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

Authors' Affiliations: ¹ Department of Experimental and Diagnostic Medicine, Section of Anatomic Pathology, University of Ferrara, Ferrara, Italy; ² Unit of Medical Statistics and Biometry, National Cancer Institute of Milano; ³ Institute of Medical Statistics and Biometry, University of Milano, Milan, Italy; and ⁴ Department of Oncology and Neurosciences and Unit of Cancer Pathology, CeSI, "G. d'Annunzio" Chieti University Foundation, Chieti, Italy

Requests for reprints: Saverio Alberti, Unit of Cancer Pathology, Center of Excellence in Research on Aging, University "G. d' Annunzio," Via Colle dell' Ara, 66013 Chieti Scalo (Chieti), Italy. Phone: 39-0871-541-551; Fax: 39-0871-541-551; E-mail: s.alberti{at}unich.it.

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_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. pN₀ 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 pN₀ patients was compared with that of pN_0(i+), pN_1mi, and pN₁ cases.

Results: Minimal lymph node deposits were revealed in 13% of pN₀ patients. The hazard ratio for all adverse events of pN_0(i+) versus pN_0(i–) 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(i–) (P = 0.0005). Crude cumulative incidence curves for metastatic relapse were also significantly different (Gray's test 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.

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