The development and wide acceptance of sentinel lymph node biopsy (SLNB) has profoundly affected the management of breast cancer. SLNB has spared the additional morbidity of axillary lymph node dissection (ALND) without compromising diagnostic accuracy and prognostic information in patients with clinically node-negative early-stage breast cancer. It has become an invaluable tool to clinicians to guide decisions regarding adjuvant treatment. The management of breast cancer continues to advance to more minimally invasive approaches, and the role of ALND is likely to become less important in the future.
Key points
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The presence of axillary nodal metastasis in breast cancer is the most important predictor of survival and recurrence.
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Sentinel lymph node biopsy (SLNB) allows accurate axillary staging of patients with invasive breast cancer and a clinically negative axilla.
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SLNB has replaced axillary lymph node dissection for staging of the axilla.
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SLNB has less morbidity and fewer complications than standard axillary lymph node dissection.
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Completion axillary lymph node dissection can be avoided in patients with a positive sentinel lymph node who undergo lumpectomy, whole-breast radiation, and systemic therapy.
Introduction
Over the past 3 decades, there have been significant advances in the surgical and clinical management of patients with breast cancer. Screening mammography, advances in both systemic and radiation therapy, the implementation of breast-conserving surgery, and the use of sentinel lymph node biopsy (SLNB) have substantially affected the care of patients with breast cancer.
The presence or absence of lymph node metastasis and the number of positive lymph nodes with metastasis determines the pathologic stage of the patient. Axillary lymph node metastasis remains the most important predictor of overall recurrence and survival in patients with breast cancer. However, the value of axillary lymph node dissection (ALND) has been an area of controversy for more than a decade. The prognostic information gained from an ALND had been deemed so important that removal of clinically uninvolved lymph nodes was widely viewed as a procedure for complete axillary staging and improved local control, with no measurable survival benefit. More recently, decisions by medical oncologists to initiate adjuvant chemotherapy are now individualized and are no longer limited to patients with nodal involvement but include characteristics of the primary tumor including tumor size, grade, histologic subtype, lymphovascular invasion, and receptor status.
ALND has been associated with significant short-term and long-term morbidity including increased risk of infection, pain, cosmetic deformity, and occasionally injury to major vessels or motor nerves. Significant lymphedema may occur early after surgery or years later, with some studies reporting an incidence as high as 30%. Because the use of screening mammography has increased over the last few decades, the size of the primary breast lesion has continued to decrease, as did the number of patients who had axillary metastases. For all these reasons, the appeal of a smaller operation as an alternative to ALND for patients with node-negative breast cancer was entertained. This minimally invasive procedure using a vital blue dye to identify the sentinel node, which is the lymph node most likely to harbor metastases, was developed. Patients with early-stage breast cancer could be spared the morbidity and complications without compromising prognostic information.
Introduction
Over the past 3 decades, there have been significant advances in the surgical and clinical management of patients with breast cancer. Screening mammography, advances in both systemic and radiation therapy, the implementation of breast-conserving surgery, and the use of sentinel lymph node biopsy (SLNB) have substantially affected the care of patients with breast cancer.
The presence or absence of lymph node metastasis and the number of positive lymph nodes with metastasis determines the pathologic stage of the patient. Axillary lymph node metastasis remains the most important predictor of overall recurrence and survival in patients with breast cancer. However, the value of axillary lymph node dissection (ALND) has been an area of controversy for more than a decade. The prognostic information gained from an ALND had been deemed so important that removal of clinically uninvolved lymph nodes was widely viewed as a procedure for complete axillary staging and improved local control, with no measurable survival benefit. More recently, decisions by medical oncologists to initiate adjuvant chemotherapy are now individualized and are no longer limited to patients with nodal involvement but include characteristics of the primary tumor including tumor size, grade, histologic subtype, lymphovascular invasion, and receptor status.
ALND has been associated with significant short-term and long-term morbidity including increased risk of infection, pain, cosmetic deformity, and occasionally injury to major vessels or motor nerves. Significant lymphedema may occur early after surgery or years later, with some studies reporting an incidence as high as 30%. Because the use of screening mammography has increased over the last few decades, the size of the primary breast lesion has continued to decrease, as did the number of patients who had axillary metastases. For all these reasons, the appeal of a smaller operation as an alternative to ALND for patients with node-negative breast cancer was entertained. This minimally invasive procedure using a vital blue dye to identify the sentinel node, which is the lymph node most likely to harbor metastases, was developed. Patients with early-stage breast cancer could be spared the morbidity and complications without compromising prognostic information.
History of breast SLNB
The concepts of the spread of metastatic cancer cells in reproducible patterns and the role of lymph nodes as a barrier to distant metastatic spread were established in the 1940s. The understanding of a single draining lymph node representing a nodal basin dates back more than half a century. Virchow node for metastatic gastric cancer, Sister Mary Joseph nodule for metastatic intra-abdominal malignancies, and the Delphian node of the thyroid all represent this concept. In 1951, Gould and colleagues reported on a frozen section of a single lymph node during a parotidectomy, and on performing a radical neck dissection only if pathology confirmed metastatic disease in this single lymph node. This concept of lymphatic drainage to a single node was subsequently reported in penile cancer and testicular cancer. Morton and colleagues developed lymphatic mapping and SLNB as a staging procedure for patients with early-stage melanoma. They defined the sentinel lymph node (SLN) as the first lymph node within the nodal basin to which the primary tumor drains. The SLN was localized by either an intradermal injection with radiolabeled colloid, or vital blue dye, or both together, and strongly predicted the status of the remaining lymph nodes in that basin. This technique was subsequently modified and applied to breast cancer by Giuliano and colleagues in 1991. Their initial experience, which defined the technical aspects, criteria for selecting patients for SLNB, and feasibility, involved 174 patients with T1 to T3 breast cancers, and included patients with or without palpable axillary adenopathy. Using a peritumoral injection of 5 mL of 1% isosulfan blue dye (Lymphazurin), the technique identified SLNs in 114 of the 174 procedures (66%) and accurately predicted the tumor status of the axillary basin in 109 (96%) patients.
The SLNB technique was then prospectively evaluated in 162 clinically node-negative patients with T1 or T2 breast cancers who underwent SLNB followed by ALND compared with 134 patients who only had ALND. The SLNs were analyzed using both hematoxylin and eosin staining (HE) and immunohistochemistry (IHC). A significantly higher rate of detection of metastases was shown in the group that had an SLNB followed by completion ALND than in the group that only had ALND (42% vs 29%), suggesting that a more focused examination of 1 or 2 SLNs was more accurate than the histopathologic evaluation of the lymph node basin by HE alone. Micrometastases were found in 3% of all patients who had ALND and 16% of all patients who had SLNB because of the analysis of a smaller volume of tissue and the addition of IHC analysis. SLNB provides the pathologist with the tissue most likely to contain metastases so that it can be the focus for intense study through multiple sectioning and IHC analyses rather than the large volume of tissue in an ALND that is processed through routine HE staining.
Other investigators subsequently validated the SLNB technique in breast cancer. Albertini and colleagues published the first use of both blue dye and filtered technetium-colloid for identifying the SLN, followed by completion ALND. Of the 62 patients in this study, the SLN was successfully identified in 92% of the patients with 100% specificity. Veronesi and colleagues performed the procedure using a subdermal injection of technetium 99m ( 99m Tc) –labeled human serum albumin and reported a 98% success rate in 160 of 163 patients, and accurately predicted the axillary status in 97% of the cases. These studies subsequently led to the first multicenter trial of 443 patients who had SLNB followed by ALND using radiotracer alone, which reported identification of the SLN in 93% of the cases, with a false-negative rate of 11.4%. A meta-analysis of 11 published studies was performed with 912 patients and compared injection techniques with lymphoscintigraphy or blue dye, or a combination of both, in patients who had SLNB followed by ALND for in situ and invasive cancer. This study reported a significantly higher rate of identification if both radiocolloid and blue dye were used or radiocolloid alone compared with blue dye alone. Moreover, the SLN reflected the status of the axilla in 97% of the cases with only a 5% false-negative rate reported. These studies show that the status of the SLN accurately predicts the status of the axillary nodal basin.
Veronesi and colleagues then performed the first randomized trial with 516 patients with T1 randomized to either SLNB followed by ALND or SLNB alone. ALND was only performed if the SLN contained metastases. At a median follow-up of 46 months, both groups of patients had the same incidence of SLN metastases. This early trial showed that SLNB alone could predict axillary nodal metastases with a false-negative rate of SLNB of 8.8% in the group that underwent complete ALND. In addition, patients in the SLNB-only group had less pain and better arm mobility. Moreover, these patients developed no axillary recurrences, had the same survival as patients who underwent ALND, and had axillary lymph nodes that were tumor free.
Technical aspects of SLNB
The SLN can be localized by either lymphoscintigraphy with injection of 99m Tc-labeled sulfur colloid, or vital blue, or a combination of both. An advantage of lymphoscintigraphy with radiocolloid is that it identifies drainage to areas away from the standard axillary nodal basin, including supraclavicular, infraclavicular, and internal mammary nodes, which could be sampled or treated with postoperative radiation.
Before surgery, patients are injected with 0.5 mL of 0.5 mCi of filtered 99m Tc sulfur colloid radiocolloid into the skin, subdermally, or into the peritumoral parenchyma of the breast. Imaging documents the drainage patterns from the tumor through the lymphatics to the regional lymph nodes. During surgery, a gamma probe emits a signal that is used to guide the surgeon in identification of the sentinel node.
Intraoperative injection of isosulfan blue dye (Lymphazurin 1%) or diluted methylene blue injected subcutaneously or into the breast parenchyma surrounding the tumor migrates to the sentinel node with gentle massage. SLNs are located by visual identification of a blue lymphatic tract or blue stained node. During surgery, if the SLN is not identified, regardless of the technique used, a full ALND should be performed. In addition, any additional palpable nodes that look or feel clinically suspicious should be removed at the time of SLNB.
The SLNB technique may be performed with blue dye, radiocolloid, or both. Previous work has shown that the combination of blue dye and radiocolloid has the highest success rate in sentinel node identification and the lowest false-negative rate. In addition, surgeons decrease their false-negative rates and increase their identification rates as their experience increases. A randomized trial by Morrow and colleagues showed no significant difference in identifying the SLN when patients were randomized to either blue due alone or the combination of blue dye and radiocolloid (86% vs 88%, respectively) for surgeons learning the procedure. A significant predictor of SLN identification in this study was surgeon experience.
Several factors determine the success rate of the SLNB technique. These factors include patient selection, injection technique, addition of massage, and time of the incision. Elderly patients and patients with increased body mass index have been shown to have a decreased rate of SLN identification. The combination of blue dye and radioisotope enhances the ability to identify the SLN in all patient groups and may be especially helpful for sentinel node identification in obese or elderly patients.
There is no consensus on the optimal injection technique. Although many groups are proponents of peritumoral injections, controversy exists regarding the most appropriate technique for injection of blue dye or radiocolloid, and individual experience and comfort with a particular technique is the most important factor in successful SLNB.
SLNB indications
As the indications for adjuvant therapy for patients with breast cancer have evolved over the last decade, SLNB has provided a rational basis for identifying high-risk patients who can benefit from the use of systemic chemotherapy or hormonal therapy. SLNB may provide local control if metastases are limited to the SLN. For patients with early-stage breast cancer, the histopathologic status of the lymph nodes has become one of the deciding factors for or against adjuvant chemotherapy.
Although SLNB has become well accepted in the staging and management of patients with early-stage breast cancer, the role of SLNB in the management of patients with ductal carcinoma in situ (DCIS), previous breast and axillary surgery, clinically palpable axillary disease, neoadjuvant treatment, inflammatory breast cancer, and pregnancy-associated breast cancer continues to be debated ( Table 1 ).
| Approved Indications | Unapproved Indications |
|---|---|
| Prophylactic mastectomy | Prior axillary surgery |
| T1–T2 lesions | T3–T4 lesions |
| Multicentric tumors | Pregnancy |
| Male breast cancer | Inflammatory breast cancer |
| Elderly | After neoadjuvant treatment |
| Obesity | Suspicious palpable axillary nodes |
| DCIS with mastectomy | — |
| Before neoadjuvant treatment | — |
| Prior breast surgery | — |
Prophylactic Mastectomy
Indications for prophylactic mastectomy have become accepted for patients with increased susceptibility to breast cancer including BRCA-1 and BRCA-2 gene mutation carriers, as well as for cosmesis or phobia of developing breast cancer in patients undergoing a contralateral mastectomy for breast cancer. The risk of finding an occult cancer at the time of a prophylactic mastectomy has been reported to be about 5%; in addition, in patients with a history of breast cancer the risk of developing a contralateral breast cancer is about 0.5% to 1% per year. Patients who do not undergo an SLNB at the time of prophylactic mastectomy and are found to have invasive cancer in the breast specimen require an ALND to stage the axilla. If SLNB is performed at the time of prophylactic mastectomy, and final pathology shows an invasive cancer with histologically negative SLNs, the morbidity of an ALND can be avoided. King and colleagues reported a series of 163 women at high risk for breast cancer or diagnosed with a contralateral breast cancer who underwent prophylactic mastectomy and SLNB. Occult carcinoma was found in 13 (8%) patients. Two patients who had occult carcinoma also had sentinel nodes positive by HE. In a recent meta-analysis performed by Zhou and colleagues the rate of occult invasive cancers among 1343 pooled prophylactic mastectomies was 1.7%, with a rate of positive SLNs of 1.9%. SLNB may be offered to high-risk patients who choose to undergo prophylactic mastectomies.
Previous Breast or Axillary Surgery
There are no large studies reporting success in identifying SLNs in patients who present with either previous breast or axillary surgery. Many of the large clinical trials excluded patients who had previous breast biopsies or previous axillary surgery. Limited small studies suggest that identifying the SLN can be achieved after previous breast biopsies, regardless of the size, location, or the length of time between the initial biopsy and the SLNB procedure. Based on clinical experience, a prior breast biopsy is not considered a contraindication to SLNB.
Successful identification of the SLN after previous axillary surgery can be limited because of disruption of lymphatic channels during surgery that can lead to aberrant lymphatic drainage patterns. A small series reported 18 patients who underwent a second SLNB after developed recurrent breast cancer after breast conservation and negative SLNB at their initial surgery. All patients had successful identification of the SLN using preoperative lymphoscintigraphy with 2 patients found to have positive SLNs requiring completion ALND and, of the remaining 16 patients with negative SLNs, no recurrences were reported. In patients with prior axillary surgery, SLNB can be performed; however, both preoperative lymphoscintigraphy and blue dye should be used for optimal identification.
DCIS
By definition, DCIS does not have the ability to metastasize to axillary lymph nodes and so, in theory, should not require axillary staging. The decision to perform an SLNB on patients with a core biopsy showing DCIS is based on the possibility that invasive disease may be found on final pathology. Yen and colleagues reviewed 398 patients with DCIS on core biopsy and found that 20% had invasive disease on subsequent examination of the excised specimen. Multivariate analysis showed 4 independent risk factors for invasive disease: age less than 55 years (odds ratio [OR] 2.19, P = .024), diagnosis on core biopsy (OR 3.76, P = .006), mammographic size of DCIS greater than 4 cm (OR 2.92, P = .001), and high-grade DCIS (OR 3.06, P = .002).
American Society of Clinical Oncology (ASCO) guidelines during a consensus conference in 2005 recommended that SLNB should not be done routinely for breast conservation for DCIS, and selective use is recommended for patients undergoing mastectomy, palpable lesions, DCIS larger than 40 mm, or high nuclear grade.
Multicentric Lesions
Multicentric cancer, which is defined as distinct cancers found in different quadrants of the same breast or at a distance of 2 to 5 cm from each other, occurs in approximately 10% of patients. Multicentric tumors have been considered a contraindication to SLNB because it is postulated that different drainage patterns may occur with multiple foci of cancer, increasing the false-negative rate of the procedure. However, there is evidence that the breast may drain through the same afferent lymphatic channels to the same axillary sentinel node. Multiple nonrandomized studies have shown success in identifying SLN with false-negative rates similar to those in patients with unifocal lesions. In a large single-institution study by Gentilini and colleagues, a mean number of 1.7 SLNs were found in 337 patients, with an identification rate of 100%. At a median follow-up of 5 years, only 3 of 138 patients (2.2%) developed axillary recurrences after a negative SLNB at their initial surgery. SLNB should be offered to clinically node-negative patients with multicentric disease.
Clinically Palpable Axillary Lymph Nodes
Most SLNB studies have excluded patients with clinically positive axillary lymph nodes. Although ALND is the standard of care in patients with clinically palpable suspicious lymph nodes, determination of metastatic axillary disease by clinical examination is often unreliable. The results of several series show that clinical examination of the axilla, even by experienced surgeons, can be inaccurate with false-positive rates as high as 40%. For patients with suspicious nodes on clinical examination, axillary ultrasound and ultrasound-guided core biopsy are reliable techniques in the management of these patients. SLNB is not recommended in patients with gross axillary disease. When performing an SLNB, any lymph node that is clinically suspicious for metastatic disease during surgery because of firm texture or enlarged size must be removed. These nodes should be considered and evaluated as sentinel nodes even if they are not radioactive or blue. SLNB can be performed in patients with nodes clinically suspicious for metastatic disease; however, patients with larger primary tumors or lymphovascular invasion are likely to have nodal metastases and subsequently require ALND. ASCO guidelines recommend against performing SLNB in patients with nodes clinically suspicious for metastases.
Neoadjuvant Chemotherapy
Neoadjuvant chemotherapy for patients with locally advanced breast cancer continues to be debated. The rationale for treating patients with large operable tumors is the potential downstaging of tumors, providing the alternative of breast conservation instead of mastectomy. In addition, studies have shown that neoadjuvant chemotherapy can lead to axillary downstaging. The use of SLNB continues to be debated in patients who show a significant reduction in the number of nodes with metastatic disease, or who show a complete response. However, there is currently no evidence that ALND can be avoided in patients who had an axillary lymph node core biopsy that had metastatic disease before neoadjuvant chemotherapy, and has a negative SLN after completion of neoadjuvant chemotherapy.
The feasibility and accuracy of SLNB after neoadjuvant treatment in patients who are clinically node negative and who need axillary staging continues to be debated. For patients with large tumors with a clinically negative axilla who are being considered for neoadjuvant chemotherapy, SLNB is important for decisions on nodal radiation and ALND. The feasibility and accuracy remain controversial because difficulties in identification and retrieval of the SLN caused by fat necrosis and fibrosis, which have been reported after neoadjuvant treatment, can be avoided if the procedure is performed before the initiation of therapy.
Several studies show an acceptable identification rate and a low false-negative rate after neoadjuvant therapy in clinically node-negative patients ( Table 2 ). The largest multicenter trial showing the feasibility and accuracy of SLNB after neoadjuvant chemotherapy was conducted as part of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27 study. In this study, 428 patients were randomized to SLNB with either lymphoscintigraphy, isosulfan blue dye, or a combination of both. Accurate identification of the SLN occurred in 85% of patients; however, the rate of identification of the SLN was significantly higher in the group that underwent SLNB with radiocolloid compared with blue dye or both: 90%, 77%, and 88%, respectively. Of the 323 patients who went on to complete ALND, the SLN was the only involved node in 56% of patients. Moreover, no differences were seen in identification of the SLN based on tumor size or clinical status of the axilla.
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