For patients with primary breast cancer, nodal status remains a key determinant for overall prognosis. Sentinel lymph node biopsy (SLNB) has become standard care for staging patients who have clinically node-negative disease. However, a new dilemma has arisen: how to manage the clinically negative axilla in patients with ipsilateral breast tumor recurrences (IBTRs). Are outcomes in these patients improved with repeat SLNB? Although observational studies suggest SLNB is feasible in patients with IBTR and a clinically node-negative axilla, the overall impact on morality and local recurrence is not yet known as no randomized trials have addressed this issue.
Key points
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Axillary lymph node dissection should be performed in clinically node-negative axilla only when sentinel lymph node biopsy (SLNB) shows metastatic disease.
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Performing immunohistochemistry on routine SLNBs is not recommended.
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Sentinel lymph node biopsy on ipsilateral breast tumor recurrences is feasible and seems reliable.
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Lymphoscintigraphy provides useful information for accurately identifying the sentinel lymph node.
Introduction
For patients with primary breast cancer, nodal status remains a key determinant of overall prognosis. Thus, patients who present with metastasis to the axillary lymph nodes have a worse prognosis than those who do not. To reduce the morbidity of axillary surgery, the sentinel lymph node biopsy (SLNB) technology was introduced in the 1990s. Since then, SLNB has become the standard of care for staging patients with clinically node-negative disease. However, with the widespread implementation of SLNB technology during the past 15 years, a new dilemma has arisen: how to manage the clinically node-negative axilla in patients with ipsilateral breast tumor recurrences (IBTRs). No clear answer exists because no randomized trials have addressed the effect of SLNB remapping on locoregional recurrences and mortality. Yet, some investigators advocate for repeat SLNB in patients with an IBTR with clinically node-negative axilla.
This article therefore discusses 2 separate issues: (1) management of the axilla in patients with clinically node-negative primary breast cancer, and (2) management of the clinically node-negative axilla in patients with IBTRs.
Introduction
For patients with primary breast cancer, nodal status remains a key determinant of overall prognosis. Thus, patients who present with metastasis to the axillary lymph nodes have a worse prognosis than those who do not. To reduce the morbidity of axillary surgery, the sentinel lymph node biopsy (SLNB) technology was introduced in the 1990s. Since then, SLNB has become the standard of care for staging patients with clinically node-negative disease. However, with the widespread implementation of SLNB technology during the past 15 years, a new dilemma has arisen: how to manage the clinically node-negative axilla in patients with ipsilateral breast tumor recurrences (IBTRs). No clear answer exists because no randomized trials have addressed the effect of SLNB remapping on locoregional recurrences and mortality. Yet, some investigators advocate for repeat SLNB in patients with an IBTR with clinically node-negative axilla.
This article therefore discusses 2 separate issues: (1) management of the axilla in patients with clinically node-negative primary breast cancer, and (2) management of the clinically node-negative axilla in patients with IBTRs.
Sentinel lymph node biopsy in clinically node-negative primary breast cancer
Patients with clinically node-positive primary breast cancer should undergo axillary clearance. Sentinel lymph node biopsy is an option only for those with clinically node-negative breast cancer.
For patients with primary breast cancer, the management of the axilla has been a topic of considerable interest and controversy for many years. In the late 19th century, William Halsted argued that the axillary lymph nodes were the gateway for the distant spread of breast cancer. Thus, he maintained that extirpation of the breast, underlying pectoralis muscle, and the adjacent axillary lymphatics en bloc (radical mastectomy) was the optimal treatment of primary breast cancer.
The results of large randomized trials conducted under the auspices of the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Cancer Research Campaign Working Party (King’s/Cambridge) have challenged this hypothesis. The NSABP B-04 trial randomized patients with clinically node-negative breast cancer to radical mastectomy versus total mastectomy with postoperative axillary radiation versus total mastectomy followed by axillary dissection only in patients who subsequently developed clinically positive nodes. In the King’s/Cambridge trial, women with clinically node-negative early breast cancer were randomized to total mastectomy with immediate axillary radiation versus total mastectomy and observation of the axilla (with delayed treatment of the axilla in patients who subsequently developed axillary recurrences).
Both of these trials demonstrated that the delayed treatment of the axilla did not adversely affect survival, and therefore called into question the notion that the axillary nodes served as the nidus for the distant spread of breast cancer. However, the NSABP B-04 and King’s/Cambridge trials do indicate that treatment of the axilla (with either surgery or radiotherapy) in patients with clinically node-negative breast cancer substantially reduces the risk of axillary recurrences. Moreover, surgery is the preferred method of treating the axilla because it also enables staging of the patient (as either node-positive or node-negative). However, patients without metastasis to the axilla needlessly undergo axillary surgery, and incur the potential morbidity associated with axillary surgery. Thus, SLNB technology was developed to reduce the risk of morbidity associated with unnecessary axillary surgery.
In 1970, Kett and colleagues published results of lymphatic mapping of the breast after periareolar injection of blue dye. This procedure identified an isolated blue node that was commonly adjacent to the axillary vein. In 1993, Krag and colleagues reported the identification of an isolated node using technetium sulfur and a gamma probe. Giuliano and colleagues described the technique of blue dye mapping of sentinel lymph nodes (SNLs) of the breast, and reported that SLNB was 95.6% accurate in predicting the status of the axilla. Albertini and colleagues combined the 2 methods (blue dye and radiocolloid), and reported a similar sentinel node identification rate of 92.0%. A randomized prospective trial by Morrow and colleagues in 1999 compared the combination of blue dye and radioactive colloid versus the use of blue dye alone and showed equivalent sentinel node identification rates.
Considerable evidence now shows that SLNB is a much less morbid procedure than the standard ALND, and that the 2 procedures are associated with similar survival rates and risk of local recurrences. The NSABP B-32 trial randomized 5611 women with clinically node-negative breast cancer to ALND versus SLNB plus ALND (with ALND performed only if evidence showed metastasis to the SLN). The study used both blue dye and radiotracer to identify the SLN. Patients in the SLNB arm of the trial had equivalent survival and regional control to those in the standard ALND arm. In addition, patients in the SLNB arm had a lower risk of morbidity compared with those in the standard ALND arm. Significantly fewer shoulder abduction deficits (75% vs 41%; P <.001), lymphedema (7%–9% vs 13%–14%), arm numbness (31.0% vs 8.1%; P <.001), and tingling (13.5% vs 7.5%; P <.001) were associated with SLNB versus ALND.
Several other randomized control trials have demonstrated the reduced morbidity of SLNB compared with ALND. In the Axillary Lymphatic Mapping Against Nodal Axillary Clearance (ALMANAC) trial, Mansel and colleagues showed that the SLNB group had a lower incidence of lymphedema, shorter time of drain usage, shorter hospital stay, and faster resumption of everyday activities compared with the ALND group. The absolute risk of developing lymphedema 12 months after SLNB was 5% versus 13% (relative risk [RR], 0.37; 95% CI, 0.23–0.60) in those who underwent an ALND. Similarly, the absolute risk of experiencing sensory loss at 12 months after SLNB was 11% compared with 31% of patients who had ALND (RR, 0.37; 95% CI, 0.27–0.50).
Veronesi and colleagues reported the results of their trial undertaken in Milan, which randomized 512 patients to ALND versus SLNB (with ALND only in patients with positive SLNs) and followed them for 24 months after surgery. The patients randomized to the SLNB arm of the trial had significantly less axillary pain (8% vs 39%), less numbness (1% vs 68%), and better overall arm mobility (0% vs 21%) than those randomized to the ALND arm of the trial.
Purushotham and colleagues randomized 298 patients with tumors smaller than 3 cm to similar groups (ALND vs SLNB followed by ALND if sentinel node–positive). They reported decreased sensory deficits, decreased seroma occurrence, and reduction in lymphedema in the SLNB arm. Similarly, the GIVOM (Gruppo Interdisciplinare Veneto di Oncologia Mammaria) trial in Italy randomized 697 patients to ALND versus SLNB (with ALND in node-positive cases). In addition to the decrease in lymphedema and numbness and better range of motion, they noted improved quality of life for patients randomized to SLNB.
The Sentinel Node versus Axillary Clearance (SNAC) trial randomized 1083 patients either to SLNB followed by axillary clearance if the SLN was positive or not detected, or to routine axillary clearance. A significant decrease in wound infection, seroma formation, impairment of range of motion, and numbness was seen in the group randomized to SLNB.
Kell and colleagues published a meta-analysis of 7 randomized controlled trials with a total of 9608 patients comparing standard ALND versus SLNB. The goal of this overview was to determine morbidity reduction with SLNB versus standard ALND. This meta-analysis showed a reduction in risk of infection (odds ratio [OR], 0.58; 95% CI, 0.42–0.80; P = .0011), seroma (OR, 0.40; 95% CI, 0.31–0.51; P = .0071), arm swelling (OR, 0.30; 95% CI, 0.14–0.66; P = .0028), and numbness (OR, 0.25; 95% CI, 0.1–0.59; P = .0018) in patients in the SLNB arm compared with those in the standard ALND arm.
These results indicate that standard ALND can no longer be justified as the standard means of staging patients with clinically node-negative primary breast cancer ( Table 1 ). Rather, SLNB is the standard method of staging these patients.
| Number of Patients | Limb Swelling (%) | Numbness (%) | Abduction Deficits (%) | Seroma (%) | |
|---|---|---|---|---|---|
| NSABP-B32 | N = 5611 | ||||
| SLNB | 2697 | 8.0 | 8.1 | 13.0 | N/A |
| ALND | 2619 | 14.0 | 31.1 | 19.0 | |
| ALMANAC | N = 954 | ||||
| SLNB | 478 | 5.0 | 11.0 | N/A | N/A |
| ALND | 476 | 13.0 | 31.0 | ||
| Milan | N = 516 | ||||
| SLNB | 259 | 7.0 | 1.0 | 0 | N/A |
| ALND | 257 | 75.0 | 68.0 | 21.0 | |
| Purushotham et al | N = 298 | ||||
| SLNB | 143 | N/A | 66.0 | N/A | 14.0 |
| ALND | 155 | 84.0 | 21.0 | ||
| SNAC | N = 1083 | ||||
| SLNB | 544 | 2.8 | N/A | 2.5 | 17.0 |
| ALND | 539 | 4.2 | 4.4 | 36.0 | |
| GIVOM | N = 697 | ||||
| SLNB | 345 | 10.0 | 8.0 | N/A | N/A |
| ALND | 352 | 5.0 | 15.0 | ||
| Z0011 | N = 744 | ||||
| SLNB | 371 | 6.0 | 9.0 | N/A | 6.0 |
| ALND | 373 | 11.0 | 39.0 | 14.0 |
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