Multiple Esophageal Squamous Cell Carcinoma Research Articles

Characteristics of multiple esophageal squamous cell carcinomas detected in the surveillance after endoscopic resection.

Endoscopic resection (ER) of esophageal squamous cell carcinoma (ESCC) is an organ-preserving treatment; however, heterochronic carcinomas are often encountered. Most patients are treated using ER; however, for some, this is inadequate and requires additional treatment. We sought to identify the characteristics and frequency of lesions at high risk of metastasis during surveillance based on Lugol-voiding lesion (LVL) grading and esophagogastroduodenoscopy (EGD) intervals. Of the 1301 patients who underwent ER, 956 underwent surveillance EGD at our hospital for at least 1year (median, 59months). We analyzed identified multiple ESCCs to reveal the characteristic of high-metastasis-risk lesions, which was defined ESCC with submucosal or lymphovascular invasion. In the 956 patients, 444 multiple ESCCs were identified in 216 patients and the cumulative incidence of multiple ESCCs was 15.4% and 22.9% at 3 and 5years, respectively, while for high-risk lesions, it was 1.0% and 1.8%. The risk factors for high-metastasis-risk lesions were being female (odds ratio (OR):5.58, 95% confidence interval (CI):1.96-15.9), lesions located in the cervical/upper thoracic esophagus (OR: 4.81, 95% CI:1.80-12.8), and the presence of submucosal tumor (SMT)-like marginal elevation (OR:65.4, 95% CI:11.0-390). No significant differences in the frequency of high-risk lesions were found based on LVL grade at any EGD intervals. During endoscopic surveillance, attention should be given to the cervical/upper thoracic esophagus and lesions with SMT-like marginal elevation. The frequency of high-metastasis-risk lesions was not different by LVL grade or EGD intervals.

McKeown esophagectomy for a thoracic esophageal carcinoma patient who has a history of definitive chemoradiotherapy for esophageal carcinoma and total pharyngolaryngectomy for hypopharyngeal cancer

A 64-year-old man, who had previously undergone definitive chemoradiotherapy (dCRT) and endoscopic resections for metachronous multiple esophageal squamous cell carcinoma (ESCC) and had also received total pharyngolaryngectomy (TPL) for hypopharyngeal cancer, was diagnosed with ESCC in the middle thoracic esophagus (cT3N0M0). Thoracoscopic McKeown esophagectomy was performed for the patient. Although the tumor was tightly adherent to the thoracic duct and both main bronchi, they were successfully mobilized. In order to maintain the blood supply to the trachea, we preserved the bilateral bronchial arteries and avoided prophylactic upper mediastinal lymph node dissection. Cervical end-to-side anastomosis between the jejunum and a gastric conduit was performed. Minor pneumothorax was managed conservatively, and the patient was discharged 44 days after the surgery. Overall, thoracoscopic McKeown esophagectomy was safely performed in a patient with a history of TPL and dCRT. Surgeons should be very careful to prevent tracheobronchial ischemia by optimizing the extent of lymph node dissection.

Survival and prognostic factors in patients with synchronous multiple primary esophageal squamous cell carcinoma receiving definitive radiotherapy: A propensity score-matched analysis.

To compare the lesion characteristics and radiotherapy efficacy of patients with single and multiple esophageal squamous cell carcinoma (ESCC), to evaluate the effect of multiple lesions on ESCC, and establish a nomogram survival prediction model for patients with synchronous multiple primary esophageal squamous cell carcinoma (SMPESCC) who received definitive radiotherapy. The study enrolled 1,034 patients with ESCC who underwent definitive radiotherapy between 2010 and 2020. The efficacy of radiotherapy was compared between 101 patients with SMPESCC and 933 patients with single ESCC. Propensity score matching was used to control for potential confounders. For patients with SMPESCC, a nomogram prediction model was established based on the Cox regression model. The median OS was 30.00 (95% CI = 25.08-34.92) months for the single lesion group and 19.00 (95% CI = 15.51-22.48) months for the multiple cancer group respectively. Multivariate COX regression analysis showed that multiple cancer was an independent prognostic factor for ESCC patients (HR=1.89, 95%CI=1.49-2.38, P<0.001). Cox multivariate analysis of SMPESCC patients showed that T stage (P =0.002), chemotherapy (P =0.006), and lesion spacing (P =0.004) were independent prognostic factors associated with OS. The nomogram was established by combining T stage, chemotherapy, and lesion spacing, and Harrell's C index was 0.711 after internal cross-validation. The calibration curve and decision curve analysis confirmed that the nomogram survival prediction model had a good predictive value for individual survival. The survival rate of single esophageal cancer is significantly better than that of multiple lesions. Patients with SMPESCC exhibit worse survival than patients with single ESCC. Multiple lesions have a significant impact on the survival of patients with ESCC. The nomogram model established for SMPESCC patients can well predict the individual survival of patients.

Differential expression profiles of long noncoding RNAs in synchronous multiple and solitary primary esophageal squamous cell carcinomas: A microarray analysis.

As a unique subtype of esophageal cancer, synchronous multiple primary esophageal squamous cell carcinomas (ESCCs) mostly occur in Asian patients with alcohol and/or tobacco abuse, or with a family history of cancer. Multiple ESCCs are associated with poor clinical outcomes. Growing evidence has addressed that long noncoding RNAs (lncRNAs) are involved in the carcinogenesis of various malignancies. We compared the lncRNA and messenger RNA (mRNA) profiles between solitary and multiple ESCC tissues through microarray analysis, aiming at studying their different mechanisms in tumor development. As a result, in multiple ESCCs, a total of 5257 lncRNAs and 3371 mRNAs were consistently differentially expressed compared with solitary ESCC, including 2986 upregulated and 2271 downregulated lncRNAs, and 2313 upregulated, and 1058 downregulated mRNAs. We validated the results in four differentially expressed lncRNAs using quantitative real-time polymerase chain reaction. There were 38 and 20 pathways significantly related to up- and downregulated transcripts. The pathways associated with mostly enriched up- and downregulated mRNAs were hsa01200 (carbon metabolism) and hsa05221 (acute myeloid leukemia- homo sapiens [human]). Gene ontology analysis suggested that upregulated and downregulated mRNAs were mainly enriched in bounding membrane of organelle involved in the cellular component and positive regulation of transport involved in the biological process. Further analysis identified 189 differentially expressed paired antisense lncRNAs and relative sense mRNA, as well as 2134 differentially expressed long intergenic noncoding RNAs and their adjacent mRNA pairs. In conclusion, the aberrantly expressed lncRNAs might play a role in the carcinogenesis of multiple ESCCs and could be candidates as diagnostic biomarkers and therapeutic targets.

Endoscopic findings corresponding to multiple Lugol-voiding lesions in the esophageal background mucosa.

Multiple Lugol-voiding lesions (LVLs) on Lugol chromoendoscopy can predict the development of metachronous multiple cancers in the esophagus and the head and neck regions. However, Lugol chromoendoscopy sometimes causes adverse events such as chest pain and discomfort. We therefore investigated the endoscopic findings on narrow band imaging (NBI) or blue laser imaging (BLI) that correspond to the presence of multiple LVLs in patients with esophageal squamous cell carcinoma. First, we investigated the NBI/BLI findings corresponding to individual small LVLs (one-to-one correspondence). Second, we investigated the association between the grade of multiple LVLs and the five endoscopic findings, including multiple foci of dilated vessels (MDV), multiple small brownish areas without microvascular irregularity, and a nonuniform color tone. One-to-one correspondence of endoscopic findings was analyzed in 106 small LVLs. The main findings matched with small LVLs were a focus of dilated vessels (44 lesions), a small brownish area (17 lesions), and a small brownish area with a focus of dilated vessels (19 lesions). The relationship between multiple LVLs and each finding assessed by NBI/BLI was assessed in 155 patients. Multivariate logistic regression indicated that the presence of MDV was the only finding independently associated with multiple LVLs (P<0.01). The presence of MDV in the noncancerous background esophageal mucosa was significantly associated with multiple LVLs. This pilot study demonstrates that MDV has the potential to be a new risk factor for the development of metachronous multiple esophageal squamous cell carcinoma.

FGFR1 signaling potentiates tumor growth and predicts poor prognosis in esophageal squamous cell carcinoma patients

ABSTRACTFibroblast growth factor receptor-1 (FGFR1) over-expression was broadly found in squamous cancer, where it induced cellular proliferation, differentiation, and metastasis by activating various signaling pathway. However, the role of FGFR1 gene expression in predicting prognosis of Esophageal Squamous Cell Carcinoma (ESCC) and its regulatory function in the progression of ESCC are not well understood. Therefore, we performed an analysis of FGFR1 mRNA expression by quantitative RT-PCR in tumor tissue of 145 patients with ESCC. The relationships between FGFR1 gene expression and clinicopathological parameters, also the prognosis were further examined. Results suggested that higher FGFR1 gene expression predicted worse overall survival (HR = 1.502, 95%[CI] = 1.005–2.246, P = 0.045). Disease-free survival tends to be shorter in patients with higher FGFR1 expression but without statistical significance (HR = 1.398, 95%[CI] = 0.942–2.074, P = 0.096). FGFR1 was up regulated in multiple ESCC cell lines. Subsequent in vitro experiments demonstrated that anti-FGFR1 treatment by PD173074 inhibited TE-1 and EC9706 cell viability along with the attenuation of MEK-ERK signaling pathway. In vivo, PD173074 administration also had shown potent ESCC growth arresting effect. Overall, our study suggested that FGFR1 gene expression could be an independent prognosis predictive factor in patients with ESCC. Anti-FGFR1 inhibited ESCC growth and could be a potential strategy in ESCC targeted therapy.

Abstract 4980: Upregulation of PD-L1 expression by cisplatin in esophageal squamous cell carcinoma cells is independent of interferon/JAK/STAT pathway

Abstract Introduction Blockade of immune check points, especially the program cell death 1 (PD-1) and its major ligand PD-L1 signaling, has become an important mode of therapy against cancers. The upregulation of PD-L1 expression in cancer cells is an important mechanism contributing to immune evasion of cancers. The PD-L1 upregulation in cancer cells could be mediated by intrinsic genetic or signaling alterations, or could be induced in response to specific cytokines, in particular interferon (IFN)-gamma, produced by tumor-infiltrating immune cells. Whether chemotherapy per se has direct impact on PD-L1 expression in cancer cells is currently unclear. Materials and Methods Four esophageal squamous cell carcinoma (ESCC) cell lines, TE5, KYSE70, KYSE270, KYSE510, were included. The expression of PD-L1 in ESCC cells, treated with various concentrations of cisplatin, were evaluated by flow cytometry, Western blotting, and qRT-PCR. To study the potential signaling pathways involved in the PD-L1 upregulation induced by cisplatin, we evaluated the nuclear expression of p-STAT1 and IRF1 (for IFN/JAK/STAT pathway), and p65 and p50 (for NF-kB pathway). Finally, we used BAY-11-7082, an irreversible inhibitor of IKKα, to validate the significance of NF- kB pathway in mediating the PD-L1 upregulation induced by cisplatin. Results Cisplatin at the doses of 5∼ 10 μM increased the proportions of PD-L1-expressing cells detected by flow cytometry in all tested ESCC cells. The folds of increase were 19.29±2.27, 10.13±8.42, 23.19±10.12, 6.20±0.81 for TE5, KYSE70, KYSE270, and KYSE510 treated with 10 μM of cisplatin, respectively. The kinetics of this cisplatin- induced PD-L1 expression, evaluated in TE5 cells, was: after exposure to cisplatin for 24 hours, the PD-L1 expression peaked at 48 hours, and remained elevated at 144 hours after drug exposure. In multiple ESCC cells, exposure to cisplatin did not increase the expression of p-STAT1 and IRF1, suggesting that IFN/JAK/STAT pathway did not involve in the PD-L1 upregulation induced by cisplatin. In co-culture experiments with cisplatin-treated TE5 cells or with condition medium from cisplatin-treated TE5 cells, we confirmed that the PD-L1 upregulation in ESCC cells was not through paracrine manners. In TE5 cells, cisplatin treatment induced nuclear translocation of p65, suggesting that NF-kB pathway was activated. The cotreatment of BAY11-7082 could partially abrogate the PD-L1 upregulation induced by cisplatin in TE5 cells. Conclusion PD-L1 expression in ESCC cancer cells can be up-regulated by cisplatin. Our data indicated that this activation is not mediated through the IFN/JAK/STAT pathway, but may involve in activation of NF-κB signaling. (The study was supported by the grant NTUH 104-M2891 and the grant MOST 104-2314-B-002-111) Citation Format: Ta-Chen Huang, Kuan-Ling Lin, Ann-Lii Cheng, Chih-Hung Hsu. Upregulation of PD-L1 expression by cisplatin in esophageal squamous cell carcinoma cells is independent of interferon/JAK/STAT pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4980.

Genetic pathways of multiple esophageal squamous cell carcinomas

Whether multiple esophageal squamous cell carcinomas (SCCs) in a patient develop through an identical genetic pathway is still unclear. We examined multiple esophageal SCCs for alterations of p53, p16, IRF and mitochondrial DNA (mtDNA) and microsatellite instability (MSI). Thirty patients with multiple superficial esophageal SCCs, 23 with double lesions and 7 with triple lesions, were enrolled. Loss of heterozygosity (LOH) of p53 (TP53), p16 (D9S171), IRF (IRF) and other microsatellite loci including D1S191, D17S858, D18S58 and D18S61 of the tumors was examined by microsatellite assay. Mutations of p16 and mtDNA were examined with PCR single-strand conformation polymorphism (SSCP) analysis. LOH of p53, p16 and IRF were detected in 16 of 50 (32%), 5 of 38 (13%) and 5 of 48 (10%) tumors, respectively. Mutations of p16 were detected in 4 of 67 (6%) tumors. Six of 67 (9%) tumors had mtDNA alterations and none of the tumors showed high-frequency MSI. All 30 patients showed one or more gene alterations in one or more genetic loci. Discordant genetic patterns among individual lesions within a patient were observed in 28 of the 30 (93%) patients. The most discordant locus was TP53, present in 11 of 29 (38%) informative cases, followed by D18S61, present in 11 of 30 (37%) informative cases. These results suggest that the genetic pathways of multiple esophageal SCCs may differ even within the same patient.

Metachronous multiple esophageal squamous cell carcinomas and Lugol-voiding lesions after endoscopic mucosal resection

Endoscopic mucosal resection (EMR) has been applied to the treatment of superficial esophageal squamous cell carcinoma (SCC). The incidence and characteristics of metachronous multiple esophageal SCCs and Lugol-voiding lesions (LVLs) were investigated in a retrospective study in patients who had undergone EMR for superficial esophageal SCC. 96 patients with esophageal SCC who had been treated by EMR were followed up by endoscopy for 12 months or longer. Clinicopathologic parameters such as tumor size and location and presence of LVLs were examined. 10 patients (10 %) had synchronous multiple SCCs, and 12 (13 %) developed metachronous multiple SCCs. The mean annual incidence of newly diagnosed tumor was 4.4 %. The incidence of a speckled pattern of LVLs was 20/74 (27 %) in patients with solitary SCC, 5/10 (50 %) in synchronous multiple SCC, and 10/12 (83 %) in metachronous multiple SCC. The incidence of the presence of speckled pattern of LVLs was significantly higher in patients with multiple SCCs than in those with solitary SCC (68 % vs. 27 %, P = 0.0004). Patients who have undergone EMR for esophageal SCC, especially those with metachronous multiple LVLs in the background mucosa, should undergo follow-up with close endoscopic observation using Lugol staining.

The relation of alcohol consumption and cigarette smoking to the multiple occurrence of esophageal dysplasia and squamous cell carcinoma

The unique pathologic features of esophageal tumors in patients with esophageal cancer includes the presence of multiple occurrence within the esophagus. The aim of this study is to clarify the molecular mechanism of carcinogenesis of multiple esophageal squamous cell carcinomas in the Japanese. We studied the relationship between the incidence of patients with multiple carcinomas and the coexistence of dysplasia lesions with p53 protein accumulation, alcohol consumption, and cigarette smoking. Among 76 cancer lesions and 60 cases of dysplasia, p53 accumulation was studied by means of immunohistochemical analysis. The incidence of patients with multiple carcinomas in the high-risk group was 33%, and the incidence of patients with a coexistence of dysplasia in the high-risk group was 67%. The incidence of patients with multiple carcinomas or the coexistence of dysplasia in the high-risk group was much higher than that of the middle-risk and low-risk groups (P <.0001 and P =.04, respectively). The average number of abnormal epitheliums, such as cancer and dysplasia, in the high-risk group was 3.2 +/- 2.1. The average number of abnormal epitheliums was much higher than that of the other groups (P =.02). For carcinoma lesions, the incidence of lesions with a positive p53 protein accumulation in the high-risk group was 91%. Regarding dysplasia lesions, the incidence of lesions with a positive p53 protein accumulation in the high-risk group was 80%. The incidence of both cancer and dysplasia lesions with a positive p53 protein accumulation in the high-risk group was higher than that of the other groups. The pattern of p53 accumulation in dysplasia in the high-risk group was closely similar to that in cancer of the high-risk group. These findings support the concept of field carcinogenesis of the esophagus.