Analysis of micrometastatic disease in histologically negative lymph nodes of patients with adenocarcinoma of the distal esophagus or gastric cardia

Lymphatic dissemination is the most important prognostic factor in patients with esophageal carcinoma. However, the clinical significance of lymph node micrometastases is still debated due to contradictory results. The aim of the present study was to identify the incidence of potentially relevant micrometastatic disease in patients with histologically node-negative esophageal adenocarcinoma and to analyze the sensitivity and specificity of three different immunohistochemical assays. From a consecutive series of 79 patients who underwent a transthoracic resection with extended 2-field lymphadenectomy, all 20 patients with pN0 esophageal adenocarcinoma were included in this study. A total of 578 lymph nodes were examined for the presence of micrometastases by immunohistochemical analysis with the antibodies Ber-EP4, AE1/AE3 and CAM 5.2. Lymph node micrometastases were detected in five of the 20 patients (25%). They were identified in 16 of the 578 lymph nodes examined (2.8%) and most frequently detected with the Ber-EP4 and AE1/AE3 antibody (sensitivity 95% and 79% respectively). In 114 of the 559 negative lymph nodes (20.4%), positive single cells were found that did not demonstrate malignant characteristics. These false-positive cells were more frequently found with the AE1/AE3 staining (specificity of the Ber-Ep4 and AE1/AE3 antibody 94% and 84% respectively). The presence of nodal micrometastases was associated with the development of locoregional recurrences (P=0.01), distant metastases (P=0.01), and a reduced overall survival (log rank test, P=0.009). For the detection of clinically relevant micrometastatic disease in patients operated upon for adenocarcinoma of the distal esophagus or gastric cardia, Ber-EP4 is the antibody of first choice because of its high sensitivity and specificity. Immunohistochemically detected micrometastases in histologically negative lymph nodes have potential prognostic significance and are associated with a high incidence of both locoregional and systemic recurrence. Therefore, this technique has the potential to refine the staging system for esophageal cancer and to help identify patients who will not be cured by surgery alone.