression was found to correlate with the survival of ESCC patients, especially those at relatively early stage, suggesting that ABCG2-positive cancer cells may represent a pool of CSCs in ESCC, and relatively early-stage patients with ABCG2 expression may deserve more intensive or targeted therapy.     

Tumor budding as a useful prognostic marker in esophageal squamous cell carcinoma

We examined the prognostic significance of tumor budding in patients with esophageal squamous cell carcinoma, particularly in comparison to other routine pathological findings. Fifty-six cases who underwent an esophagectomy were reviewed. We defined tumor budding as an isolated single cancer cell or a cluster composed of fewer than five cancer cells and divided these into two grades; low-grade (< 5 budding foci) and high-grade (> or = 5 budding foci) within a microscopic field of x 200. There were 22 (39.3%) and 34 (60.7%) cases with low- and high-grade budding, respectively. There were significant differences in the patients with low- and high-grade budding in relation to tumor size, pT stage, lymphovascular invasion, perineural invasion, circumferential resection margin involvement, and AJCC stage (P < 0.05). The 3-year survival rates of the patients with low- and high-grade budding were 72.3% and 30.7%, respectively (P = 0.04). We propose that tumor budding may be a pathological marker suggesting high malignancy potential and decreased postoperative survival in patients with esophageal squamous cell carcinoma.     

Survivin和Ki67在食管鳞癌组织中的表达及意义

目的探讨Survivin和Ki67蛋白表达在食管鳞癌发生、发展中的作用。方法应用免疫组化SP法检测40例食管鳞癌患者癌组织中Survivin和Ki67蛋白表达情况,并分析其与临床特征的关系以及二者的相关性。结果食管鳞癌患者癌组织中Survivin和Ki67蛋白的阳性表达率分别为72．5％和75．0％。两种蛋白表达与肿瘤组织分化程度、浸润程度相关,而与性别、年龄、淋巴结转移情况无关。二者表达呈显著正相关（r=0．420,P〈0．05）。结论Survivin和Ki67蛋白与食管鳞癌组织的分化和恶性进展有关,Survivin在抑制细胞凋亡的同时可能促进了细胞增殖。     

Invasive and prognostic significance of pRB in esophageal squamous cell carcinoma: a meta‐analysis

This paper investigates the association between protein retinoblastoma (pRB) loss and the T,N stage and prognosis in esophageal squamous cell carcinomas (ESCCs) using meta‐analysis. We conducted a meta‐analysis of 16 studies, comprising 1,117 patients to clarify this issue. All the studies searched by the electronic literature PubMed and http://www.KJEBM.com , which had been published during the period from January 1996 to January 2012 according to the inclusion criteria. Summary odds ratios (OR) were calculated using fixed or random‐effects models. The summary odds ratios (ORs) for pRB inactive were 0.64 (95% confidence interval [CI]:0.45–0.91, P = 0.01) for T1/T2 versus T3/T4 tumors; summary OR = 0.69 (95% CI:0.51–0.94, P = 0.02) for N0 versus N1 tumors. The association between pRB loss and prognosis was examined in nine studies, and the summary hazard ratio was 1.39 (95% CI:1.11–1.74, P = 0.004). pRB inactive was significant associated with T3/T4 tumors and N1 stage as well as adverse prognosis for ESCCs. It appears warranted to prospectively validate that pRB loss may be used for subdividing the T,N stage evaluation of patients with ESCCs, and these patients may be the preponderant people for individualized treatment or target therapy.     

Cyclin D1, E2F1 expression levels are associated with characteristics and prognosis of esophageal squamous cell carcinoma

SUMMARY. We performed a multi-institutional analysis of E2F1 and cyclin D1 expression in cases of esophageal squamous cell carcinoma (ESCC). Cyclin D1 and E2F1 are involved in the transition of cell cycle phases and associated with tumor progression. However, no previous studies have concurrently analyzed combined E2F1 and cyclin D1 expression. The purpose of this study was to clarify the relationship of E2F1 and cyclin D1 in ESCC. We studied 122 patients with primary ESCC who underwent surgical tumor resection. Immunohistochemical analyses were performed for E2F1 and cyclin D1. A statistical analysis of immunohistochemistry results, clinicopathological features, and prognosis was performed. E2F1/cyclin D1 (-/-) tumors were present in 31 patients (25.4%) and correlated with reduced tumor progression. In these patients, pT (P=0.0001), pN (P<0.0001), p-Stage (P=0.0019), and survival rates were better than in patients who were positive for either E2F1 or cyclin D1 (P=0.0232). The expression of E2F1 and cyclin D1 is an indicator of tumor progression and prognosis in patients with ESCC. Combined analysis of E2F1 and cyclin D1 expression helps to determine the characteristics and prognosis of ESCC.     

Absence of Epstein-Barr virus in esophageal squamous cell carcinoma

It is strongly suspected that the Epstein-Barr virus (EBV) plays a role in the genesis of nasopharyngeal and gastric carcinoma. The aim of this study was to search for such a connection between esophageal squamous cell carcinoma (ESCC) and EBV. We investigated 104 surgically resected esophageal cancers using in situ hybridization (ISH) for EBV-encoded RNA (EBER). We found no EBER-positive cancer cells in any tests, although there were five samples in which EBER-positive tumor-infiltrating lymphocytes (TILs) were found. We conclude from this study that EBV is not associated with ESCC.     

Targets for molecular therapy in esophageal squamous cell carcinoma: an immunohistochemical analysis

SUMMARY.  Neoadjuvant chemotherapy may improve the outcome of esophageal cancer after esophagectomy, but is accompanied by considerable toxicity by collateral destruction of normal cells. Such side effects may be avoided by developing therapies that specifically target molecular characteristics of tumors. The aim of the present study was to determine the proportion of esophageal squamous cell carcinoma (ESCC) patients that could possibly benefit from (a combination of) currently available targeted therapies, by assessing the frequency of immunohistochemical expression of their target molecular markers in ESCC tissues. Sections from a validated tissue microarray comprising 108 ESCCs were immunohistochemically stained for Bcl-2, c-KIT, cyclo-oxygenase-2 (COX-2), cyclin D1, estrogen receptor (ER), epidermal growth factor receptor (EGFR), Her-2/neu, progesterone receptor (PR), and vascular endothelial growth factor (VEGF). VEGF, cyclin D1, EGFR, and COX-2 could be detected in 55, 42, 40, and 40%, respectively. Her-2/neu, Bcl-2, and c-KIT were detected in 12, 11, and 10% of the tumors, respectively. No nuclear expression of ER or PR was noticed. Concurrent expression of two markers was noticed in 28% of ESCCs, whereas 25% of ESCCs showed concurrent expression of three markers. The concurrent expression of two of the most frequently expressed markers (VEGF, cyclin D1, EGFR, and COX-2) ranged from 11 (COX-2 and EGFR) to 26% (cyclin D1 and VEGF). The expression of all of these four markers was seen in 5% of ESCCs. Promising targets for molecular therapy in ESCC appear to be COX-2, VEGF, EGFR, and cyclin D1, as they are frequently overexpressed. Phase II clinical studies on these molecular markers may therefore be warranted. The role for targeted therapy against ER, PR, Her-2/neu, c-KIT, or Bcl-2 in ESCC seems limited.     

Prognostic significance of preoperative absolute peripheral monocyte count in esophageal squamous cell carcinoma

The objective of this study was to investigate the prognostic value of peripheral blood monocytes in esophageal squamous cell carcinoma (ESCC) patients who underwent esophagectomy. Records from 218 consecutive patients with histologically diagnosed ESCC who underwent esophagectomy at Qilu Hospital of Shandong University from January 2007 to December 2008 were retrospectively reviewed. The median disease‐free survival (DFS) of this cohort was 29.0 months, and the 5‐year DFS rate was 34.4%. The median overall survival (OS) was 35.0 months, and the 5‐year OS rate was 37.6%. The cut‐off value of 0.42 × 10⁹/L for the absolute monocyte count (AMC) was chosen as optimal to discriminate between survival and death by applying receiver operating curve analysis. There were 131 patients (60.1%) who had high AMC (≥0.42 × 10⁹/L) preoperatively. We found that AMC was significantly associated with gender, tumor location, and platelet count. Kaplan–Meier survival analysis of patients with high preoperative AMC had a significant worse prognosis for DFS (high vs. low: 27.5% vs. 39.0%, P = 0.015) and OS (high vs. low: 31.1% vs. 44.8%, P = 0.009) than those with low preoperative AMC. In a multivariate analysis, preoperative AMC was an independent prognostic factor for DFS (P = 0.025, hazard ratio [HR]: 1.469, 95% confidence interval [CI]: 1.050–2.054) and OS (P = 0.015, HR: 1.547, 95% CI: 1.088–2.200). In addition, among 140 patients without both preoperative and postoperative therapy, significantly worse OS (P = 0.012) and marginally reduced DFS (P = 0.079) were found in the high AMC cohort versus the low AMC cohort. A higher preoperative absolute peripheral monocyte count can be considered as a useful prognostic marker of ESCC patients who underwent esophagectomy.     

Human papillomavirus type 16 infection may be involved in esophageal squamous cell carcinoma carcinogenesis in Chinese Kazakh patients

The aim of this study was to investigate human papillomavirus type 16 (HPV16) prevalence in esophageal squamous cell carcinoma (ESCC) in Xinjiang Kazakh patients and its role in ESCC carcinogenesis. One hundred and fifty cases of ESCC and 150 cases of corresponding normal esophageal mucosa (CNGM) samples were collected from north Xinjiang where the Kazakh ethnic group has lived since ancient times. HPV16 infection in ESCC and CNGM was detected by genotype‐specific polymerase chain reaction. HPV16 DNA was detected in 55 of 150 ESCC samples (36.7%) and 24 of 150 corresponding normal esophageal mucosa samples (16%) with significant differences (P < 0.001, odds ratio = 3.039, 95% confidence interval: 1.756–5.260). No statistically significant correlations were found between HPV16 infection and the age or gender of patients, tumor site, tumor cell differentiation, or lymph node metastasis (P > 0.05). HPV16 infection is common in cases of ESCC in the Kazakh ethnic group in Xinjiang and may be involved in ESCC carcinogenesis.     

Cortactin overexpression in the esophageal squamous cell carcinoma and its involvement in the carcinogenesis

SUMMARY.  The aim of this study is to examine whether dysregulated expression of cortactin occurs in esophageal squamous cell carcinoma (ESCC) and is involved in the development of ESCCs. An immunohistochemistry study for cortactin expression was performed on 46 pairs of surgically resected non-tumor and ESCC tumor tissues and murine tumors of esophagi induced by a carcinogen. The results show increased cortactin expression in 20 and in 22 to a lesser extent, out of a total 46 ESCC tumor tissues. Increased cortactin was also detected in the premalignant lesions, the early stage dysplasia and carcinoma in situ , of ESCC tumor tissues. Differential polymerase chain reaction results showed slight increases in the EMS1 gene only in two of 10 ESCC tumor tissues, suggesting that EMS1 gene amplification is not the only mechanism for cortactin overexpression. In the mouse model induced by treatment with 4-nitroquinoline 1-oxide and arecoline, increased cortactin was detected in the epithelia with hyperkeratosis, papillomas, and ESCCs with invasion into the submucosa, respectively. Overall, we observed cortactin overexpression in early and late stages of human ESCCs and carcinogen-induced murine ESCCs, suggesting a role for cortactin in esophageal carcinogenesis.     

Risk factors of lymph node metastasis in T1 esophageal squamous cell carcinoma

Background and Aim: To perform endoscopic mucosal resection (EMR) for T1 esophageal cancer, it is essential to estimate the lymph node status exactly. In order to evaluate the feasibility of EMR for esophageal cancers, we evaluated the clinicopathological features of T1 esophageal squamous carcinomas with an emphasis on the risk factors and distribution patterns of lymph node metastasis. Methods: From 1994 to 2006, a total of 200 patients with T1 esophageal carcinoma were treated surgically in our institution. Among them, clinicopathological features were evaluated for 197 consecutive patients with T1 squamous cell carcinoma. Results: The frequency of lymph node involvement was 6.25% (4/64) in mucosal cancers and 29.3% (39/133) in submucosal cancers (P < 0.001). In patients with M1 (n = 32) and M2 (n = 14) cancers, no lymph node metastasis was found. In multivariate analysis, size larger than 20 mm, endoscopically non‐flat type, and endo‐lymphatic invasion were significant independent risk factors for lymph node metastasis. The differentiation of tumor cell was not a risk factor for lymph node metastasis. Conclusions: We suggest that EMR may be attempted for flat superficial squamous esophageal cancers smaller than 20 mm. After EMR, careful histological examination is mandatory.