Factors associated with the presence of multiple Lugol‐voiding lesions in patients with esophageal squamous‐cell carcinoma

Multicentric squamous dysplasia of the esophagus is characterized by multiple Lugol‐voiding lesions (LVLs) on Lugol chromoendoscopy. Multiple LVLs are associated with a very high risk of multiple cancers arising in the esophagus as well as the head and neck. To gain insight into the pathogenesis of multiple LVLs of the esophageal mucosa, we studied risk factors for the development of such lesions in 76 patients who had a current or previous diagnosis of esophageal squamous cell carcinoma. All patients underwent Lugol chromoendoscopy of the esophageal mucosa. The history of tobacco and alcohol use was documented. Polymorphisms of the aldehyde dehydrogenase type 2 (ALDH2) gene were identified by polymerase chain reaction using sequence‐specific primers. Clinical factors related to multiple LVLs were analyzed. All patients with multiple LVLs were drinkers. On univariate analysis, male sex (odds ratio [OR] 15, 95% confidence interval [CI] 1.84–122.45: P = 0.011), presence of the ALDH2‐2 allele (OR 4.5, 95% CI 1.55–13.24: P = 0.006), and smoking index ≥1000 (OR 2.6, 95% CI 1.02–6.6: P = 0.045) were associated with multiple LVLs. On multivariate analysis, male sex (OR 10.02, 95% CI 1.13–88.44: P = 0.038) and presence of the ALDH2‐2 allele (OR 4.56, 95% CI 1.4–14.82: P = 0.012) were associated with multiple LVLs. Among drinkers, a daily alcohol intake of ≥100 g pure ethanol with the ALDH2‐2 allele (OR 17.5, 95% CI 1.97–155.59: P = 0.01) and a daily alcohol intake of <100 g pure ethanol with the ALDH2‐2 allele (OR 8.85, 95% CI 1.68–46.69: P = 0.01) more strongly correlated with multiple LVLs than did a daily alcohol intake of <100 g pure ethanol without the ALDH2‐2 allele, whereas a daily alcohol intake of ≥100 g pure ethanol without the ALDH2‐2 allele (OR 4.0, 95% CI 0.54–29.81: P = 0.18) did not. In conclusion, male sex and the ALDH2‐2 allele are associated with an increased risk for multiple LVLs of the esophageal mucosa in patients with esophageal squamous cell carcinoma. Among drinkers with the ALDH2‐2 allele, the risk of multiple LVLs increased in parallel to the daily alcohol intake.     

Lugol chromo‐endoscopy versus Narrow Band Imaging for endoscopic screening of esophageal squamous‐cell carcinoma in patients with a history of cured esophageal cancer: a feasibility study

To date, Lugol chromo‐endoscopy is the reference technique to detect an esophageal neoplasia in patients with prior esophageal squamous‐cell carcinoma (ESCC), but is not easy to perform without general anesthesia, which can limit its use in routine practice. The objective of this study were to compare the accuracy of white light, narrow band imaging (NBI), and Lugol to detect esophageal neoplasia in patients with a history of cured ESCC, in a prospective study. Thirty patients were prospectively included between June 2006 and June 2009. They all had a history of cured ESCC. Esophageal mucosa was examined first using white light, second NBI, and third after Lugol staining. Histology was obtained in all abnormalities detected by white light, NBI, and/or Lugol. Five neoplastic lesions in five different patients were identified at histology, four cancers, and one high‐grade dysplasia. NBI and Lugol both detected all esophageal neoplastic lesions, whereas white light detected the four cancers but missed the high‐grade dysplasia. In this feasibility study, NBI and Lugol both detected all identified esophageal neoplasia in very high‐risk patients of ESCC. This result suggests that NBI could be used instead of Lugol to detect an esophageal neoplasia in patients with high risk of ESCC, but needs to be confirmed in a larger study.     

色素内镜及其在食管疾病诊断中应用价值

色素内镜是利用化学染料或电子分光技术来显示黏膜结构,从而进行观察诊断的方法。在消化道疾病,尤其是消化道早癌的诊断和治疗中发挥着重要作用。色素内镜可分为化学染色内镜和物理染色内镜两种。化学染色内镜是将各种色素散布或喷洒在消化道黏膜表面后,加强病变部位与周围的对比,利用黏膜的细微凹凸及色调变化,观察到普通内镜     

Narrow‐band imaging endoscopy with magnification is useful for detecting metachronous superficial pharyngeal cancer in patients with esophageal squamous cell carcinoma

Background and Aims: Head and neck cancers, especially pharyngeal cancers, as well as esophageal cancers frequently coexist either synchronously or metachronously, but most cases of pharyngeal cancer are detected at an advanced stage resulting in poor prognosis. The aim of this study is to evaluate the effectiveness of using narrow‐band imaging (NBI) endoscopy with magnification for early detection of pharyngeal cancer on patients following their treatment for esophageal squamous cell carcinoma (SCC). Methods: This case series was conducted at the National Cancer Center Hospital in Tokyo between April and October 2005 and included 424 consecutive patients for surveillance endoscopy who had previously undergone chemoradiotherapy (CRT) and/or surgery for esophageal SCC. Observation of the pharyngeal region was randomly conducted on 91 patients using NBI endoscopy with magnification (NBI group) and 333 patients using conventional white light endoscopy (control group). Results: The detection rate for pharyngeal cancer was significantly higher using NBI endoscopy with magnification (10.9%; 10/91) compared with conventional endoscopy (1.2%; 4/333) (P < 0.0001). In particular, the detection rate in CRT patients was significantly higher in the NBI group (12.9%; 7/54) than the control group (0.5%; 1/191) (P < 0.0001). In addition, diagnostic sensitivity, specificity, accuracy, positive predictive value and negative predictive value for the NBI group were 100% (10/10), 97.5% (79/81), 97.8% (89/91), 83.3% (10/12) and 100% (79/79), respectively. Conclusion: NBI endoscopy with magnification is a promising technique for detecting superficial pharyngeal cancer at an early stage in patients previously treated for esophageal SCC.     

Clinicopathological features of narrow‐band imaging endoscopy and immunohistochemistry in ultraminute esophageal squamous neoplasms

To reveal clinicopathological features of narrow‐band imaging (NBI) endoscopy and immunohistochemistry in ultraminute esophageal squamous neoplasms. If a lesion diameter was smaller or same compared with a width of closed biopsy forceps, a lesion was defined to be an ultraminute lesion. Twenty‐five consecutive patients with 33 ultraminute esophageal lesions that were removed by endoscopic mucosal resection were included in the present study. We conducted two questionnaire surveys of six endoscopists by their retrospective review of endoscopic still images. The six endoscopists evaluated the endoscopic findings of the ultraminute lesions on still images taken by conventional white‐light imaging endoscopy and non‐magnified NBI endoscopy in the first questionnaire, and taken by magnified NBI endoscopy in the second questionnaire. An experienced pathologist who was unaware of any endoscopic findings made histological diagnosis and evaluated immunoexpression of p53 and Ki67. The 33 ultraminute lesions were all determined to be either 11 high‐grade intraepithelial neoplasias (HGIENs) or 22 low‐grade intraepithelial neoplasias (LGIENs). The tumor diameters were histologically confirmed to be <3 mm. All of the ultraminute tumors were visualized as unstained areas and brownish areas by real‐time endoscopy with Lugol dye staining and non‐magnified NBI endoscopy, respectively. All of the ultraminute IENs were visualized as brownish areas by real‐time non‐magnified NBI endoscopy. Three of the 25 patients with the ultraminute IENs (12%) had multiple brownish areas (more than several areas) in the esophagus on real‐time non‐magnified NBI endoscopy. All of the ultraminute IENs were visualized as unstained areas by real‐time Lugol chromoendoscopy. Twenty of the 25 patients (80%) had multiple unstained areas (more than several areas) in the esophagus on real‐time Lugol chromoendoscopy. The first questionnaire survey revealed that a significantly higher detection rate of the ultraminute IENs on non‐magnified NBI endoscopy images compared with conventional white‐light imaging endoscopy ones (100% vs. 72%, respectively: P < 0.0001). The second questionnaire survey revealed that presence rates of any magnified NBI endoscopy findings were not significantly different between HGIENs and LGIENs. Proliferation, dilation, and various shapes of intrapapillary capillary loops indicated remarkably high presence rates of more than 90% in both HGIENs and LGIENs. Six of 22 LGIENs (27%) and 3 of 11 HGIENs (27%) show a positive expression for p53. None of peri‐IEN epithelia was positive for p53. A mean of Ki67 labeling index of LGIENs was 33% and that of HGIENs 36%. Ki67 labeling index was significantly greater in the LGIENs and HGIENs compared with that in the peri‐IEN epithelia. There were no significant differences in p53 expression and Ki67 labeling index between the HGIENs and LGIENs. Non‐magnified/magnified NBI endoscopy could facilitate visualization and characterization of ultraminute esophageal squamous IENs. The ultraminute HGIENs and LGIENs might have comparable features of magnified NBI endoscopy and immunohistochemistry.     

Magnifying endoscopy with narrow band imaging for predicting the invasion depth of superficial esophageal squamous cell carcinoma

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.     

Usefulness of confocal laser endomicroscopy to diagnose ulcerative colitis‐associated neoplasia

Chromoendoscopy, narrow‐band imaging (NBI), and confocal laser endomicroscopy (CLE) have been introduced in ulcerative colitis (UC)‐associated neoplasia surveillance. We aimed to determine the ability of CLE to differentiate among UC‐associated neoplasia (differentiated type or undifferentiated type), sporadic adenoma, and circumscribed regenerative lesions. Of 665 patients with UC, we carried out probe‐based CLE (pCLE) on 12 patients with suspected UC‐associated neoplasia in addition to magnifying chromoendoscopy with crystal violet and NBI. We compared pCLE findings with pathological diagnoses. pCLE could differentiate UC‐associated differentiated cancer from other pathologies such as solitary adenoma and non‐neoplastic circumscribed regenerative lesions on the basis of back‐to‐back orientation of crypts (P = 0.048), and UC‐associated undifferentiated cancer from other pathologies on the basis of dark trabecular architecture (P = 0.015). Sensitivity, specificity, and accuracy of combination of back‐to‐back orientation of crypts and dark trabecular architecture for carcinoma or dysplasia were 100%, 83%, and 92%, respectively. In vivo microscopic observation with pCLE was helpful to evaluate the suspected UC‐associated neoplasia.     

FLAT AND SMALL SQUAMOUS CELL CARCINOMA OF THE ESOPHAGUS DETECTED AND DIAGNOSED BY ENDOSCOPY WITH NARROW‐BAND IMAGING SYSTEM

Reported herein is the case of a 65‐year‐old man who had completely flat and small squamous cell carcinoma in the esophagus. The subtle lesion was initially detected as a brownish area depicted by non‐magnified endoscopy with the narrow‐band imaging system (NBI). The lesion was predicted to be type 0‐IIb mucosal cancer due to assessment of morphologic change of intrapapillary capillary loop under magnified NBI observation. Endoscopic mucosal resection was performed for the lesion. The histological finding of the removed specimen indicated mucosal squamous cell carcinoma. Endoscopic observation with the NBI system was useful for detecting obscure squamous cell carcinoma and predicting the histological finding.     

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.     

Association of Helicobacter pylori infection with esophageal adenocarcinoma and squamous cell carcinoma: a meta‐analysis

To evaluate the relationship of Helicobacter pylori and cytotoxin‐associated gene A (CagA) positive strains with esophageal neoplasm, including esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), the authors conducted a meta‐analysis using a predefined protocol. PubMed, Web of Science, China biology medical literature database, Wanfang, and China National Knowledge Infrastructure were searched for relevant articles from the first available year to April 8, 2013. The fixed or random effect pooled measure was selected based on heterogeneity among studies, which was evaluated using Q test and the I² of Higgins and Thompson. Metaregression was used to explore the sources of between‐study heterogeneity. Publication bias was analyzed by Begg's funnel plot and Egger's regression test. The association was assessed by odds ratio (OR) with 95% confidence interval (CI). A total of 28 eligible studies were included in the meta‐analysis. There was a significant inverse association between H. pylori infection (pooled OR, 0.57; 95% CI, 0.44–0.73) and EAC; CagA‐positive H. pylori strains were less likely to be associated with EAC compared with CagA‐negative strains (pooled OR, 0.64; 95% CI, 0.52–0.79). However, there was no statistically significant association between H. pylori/CagA‐positive H. pylori strains infection and ESCC, and the pooled ORs were 1.16 (95% CI, 0.83–1.60) and 0.97 (95% CI, 0.79–1.19). But significant associations between CagA‐positive H. pylori strains infection and ESCC risk were found in the stratified analysis of the study location (Asian and non‐Asian), and the summary ORs were 0.74 (95% CI, 0.57–0.97) and 1.41 (95% CI, 1.02–1.94). H. pylori infection and CagA‐positive strains are associated with decreased risk of EAC in the overall population. No significant association was found between H. pylori infection/CagA‐positive strains and ESCC. But CagA‐positive strains might have a positive association with ESCC in non‐Asian population and an inverse association in Asian population.     

Preoperative level of serum amyloid A is superior to C‐reactive protein in the prognosis of esophageal squamous cell carcinoma

Preoperative elevations in the levels of serum amyloid A (SAA) or C‐reactive protein (CRP) have been reported to be prognostic indicators in several malignancies. The aim of this study is to evaluate the serum levels of SAA and CRP in the prognosis of esophageal squamous cell carcinoma (ESCC). In total, 252 patients with ESCC who had undergone surgery with curative‐intent were retrospectively recruited. The specificity, sensitivity, and prognostic value of SAA or CRP levels were measured as the area under the receiver operating characteristic (ROC) curve (AUC). The clinical value of SAA and CRP levels as prognostic indicators was evaluated using Cox's proportional hazards model. The 1‐, 3‐, and 5‐year overall survival (OS) rates for the entire cohort of patients with ESCC were 71.0%, 61.0%, and 43.0%, respectively. The correlation between the levels of SAA and CRP was significant (r² = 0. 685, P < 0.001). The ROC analysis showed that the levels of CRP were associated with a significantly lower overall accuracy than were the SAA levels (AUC, 0.615 vs. 0.880; P < 0.001). For the complete cohort, the median OS was 52.0 months longer in patients with low preoperative serum levels of SAA (72.0 months) compared with patients who had high SAA levels (20.0 months, P < 0.001). The median OS among patients with low CRP levels was also longer compared with the patients who had high CRP levels (72.0 vs. 51.0 months, respectively; P < 0.001). Subgroup analyses showed that the preoperative elevated levels of SAA could find significant differences in OS for stage I, stage II, and stage III (P < 0.001, P = 0.001, and P < 0.001, respectively), whereas the increased levels of CRP could only find a difference in OS for stage II cancers. After a multivariate analysis, preoperative elevated level of SAA was found to be an independently and significant prognostic factor (P < 0.001). Our study indicates that the preoperative levels of SAA and CRP can act as prognostic factors, and that elevated levels of these proteins are associated with negative effects on the survival of patients with ESCC. SAA showed a higher prognostic value than CRP in both cohort and subgroup analysis.     

Advantages of positron emission tomography‐computed tomography imaging in esophageal squamous cell carcinoma

To explore the value of positron emission tomography‐computed tomography (PET‐CT) scan in esophageal squamous cell carcinoma (ESCC), we retrospectively summarize the results of PET‐CT scan from 118 patients, with ESCC who underwent PET‐CT scan in the different courses during treatment. Then, the results of PET‐CT scan plus other conventional methods were analyzed to identify the value of PET‐CT scan in diagnosis, staging, response evaluation, monitoring recurrence, and metastasis following treatment. It is suggested that PET‐CT scan possess high value in diagnosis and gives more favorable indication in N and M staging. PET‐CT scan should be translated into routine surveillance for postoperation follow up and is one of more helpful evaluators of response to chemoradiotherapy or chemotherapy.     

Common single nucleotide polymorphism of hypoxia‐inducible factor‐1α and its impact on the clinicopathological features of esophageal squamous cell carcinoma

OBJECTIVE: Angiogenesis is one of the most important molecular events in solid tumor development and growth, in which hypoxia‐inducible factor (HIF)‐1α is a key regulator and plays an important role. Studies have shown that a single nucleotide polymorphism (C1772T) in the HIF‐1α 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.     

Immunohistochemical study of nuclear factor‐κB expression in esophageal squamous cell carcinoma: prognostic significance and sensitivity to treatment with 5‐FU

Nuclear factor‐κB (NF‐κB) is expressed in many types of cancers. It has been suggested that the expression of NF‐κB is associated with poor prognosis and resistance to chemoradiation therapies. This study evaluated the relationship between the expression of NF‐κB and the prognosis and sensitivity of esophageal squamous cell carcinoma (ESCC) to chemotherapy. One hundred and nine ESCC specimens, from patients who had undergone radical esophagectomy, were divided into two groups depending on the expression of NF‐κB. Surgical data and prognosis were compared between the two groups. NF‐κB‐positive tumors were detected in 61.5% of the cases. In 69 patients with stage II and III disease, 41 patients who were NF‐κB‐positive showed poor survival. The sensitivity of esophageal squamous cell carcinoma cell lines to 5‐fluorouracil (5‐FU) was analyzed by their NF‐κB expression, and the effect of 5‐FU was evaluated on the proliferation and activity of two cell lines of cultured ESCCs expressing NF‐κB. ESCCs with activated NF‐κB had poor sensitivity to 5‐FU. These results suggest that the increased expression of NF‐κB is associated with poor prognosis in patients with ESCC. NF‐κB may be a target for ESCC therapy because of its selective expression in this type of cancer.     

Prognostic significance of gamma‐glutamyltransferase in patients with resectable esophageal squamous cell carcinoma

Gamma‐glutamyltransferase (GGT) is a membrane‐bound enzyme involved in the glutathione metabolism. Studies suggested that GGT was a marker of apoptotic balance and modulated tumor progression, invasion and drug resistance. Recently, GGT was shown to be associated with the progression of high‐grade esophageal epithelial dysplasia to invasive carcinoma. This study was conducted to investigate the value of pre‐therapeutic serum GGT levels as prognostic parameter in esophageal squamous cell carcinoma. Six hundred thirty‐nine resectable esophageal squamous cell carcinoma patients were recruited in this study and were stratified into two GGT risk groups. The association of pre‐therapeutic serum GGT levels and clinical–pathological parameters was examined. Univariate and multivariate survival analyses were performed. GGT serum levels were associated with gender, smoking status, TNM stage and lymph node involvement. Higher pre‐therapeutic serum GGT was found in males, smoker, advanced TNM stage and lymph node positive patients. Patients assigned to the low‐risk group had higher 5‐year overall survival rate (53.1% vs. 33.0%, P < 0.01) and disease‐free survival rate (45.2% vs. 23.4%, P < 0.01) than the high‐risk group. Patients with high‐risk group of GGT had 1.568 (95% confidence interval [CI], 1.259 ∼ 1.952) times the risk of death and 1.582 (95% CI, 1.286 ∼ 1.946) times the risk of disease recurrence contrast with those with low‐risk group of GGT. The pre‐therapeutic serum GGT is a novel independent prognostic parameter for disease‐free survival and overall survival in resectable esophageal squamous cell carcinoma.