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Diagnosis, staging and the role of sentinel lymph node biopsy in the nodal evaluation of breast cancer
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Diagnosis, staging and the role of sentinel lymph node biopsy in the nodal evaluation of breast cancer

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 Grant/Research/Clinical Trial Support: Janssen R&D, LLC [Breast cancer (Abiraterone)]; Janssen R&D, LLC [Breast cancer (CellSearch)]; Puma Biotechnology, Inc. [Breast cancer (Neratinib)]; Pfizer [Breast cancer (Palbociclib)]; Astra Zeneca [Breast cancer (Circulating tumor cells)]. Speaker's Bureau: Lilly Oncology (Breast cancer). Consultant/Advisory Boards: Pfizer [Breast cancer (Palbociclib)]. Other Financial Interest: Janssen R&D, LLC [Breast cancer (CellSearch)]. 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.

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2015. | This topic last updated: Apr 12, 2015.

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 biopsy (SLNB) is a method of staging the axilla with less morbidity than ALND.

Indications for and outcomes of SLNB will be reviewed here. The technique of SLNB in patients with breast cancer is discussed separately. (See "Sentinel lymph node biopsy in breast cancer: Techniques".)

DEVELOPMENT AND VALIDATION OF THE SENTINEL LYMPH NODE BIOPSY TECHNIQUE — The importance of the sentinel lymph node (SLN) is based upon the observation that tumor cells migrate from a primary tumor and 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, sentinel lymph node biopsy (SLNB) identifies patients without axillary node involvement, thereby obviating the need for more extensive surgery [1]. Several studies have shown that the risk of arm morbidity, particularly lymphedema, sensory loss, and shoulder abduction deficits, is significantly less for SLNB than with standard axillary lymph node dissection (ALND) [2-8]. 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 [2]. (See "Clinical manifestations and diagnosis of lymphedema".)

Most surgeons and major cancer centers have adopted SLNB 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 SLNB increased from 27 to 66 percent between 1998 and 2005 in the United States [9]. Similar trends have been reported from Canada and the United Kingdom [10,11]. SLNB is endorsed as an alternative to ALND for the diagnosis of axillary metastases in patients with clinically node-negative early breast cancer in multiple guidelines [12-15].

Despite variability in selection criteria and technique, an 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 SLNB 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 SLNB 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 SLNB found in studies in which completion ALND has been done, several series suggest that axillary recurrence rates are low after a negative SLNB alone in early-stage breast cancer (range 0 to 4.5 percent) [17-27]. The details of key trials validating the SLNB are described below:

A landmark multicenter study of 443 patients with early breast cancer demonstrated that the SLNB technique could be learned and successfully applied by a diverse group of surgeons spanning private and academic practice [28,29]. All patients underwent SLNB 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 [30]. There is little clinical significance of micrometastasis, and the contemporary approach is not to perform a completion ALND.

A systematic review included 69 eligible trials of SLNB 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 SLNB followed by ALND versus SLNB 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 SLNB followed by ALND versus SLNB followed by ALND only if the SLN was positive [36].

INDICATIONS — Sentinel lymph node biopsy (SLNB) should be performed in most women with clinically node-negative invasive or microinvasive breast cancer [15]. Patients with clinical findings that raise suspicion of axillary node involvement should undergo an axillary ultrasound with fine needle aspiration (FNA) or biopsy before decisions are made about pursuing an SLNB. Patients who have pathologic confirmation of nodal involvement should proceed with an axillary lymph node dissection (ALND) rather than an SLNB [37-43]. As an example, in a series of 653 consecutive patients, the preoperative diagnosis rate of axillary disease was 23 percent using axillary ultrasound and FNA, thereby avoiding the need for a second operation in 150 women [43]. The efficacy of this approach is somewhat variable between centers because the accuracy of ultrasound examination is operator dependent (image 4 and image 5 and image 6). (See "Diagnostic evaluation of women with suspected breast cancer" and "Breast biopsy".)

SLNB should also be performed in women with extensive ductal carcinoma in situ (DCIS) who are undergoing mastectomy. Of note, an SLNB is not possible after mastectomy. Therefore, if invasive disease is found on final pathology in these patients, an ALND should be performed. (See 'Ductal carcinoma in situ' below.)

However, an SLNB 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 an SLNB. 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'.)

When an SLNB 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 [12]. (See "Management of the regional lymph nodes in breast cancer".)

PATHOLOGIC STAGING OF NODAL METASTASES — Approximately 40 percent of patients with a positive sentinel lymph node (SLN) will be found to have residual disease in the axilla [12,28,32,44-51]. SLN metastases are categorized as isolated tumor cells, micrometastases, or macrometastases, depending upon the size of the largest tumor deposit in the sentinel node. However, the risk of an axillary recurrence rate among these patients appears to be low overall, regardless of the volume of disease identified within the involved axillary node. This was shown in a review of the literature that included 30 studies of women with a positive SLN who did not undergo a completion axillary lymph node dissection (ALND) (n = 7151) [52]. 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. (See "Prognostic and predictive factors in early, non-metastatic breast cancer", section on 'Nodal involvement' and "Tumor node metastasis (TNM) staging classification for breast cancer".)

Although routine immunohistochemistry (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 hematoxylin and eosin (H&E) of axillary lymph nodes [53,54]. 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.

Isolated tumor cells — Isolated tumor cells are defined as 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 [55]. Prognostically, they appear to do as well as patients without pathologic node involvement. According to the Tumor, Nodes, Metastasis (TNM) staging system, isolated tumor cells are designated as pN0(i+). Of note, 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 [56-59]. (See "Tumor node metastasis (TNM) staging classification for breast cancer".)

Micrometastases — Micrometastatic nodal involvement is defined as a cluster of cancer >0.2 mm but no greater than 2.0 mm. If present, this is designated pN1mic in the American Joint Committee on Cancer (AJCC) staging system. Of note, data suggest that patients with pN1mic breast cancer have a worse prognosis compared with those with node-negative breast cancer. (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 cluster >2.0 mm. The presence of macrometastases within the axillary nodes is a well established and independent prognostic factor, with a worse prognosis associated with greater nodal involvement. (See "Prognostic and predictive factors in early, non-metastatic breast cancer", section on 'Nodal involvement'.)

Occult metastatic disease — Occult micrometastases refers to nodal metastases that are not seen on initial H&E examination but are detected subsequently by additional level or by 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 [60-63].

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 [63]. Thus, routine IHC or PCR is not recommended for the evaluation of SLNs in guidelines published by the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), and others [12,15,64]. 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".)

OVERVIEW OF THE MANAGEMENT OF A POSITIVE SLNB — For patients undergoing sentinel lymph node biopsy (SLNB), the role of a completion axillary lymph node dissection (ALND) is dependent upon the SLNB findings:

A completion ALND is not indicated in patients with a negative SLNB, which includes patients with a sentinel node showing histological evidence of isolated tumor cells (ITCs).

Whether an ALND should be carried out in patients with evidence of micrometastatic disease is not entirely clear. While we proceed with an ALND in patients with more than three pathologically involved nodes, which is consistent with the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines [12,15], we individualize the decision for women with fewer than three nodes involved. There is some debate about the prognostic value of the size of the sentinel lymph node (SLN) micrometastases (≤0.2 mm versus larger) in predicting the likelihood and significance of involvement of axillary non-sentinel lymph nodes (SLNs) (table 1) [65-69].

For patients with limited micrometastatic sentinel node involvement (ie, one to three pathologically involved nodes), contemporary clinical trials suggest that regional radiation therapy (RT) is a reasonable alternative to ALND. However, the follow-up of these trials has been relatively short, and additional analyses are needed before regional RT is accepted as a standard approach for these patients. In the meantime, we suggest that the decision regarding further treatment of the axilla among these patients be individualized. This issue is discussed in further detail separately. (See 'One to three involved nodes' below and "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Positive sentinel node biopsy'.)

For patients with >3 pathologically involved sentinel nodes, we proceed with an ALND 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). This recommendation is consistent with a 2013 systematic review that included 17 studies with at least two years of follow-up [70]. Criteria that support performing a complete ALND include:

Palpable or needle-biopsy-proven axillary metastasis

Positive sentinel node in patients undergoing a mastectomy without planned RT

More than three positive sentinel nodes

Historically, all patients with positive sentinel nodes were recommended to undergo an ALND. However, contemporary clinical trials have shown that for women with limited disease in the sentinel nodes, omitting an ALND appears to be reasonable. While there is a lack of consensus as to what constitutes "limited" disease, this discussion reflects data below as well as data on the role of regional node irradiation in women with up to three positive sentinel nodes, which is discussed elsewhere. However, we also acknowledge that the American Society of Clinical Oncology has published guidelines that state an ALND is not needed for patients with two or fewer positive sentinel nodes [12]. In light of this lack of consensus, the approach to decisions regarding ALND based on positive sentinel nodes should be individualized as much as possible, taking into account the goals and preferences of each patient, and the center's expertise in both surgical technique and the availability of RT. (See "Management of the regional lymph nodes in breast cancer" and "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Approach to patients with pathologically involved regional lymph nodes'.)

Estimating risk for additional positive nodes after SLNB — Because the majority of patients with SLNB 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 [20,71-77]. However, none are sufficiently reliable for clinical use.

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 [77]. A retrospective analysis of 319 patients with a positive SLNB who underwent completion axillary dissection compared the performance of four different nomograms [73].

One to three involved nodes — The need for a completion ALND in patients with a positive SLNB in one to three nodes is not clear [78]. Contemporary clinical trials indicate that a completion ALND may not be necessary for all women with T1 tumors that are clinically node-negative, have pathologic involvement in fewer than three positive SLNs, and agree to proceed with adjuvant whole-breast radiation. This is particularly true for women with estrogen receptor-positive breast cancers. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'One to three involved nodes'.)

Of note, if partial-breast radiation is planned, completion ALND should be performed.

Important contemporary trials have evaluated the impact of ALND versus adjuvant RT in these patients. Surgically relevant aspects of these trials are reviewed below. Other discussions of these and other trials are covered separately. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Approach to patients with pathologically involved regional lymph nodes'.)

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 fewer than three positive sentinel nodes; all patients were treated with radiation to the breast [2,79,80]. SLNB alone resulted in:

No significant difference in five-year overall survival compared with SLNB followed by an ALND (91.9 versus 92.5 percent, respectively; hazard ratio [HR] 0.79, 90% CI 0.56-1.10)

No significant difference in five-year disease-free survival (82.2 versus 83.9 percent)

Similar rates of recurrence (four versus two events)

Despite these results, this trial has been criticized for a number of reasons, including [81,82]:

Premature study termination – Target accrual for the 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 SLNB alone arm and 420 in the SLNB plus ALND arm. Therefore, this trial was not adequately powered to meet the predetermined statistical survival primary endpoint due to low accrual.

Protocol noncompliance – Eleven patients assigned to the SLNB only arm underwent an ALND, and 32 patients assigned to the SLNB plus ALND arm did not proceed with an ALND.

Loss to follow-up – Almost 20 percent of patients were lost to follow-up.

Lack of analysis that took into account the numbers of patients with isolated tumor cell clusters, micrometastases, or macrometastases in the two arms.

Impact of other factors on outcomes could not be controlled – The majority of patients had T1 (almost 70 percent), hormone receptor-positive tumors (85 percent). At analysis, estrogen receptor status and adjuvant systemic therapy were independent predictors of survival.

Further discussion of this trial as it pertains to the administration of RT is covered separately. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'One to three involved nodes'.)

AMAROS trial — The After Mapping of the Axilla: Radiotherapy or Surgery (AMAROS) trial was a multi-institutional trial conducted by the European Organisation for the Research and Treatment of Cancer (EORTC) that included over 4800 patients with T1 to T2 breast cancer, clinically node-negative disease at presentation, and who had undergone SLNB. Patients with up to two positive SLNs (n = 1425) were randomly assigned to ALND versus RT, including regional node irradiation (RNI) [83]. Of those randomly assigned to ALND (n = 672), 33 percent had additional pathologically involved lymph nodes removed. With a median follow-up of 6.1 years, there were very few axillary recurrences in both the ALND (n = 4) and the RNI (n = 7) group. However, patients who underwent ALND had a significantly greater incidence of lymphedema up to five years later. Unfortunately, the study results are limited because of the low event rate and the relatively short follow-up time. In addition, these patients had a relatively good prognostic breast tumor; 77 and 40 percent had either one positive SLN or micrometastatic nodal disease, respectively.

IBCSG 23-01 trial — The International Breast Cancer Study Group trial 23-01 (IBCSG 23-01) randomized patients with a primary tumor <5 cm in size and clinically non-palpable axillary nodes to either completion ALND or no additional axillary surgery [84]. 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.

Among those enrolled, treatment consisted of:

Breast-conserving surgery in 90 percent; the remaining 10 percent underwent a total mastectomy

Among patients treated with SLNB followed by ALND versus SLNB alone, adjuvant treatment consisted of:

RT in 89 and 92 percent, respectively  

Endocrine therapy in 63 and 67 percent

Adjuvant chemotherapy in 7 and 9 percent

The primary endpoints included five-year disease-free survival (DFS) and overall survival (OS) rates. However, as with the Z11 trial, this trial also was closed prematurely after 931 of a planned 1960 patients were enrolled. After a median follow-up of five years [84]:

There was no significant difference in the DFS rate at five years for patients treated without an ALND compared with those treated with an ALND (88 versus 84 percent, respectively; HR 0.78, 95% CI 0.55-1.11).

There was no significant difference in the five-year OS rate for patients treated with an ALND compared with those treated with an SLNB (97.6 versus 98.0 percent).

Three or more positive nodes — For patients with three or more positive sentinel lymph nodes, we continue to perform an ALND. These patients were not included in the aforementioned trials and therefore, should undergo further surgery to inform axillary staging, decisions regarding subsequent treatment, and prognosis. Further discussion on the role of ALND in these patients is covered separately. (See "Management of the regional lymph nodes in breast cancer", section on 'Axillary dissection'.)

SPECIAL SCENARIOS — Sentinel lymph node biopsy (SLNB) is evolving in selected clinical settings.

Older women — A positive SLNB followed by a completion axillary lymph node dissection (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) [85]. In addition, there was no significant difference in five-year breast-cancer-specific survival (94.6 versus 91.6 percent). An analysis of prospective data is needed to confirm these retrospective findings. (See "General principles on the treatment of early stage and locally advanced breast cancer in older women", section on 'Management of the axilla'.)

Male breast cancer — The vast majority of published studies of SLNB 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 SLNB identification rate and a false-negative rate of 0 percent [86]. Prospective studies establishing the sensitivity and specificity of SLNB in MBC have not been carried out. However, the principles guiding SLNB in women appear to apply to men.

Due to the limited amount of data, the 2005 American Society of Clinical Oncology (ASCO) guidelines on SLNB did not make a specific recommendation about the use of SLNB in MBC, although it was deemed "acceptable" [12]. 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 — The 2005 ASCO guidelines on SLNB did not recommend the routine use of SLNB in patients with locally advanced or inflammatory breast cancer for whom ALND was recommended to ensure locoregional control [12]. Consensus recommendations from an International Expert Panel published in 2010 considered inflammatory breast cancer to be the one of the few absolute contraindications to SLNB [64].

Most studies have restricted SLNB 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 SLNB is accurate in patients with T3 tumors and clinically negative axillae [87,88]. Thus, many clinicians do not recognize large breast tumors as a contraindication to SLNB, as long as the axilla is clinically negative. However, patients with T4 tumors (locally advanced) or inflammatory breast cancer are not considered candidates for SLNB [89,90]. The false-negative rate is high in patients with inflammatory breast cancer, presumably because of the presence of partially obstructed, functionally abnormal subdermal lymphatics.

Neoadjuvant chemotherapy — Many women with large primary breast tumors are offered neoadjuvant chemotherapy prior to definitive locoregional therapy. The optimal timing for SLNB in patients receiving neoadjuvant therapy remains controversial and is discussed separately. (See "Neoadjuvant systemic therapy for breast cancer: Response, subsequent treatment, and prognosis", section on 'Nodal evaluation'.)

Multicentric disease — We concur with ASCO guidelines that indicate an SLNB is appropriate for patients with multicentric disease [91]. 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) [92,93]. Thus, subareolar and intradermal (rather than peritumoral) injection of radiolabeled colloid or blue dye render SLNB feasible for patients with multicentric disease [92,94-96]. (See "Sentinel lymph node biopsy in breast cancer: Techniques".)

The success of SLNB for multicentric disease has been demonstrated in several studies [95,97]. For example, in a study of 142 women with multicentric breast cancer, SLNB was successful in 91 percent, with a false-negative rate of 4 percent [97]. 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.

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 SLNB will be impossible at a later time if invasive disease is found [12]. An intact breast with its lymphatic plexus is necessary for injection of both the blue dye and the radioisotope tracers.

Some recommend that SLNB 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 [12]. However, if a partial mastectomy is performed and invasive disease is identified, an SLNB can be done as a separate operation. This approach can minimize unnecessary morbidity, since SLNB can be associated with complications. SLNB 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 SLNB, the disease stage would change accordingly [98,99]. (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 — We concur with the 2014 ASCO guidelines and do not perform SLNB in women who are pregnant or lactating.

Concern for teratogenic effects with the use of isosulfan blue dye has limited the use of SLNB during pregnancy, despite the lack of studies testing the fetal safety of the dyes [100]. There are limited data that suggest it might be safe. As an example, a retrospective study that included 25 clinically node-negative pregnant patients who were administered methylene blue (n = 7), 99-Tc (n = 16), and another type of injection material not otherwise specified (n = 2) found no adverse fetal outcomes that could be attributed to the injection at 2.5 years of follow-up [101]. There were 25 livebirth infants, 24 of whom were deemed healthy at delivery; one infant had a cleft lip not attributed to the injection. Given the limitations of these data, we concur with the 2014 guidelines from ASCO recommending against the use of SLNB in pregnant women [91]. (See "Gestational breast cancer: Epidemiology and diagnosis".)

Previous breast or axillary surgery for nonmalignant conditions — The feasibility of SLNB 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 SLNB in women who have had breast reduction or augmentation because of insufficient data [12]. They suggested that if SLNB 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 — SLNB after previous axillary surgery has not been widely studied. Guidelines from ASCO recommend against SLNB in women who have undergone prior axillary surgery [12]. However, this practice is becoming more frequently employed and further study is indicated, including the optimal interval before repeat sentinel node biopsy should be attempted. (See "Management of locoregional recurrence of breast cancer after breast conserving therapy".)

There are accumulating reports of successful second SLNB in patients with local breast cancer recurrence following a previous SLNB and/or ALND [102-105]. The following review illustrates the effectiveness of a repeat lymphatic mapping and SLNB. As an example, in one retrospective review of 150 patients with a previous SLNB 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 [106]. 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 who had a previous SLNB (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.

SLN MAPPING OF NONAXILLARY NODES — Sentinel lymph node (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 [107-109], and primary tumor location and size [110]. Whether or not this 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 — The surgical management of the internal mammary (IM) nodes remains controversial. There is no consensus on the need for IM nodal dissection in women with detection of an IM SLN [12,13,111]. The IM nodes are not routinely dissected in patients undergoing breast-conserving therapy or mastectomy with axillary lymph node dissection (ALND). Thus, in the absence of definitive data, dissection of the IM nodes with sentinel lymph node biopsy (SLNB) should be considered investigational.

Positive IM nodes are most common with medial tumors over 2 cm in size [112]. Patients with axillary node-negative disease will be found to have regional metastases to the IM nodes in 8 to 10 percent of cases [110,113-118]. The diagnosis of positive IM nodes may affect treatment decisions regarding adjuvant systemic therapy and regional nodal irradiation [113]. (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 [46,110,113,114,116,119]. SLNB does not reliably identify involved IM lymph nodes because of interference from radioactivity at the primary tumor site [46]. There is a high rate of technical failure (20 to 39 percent) in patients with parasternal hot spots on lymphoscintigraphy [116-118], and hot spots in the IM region do not always represent tumor involvement [110,114,120,121]. 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 magnetic resonance imaging (MRI) or positron emission tomography (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 [113]. 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 [114,116].

Intramammary nodes — Numerous case reports document identification of intramammary lymph nodes on SLNB [122-126], 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 [127,128]. (See "Diagnostic evaluation of women with suspected breast cancer".)

If intramammary nodes contain tumor, they have the same prognostic significance as a positive axillary lymph node with respect to staging. ALND should be considered for women with a positive intramammary lymph node on SLNB, even if the axilla is clinically negative, because of the high rate of axillary lymph node involvement in these women [129].

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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 sentinel lymph node biopsy (SLNB) 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 DCIS undergoing a mastectomy, we suggest SLNB (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 SLNB has not been performed, the patient will require an ALND. (See 'Ductal carcinoma in situ' above.)

When an SLNB 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 hematoxylin and eosin (H&E). (See 'Occult metastatic disease' 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 is based on the results of SLNB (see 'Overview of the management of a positive SLNB' above):

For women with an SLNB that is negative or shows isolated tumor cells, we recommend not performing a completion ALND (Grade 1A).

For women with >3 positive SLNs, we perform an ALND. (See "Management of the regional lymph nodes in breast cancer", section on 'Axillary dissection'.)

For women with one to three 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 SLNB, 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 SLNB 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 SLNB.

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 (SLNB 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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