Axillary Lymph Node Nanometastases Are Prognostic Factors for Disease-Free Survival and Metastatic Relapse in Breast Cancer Patients

Abstract

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 V0.2 mm in diameter [pN 0(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 0(i+) versus pN 0(iÀ) was 2.51 (P = 0.00019). Hazards of pN 1mi and pN 0(i+) cases were not significantly different. A multivariate Cox model showed a hazard ratio of 2.16 for grouped pN 0(i+) /pN 1mi versus pN 0(iÀ) (P = 0.0005). Crude cumulative incidence curves for metastatic relapse were also significantly different (Gray's test m 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.The tumor-node-metastasis (TNM) staging system for breast cancer (1) has proven invaluable in categorizing the extent of neoplastic disease, and as a basis to estimate prognosis and to direct treatment (2). However, this has not lead to the definition of tightly homogeneous prognostic classes, as considerable heterogeneity of outcomes can be observed among disease cases currently categorized as similar. This is particularly evident in the case of small breast tumors (2). We argued that a diverse extent of lymph node dissemination at early stages of disease may account for diverse disease recurrence dynamics. The principle that the macroscopic burden of metastatic cells (e.g., number of invaded lymph nodes) dictates different risks of disease recurrence has been recognized (1,3). This principle might be equally important at the low end of the spectrum, i.e., in the case of microscopic tumor cell deposits (1, 4).Serial sectioning coupled to immunohistochemical analysis has considerably improved the detection of small tumor cell clusters in lymph nodes (5 -10). Occult metastases can indeed be identified in up to 30% of cases previously classified as pN 0 (7 -9), in 14% to 20% of the cases by single lymph node sections (9, 10). Studies based on these procedures have shown that axillary lymph node microinvasion is a prognostic factor for breast cancer patients, and is associated with poorer diseasefree and overall survival (7, 8, 11 -13). As a consequenc...

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