在食管腺癌中,淋巴结转移的存在可预测患者即使在根治性切除后也能生存。目前,没有高度准确的标志物来检测淋巴结转移的存在。SEMA3F/NRP2轴最初是在轴突引导中表征的,最近的证据表明它显著参与淋巴管生成,血管生成,和致癌作用。因此,本研究的目的是阐明SEMA3F及其受体NRP2在食管腺癌中的作用。我们对在科隆大学医院接受Ivor-Lewis食管切除术的776例食管腺癌患者的SEMA3F和NRP2蛋白表达进行了免疫组织化学评估。使用QuPath数字分析总癌细胞计数和阳性癌细胞计数,并由有经验的病理学家验证以确保准确性。阳性表达被确定为超过第50百分位数阈值的细胞百分比。在我们的队列中,显示SEMA3F阳性表达的患者经历显著降低的pT-和pN-阶段。相比之下,NRP2阳性表达与淋巴结转移有关。存活分析显示NRP2的表达状态对患者存活没有影响。然而,SEMA3F阳性与良好的患者生存结局相关(中位OS:38.9vs.26.5个月)。此外,SEMA3F可以被证实为肿瘤早期患者更好生存的独立因素(pT1N0-3:HR=0.505,p=0.014,pT1-4N0:HR=0.664,p=0.024,pT1N0:HR=0.483,p=0.040)。总之,SEMA3F是早期食管腺癌患者预后良好的独立预测因子。此外,NRP2表达与淋巴结转移发生的较高风险有关。我们假设低SEMA3F表达可以识别早期肿瘤患者,这些患者可能受益于更积极的治疗选择或强化的随访。此外,应探索SEMA3F及其相关途径作为潜在的肿瘤抑制剂。
In esophageal adenocarcinoma, the presence of lymph node metastases predicts patients\' survival even after curative resection. Currently, there is no highly accurate marker for detecting the presence of lymph node metastasis. The SEMA3F/NRP2 axis was initially characterized in axon guidance and recent evidence has revealed its significant involvement in lymphangiogenesis, angiogenesis, and carcinogenesis. Hence, the objective of this study was to elucidate the roles of SEMA3F and its receptor NRP2 in esophageal adenocarcinoma. We conducted an immunohistochemical evaluation of SEMA3F and NRP2 protein expression in 776 patients with esophageal adenocarcinoma who underwent Ivor-Lewis esophagectomy at the University Hospital of Cologne. Total and positive cancer cell counts were digitally analyzed using QuPath and verified by experienced pathologists to ensure accuracy. Positive expression was determined as a cell percentage exceeding the 50th percentile threshold. In our cohort, patients exhibiting SEMA3F positive expression experience significantly lower pT- and pN-stages. In contrast, positive NRP2 expression is associated with the presence of lymph node metastases. Survival analyses showed that the expression status of NRP2 had no impact on patient survival. However, SEMA3F positivity was associated with a favorable patient survival outcome (median OS: 38.9 vs. 26.5 months). Furthermore, SEMA3F could be confirmed as an independent factor for better patient survival in patients with early tumor stage (pT1N0-3: HR = 0.505, p = 0.014, pT1-4N0: HR = 0.664, p = 0.024, pT1N0: HR = 0.483, p = 0.040). In summary, SEMA3F emerges as an independent predictor for a favorable prognosis in patients with early-stage esophageal adenocarcinoma. Additionally, NRP2 expression is linked to a higher risk of lymph node metastases occurrence. We hypothesize that low SEMA3F expression could identify patients with early-stage tumors who might benefit from more aggressive treatment options or intensified follow-up. Furthermore, SEMA3F and its associated pathways should be explored as potential tumor-suppressing agents.