Immunohistochemically detected micrometastasis in lymph nodes from superficial esophageal squamous cell carcinoma

BACKGROUND AND OBJECTIVES: This study was conducted to determine the incidence and clarify the patterns of nodal micrometastasis, to elucidate the histopathologic parameters of tumor extension correlating with micrometastasis, and to evaluate whether nodal micrometastasis has clinical significance in patients with superficial esophageal cancer. METHODS: Lymph nodes resected from 78 patients with superficial esophageal squamous cell carcinoma were examined immunohistochemically using the monoclonal antibody cocktail AE1/AE3 to define histologically undetectable micrometastasis. Clinical records and pathologic features of all cases were reviewed. RESULTS: Of the 78 patients, 34 had neither micro- nor overt disease in the lymph nodes, 12 had nodal micrometastasis only, and 32 had histologically overt metastasis. Nodal micrometastasis was found in carcinomas reaching the muscularis mucosae or deeper tissues of the esophagus. Multivariate analysis showed that intraesophageal multicentric cancer and venous invasion had significant correlation with nodal micrometastasis (P = 0.005 and 0.017, respectively). However, no clinical impact of nodal micrometastasis could be detected regarding patient outcome. CONCLUSIONS: Nodal micrometastasis is not rare in patients with superficial esophageal cancer, but it does not appear to have clinical significance in these patients. Nodal micrometastasis correlates with intraesophageal multicentric cancer and venous invasion.     

Prognostic relevance of tumor-resident memory T cells in metastatic lymph nodes of esophageal squamous cell carcinoma

Tumor-resident memory T (T_RM) cells in primary tumors are reportedly associated with a favorable prognosis in several malignancies. However, the behaviors and functions of T_RM cells in regional lymph nodes (LNs) of esophageal cancer remain poorly understood. The aim of this study was to elucidate the effects of T_RM cells in regional LNs of esophageal cancer on clinicopathological findings and prognosis. Specimens of esophageal cancer and primary metastatic LNs (recurrent nerve LNs) were obtained from 84 patients who underwent radical esophagectomy between 2011 and 2017. We performed immunohistochemistry to enumerate and analyze T_RM cells, and used flow cytometry to investigate the function of T_RM cells. T_RM cells were observed in both metastatic LNs and primary tumors. T_RM cell-rich specimens exhibited reduced lymphatic invasion and LN metastasis and prolonged survival compared with T_RM cell-poor specimens. T_RM cells in metastatic LNs were more significantly associated with enhanced survival than T_RM cells in primary tumors. T_RM cells expressed high levels of granzyme B as a cytotoxicity marker. Our results suggested that high T_RM cell infiltration in metastatic LNs improves survival even though LN metastasis is commonly associated with poor prognosis. T_RM cells possibly contribute to antitumor immunity in regional LNs.     

食管癌转移淋巴结多层螺旋CT诊断标准探讨

目的：通过多层螺旋CT薄层多平面重建图像所见与病理结果对照，探讨转移淋巴结的诊断标准。方法以病理诊断为金标准，回顾性分析208例胸段食管癌患者淋巴结的术前多层螺旋CT多平面重建图像，测量淋巴结的长径、短径，计算出直径比（短径/长径，将淋巴结直径比≥0.7视为圆形淋巴结），同时观察淋巴结有无环形强化、成簇分布、边缘模糊等影像学特征，分析比较各项指标的诊断价值。结果以短径≥1.0 cm作为转移淋巴结的诊断标准，敏感度为23.6%，特异度为98.6%，约登指数为0.22。以短径≥0.8 cm作为转移淋巴结诊断标准，对于短径＜0.8 cm的淋巴结运用直径比≥0.7作为诊断转移的标准，诊断效能有了明显的提高，敏感度为83.8%，特异度为82.9%，约登指数为0.67。以淋巴结有“环形强化”或“边缘模糊”征象作为诊断标准的阳性预测值分别为62.2%、89.4%。结论用较小的短径作为转移淋巴结的诊断标准，能提高诊断效能；直径比有助于提高CT术前诊断转移淋巴结的价值；边缘模糊、环形强化可作为诊断转移淋巴结的参考标准。     

食管鳞癌上纵隔1与2区淋巴结转移适形调强放疗回顾性分析

目的：探讨食管鳞癌根治术后上纵隔1与2区淋巴结转移患者放射治疗的疗效及预后影响因素。方法：回顾性分析2008—09—22—2012—04—19南京大学医学院附属鼓楼医院收治的36例食管鳞癌根治术后上纵隔1与2区淋巴结转移患者的临床资料,36例患者均接受了三维适形或调强适形放疗,联合化疗27例。生存分析和多因素分析分别采用Kaplan Meier法和Cox比例风险模型。结果：36例患者放疗结束后总有效率（CR＋PR）为77．8％（28／36）,其中CR22．2％（8／36）,PR55．6％（20／36）,SD22．2％（8／36）,PD0（0／36）;中位生存期为13个月,6个月、1和2年生存率分别为70．4％、52．5％和26．0％。单因素分析显示,术后分期（P=0．015）、转移淋巴结最大径（P=0．017）、放疗剂量（P=0．027）及放疗后是否达CR（P=0．026）对于食管鳞癌术后上纵隔1与2区转移淋巴结放疗疗效有显著影响。Cox多因素分析表明,术后分期（P=0．006）和放疗剂量（P=0．010）为独立的预后影响因子。结论：食管鳞癌根治术后发生上纵隔1与2区淋巴结转移者,可采用三维适形或调强适形放疗作为补救治疗方案,术后临床分期较早或高剂量放疗组放射治疗后的预后分别优于术后分期晚及低剂量放疗组。     

胸段食管癌放疗靶区外淋巴结转移规律的临床研究

目的：探讨胸段食管癌的淋巴结转移规律及其放疗靶区外淋巴结转移的概率。方法：对首程行颈、胸、腹三野淋巴结清除根治术的胸段食管鳞癌患者651例,进行,临床病理资料分析。分析各段食管癌放疗靶区外淋巴结转移的概率。结果：胸上、中、下段食管癌淋巴结转移率颈部分别为43．2%（35／81）、27．2％（129／474）和7．2％（7／97）,上纵隔分别为30．9％（25／81）、23．40%（111／474）和9．3％（9／97）,中纵隔分别为13．6％（11／81）、29．1％（138／474）和30．9％（30／97）,下纵隔分别为1．2％（1／81）、3．8％（18／474）和17．5％（17／97）;腹部分别为11．1％（9／81）、24．5％（116／474）和52．6％（51／97）。胸上、中、下段食管癌总放疗靶区外淋巴结转移率分别为27．2％（22／81）、40．7％（193／474）和40．2％（39／97）。食管癌放疗靶区外淋巴结转移率与病变长度（x^2=7．093,P=0．029）、T分期（x^2=17．330,P=0．001）呈正相关;与肿瘤分化程度呈负相关,x^2=14．969,P=0．001;与病变部位无相关性,x^2=5．421,P=0．066。结论：胸段食管鳞癌淋巴结转移具有上下双向转移和跳跃性转移特点。以病变上下两端各扩大5cm为放疗靶区,靶区外有较高的淋巴结转移率,值得今后设计食管癌放疗靶区的注意。     

Paraaortic lymph node micrometastasis and tumor cell microinvolvement in advanced gastric carcinoma

Background. Paraaortic lymph node dissection in advanced gastric carcinoma is controversial. The purpose of this study was to investigate the incidence and significance of micrometastasis (MM) or tumor cell microinvolvement (TCM) in these critical lymph nodes. Methods. A total of 2339 lymph nodes, including 390 paraaortic nodes, obtained from 47 patients with advanced gastric carcinoma were examined immunohistochemically, using cytokeratin antibody. Results. Lymph node metastasis was found in 95 of the 390 paraaortic nodes of 14 patients by routine histological examination. MM or TCM was immunohistochemically detected in 45 of the 295 negative paraaortic lymph nodes from 15 of 33 patients (MM, n = 5; TCM, n = 10). The 5-year-survival rate in the paraaortic node-negative group and cytokeratin-positive group was significantly higher that that of the hematoxilin and eosin-positive group. The total number of lymph node metastases by hematoxylin and eosin staining and the pathological lymph node compartments, by cytokeratin-positive nodes, were prognostic factors by multivariate analysis. Conclusions. We demonstrated a high rate of MM or TCM in the paraaortic lymph nodes and suggest that such harbored metastases are related to the prognosis of patients with advanced gastric carcinoma. On the basis of this study, a multi-institutional study should be considered. Received for publication on June 7, 1999; accepted on Sept. 30, 1999     

56例同时性多原发食管鳞癌淋巴结转移因素分析

目的:探讨同时性多原发食管鳞癌(synchronous multiple primary esophageal squamous cell carcinoma,SMESC)淋巴结转移的特点及预后因素。方法:收集2011年1月至2018年12月收治的56例SMESC患者的临床病例资料,回顾分析各部位的淋巴结转移率,研究不同癌灶浸润深度、长度等因素对淋巴结转移的影响。结果:56例SMESC患者中34例有淋巴结转移,淋巴结转移率为60.7%,颈部、上、下纵隔和腹部的淋巴结转移率分别为16.7%、34.7%、32.7%和38.2%。不同癌灶部位淋巴结转移规律不同,但在上、下纵隔及腹部均有广泛转移。单因素分析结果显示,淋巴结转移与癌灶长度及浸润深度有关(P<0.05)。多因素分析结果表明,原发癌灶浸润深度和清扫淋巴结数目是淋巴结转移的独立预后因素。结论:食管癌McKeown术式及系统淋巴结清扫是目前治疗SMESC的最佳治疗手段。     

胸段食管鳞癌颈部淋巴结转移特点及其临床意义

背景与目的：食管癌颈部淋巴结转移率较高,但少有专门报道。本研究分析胸段食管鳞癌颈部淋巴结转移特点,探讨其临床意义。方法：选择1993年1月—2003年12月在福建省肿瘤医院行胸段食管鳞癌三野淋巴结清扫根治术患者1 131例,对术后病理证实颈部淋巴结转移患者376例的具体情况进行分析。结果：全组颈部淋巴结转移率为33.2%,其中胸上、中及下段的颈部淋巴结转移率分别为43.7%、33.0%和16.0%。单因素分析显示,颈部淋巴结转移率与肿瘤部位、病理分化程度、病变X线长度、pT分期以及淋巴结转移个数有关(P<0.05),但多因素回归分析显示,颈部淋巴结转移率只与肿瘤部位、pT分期及淋巴结转移个数有关(P<0.05)。颈段食管旁淋巴结转移最多见,其次是锁骨上淋巴结转移,颈深淋巴结及咽后淋巴结转移少见;胸上、中及下段的颈部淋巴结转移数占该段淋巴结总转移数的比率分别为57.7%、32.0%和10.0%,差异有统计学意义(P<0.05);各段食管癌右颈部淋巴结转移多于左颈部。结论：影响胸段食管鳞癌颈部淋巴结转移独立因素是肿瘤部位、pT分期及淋巴结转移数;颈段食管旁淋巴结转移最多见,其次是锁骨上淋巴结转移,颈深淋巴结及咽后淋巴结转移少见。     

Prognostic significance of the size of cancer nests in metastatic lymph nodes in human esophageal cancers

BACKGROUND: Postoperative survival of patients with esophageal cancers after curative surgery is strongly affected by the presence of lymph node metastasis. The number and location of lymph node metastases have been evaluated and graded, but the clinical significance of their size has not been well investigated. METHODS: Of 322 esophageal cancer patients who underwent curative operations with radical lymph node dissection, 170 (53%) had lymph node metastasis. A total of 784 metastatic lymph nodes were obtained, and the area of the cancer nests was measured microscopically in the cross section. The data from each patient included the area of the largest cancer nest in the positive nodes (Nmax), classified as Na (<4 mm2), Nb (4-25 mm2), Nc (25-100 mm2), or Nd (>100 mm2). RESULTS: The 170 patients were classified according to the Nmax value: Na, 31 (18.2%); Nb, 35 (20.5%); Nc, 49 (28.8%); and Nd, 55 (32.4%). The 5-year survival rate was 77.7% in patients without lymph node metastasis and 35.4% in those with lymph node metastasis. When classified by Nmax, the 5-year survival rate was 77.8% for Na, 63.9% for Nb, 18.8% for Nc, and 12.8% for Nd. There was no significant difference in the survival rate between Na patients and those without lymph node metastasis. Nmax showed significant correlation with the primary tumor size, depth of tumor invasion, and number and location of metastatic lymph nodes, but not with histologic type or primary tumor location. In multivariate analysis, the Nmax value, the number of lymph node metastases and depth of tumor invasion were independent prognostic factors, while the location of the lymph node metastases was not statistically significant. CONCLUSIONS: The area of the largest cancer nest in the lymph nodes was one of the most significant prognostic factors for esophageal cancers. This estimation is objective and reproducible and may be of great importance when deciding the therapeutic modality for patients with esophageal cancers.     

Histone demethylase GASC1, a potential prognostic and predictive marker in esophageal squamous cell carcinoma

Gene amplified in squamous cell carcinoma 1 (GASC1) is a member of Jumonji C-domain containing histone demethylases that play an essential role in affecting chromatin architecture and gene expression. The purpose of this study was to determine the expression features and the clinical significance of GASC1 in esophageal squamous cell carcinoma (ESCC). GASC1 expression was detected on tissue microarrays of ESCC samples in 185 cases using immunohistochemical staining. Strong nuclear staining for GASC1 was observed in a subset of ESCC samples. The nuclear expression of GASC1 was significantly associated with lymph node metastasis (P=0.030) and tumor-node metastasis stages (P=0.013). Kaplan-Meier survival analysis showed a tendency that high expression of GASC1 in the nucleus was associated with poor survival of ESCC patients, with a 5-year survival rate of 26.5%, as compared to 43.7% for patients with GASC1-negative/low expression. Furthermore, multivariate analysis revealed that high expression of GASC1 likely acts as a predictive factor for overall survival of ESCC patients, despite the P-value failing to reach significance (P=0.059). The findings indicate that histone demethylase GASC1 may play an important role in promoting cancer metastasis, and shed new light on the importance of targeting GASC1 to suppress metastatic disease in various tumor types, including ESCC.     

Detection of lymph node metastases in esophageal cancer

Lymph node status is the most important single prognostic factor in esophageal cancer. The detection of involved lymph nodes is therefore the key to cure. This article will provide a meta-analysis and metaregression analysis on the diagnostic performances of current lymph node-detection devices; discuss the recent status of the sentinel lymph node concept in esophageal cancer by the two sentinel node-mapping procedures (the radio-guided and the blue dye techniques) and the developing computed tomography (CT) lymphography; discuss the detection of micrometastases; and the potential clinical application of molecular-based patients’ profiles. Combined use of endoscopic ultrasonography fine-needle aspiration and CT significantly improves the diagnostic performance for regional lymph node metastases. Endoscopic ultrasonography is highly sensitive and specific for celiac lymph node metastases, while CT should mostly be performed in order to exclude other abdominal lymph node metastases. Sentinel lymph node navigation may be feasible for cT1N0 or cT2N0 esophageal cancer, and immunohistochemical staining of micrometastatic disease might be feasible in combination with this modality.     

Prognosis of patients with esophageal squamous cell carcinoma after esophagectomy using the log odds of positive lymph nodes

To compare the log odds of positive lymph nodes (LODDS) with the number of positive lymph nodes (pN), lymph node ratio (LNR), removed lymph node (RLN) count, and negative lymph node (NLN) count in determining the prognosis of patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. The records of patients with ESCC who received esophagectomy were retrospectively reviewed. The log-rank test was used to compare curves for overall survival (OS), and Cox regression analysis was performed to identify prognostic factors. The prognostic performance of the different lymph node staging systems were compared using the linear trend chi-square test, likelihood ratio chi-square test, and Akaike information criterion. A total of 589 patients were enrolled. Univariate Cox analysis showed that pN stage, LNR, RLN count, NLN count, and the LODDS were significantly associated with OS (p < 0.05 for all). Multivariate Cox analysis adjusted for significant factors indicated that LODDS was independent risk factor on overall survival (OS), and a higher LODDS was associated with worse OS (hazard ratio = 3.297, 95% confidence interval: 2.684–4.050, p < 0.001). The modified Tumor-LODDS-Metastasis staging system had better discriminatory ability, monotonicity, and homogeneity, and better optimistic prognostic stratification than the Tumor-Node-Metastasis staging system in determining the prognosis of patients with ESCC. The LODDS staging system was superior to other lymph node classifications in determining the prognosis of patients with ESCC after esophagectomy. LODDS may be incorporated into esophageal staging system if these results are eventually confirmed by other studies.     

初始无转移食管鳞癌放化疗后淋巴结转移的临床分析

目的：分析可能影响临床无转移食管鳞癌患者接受根治性放（化）疗后出现淋巴结转移的因素。方法：选取2002年1月至2009年12月于河北医科大学第四医院放疗科接受治疗的263 例食管鳞癌患者,分析患者一般临床资料及肿瘤局部因素中可能影响患者治疗后出现淋巴结转移的因素。结果：全组263 例食管癌患者治疗后出现淋巴结转移31例（11.8%）,其中18例为单纯淋巴结转移,余13例淋巴结转移患者伴有其他脏器转移和（或）食管复发。胸上段、胸中段及胸下段食管癌患者淋巴结转移分别为11例（13.3%）、13例（10.1%）及7 例（13.7%）。 单因素分析结果显示患者近期疗效、食管病变造影长度、病变最大横径及病变体积为影响患者治疗后出现淋巴结失败的因素（χ2= 7.597、9.717、5.361、4.815;P = 0.006、0.002、0.021、0.028）;Logistic多因素分析结果显示食管病变造影长度及近期疗效为患者治疗后出现淋巴结转移的独立影响因素（P = 0.004、0.026）。 结论：食管病变造影长度及即时疗效为影响临床无转移食管鳞癌患者接受根治性放（化）疗后出现淋巴结转移的主要因素。     

Phosphatase of regenerating liver‐3 as a convergent therapeutic target for lymph node metastasis in esophageal squamous cell carcinoma

Phosphatase of regenerating liver‐3 (PRL‐3) is a molecule associated with metastasis in a diverse of cancers, which, however, remains largely unknown in esophageal squamous cell carcinoma (ESCC). We examined both the clinical significance of PRL‐3 expression and its biological roles, and assessed possibilities as a therapeutic target in ESCC. PRL‐3 expression was found in 78% (69 of 88) of the primary ESCC on immunohistochemistry; it was the strong independent predictor for lymph node metastasis (LNM) on a multivariate logistic regression model (p = 0.0014, relative risk =15.20). Additionally, gene amplification was found in 3 (7.9%) of the 38 primary tumors with PRL‐3 overexpression by fluorescence in situ hybridization, but in none of the 19 tumors without it. PRL‐3 small interfering RNA robustly repressed cell proliferation, anchorage‐independent colony formation and invasion and augmented 5‐FU‐induced apoptosis in all the tested ESCC cell lines with PRL‐3 overexpression, irrespective of its gene amplification status. PRL‐3 inhibitor (1‐4‐bromo‐2‐benzylidene rhodanine) also suppressed such metastatic properties in the cell lines with PRL‐3 overexpression, but not with its low expression. Inverse effects were observed by PRL‐3 forced expression. Collectively, PRL‐3 overexpression is a frequent event associated with LNM and plays a causative role in promoting cancer progression. Moreover, the expression status may be a landmark to select patients with benefit from PRL‐3‐targeted therapy. Thus, PRL‐3 could be a convergent therapeutic target against ESCC with LNM.