The prognostic importance of immunohistochemically detected node metastases in resected esophageal adenocarcinoma.

BACKGROUND: The number or ratio of lymph node metastases detected by hematoxylin & eosin (H&E) staining is the most important predictor of survival in esophageal cancer. The survival effect of lymph node metastases detected on immunohistochemistry (IHC) is controversial. My colleagues and I hypothesized that the extent of nodal disease determined by both H&E and IHC examination would more accurately predict survival than either technique alone.
METHODS: The study population consisted of 37 patients who underwent en bloc esophagectomy as primary therapy for esophageal adenocarcinoma 5 or more years ago. All had mediastinal and upper abdominal lymphadenectomy. No patient received neoadjuvant or adjuvant therapy. Tissue blocks were sectioned for H&E staining to confirm the initial histology, and a second slide was stained with monoclonal antibodies AE1 and CAM 5.2, which are directed at a number of cytokeratin antigens. The slides were reviewed by an investigator blinded to clinical outcome. The effect of IHC staining on prognosis was assessed by comparing 5-year survival based on H&E and IHC findings.
RESULTS: A total of 1,970 nodes were examined in the 37 patients. Routine H&E staining detected metastases in 29 patients (78%); the remaining 8 with N0 disease all survived at least 5 years after operation (median not reached). In the 29 patients with N1 disease, survival was 41% at 5 years. In 20 of the 29 N1 patients, metastases were detected by H&E in less than 10% of the nodes removed; 55% of the patients survived 5 years, and 39% survived 8 years. Nine of the 29 patients had metastases detected in more than 10% of the nodes removed, and all died at a median of 17 months. IHC staining was performed on the nodes from the 8 N0 patients and the 20 patients with less than 10% nodal involvement (a total of 28 patients). Additional nodal metastases, not identified on H&E examination, were found in 51 nodes from 17 patients (60.7%). Of the 8 patients who were node negative on H&E examination, 3 had metastases detected by IHC, and all survived 5 years or more free of disease. Of the 20 patients with less than 10% nodal metastases on H&E, 14 (70%) had additional metastases detected by IHC (median, 2 nodes per patient). When combined with the results of H&E staining, the node ratio remained less than 10% in 13 patients and exceeded 10% in 7. Survival in patients whose ratio remained less than 10% was significantly better than in those whose ratio exceeded 10% (actual 5-year survival, 77% vs 14%; chi2 = 4.662; p = 0.03).
CONCLUSIONS: IHC staining techniques can identify nodal metastases missed by routine H&E examination in a large number of patients. The combination of H&E and IHC examination is useful in patients with less than 10% nodal involvement by H&E examination in that IHC detection of micrometastases allows classification into low-risk (> 75% survival) and high-risk (< 15% survival) groups. IHC-detected micrometastases are not of prognostic importance in N0 patients or those with greater than 10% nodal metastases on H&E.