Primary Small Cell Carcinoma Of The Esophagus Research Articles

Treatment Strategies for Limited-Stage Primary Small Cell Carcinoma of the Esophagus: A Multicenter Retrospective Trial from China

<h3>Purpose/Objective(s)</h3> Primary small cell carcinoma of the esophagus (PSCCE) is a rare and highly malignant disease that carries a poor prognosis. The optimal treatment strategies for limited-stage PSCCE have not been established. <h3>Materials/Methods</h3> We retrospectively reviewed the clinical records of limited-stage PSCCE patients who received chemotherapy (CT) or chemotherapy-based combined modality therapy (CMT) between December 2000 and December 2020 from the 15 hospitals in China. Patients were divided into the following two groups according to the treatment strategies: the CT group and the CMT group. A 1:3 propensity score matching (PSM) approach was applied to balance observable potential confounding factors between the two groups. The primary endpoint was overall survival (OS). <h3>Results</h3> A total of 544 patients were enrolled in our study, including 84 patients in the CT group and 460 patients in the CMT group. Univariate analysis and multivariate analysis found that Eastern Cooperative Oncology Group classification, primary tumor length, TNM stage, number of chemotherapy cycles, and treatment strategies were the independent predictors of OS. The 3-year rate of brain metastasis was 11.1% in the CMT group. After PSM, the patients' characteristics between the CT group (n=82) and the CMT group (n=218) were well balanced. The median OS in the CT and CMT group was 17.34 and 24.60 months, respectively, and the difference was statistically significant (<i>P</i> < 0.001). Moreover, progression-free survival (PFS), locoregional PFS, and distant PFS were also significantly different between the two groups (<i>P</i> < 0.05). <h3>Conclusion</h3> Compared with CT, chemotherapy-based CMT may improve OS and PFS and was the optimal treatment strategy for limited-stage PSCCE. On the other hand, prophylactic brain irradiation is not recommended.

Development and validation of a prognostic nomogram model for Chinese patients with primary small cell carcinoma of the esophagus.

BACKGROUNDPrimary small cell carcinoma of the esophagus (PSCE) is a highly invasive malignant tumor with a poor prognosis compared with esophageal squamous cell carcinoma. Due to the limited samples size and the short follow-up time, there are few reports on elucidating the prognosis of PSCE, especially on the establishment and validation of a survival prediction nomogram model covering general information, pathological factors and specific biological proteins of PSCE patients.AIMTo establish an effective nomogram to predict the overall survival (OS) probability for PSCE patients in China.METHODSThe nomogram was based on a retrospective study of 256 PSCE patients. Univariate analysis and multivariate Cox proportional hazards regression analysis were used to examine the prognostic factors associated with PSCE, and establish the model for predicting 1-, 3-, and 5-year OS based on the Akaike information criterion. Discrimination and validation were assessed by the concordance index (C-index) and calibration curve and decision curve analysis (DCA). Histology type, age, tumor invasion depth, lymph node invasion, detectable metastasis, chromogranin A, and neuronal cell adhesion molecule 56 were integrated into the model.RESULTSThe C-index was prognostically superior to the 7th tumor node metastasis (TNM) staging in the primary cohort [0.659 (95%CI: 0.607-0.712) vs 0.591 (95%CI: 0.517-0.666), P = 0.033] and in the validation cohort [0.700 (95%CI: 0.622-0.778) vs 0.605 (95%CI: 0.490-0.721), P = 0.041]. Good calibration curves were observed for the prediction probabilities of 1-, 3-, and 5-year OS in both cohorts. DCA analysis showed that our nomogram model had a higher overall net benefit compared to the 7th TNM staging .CONCLUSIONOur nomogram can be used to predict the survival probability of PSCE patients, which can help clinicians to make individualized survival predictions.

The prognostic value of TCF1+CD8+T in primary small cell carcinoma of the esophagus.

TCF1+CD8+T cells are reported to exhibit stem‐like properties with the ability to self‐renew and differentiate into terminal effector T cells (TCF1‐CD8+T cells) to enhance antitumor response. Previous studies indicated that TCF1+CD8+ tumor‐infiltrating lymphocytes (TILs) are related to response to immunotherapy. However, their role in predicting prognosis for patients with primary small cell carcinoma of the esophagus (PSCCE) remains unclear. In this study, the expression of TCF1+CD8+T was analyzed by multiplex fluorescence immunohistochemistry in tumor tissues of 79 patients with PSCCE. High infiltration of TCF1+CD8+T cells had longer overall survival (OS) than low infiltration (P = .009, hazard ratio [HR] = 0.506). High TCF1+CD8/CD8 ratio (>21%) showed superior OS compared with low ratio (≤21%) (P < .001, HR = 0.394). In the validation set (n = 20), the prognostic value of TCF1+CD8+T cells on OS was also verified. TCF1+CD8+T cells are strong prognostic predictors.

P-151 The prognostic value of TCF1+CD8+T cell in primary small cell carcinoma of the esophagus

TCF1+CD8+T cells are reported to exhibit stem-like properties with the ability to self-renew and differentiate into terminal effector T cells (TCF1-CD8+T cells) to enhance anti-tumor response. Previous studies indicated that TCF1+CD8+TILs are related to response to immunotherapy. However, their role in predicting prognosis remains unclear. Here, we investigated the prognostic value of TCF1+CD8+T cells in patients with primary small cell carcinoma of the esophagus (PSCCE). The tumor tissues from 79 patients with PSCCE were analyzed by multiple immunofluorescence staining. The optimal cut-off value and corresponding sensitivities and specificities were determined by time-dependent receiver-operating characteristic (ROC) curves. The percentage of indicators in all tumor cells were used to define expression levels. The Kaplan–Meier method and Cox proportional hazards model were used to analyze survival distributions. High TCF1+CD8+T cells infiltration has longer OS than low infiltration (31 vs 17 months, p=0.009, HR=0.506). TCF1+CD8/ CD8 ratio＞21% showed superior OS than ≤21% (31 vs 16 months, p＜0.001, HR=0.394). In patients with high CD8+T infiltration, high ratio shows better OS (32 vs 19 months, P=0.042, HR=0.511). We identified intratumoral stem-like T cells (TCF1+CD8+T) abundance in PSCCE. High infiltration of TCF1+CD8+T cell is related to better clinical outcomes. TCF1+CD8/CD8 ratio is a strong and independent prognostic predictor.

Multi-omics profiling of primary small cell carcinoma of the esophagus reveals RB1 disruption and additional molecular subtypes

Primary small cell carcinoma of the esophagus (PSCCE) is a lethal neuroendocrine carcinoma. Previous studies proposed a genetic similarity between PSCCE and esophageal squamous cell carcinoma (ESCC) but provided little evidence for differences in clinical course and neuroendocrine differentiation. We perform whole-exome sequencing, RNA sequencing and immunohistochemistry profiling on 46 PSCCE cases. Integrated analyses enable the discovery of multiple mechanisms of RB1 disruption in 98% (45/46) of cases. The transcriptomic landscape of PSCCE closely resembles small cell lung cancer (SCLC) but differs from ESCC or esophageal adenocarcinoma (EAC). Distinct gene expression patterns regulated by ASCL1 and NEUROD1 define two molecular subtypes, PSCCE-A and PSCCE-N, which are highly similar to SCLC subtypes. A T cell excluded phenotype is widely observed in PSCCE. In conclusion, PSCCE has genomic alterations, transcriptome features and molecular subtyping highly similar to SCLC but distinct from ESCC or EAC. These observations are relevant to oncogenesis mechanisms and therapeutic vulnerability.

Survival outcomes and prognostic factors of primary small cell carcinoma of the esophagus.

BackgroundPrimary small cell carcinoma of the esophagus (PSCCE) is a rare and aggressive malignancy. It has a poor survival rate, and there is no consensus as to a standard therapeutic modality. In this study, we aimed to investigate the prognostic factors and evaluate the outcomes of patients with PSCCE who had been treated with different therapeutic methods.MethodsWe retrospectively evaluated 113 consecutive patients with PSCCE who received treatment at our center from 2003 to 2016. The primary endpoint was overall survival (OS). The Cox regression model was used to analyze the prognostic factors. The survival analysis was calculated using the Kaplan-Meier and log-rank methods.ResultsThe 12- and 36-month OS rates of all 113 enrolled patients were 45% and 12%, respectively. A significantly prolonged OS rate was associated with lymph node stages N0–N1 (P=0.022), the Veterans’ Administration Lung Study Group (VALSG) system limited-disease (LD) staging (P=0.040), and multimodality treatments (P=0.047). Patients with regional lymph node metastasis benefited more from surgery combined with chemotherapy than surgery or chemotherapy alone (P=0.046). Concerning chemotherapy, cisplatin plus etoposide was the regimen most commonly used to treat PSCCE patients (67.5%).ConclusionsAn early lymph node stage, the VALSG LD staging, and multimodality treatments were identified as independent prognostic factors of PSCCE. Surgery combined with adjuvant chemotherapy was especially necessary for LD stage PSCCE patients with lymph node stages N1–3.

CD155 Overexpression Correlates With Poor Prognosis in Primary Small Cell Carcinoma of the Esophagus.

CD155/TIGIT overexpression has been detected in various human malignancies; however, its expression status in primary small cell carcinoma of the esophagus (PSCCE) and its prognostic significance remain unclear. In this study, we aimed to explore the expression and prognostic value of CD155 and TIGIT in PSCCE. We detected CD155 and TIGIT expression in 114 cases of PSCCE using immunohistochemistry (IHC) and evaluated their relationship with the clinicopathological characteristics and survival of the patients. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards model. Nomogram performance was assessed via the concordance index (C-index) and calibration plots. Decision curve analysis (DCA) was performed to evaluate the net benefit of the nomogram. We found that CD155 and TIGIT were overexpressed in PSCCE tissues, CD155 expression correlated positively with TIGIT (p < 0.001) and was significantly associated with tumor size, T stage, distant metastasis, TNM stage, and Ki-67 score. TIGIT expression was also significantly associated with T stage, distant metastasis, and TNM stage. Patients with high CD155 and TIGIT expression had a significantly shorter overall survival (OS) and progression-free survival (PFS), while the multivariate model showed that CD155 expression and the therapeutic strategy are independent prognostic factors for PSCCE. In the validation step, OS was shown to be well-calibrated (C-index = 0.724), and a satisfactory clinical utility was proven by DCA. In conclusion, our findings revealed that CD155 and TIGIT are highly expressed in patients with PSCCE and are associated with shorter OS and PFS, supporting their role as prognostic biomarker.

Use of Chemoradiotherapy as a Treatment Option for Patients with Limited-Stage Primary Small Cell Carcinoma of the Esophagus.

PurposeCurrently, there are no standard treatments for primary small cell carcinoma of the esophagus (PSCCE), particularly in cases of limited-stage disease. This retrospective study aimed to assess the treatment strategies and the relevant prognostic factors of limited-stage PSCCE (LS-PSCCE).Patients and MethodsWe retrospectively evaluated 129 patients with LS-PSCCE between June 2009 and December 2018. The χ2 test was performed to examine the frequencies between different groups. The Kaplan-Meier and log-rank methods were used to estimate and compare survival rates. Univariate and multivariate analyses were performed to determine the prognostic factors for overall survival (OS).ResultsThrough a median follow-up of 23 months, the median OS of all patients was 25.0 months and the median recurrence-free survival (RFS) was 15.0 months. Univariate and multivariate analyses showed that alcohol abuse (p=0.046) and TNM stage (p<0.001) were independent prognostic factors. There was no significant difference in OS and RFS rates between the patients treated with chemoradiotherapy (CRT) and those treated with surgery and chemotherapy with or without radiotherapy (S+CT±RT) (p>0.05). Patients who received concurrent CRT had better OS and RFS than those who received sequential CRT (p<0.05). Postoperative adjuvant RT for high-risk patients can further improve the local control rate but has no significant effect on OS.ConclusionLS-PSCCE patients treated with CRT had similar OS and RFS compared to those treated with S+CT±RT. This study shows that concurrent CRT confers a survival advantage for patients with LS-PSCCE compared to those with sequential CRT.

Primary small cell carcinoma of the esophagus: progression in the last decade.

Primary small cell carcinoma of the esophagus (PSCCE) is a highly malignant tumor that is diagnosed by endoscopic biopsy and immunohistochemistry. Because of its low incidence, a high degree of malignancy, and rapid progress, it is difficult to conduct large, randomized controlled trials and to establish a standard treatment plan for this disease. In recent years, several retrospective studies have been reported, and with the rise of emerging therapies, PSCCE has gradually become a focus of thoracic surgery. This paper reviews progress in the diagnosis and treatment of PSCCE in recent years.

Prognostic value of pretreatment inflammatory biomarkers in primary small cell carcinoma of the esophagus.

BackgroundGrowing evidence indicates that several inflammatory biomarkers may predict survival in patients with malignant tumors. The aim of this study was to evaluate the prognostic value of pretreatment biomarkers in patients with primary small‐cell carcinoma of the esophagus (PSCCE).MethodsA total of 73 PSCCE patients enrolled between January 2009 and December 2017 at the Affiliated Cancer Hospital of Zhengzhou University. The total lymphocyte counts (TLC), neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐lymphocyte ratio (PLR) prior to anticancer therapy were collected as inflammation biomarkers. The cutoff value was determined by Receiver operating characteristic (ROC). The Kaplan‐Meier method was utilized to analyze overall survival (OS). Cox proportional hazards regression was used to identify univariate and multivariate prognostic factors.ResultsUnivariate analysis showed that high NLR group (hazard ratio [HR] = 1.685; 95% CI: 1.001–2.838; P = 0.047) and high PLR group (hazard ratio [HR] = 1.716; 95% CI: 1.039–2.834; P = 0.033) were associated with poor OS, and TLC was not correlated with OS. On multivariate analysis, high PLR (hazard ratio [HR] = 1.751; 95% CI: 1.042–2.945; P = 0.035) was an independent prognostic factor of unfavorable OS.ConclusionsPretreatment PLR and NLR are correlated with OS. These biomarkers are easily accessible, cost effective, and can serve as a marker to identify high‐risk patients for further designing personalized treatment and predicting treatment outcomes.

Lymph Node Metastasis and Recurrence in Primary Small Cell Carcinoma of the Esophagus: A Retrospective Study of 125 Cases.

Objective: The aim of this study was to investigate and analyze the prognostic factors affecting lymph node (LN) metastasis and postoperative recurrence in patients with primary small cell carcinoma of the esophagus (SCCE). Methods: A total of 125 primary SCCE patients who received surgical resection in the Fourth Hospital of Hebei Medical University between March 2005 and August 2009 were included in this retrospective study. All the potential prognostic variables, including the patients' characteristics, tumor features, and treatment modalities, were analyzed by a Cox regression model to explore LN metastasis and the factors associated with postoperative recurrence. Results: LN metastasis rate was significantly correlated with depth of tumor invasion (p < 0.001) and tumor length (p = 0.006). LN metastasis ratio was positively correlated with pathological type (p < 0.001), tumor location (p = 0.002), depth of tumor invasion (p < 0.001), and tumor length (p < 0.001). LN stage and chemotherapy were found to be the independent risk factors for progression-free survival (PFS). Conclusion: Depth of tumor invasion and tumor length were main factors associated with LN metastasis in primary SCCE. The stage of LN metastasis and chemotherapy was independent factors affecting the postoperative PFS.

Treatment Strategies and Prognostic Factors of Limited-Stage Primary Small Cell Carcinoma of the Esophagus.

Primary small cell carcinoma of the esophagus (PSCCE) is characterized by high malignancy, early metastasis, and poor prognosis. This retrospective study aimed to review the clinical characteristics of patients with limited-stage PSCCE and determine the relevant prognostic factors and optimal treatment strategies. We retrospectively evaluated 152 consecutive patients with limited-stage PSCCE between January 2007 and December 2015. Prognostic factors were analyzed using univariate analysis and a Cox regression model. Subgroup analysis was applied to evaluate the effect of treatment strategy on survival. Univariate and multivariate analyses showed that treatment modality (p= 0.034) and N stage (p= 0.002) were independent prognostic factors. Patients with stage I or IIA PSCCE who underwent an operation alone exhibited better survival than those who did not undergo an operation (median survival time 29 versus 17.4 months [p= 0.031]), and postoperative adjuvant therapy did not increase overall survival or disease-free survival (p > 0.05). The overall survival rate of patients with stage III PSCCE who underwent neoadjuvant chemotherapy (nCT) was significantly better than that of patients who underwent an operation alone or did not undergo an operation (p= 0.021 and p= 0.026, respectively); additionally, nCT could increase disease-free survival (p= 0.031). Treatment modalities and N stage are independent prognostic factors. Radical esophagectomy should be considered as the primary treatment for stage I or IIA PSCCE, and nCT followed by esophagectomy could be an effective treatment option for stage III PSCCE. Multicenter randomized studies are required to confirm the role of nCT in the management of limited-stage PSCCE.

A retrospective study on the prognostic value of preoperative neutrophil/lymphocyte ratio in patients with primary small-cell carcinoma of the esophagus.

IntroductionThere is increasing evidence that systemic inflammation influences the prognosis in patients with malignant tumors. The aim of this research was to investigate the prognostic value of neutrophil/lymphocyte ratio (NLR) in patients with primary small-cell carcinoma of the esophagus.MethodsThis study retrospectively analyzed 129 patients with primary small-cell carcinoma of the esophagus who underwent esophagectomy in The Fourth Hospital of Hebei Medical University between January 2008 and December 2010. NLRs were calculated by using the following formula: peripheral neutrophil count/lymphocyte count (109/L). Correlations of NLR with other clinicopathologic data and prognosis were analyzed. The survival rate was calculated by Kaplan–Meier analysis. The differences between groups were compared by using the log-rank test. Cox regression was used to analyze the factors that may affect the survival of the patients.ResultsThe survival rate was found to be related to tumor stage, tumor location, nodal metastasis, TNM stage, histology, adjuvant therapy, and NLR (all P<0.05). High-NLR group had significantly poorer survival than low-NLR group (1-, 3-, and 5-year survival rates: 46.6% vs 57.1%, 21.9% vs 50.0%, and 5.5% vs 23.2%, respectively, P=0.002). NLR was identified as an independent prognostic factor for patients with primary small-cell carcinoma of the esophagus.ConclusionNLR is a valuable clinical marker in preoperative estimation as well as prognosis prediction for patients with primary small-cell carcinoma of the esophagus.

Adjuvant Therapeutic Modalities in Primary Small Cell Carcinoma of Esophagus Patients: A Retrospective Cohort Study of Multicenter Clinical Outcomes.

To evaluate the treatment pattern and survival of patients receiving radical resection for primary small cell carcinoma of the esophagus (PSCCE).This retrospective study included 150 patients who received radical resection of PSCCE. Data were retrieved from 4 centers in Western China. Thirty-nine of 150 patients received postoperative chemo-radiotherapy, 62 received postoperative chemotherapy, and 49 received radical resection only. The median radiation dosage was 50 Gy. The chemotherapeutic regimen was platinum-based and lasted for 2 to 6 cycles (median, 3).Median disease-free survival (mDFS) and overall survival (mOS) were 12.0 and 18.3 months, respectively. Subgroup analysis revealed that postoperative therapy did not improve survival in limited stage I (LSI) disease, whereas postoperative chemotherapy improved survival in limited stage II (LSII) disease. Relative to chemotherapy alone, chemoradiotherapy did not improve survival in patients with completely resected LSII disease. A multivariate analysis indicated an association of no postoperative chemotherapy with shorter DFS (P = 0.050) and OS (P = 0.010). Higher lymph node stage and length of disease longer than 3 cm were poor prognostic factors for both DFS and OS.Adjuvant chemotherapy improves survival in PSCCE patients with completely resected LSII disease. Adjuvant treatment with postoperative chemotherapy alone or postoperative chemo-radiotherapy does not increase survival in completely resected LSI disease.

Nuclear, cytoplasmic, and stromal expression of ZEB1 in squamous and small cell carcinoma of the esophagus.

Zinc finger E-box-binding homeobox 1 (ZEB1) is a transcriptional factor known to repress E-cadherin promoter and thus induce EMT. Expression of ZEB-1 has in numerous cancers been associated with aggressive disease and poor clinical outcome. Our aim was to investigate the expression of ZEB1 in esophageal squamous- and small-cell carcinomas. Immunohistochemical staining was performed on tissue sections obtained from 151 patients with esophageal squamous cell carcinoma (ESCC) and 25 patients with primary small-cell carcinoma of the esophagus (PSCCE). Semi-quantitative analysis, and thus statistical analysis, has been accomplished on the samples. Immunohistochemistry revealed ZEB1 expression in the cytoplasm (64.9% of cases), in nuclei (11.3% of cases) and in tumor stroma (80.1% of cases) of ESCC. In PSCCE only nuclear staining (88.0% of cases) was observed. Weak cytoplasmic expression of ZEB1 in ESCC was associated with longer survival. Immunohistochemical evaluation of ZEB1 cytoplasmic expression in ESCC may have clinical prognostic value, but further studies are needed to fully understand the function as well as potential clinical and therapeutic implications of ZEB1 expression in cancers.

The 2002 AJCC TNM classification is a better predictor of esophageal primary small cell carcinoma outcome than the VALSG staging system

Small cell carcinoma of the esophagus (SCCE) is a rare and aggressive malignant tumor with a poor prognosis. The optimal disease staging system and treatment approaches have not yet been defined. This study aimed to evaluate the prediction of different staging systems for prognosis and treatment options of SCCE. We retrospectively accessed the clinicopathologic characteristics, treatment strategy, and prognosis of 76 patients diagnosed with primary SCCE between 2001 and 2011. The 1-, 2-, 3-, and 5-year overall survival rates were 58%, 31%, 19%, and 13%, respectively. Univariate analysis showed that the 2002 American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) classification (P = 0.002), Veterans Administration Lung Study Group (VALSG) stage (P = 0.001), predisposing factors (P < 0.001), T category (P = 0.023), and M category (P < 0.001) were prognostic factors for overall survival. Multivariate analysis showed that the 2002 AJCC TNM stage (P < 0.001) was the only independent prognostic factor for survival. The value of the area under the receiver operator characteristic (ROC) curve (AUC) of the 2002 AJCC TNM staging system was larger than that of VALSG staging system with regard to predicting overall survival (0.774 vs. 0.620). None of the single treatment regimens showed any benefit for survival by Cox regression analysis. Thus, the 2002 AJCC TMN staging system improved the prediction of SCCE prognosis; however, the optimal treatment regimen for SCCE remains unclear.

The radiological features of primary small-cell carcinoma of the esophagus

Primary small cell carcinoma of the esophagus is a rare neoplasm. The incidence was 2% in our series. A primary lung tumor must be excluded before the diagnosis can be made. Two cases of primary small-cell carcinoma of the esophagus are presented. The radiological features of this tumor are nonspecific. Its unusual histological appearance is described. One patients had received radiotherapy for breast carcinoma 21 years earlier and the possible relationship of this type of cancer to radiotherapy has not been previously described in the literature. Each patient had a short-term response to therapy.

Primary Small-Cell Carcinoma of the Esophagus

Primary small-cell carcinoma of the esophagus is an uncommon esophageal malignancy. This report details the clinical and pathologic aspects of 11 cases seen at our institution over 20 years, as well as 123 other cases reported in the literature. Small-cell carcinomas of the esophagus show considerable histologic heterogeneity. Neurosecretory granules can be found in the majority of cases and some show evidence of multidifferentiation. Like primary small-cell cancers of the lung, those in the esophagus are highly aggressive, are usually associated with spread at the time of diagnosis, and have a dismal prognosis regardless of treatment. The possible origin of this interesting variety of esophageal neoplasm is also discussed.