The standard operation for patients with early breast cancer and clinically negative nodes includes total or partial mastectomy and SLNB. In the present study, we studied the FNSN of frozen sections during the first operation. A case-matched control study was designed with a one-to-three ratio. The patients with FNSN had a larger tumor size in preoperative mammography and an increased ratio of LTE in CNB. The patients with FNSN had a greater number of SNs during the first operation. LTE was the only predictive variable for FNSN in multivariate analysis. Metastasis was detected in non-relevant SNs of four FNSN patients and in relevant SNs from FFPE sections of 16 patients, which was not found during intraoperative frozen sections. Seven FNSN patients had micrometastasis in SNs. Two FNSN patients had metastasis in SNs and non-sentinel axillary lymph nodes (ALNs). All 20 FNSN patients received secondary operation with ALND. Long-term outcomes of patients with FNSN or controls were similar, with no difference in DFS, BCSS, and OS between the two groups. No breast cancer-associated events developed in patients with FNSN.
Some investigators advise that intraoperative assessment is reserved for patients with clinically positive nodes or those with aggressive diseases after neoadjuvant chemotherapy (16). The cost-benefit characteristic of the frozen section is one of the reasons. Other researches still recommend intraoperative assessment of SNs. For breast cancer with clinically negative nodes, intraoperative frozen section has a sensitivity of 87%, a specificity of 100%, and a patient recall rate of 3% (9). Risk factors of FNSN include tumor location, lymphovascular invasion, suspicious node in the preoperative study, less than three SNs, invasive lobular carcinoma, and poorly differentiated cancer (17, 18). In the present study, we excluded patients with invasive lobular carcinoma because of the difficulty in the diagnosis by H&E stain in these samples. There were 20 patients with FNSN among 333 SLNB patients. The proportion of FNSN is 6.0% in our hospital. Larger tumor size in preoperative mammography and LTE in samples of CNB were associated with increased risk of FNSN (Table 2). The patients with FNSN had a greater number of total SNs during the first operation. For a patient with LTE in CNB specimen, a tumor larger than 2.5 cm in preoperative mammography, and a high residual radioactivity over the axillary region during operation, the patient, and family should be informed of the higher risk of FNSN. LTE was the most powerful predictor in multivariate analysis (Table 3). The present study was a retrospective review of real-world data, and patient populations were not selected or well-designed. The study power might be diminished because of the heterogeneity of patients/surgeons. However, we kept monitoring these patients for more than 10 years. Our data provided real-world evidence on treatment practices for patients with FNSN.
The clinical significance of underestimating nodal staging is discussed. Anderson et al re-evaluated FFPE tissue blocks of SNs and found that 11% of patients have undiagnosed metastases in SNs during re-evaluation (19). In the present study, four patients had cancer metastasis in non-relevant SNs but were negative for metastasis in relevant SNs. Superselection of SNs as relevant or non-relevant SNs by surgeon is not necessary. All SNs identifying with either methyl blue or with radioactive compounds should be sent for frozen section.
Sixteen other FNSN patients had results of benign lymphoid hyperplasia in the frozen section of relevant SNs, whereas the final pathological report detected metastatic carcinomas in FFPE blocks of the same nodes. The proportion of micrometastasis in SNs was seven of 20 FNSN patients. The survival rates of FNSN patients undergoing ALND and those without SNs metastasis were similar (Fig. 2). The long-term recurrence rates were also the same (Table 4). Our results were consistent with those of other studies. The breast cancer patients with micrometastasis in SNs have similar survival as others without metastasis (6). For the patients with early breast cancer and one or two SNs containing metastasis, 10 year OS in those treating with SLNB was noninferior to ALND (7). The SLNB successfully replaces ALND in early breast cancer (20).
The present study gathered patients from 2005 to 2009, before the publication of results in the ACOSOG Z0011 trial (6). It was the reason to perform ALND for our FNSN patients. The two-step operation with delayed ALND has similar long-term morbidity but with a longer operative time (21, 22). The number of lymph nodes identified is slightly reduced in delayed ALND patients without clinical significance, and the risk of lymphedema is similar between delayed and immediate ALND (23, 24). The major risk from delayed ALND for FNSN patients comes from perioperative and anesthesia-related distress, especially in elderly patients (25, 26). In the present study, two patients had metastasis in SNs and non-sentinel ALNs. These two patients benefited from delayed ALND with good survival. From the results of the present study and the ACOSOG Z0011 trial, delayed ALND could be held for the patients with micrometastasis in SNs and undergoing partial mastectomy. However, delayed ALND should be considered for those with macrometastasis in SNs after evaluating the risks of a secondary operation.