Axillary lymph node nanometastases are prognostic factors for disease-free survival and metastatic relapse in breast cancer patients

Purpose: Early breast cancer presents with a remarkable heterogeneity of outcomes. Undetected, microscopic lymph node tumor deposits may account for a significant fraction of this prognostic diversity. Thus, we systematically evaluated the presence of lymph node tumor cell deposits <= 0.2 mm in diameter [pN(o(i+)), nanometastases] and analyzed their prognostic effect. Experimental Design: Single-institution, consecutive patients with 8 years of median follow-up (n= 702) were studied. To maximize chances of detecting micrometastases and nanometastases, whole-axilla dissections were analyzed. pN(0) cases (n= 377) were systematically reevaluated by lymph node (n= 6676) step-sectioning and anticytokeratin immunohistochemical analysis. The risk of first adverse events and of distant relapse of bona fide pN(0) patients was compared with that of pN(0(i+)), pN(1mi), and pN(1) cases. Results: Minimal lymph node deposits were revealed in 13% of pN(0) patients. The hazard ratio for all adverse events of pN(o(i+)) versus pN(o(i-)) was 2.51 (P= 0.00019). Hazards of pN(1mi) and pN(o(i+)) cases were not significantly different. A multivariate Cox model showed a hazard ratio of 2.16 for grouped pN(o(i+))/pN(1mi) versus pN(o(i-)) (P= 0.0005). Crude cumulative incidence curves for metastatic relapse were also significantly different (Gray's test chi(2)= 5.54, P= 0.019). Conclusion: Nanometastases are a strong risk factor for disease-free survival and for metastatic relapse. These findings support the inclusion of procedures for nanometastasis detection in tumor-node-metastasis staging.