Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, we aim to collect the current evidence on CSCs in esophageal cancer, including the biomarkers/characterization strategies of CSCs, heterogeneity of CSCs, and the key signaling pathways (Wnt/β-catenin, Notch, Hedgehog, YAP, JAK/STAT3) in modulating CSCs during esophageal cancer progression. Exploring the molecular mechanisms of therapy resistance in EC highlights DNA damage response (DDR), metabolic reprogramming, epithelial mesenchymal transition (EMT), and the role of the crosstalk of CSCs and their niche in the tumor progression. According to these molecular findings, potential therapeutic implications of targeting esophageal CSCs may provide novel strategies for the clinical management of esophageal cancer.

Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies, and limits promising treatments. AKR1C3 represents a therapeutic target to combat the resistance in many cancers. However, the molecular mechanism of AKR1C3 in the chemotherapy resistance of EAC is still unclear. We found that the mRNA level of AKR1C3 was higher in EAC tumor tissues, and that high AKR1C3 expression might be associated with poor overall survival of EAC patients. AKR1C3 overexpression decreased cell death induced by chemotherapeutics, while knockdown of AKR1C3 attenuated the effect. Furthermore, we found AKR1C3 was inversely correlated with ROS production. Antioxidant NAC rescued chemotherapy-induced apoptosis in AKR1C3 knockdown cells, while the GSH biosynthesis inhibitor BSO reversed a protective effect of AKR1C3 against chemotherapy. AKT phosphorylation was regulated by AKR1C3 and might be responsible for eliminating over-produced ROS in EAC cells. Intracellular GSH levels were modulated by AKR1C3 and the inhibition of AKT could reduce GSH level in EAC cells. Here, we reported for the first time that AKR1C3 renders chemotherapy resistance through controlling ROS levels via AKT signaling in EAC cells. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy.

Purpose: The inflammatory microenvironment and hemostatic system are involved in several stages of tumor progression. The aim of this study was to assess the prognostic effect of fibrinogen-to-lymphocyte ratio (FLR) in esophageal squamous cell carcinoma (ESCC) patients who underwent radical esophagectomy. Patients and methods: We retrospectively reviewed 673 consecutive patients with ESCC who underwent radical esophagectomy from January 2009 to December 2012 at a major cancer hospital in Guangzhou, southern China. The cutoff points were defined by the X-tile software. The prognostic value of FLR for overall survival (OS), disease-free survival (DFS), and first-year mortality after surgery were analyzed using Cox proportional hazard regression model and logistic regression model. Survival was estimated by the Kaplan–Meier estimator and compared using the log-rank test. Results: The optimal cutoff point of FLR was 3.03. Compared with the FLR-low (≤3.03) group, the FLR-high (>3.03) group included older patients (χ²=7.267, P=0.007), showed higher postoperative overall morbidity (24.7% vs 14.8%, χ²=5.414, P=0.020) and tended to die within one year (23.5% vs 10.9%, χ²=10.871, P=0.001). The FLR-high group showed significant lower 5-year OS rates (41.2% vs 53.7%, log-rank=6.827, P=0.009) and 5-year DFS rates (35.3% vs 48.0%, log-rank=5.954, P=0.015) than the FLR-low group. Multivariate analyses suggested that high FLR was an independent negative predictor of OS (HR: 1.448, 95%CI: 1.073–1.952, P=0.015), DFS (HR: 1.445, 95%CI: 1.084–1.925, P=0.012) and first-year mortality (HR: 2.123, 95%CI: 1.157–3.898, P=0.015). Conclusion: The preoperative FLR level could be used as a simple, noninvasive, inexpensive, and potentially effective indicator to evaluate the prognosis of ESCC patients following radical esophagectomy.

OBJECTIVES: Our goal was to compare short- and long-term outcomes between 3-field lymphadenectomy (3-FL) and modern 2-field lymphadenectomy (2-FL) in patients with thoracic oesophageal squamous cell carcinoma.METHODS: We reviewed clinical outcomes for 298 patients with thoracic oesophageal squamous cell carcinoma who underwent 3-FL or modern 2-FL from March 2008 to December 2013 at a major cancer hospital in Guangzhou, southern China. Propensity score matching was used to balance baseline differences, and 83 pairs of cases were selected. Postoperative complications, recurrence patterns and survival outcomes were compared between the 2 groups.RESULTS: Compared with modern 2-FL, 3-FL led to higher overall operative morbidity rates [78.3% vs 61.4%, odds ratio (OR) 2.266, 95% confidence interval (CI) 1.143–4.490; P = 0.019], with higher recurrent nerve palsy rates (47.0% vs 19.3%, OR 3.712, 95% CI 1.852–7.438; P < 0.0001), more respiratory failures (18.1% vs 6.0%, OR 3.441, 95% CI 1.189–9.963; P = 0.023) and longer postoperative hospital stays (23 vs 17 days, P = 0.002). The 5-year overall survival rate (58.5% vs 59.4%; P = 0.960) and the 5-year disease-free survival rate 50.1% vs 54.5%; P = 0.482) were comparable between the 2 groups. Multivariable analysis showed that additional cervical lymph node dissection was not associated with overall survival [hazard ratio (HR) 1.039, 95% CI 0.637–1.696; P = 0.878] and disease-free survival (HR 0.868, 95% CI 0.548–1.376; P = 0.547). The overall recurrence rate and cervical nodal recurrence rate were not significantly different between the 2 groups.CONCLUSIONS: Additional cervical lymphadenectomy did not lead to added survival benefit when compared with modern 2-FL in patients with thoracic oesophageal squamous cell carcinoma. Recurrence was similar in patients undergoing 3-FL and modern 2-FL. 3-FL resulted in more postoperative complications.

Background: Patients with esophageal cancer (EC) frequently have multiple primary cancers. We conducted the present study to assess the risk of multiple primary malignancies for patients with squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the esophagus and to investigate the influence of multiple primary tumors on the prognosis of EC patients. Methods: Using the data of 44,091 EC patients from the Surveillance Epidemiology and End Results (SEER) database, we calculated the standardized incidence ratios (SIRs) for overall multiple primary cancers and cancers at particular sites among EC survivors. The SIRs of esophageal SCC and AC patients were compared using Poisson regression. The Kaplan-Meier (KM) method was used for survival analysis. Results: Multiple primary cancer risk was significantly increased among both esophageal SCC and AC survivors (SIR: 2.28 and 1.57, respectively; P<0.001). Among SCC patients, the highest SIRs were found in the oral cavity and pharynx (SIR: 16.54), esophagus (SIR: 10.02), and larynx (SIR: 10.34). Also, the highest SIRs following AC cases were observed in the esophagus (SIR: 8.81), stomach (SIR: 9.29), and small intestine (SIR: 4.95). SIRs for the oral cavity and pharynx, lung, and larynx were significantly higher among SCC survivors than AC survivors (all P<0.05). KM analysis revealed no significant difference of overall survival (OS) for multiple primary cancers, including those of the esophagus, stomach, oral cavity and pharynx, and lung among EC patients (log rank =2.04; P=0.564), except for prostate cancer (log rank =96.65; P<0.001). Conclusions: Multiple primary malignancy risk differed by the histological type of esophageal SSC and AC survivor. However, no significant relationship between survival and the multiple primary cancer sites, except for prostate cancer, was observed.

Primary small cell carcinoma of the esophagus (SCCE) is a rare and extremely fatal disease. We aim to evaluate the efficacy of radical surgery for resectable SCCE and to explore potential prognostic factors. We retrospectively reviewed 52 consecutive SCCE patients who underwent radical surgery from February 1993 to November 2014 at a single institution. The Kaplan-Meier estimator with log-rank test was used to assess overall survival (OS), disease-free survival (DFS) and median survival time. Univariate and multivariable analyses were used to evaluate prognostic factors through Cox proportional hazard regression model. Twenty-five (48.1%) patients were treated with surgery alone, whereas 27 (51.9%) patients underwent adjuvant therapy after surgery. The median OS time was 17.4 months (95% CI: 13.5-21.3). The median DFS time was 13.4 months (95% CI: 7.7-19.0). Patients whose tumors were located in the lower part of thoracic esophagus and the esophagogastric junction showed significantly better OS (27.0 vs. 13.2 months, P = 0.016) and DFS (27.0 vs. 11.3 months, P = 0.017) than those located in the upper and middle parts. Patients with N0 status experienced significantly better OS (21.4 vs. 11.6 months, P = 0.012) and DFS (21.4 vs. 8.6 months, P = 0.012) than those with N+ status. Patients whose tumor lengths were shorter than 5 cm had a better OS (17.4 vs. 5.7 months, P = 0.035) than those longer than 5 cm. Patients who underwent chemotherapy experienced a significantly improved OS (21.0 vs. 14.1 months, P = 0.032) compared to surgery alone. Multivariable analysis showed that lower tumor location, shorter tumor length, pN0 status and chemotherapy independently predicted better OS; lower tumor location and pN0 status independently predicted better DFS. Radical surgery in combination with chemotherapy has better outcomes than surgery alone for resectable SCCE. Higher tumor location, longer tumor length, lymph node metastasis and not undergoing chemotherapy independently predict worse prognoses.