Anees B Chagpar, MD, MSc, MA, MPH, MBA, FACS, FRCS(C)
Daniel F Hayes, MD
Lori J Pierce, MD
Disclosures: Seth P Harlow, MD Nothing to disclose. Donald L Weaver, MD Nothing to disclose. Anees B Chagpar, MD, MSc, MA, MPH, MBA, FACS, FRCS(C) Nothing to disclose. Daniel F Hayes, MD Clinical Research Support: Janssen [Circulating Tumor Cell (Circulating Tumor Cell Kit)], Breast cancer (abiraterone)]. Patent Holder: Circulating tumor cells (Circulating Tumor Cell Kit). Equity Ownership/Stock Options: Inbiomotion; OncImmune. Lori J Pierce, MD Nothing to disclose. Don S Dizon, MD, FACP Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — The status of the axillary lymph nodes is one of the most important prognostic factors in women with early stage breast cancer. Histologic examination of lymph nodes is the most accurate method for assessing spread of disease to these nodes. (See "Management of the regional lymph nodes in breast cancer" and "Prognostic and predictive factors in metastatic breast cancer", section on 'Prognostic versus predictive factors'.)
Axillary lymph node dissection (ALND) has traditionally been a routine component of the management of early breast cancer. The benefits of ALND include its impact on disease control (ie, axillary recurrence and survival), its prognostic value, and its role in treatment selection. However, the anatomic disruption caused by ALND may result in lymphedema, nerve injury, and shoulder dysfunction, which compromise functionality and quality of life.
ALND is the typical approach for women who have clinically palpable axillary nodes or positive nodes confirmed by methods such as ultrasound guided fine needle aspiration. For patients who have clinically negative axillary lymph nodes, sentinel lymph node dissection (SLND) is a method of staging the axilla with less morbidity than ALND.
Indications for and outcomes of SLND will be reviewed here. The technique of SLND in patients with breast cancer is discussed separately. (See "Sentinel lymph node biopsy in breast cancer: Techniques".)
DEVELOPMENT AND VALIDATION OF THE SLND TECHNIQUE — The importance of the sentinel lymph node (SLN) is based upon the observation that tumor cells migrate from a primary tumor metastasize to one or a few lymph nodes (LNs) before involving other LNs. Injection of vital blue dye and/or radiolabeled colloid around the area of the tumor permits identification of a SLN in the majority of patients, and its status accurately predicts the status of the remaining regional LNs (picture 1 and image 1 and image 2 and image 3). (See "Sentinel lymph node biopsy in breast cancer: Techniques".)
In patients with clinically node negative breast cancer, SLND identifies patients without axillary node involvement, thereby obviating the need for more extensive surgery . Several studies have shown that the risk of arm morbidity, particularly lymphedema, sensory loss, and shoulder abduction deficits, is significantly less for SLND than with standard axillary dissection [2-8]. As an example, the risk of lymphedema after 12 months was reported as 2 percent after SLND alone as compared with 13 percent after SLND with axillary lymph node dissection (ALND) in the American College of Surgeons Oncology Group (ACOSOG) Z-0011 trial . (See "Clinical manifestations and diagnosis of lymphedema".)
Most surgeons and major cancer centers have adopted SLND as a standard means of axillary nodal assessment. In a study of over 490,000 women with early breast cancer from the National Cancer Database, use of SLND increased from 27 to 66 percent between 1998 and 2005 in the United States . Similar trends have been reported from Canada and the United Kingdom [10,11]. SLND is endorsed as an alternative to ALND for the diagnosis of axillary metastases in patients with clinically node-negative early breast cancer in guidelines from the American Society of Clinical Oncology (ASCO) , the International Expert Consensus Panel on the Primary Therapy of Early Breast Cancer , and others [14,15].
Despite variability in selection criteria and technique, a SLN is consistently identified in approximately 96 percent of cases, and predicts the status of the remaining axillary LNs in ≥95 percent of cases in most series [1,16]. The false negative rate of SLND was originally reported as 5 to 10 percent (sensitivity 90 to 95 percent), but lower rates are attainable by experienced surgeons [1,17].
One of the greatest concerns with SLND is the potential of a false negative result, which could increase the potential for axillary recurrence. However, despite the approximately 5 to 10 percent false negative rate with SLND found in studies in which completion ALND has been done, several series suggest that axillary recurrence rates are low after a negative SLND alone in early stage breast cancer (range 0 to 4.5 percent) [17-27]. The details of key trials validating the SLND are described below:
●A landmark multicenter study of 443 patients with early breast cancer demonstrated that the SLND technique could be learned and successfully applied by a diverse group of surgeons spanning private and academic practice [28,29]. All patients underwent SLND using radiolabeled colloid followed by completion ALND. At least one SLN was identified in 98 percent of cases and the predictive value of a negative SLN was 96 percent, with a false negative rate of 11 percent (sensitivity 88 percent). More intensive pathologic evaluation of the nodes in false negative cases with deeper sectioning of the sentinel node and immunohistochemical staining increased the yield of occult metastases and led to an overall case conversion rate of 10.3 percent . There is little clinical significance of micrometastasis and the contemporary approach is not to perform a completion axillary lymph node dissection. (See 'Completion axillary dissection with BCT' below.)
●A systematic review, performed by the ASCO expert guidelines panel, included 69 eligible trials of SLND in early stage breast cancer, representing 8059 patients [12,31]. The SLN was identified using radiocolloid, blue dye, or both. SLN identification was successful in 95 percent of patients. The false negative rate was 7.3 percent (range 0 to 29 percent). The combination of radiocolloid and blue dye resulted in a significantly higher success rate in SLN mapping with a lower false negative rate as compared with blue dye alone.
●The NSABP B-32 trial, published after the systematic review, enrolled 5611 breast cancer patients with clinically negative nodes and compared SLND followed by ALND versus SLND followed by ALND only if the SLN was positive [32,33]. Lymphatic mapping was successful in 97 percent, and the false negative rate was 9.8 percent. No significant differences were observed in regional control, overall survival (OS), or disease free survival (DFS) between the groups at a median follow-up of almost eight years [34,35]. Similar findings were reported from the KiSS study (German Clinical Interdisciplinary Sentinel Study), a trial of 1182 patients randomized to SLND followed by ALND versus SLND followed by ALND only if the SLN was positive .
INDICATIONS — SLND should be performed in most women with clinically node negative invasive or microinvasive breast cancer . SLND can be omitted if the nodal information will not affect adjuvant treatment decisions. As an example, women ≥70 years of age who have a small (<2 cm) estrogen receptor-positive tumor and a clinically uninvolved axilla may be treated without a SLND. The management of early breast cancer in older women is discussed in detail elsewhere. (See "General principles on the treatment of early stage and locally advanced breast cancer in older women", section on 'Management of the axilla'.)
SLND should be performed in women with extensive ductal carcinoma in situ (DCIS), who are undergoing mastectomy. A SLND will not be possible after mastectomy if invasive disease is found on final pathology, necessitating an axillary dissection for staging purposes. (See 'Ductal carcinoma in situ' below.)
When a SLND is not successful or when clinically suspicious nodes are encountered in the axilla the surgeon should perform an axillary dissection for staging purposes and to ensure locoregional control . (See "Management of the regional lymph nodes in breast cancer".)
THE ROLE OF ULTRASOUND IN SENTINEL NODE EVALUATION — For women with clinically suspicious lymph nodes, preoperative axillary ultrasound (US) with fine needle aspiration (FNA) or core biopsy of suspicious areas provides a means to identify patients who have positive nodes, and thus may need axillary lymph node dissection (ALND) rather than a SLND [37-50]. As an example, in a series of 653 consecutive patients, the preoperative diagnosis rate of axillary disease was 23 percent using axillary US and FNA, thereby avoiding the need for a second operation in 150 women . The efficacy of this approach is somewhat variable between centers because the accuracy of US examination is operator dependent (image 4 and image 5 and image 6). (See "Diagnostic evaluation of women with suspected breast cancer" and "Breast biopsy".)
MANAGEMENT OF SLN METASTASES — Approximately 40 percent of patients with a positive sentinel lymph node (SLN) will be found to have residual disease in the axilla [12,28,32,51-58]. SLN metastases are categorized as isolated tumor cells, micrometastases, or macrometastases, depending upon the size of the largest tumor deposit in the sentinel node. Each of these is discussed below.
Isolated tumor cells — The seventh edition of the American Joint Committee on Cancer (AJCC) tumor node metastasis (TNM) staging system for breast cancer includes a stringent classification for lymph node findings of isolated tumor cell clusters and single cells. Small clusters of 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, are classified as isolated tumor cells and are considered prognostically similar to node negative patients. Malignant cells in regional lymph node(s) no greater than 0.2 mm are designated as pN0(i+). Isolated tumor cells are not considered an indication for further axillary surgery, radiation treatment, or adjuvant systemic therapy. The finding of isolated tumor cells in lymphatics as a result of iatrogenic displacement from core biopsy procedures has been observed and is not considered to be clinically significant [59-62]. (See "Tumor node metastasis (TNM) staging classification for breast cancer".)
Micrometastases — SLND allows the pathologist to perform a more detailed study of one or a few LNs that are most likely to contain metastases, compared with the 15 to 25 LNs obtained with ALND. This has the potential to improve staging accuracy , but has led to an increase in the identification of micrometastatic nodal involvement [64,65]. For this reason, there is a separate designation of pN1mi (>0.2 mm and no greater than 2.0 mm) to indicate micrometastases alone. (See "Tumor node metastasis (TNM) staging classification for breast cancer".)
Although patients with micrometastases are considered node positive and it seems intuitive that the finding of axillary micrometastases should worsen prognosis, most studies show no change or only a small reduction in patient survival compared with those without micrometastases [66-72]. However, some analyses suggest a negative impact of micrometastases on breast cancer outcomes, including regional recurrence rate [73-80]. In a retrospective review of patients undergoing a SLND without a completion axillary node dissection, patients with micrometastatic disease (n = 141) had a significantly higher five-year regional recurrence rate compared with patients with isolated cancer cells (n = 345) and SLN negative findings (n = 732) (5.6 versus 2.0 versus 2.3 percent, respectively) . Patients with micrometastatic disease in SLN without a completion axillary node dissection also had a significantly higher rate of recurrence compared with patients with micrometastatic disease and a completion axillary dissection (n = 887) (5.6 versus 1.0 percent, hazard ratio [HR] 4.39, 95% CI 1.46-13.24). There was no significant difference based upon axillary completion in the other two cohorts. There were no regional recurrences if the axilla was treated with radiation therapy for patients with isolated cancer cells (n = 54) or micrometastatic disease (n = 94). Patients with grade 3 breast cancer (HR 5.05, 1.26-16.62) and negative hormone receptor status (HR 4.96, 1.48-16.62) were significantly more likely to recur.
Pathologic evaluation for occult metastases in a randomized trial of 3887 women who underwent SLND alone or SLND plus ALND for invasive breast cancer detected occult metastases in 16 percent of patients (isolated tumor cell clusters in 11 percent, micrometastases in 4 percent, and macrometastases in 0.4 percent) . The following findings were noted:
●Occult metastases were an independent adverse prognostic factor with an increased risk of distant disease and death.
●Smaller metastases had less of an adverse effect on outcomes than larger metastases, and the risk associated with isolated tumor cell clusters was less than the risk associated with micrometastases.
●At five years, the differences in outcomes for patients with and without occult metastases were statistically significant but relatively small with respect to overall survival (95 versus 96 percent), disease free survival (86 versus 89 percent), and distant disease free interval (90 versus 92 percent).
●The presence of occult metastases was not a discriminatory predictive factor; 85 percent of women with occult metastases were alive without recurrent breast cancer.
There is some debate about the prognostic value of the size of the SLN micrometastases (≤0.2 mm versus larger) in predicting the likelihood and significance of involvement of axillary non-SLNs (table 1) [82-86]. Although guidelines from ASCO and NCCN recommend that routine completion ALND be carried out for micrometastases detected on SLND with standard hematoxylin and eosin (H&E) examination, this practice is now being questioned for women with less than three positive lymph nodes [12,15]. This is discussed in detail below. (See 'Completion axillary dissection with BCT' below.)
Macrometastases — The 2005 American Society of Clinical Oncology (ASCO) guidelines and 2010 National Comprehensive Cancer Network (NCCN) guidelines recommend that routine completion ALND be carried out for patients with SLND macrometastases (≥2 mm) [12,15]. However, the indications for a completion ALND in patients with <3 positive sentinel nodes is the subject of controversy. This is discussed in detail below. (See 'Completion axillary dissection with BCT' below.)
Role of IHC and RT-PCR in sentinel node evaluation — Occult micrometastases refers to nodal metastases that are not seen on initial hematoxylin and eosin (H&E) examination but are detected subsequently by additional level or by immunohistochemistry (IHC) or reverse transcriptase polymerase chain reaction (RT-PCR). The significance of occult micrometastases in terms of surgical management and patient outcome appears to be negligible [79,87-89].
Results from the American College of Surgeons Oncology Group (ACOSOG) study Z0010, a prospective multicenter study of 5210 patients with almost eight-year follow-up, confirm that IHC-detected metastases have no significant impact on overall survival . Thus, routine IHC or PCR is not recommended for the evaluation of SLNs in guidelines published by ASCO, NCCN, and others [12,15,90]. Histologically negative nodes that are IHC or RT-PCR-positive are classified as pN0 disease in the TNM staging system for breast cancer. (See "Tumor node metastasis (TNM) staging classification for breast cancer".)
Role of IHC in invasive lobular carcinoma — Although routine IHC staining with cytokeratin is not indicated for most breast cancers, it can be helpful for examination of the sentinel nodes in patients with invasive lobular carcinoma since the morphology of lobular cancer can be difficult to detect on H&E of axillary lymph nodes [91,92]. In general, IHC should be used to definitively diagnose an area that is suspicious for, but not diagnostic of, lymph node metastases on H&E rather than as a routine method of evaluating nodes in cases of invasive lobular cancer.
Completion axillary dissection with BCT — The need for completion axillary lymph node dissection (ALND) in women with clinically node negative T1 or T2 tumors is dependent upon the SLND findings. The indications for a completion axillary dissection are evolving .
There is general acceptance for the following approaches:
●For patients with a negative sentinel lymph node biopsy (SLND), completion ALND is not indicated [35,94].
●Patients with a SLND showing isolated tumor cells only are considered node negative for prognostic purposes and completion ALND is not indicated .
●For patients with a positive SLND showing micrometastases or macrometastases in three or more nodes, detected with standard hematoxylin and eosin (H&E) examination, completion ALND is recommended for staging purposes and to ensure local control [12,15]. 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) .
The need for a completion ALND in patients with a positive SLND showing micrometastases or macrometastases in less than three nodes has been questioned . The SLN is the sole tumor-bearing node in up to 60 percent of cases overall, and in almost 90 percent of patients who harbor only micrometastatic disease. These observations have led to speculation that completion ALND may not be necessary in selected patients with a positive SLND in less than three nodes because the need for systemic therapy is established [28,51-55,97] and the risk of an axillary recurrence appears to be low [18,98-100].
However, a retrospective review of 17 studies (randomized control trials, prospective studies) with at least two years of follow-up supports performing a complete axillary node dissection in select patients that meet the following criteria :
●Palpable or needle-biopsy-proven axillary metastasis
●Positive sentinel node undergoing a mastectomy without radiation therapy
●Three or more positive sentinel nodes
Patients who undergo an ALND are at a higher risk of complications, such as lymphedema, arm pain or numbness, or reduced quality of life, in comparison with women who undergo a SLND only.
In a retrospective review of 30 studies including 7151 women with a positive SLN not undergoing a completion ALND with a median follow-up of 45 months, the axillary recurrence rate was 0.3 percent for patients with micrometastases and 0.7 percent for patients with macrometastases .
ACOSOG Z-0011 trial — The American College of Surgeons Oncology Group (ACOSOG) study Z0011 (ACOSOG Z-0011) trial was designed to address the need for completion ALND for patients with T1 or T2 tumors that were clinically node negative and had less than three positive sentinel nodes; all patients were treated with radiation to the breast [2,103,104].
The pertinent results of the trial included:
●At a median follow-up of 6.3 years, there were no significant differences in survival or locoregional recurrence between the SLND plus ALND group versus the SLND alone group.
●The five-year overall survival was similar whether women were treated with SLND plus ALND or with SLND alone (91.9 versus 92.5 percent, respectively) (HR 0.79, 90% CI 0.56-1.10).
●The five-year disease-free survival was also similar between the two arms (82.2 versus 83.9 percent, respectively).
●Recurrence rates in the ipsilateral axilla were similar between the two arms with four recurrences (0.9 percent) in the SLND alone arm compared with two recurrences (0.5 percent) in the SLND plus ALND arm.
The ACOSOG Z-0011 trial was criticized for a number of performance deficiencies, including [105,106]:
●Target accrual for ACOSOG Z-0011 study was 1900 patients. The study closed prematurely because of low accrual and low event rate after enrolling 436 patients in the SLND alone arm and 420 in the SLND plus ALND arm.
●The trial was not adequately powered to meet the predetermined statistical survival primary endpoint due to low accrual.
●Eleven patients assigned to the SLND only arm did have an ALND and 32 patients assigned to the SLND plus ALND arm did not have an ALND.
●Almost 20 percent of patients were lost to follow-up and 7 percent of patients in the SLND arm were found to be node negative compared with 1 percent of the ALND arm.
●There was no breakdown of the numbers of patients with isolated tumor cell clusters, micrometastases or macrometastases in the two arms.
●The majority of patients had T1 (almost 70 percent), hormone receptor positive tumors (85 percent). Estrogen receptor status and adjuvant systemic therapy were independent predictors of survival.
Based upon the apparent lack of regional benefit and low risk of events in this trial, completion ALND may not be necessary for all women with T1 tumors that are clinically node negative, with less than three positive SLNs, who will be treated with whole breast radiation, particularly in women with estrogen receptor positive tumors. This was also shown in a retrospective review of 242 consecutive patients who met the ACOSOG Z0011 criteria . When completion ALND is omitted in patients with a positive SLND, whole breast radiotherapy is indicated. If partial breast radiation is planned, completion ALND should be performed.
IBCSG 23-01 trial — The International Breast Cancer Study Group trial 23-01 (IBCSG 23-01) randomized patients with SLN micrometastases (<2 mm) and primary tumors <5 cm in size to either completion ALND or no additional axillary surgery . The primary end-points included five-year disease-free survival (DFS) and overall survival (OS) rates. The target accrual of this trial was 1960 patients; however, the trial closed early with 931 patients accrued and is underpowered. Only one or two sentinel nodes were positive for 85 percent of patients. In addition, no patient had metastases greater than 2 mm in size and 67 percent had less than 1.0 mm of microscopic disease in the sentinel node.
The pertinent results of the trial include:
●With a median follow-up of 49 months, there was no significant difference in DFS rate for patients treated with an ALND compared with those treated with a SLND (87 versus 92 percent).
●There was no significant difference in OS rate for patients treated with an ALND compared with those treated with a SLND (97.6 versus 98.0 percent).
Treatment regimen included:
●Breast conserving surgery was performed for 90 percent; the remaining 10 percent underwent a total mastectomy.
●Adjuvant radiation therapy was administered in 89 percent of patients undergoing an ALND and 92 percent of patients undergoing a SLND only.
●Adjuvant anti-estrogen hormone therapy was administered in 63 percent of patients undergoing an ALND and 67 percent of patients undergoing a SLND.
●Chemotherapy was administered to 7 percent of patients undergoing an ALND and 9 percent of patients undergoing a SLND.
The results of this trial, when considered in the context of the ACOSOG Z0011 trial, offer additional support to the concept that a subset of patients with metastases to sentinel nodes may in fact do well with SLND alone as compared with a completion ALND. However, the data are derived from studies that are underpowered and have relatively short follow-up.
NCIC-CTG MA. 20 trial — The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) MA.20 trial randomized 1832 node positive or high-risk node negative breast cancer patients treated with breast conserving surgery and ALND to whole breast irradiation (WBI, 50Gy in 25 fractions +/- boost irradiation) alone or WBI plus regional nodal irradiation (RNI, 45Gy in 25 fractions) . RNI was administered to the internal mammary, supraclavicular, and high axillary lymph nodes. The mean follow-up was 62 months.
It is not certain that the same benefit of RNI would be seen in patients treated with SLN biopsy alone as compared with those getting a complete ALND .
Characteristics of the study population included:
●Node negative breast cancer in 10 percent
●One to three positive ALNs in 85 percent
●Greater than 4 ALNs positive in 5 percent
●Adjuvant chemotherapy administered to 91 percent
●Adjuvant endocrine therapy administered to 71 percent
The pertinent results of the trial reported only in abstract form include :
●Patients treated with WBI and RNI had a significantly improved risk of isolated locoregional five-year DFS compared with patients treated with WBI alone (96.8 versus 94.5 percent, hazard ratio [HR] 0.59).
●Patients treated with WBI and RNI had a significantly improved risk of distant five-year DFS compared with patients treated with WBI alone (92.4 versus 87.0 percent, HR 0.64).
●Patients treated with WBI and RNI had a significantly improved risk of five-year OS compared with patients treated with WBI alone (92.3 versus 90.7 percent, HR 0.76).
●Grade 2 or greater pneumonitis was significantly more common in patients treated with WBI and RNI (1.3 versus 0.2 percent).
●Upper extremity lymphedema was significantly more common in patients treated with WBI and RNI (7.3 versus 4.1 percent).
The results of this trial are preliminary; however, the findings are no less compelling than those of the ACOSOG Z0011 and IBCSG 23-01 trials. While the benefit may be strictly due to the additional axillary radiation, it is not certain that RNI would benefit patients treated with SLND alone as compared with those getting a complete ALND. Additional follow-up is needed before the results of this trial can be used to recommend RNI as standard treatment for node positive patients. The additional morbidity (eg, extremity lymphedema) and its impact on quality of life will also need to be considered.
NCCN — The National Comprehensive Cancer Network (NCCN) has not changed their guidelines and continues to recommend completion ALND for all women with positive sentinel nodes until additional randomized trial results are available . However, a distinction can be made between isolated tumor cells, micrometastases, and macrometastases, in terms of clinical management, especially because at least 22 percent misclassification of sentinel node metastases has been demonstrated . In light of this, omission of the ALND can be considered if the tumor burden appears low (eg, in cases with isolated tumor cells or micrometastases) when whole breast radiation with high axillary tangents is planned. Additional results are pending from two ongoing randomized trials studying the benefit of ALND for clinically node negative women with positive SLNs: the EORTC 10981-22023 AMAROS trial; and Trial 23-01 of the International Breast Cancer Study Group (IBCSG) [16,112]. (See "Management of the regional lymph nodes in breast cancer", section on 'Axillary radiation therapy'.)
ASCO 2014 guidelines — For patients with <3 positive sentinel lymph nodes (with or macro metastases found by sentinel node biopsy), ASCO 2014 guidelines advise a completion axillary node dissection should not be performed if there is no evidence of bulky metastatic disease or gross extra capsular extension and the patient is treated with whole breast irradiation .
Predictive nomograms — SLND followed by a completion ALND results in significantly greater arm morbidity than SLND alone . Because the majority of patients with SLND metastases will not have additional positive nodes on completion ALND, several predictive nomograms for estimating the risk of additional positive nodes have been developed in an effort to spare women from unnecessary and potentially morbid surgery [20,114-120]. These nomograms include both clinical and pathologic features, such as the size and/or number of the SLN metastases, extranodal extension, the size and/or presence of lymphovascular invasion in the primary tumor, and the size of the metastatic disease in the SLN as a continuous variable from a prospective cohort of 561 patients with positive SLN . A retrospective analysis of 319 patients with a positive SLND who underwent completion axillary dissection compared the performance of four different nomograms . None of the nomograms was sufficiently reliable for clinical use.
Age >65 years — A positive SLND followed by a completion ALND did not improve all-cause or breast-cancer-specific survival in women over 65 years of age. In a retrospective review of the Surveillance, Epidemiology, and End Results (SEER) database, the five-year all-cause survival for patients with a positive sentinel node who underwent a completion ALND (n = 4586) did not statistically differ from similar women who did not undergo an ALND (n = 629), (84 verus 83 percent) . In addition, there was no significant five-year breast-cancer-specific survival (94.6 versus 91.6 percent). An analysis of prospective data is needed to confirm these retrospective findings.
Mastectomy and completion ALND — Management of a negative and positive SLN identified in conjunction with a mastectomy is discussed separately. (See "Mastectomy: Indications, types, and concurrent axillary lymph node management", section on 'Evaluation and management of the axilla'.)
SLND IN SPECIAL CIRCUMSTANCES — Sentinel lymph node dissection (SLND) is evolving in selected clinical settings.
Male breast cancer — The vast majority of published studies of SLND for breast cancer are in women. Data are limited in men with breast cancer (MBC), because it is uncommon. A retrospective study of 30 men with breast cancer reported a 100 percent SLND identification rate and a false negative rate of 0 percent . Prospective studies establishing the sensitivity and specificity of SLND in MBC have not been carried out. However, the principles guiding SLND in women appear to apply to men.
Due to the limited amount of data, the 2005 American Society of Clinical Oncology (ASCO) guidelines on SLND did not make a specific recommendation about the use of SLND in MBC, although it was deemed "acceptable" . This topic is addressed in detail elsewhere. (See "Breast cancer in men", section on 'Management of the regional nodes'.)
Locally advanced and inflammatory breast cancer — Most studies have restricted SLND to T1 or T2 breast cancers <5 cm in size, since larger tumors have a higher likelihood of positive axillary nodes. However, some studies have shown that SLND is accurate in patients with T3 tumors and clinically negative axillae [123,124]. Thus, many clinicians do not recognize large breast tumors as a contraindication to SLN dissection, as long as the axilla is clinically negative.
However, patients with T4 tumors (locally advanced) or inflammatory breast cancer are not considered candidates for SLND [125,126]. The false negative rate is high in patients with inflammatory breast cancer, presumably because of the presence of partially obstructed, functionally abnormal subdermal lymphatics.
The 2005 ASCO guidelines on SLND did not recommend the routine use of SLND in patients with locally advanced or inflammatory breast cancer for whom ALND was recommended to ensure locoregional control . Consensus recommendations from an International Expert Panel published in 2010 considered inflammatory breast cancer to be the one of the few absolute contraindications to SLND . In addition, SLND was not recommended for T4 tumors.
Neoadjuvant chemotherapy — Many women with large primary breast tumors are offered neoadjuvant chemotherapy prior to definitive locoregional therapy. The optimal timing for sentinel lymph node biopsy (SLND) in patients receiving neoadjuvant therapy has been debated, as some have reported a higher false negative rate for SLND performed after induction therapy , while others have not [128-135].
In a prospective, multicenter study (SENTinel NeoAdjuvant [SENTINA]) that included 1022 women with a clinical axillary node-negative breast cancer undergoing a SLND before neoadjuvant therapy, the detection rate of a SLN was 99 percent; 35 percent (360) had a histologically positive node identified . Included in this study were an additional 715 women who presented with clinical axillary node-positive disease who underwent neoadjuvant therapy without a SLN procedure; 592 (83 percent) converted to clinical axillary node-negative status but only 25 percent had pretreatment nodal status confirmed histologically. Pertinent findings for post-treatment SLN detection and false negative rates included:
●Of the 592 women who converted from clinical node-positive to node-negative status, the SLN detection rate was 80 percent. The false negative rate was 14.2 percent (32 of 226 patients undergoing completion ALND).
●Of the 360 women with a positive SLN identified before treatment, a post-treatment SLN detection rate was 61 percent and the false negative rate was 52 percent (33 of 64 patients undergoing completion ALND).
The 2011 NCCN guidelines recommend that SLND be performed prior to neoadjuvant chemotherapy because it provides valuable prognostic information for planning locoregional treatment . However, a complete pathologic response cannot be assessed if the SLN is removed. A core biopsy or a fine needle aspiration (FNA) of the sentinel node can preserve the SLN for post-chemotherapy evaluation. Completion axillary dissection, if indicated, can be performed following chemotherapy at the time of definitive surgery. In 2013, the ACOSOG trial Z1071 found a 12.6 percent false negative rate when a repeat SLND was performed after neoadjuvant chemotherapy in patients previously shown to be node positive . This high false negative rate limits the utility of the procedure until there is either refinement in technique or patient selection. The 2014 ASCO guidelines indicate that the data are not sufficient to support the use of sentinel node biopsy after neoadjuvant chemotherapy given the high false negative rates in the published trials . (See "Neoadjuvant systemic therapy for breast cancer: Response, subsequent treatment, and prognosis", section on 'Nodal evaluation'.)
Multicentric disease — Studies that evaluated the functional anatomy of lymphatic drainage support the theory that all quadrants of the breast drain into the same lymph node(s) [137,138]. Thus, subareolar and intradermal (rather than peritumoral) injection of radiolabeled colloid or blue dye render SLND feasible for patients with multicentric disease [137,139-141]. (See "Sentinel lymph node biopsy in breast cancer: Techniques".)
The success of SLND for multicentric disease has been demonstrated in several studies [140,142]. In a study of 142 women with multicentric breast cancer, SLND was successful in 91 percent, with a false negative rate of 4 percent . However, the number of patients requiring completion ALND because of a positive SLN is higher in multicentric compared with unicentric disease. The likelihood of finding additional disease at the time of completion ALND is also higher with multicentric disease. The ASCO guidelines recommend SLND as appropriate for patients with multicentric disease .
Ductal carcinoma in situ — Most women with ductal carcinoma in situ (DCIS) do not require assessment of the axillary nodes, particularly if they are undergoing breast-conserving therapy. However, women with DCIS may be candidates for SLN mapping if they are undergoing mastectomy, because the performance of SLND will be impossible at a later time if invasive disease is found . An intact breast with its lymphatic plexus is necessary for injection of both the blue dye and the radioisotope tracers.
Some recommend that SLND be considered in patients who are undergoing breast conserving therapy or mastectomy for DCIS only if the risk of node metastases is increased, as with extensive high-grade DCIS, a strong suspicion of invasive disease based upon ancillary imaging, or documented microinvasive disease in the core biopsy . However, if a partial mastectomy is performed and invasive disease is identified, a SLND can be done as a separate operation. This approach can minimize unnecessary morbidity, since SLND can be associated with complications. SLND is generally performed if microinvasion is found in the breast biopsy or if mastectomy is required for extensive or multifocal DCIS, where the risk of an occult invasive component is increased. If metastases are found on SLND, the disease stage would change accordingly [143,144]. (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".)
Pregnancy — Concern for teratogenic effects has limited the use of SLND during pregnancy. Supravital dyes such as isosulfan blue dye should not be administered to pregnant women due to lack of studies testing the fetal safety of the dyes . Caution is also advised when administering during lactation.
However, methylene blue and 99 m-Technetium (99-Tc) may be safely administered without fetal harm. A retrospective study that included 25 clinically node negative pregnant patients who were administered methylene blue (n = 7) or 99-Tc (n = 16), and two with unknown injection material, found at 2.5 years of follow-up no adverse fetal outcomes that could be attributed to the injection . Injections were performed at various trimesters. There were 25 livebirth infants, 24 of whom were deemed healthy at delivery; one infant had a cleft lip not attributed to the injection.
Available data suggest that the dose of radiation to the fetus is minimal using radiocolloid during SLND and 2011 NCCN guidelines conclude that radiocolloid is safe during pregnancy [15,147,148]. Nonetheless, 2014 guidelines from ASCO recommend against the use of SLND in pregnant women . We advise administration of radiocolloid during pregnancy with discretion and in the clinical setting where the management of the patient would be significantly altered based upon the status of the SLN. (See "Gestational breast cancer: Epidemiology and diagnosis".)
Previous breast or axillary surgery for nonmalignant conditions — The feasibility of SLND in women who have undergone other non-oncologic types of breast surgery such as reduction mammoplasty or augmentation with breast implants is unclear. The expert panel convened by ASCO did not make a recommendation for or against SLND in women who have had breast reduction or augmentation because of insufficient data . They suggested that if SLND were considered in this setting that it might best be performed with preoperative lymphoscintigraphy. (See "Sentinel lymph node biopsy in breast cancer: Techniques".)
Recurrent breast cancer and previous axillary procedures — SLND after previous axillary surgery has not been widely studied. Guidelines from ASCO recommend against SLND in women who have undergone prior axillary surgery . However, there are accumulating reports of successful second SLND in patients with local breast cancer recurrence following a previous SLND and/or axillary lymph node dissection (ALND) [149-152]. The following review illustrates the effectiveness of a repeat lymphatic mapping and SLND:
●In a retrospective review of 150 patients with a previous SLND or ALND, lymphatic mapping (lymphoscintigraphy) using 99mTc-colloidal albumin identified a sentinel node in 63 percent and the sentinel node was successfully removed in 52 percent of patients . Aberrant drainage patterns were identified overall in 59 percent; patients with a previous ALND were more likely to have an aberrant pattern compared with patients undergoing a previous SLND (79 versus 25 percent, p <0.001). Micrometastasis was identified in 18 patients (23 percent), and a confirmation ALND in all 18 patients identified no additional positive axillary lymph nodes.
This practice is becoming more frequently employed and further study is indicated, including the optimal interval before repeat sentinel node biopsy should be attempted. Lymphoscintigraphy should be performed if repeat sentinel node biopsy is planned, given that these patients often have alternate drainage patterns. (See "Management of locoregional recurrence of breast cancer after breast conserving therapy".)
SLN MAPPING OF NONAXILLARY NODES — SLN techniques can identify non-axillary metastases (eg, internal mammary nodes and intramammary nodes) in up to 43 percent of cases, depending upon the volume and type of colloid injected, injection technique [154-156], and primary tumor location and size . Whether or not this is useful remains controversial, since the majority of the data regarding treatment decisions and outcomes comes from evaluation of only axillary nodes.
Internal mammary nodes — Positive IM nodes are most common with medial tumors over 2 cm in size . Patients with axillary node negative disease will be found to have regional metastases to the IM nodes in 8 to 10 percent of cases [157,159-164]. The diagnosis of positive IM nodes may affect treatment decisions regarding adjuvant systemic therapy and regional nodal irradiation . (See "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer", section on 'Regional field'.)
There are limitations to the SLN technique for identification of IM nodes [53,157,159,160,162,165]. SLND does not reliably identify involved IM LNs because of interference from radioactivity at the primary tumor site . There is a high rate of technical failure (20 to 39 percent) in patients with parasternal hot spots on lymphoscintigraphy [162-164], and hot spots in the IM region do not always represent tumor involvement [157,160,166,167]. In addition, some surgeons do not employ radiotracer injection and use only an intraoperative injection of blue dye to identify the sentinel nodes. Accordingly, additional noninvasive methods for IM node assessment may be helpful, including MRI or PET scanning, although these imaging modalities are unable to definitively identify positive nodes.
The IM nodes are difficult to sample surgically if a positive hot spot is identified in this area . Although IM biopsy can be accomplished at the time of mastectomy by splitting the fibers of the pectoralis major, an IM node biopsy in a patient undergoing breast conserving surgery usually requires a second incision, which is cosmetically visible in many types of clothing. The procedure can be complicated by pneumothorax, pleural effusion or bleeding [160,162].
The surgical management of the IM nodes remains controversial. There is no consensus on the need for IM nodal dissection in women with detection of an IM SLN [12,13,168]. Internal mammary nodes are not routinely dissected in patients undergoing breast conserving therapy or mastectomy with axillary lymph node dissection. Thus, in the absence of definitive data, dissection of the IM nodes with sentinel lymph node biopsy should be considered investigational.
Intramammary nodes — Numerous case reports document identification of intramammary lymph nodes on SLND [169-173], although few have explored the clinical significance of this finding. Intramammary LNs 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 [174,175]. (See "Diagnostic evaluation of women with suspected breast cancer".)
If intramammary nodes contain tumor, they have the same prognostic significance as a positive axillary LN with respect to staging. ALND should be considered for women with a positive intramammary LN on SLND, even if the axilla is clinically negative, because of the high rate of axillary LN involvement in these women .
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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 information: Sentinel lymph node biopsy for breast cancer (The Basics)")
●Beyond the Basics topic (see "Patient information: Breast cancer guide to diagnosis and treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The status of the axillary lymph nodes is one of the most important prognostic factors in women with early stage breast cancer. Histologic examination of removed lymph nodes is the most accurate method for assessing spread of disease to these nodes. Evaluation of the axilla is required for treatment decisions in patients with invasive breast cancer, and axillary lymph node dissection (ALND) remains the standard approach for women who are clinically node positive. (See 'Introduction' above.)
●For patients with early stage breast cancer who are clinically node negative, we recommend initial axillary evaluation with SLND rather than ALND (Grade 1B).
●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 extensive ductal carcinoma in situ undergoing a mastectomy, we suggest SLND (Grade 2B). Patients with DCIS extensive enough to require a mastectomy have a 20 percent chance of having occult invasive disease. If invasive disease is found and an SLND has not been performed, the patient will require an ALND. (See 'Ductal carcinoma in situ' above.)
●When a SLND is not successful or when clinically suspicious nodes are present after all sentinel lymph nodes have been removed, an axillary dissection should be performed. (See 'Indications' above.)
●Immunohistochemical assessment (IHC) should be 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 H&E. (See 'Role of IHC and RT-PCR in sentinel node evaluation' above.)
●For women with clinically suspicious lymph nodes, preoperative axillary ultrasound (US) with fine needle aspiration (FNA) or core biopsy of suspicious areas provides a means to identify patients who have positive nodes, and thus need axillary lymph node dissection (ALND) rather than a SLND. (See 'The role of ultrasound in sentinel node evaluation' above.)
●For older patients, who are clinically node negative, in whom the nodal information will not affect adjuvant treatment decisions, we suggest not performing surgical evaluation of the axilla (Grade 2B). (See 'Indications' above.)
●The decision about proceeding with ALND in women who are having breast conserving surgery for clinically node negative T1 or T2 breast cancer is based on the results of SLND (see 'Completion axillary dissection with BCT' above):
•For women with a SLND that is negative or shows isolated tumor cells, we recommend not performing a completion ALND (Grade 1A).
•For women with three or more positive SLNs, we recommend performing ALND (Grade 1A).
•For women with one or two positive sentinel nodes, who will be treated with whole breast radiation, 2014 guidelines indicate that a completion axillary dissection is not needed. When completion axillary dissection is omitted in patients with a positive SLND, whole breast radiotherapy is indicated. If partial breast irradiation is planned, completion ALND should be performed (Grade 2B). However, for women with T1, hormone receptor positive tumors, who are comfortable with some level of uncertainty about long-term outcomes, avoidance of completion ALND is an option.
●Women who are having mastectomy rather than breast conserving therapy should be counseled that they will need completion ALND if the SLND is positive in order to determine the need for postmastectomy radiation. In some cases it may be preferable to perform the sentinel node biopsy as a separate procedure before the mastectomy, especially if reconstruction is desired, so that the proper sequencing of reconstruction and radiation can be arranged. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Patients treated with mastectomy'.)
●The use of sentinel node biopsy in special circumstances including patients with locally advanced disease, patients undergoing neoadjuvant chemotherapy, pregnant patients, and those who have had prior breast or axillary surgery remains controversial. Inflammatory breast cancer is one of the few absolute contraindications to SLND
●We suggest performing a lymphoscintigraphy using 99mTc-colloidal albumin to identify the sentinel node in patients who have recurrent breast cancer and previous axillary procedures (SLND or ALND) rather than proceeding directly to an axillary dissection (Grade 2C). (See 'Recurrent breast cancer and previous axillary procedures' above.)
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