Clinical significance of mucin staining in keratinizing-type squamous cell carcinoma of the uterine cervix

Tumor tissue from 57 cases of keratinizing-type squamous cell carcinoma of the uterine cervix that had been stored in the archives of Osaka City University Hospital between May 1986 and October 1994 were stained with periodic acid-Schiff (PAS) reagent following amylase and alcian blue to identify the presence of intracellular mucin and to assess the value and significance of demonstrating the presence of mucin. Nineteen specimens (33.3%) stained positive for mucin with alcian blue or PAS following diastase. The results of mucin staining were not significant in terms of survival by Kaplan-Meier's analysis.     

Angiogenesis in ovarian clear cell carcinoma and its relation to endometriosis

Twenty-five patients with ovarian clear cell carcinoma (CC-Ca) were enrolled in this study, and tumor cell expression of vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) was investigated, and correlated with the microvessel count (MVC) and the impact of complication endometriosis. Expression of VEGF was strongly positive in 16 cases, weakly positive in 6 cases, and negative in 3 cases. Expression of PD-ECGF was strongly positive in 11 cases, weakly positive in 6 cases, and negative in 8 cases. VEGF expression and the MVC were significantly correlated (p<0.01), and there were no correlations among complication by endometriosis, expression of VEGF, expression of PD-ECGF, and MVC.     

Pd-ECGF positivity correlates with better survival,while iNOS has no predictive value for cervical carcinomas treated with radiotherapy

PURPOSE: Platelet-derived endothelial cell growth factor (PD-ECGF), which has angiogenic activity, is identical to thymidine phosphorylase. Tumor vascularization is considered to be an important prognostic factor. Nitric oxide synthases (NOSs) are a kind of enzyme that generates nitric oxide. Nitric oxide has not only a self defense against neoplastic cells but also tumor growth stimulation by promoting new blood vessel formation. Our purpose was to investigate the correlation between the expression of PD-ECGF or inducible NOS (iNOS) in cancer cells and prognosis. METHODS AND MATERIALS: Formaldehyde-fixed and paraffin-embedded biopsy specimens excised from 71 cervical squamous cell carcinoma patients who were treated with radiotherapy alone were investigated using an immunohistochemical method. RESULTS: Cancer cells that were positive for PD-ECGF showed intranuclear and cytoplasmic staining patterns. Of the 71 patients, 40 (56%) were positive for PD-ECGF and 31 (44%) were negative. The 5-year survival of the PD-ECGF-positive patients was significantly better than that of the PD-ECGF-negative patients (p = 0.026). Cancer cells that were positive for iNOS showed a cytoplasmic staining pattern. Twenty-seven patients (38%) were positive for iNOS and 44 (62%) were negative. No significant prognostic correlation was observed between iNOS-positive and iNOS-negative patients. CONCLUSION: PD-ECGF positivity in cancer cells is a predictive factor for a good prognosis in cervical squamous cell carcinoma treated with radiotherapy alone.     

Expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in cervical intraepithelial neoplasia

Angiogenesis contributes to the growth and secondary spreading of solid tumors. Platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase (TP) has been identified as such an angiogenic factor. In this study, the expression of PD-ECGF/TP and VEGF was evaluated by immunohistochemical staining of tumor specimens from 40 patients with cervical intraepithelial neoplasia (10 with moderate dysplasia; 10 with severe dysplasia; 10 with carcinoma in situ; 10 with invasive carcinoma). The microvessel density was assessed by immunostaining for factor VIII-related antigen in the most highly neovascularized area. In both the nucleus and cytoplasm, the intensity of PD-ECGF/TP expression in carcinoma in situ and invasive carcinoma was significantly stronger than that in moderate dysplasia. However, the intensity of VEGF expression was not significantly different in the various specimens. The microvessel density in mild dysplasia was significantly different from that in carcinoma in situ (p<0.05), and that in invasive carcinoma (p<0.05). There was no significant relationship between the microvessel density and the expression of PD-ECGF/TP or that of VEGF. These results show that the expression of PD-ECGF/TP appears to be involved in the promotion of angiogenesis in cervical intraepithelial neoplasia.     

TGF-alpha as well as VEGF, PD-ECGF and bFGF contribute to angiogenesis of esophageal squamous cell carcinoma

It has been demonstrated that vascular endothelial growth factor (VEGF) is associated with tumor progression as an angiogenic factor in esophageal squamous cell carcinoma (SCC)s. However, the role of other angiogenic factors such as transforming growth factor-alpha (TGF-alpha), platelet-derived endothelial cell growth factor (PD-ECGF), and basic fibroblast growth factor (bFGF) are still unknown in esophageal SCCs. In this study, we detected the expression of VEGF, TGF-alpha, PD-ECGF and bFGF in tissue specimens from 96 patients with SCC of the esophagus by immunohistochemical staining. To evaluate angiogenesis, endothelial cells were stained immunohistochemically and microvessel density (MVD) was counted in 24 cases. The positive rates for VEGF, TGF-alpha, PD-ECGF and bFGF were 65% (62/96), 67% (64/96), 66% (63/96), and 49% (47/96), respectively. Only TGF-alpha expression had a strong correlation with the average MVD (p=0.0059). However, the MVD increased as the number of positive factors for these 4 factors increased (p=0.0023). The expression of all of these factors significantly correlated to the depth of tumor invasion, and lymph node metastasis. Finally, survival analysis of the patients revealed that VEGF, TGF-alpha, and PD-ECGF were significant prognostic factors. However, multivariate analysis revealed that these factors were not prognostic. Thus, we suggest that TGF-alpha as well as VEGF, PD-ECGF and bFGF may be associated with angiogenesis, and the progression and metastasis of esophageal squamous cell carcinoma.     

Increased expression of platelet-derived endothelial cell growth factor in human hepatocellular carcinomas correlated with high Edmondson grades and portal vein tumor thrombosis.

Platelet-derived endothelial cell growth factor (PD-ECGF), identical to thymidine phosphorylase, has been reported as an angiogenic factor in human malignancies. However, the role of PD-ECGF in human hepatocellular carcinoma (HCC) is still unconfirmed. Herein, we studied the expression of PD-ECGF in 27 human HCC cases by immunohistochemistry, to clarify the relationship to tumor angiogenesis. The immunoreaction of PD-ECGF in HCC cells was scored in both the staining percentage and intensity. CD34, an endothelial cell marker, was used to evaluate the intratumoral microvessel density (IMVD). PD-ECGF expression was noted in carcinoma cells in 14 (51.9%) of 27 HCCs. In these cases, the carcinoma cells showed heterogeneous staining in both the nucleus and cytoplasm. Tumor-associated stroma cells and infiltrating lymphocytes were also stained. Kupffer cells in non-tumor areas were strongly positive. Statistically, the expression of PD-ECGF increased in HCC specimens with high Edmondson grades (III-IV) or portal vein tumor thrombosis (PVTT) (P<0.05). Additionally, the IMVD of PD-ECGF-positive HCC specimens (136.071+/-31.008, mean +/- SD) was higher than that of the PD-ECGF-negative HCC specimens (61.077+/-15.795) (P<0.05). These findings may suggest that PD-ECGF is one of the angiogenic factors in human HCCs. Furthermore, with the increasing expression of PD-ECGF, HCC cells show poor differentiation and invasive behavior.     

Expression of PTEN in the progression of cervical neoplasia and its relation to tumor behavior and angiogenesis in invasive squamous cell carcinoma

BACKGROUND AND OBJECTIVES: Loss of PTEN expression has been associated with tumor progression and adverse patient outcome. The purpose of this study was to evaluate PTEN expression in the successive steps of progression in cervical neoplasia and to determine its correlation with tumor angiogenesis and clinicopathologic features in squamous cell carcinoma of the uterine cervix. METHODS: Immunohistochemical staining with anti-PTEN antibody was performed in a total of 160 patients with 12 normal cervical epithelium, 63 cervical intraepithelial neoplasia (33 CIN I, 30 CIN III), and 85 cervical squamous cell carcinomas. Microvessels were immunohistochemically labeled with an antibody for CD34. Computerized image analysis was used to evaluate microvessel density (MVD). RESULTS: Reduced PTEN expression progressively increased along the continuum from normal epithelium to squamous cell carcinoma (P < 0.01). There was no significant correlation between PTEN expression and MVD. On univariate analysis, stage and reduced PTEN expression were significant prognostic factors for both disease-free and overall survival. However, stage was the only independent prognostic factor by multivariate analysis. CONCLUSIONS: Our results suggest that tumor progression in the cervical epithelium is accompanied by loss of PTEN protein expression. Reduced PTEN expression is not associated with tumor angiogenesis of squamous cell carcinoma of the uterine cervix.     

Expression of platelet-derived endothelial cell growth factor correlates with good prognosis in patients with colorectal carcinoma

BACKGROUND: Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic factor that has potent chemotactic activity for endothelial cells. Although it is expressed in the majority of colorectal tumors, and some reports suggest that its high expression is related to poor prognosis, to the authors' knowledge there is yet no consensus regarding whether PD-ECGF expression is a prognostic factor. To investigate the prognostic value of PD-ECGF and its role in tumor angiogenesis, an immunohistochemical study of PD-ECGF expression and tumor vasculature was performed and their relation with the clinicopathologic factors in patients with advanced colorectal carcinoma was evaluated. METHODS: Formalin fixed, paraffin embedded specimens from 86 colorectal carcinoma patients (40 cases in the muscularis propria and 46 cases in the subserosa) were immunostained for PD-ECGF and CD31 as a marker for vascular endothelial cells and expression of PD-ECGF was evaluated using an image analysis system. Patients were divided into high expression and low expression groups based on PD-ECGF expression, and were divided into high vascular grade and low vascular grade groups based on the microvessel density. Correlations between PD-ECGF expression and vascular grade and between PD-ECGF expression,vascular grade, and the clinicopathologic features of the patients were evaluated statistically. RESULTS: PD-ECGF expression was observed predominantly in the tumor stroma and not in tumor cells. The cells that stained strongly for PD-ECGF were confirmed to be macrophages infiltrating the interstitial tissue of the tumor. High PD-ECGF expression was found in 56 cases (65.1%) and low expression was detected in 30 cases (34.9%). Thirty-one of 86 tumors (36.0%) showed high vascular grade and 55 (64.0%) showed low vascular grade. No correlation between PD-ECGF expression and vascular grade was found, but there was an inverse correlation between PD-ECGF expression and the rate of incidence of lymph node and hematogenous metastasis. These correlations were statistically significant. Vascular grade was not found to correlate with the clinicopathologic features. CONCLUSIONS: Patients with high PD-ECGF expression had a lower rate of incidence of lymphatic and hematogenous metastasis, with a consequently better prognosis than patients with low PD-ECGF expression. PD-ECGF expression did not correlate with vascular grade, suggesting that PD-ECGF plays little role in tumor angiogenesis of colorectal carcinoma. Based on these data, the authors conclude that macrophages infiltrating the tumor stroma produce PD-ECGF and play important roles in the immune reaction against the tumor rather than in tumor angiogenesis.     

TP/PD-ECGF表达与血小板增多在胃癌中的意义

目的:研究血小板衍化内皮细胞生长因子(TP/PD-ECGF)在胃癌中的表达及血小板增多情况,并对其与胃癌患者临床病理特征和预后的关系进行探讨。方法:采用免疫组化EnVision两步法检测107例胃癌组织中TP/PD-ECGF的表达,记录血小板增多情况,并分析二者与胃癌患者临床病理特征及预后的关系。结果:胃癌患者中TP/PD-ECGF阳性表达率为71.0%,与血小板增多呈正相关(P<0.01)。TP/PD-ECGF表达、血小板增多与肿瘤分期、淋巴结转移、远处转移及分化程度呈正相关。TP/PD-ECGF阳性与阴性表达患者3年、5年总生存率分别为69.04%、18.12%和88.87%、75.20%,二者差异有统计学意义(P=0.0383);3年、5年无进展生存率分别为64.87%、17.92%和82.73%、35.00%,二者差异有统计学意义(P=0.0350)。Cox比例风险模型多因素分析显示,肿瘤分期、淋巴结转移、远处转移、TP/PD-ECGF及血小板增多均是影响胃癌预后独立的危险因素。结论:TP/PD-ECGF表达与血小板增多呈正相关,二者与胃癌生长和浸润转移关系密切,可作为胃癌独立的预后因素。     

Expression of platelet-derived endothelial cell growth factor (PD-ECGF) and its mRNA in uterine cervical cancers

Angiogenesis contributes to the growth and secondary spreading of solid tumours. Platelet-derived endothelial cell growth factor (PD-ECGF) is identified as such an angiogenic factor. In the present study, the prognosis of the patients with high PD-ECGF uterine cervical cancers was worse than those with low PD-ECGF cancers, and PD-ECGF expression correlated with cellular proliferation and with vascular density and venous invasion in uterine cervical cancers. Therefore, PD-ECGF might contribute to the growth of uterine cervical cancers via angiogenesis related to vascular spreading. Furthermore, PD-ECGF and its mRNA had a wide range and were highly expressed in uterine cervical cancers, especially squamous cell carcinoma, regardless of clinical stage. Therefore, PD-ECGF in uterine cervical cancers might play a role of basic angiogenesis in all processes of advancing of uterine cervical cancers. This indicates that 5'-deoxy-5-fluorouridine might be highly effective in squamous cell carcinoma of the cervix, which possesses a high activity of thymidine phosphorylase to convert 5'-deoxy-5-fluorouridine to 5-fluorouracil, and that some angiogenic inhibitors of new capillary formation might be effective in the inhibition of tumour growth and spreading associated with angiogenesis.     

The value of platelet-derived endothelial cell growth factor as a novel predictor of advancement of uterine cervical cancers

Serum platelet-derived endothelial cell growth factor (PD-ECGF) in patients with uterine cervical cancers revealed a significantly positive correlation with clinical stage and tumor size and with the advancement indicators lymph node metastasis, parametrial involvement, and vessel permeation in both squamous cell carcinomas and adenocarcinomas. The prognosis of the patients with high serum PD-ECGF was extremely poor, whereas the 36-month survival rate of the other patients with low serum PD-ECGF was 81.3% in squamous cell carcinomas and 80.0% in adenocarcinomas. Our data indicate that serum PD-ECGF levels reflect the status of advancement of uterine cervical cancers and thus may be recognized as a novel tumor marker for both squamous cell carcinomas and adenocarcinomas of the uterine cervix.     

IL-10 expression is associated with the expression of platelet-derived endothelial cell growth factor and prognosis in oral and oropharyngeal carcinoma

We investigated the expression of IL-10 in oral and oropharyngeal squamous cell carcinoma (SCC) specimens by an immunohistochemical technique. Of 58 SCC, 13 (22%) and 35 (60%) cases showed intense and moderate positive staining of IL-10, respectively. There was no association between the staining of IL-10 and clinicopathological features. However, the patients with intense staining of IL-10 had a significantly lower overall survival rate than those with moderate or negative staining of IL-10 (P = 0.019). In addition, the patients with intense staining of IL-10 had the highest score of platelet-derived endothelial cell growth factor (PD-ECGF), which is established as a poor prognostic indicator (P = 0.0105). These results suggested that IL-10 contributes to the clinical outcome of oral and oropharyngeal SCC.     

Prognostic value of TP/PD-ECGF and thrombocytosis in gastric carcinoma

Aim

Thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) is upregulated in several cancers and plays an important role in angiogenesis and invasion of solid tumors. In this study, we investigated the expression of TP/PD-ECGF in gastric carcinoma and its correlation with clinicopathological features and thrombocytosis, and also determined their prognostic significance.

Methods

Ninety-eight tissue specimens were resected from patients with gastric carcinoma. The immunohistochemical staining was used for expression of TP/PD-ECGF, platelet counts (PLT) of all patients before surgery were recorded. Patients were divided into high and low TP/PD-ECGF expression groups. Correlations among TP/PD-ECGF expression, PLT and the clinicopathological features of the patients and their prognostic values were studied statistically.

Results

Sixty-one cases of high TP/PD-ECGF expression (62%) and 37 cases of low TP/PD-ECGF expression (38%) were detected. There were 21 patients with thrombocytosis (21%). The results show that high TP/PD-ECGF expression was correlated positively with thrombocytosis (P = 0.046, r = 0.20). The 5-year overall survival rate was 46.0% in patients with low TP/PD-ECGF expression, whereas it was only 14.8% in patients with high TP/PD-ECGF expression (P = 0.000). The 5-year survival rate for patients with and without thrombocytosis were 9.5% and 31.2%, respectively, and there was a significant difference between them (P = 0.0001). The multivariate Cox regression analysis showed that high TP/PD-ECGF expression and thrombocytosis would play a role as independent prognostic factors in patients with gastric carcinoma.

Conclusions

High TP/PD-ECGF expression and thrombocytosis can be regarded as valuable tools for predicting overall survival in patients with gastric carcinoma.     

Angiogenesis and platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in cervical cancer.

The object of this study was to clarify the association of platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase (dThdPase), separately assessed in cancer cells and in stroma cells, with clinicopathological factors including tumor angiogenesis and prognosis in cervical cancer. The expression of PD-ECGF was evaluated by immunohistochemical staining in 92 patients with stage Ib-II cervical cancer. The microvessel count was assessed by immunostaining for factor VIII-related antigen in the most neovascularized area. Microvessel count was significantly higher in tumors with non-squamous cell carcinoma. PD-ECGF expression in cancer cells was significantly higher in tumors with pelvic node metastasis and squamous cell carcinoma. Immunopositivity for PD-ECGF in stroma cells was significantly higher in tumors with large size and deep stromal invasion. The microvessel counts in cases with positive PD-ECGF expression in stroma cells were significantly higher than those in cases with negative PD-ECGF expression in stroma cells (p=0.048). Disease-free survival and overall survival were significantly worse in patients with deep stromal invasion, parametrial involvement, vaginal involvement, lymph-vascular space involvement, pelvic lymph node metastasis and high microvessel count. A multivariate analysis using Cox's proportional hazard model showed that high microvessel count independently predicted disease-free and overall survival. The expression of PD-ECGF in stroma cells may play a crucial role in the promotion of angiogenesis and tumor angiogenesis can be used as a useful prognostic marker for cervical cancer.     

TP/PD-ECGF表达与血小板增多在胃癌中的意义

目的：研究血小板衍化内皮细胞生长因子（TP/PD-ECGF）在胃癌中的表达及血小板增多情况,并对其与胃癌患者临床病理特征和预后的关系进行探讨。方法：采用免疫组化EnVision两步法检测107例胃癌组织中TP/PD-ECGF的表达,记录血小板增多情况,并分析二者与胃癌患者临床病理特征及预后的关系。结果：胃癌患者中TP/PD-ECGF阳性表达率为71.0%,与血小板增多呈正相关（P〈0.01）。TP/PD-ECGF表达、血小板增多与肿瘤分期、淋巴结转移、远处转移及分化程度呈正相关。TP/PD-ECGF阳性与阴性表达患者3年、5年总生存率分别为69.04%、18.12%和88.87%、75.20%,二者差异有统计学意义（P=0.0383）;3年、5年无进展生存率分别为64.87%、17.92%和82.73%、35.00%,二者差异有统计学意义（P=0.0350）。Cox比例风险模型多因素分析显示,肿瘤分期、淋巴结转移、远处转移、TP/PD-ECGF及血小板增多均是影响胃癌预后独立的危险因素。结论：TP/PD-ECGF表达与血小板增多呈正相关,二者与胃癌生长和浸润转移关系密切,可作为胃癌独立的预后因素。     

Reduced expression of thrombospondin-1 correlates with a poor prognosis in patients with non-small cell lung cancer

Thorombospondin-1 (TSP-1) is a 450 kDa extracellular matrix glycoprotein, with anti-angiogenic activity. We analyzed the relationship in TSP-1 expression and Microvessel count (MVC), and also clinical factors, using immunohistochemical methods for non-small cell cancer (NSCLC). Histopathologically, there was inverse correlation between TSP-1 expression and MVC for squamous cell carcinoma, but not for adenocarcinoma cases. Among 199 completely resected cases of NSCLC, the 5-year survival was 77.0% when the expression of TSP-1 was maintained and 55.1% when the expression were reduced, respectively (P=0.0046). When compared with TSP-1 expression in the high MVC subgroup, there was significantly shorter survival time when TSP-1 expression was reduced (P=0.0091), and no significant difference was seen for the low MVC subgroup. Multivariate analysis revealed that expression of TSP-1 is as a prognostic factor of NSCLC. Our present data suggest that TSP-1 might not be a direct anti-angiogenic factor and the TSP-1 expression is a prognostic indicator of NSCLC.     

Coexpression of cyclooxygenase-2 and thymidine phosphorylase as a prognostic indicator in patients with FIGO stage IIB squamous cell carcinoma of uterine cervix treated with radiotherapy and concurrent chemotherapy

PURPOSE: To evaluate the prognostic significance of thymidine phosphorylase (TP) and coexpression of cyclooxygenase-2 (COX-2)/TP, and to investigate the relationship between COX-2 and TP expression in squamous cell carcinoma of the uterine cervix. METHODS AND MATERIALS: Cancer specimens from 75 patients with International Federation of Gynecology and Obstetrics Stage IIB squamous cell carcinoma of the uterine cervix who had undergone radiotherapy and concurrent chemotherapy were immunohistochemically stained with COX-2 and TP antibodies and scored. The prognostic significance of their expression status, and the relationship between COX-2 and TP was investigated. RESULTS: TP predominantly stained cytoplasm and the cell membrane of the tumor cells mainly in a diffuse and intense manner. TP was negative (<10% distribution) in 17%, 1+ (10-50%) in 25%, and 2+ (>50%) in 57% of patients. TP overexpression was related to a marginal prognostic significance of a poor 5-year overall survival (p = 0.082, log-rank test) and a high locoregional recurrence rate (p < 0.1, chi-square test). COX-2 and TP coexpression was observed in 24% of patients and was significantly related to poor 5-year disease-free and overall survival rates (p = 0.0083 and p = 0.025, respectively), a high pelvic lymph node involvement rate, a poor response to treatment, and a greater incidence of locoregional recurrence (p < 0.05). By multivariate analyses, only COX-2, TP, and coexpression of COX-2/TP were significant independent prognostic indicators of patient survival. All tumors showed 1+ or 2+ TP expression when COX-2 was positive, and no tumor expressed COX-2 when TP was negative (p = 0.03). In contrast, 77% of tumors expressed 1+ or 2+ TP without the synchronous expression of COX-2. CONCLUSIONS: Thymidine phosphorylase expression or COX-2/TP coexpression may be used as a molecular prognostic marker for squamous cell carcinoma of the uterine cervix. TP appears to be an important downstream molecule of COX-2 during angiogenesis and may be a new target for the treatment of uterine cervical cancer.     

Expression of basic fibroblast growth factor is associated with a good outcome in patients with squamous cell carcinoma of the esophagus

Angiogenesis is an essential step in tumor growth and metastasis, but rather than being controlled by means of a simple mechanism, the control of tumor angiogenesis may be mediated by several angiogenic factors. We investigated the expression of basic fibroblast growth factor (b-FGF) and platelet-derived endothelial cell growth factor (PD-ECGF) in squamous cell carcinoma of the esophagus in order to clarify the mechanism of angiogenesis. Expression of b-FGF and PD-ECGF was immunohistochemically investigated in tissue specimens from the tumors of 79 patients with squamous cell carcinoma of the esophagus who underwent curative esophagectomy without preoperative chemotherapy or radiation therapy, and the relationship between expression of b-FGF/PD-ECGF, microvessel density (MVD), and clinicopathological background factors was assessed. Tumor cells that expressed b-FGF were found in 41 patients (51.9%), and tumor cells that expressed PD-ECGF were found in 57 patients (72.2%). Although the mean vascular density (47.9/mm(2)) of b-FGF-positive tumors was significantly lower than that (67.2/mm(2)) of b-FGF-negative tumors (p=0.014), the difference between the 56.0/mm2 in PD-ECGF-positive tumors and 60.3/mm2 in PD-ECGF-negative tumors was not significant. Although the survival rate of patients with b-FGF-positive tumors was significantly higher than those with b-FGF-negative tumors (p=0.033), there was no significant difference between the survival rates of patients with PD-ECGF-positive and -negative tumors (p=0.580). Expression of b-FGF may be associated with promotion of angiogenesis and a good prognostic factor in squamous cell carcinoma of the esophagus.