Background: Recent clinical trials attempt to determine whether it is appropriate to omit axillary lymph node surgery in patients with cT1–2N0 breast cancer. The study aimed to investigate the true extent of axillary node disease in patients with clinically negative nodes and explore the differences between negative axillary ultrasound (AUS-cN0) and suspicious axillary ultrasound with negative fine-needle aspiration (FNA-cN0). Methods: Pathologically identified T1–2 invasive breast cancer patients with clinically negative nodes were retrospectively analyzed at our center between January 2019 and December 2022. Patients who received any systematic treatment before surgery were excluded from this study. Results: A total of 538 patients were enrolled in this study. 134 (24.9%) patients had pathologically positive nodes, and 404 (75.1%) patients had negative nodes. Univariate analysis revealed that tumor size, T stage, Ki67 level, and vascular invasion (VI) were strongly associated with pathological axillary lymph node positivity. In multivariate analysis, VI was the only independent risk factor for node positivity in patients with cT1–2N0 disease (OR: 3.723, confidence interval [CI]: 2.380–5.824, p < 0.001). Otherwise, pathological node positivity was not significantly different between AUS-cN0 and FNA-cN0 groups (23.4% vs. 28.8%, p = 0.193). However, the rate of high nodal burden (≥3 positive nodes) was significantly higher in FNA-cN0 group. Further investigation revealed that FNA-cN0 and VI were independently associated with a high nodal burden (OR: 2.650, CI: 1.081–6.496, p = 0.033; OR: 3.521, CI: 1.249–9.931, p = 0.017, respectively). Conclusions: cT1–2 breast cancer patients with clinically negative axillary lymph nodes may have pathologically positive lymph nodes and even a high nodal burden. False negatives in AUS and AUS-guided FNA should not be ignored, and sentinel lymph node biopsy remains an ongoing necessity for cT1–2N0 breast cancer patients.

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