Surgical Management of the Axilla

Clinical circumstances

Recommendations for use of sentinel node biopsy

Level of evidence

T1 or T2 tumors

Acceptable

Good

T3 or T4 tumors

Not recommended

Insufficient

Multicentric tumors

Acceptable

Limited

Inflammatory breast cancer

Not recommended

Insufficient

DCIS with mastectomy

Acceptable

Limited

DCIS without mastectomy

Not recommended except for large DCIS (>5 cm) on core biopsy or with suspected or proven microinvasion

Insufficient

Suspicious, palpable axillary nodes

Not recommended

Good

Older age

Acceptable

Limited

Obesity

Acceptable

Limited

Male breast cancer

Acceptable

Limited

Pregnancy

Not recommended

Insufficient

Evaluation of internal mammary lymph nodes

Acceptable

Limited

Prior diagnostic or excisional breast biopsy

Acceptable

Limited

Prior axillary surgery

Not recommended

Limited

Prior non-oncologic breast surgery (reduction or augmentation mammoplasty, breast reconstruction, etc.)

Not recommended

Insufficient

After preoperative systematic therapy

Not recommended

Insufficient

Before preoperative systematic therapy

Acceptable

Limited

While these recommendations remain in effect, most surgeons do not strictly adhere to these guidelines and are doing sentinel node biopsies in select cases for T3 or T4 tumors, high-grade DCIS in breast-conserving surgery (BCS), suspicious palpable axillary nodes, prior axillary surgery, prior non-oncologic breast surgery, and prior preoperative systemic therapy

Lyman GH, ASCO Guideline recommendations, J Clin Oncol. 2005 [27]

Controversial Circumstances

Pregnancy

The safety and test performance of SLNB during pregnancy has not been fully evaluated; however, radiolabelled colloids are safe based on the rapid clearance and uptake of the colloid into the reticuloendothelial system. Data has demonstrated that the dose of radiation to the fetus is minimal. Recent studies have confirmed the safety of SLNB during pregnancy using low-dose lymphoscintigraphy (10 MBq on average) with (99m)Tc, advising a 1-day protocol to reduce the time and dose of radiation [28–30]. Blue dye should not be used during pregnancy, as it currently is classified as a category C drug and there is limited data on its teratogenic effects. Furthermore, its use has a possible risk of anaphylactic maternal reaction, which can be harmful for the fetus [30]. While some centers do offer lymphoscintigraphy and SLNB for pregnant patients, some surgeons prefer routine elective ALND. Alternatively, the SLNB procedure can be delayed until postpartum if the patient is close to term.

Special Situations

DCIS

SLNB is generally not recommended for patients with DCIS; however, in certain clinical circumstances, sentinel node staging may be performed in order to avoid a second operation. While 5–15 % of patients with DCIS will have involved sentinel nodes, virtually all have micrometastases or isolated tumor cells of no significance [31–33]. SLNB is recommended for patients with DCIS when a mastectomy is indicated or when immediate reconstruction is planned, as axillary staging by SLNB is no longer possible if an invasive tumor is subsequently found. To avoid a second operation on the axilla if invasive cancer is found, selective use of SLNB is recommended in patients with large (>4 cm) or high-grade DCIS diagnosed with core needle biopsy who are having BCS [27]. Invasive cancer will subsequently be found upon excision in 10–20 % of patients with DCIS diagnosed by core biopsy.

Male Breast Cancer

Although the diagnosis of breast cancer in men is often delayed, resulting in presentations with more advanced tumors, relative survival by stage of disease is similar to that for women [34]. Thus, the most common surgical procedure for male breast cancer is modified radical mastectomy followed by radiation therapy for large tumors or those with nodal metastases [35]. Numerous small institutional studies support the feasibility and accuracy of SLNB in male breast cancer patients [36–38]. As in women, sentinel node analysis has been shown to be a reliable tool in male breast cancer patients, sparing a significant number of patients unnecessary axillary lymph node dissections [39].

Prior Axillary Surgery

The success of SLNB after prior axillary surgery has been previously thought to be decreased due to the disruption of the lymphatic drainage pattern. Multiple recent studies have shown that reoperative SLNB is feasible in the setting of local recurrence after previous BCS and axillary surgery [40–42] with the success of identifying a sentinel node being inversely related to the number of nodes removed previously [43]. In patients who have had a previous complete axillary dissection, the success of reoperative SLNB has been reported to be between 29 and 38 % [43, 44]. Non-axillary drainage has been found in 11–30 % of reoperative SLNB patients after a prior complete axillary dissection [41, 43]. Lymphoscintigraphy, in addition to dye-directed lymphatic mapping, is necessary in these scenarios to aid in identifying aberrant non-axillary lymphatic drainage patterns [43, 45, 46].

Multicentric Lesions

Multicentric cancer, defined as distinct cancers occurring in different quadrants of the same breast, or at a distance of more than 2–5 cm from each other, occurs in approximately 10 % of cases. Some concerns regarding SLNB in this setting are due to the possibility that multiple foci of the cancer might drain to different lymph nodes and increase the false-negative rate of the procedure. Anatomically, the embryologic development of the lymphatic pathways support the notion that the entire breast drains through the same axillary node or nodes [47]. Studies have shown greater success in identifying the sentinel nodes in these patients with acceptable false-negative rates using subdermal [48], intradermal [21], and subareolar [17] injections over peritumoral injection. Recent data following 5-year results of a large single-institution series have demonstrated that the rate of axillary recurrence is acceptably low following SLNB in multicentric disease, thus confirming the use of SLNB as a standard procedure in this setting [49].

Suspicious Palpable Axillary Lymph Nodes

Most SLNB studies have excluded patients with clinically positive axillary nodes. While ALND is the standard of care in patients with suspicious palpable axillary lymph nodes, determination of metastatic disease in the axilla by clinical exam is often unreliable. Previous studies have shown that clinical examination of the axilla can be inaccurate and falsely positive in up to 41 % of patients [50]. In these circumstances, axillary ultrasound and ultrasound-guided needle biopsy is a reliable technique which can be used to guide axillary management [51]. Alternatively, patients with suspicious nodes can undergo SLNB, with the clinically suspicious nodes removed and evaluated as sentinel nodes regardless of whether they take up blue dye or radiolabeled colloid.

Prophylactic Mastectomy

The popularity of prophylactic mastectomy has more than doubled between 1998 and 2003 in the SEER database [52]. The risk of discovering an occult breast cancer in a prophylactic mastectomy specimen is approximately 5 % in high-risk women [53, 54]. Additionally, in patients with a history of breast cancer, the risk of developing a contralateral breast cancer is about 0.5–1 % per year [55–57]. However, the widespread use of hormonal therapy may reduce the risk to less than 0.5 % [58]. Because the ability to perform a SLNB is lost if an occult breast cancer is discovered in a prophylactic mastectomy specimen, some surgeons advocate the use of SLNB at the time of prophylactic mastectomy in high-risk patients. While routine SLNB is not warranted in all patients undergoing prophylactic mastectomy, it may be considered in higher risk patients such as older women, patients with invasive lobular carcinoma or LCIS [59], or those with ambiguous imaging abnormalities. Patients with locally advanced primary breast cancers [54] and inflammatory breast cancer [60] may be advised to undergo a SLNB at the time of contralateral prophylactic mastectomy due to a significantly increased risk of crossover metastasis. Overall, in patients undergoing prophylactic mastectomy associated with early-stage disease, SLNB is not indicated. Patients with undiagnosed imaging abnormalities on ultrasound or MRI may be candidates for SLNB where the breast with the abnormality is removed prophylactically.

Neoadjuvant Chemotherapy

The timing of when to perform SLNB with neoadjuvant chemotherapy (NAC) is still under considerable debate. Neoadjuvant chemotherapy can downstage locally advanced breast cancers, making many patients good candidates for BCS. Additionally, neoadjuvant chemotherapy can downstage the axillary lymph nodes in a considerable proportion of patients [61, 62] (30–40 %) and can lead to clearance of microscopic nodal disease. At M.D. Anderson Cancer Center, investigators reported that up to 23 % of patients with locally advanced breast cancer with axillary metastases were cleared of cytologically positive axillary nodes after four cycles of doxorubicin-based neoadjuvant chemotherapy [63]. Occult metastases were discovered with IHC stain on an additional 10 % of the negative nodes.

The feasibility and accuracy of SLNB after neoadjuvant chemotherapy remains controversial despite the increasing use of neoadjuvant chemotherapy for operable breast cancer. There are concerns that SLNB after NAC may decrease the accuracy of identification of the sentinel node and increase the chance of a false-negative finding [64, 65]. The false-negative rates of sentinel nodes after NAC have been reported to be between 0 and 33 % in several single-institution series [66–77]. Several meta-analyses have shown that SLNB after neoadjuvant chemotherapy in clinically node-negative patients has an acceptable sentinel node identification rate and false-negative rate [78] (see Table 17.2).

Table 17.2

Studies of sentinel lymph node biopsy after neoadjuvant chemotherapy.

Author	Year	No. of patients	Mapping failure (%)	FNR (%)
Takei	2012	105	0	6
Canavese	2011	64	6	5
Schwartz	2010	79	1	4
Hunt	2009	575	3	6
Classe	2009	195	10	12
Tausch	2008	167	15	8
Gimbergues	2008	129	6	14
Yu	2007	127	9	8
Newman	2007	54	2	9
Lee	2007	219	6	16
Shen	2007	69	7	25
Yamamoto	2007	20	0	14
Tanaka	2006	70	10	3
Kinoshita	2006	77	6.50	11
Mamounas	2005	428	15	11
Jones	2005	36	19	11
Kang	2004	54	28	11
Shimazu	2004	47	6	12
Lang	2004	53	6	4
Patel	2004	42	5	0
Reitsamer	2003	30	13	7
Piato	2003	42	2.40	17
Vigario	2003	37	3	39
Miller	2002	35	14	0
Julian	2002	34	9	0
Stearns	2002	34	15	14
Haid	2001	33	12	0
Fernandez	2001	40	10	20
Tafra	2001	29	7	0
Breslin	2000	51	18	12
Cohen	2000	38	18	17

Adapted from: Chung A, Giuliano AE. Axillary staging in the neoadjuvant setting. Ann Surg Oncol 2010;17:2401–10 [77]

The largest series examining the feasibility of SLNB after NAC was completed as part of the NSABP B-27 trial [79]. 428 patients treated with NAC underwent SLNB with either radioactive colloid, lymphazurin blue dye, or both. The success rate for identification of the sentinel nodes was 84.8 %. Although further data is needed to fully evaluate the role of SLNB after neoadjuvant chemotherapy, the study suggested that the technique of SLNB can be best applicable to those patients who demonstrate a complete clinical response after NAC.

Advocates in favor of performing SLNB before NAC argue that the status of the axillary nodes can be obtained without the potential confounding effects of NAC [80]. Furthermore, the information from axillary staging before NAC is important in determining which patients will subsequently need a completion axillary dissection or axillary nodal radiation. Tumor-negative sentinel node patients can avoid ALND, while those with tumor-involved sentinel nodes prior to NAC ultimately will undergo ALND after chemotherapy [77, 81]. Currently there is no convincing evidence that patients with abnormal axillary nodes who receive NAC and then have a negative sentinel lymph node following treatment can be spared ALND. NAC is thought to affect axillary staging by causing fibrosis and obstruction of tumor-involved lymphatic channels, thus leading to inaccurate mapping. The response of lymph nodes to chemotherapy may occur nonuniformly, limiting the accuracy of the SLNB in this setting [24]. Additionally, because NAC may clear microscopic disease in axillary lymph nodes, the long-term clinical significance of negative findings on SLNB after NAC is unknown. This has implications in clinical decision-making for further axillary treatment, such as the need for completion ALND, post-mastectomy radiation, and radiation fields after lumpectomy. The real question remains the fate of patients who have positive nodes that have converted to negative with neoadjuvant chemotherapy and do not undergo ALND.

After consideration of the available data on SLNB and NAC, an algorithm for pre-NAC axillary evaluation has been suggested, avoiding the situation in which patients with positive nodes converted to negative do not get ALND [77]. Patients with clinically suspicious nodes can be advised to undergo needle biopsy, while those with clinically negative nodes can undergo sentinel node biopsy prior to neoadjuvant treatment to assess the true status of the axilla.

To date, there have been no randomized trials investigating SLNB in the setting of NAC. The ACOSOG Z1071 trial is currently accruing patients with T1-4, N1-2, M0 breast cancer who will undergo preoperative NAC followed by SLNB and ALND. The primary objective is to determine the false-negative rate for sentinel nodes in women with node-positive breast cancer at initial diagnosis who have a SLNB performed after NAC [82]. This study, however, does not answer the important question of the untreated axilla after conversion from positive to negative.

The current ASCO guidelines have concluded that there is insufficient data to recommend SLNB or suggest appropriate timing of SLNB in patients undergoing NAC. The Panel also emphasizes that a SLNB should only be performed in the setting of clinically negative axillary lymph nodes.

Other Circumstances

SLNB should not be performed in inflammatory breast cancer, because the subdermal lymphatics can be partially obstructed and contain tumor emboli. This lymphatic abnormality has led to an unacceptably high false-negative SLNB rate [75]. Thus, for patients with inflammatory breast cancer, an ALND should be performed.

In older age and obesity, the accurate identification of the sentinel node decreases with increasing age and body mass; however, advanced age and BMI are not a contraindication for SLNB.

Indications for Completion Axillary Lymph Node Dissection

Axillary node dissection, with the removal of levels I and II nodes, remains the standard for patients with grossly palpable axillary nodes or needle-biopsy proven axillary node involvement. A completion axillary node dissection should be done when clinically suspicious nodes are still present in the axilla after all sentinel nodes have been removed. ALND should also be done when the SLNB procedure fails or is technically unsatisfactory [27].

Currently, the ASCO guidelines from 2005 recommend routine ALND for micrometastases (>0.2 to ≤2 mm and/or more than 200 cells) found on SLNB, regardless of method of detection. However, recent data from the ACOSOG Z0010 and Z0011 trials suggest that a completion axillary node dissection is not necessary in all women found with tumor-involved sentinel nodes under certain circumstances. Data from Z0011 suggest that ALND is only necessary in women who undergo BCS with planned whole-breast irradiation who are found to have three or more tumor-involved sentinel lymph nodes (macrometastases) or have extranodal extension [33, 83]. Women undergoing mastectomy who are found with tumor-involved sentinel nodes still require completion axillary node dissections [83].

Indications for Sentinel Node Biopsy Only: Management of Node-Negative Patients

Current guidelines recommend that patients with tumor-free sentinel nodes be adequately treated with SLNB only without further ALND. This is supported by data from several randomized controlled trials with long-term follow-up comparing axillary failure rates for SLNB and ALND. These studies have demonstrated low axillary recurrence in patients who underwent SLNB only in node-negative patients. Veronesi recently reported a 10-year follow up comparing outcomes in 516 patients at a single-institution randomized to SLNB alone versus SLNB with routine completion ALND if the sentinel node was negative. The study showed no difference between the two groups with respect to disease-free survival (DFS) (89.9 % in the SLNB alone arm vs. 88.8 % in the SLNB + ALND arm); the overall survival (OS) was slightly greater in the SLNB alone arm (93.5 % vs. 89.7 % in the SLNB + ALND arm), but this was not statistically significant (P = 0.15) [84].

The NSABP B-32 is the largest randomized surgical trial designed to answer the question of whether SLNB in patients with sentinel lymph node-negative breast cancer is equivalent to ALND with regard to regional control, DFS, OS [32]. Between 1999 and 2004, 5,611 women in 80 centers in Canada and the USA with clinically node negative invasive breast cancer, undergoing either lumpectomy or mastectomy, were randomized to SLNB + ALND versus SLNB alone (followed by ALND if the sentinel node was positive on H&E staining). 3,986 had pathologically negative sentinel node and follow-up information. After a mean follow-up time of 95.6 months, there were 309 deaths. The 5-year overall survival was 96.4 % (SLNB + ALND) versus 95.0 % (SLNB alone) and 8-year estimates are 91.8 % versus 90.3 % (HR 1.19, 95 % CI: 0.95–1.49, p = 0.13). DFS (651 events) was 89.0 % (SLNB + ALND) versus 88.6 % (SLNB alone) at 5 years, 82.4 and 81.5 % at 8 years. There were 8 regional node recurrences as first events in the SLNB + ALND group, and 14 in the SLNB alone group (p = 0.22). Both groups had less than 1 % regional recurrences as first events. The B-32 results confirmed the low rate of regional-node recurrences after SLNB as previously reported in non-randomized studies. This study demonstrated no significant difference in OS, DFS, and regional control among patients treated with SLNB followed by ALND or SLNB alone in patients with histopathologically tumor-free sentinel nodes. This large multicenter randomized study proved that SLNB alone with no further ALND is appropriate, safe, and effective therapy for patients with sentinel node-negative breast cancer.

Management of Patients with Sentinel Node Micrometastases or Isolated Tumor Cells

SLNB has dramatically changed the approach to early-stage breast cancer by allowing minimally invasive nodal staging and more intensive examination of the sentinel nodes. This has led to the detection of micrometastases (greater than 0.2 mm and/or more than 200 cells, but none greater than 2.0 mm) and isolated tumor cells (ITCs, defined as small clusters of cells not greater than 0.2 mm, or non-confluent or nearly confluent clusters of cells not exceeding 200 cells in a single histologic lymph node cross section) of uncertain significance according to the AJCC Breast Cancer Staging, seventh edition [85]. Although current guidelines from ASCO recommend completion axillary dissection when micrometastatic disease is found regardless of the method of detection [27], recent studies show this to be unnecessary.

The ACOSOG Z0010, accruing from 1999 to 2003, is one of the largest prospective trials to assess immunochemically detected metastases in the sentinel lymph nodes and bone marrow of women with early-stage breast cancer [33]. This multicenter observational study determined the prevalence and significance of occult metastases in the sentinel nodes and bone marrow of patients who underwent BCS, SLNB, and whole breast irradiation for treatment of T1 or T2, clinically node-negative breast cancer. 5,210 patients underwent BCS and SLNB. Occult metastases discovered by immunohistochemistry (IHC) were found in 349 (10.5 %) of 3,326 sentinel lymph nodes which were hematoxylin and eosin (H&E) negative. Of 3,413 bone marrow specimens examined by immunocytochemistry, 104 (3.0 %) were positive for occult metastases. Over a median of 6.3 years, among women undergoing BCS, SLNB, and whole breast irradiation, occult sentinel lymph node metastases were not significantly associated with differences in overall survival, disease-free survival, or recurrence when compared to patients with IHC-negative sentinel nodes. 5-year rates of overall survival for patients with IHC-negative sentinel nodes were 95.7 % (95 % CI, 95.0–96.5 %) versus 95.1 % (95 % CI, 92.7–97.5 %; P = 0.64) in patients with IHC-positive sentinel nodes. Corresponding 5-year rates of disease-free survival were 92.2 % (95 % CI, 91.1–93.2 %) and 90.4 % (95 % CI, 87.2–93.8 %, P = 0.82), respectively. Occult bone marrow metastases were found to be significantly associated with increased mortality. At 5 years, mortality rates were 5 % (95 % CI, 4.2–5.7 %) for patients with immunocytochemistry-negative bone-marrow specimens versus 9.9 % (95 % CI, 3.9–15.5 %) for those with immunocytochemistry-positive specimens on univariable analysis. This finding was not statistically significant on multivariable analysis. The authors concluded that in this study, sentinel node IHC-detected metastases appear to have no significant impact on overall survival among women receiving BCS for T1/T2 N0 M0 breast cancer, whereas occult bone marrow metastases, although rare, were associated with decreased survival. The routine examination of sentinel nodes by IHC was not supported in this study.

A secondary aim of the NSABP B-32 trial was to determine whether patients with occult micrometastases and ITCs have worse survival compared to patients with negative axillary lymph nodes, assessed by both H&E and IHC analysis [86]. The pathologically H&E negative sentinel lymph nodes in 3,887 patients were centrally evaluated for occult metastases by H&E and IHC analysis. In the 3,887 patients, occult metastases were detected in 15.9 % (11.1 % ITC, 4.4 % micrometastases, 0.4 % macrometastases). They found a statistically significant difference between patients with and without occult metastases in overall survival (94.6 % vs. 95.8 %, p = 0.03), disease-free survival (86.4 % vs. 89.2 %, p = 0.02), and distant disease-free survival (89.7 % vs. 92.5 %, p = 0.04), respectively. Occult metastases were an independent prognostic variable in patients with sentinel nodes that were negative on initial examination, and were associated with a small but statistically significant 1.2 % decrease in 5-year overall survival, 2.8 % decrease in disease-free survival, and 2.8 % decrease in distant disease-free survival. While the NSABP B-32 trial showed a small but significant difference in 5-year overall survival in patients with occult sentinel node metastases, this difference was concluded to be insufficient to affect systemic treatment or justify routine immunohistochemistry. These findings are congruent with the conclusions of Z0010. Most patients in the Z0010 trial and NSABP B-32 trial received adjuvant systemic therapy, which demonstrates practice patterns independent of immunohistochemical findings.

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