Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
Department of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
Mod Pathol. 2018 Jan;31(1):83-92. doi: 10.1038/modpathol.2017.112. Epub 2017 Sep 1.
This study originally aimed to investigate whether the overexpression of SOX2 is associated with the poor prognosis of patients with squamous cell carcinoma of the esophagus. However, we unexpectedly found that esophageal squamous cell carcinomas completely lacking SOX2 expression showed distinct pathologic features and highly aggressive clinical courses. The study cohort consisted of 113 consecutive patients with esophageal squamous cell carcinoma who underwent surgical resection without neoadjuvant therapy. Immunostaining on tissue microarrays and whole sections revealed that 8/113 (7%) cases were entirely negative for this transcriptional factor. SOX2-negative cancers were histologically less differentiated (P=0.002) and showed higher pT and pStages (P=0.003 and 0.007, respectively) than SOX2-positive cases. A remarkable finding was widespread lymphatic infiltration distant from the primary invasive focus, which was observed in 4 SOX2-negative cancers (50%), but none of the SOX2-positive cases. All separate dysplastic lesions observed in SOX2-negative cases were also SOX2-negative. The negative expression of SOX2 appeared to be an independent poor prognostic factor (OR=7.05, 95% CI=1.27-39.0). No mutations were identified in the coding or non-coding regions of SOX2. Fluorescent in situ hybridization did not show any copy-number variations in this gene. Since the SOX2 promoter contains an extensive CpG island, SOX2-negative cases underwent methylation-specific PCR, which disclosed promoter hypermethylation in all cases. In conclusion, SOX2-silenced squamous cell carcinomas of the esophagus appear to be a minor, but distinct form of malignancy characterized by extensive lymphatic invasion, a poor prognosis, and potential association with multiple SOX2-negative neoplastic lesions. The hypermethylation of the promoter region is seemingly a critical epigenetic event leading to SOX2 silencing.
本研究最初旨在探讨 SOX2 的过表达是否与食管鳞状细胞癌患者的不良预后相关。然而，我们意外地发现，完全缺乏 SOX2 表达的食管鳞状细胞癌具有明显的病理特征和高度侵袭性的临床病程。研究队列包括 113 例连续接受手术切除且未接受新辅助治疗的食管鳞状细胞癌患者。组织微阵列和全切片的免疫组化染色显示，有 8/113（7%）例患者完全缺乏这种转录因子。SOX2 阴性癌症在组织学上分化程度较低（P=0.002），且 pT 和 pStages 更高（分别为 P=0.003 和 0.007）。一个显著的发现是广泛的淋巴管浸润远离原发性浸润灶，在 4 例 SOX2 阴性癌症（50%）中观察到，但在 SOX2 阳性病例中则没有。在 SOX2 阴性病例中观察到的所有单独的发育不良病变也是 SOX2 阴性。SOX2 的阴性表达似乎是一个独立的不良预后因素（OR=7.05，95%CI=1.27-39.0）。在 SOX2 的编码或非编码区未发现突变。荧光原位杂交也未显示该基因的任何拷贝数变异。由于 SOX2 启动子含有广泛的 CpG 岛，SOX2 阴性病例进行了甲基化特异性 PCR，结果显示所有病例均存在启动子超甲基化。总之，沉默的食管鳞状细胞癌似乎是一种少见但独特的恶性肿瘤形式，其特征为广泛的淋巴管浸润、不良预后以及与多个 SOX2 阴性肿瘤病变的潜在关联。启动子区域的甲基化似乎是导致 SOX2 沉默的关键表观遗传事件。
