In this prospective multicenter study, the sentinel node identification rate was 97%. Lymphatic mapping with the sentinel node procedure was first reported in breast cancer in 1994 and is therefore a relatively young procedure. The patients described in this study were included in the period from 2001 and 2004, and were thus in the relatively early days of the general introduction of this procedure. Nevertheless, the success rate was high. The identification rate was influenced by several variables that we will discuss separately.
The reduced identification rate in older patients is consistently reported.11–13 The increased fatty tissue in the breast in elderly patients might cause an decreased lymphatic flow.14 It is also suggested that the replacement of lymph nodes by fatty tissue decreases the capacity of lymph nodes to retain the radioactive colloid.15
Tumor size was also associated with the detection rate, showing a low identification rate in tumors >5 cm in size. It must be noted that only 13 patients in this study had tumors of >5 cm. Patients with large tumors have a greater risk of extensive axillary tumor burden, which decreases the lymphoscintigraphic visualization.16,17 Patients with more than four tumor-positive lymph nodes have nonvisualization in >50%.18 Performance of ultrasound-guided fine-needle aspiration before the SNB procedure will identify at least some of these patients and thus increase the identification rate.
In this study, the identification rate was slightly lower in patients with other than ductal and lobular carcinomas. This group includes mainly tubular, mucinous, and mixed ductolobular tumors. Because of the heterogeneity of this group, this finding is difficult to explain. Others have not found a correlation with histology.19,20
The association between method of detection and the sentinel node identification is notable, showing a higher detection rate with the combined method (radioactive tracer and blue dye). With blue dye, the lymphatic channel can be identified until it enters and stains the first node. The value of the gamma detection probe is that the location of the node can be determined through the intact skin, and the sentinel can be identified once the lymphatic channel is accidentally damaged. Relying on the gamma detection probe only and omitting blue dye leads to a situation where relevant nodes are left behind, because 5–17% of the sentinel nodes are only blue.5,21,22 Some investigators, however, still use only one of the detection methods. On the basis of our results, which have been confirmed by others, we recommend the use of the combined method.3,11,13
The year of accrual also influenced the identification rate and reflected a learning curve, although surgeons participating in this trial were past their learning period of 30 SNB procedures with a completion axillary clearance. Remarkably, the detection rate was lowest in 2002 and not at the start of the study in 2001. This might be explained by the relatively high number of patients accrued by highly experienced academic institutes at the beginning of the AMAROS trial.
In this study, lymphoscintigraphy did not visualize sentinel nodes in a small number of patients. Despite the nonvisualization, the sentinel node could still be identified in 77% of these patients, particularly by blue dye. This suggests that SNB procedure ought to be pursued in these patients, and that nonvisualization is not an absolute indication for ALND.
Finally, we observed that in 3% of the patients in whom nonsentinel nodes were removed, these nonsentinel nodes were the only tumor-positive nodes. In these patients, the SNB procedure can be considered as falsely negative. Extensive tumor burden may obstruct the lymph flow and thus lead to falsely negative sentinel nodes. This finding emphasizes the importance of palpation after removing the sentinel node. The false-negative rate could also be diminished by performing preoperative axillary ultrasound.
In the patient population of the AMAROS trial—that is, patients with a clinically negative axilla and breast tumor of <3 cm—34% of the patients had a tumor-positive sentinel node. Isolated tumor cells within the sentinel node were classified as having node-positive disease at this time, according to the previous edition (5th edition) of the American Joint Committee on Cancer staging manual.23 Yet in the current substudy of this prospective clinical trial, we were able to assess the further nodal involvement in macrometastases, micrometastases, and isolated tumor cells separately. Further nodal involvement was seen in 18% of the patients with both micrometastases (15 of 84) and isolated tumor cells (6 of 33), whereas extensive nodal involvement was slightly higher in patients with micrometastases. In the current staging classification systems, isolated tumor cells are classified as node-negative (pN0(i+)) disease.24,25 Since 2008, in the AMAROS trial, isolated tumor cells are also considered to be sentinel node negative and do not require further axillary treatment.
In the most recent meta-analysis, the overall pooled risk for additional nodal involvement in patients with isolated tumors cells was 12.3% (95% confidence interval 9.5–15.7).26 Omitting ALND is probably acceptable for most patients whose sentinel node contains isolated tumor cells, especially given a marginally lower false-negative rate of 7% of the SNB procedure.3 Additional microscopic axillary metastases might be eradicated by adjuvant radiotherapy to the breast, including the caudal half of the axilla, or by adjuvant chemotherapy or endocrine therapy. These hypotheses are reflected by a low axillary recurrence rate in sentinel node–positive patients treated with a SNB procedure only (i.e., without axillary clearance).27–32
The retrospective Dutch MIRROR trial recently showed that omission of further axillary treatment in patients with micrometastases resulted in a far higher 5-year axillary recurrence rate (1.2 vs. 6.2%, hazard ratio 4.45; 95% confidence interval 1.46–13.54).33 The International Breast Cancer Study Group trial IBCSG-23-01 is currently addressing whether differences in survival exist between patients with micrometastases who have a SNB procedure compared with ALND.34 However, the size of the sentinel node metastases is not the only predictor for further nodal involvement. Increased tumor size, more than one positive sentinel lymph node, lymphovascular invasion in the primary tumor, and lobular histology also have statistically significant predictive value.35 Several nomograms and models including these variables have been established to estimate the risk of further nodal involvement and might be used to select those patients with micrometastases and isolated tumor cells who may benefit from axillary treatment and those who can be safely spared axillary clearance.36 Further studies addressing which patients with microscopic metastases in the sentinel node can be safely withhold axillary treatment are warranted.
In conclusion, this study indicates that with a 97% detection rate in this prospective international multicenter study the sentinel node procedure is highly effective. The success rate is influenced by the method of the SNB procedure and by several patient and tumor characteristics. In patients with micrometastases and isolated tumor cells in the sentinel node, further nodal involvement was low (18%) but not negligible. The final analysis of the AMAROS trial will show whether patients with a tumor-positive sentinel node will be adequately treated with ART compared to ALND in terms of axillary control and arm and shoulder morbidity.