Version May 2024
INTRODUCTION — The status of the axillary lymph nodes is one of the most important prognostic factors in patients with breast cancer. Histologic examination of lymph nodes is the most accurate method for assessing lymph node metastasis; approximately one in four patients with clinically negative lymph nodes will have pathologically identified nodal metastases. When the axilla is clinically negative by palpation and ultrasound examination, the pathologic node-positive rate decreases to approximately 18 percent.
Axillary dissection has traditionally been used in breast surgery to obtain lymph nodes. Sentinel lymph node biopsy has replaced axillary lymph node dissection in most patients with early breast cancer. (See "Overview of management of the regional lymph nodes in breast cancer" and "Prognostic and predictive factors in metastatic breast cancer", section on 'Prognostic versus predictive factors'.)
Indications for and outcomes of sentinel lymph node biopsy will be reviewed here. The technique of sentinel lymph node mapping in patients with breast cancer is discussed separately. (See "Sentinel lymph node biopsy in breast cancer: Techniques".)
PREOPERATIVE AXILLA EVALUATION — It is essential that patients receive adequate evaluation of the axilla prior to surgery. Preoperative evaluation of axillary lymph nodes separates patients into two categories: patients with clinically positive nodes typically undergo axillary lymph node dissection (ALND), and patients with clinically negative nodes may undergo sentinel lymph node biopsy (SLNB) (algorithm 1). (See "Overview of management of the regional lymph nodes in breast cancer", section on 'Axillary management'.)
There may be some exceptions in patients who receive and have a good response to neoadjuvant therapy. (See "General principles of neoadjuvant management of breast cancer", section on 'Node evaluation'.)
PATIENT SELECTION
Indications — We recommend the use of sentinel lymph node biopsy (SLNB) to assess axillary lymph nodes in patients with early breast cancer (T1 or T2) who have clinically negative nodes and in patients with ductal carcinoma in situ (DCIS) when mastectomy is performed. These recommendations are consistent with those made by the American Society of Clinical Oncology in 2014 [1].
Early breast cancer with clinically negative nodes — SLNB should be performed in women with clinically node-negative early breast cancer [2]. For these patients, SLNB is a method of staging the axilla with less morbidity than axillary lymph node dissection (ALND). Patients with negative pathology results from fine needle aspirate or core biopsy of imaging-detected abnormal lymph nodes should also be considered for SLNB.
DCIS with planned mastectomy or suspicious features — Most women with DCIS do not require assessment of the axillary nodes, because DCIS is not invasive cancer and does not metastasize. However, two groups of women undergoing breast surgery for DCIS may benefit from SLNB.
DCIS with planned mastectomy — SLNB should be performed in all patients with DCIS undergoing total mastectomy. The technique of SLNB involves injecting radiolabeled tracer into the breast parenchyma near the area of DCIS or, alternatively, in a periareolar location. After a total mastectomy, the lymphatic drainage pattern will be permanently altered, making it impossible to accurately perform SLNB at a later date if invasive cancer is found unexpectedly in the mastectomy specimen [3].
DCIS with suspicious features — Some also recommend SLNB to patients undergoing breast-conserving surgery for DCIS clinically suspected of harboring invasive cancer, including DCIS larger than 5 cm and DCIS with a palpable mass. Offering SLNB with breast-conserving surgery to DCIS patients who have a high clinical or pathological suspicion of synchronous invasive cancer may spare them the inconvenience of a second operation. In a study of over 15,000 women undergoing breast-conserving surgery for DCIS, 18 percent underwent SLNB; metastatic disease was found in 0.9 percent of those who underwent SLNB [4].
The practice of performing SLNB with breast-conserving surgery for DCIS is controversial [1]. Invasive carcinoma has only been reported in 10 to 20 percent of excision specimens following a biopsy diagnosis of DCIS [5]. Thus, most women will not have any invasive disease on final pathology. For them, omitting SLNB at the time of their breast-conserving surgery eliminates any perioperative morbidity associated with SLNB [6-8]. If invasive breast cancer is identified after a breast-conserving surgery is performed for DCIS, SLNB can be performed as a second procedure to stage the axilla. Disease stage and subsequent axillary management may change for such patients [7,8]. (See "Breast ductal carcinoma in situ: Epidemiology, clinical manifestations, and diagnosis" and "Ductal carcinoma in situ: Treatment and prognosis" and "Microinvasive breast carcinoma" and "Tumor, node, metastasis (TNM) staging classification for breast cancer".)
A new strategy for patients with high-risk DCIS has been proposed using superparamagnetic iron oxide (SPIO), a novel tracer agent. In a proof-of-concept study (SentiNot) [9], investigators injected SPIO at the time of mastectomy or breast-conserving surgery for patients with high-risk DCIS. The SPIO signal persisted for up to one month after injection, and a sentinel node biopsy was then performed if invasive carcinoma was found on the final specimen. In this small study, the SPIO plus blue dye outperformed isotope and blue dye in detecting sentinel nodes, and sentinel node biopsy was avoided in 78 percent of patients when invasive carcinoma was not identified in the final breast specimen. It should be noted that these data are preliminary, but if such a strategy is proven to be effective in prospective studies, it may be an alternative axillary management strategy in patients with high-risk DCIS. This would, however, require all patients to be injected with the SPIO, which can lead to skin discoloration in up to 22 percent of patients per their report. Peritumoral injection reduced staining compared with retroareolar injection without affecting detection rate [10]. Rare anaphylactic reactions may occur [11], and residual iron oxide particles in the breast may induce mammographic abnormalities [12].
Contraindications — Clinically positive nodes and inflammatory breast cancer (T4d) are absolute contraindications for SLNB; both should be treated with ALND [1]. Locally advanced breast cancer is a relative contraindication for SLNB. Certain large tumors (eg, T3) may be amenable to SLNB, while others with skin or chest wall involvement (eg, T4a-c) should be treated with ALND (see "Tumor, node, metastasis (TNM) staging classification for breast cancer", section on 'Primary tumor classification'). Additionally, SLNB should be omitted in patients whose axillary status does not guide adjuvant therapy.
Clinically positive nodes — We recommend that patients who have clinically positive nodes that have been pathologically proven to contain metastatic cancer should undergo ALND for axillary clearance, rather than SLNB.
Those who undergo neoadjuvant therapy should be reevaluated for the suitability of SLNB prior to surgery. (See "General principles of neoadjuvant management of breast cancer", section on 'Post-treatment evaluation and management'.)
Locally advanced and inflammatory breast cancer — The 2014 American Society of Clinical Oncology and the 2010 International Expert Panel guidelines on SLNB recommend against the use of SLNB in patients with locally advanced or inflammatory breast cancer [1,6,13]. ALND is recommended for this group of patients to maximize locoregional control [6].
Since larger tumors have a higher likelihood of axillary node metastases, most trials have restricted SLNB use to T1 or T2 breast cancers (<5 cm). However, some studies have shown that SLNB can be accurate in patients with T3 tumors and clinically negative axilla [14,15]. Thus, many clinicians, including the authors of this topic, do not recognize tumor size of larger than 5 cm (T3) as an absolute contraindication to SLNB, as long as the axilla is clinically negative.
Patients with locally advanced tumors with skin and/or chest wall involvement (T4a-c) or inflammatory breast cancer (T4d) are not candidates for SLNB [16,17]. The false negative rate is high in such patients, presumably because of partially obstructed and/or functionally abnormal subdermal lymphatics.
Patients whose axillary status does not guide adjuvant treatment — We do not consider advanced age an absolute contraindication to SLNB in women with breast cancer, as age has never been shown to influence the accuracy, safety, and value of SLNB. However, SLNB should be omitted if the nodal information gained through the procedure will not affect adjuvant treatment decisions.
We suggest that the decision to omit SLNB in older women be made in a multidisciplinary setting with input from the treating medical and radiation oncologists to ensure all providers are in agreement as to whether or not axillary staging information is important for adjuvant therapy decisions. The management of early breast cancer in older women is discussed in detail elsewhere. (See "Overview of the approach to early breast cancer in older women", section on 'Management of the axilla'.)
Special circumstances — Although SLNB has been performed in the following special circumstances, its use remains controversial and not universally accepted [1].
Neoadjuvant chemotherapy — Neoadjuvant systemic therapy is the accepted approach for women with locally advanced breast cancer, women with inflammatory breast cancer, and women who have operable breast cancer but desire breast-conserving surgery. It is controversial whether SLNB or ALND should be performed and whether it should be performed prior to or following the completion of neoadjuvant chemotherapy in such patients. This issue is further discussed elsewhere. (See "General principles of neoadjuvant management of breast cancer", section on 'Node evaluation'.)
Multicentric disease — Multicentric disease is not a contraindication to SLNB [1]. Studies of breast lymphatic drainage indicate that all quadrants of the breast drain into the same lymph node(s) [18,19]. Thus, subareolar and intradermal (rather than peritumoral) injection of radiolabeled colloid or blue dye makes SLNB feasible for patients with multicentric disease [18,20-22]. (See "Sentinel lymph node biopsy in breast cancer: Techniques".)
Successful SLNB for multicentric disease has been demonstrated by several studies [21,23]. In one study of 142 women with multicentric breast cancer, SLNB was successful in 91 percent of patients, with a false negative rate of 4 percent [23]. However, more patients undergo completion ALND after SLNB in multicentric compared with unicentric disease. The likelihood of finding additional disease at the time of completion ALND is also higher with multicentric disease.
Previous breast and axillary procedures for benign conditions — Two studies have demonstrated the feasibility and accuracy of SLNB in patients who had prior excisional breast biopsy [24,25]. However, it is unclear whether women who have undergone cosmetic breast surgeries, such as reduction mammoplasty or breast augmentation, can undergo SLNB. Patients who have had extensive breast or axillary surgery may have disruption or alteration to the normal pattern of lymphatic drainage, which may increase the false negative rate of SLNB. Thus, in these patients, we perform preoperative lymphoscintigraphy prior to SLNB. (See "Sentinel lymph node biopsy in breast cancer: Techniques".)
Recurrent breast cancer and previous axillary procedures — SLNB after previous axillary surgery has not been widely studied. However, there are accumulating reports of successful second SLNB in patients with local recurrences of breast cancer following a previous SLNB or ALND [26-29].
In women who were previously treated with breast-conserving therapy and have in-breast recurrence or a new ipsilateral breast cancer, we perform a lymphoscintigraphy to identify the sentinel node(s) before attempting a repeat SLNB.
Technical failure rates and false negative rates of an SLNB in this setting are related to the extent of previous axillary surgery and are in general higher compared with those of an initial SLNB. Although the success rate of identifying a sentinel node may be lower with prior axillary surgery, SLNB can be as accurate as in patients without prior axillary surgery when a sentinel node can be identified [30-34]. (See "Surgery and radiation for locoregional recurrences of breast cancer", section on 'Surgical management'.)
Male breast cancer — The vast majority of published studies of SLNB for breast cancer were done in women. Data are limited in men with breast cancer because they are uncommon, and most male breast cancers are treated with mastectomy rather than breast-conserving surgery.
Prospective studies establishing the sensitivity and specificity of SLNB in male breast cancer patients have not been carried out. However, we feel it is acceptable to proceed with SLNB in men and that the principles guiding SLNB in women appear to apply to men. (See "Breast cancer in men", section on 'Management of the regional nodes'.)
Pregnancy — SLNB is best avoided in women who are pregnant because of potential teratogenic effects on the developing fetus from isosulfan blue dye and a lack of safety studies on other tracer agents [1]. Also, it is not clear whether lymphatic pathways in the breasts of pregnant women are altered, making identification of the sentinel node more difficult.
Although some consider the use of methylene blue or radioactive colloid to be safe for the fetus in pregnant women with breast cancer, isosulfan blue dye (Lymphazurin) is systemically absorbed after subcutaneous injection and therefore should not be used during pregnancy [35,36].
When axillary surgery is necessary during pregnancy, limited data suggest that SLNB can be performed, but with radioactive colloid alone, which is not teratogenic at the dose administered for SLNB. Some authors suggest that SLNB is safe in pregnant patients with a minimal dose of 500 to 600 microCurie using double-filtered technetium sulfur colloid, but no supporting studies for this approach are available [37,38]. Others, by deriving estimates of absorbed dose at the level of the epigastrium, umbilicus, and hypogastrium in nonpregnant women undergoing sentinel node biopsy for breast cancer, have concluded that expected levels of fetal exposure would be below the 50 milligray (mGy) threshold absorbed dose for adverse effects [39,40].
Small series of SLNB in pregnant patients have reported successful sentinel lymph node mapping with no apparent adverse effects [36,41]. In one retrospective study, 25 pregnant women with breast cancer were injected with methylene blue (7), radioactive colloid (16), or another type of tracer (2) during SLNB procedures [42]. There were 25 livebirth infants, 24 of whom were deemed healthy at delivery; one infant had a cleft lip not attributed to the injections. At 2.5 years, no adverse outcomes were attributed to the injection.
VALIDATION AND PATHOLOGY — Sentinel lymph node biopsy (SLNB) utilizes the lymphatic mapping technique to locate and remove one or more (on average, three) axillary lymph nodes in patients with breast cancer [43]. The sentinel lymph nodes are then submitted for pathologic examination, providing vital information about the axillary nodal status of the patient and guiding further treatment. (See "Overview of management of the regional lymph nodes in breast cancer".)
The SLNB technique is discussed elsewhere. (See "Sentinel lymph node biopsy in breast cancer: Techniques".)
Development and validation of SLNB technique — The SLNB technique has been developed and validated over the past three decades. It has been demonstrated to be feasible, accurate, and less morbid than axillary lymph node dissection (ALND). It has been adopted by medical centers worldwide as the standard initial approach for patients with early-stage breast cancer.
Despite variability in selection criteria and technique, a sentinel lymph node is consistently identified in approximately 96 percent of patients and predicts the status of the remaining axillary lymph nodes in ≥95 percent of patients in most series [44,45].
A systematic review of 69 trials of SLNB, including 8059 patients, showed that sentinel lymph nodes could be identified in 95 percent of patients with a false negative rate of 7.3 percent (range 0 to 29 percent) [46]. Using a combination of isosulfan blue dye and radioactive colloid resulted in a significantly higher success rate and lower false negative rate in sentinel node mapping compared with using isosulfan blue dye alone.
The false negative rate of SLNB was originally reported as being 5 to 10 percent (sensitivity 90 to 95 percent), but lower rates were attained by experienced surgeons [44,47]. Despite initial concerns that this false negative rate would translate into increased axillary recurrence, subsequent trials found that recurrence rates with SLNB were comparable to those with ALND [43,48].
In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial, for example, axillary recurrence after SLNB was 0.4 percent with ALND versus 0.7 percent without ALND [43]. Similar findings were demonstrated in the Veronesi study (0 percent with ALND versus 0.8 percent without ALND) [48]. The low axillary recurrence rates in these trials, even without ALND, were presumably due to the effects of adjuvant therapy (chemotherapy or radiotherapy) that may treat residual axillary disease burden. In patients who did not receive adjuvant therapy or ALND, the axillary recurrence rate was as high as 20 percent, as reported for the NSABP-04 trial [49].
SLNB is less morbid for patients than ALND. Several studies have shown that the risk of arm morbidity, particularly lymphedema, sensory loss, and shoulder abduction deficits, is significantly less for SLNB than ALND (table 1) [50-56]. As an example, in one trial, the risk of lymphedema after 12 months was reported as 2 percent after SLNB alone as compared with 13 percent after SLNB with ALND [50]. In addition, SLNB identifies patients without axillary node involvement, thereby obviating the need for more extensive surgery for those patients [44].
The SLNB technique has been adopted by virtually all medical centers in the world as a standard means of axillary nodal assessment [57,58]. It is endorsed by multiple guidelines as an alternative to ALND for the diagnosis of axillary metastases in patients with clinically node-negative early breast cancer [1,2,6,59,60].
Pathologic analysis of nodal metastases — Sentinel node metastases are subgrouped into isolated tumor cell clusters, micrometastases, and macrometastases based upon the size of the largest contiguous tumor deposit present in the sentinel node, as determined by routine histologic examination of slides stained by hematoxylin and eosin.
Immunohistochemistry staining with cytokeratin is not routinely indicated in the pathologic examination of sentinel lymph nodes for breast cancer. Immunohistochemistry stains can be helpful in establishing the size and extent of metastatic disease and in confirming invasive, metastatic lobular carcinoma, a cancer subtype with morphology that can be difficult to discern by hematoxylin and eosin stain alone [61,62]. The use of immunohistochemistry staining, however, is reserved for cases in which metastatic cancer of any subtype, including lobular, is suspected but cannot be confirmed based on hematoxylin and eosin stain alone.
Isolated tumor cell clusters — Isolated tumor cell clusters are defined as small clusters of tumor cells not greater than 0.2 mm or nonconfluent or nearly confluent clusters of cells not exceeding 200 cells in a single histologic lymph node cross section [63]. According to the Tumor, Node, Metastasis (TNM) staging system, isolated tumor cell clusters are designated as pN0(i+). Prognostically, patients with isolated tumor cell clusters appear to do as well as patients without any pathologic node involvement. Of note, the finding of isolated tumor cells or clusters in lymphatic channels as a result of iatrogenic displacement from core biopsy procedures has been observed but does not significantly change prognosis [64-67]. (See "Tumor, node, metastasis (TNM) staging classification for breast cancer".)
Micrometastases — Micrometastatic nodal involvement is defined as a metastatic deposit >0.2 mm but ≤2.0 mm. If present, it is designated as pN1mi in the American Joint Committee on Cancer (AJCC) staging system. Patients with pN1mi breast cancer have a slightly worse prognosis compared with those with node-negative breast cancer, but micrometastases do not predict recurrence [68]. (See "Tumor, node, metastasis (TNM) staging classification for breast cancer" and "Prognostic and predictive factors in early, non-metastatic breast cancer", section on 'Nodal involvement'.)
Macrometastases — Macrometastatic involvement of the axillary nodes (classically designated as "node-positive") is defined by any tumor cell deposit >2.0 mm. The presence of macrometastases within the axillary nodes is a well-established independent prognostic factor, with prognosis worsening with increasing nodal involvement and tumor burden. (See "Prognostic and predictive factors in early, non-metastatic breast cancer", section on 'Nodal involvement'.)
Extranodal extension — Extranodal (extracapsular) extension is defined as invasive tumor cells or clusters that are present outside of the lymph node capsule and parenchyma. In cases of extranodal extension, there is generally tumor present in both a subcapsular location and the adjacent extranodal fat. However, a fibrous reaction (desmoplasia) to the tumor cells may obscure tumor invasion of the extranodal fat.
Focal or minimal extracapsular extension of metastatic tumor is less significant than extensive or more obvious extranodal extension [69]. Isolated tumor cells or clusters within perinodal or axillary lymphatic channels are not considered extranodal extension. Instead, they should be measured and classified as isolated tumor cell clusters (ITCs) or micrometastases. (See 'Isolated tumor cell clusters' above and 'Micrometastases' above.)
An axillary fat tumor deposit is typically classified as a "positive node" and counts toward the total number of positive nodes that will determine if the patient should undergo ALND. One retrospective study of over 1000 patients with T1-T2cN0 breast cancer undergoing sentinel node biopsy and ALND for sentinel node metastases found that the presence of extranodal tumor deposits was strongly associated with four or more positive nonsentinel lymph nodes (odds ratio 7.15, 95% CI 4.04-12.67) among patients with one to two positive sentinel lymph nodes (n = 925) [70].
Occult metastatic disease — Occult micrometastases refer to nodal metastases that are not seen on initial hematoxylin and eosin examination but are detected subsequently by additional levels or by immunohistochemical staining or reverse transcriptase polymerase chain reaction. In one study, more intensive pathologic evaluation of the nodes by deeper sectioning and immunohistochemical staining increased the yield of occult metastases and led to an overall case conversion rate of 10.3 percent in patients who had an initial negative SLNB [71].
Occult micrometastases have no significance in terms of surgical management and patient outcomes [68,72]. Thus, routine immunohistochemistry staining or reverse transcriptase polymerase chain reaction is not recommended for the evaluation of sentinel lymph nodes in guidelines published by the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and others [2,6,13]. Histologically negative nodes that are immunohistochemistry staining or reverse transcriptase polymerase chain reaction-positive are still classified as pN0 disease in the TNM staging system for breast cancer. (See "Tumor, node, metastasis (TNM) staging classification for breast cancer".)
MANAGEMENT AFTER SENTINEL LYMPH NODE BIOPSY — Sentinel lymph node biopsy (SLNB) has replaced axillary lymph node dissection (ALND) as the initial assessment of axillary nodes in patients with early breast cancer. Based upon pathologic results obtained by SLNB, we recommend no further axillary surgery for patients who meet all of the following criteria ("Z-0011-eligible" criteria) (see 'One or two sentinel node metastases' below):
●Clinically negative nodes based on an adequate clinical node evaluation, including imaging when necessary (eg, obesity).
●A T1 or T2 (≤5 cm) primary breast cancer.
●Fewer than three metastatic sentinel lymph nodes on SLNB.
●Patients undergoing breast-conserving surgery followed by whole-breast irradiation.
A completion ALND is required for patients who have:
●Three or more metastatic sentinel lymph nodes on SLNB.
●One or two metastatic sentinel lymph nodes on SLNB but who do not desire whole-breast irradiation.
These recommendations are consistent with the 2014 American Society of Clinical Oncology (ASCO) guidelines [1].
In patients who are otherwise Z0011 eligible, there is no evidence to suggest that the status of the estrogen (ER) and progesterone (PR) receptors, and expression of the human epidermal growth factor 2 (HER2) receptor, is relevant to the accuracy of SLNB or to the need for completion ALND [1]. The original American College of Surgeons Oncology Group (ACOSOG) Z-0011 trial did not stratify patients based on their HER2 status. Sixteen percent of patients included in that trial had ER-negative/PR-negative tumors, and patients with ER-negative/PR-negative tumors and those with ER-positive tumors had comparable overall and disease-free survival [73].
No sentinel node metastasis — We do not perform ALND in patients with early breast cancer who do not have nodal metastasis on SLNB, including those with isolated tumor cells present in the sentinel node(s).
Seven randomized trials compared patients with early breast cancer who underwent SLNB first followed by ALND only if SLNB was positive with those who underwent ALND (table 1). Compared with ALND, SLNB first followed by selective ALND in patients with positive sentinel lymph nodes resulted in similar overall survival (OS), disease-free survival (DFS), and disease recurrence rates but fewer adverse events and better quality of life. This conclusion is best illustrated by the results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial, which included the largest number of patients of all the trials.
The NSABP B-32 trial enrolled 5611 early-stage breast cancer patients with clinically negative nodes and compared SLNB followed by ALND with SLNB followed by ALND only if the sentinel lymph node was positive [74,75]. SLNB was successfully performed in 97 percent of patients, and the false negative rate was 9.8 percent. No significant differences were observed in regional control, OS, or DFS between the groups at a median follow-up period of almost eight years [76,77].
Micrometastasis — Micrometastatic nodal involvement is defined as a metastatic deposit >0.2 mm but ≤2.0 mm. In patients with micrometastasis only on SLNB, no completion ALND is needed (as long as the patient otherwise fits the Z-0011 criteria). This is supported by the following studies:
●In the IBCSG 23-01 trial, which included 6681 patients with one or more micrometastatic sentinel nodes and no extracapsular extension, the disease-free survival at 10 years was similar with or without completion ALND (74.0 versus 76·8 percent) [78].
●In the Swedish prospective multicenter cohort study SENOMIC, the event-free survival at three years was excellent in 566 patients with breast cancer and sentinel node micrometastases despite omission of ALND [79].
Occult metastasis — Occult metastasis refers to tumor cells in the lymph node that are not seen on initial hematoxylin and eosin examination but are detected subsequently by examining additional levels or by performing immunohistochemistry staining or reverse transcriptase polymerase chain reaction. (See 'Occult metastatic disease' above.)
In patients with occult metastasis found by SLNB, no completion ALND is needed, and no alteration in subsequent adjuvant therapy is recommended [68,72,80-82].
Clinical trials have examined the significance of occult metastases in sentinel nodes. Blinded analysis of occult metastases in clinical trials provides prognostic data on the significance of micrometastases and isolated tumor cell clusters. The NSABP B-32 trial demonstrated that the presence of occult metastases was associated with a 1.2 percent lower OS rate and a 2.8 percent lower DFS rate; patients with occult metastases did not have a higher incidence of regional or distant recurrences [68]. The ACOSOG Z-0010 trial found a 0.6 percent lower overall survival rate in patients with occult metastases, but this was not statistically significant [72]. The two trials used different protocols for detecting occult metastases, and although the B-32 trial had higher statistical power, both trials demonstrated similar outcomes related to occult metastases. In addition, the occult metastases detected were almost entirely isolated tumor cell clusters or micrometastases and only rarely macrometastases [71].
In a retrospective study, 93,070 patients with invasive breast adenocarcinoma and negative lymph nodes on routine pathology underwent immunohistochemistry staining to evaluate for occult nodal disease. The presence of micrometastases was associated with a worse overall survival rate (hazard ratio [HR] 1.40, 95% CI 1.28-1.53), while the presence of isolated tumor cells was not (HR 1.05, 95% CI 0.92-1.20) [83].
One or two sentinel node metastases — There is compelling evidence that ALND is not necessary in most women with early-stage breast cancer who have only one or two sentinel lymph node metastases and who will receive whole-breast irradiation as part of breast-conserving therapy. If, however, whole-breast irradiation is not planned, then ALND is indicated for such patients.
Historically, patients with any nodal metastasis underwent completion ALND [6]. However, only approximately 40 percent of patients with a positive sentinel lymph node had residual disease in the axilla [6,44,45,47,74,84-89]; the rest derived no benefit from the addition of ALND. Thus, several predictive nomograms were developed to estimate the risk of additional positive nodes based on known clinical and pathologic data derived from SLNB [90-97]. Most of these nomograms included data such as the size and number of the sentinel lymph node (SLN) metastases, extranodal extension, the size and presence of lymphovascular invasion in the primary tumor, and the size of the metastatic disease in the SLN [97]. However, retrospective analyses of patients with positive SLNs who underwent completion ALND found none of the popular nomograms to be sufficiently reliable for clinical use [93,98].
Two randomized trials, the ACOSOG Z-0011 trial and the International Breast Cancer Study Group 23-01 (IBCSG 23-01) trial, demonstrated that many of these patients with one or two metastatic sentinel nodes can safely avoid a completion ALND.
●The ACOSOG Z-0011 trial was designed to address the need for completion ALND for patients with T1 or T2 breast cancer who were clinically node negative and had fewer than three positive sentinel nodes (table 1) [50,73,99]. All patients were treated with radiation to the whole breast. Compared with SLNB plus completion ALND, SLNB alone resulted in similar five-year OS rates (91.9 percent SLNB alone group versus 92.5 percent), DFS rates (82.2 SLNB alone group versus 83.9 percent), and recurrence events (four SLNB alone group versus two). The ACOSOG Z-0011 trial has been criticized for premature study termination due to low accrual and low event rates, protocol noncompliance, and a high percentage (20 percent) of patients lost to follow-up [48,51]. In addition, the ACOSOG Z-0011 trial did not account for the number of patients in each study group who had isolated tumor cell clusters, micrometastases, or macrometastases. The majority of the study population had T1 (almost 70 percent) hormone receptor-positive (85 percent) tumors, which may influence survival outcomes in ways that cannot be controlled for. Nevertheless, the ACOSOG Z-0011 trial has widely changed the practice of early breast cancer treatment. Its results have been incorporated into treatment guidelines such as the ASCO 2014 practice guidelines for SLNB [1].
At a median follow-up of 9.3 years, the 10 year OS (86.3 percent SLND alone versus 83.6 percent ALND) and DFS (80.2 percent SLND alone versus 78.2 percent ALND) were statistically similar between the SLND alone group and the ALND group [100]. The cumulative incidence of ipsilateral axillary recurrences at 10 years was 1.5 percent (5 patients) in the SLND alone arm and 0.5 percent (2 patients) in the ALND arm; the 10 year cumulative incidence of local regional recurrences was 5.3 percent with SLND alone and 6.2 percent with ALND [101].
●The IBCSG 23-01 trial randomly assigned patients with a primary tumor <5 cm in size and clinically nonpalpable axillary nodes to either completion ALND or no additional axillary surgery after a finding of positive sentinel lymph node(s) (table 1) [52]. Only one or two sentinel nodes were positive in 85 percent of the patients. All patients had nodal metastases less than 2 mm in size, and 67 percent had micrometastases less than 1 mm. Ninety percent of patients underwent breast-conserving surgery; 10 percent underwent mastectomy. A similar proportion of patients in each group received adjuvant radiation, hormonal therapy, and chemotherapy. Approximately 90 percent of patients in both groups received whole-breast irradiation. At five years, there was no statistically significant difference in DFS rates (84 percent with ALND versus 88 percent without ALND) with OS rates (98 percent versus 97.6 percent) between the two groups. The IBCSG 23-01 trial was also closed prematurely due to low enrollment and low event rates.
Because of these two randomized trials and other studies that examined the role of ALND in managing limited axillary disease in women with early-stage clinically node-negative breast cancer, the ASCO changed its guidelines from recommending ALND for all patients with a positive sentinel lymph node (2005) to recommending against ALND for patients with fewer than three positive sentinel lymph nodes (2014). As a result, the eligibility criteria for one of the trials have become descriptive for this group of patients [1]. These so-called "Z-0011-eligible" patients are women with early-stage clinically node-negative breast cancer metastatic to one to two sentinel lymph nodes who undergo breast-conserving surgery with whole-breast radiotherapy. It is now a widespread practice that women with similarly favorable breast cancer no longer receive completion ALND.
In a prospective validation study to the ACOSOG Z-0011 trial, 793 patients underwent breast-conserving therapy for cT1-2 N0 breast cancers. Sixteen percent underwent ALND, most commonly for metastasis in ≥3 sentinel nodes or gross extracapsular extension in involved sentinel nodes [102]. For the remaining 84 percent who underwent SLNB alone, the five-year event-free survival was 93 percent (95% CI 89 to 94 percent). There were no isolated axillary recurrences, and the five-year cumulative rates of breast plus nodal and nodal plus distant recurrence rates were both 0.7 percent. Among a subset of 509 patients with known radiation therapy fields, only 21 percent of patients received both breast and nodal irradiation. The cumulative rate of nodal recurrence was 1 percent and did not differ by radiation fields.
Sentinel node metastasis with extranodal extension — Although the ACOSOG Z-0011 trial established that completion ALND is not necessary for patients who have only one or two positive sentinel nodes, patients who had gross extranodal extension were excluded from the trial. Thus, completion ALND is still considered the standard of care for patients with gross extranodal extension of sentinel node metastasis, regardless of the number.
The presence of extranodal extension is associated with increased axillary nodal disease burden. The reported incidence of nonsentinel lymph node metastases in patients with extranodal extension ranged from 58 to 84 percent [103-105]. In contrast, the ACOSOG Z-0011 trial, which excluded patients with extranodal extension, reported nonsentinel nodal metastases in 27 percent of patients. In two studies, the presence of extranodal extension, regardless of size, was associated with a greater risk of having pN2 disease (four or more positive nodes) [69,106].
Some, but not all, studies also reported increased disease recurrence [103,107] and decreased survival [103,108-112] with extranodal extension. However, none of these studies was prospective. Thus, most experts recommend that all patients who are found to have extranodal extension in any number of sentinel nodes should be offered completion ALND because of the high axillary nodal disease burden associated with extranodal extension.
Other experts suggested that only extranodal extension that is >2 mm should be considered an indication for ALND when applying Z0011 criteria to patients with fewer than three metastatic sentinel lymph nodes [69]. In one study, 331 patients with pT1-2, cN0 disease with <3 positive SLNs underwent completion ALND. Thirty-three percent of patients with extranodal extension >2 mm had ≥4 additional positive nodes at completion ALND, compared with only 9 percent of patients with extranodal extension ≤2 mm. This observation was further supported by a report of patients meeting the Z0011 criteria who had microscopic extracapsular extension (mECE) and were prospectively followed. Those patients having mECE of <2 mm (n = 117) had no isolated axillary recurrences, and those having mECE of >2 mm (n = 93) had a 3.2 percent isolated axillary recurrence rate at a mean of 41 months follow-up [113]. However, given that patients with any extranodal extension were excluded from the Z0011 trial, we recommend that all such patients should be considered for completion ALND until further data on survival and recurrence rate become available.
Sentinel node metastasis with large tumor — Patients with large tumors (eg, T3) but clinically negative axilla were excluded from the ACOSOG Z-0011 trial. Although SLNB can be performed in such patients, conclusions drawn from the Z-0011 trial cannot be applied to such patients. Thus, completion ALND is still offered as the standard of care for any patient who has a large (>5 cm or T3) tumor with any positive sentinel nodes. (See 'Locally advanced and inflammatory breast cancer' above.)
Three or more sentinel node metastases — For patients with three or more pathologically involved sentinel nodes, we recommend a completion ALND for staging purposes and to maximize local control [2,6]. The timing of the procedure (ie, immediate [one operation] versus delayed [two separate operations]) does not seem to affect the total lymph node yield or the rate of long-term complications (particularly lymphedema).
This recommendation is consistent with the 2014 guidelines from the ASCO [1] and is also supported by data from a 2013 systematic review that included 17 studies with at least two years of follow-up [54].
The use of ALND in breast cancer treatment is discussed elsewhere. (See "Technique of axillary lymph node dissection" and "Overview of management of the regional lymph nodes in breast cancer".)
Role of radiotherapy — All of the women in the ACOSOG Z-0011 trial received whole-breast irradiation, as did 90 percent of the women in the IBCSG 23-01 trial. Given that part of the axilla is included in the treatment field with whole-breast radiation, women who received radiation in the two trials probably experienced a therapeutic effect from radiation sterilizing any residual tumor cells in the axilla [114]. The same benefit would not be conferred by partial-breast radiation unless axillary radiation was used separately to control the axilla [53]. Thus, we recommend omitting ALND in patients with one or two positive SLNs who plan to undergo whole-breast irradiation but not partial-breast irradiation until there are trials demonstrating its safety in this population.
Reported in 2014, the After Mapping of the Axilla: Radiotherapy or Surgery (AMAROS) trial was a multi-institutional trial conducted by the European Organization for the Research and Treatment of Cancer (EORTC) [53]. The trial included 4806 patients with T1 or T2, primary, unifocal, invasive breast cancer without palpable axillary lymphadenopathy. Of the 1425 patients who were found to have positive sentinel node(s) by SLNB, 744 were randomly assigned to receive ALND and 681 to receive axillary radiotherapy. Ninety-five percent of patients in both groups had one or two positive SLNs. The five-year axillary recurrence rate was 0.43 percent (0 to 0.92) in the ALND group and 1.19 percent (0.31 to 2.08) in the axillary radiation group. There were no statistically significant differences in DFS and OS between treatment groups. Lymphedema was noted significantly more often after ALND than after axillary radiation at one, three, and five years. This trial was limited by a low number of events and a short follow-up period.
The 10 year follow-up results of the AMAROS trial have been reported in abstract form [115]. After 10 years, axillary recurrence remained low and comparable between the ALND group (7/744 patients; 0.93 percent) and the axillary radiotherapy group (11/681 patients; 1.82 percent). Distant metastasis-free survival and overall survival rates were similar. More second primary cancers developed in patients treated with axillary radiotherapy (11.0 versus 7.7 percent, p = 0.035). Some of these cancers were contralateral breast cancers. Although the risk of developing a contralateral breast cancer from scatter dose from the treated ipsilateral axilla should be negligible, it will be important to see the full list of the locations of the second primary cancers to assess whether any of these cancers could have been associated with radiotherapy.
The AMAROS trial showed axillary radiation to be an acceptable alternative to ALND in patients who have positive sentinel node(s) but do not meet the Z0011 criteria. For those who meet the Z0011 criteria, axillary radiation is likely to add morbidity without conferring any additional benefit compared with whole-breast irradiation alone. Additional studies are needed before regional radiotherapy can be accepted as a standard approach for patients with axillary metastases.
NONAXILLARY LYMPH NODE BIOPSY — Sentinel lymph node biopsy (SLNB) techniques can identify nonaxillary metastases (eg, internal mammary nodes and intramammary nodes) in up to 43 percent of patients, depending upon the volume/type of colloid injected, the injection technique [55-57], and the primary tumor location/size [58]. Whether identifying nonaxillary sentinel nodes is useful remains controversial since the majority of the data regarding treatment decisions and outcomes come from evaluation of only axillary nodes.
Internal mammary nodes — Internal mammary nodes are only visualized in 20 percent of patients during SLNB and can be difficult to remove because of their location. Thus, in the absence of definitive data, dissection of the internal mammary nodes with SLNB should be considered investigational.
There is no consensus on the need for internal mammary nodal dissection in women with detection of an internal mammary node by lymphoscintigraphy [6,59]. Several trials failed to demonstrate a survival benefit with surgical dissection of internal mammary nodes [116,117], and therefore the internal mammary nodes are not routinely dissected in patients undergoing breast-conserving therapy or mastectomy with axillary lymph node dissection (ALND).
Experienced surgeons may elect to remove internal mammary nodes if they are identified during SLNB. However, surgeons with less experience removing internal mammary nodes may elect to remove an internal mammary node if it is the only identifiable sentinel node.
When internal mammary nodes are biopsied, tumor involvement is found in approximately 20 percent of patients [118]. Eight to 10 percent of patients without axillary disease are found to have regional metastases to the internal mammary nodes [58,118-123]. Positive internal mammary nodes are most commonly found with medial tumors over 2 cm in size [124]. Tumor involvement of internal mammary nodes is associated with a poor prognosis [116,125]. The diagnosis of positive internal mammary nodes may affect treatment decisions regarding adjuvant systemic therapy and regional nodal irradiation [119]. (See "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer", section on 'Regional field'.)
Internal mammary nodes are only visualized in approximately 20 percent of patients during SLNB [118]. This is partly explained by limitations of the SLNB technique [44,58,119,120,122,126]. The procedure does not reliably identify involved internal mammary nodes, because of interference from radioactivity at the primary tumor site [44]. There is a high rate of technical failure (20 to 39 percent) in patients with parasternal hot spots on lymphoscintigraphy [118,122,123], and hot spots in the internal mammary region do not always represent tumor involvement [58,120,127,128]. In addition, some surgeons do not employ radioactive colloid injection and only rely on blue dye to identify the sentinel nodes.
Accordingly, additional noninvasive methods have been used to assess internal mammary nodes, including magnetic resonance (MR) imaging and positron emission tomography (PET) scanning. Breast MR imaging visualized at least one internal mammary lymph node (range 1 to 3) in 50 of 108 women with an average size of 4.5 mm (range 2 to 9 mm) [129]. However, these imaging modalities are unable to definitively identify positive nodes.
The internal mammary nodes are difficult to sample surgically even when they are identified by lymphoscintigraphy [119]. Although internal mammary lymph node biopsy can be accomplished at the time of mastectomy by splitting the fibers of the pectoralis major muscle, an internal mammary lymph node biopsy in a patient undergoing breast-conserving surgery usually requires a second incision, which is cosmetically visible through many types of clothing. Biopsy of the internal mammary node can be complicated by pneumothorax, pleural effusion, or bleeding and therefore should be performed only when, in the judgment of the surgeon, it can be performed safely [120,122].
Intramammary nodes — Numerous case reports document identification of intramammary lymph nodes on SLNB [130-134], although few have explored the clinical significance of this finding. Intramammary lymph nodes are present in 1 to 28 percent of women with breast cancer. Most series report a high likelihood of additional axillary nodal metastases when the intramammary nodes contain cancer [135,136]. (See "Diagnostic evaluation of suspected breast cancer".)
If intramammary nodes contain tumor, they are considered the same as a positive axillary lymph node for staging and prognostic purposes [137].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast surgery".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Sentinel lymph node biopsy for breast cancer (The Basics)")
●Beyond the Basics topic (see "Patient education: Breast cancer guide to diagnosis and treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Axillary lymph nodes in breast cancer – The status of the axillary lymph nodes is one of the most important prognostic factors in patients with breast cancer. Histologic examination of removed lymph nodes is the most accurate method for assessing nodal metastasis. An adequate clinical (and in some patients radiographic) evaluation of the axilla is required for treatment decisions in patients with invasive breast cancer. Axillary lymph node dissection (ALND) remains the standard approach for women who are clinically node positive. (See 'Introduction' above and 'Preoperative axilla evaluation' above.)
●Early-stage breast cancer – For patients with early-stage breast cancer who are clinically node negative, we recommend an initial axillary evaluation with sentinel lymph node biopsy (SLNB) rather than ALND (Grade 1A). (See 'Early breast cancer with clinically negative nodes' above.)
●Ductal carcinoma in situ – For patients with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery, we recommend not performing surgical evaluation of the axilla (Grade 1A). For patients with DCIS undergoing a mastectomy, we suggest that an SLNB be performed as SLNB is not possible after a mastectomy, even if invasive disease is later found (Grade 2B). (See 'DCIS with planned mastectomy or suspicious features' above.)
●Select older patients – For older patients who are clinically node negative, we suggest omitting surgical evaluation of the axilla when the nodal information will not affect adjuvant treatment decisions (Grade 2B). (See 'Patients whose axillary status does not guide adjuvant treatment' above.)
●Repeat axillary procedure – In patients who have recurrent breast cancer and previous axillary procedures (SLNB or ALND), we suggest performing a lymphoscintigraphy using 99mTc-colloidal albumin or sulfur colloid to identify the sentinel node rather than proceeding directly to an SLNB (Grade 2C). (See 'Recurrent breast cancer and previous axillary procedures' above.)
●Pathologic analysis of sentinel nodes – Immunohistochemical assessment (IHC) should not be used as a routine method of evaluating sentinel nodes. IHC should be employed to definitively diagnose an area that is suspicious for, but not diagnostic of, lymph node metastases on hematoxylin and eosin (H&E). (See 'Pathologic analysis of nodal metastases' above.)
●Management after sentinel lymph node biopsy – The decision to proceed with completion ALND after SLNB is based on the results of the SLNB and whether the patient is "Z-0011 eligible" (defined as clinically node negative, early-stage [T1/T2, ≤5 cm] breast cancer metastatic to one to two sentinel lymph nodes [without extranodal extension] undergoing breast-conserving surgery followed by whole-breast radiotherapy) (see 'Management after sentinel lymph node biopsy' above):
•For patients who are clinically node negative and have an SLNB that is negative or shows only isolated tumor cells, we recommend not performing completion ALND (Grade 1A). (See 'No sentinel node metastasis' above.)
•For patients who have an SLNB with one or two positive sentinel nodes and are "Z-0011 eligible," we recommend not performing completion axillary dissection (Grade 1A). If only partial-breast irradiation is planned, completion ALND should be performed. (See 'One or two sentinel node metastases' above.)
•For women who have one or two positive sentinel nodes but are not "Z-0011 eligible" (eg, large [T3, >5 cm] tumor or the presence of extranodal extension), we recommend performing completion ALND or axillary radiation (Grade 1C). (See 'Sentinel node metastasis with large tumor' above and 'Sentinel node metastasis with extranodal extension' above and 'Role of radiotherapy' above.)
•For patients with three or more positive sentinel nodes, we recommend performing completion ALND (Grade 1B). (See 'Three or more sentinel node metastases' above.)
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