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Esophageal Squamous Cell Carcinoma (esophageal + squamous_cell_carcinoma)
Kinds of Esophageal Squamous Cell Carcinoma Selected AbstractsSUPERFICIAL ESOPHAGEAL SQUAMOUS CELL CARCINOMA WITH BULKY GASTRIC HIATUS LYMPH NODE METASTASIS: A CASE REPORTDIGESTIVE ENDOSCOPY, Issue 4 2009Yoshiaki Takahashi In patients with superficial esophageal cancer, especially in those with tumor invasion above the muscularis mucosae, lymph node metastasis is very rare. We report a case of superficial esophageal cancer who presented with lymph node metastasis. In another hospital a 49-year-old man was found to have a bulky tumor adjacent to the cardiac area of the stomach and a total gastrectomy was carried out. Postoperatively, the tumor was identified as a lymph node containing metastatic squamous cell carcinoma. The main lesion could not be identified on fluorodeoxyglucose positron emission tomography. On esophagogastric endoscopy, using the iodine spray technique, we found an unstained lesion about 32 cm from the incisor teeth. The tumor was removed using endoscopic mucosal resection. The entire resected specimen was examined histopathologically; the depth of the tumor was above the muscularis mucosae. Thirty-four months after endoscopic mucosal resection, there is no sign of tumor recurrence or metastasis. [source] Chronic Atrophic Gastritis and Metachronous Gastric Cancer in Japanese Alcoholic Men With Esophageal Squamous Cell CarcinomaALCOHOLISM, Issue 5 2009Akira Yokoyama Background:, The risk of metachronous gastric cancer is high in Japanese with esophageal squamous cell carcinoma (SCC), especially in alcoholic men, suggesting a common background underlying the gastric and esophageal cancers. Methods:, Endoscopic follow-up ranging from 7 to 160 months (median, 47 months) after the initial diagnosis was performed in 99 Japanese gastric-cancer-free alcoholic men (56.8 ± 6.4 years) with esophageal SCC detected by an endoscopic screening examination. Chronic atrophic gastritis (CAG) assessed by the serum pepsinogen test and Helicobacter pylori status was compared between 90 of the 99 esophageal SCC cases and 180 age-matched Japanese gastric- and esophageal-cancer-free alcoholic men. Results:, The serum pepsinogen test showed a higher seroprevalence of severe CAG among the cases than among the age-matched controls (35.4% vs. 14.2% for H. pylori -seropositive, 71.4% vs. 7.7% for H. pylori -indeterminate, and 17.1% vs. 9.8% for H. pylori -negative, respectively; H. pylori status-adjusted p = 0.0008), whereas their H. pylori status was similar. The accelerated progression of severe CAG observed in the Japanese alcoholic men with esophageal SCC suggests the existence of common mechanisms by which both esophageal SCC and H. pylori -related severe CAG develop in this population. Metachronous gastric adenocarcinoma was diagnosed in 11 of the 99 gastric-cancer-free patients, and the cumulative rate of metachronous gastric cancer within 5 years was estimated to be 15% according to the Kaplan,Meier method. The age-adjusted hazard ratios were 7.87 (95% confidence interval: 1.43 to 43.46) and 4.84 (1.16 to 20.21), respectively, in the patients with severe CAG in comparison with those without CAG and those without severe CAG. Inactive heterozygous aldehyde dehydrogenase-2, a very strong risk factor for esophageal SCC in the alcoholics, was not associated with an increased risk of metachronous gastric cancer. Conclusions:, Accelerated development of severe CAG at least partially explained the very high frequency of development of metachronous gastric cancer in this population. [source] Protein alterations in ESCC and clinical implications: a reviewDISEASES OF THE ESOPHAGUS, Issue 1 2009D.-C. Lin SUMMARY Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer in Asia, characterized by high incidence and mortality rate. Although significant progress has been made in surgery and adjuvant chemoradiotherapy, the prognosis of the patients with this cancer still remains poor. Investigation into protein alterations that occurred in tumors can provide clues to discover new biomarkers for improving diagnosis and guiding targeted therapy. Hundreds of papers have appeared over the past several decades concerning protein alterations in ESCC. This review summarizes all the dysregulated proteins investigated in the disease from 187 published papers and analyzes their contributions to tumor development and progression. We document protein alterations associated with tumor metastasis and the transition from normal esophageal epithelia to dysplasia in order to reveal the most useful markers for prediction of clinical outcome, early detection, and identification of high-risk patients for targeted therapies. In particluar, we discuss the largest and most rigorous studies on prognostic implications of proteins in ESCC, in which cyclin D1, p53, E-cadherin and VEGF appeared to have the strongest evidence as independent predictors of patient outcome. [source] Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinomaJOURNAL OF SURGICAL ONCOLOGY, Issue 4 2005Hideaki Kobayashi MD Abstract Background and Objectives It has been reported that amino acid transport systems play an important role in cell proliferation. Their activity is increased in malignant cells compared to benign cells. In this study, we investigated whether L-type amino acid transporter 1 (LAT1) is expressed in human non-cancerous esophageal mucosa and esophageal squamous cell carcinoma. We also examined whether LAT1 expression is correlated with histopathological features. Methods From January 1999 to December 2001, sections of formalin-fixed, paraffin-embedded tissue from 11 cases of early esophageal carcinoma (T1) and 19 cases of advanced esophageal carcinoma (T2, T3) were entered in the study. Histopathologically, all 30 cases were squamous cell carcinoma. Immunohistochemical staining was performed using rabbit anti-LAT1 IgG, with the standard avidin-streptavidin immuno-peroxidase method. Measurement was performed by means of computer-assisted image analysis. The ratio of cells with LAT1 expression in esophageal squamous cell carcinoma and non-cancerous esophageal mucosa was used for analysis in this study. Results Non-cancerous esophageal mucosa expressed LAT1 only in the basal layer of the esophageal wall. Esophageal squamous cell carcinoma expressed LAT1 throughout the tumor. LAT1 expression in esophageal squamous cell carcinoma was significantly higher than that in non-cancerous esophageal mucosa. LAT1 expression in esophageal squamous cell carcinoma increased as the depth of invasion progressed (T1,<,T2 (P,=,0.0477), T2,<,T3 (P,=,0.0415), T1,<,T3 (P,=,0.0044)), and as the tumor size increased. Also, high LAT1 expression was significantly associated with well-differentiated carcinoma. Conclusion These results suggest that LAT1 plays a significant role in cell proliferation, differentiation, and invasion in esophageal squamous cell carcinoma. J. Surg. Oncol. 2005;90:233,238. © 2005 Wiley-Liss, Inc. [source] The presence of aberrant DNA methylation in noncancerous esophageal mucosae in association with smoking historyCANCER, Issue 15 2009A target for risk diagnosis, prevention of esophageal cancers Abstract BACKGROUND: Esophageal squamous cell carcinomas (ESCCs) tend to have multiple primary lesions, and it is believed that they arise from background mucosae with accumulation of genetic/epigenetic alterations. In this study, the objective was to elucidate the effects of smoking and drinking on the accumulation of epigenetic alterations in background mucosae. METHODS: Genes that are silenced in human ESCCs were searched for by treating 3 ESCC cell lines with the demethylating agent, 5-aza-2,-deoxycytidine and performing oligonucleotide microarrays. Methylation levels were analyzed by quantitative methylation-specific polymerase chain reaction analysis of 60 ESCCs and their corresponding background mucosae. RESULTS: Forty-seven genes were identified as methylation-silenced in at least 1 of the 3 ESCC cell lines, and 14 of those genes (claudin 6 [CLDN6]; G protein-coupled receptor 158 [GPR158]; homeobox A9 [HOXA9]; metallothionein 1M [MT1M]; neurofilament, heavy polypeptide 200 kDa [NEFH]; plakophilin 1 [PKP1]; protein phosphatase 1, regulatory [inhibitor] subunit 14A [PPP1R14A]; pyrin domain and caspase recruitment domain containing [PYCARD]; R-spondin family, member 4 [RSPO4]; testis-specific protein, Y-encoded,like 5 [TSPYL5]; ubiquitin carboxyl-terminal esterase L1 [UCHL1]; zinc-finger protein 42 homolog [ZFP42]; zinc-finger protein interacting with K protein 1 homolog [ZIK1]; and zinc-finger and SCAN domain containing 18 [ZSCAN18]) were used as markers. In the background mucosae, methylation levels of 5 genes (HOXA9, MT1M, NEFH, RSPO4, and UCHL1) had significant correlations with smoking duration (, = .268; P = .044; , = .405; P = .002; , = .285; P = .032; , = .300; P = .024; and , = .437; P = .001, respectively). In contrast, an inverse correlation between PYCARD methylation levels and alcohol intake was observed (, = ,.334, P = .025) among individuals with the inactive aldehyde dehydrogenase 2 (ALDH2) genotype. CONCLUSIONS: The current results suggested that ESCCs developed from an epigenetic field for cancerization, which was induced by exposure to carcinogenic factors, such as tobacco smoking. The epigenetic field defect will be a novel target for risk diagnosis and prevention of ESCCs. Cancer 2009. © 2009 American Cancer Society. [source] Original article: The expression of CFL1 and N-WASP in esophageal squamous cell carcinoma and its correlation with clinicopathological featuresDISEASES OF THE ESOPHAGUS, Issue 6 2010Wei-Sen Wang SUMMARY Cofilin1 (CFL1) is an actin-modulating protein, which belongs to the ADF/Cofilin family. Neural Wiskott,Aldrich syndrome protein (N-WASP) is the key regulator of the actin cytoskeleton, a member of Wiskott-Aldrich syndrome protein family. They have been suggested to be involved in cancer cell invasion and metastasis. In this study, the expression patterns of CFL1 and N-WASP in normal esophageal mucosa and esophageal squamous cell carcinoma (ESCC) and their correlation with clinical characteristics were investigated. Immunohistochemical staining showed that CFL1 was expressed in nuclear and cytoplasm of cancer cells. However, N-WASP was mainly found in the cytoplasm of the cancer cells. There were significant evidences that proved that CFL1 is correlated with clinicopathological factors in ESCC, such as infiltration depth, lymph node metastasis and pathological staging (P < 0.05). It is also proved that N-WASP is related to lymph node metastasis and pathological staging in ESCC (P < 0.05). Kaplan,Meier analysis showed that there was no correlation between CFL1 and N-WASP protein expression and survival (P > 0.05). Moreover, the mRNA expression of CFL1 and N-WASP was detected by quantitative real time PCR in 70 tissue specimens. The results showed that CFL1 mRNA level was over-expressed in ESCC tissue (P < 0.05), while N-WASP mRNA expression level was not different between cancerous tissues and adjacent normal esophageal mucosa (P > 0.05). Also, CFL1 mRNA expression was significantly associated with regional lymph node metastasis and pathological staging (P < 0.05). Kaplan,Meier analysis showed that there was no correlation between CFL1 and N-WASP mRNA expression and survival (P > 0.05). Our findings suggested that CFL1 and N-WASP may play an important role in the tumorigenesis of ESCC, and to be the candidate novel biomarkers for the diagnosis and prognosis of ESCC. These findings may have implications for targeted therapies in patients with ESCC. [source] CK19 mRNA expression in the bone marrow of patients with esophageal squamous cell carcinoma and its clinical significanceDISEASES OF THE ESOPHAGUS, Issue 5 2010X. Zhang SUMMARY The 5-year survival rate in resectable patients with esophageal cancer is only 20% to 36%. Regional relapse and distant metastasis are responsible for the failure of treatment and the majority of cancer-related deaths. Earlier detection of metastases, especially micrometastases, has the potential for more accurate risk stratification in subsequent therapy decisions. No effective techniques have yet been found to detect metastases in erroneously thought to have early stage disease. This study was designed to investigate the clinical significance of bone marrow micrometastases detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in patients with esophageal cancer. Expression of CK19 mRNA in the bone marrow of 61 patients with esophageal squamous cell carcinoma (ESCC) and 15 benign pulmonary and esophageal disease patients was assessed via RT-PCR. Correlation of CK19 mRNA expression to the clinicopathologic features and prognosis of the 61 patients was analyzed: 21.3% (13/61) were positive for expression of CK19 mRNA in patients with ESCC. No CK19 mRNA was detected of the 15 benign pulmonary and esophageal disease patients. CK19 mRNA expression did not correlate with the clinicopathologic features of the patients with ESCC, but patients with CK19 mRNA-positive bone marrow had earlier recurrence and shorter survival after surgery. In multivariate analysis, CK19 mRNA was found to be an independent predictor of a poor outcome. CK19 mRNA may be used as a molecular maker to detect bone marrow micrometastases in patients with ESCC and may help to select the proper therapy and predict the prognosis. [source] Prognostic factors of radiotherapy in patients with node-positive thoracic esophageal squamous cell carcinoma after radical surgeryDISEASES OF THE ESOPHAGUS, Issue 6 2009Jin-Cheng Lu SUMMARY The aim of this study was to retrospectively analyze and assess the outcomes and prognostic factors of radiotherapy in patients with node-positive thoracic esophageal squamous cell carcinoma after radical surgery. One hundred twenty-six patients with node-positive thoracic esophageal squamous cell carcinoma who had undergone adjuvant therapy (postoperative radiotherapy alone or postoperative sequential chemoradiotherapy without receiving postoperative concurrent chemoradiotherapy) after radical surgery, were retrospectively reviewed from January 1996 to December 2003. Univariate and multivariate analyses were performed using log-rank and Cox proportional hazard models, and survival curves were estimated using the Kaplan-Meier method. The 1-, 3- and 5-year overall survival rates of all 126 patients were 71.4, 39.1, and 22.0%, and disease-free survival rates were 64.3, 36.4, and 21.5%, respectively. Lymph node ratio (the ratio of the number of metastatic lymph nodes to the number of lymph nodes removed, LNR) ,0.2 (P= 0.006), pT3 + pT4 (P= 0.06) and sequential chemoradiotherapy (P= 0.08) were associated with a poorer survival by univariate analysis. In multivariate analysis, LNR (P= 0.01, hazard ratio = 0.57, 95% confidence interval, 0.37,0.87) and tumor depth of invasion (P= 0.03, hazard ratio = 0.62, 95% confidence interval, 0.41,0.96) were the independent predictors of survival. Sequential chemoradiotherapy receded survival tendency without significant difference (P= 0.09, hazard ratio = 0.64, 95% confidence interval, 0.37,1.08). Therefore, LNR and tumor depth of invasion were the independent prognostic factors of radiotherapy in patients with node-positive thoracic esophageal squamous cell carcinoma after radical surgery. The addition of chemotherapy does not seem to confer a survival benefit. [source] Magnifying endoscopy with narrow band imaging for predicting the invasion depth of superficial esophageal squamous cell carcinomaDISEASES OF THE ESOPHAGUS, Issue 5 2009K. Goda SUMMARY The invasion depth of superficial esophageal squamous cell carcinoma is important in determining therapeutic strategy. The aim of this study was to prospectively investigate the clinical utility of magnifying endoscopy with narrow band imaging compared with that of non-magnifying high-resolution endoscopy or high-frequency endoscopic ultrasonography in predicting the depth of superficial esophageal squamous cell carcinoma. The techniques were carried out in 72 patients with 101 superficial esophageal squamous cell carcinomas, which were then resected by either endoscopic mucosal resection or esophagectomy. The histological invasion depth was divided into two: mucosal or submucosal carcinoma. We investigated the relationship between endoscopic staging and histology of tumor depth. Non-magnifying high-resolution endoscopy, magnifying endoscopy with narrow band imaging, and high-frequency endoscopic ultrasonography had overestimation/underestimation rates of 7/5, 4/4 and 8/3%, respectively. The sensitivity rates for the three techniques were 72, 78, and 83%, respectively, and the specificity rates were 92, 95, and 89%, respectively. There were no statistically significant differences among the three endoscopic techniques. Clinical utility of magnifying endoscopy with narrow band imaging does not seem to be significantly different from that of non-magnifying high-resolution endoscopy or high-frequency endoscopic ultrasonography in predicting the depth of superficial esophageal squamous cell carcinoma. Magnifying endoscopy with narrow band imaging may have potential to reduce overestimation risks of non-magnifying high-resolution endoscopy or high-frequency endoscopic ultrasonography. [source] Overexpression of cyclooxygenase-2 is associated with chemoradiotherapy resistance and prognosis in esophageal squamous cell carcinoma patientsDISEASES OF THE ESOPHAGUS, Issue 8 2008W.-Z. Huang SUMMARY Our objective was to investigate whether cyclooxygenase-2 (COX-2) expression can predict the patient's response to chemoradiotherapy (CRT) and ensuing prognosis in esophageal squamous cell carcinoma (ESCC). The clinicopathological and follow-up data of 112 patients with ESCC who underwent CRT from January 2001 to June 2006 were analyzed retrospectively. The immunohistochemical expression level of COX-2 was examined for all biopsy specimens of primary tumors, and the correlation of COX-2 expression with the patient's response to CRT and prognosis was examined. COX-2 positive immunostaining was detected in 111 (99.1%) of the patients, including overexpression in 54 (48.2%) patients and low expression in 58 (51.8%) of the patients. The response of tumors with a low level expression of COX-2 (70.7%, 41/58) was significantly higher than that of tumors with COX-2 overexpression (42.6%, 23/54; P = 0.003). Patients with a low level of COX-2 expression had a higher downstaged rate than those with a high level of COX-2 expression (9/13 vs 2/8), but the difference was not statistically significant (P = 0.08). In the definitive CRT group (91 cases), COX-2 overexpression was significantly associated with poor 3-year overall survival (P = 0.028). Multivariate analysis showed that only metastatic stage (nonregional node metastasis) was an independent prognosis factor. The assessment of COX-2 status may provide additional information to identify ESCC patients with poor chances of response to CRT and potential candidates for more individualized treatment. [source] Aberrant promoter methylation of the TPEF gene in esophageal squamous cell carcinomaDISEASES OF THE ESOPHAGUS, Issue 7 2008B.-J. Zhao SUMMARY., Aberrant methylation of tumor suppressor genes plays an important role in the development of esophageal squamous cell carcinoma (ESCC). The purpose of the present study was to identify the epigenetic changes in ESCC. Methylation-sensitive arbitrarily primed polymerase chain reaction (MS AP-PCR) analysis was used on 22 matched ESCC tumors and adjacent normal tissues. Through this screen we identified a frequently methylated fragment that showed a high homology to the 5,-CpG island of the gene encoding a transmembrane protein containing epidermal growth factor and follistatin domains (TPEF). The methylation status of the TPEF gene was then detected by bisulfite sequencing and the levels of TPEF mRNA were detected by RT-PCR. In addition, the effects of a methylation inhibitor 5-aza-2,-deoxycytidine on TPEF mRNA expression was determined in cells of ESCC cell lines. Hypermethylation of the 5,-CpG island of TPEF was found in 12 of 22 (54.5%) primary tumors. Reverse transcription PCR analysis demonstrated that TPEF mRNA expression was significantly lower in tumors than in adjacent normal tissues, which is associated with promoter hypermethylation. In addition, treatment of ESCC cell lines with 5-aza-2,-deoxycytidine led to re-expression of the TPEF transcript. In conclusion, we observed promoter of TPEF gene is frequently hpermethylated, and is associated with the loss of TPEF mRNA expression in ESCC samples. Promoter hypermethylation of TPEF gene may play a role in the development of ESCC. [source] COX-2 mRNA expression in esophageal squamous cell carcinoma (ESCC) and effect by NSAIDDISEASES OF THE ESOPHAGUS, Issue 1 2008X. Liu SUMMARY., To investigate cyclooxygenase-2 (COX-2) mRNA expression in human esophageal squamous cell carcinoma and the effect of a non-steroidal anti-inflammatory drug (NSAID) on it, in order to explore the mechanism of COX-2 in esophageal squamous cell carcinoma (ESCC) carcinogenesis and the ability of NSAID to prevent or treat ESCC. Frozen specimens of human ESCC and adjacent normal esophageal squamous epithelium pairs (n = 22) were examined for COX-2 mRNA expression by reverse-transcription polymerase chain reaction (RT-PCR). After incubation with aspirin (a non-selective COX inhibitor) or Nimesulide (a selective COX-2 inhibitor), the proliferation status of two human esophageal squamous cancer cell lines, EC-9706 and EC-109, was quantified by 3-(4,5-dimethyl-thiazol-2yl)-2,5-diphenyltetrazolium bromide assay. The expression of COX-2 mRNA in these cells was detected by RT-PCR. COX-2 mRNA was expressed in 12 of 22 (54.5%) ESCC tissue samples, but it was undetectable in all the specimens of adjacent normal esophageal squamous epithelium COX-2 mRNA expression. Both aspirin (5,20 mmol/L) and Nimesulide (0.1,0.8 mmol/L) inhibited EC-9706 cell line proliferation and suppressed its COX-2 mRNA expression dose-dependently. However, only aspirin (5,20 mmol/L) could inhibit proliferation in the EC-109 cell line and suppress COX-2 mRNA expression. Nimesulide (0.1,0.8 mmol/L) could neither inhibit EC-109 cell growth nor suppress COX-2 mRNA expression. COX-2 mRNA expression is a frequent phenomenon in human ESCC tissue samples and plays an important role in the carcinogenesis of ESCC. NSAID may be useful in the chemoprevention and therapy of human ESCC and its effects are likely to be mediated by modulating COX-2 activity. [source] The p73 polymorphisms are not associated with susceptibility to esophageal squamous cell carcinoma in a high incidence region of ChinaDISEASES OF THE ESOPHAGUS, Issue 4 2007H. Ge SUMMARY., P73, a p53 homolog, has some p53-like activities and plays an important role in modulating cell cycle, apoptosis and DNA repair. The two linked polymorphisms in the non-coding region of exon2 of p73 gene, named G4C14-A4T14, may alter translation efficiency of the gene. The transcription of p73 gene is initiated by three promoters, termed P1-P3. There is a single nucleotide substitution (,386G/A) in the P3 promoter region with unknown function. To test the hypothesis that the genetic variations in the exon2 and P3 promoter play a role in the etiology of esophageal squamous cell carcinoma (ESCC), we conducted a population-based case-control study in 348 ESCC patients and 583 healthy controls from a high incidence region of Hebei province, China. The p73 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). The results showed that the family history of upper gastrointestinal cancer (UGIC) significantly increased the risk of developing ESCC (the age, sex and smoking status adjusted OR = 2.02, 95% CI = 1.54,2.67). The overall distribution of the p73 genotype, allelotype and haplotype in cancer patients and controls were not significantly different (all P -values are above 0.05). Stratification analysis by smoking status and family history of UGIC also did not show the significant influence of the polymorphisms on the risk of ESCC development. The results suggested that the p73 exon2 G4C14-A4T14 and P3 promoter ,386G/A polymorphisms might not be used as potential markers to predicate the risk of ESCC development in northern China. [source] Expression of EMMPRIN and matriptase in esophageal squamous cell carcinoma: Correlation with clinicopathological parametersDISEASES OF THE ESOPHAGUS, Issue 6 2006M.-F. Cheng SUMMARY., Extracellular matrix metalloproteinase inducer (EMMPRIN) and the type II transmembrane serine protease, matriptase, are expressed in several human cancers and play an important role in tumor progression. The aim of the present study was to investigate the immuno-staining patterns of EMMPRIN and matriptase in patients with esophageal squamous cell carcinomas (SCC) and correlate the percentage tumor staining with tumor differentiation and clinical parameters. EMMPRIN and matriptase immunoreactivity was seen on the cell membrane and in the cytoplasm of tumor cells in all 41 cases of esophageal SCC evaluated. The percentage tumor staining of EMMPRIN was 48 ± 3% for well differentiated, 73 ± 3% for moderately differentiated, and 92 ± 3% for poorly differentiated esophageal SCC. Higher percentage tumor staining with EMMPRIN correlated significantly with poorly differentiated esophageal SCC (P < 0.05). The percentage tumor staining with matriptase correlated significantly with tumor differentiation (52 ± 3% for well differentiated, 85 ± 2% for moderately differentiated, and 88 ± 3% for poorly differentiated esophageal SCC). Additionally, higher percentage tumor staining with matriptase was significantly correlated with the advanced N and M stages (P < 0.05). Our results demonstrate that EMMPRIN and matriptase are over-expressed in esophageal SCC and are correlated with advanced clinicopathological stages. Pharmacological agents targeting EMMPRIN and matriptase expressions may be beneficial in the treatment of esophageal SCC. [source] Detection of human papillomavirus DNA in squamous cell carcinoma of the esophagus by auto-nested PCRDISEASES OF THE ESOPHAGUS, Issue 2 2006A. P. Souto Damin SUMMARY., The aim of the present study was to investigate the presence of human papillomavirus (HPV) in surgical specimens of esophageal squamous cell carcinoma. One hundred and sixty-five paraffin-embedded specimens of esophageal carcinoma were analyzed through high-sensitivity auto-nested polymerase chain reaction (PCR) using the consensus GP5+/GP6+ primer. Twenty-six specimens of esophageal mucosa without malignant disease were also studied as a control group. Two different specific primer sets targeting the E6 region of the HPVs 16 and 18 were used for typing. Direct DNA sequence analysis was conducted to confirm positive PCR results. HPV DNA was detected in 26 esophageal carcinomas (15.75%), but in none of the benign esophageal specimens (P < 0.05). Out of the 26 positive cases, 24 were HPV-16 and one was HPV-18. One tumor contained both HPV-16 and -18 DNA. Positive PCR results were confirmed by the amplified viral sequences. Our findings suggest that the presence of either HPV-16 or -18 might be related to development of the malignant phenotype in the esophagus. [source] Tumor budding as a useful prognostic marker in esophageal squamous cell carcinomaDISEASES OF THE ESOPHAGUS, Issue 4 2004M. S. Roh SUMMARY, 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 (, 5 budding foci) within a microscopic field of ×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. [source] Differences and relationships of thymidine phosphorylase expression in tumor-associated macrophages and cancer cells in squamous cell carcinoma of the esophagusDISEASES OF THE ESOPHAGUS, Issue 1 2002N. Koide SUMMARY. Thymidine phosphorylase (TP), which has been shown to be identical to platelet-derived endothelial cell growth factor, is expressed in tumor-associated macrophages (TAMs) as well as cancer cells. The aim of this study was to clarify the differences or relationships of TP expression in TAMs and cancer cells in esophageal squamous cell carcinoma (SCC). Tissues samples were taken from 56 patients with esophageal SCC after curative surgery. The expression of TP in TAMs or SCC cells was examined using a monoclonal antibody to TP (clone 654,1). Microvessels in SCC that stained positively for Factor VIII-related antigen were counted (microvessel density, MVD). Macrophages in SCC that stained positively for CD68 antigen were counted (monocytic count). Ki-67 antigen was immunostained with MIB-1, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling was performed, and Ki-67 labeling index (LI) and apoptotic index were calculated. The expression of TP in stromal cells and cancer cells was observed in 43 (76.8%) and 33 patients (58.9%), respectively. There were significant correlations between TP expression in stromal cells (TAMs) as well as in cancer cells and venous invasion, distant metastasis, or MVD. There was a correlation between TP expression in cancer cells and lymph node metastasis, and there were correlations between TP expression in TAMs and monocytic count or Ki-67 LI; however, there was no correlation between TP expression in TAMs and lymph node metastasis. On the other hand, in SCCs with TP expression in both TAMs and cancer cells, higher frequencies of venous invasion and distant metastasis, higher MVD and lower apoptotic index were observed than in other SCCs. The 5-year survival rate in patients with TP expression in both TAMs and cancer cells was poorer than that in patients with TP expression in neither TAMs and cancer cell. In conclusion, these results suggest that co-expression of TP in TAMs and cancer cells is strongly associated with angiogenic promotion and distant metastasis. However, other effects of TP, such as promotion of tumor growth and lymph node metastasis, may be different depending on whether these are expressed in TAMs or cancer cells in esophageal SCCs. Patients with coexpression of TP in TAMs and cancer cells may be associated with a poor prognosis. [source] Association of mast cells with tumor angiogenesis in esophageal squamous cell carcinomaDISEASES OF THE ESOPHAGUS, Issue 2 2001M. Tomita The association of mast cells with tumor angiogenesis was investigated in patients with esophageal squamous cell carcinoma. Surgical specimens from 48 patients with esophageal squamous cell carcinoma were studied. Mast cells in tumor sections were stained with Alcian blue and safranin O. The number of mast cells was counted under light microscopy and the average count recorded. To highlight the microvessels, endothelial cells were stained with anti-human factor VIII antibody. Microvessel density was also counted. We found a significant correlation between mast cell count and microvessel density in patients with esophageal squamous cell carcinoma. Double staining of the microvessels revealed highly angiogenic areas densely populated with mast cells. There appears to be a direct correlation between the number of mast cells and tumor angiogenesis in patients with esophageal squamous cell carcinoma. [source] Expression of p53, bcl-2, and bax as predictors of response to radiotherapy in esophageal cancerDISEASES OF THE ESOPHAGUS, Issue 3 2000H. Shimoji The sensitivity of cancers to radiotherapy or chemotherapy may be influenced by susceptibility to apoptosis. We evaluated whether expression of three proteins regulating apoptosis, p53, bcl-2, and bax, could predict the effect of radiotherapy in esophageal cancers. We used immunohistochemical staining for these protein regulators of apoptosis to study biopsy specimens obtained from 25 patients with esophageal squamous cell carcinoma before they underwent preoperative radiotherapy. Effectiveness of radiotherapy was assessed by barium esophagography, esophagoscopy, and computed tomography. Radiotherapy was effective in 12 patients and ineffective in 13 patients. Biopsy specimens from the 25 patients showed expression of p53, bcl-2, and bax to be 48.0%, 32.0%, and 76.0% respectively. Effectiveness of radiotherapy was correlated with p53 expression (p = 0.047), but bcl-2 and bax expression showed no relationship to effectiveness of radiotherapy. Expression of p53 protein in biopsy specimens may predict effectiveness of preoperative radiotherapy in esophageal cancers. [source] Assessment of the predictive value of clinical and histopathological factors as well as the immunoexpression of p53 and bcl-2 proteins in response to preoperative chemotherapy for esophageal squamous cell carcinomaDISEASES OF THE ESOPHAGUS, Issue 3 2000J. Szumilo The aim of the study was to determine the predictive value of selected clinical and histopathological factors as well as the immunohistochemical expression of p53 and bcl-2 proteins in the prediction of the pathological response to preoperative chemotherapy in esophageal squamous cell carcinoma. Thirty-four patients with advanced squamous cell carcinoma of the thoracic esophagus (T2,4 N0,1 M0), who underwent one cycle of cisplatin and 5-fluorouracil therapy followed by subtotal esophagectomy, were studied. All clinical factors (tumor longitudinal diameter in a computed tomographic scan, invasion depth, the presence of lymph node metastasis and clinical tumor staging) were evaluated before the onset of the therapy. The histopathological features (grade of differentiation, degree of keratinization, nuclear polymorphism, mitotic index, pattern of cancer invasion and inflammatory response), and the expression of p53 and bcl-2 proteins were also estimated in prechemotherapy endoscopic biopsy specimens. Pathological response to chemotherapy was assessed in surgically resected specimens. Of 34 patients, two (5.9%) showed complete response (CR), six patients (17.6%) exhibited major histological changes (partial response 1; PR1), 24 (70.6%) showed minor histological changes (partial response 2; PR2), and two patients (5.9%) exhibited no response to chemotherapy (stable disease; SD). There were no significant relationships between the response to preoperative chemotherapy (CR + PR1 vs. PR2 + SD) and the majority of the clinical and all the histopathological features. Deeper cancer invasion before chemotherapy was the only factor that tended to worsen the therapy effect (p < 0.01). The pathological response to treatment had no significant associations with the expression of p53 and bcl-2 proteins in esophageal squamous cell carcinoma. It should be noted, however, that both patients in CR were p53 and bcl-2 protein-negative. [source] Prostaglandin E2 promotes cell proliferation via protein kinase C/extracellular signal regulated kinase pathway-dependent induction of c-Myc expression in human esophageal squamous cell carcinoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 11 2009Le Yu Abstract Overexpression of cyclooxygenase-2 (COX-2) and elevation of its derivative prostaglandin E2 (PGE2) are implicated in human esophageal squamous cell carcinoma. The expression of c-Myc, an oncogenic transcription factor, is also upregulated in this malignant disease. This study sought to elucidate whether a functional connection exists between COX-2/PGE2 and c-Myc in esophageal squamous cell carcinoma. Results showed that PGE2 substantially increased the proliferation of cultured esophageal squamous cell carcinoma cells. In this regard, PGE2 substantially increased the mRNA and protein expression of c-Myc and its association with the binding partner Max. Knockdown of c-Myc by RNA interference also significantly attenuated PGE2 -induced cell proliferation. Further, mechanistic study revealed that PGE2 increased the protein stability and nuclear accumulation of c-Myc via phosphorylation on serine 62 in an extracellular signal regulated kinase (ERK)-dependent manner. To this end, ERK activation by PGE2 was completely abolished by protein kinase C (PKC) inhibitors. Moreover, the effect of PGE2 on c-Myc expression was mimicked by EP2 receptor agonist. In addition, knockdown of EP2 receptor by EP2 siRNA attenuated PGE2 -induced c-Myc expression. Collectively, our findings suggest that PGE2 upregulates c-Myc via the EP2/PKC/ERK pathway. This study sheds new light on the carcinogenic mechanism of PGE2 in esophageal squamous cell carcinoma. © 2009 UICC [source] Transglutaminase 3 as a prognostic biomarker in esophageal cancer revealed by proteomicsINTERNATIONAL JOURNAL OF CANCER, Issue 9 2009Norihisa Uemura Abstract To develop a prognostic biomarker for esophageal squamous cell carcinoma (ESCC), we examined the proteomic profile of ESCC using two-dimensional difference gel electrophoresis (2D-DIGE), and identified proteins associated with prognosis by mass spectrometry. The prognostic performance of the identified proteins was examined by immunohistochemistry in additional cases. We identified 22 protein spots whose intensity was statistically different between ESCC cases with good (N = 9; survived more than 5 years without evidence of recurrence) and poor (N = 24; died within 2 years postsurgery) prognosis, within the patient group that had two or more lymph node metastases. Mass spectrometric protein identification resulted in 18 distinct gene products from the 22 protein spots. Transglutaminase 3 (TGM3) was inversely correlated with shorter patient survival. The prognostic performance of TGM3 was further examined by immunohistochemistry in 76 ESCC cases. The 5-year disease-specific survival rate was 64.5% and 32.1% for patients with TGM3-positive and TGM3-negative tumors, respectively (p = 0.0033). Univariate and multivariate analyses revealed that TGM3 expression was an independent prognostic factor among the clinicopathologic variables examined. It is noteworthy that the prognostic value of TGM3 was shown to be higher than those of the lymph node metastasis, intramural metastasis and vascular invasion status. These results establish TGM3 as a novel prognostic biomarker for ESCC for the first time. Examination of TGM3 expression may provide novel therapeutic strategies to prevent recurrence of ESCC. © 2008 Wiley-Liss, Inc. [source] Promoter hypermethylation of CDH13 is a common, early event in human esophageal adenocarcinogenesis and correlates with clinical risk factorsINTERNATIONAL JOURNAL OF CANCER, Issue 10 2008Zhe Jin Abstract Although the CDH13 gene has been shown to undergo epigenetic silencing by promoter methylation in many types of tumors, hypermethylation of this gene in Barrett's-associated esophageal adenocarcinogenesis has not been studied. Two hundred fifty-nine human esophageal tissues were therefore examined for CDH13 promoter hypermethylation by real-time methylation-specific PCR. CDH13 hypermethylation showed discriminative receiver-operator characteristic curve profiles, sharply demarcating esophageal adenocarcinoma (EAC) from esophageal squamous cell carcinoma (ESCC) and normal esophagus (NE) (p < 0.0001). CDH13 normalized methylation values (NMV) were significantly higher in Barrett's esophagus (BE), dysplastic BE (D) and EAC than in NE (p < 0.0000001). CDH13 hypermethylation frequency was 0% in NE but increased early during neoplastic progression, rising to 70% in BE, 77.5% in D and 76.1% in EAC. Both CDH13 hypermethylation frequency and its mean NMV were significantly higher in BE with than without accompanying EAC. In contrast, only 5 (19.2%) of 26 ESCCs exhibited CDH13 hypermethylation. Furthermore, both CDH13 hypermethylation frequency and its mean NMV were significantly higher in EAC than in ESCC, as well as in BE or D vs. ESCC. Interestingly, mean CDH13 NMV was significantly lower in short-segment than in long-segment BE, a known clinical risk factor for neoplastic progression. Similarly, BE segment length was significantly lower in specimens with unmethylated than with methylated CDH13 promoters. 5-aza-2,-deoxycytidine treatment of OE33 EAC and KYSE220 ESCC cells reduced CDH13 methylation and increased CDH13 mRNA expression. These findings suggest that hypermethylation of CDH13 is a common, tissue-specific event in human EAC, occurs early during BE-associated neoplastic progression, and correlates with known clinical neoplastic progression risk factors. © 2008 Wiley-Liss, Inc. [source] Carcinogenetic impact of ADH1B and ALDH2 genes on squamous cell carcinoma risk of the esophagus with regard to the consumption of alcohol, tobacco and betel quidINTERNATIONAL JOURNAL OF CANCER, Issue 6 2008Chien-Hung Lee Abstract The consumption of alcohol, tobacco and betel quid has been found to be an important contributor to esophageal squamous cell carcinoma (ESCC) in Taiwan. The genotoxic effect of the ADH1B and ALDH2 genes modulating an individual's alcohol-metabolizing capacity on ESCC may be linked to drinking behavior, intake pattern and other exogenous factors. To investigate the interplay of these genetic and environmental factors in determining the risk of ESCC, a multicenter case-control study was conducted. Here, 406 patients with pathology-proven ESCC, as well as 656 gender, age and study hospital matched controls were recruited. Genetic polymorphisms of ADH1B and ALDH2 appeared to correlate with the abstinence of alcohol, though not with tobacco and betel quid. Within the same levels of alcohol consumption, carcinoma risks increased along with an increase in the numbers of ADH1B*1 and ALDH2*2 alleles. The inactive ALDH2*1/*2 genotype was found to multiplicatively interact with a low-to-moderate (0.1,30 g/day) and a heavy (>30 g/day) ethanol intake to increase the ESCC risk (the joint aOR = 14.5 and 102.6, respectively). Among low-to-moderate drinkers, a smoking-dependent carcinogenetic effect for the ADH1B*1/*1 and ALDH2*1/*2+*2/*2 genotypes was recognized, with significant risks found in smokers, but not in nonsmokers. Further, a supra-multiplicative combined risk of ESCC for alcohol and tobacco use was identified among carriers of the ADH1B*1/*1 genotype (p for interaction = 0.042). In conclusion, the interplay of the ADH1B and ALDH2 genotypes, in conjunction with a behaved drinking habit and a practiced drinking pattern, along with continued tobacco consumption, plays an important pathogenic role in modulating ESCC risk. © 2007 Wiley-Liss, Inc. [source] Frequent decreased expression of candidate tumor suppressor gene, DEC1, and its anchorage-independent growth properties and impact on global gene expression in esophageal carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 3 2008Alfred Chi Chung Leung Abstract Previous studies showed that expression of the novel candidate tumor suppressor gene, DEC1 (Deleted in Esophageal Cancer 1), is reduced in esophageal carcinoma and suppresses cancer cell growth in vitro and tumor growth in vivo in nude mice. This study shows that DEC1 gene expression was downregulated in 100% of 16 esophageal squamous cell carcinoma (ESCC) cell lines and 52 and 45%, respectively, of esophageal tumor specimens from Hong Kong and a high-risk ESCC region of Henan, China. Using epitope tagging, the DEC1 protein was localized to both the cytoplasm and nucleus of the cell. In 3D Matrigel culture, no significant difference in colony numbers formed was observed for DEC1 stable transfectants, as compared to vector-alone transfectant controls. However, significantly smaller colony sizes were observed for the DEC1 transfectants. In in vitro cell migration, invasion and soft agar assays of DEC1 transfectants, only the soft agar assay showed statistically significant differences in colony numbers with the vector-alone controls, indicating that DEC1 may be involved in anchorage-independent cell growth. In addition, the global gene expression affected by DEC1 in tumor-suppressive stable transfectants was investigated using cDNA oligonucleotide microarray hybridization. Three candidate genes, TFPI-2, GDF15 and DUSP6, were identified through this approach; they are downregulated in tumor segregants of DEC1 stable transfectants, ESCC cell lines and esophageal tumors and have a potential role in tumor growth and progression. These studies show that DEC1 is involved in esophageal cancer development and help elucidate its functional role in tumor development. © 2007 Wiley-Liss, Inc. [source] Survivin in esophageal cancer: An accurate prognostic marker for squamous cell carcinoma but not adenocarcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 7 2006Antonio Rosato Abstract We quantified the expression of survivin, both as mRNA in real-time PCR and protein in immunohistochemistry, in tumor samples of 112 patients with esophageal cancer (56 squamous cell carcinomas and 56 adenocarcinomas). Overall survival of squamous cell carcinoma patients with high survivin mRNA levels was significantly less than that of patients with low survivin mRNA levels (p = 0.0033). Distribution pattern of survivin (nuclear vs. cytoplasmic or mixed) was not correlated to survival, while the extent of immunostaining was significantly correlated to survivin mRNA values (p = 0.016) and had prognostic relevance in univariate analysis (p = 0.0012). Cox's proportional-hazard regression model showed that tumor survivin expression in esophageal squamous cell carcinoma was the most important prognostic factor, independent of tumor stage and other histopathological factors, both as mRNA relative value (p = 0.0259) and protein immunostaining (p = 0.0147). In esophageal adenocarcinoma, survivin expression and pattern of distribution had no prognostic relevance. Thus, quantifying survivin expression provides a prognostic marker only for esophageal squamous tumors. © 2006 Wiley-Liss, Inc. [source] Nicotine induces the fragile histidine triad methylation in human esophageal squamous epithelial cellsINTERNATIONAL JOURNAL OF CANCER, Issue 5 2006Toshiya Soma Abstract The fragile histidine triad (FHIT) gene has been proposed to have an important role in very early carcinogenesis. Methylation of the FHIT gene is associated with transcriptional inactivation in esophageal squamous cell carcinoma, and FHIT inactivation has been linked to smoking-related carcinogenesis. In this study, we confirmed methylation of the FHIT gene in human esophageal squamous epithelial cells (HEECs) and examined whether nicotine induced alteration of FHIT. Methylation status in the promoter region of the FHIT gene and p16INK4A gene was determined by methylation-specific PCR in HEECs exposed to nicotine under various conditions. Methylation status of the FHIT gene was confirmed by DNA-sequencing analysis. Protein expression of Fhit and the DNA methyltransferases (DNMTs) DNMT1 and DNMT3a were assessed by immunoblot analysis. In the absence of nicotine, methylation of the FHIT gene and attenuation of Fhit protein were not detected in HEECs. Nicotine induced the methylation of FHIT gene and attenuated Fhit protein in association with increased expression of DNMT3a. Reexpression of Fhit protein in HEECs was found after cessation of moderate- to long-term exposure to nicotine. Our results show that nicotine induces methylation of the FHIT gene followed by loss of Fhit protein expression in HEECs. Continuous smoking may thus increase the risk of esophageal cancer. © 2006 Wiley-Liss, Inc. [source] Targeting the epidermal growth factor receptor by erlotinib (TarcevaÔ) for the treatment of esophageal cancerINTERNATIONAL JOURNAL OF CANCER, Issue 7 2006Andreas P. Sutter Abstract Esophageal cancer is the sixth most common cause of cancer-related death worldwide. Because of very poor 5-year survival new therapeutic approaches are mandatory. Erlotinib (TarcevaÔ), an inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK), potently suppresses the growth of various tumors but its effect on esophageal carcinoma, known to express EGFR, remains unexplored. We therefore studied the antineoplastic potency of erlotinib in human esophageal cancer cells. Erlotinib induced growth inhibition of the human esophageal squamous cell carcinoma (ESCC) cell lines Kyse-30, Kyse-70 and Kyse-140, and the esophageal adenocarcinoma cell line OE-33, as well as of primary cell cultures of human esophageal cancers. Combining erlotinib with the EGFR-receptor antibody cetuximab, the insulin-like growth factor receptor tyrosine kinase inhibitor tyrphostin AG1024, or the 3-hydroxy-3-methylglutaryl coenzyme. A reductase (HMG-CoAR) inhibitor fluvastatin resulted in additive or even synergistic antiproliferative effects. Erlotinib induced cell cycle arrest at the G1/S checkpoint. The erlotinib-mediated signaling involved the inactivation of EGFR-TK and ERK1/2, the upregulation of the cyclin-dependent kinase inhibitors p21Waf1/CIP1 and p27Kip1, and the downregulation of the cell cycle promoter cyclin D1. However, erlotinib did not induce immediate cytotoxicity or apoptosis in esophageal cancer cells. The inhibition of EGFR-TK by erlotinib appears to be a promising novel approach for innovative treatment strategies of esophageal cancer, as it powerfully induced growth inhibition and cell cycle arrest in human esophageal cancer cells and enhanced the antineoplastic effects of other targeted agents. © 2005 Wiley-Liss, Inc. [source] Serological identification of TROP2 by recombinant cDNA expression cloning using sera of patients with esophageal squamous cell carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 6 2004Kazue Nakashima Abstract We applied serological analysis of recombinant cDNA expression libraries (SEREX) to cases of esophageal squamous cell carcinoma (SCC) to identify tumor antigens. One of the clones identified was TROP2, which is known as calcium signal transducer. To evaluate the clinical significance of serum anti-TROP2 antibodies (s-TROP2-Abs) in patients with esophageal SCC, the presence of s-TROP2-Abs was analyzed by Western blotting using bacterially expressed TROP2 protein. We found that 23 of 75 (31%) patients were positive for s-TROP2-Abs. Positivity in terms of s-TROP2-Abs showed a significant association with tumor size but not with other clinicopathological features. The protein expression levels of TROP2 were much higher in esophageal SCC cell lines as compared to those in normal esophageal mucosa and its immortalized cells although the mRNA expression levels were not necessarily elevated in malignant cell lines and tissues. Immunohistochemical studies showed that the expression of TROP2 protein in esophageal SCC specimens was noticeably higher than that found in mild hyperplasia of esophageal mucosae. Thus, s-TROP2-Abs seemed useful in the diagnosis of SCC and may be a candidate for serum tumor markers. © 2004 Wiley-Liss, Inc. [source] Common single nucleotide polymorphism of hypoxia-inducible factor-1, and its impact on the clinicopathological features of esophageal squamous cell carcinomaJOURNAL OF DIGESTIVE DISEASES, Issue 4 2005Ting Sheng LING OBJECTIVE: Angiogenesis is one of the most important molecular events in solid tumor development and growth, in which hypoxia-inducible factor (HIF)-1, is a key regulator and plays an important role. Studies have shown that a single nucleotide polymorphism (C1772T) in the HIF-1, gene exerts a large effect on the phenotype of human head and neck squamous cell carcinoma and renal cell carcinoma. But the impact of the C1772T polymorphism on the clinicopathological features of human esophageal squamous cell carcinoma (ESCC) remains unknown, and thus it is the main focus of our study. METHODS: The C1772T genotype of 95 ESCC patients and 104 healthy controls were studied by using the polymerase chain reaction and restriction fragment length polymorphism. Mutations were confirmed by direct DNA sequencing. The impact of C1772T on tumor size, invasive depth, lymph node metastasis, distant metastasis, histological grade and TNM stage was also studied. RESULTS: The genotype frequency observed in the patients and controls was 11.58% versus 10.58%, respectively, for genotype C/T (P > 0.05). Genotype T/T was not found in our study. Larger tumors and a higher rate of lymph node metastasis was found for the C/T group. CONCLUSIONS: Although there is no significant difference of genotype distribution between ESCC patients and healthy controls, genotype C/T is associated with larger tumor and higher rate of lymph node metastasis. [source] | ||||||||||||||||||||||||||||