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. 2001 Jul 24;165(2):166–173.

Clinical practice guidelines for the care and treatment of breast cancer: 13. Sentinel lymph node biopsy

Jacques Cantin 1, Hugh Scarth 1, Mark Levine 1, Maria Hugi 1; The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer1
PMCID: PMC81283  PMID: 11501455

Abstract

Objective

To provide information and recommendations to women with breast cancer and their physicians regarding what is now known about sentinel lymph node (SLN) biopsy.

Options

Axillary dissection; SLN biopsy followed by backup axillary dissection; SLN biopsy.

Outcomes

Accurate determination of cancer stage, resulting in better-informed therapeutic decisions.

Evidence

Systematic review of English-language literature published from January 1991 to December 2000 retrieved primarily from MEDLINE and CANCERLIT.

Recommendations

· Axillary dissection is the standard of care for the surgical staging of operable breast cancer. · If a patient requests or is offered SLN biopsy, the benefits and risks as well as what is and is not known about the procedure should be outlined. · Patients should be informed of the number of SLN biopsies performed by the surgeon and the surgeon's success rate with the procedure, as determined by the identification of the SLN and the false-negative rate (the presence of tumour cells in the axillary nodes when the SLN biopsy result is negative). · Before surgeons replace axillary dissection by SLN biopsy as the staging procedure at their institution, they should (a) familiarize themselves with the literature on the topic and the techniques needed to perform the procedure, (b) follow a defined protocol for all 3 aspects of the procedure (nuclear medicine, surgery, pathology) and (c) perform backup axillary dissection until an acceptable success rate (as determined by the identification of the SLN and the false-negative rate) is achieved. · A surgeon who performs breast cancer surgery infrequently should not perform SLN biopsy. · A positive SLN biopsy result or failure to identify an SLN should prompt full axillary dissection. · SLN biopsy is contraindicated in women who have clinically palpable nodes, locally advanced breast cancer, multifocal tumours, previous breast surgery or previous irradiation of the breast. · Staining of tissue sections with hematoxylin and eosin, and not immunohistochemical analysis for cytokeratin, should determine adjuvant therapy. · Participation in randomized clinical trials is encouraged. [A patient version of these guidelines appears in Appendix 1.]

Validation

Internal validation within the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer; no external validation.

Sponsor

The steering committee was convened by Health Canada.

Completion date

Apr. 9, 2001.

Over the past several years, the technique of sentinel lymph node (SLN) biopsy has been introduced as an alternative to axillary dissection for operable breast cancer. Like laparoscopic surgery in the late 1980s, SLN biopsy is a promising new medical technique that is gaining popularity before the medical community has had time to provide adequate training and put the procedure into practice in a safe and organized manner.

In many of the clinical practice guidelines previously produced by the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer, results from randomized trials (level I and II evidence) were available to support the use of the therapy in question.1 Such evidence is not yet available for the performance of SLN biopsy without axillary dissection. Although randomized trials evaluating SLN biopsy are underway, it will likely be a number of years before the results will be available.

The steering committee feels that women with breast cancer and their physicians should know more about SLN biopsy and the unanswered questions related to its performance. Women with breast cancer need this information to help them make decisions about their treatment, particularly axillary dissection. SLN biopsy is widely used in the United States, and it is increasingly being used in Canada despite the lack of data from randomized trials. The steering committee felt that it would not be feasible for all surgeons interested in using this technique to participate in the current trials open to recruitment. Based on these considerations the committee chose to review the current data, point out their limitations and make recommendations on how SLN biopsy may be adopted in practice. The recommendations that follow are consistent with those recently made by McCready and associates2 on behalf of the Canadian Society of Surgical Oncology and by Spillane and Sachs.3

Methods

This guideline is based on a systematic review of the English-language literature published from January 1991 to December 2000 retrieved primarily from MEDLINE and CANCERLIT. Key words combined in the search were “breast neoplasms,” “lymph nodes” and “sentinel.” Because data from randomized controlled trials comparing outcomes from SLN biopsy alone versus axillary dissection are not currently available, a broader search strategy without limits set by methodological search criteria was used. Review articles and protocols of randomized trials underway were also examined to provide background information and secure additional references. Rules of evidence as described by Sackett4 were used for grading the levels of experimental studies.

Given the lack of data from randomized trials, the recommendations are based on a consensus, reached after extensive discussions within the steering committee. The initial draft was prepared by a member of the committee and was revised according to the reviews and feedback of several committee members. The document was then discussed by the entire committee at 3 meetings, in November 1999, March 2000 and September 2000, and further revisions were made. The final draft of the manuscript was approved by the committee before submission for publication.

Recommendations (including evidence and rationale)

Axillary dissection

· Axillary dissection is the standard of care for the surgical staging of operable breast cancer.

Knowledge of the histologic status of axillary lymph nodes is essential when treating a woman with operable breast cancer. The clinical guideline on axillary dissection published in 1998 states: “Removal and pathological examination of axillary lymph nodes should be standard procedure for patients with early, invasive cancer” and “For accurate staging and to reduce the risk of recurrence in the axilla, level 1 and level 2 nodes should be removed” (see guideline 4).5

The status of the axillary lymph nodes is an important prognostic factor. Axillary dissection allows accurate staging of the cancer and guides the selection of appropriate adjuvant therapy. Furthermore, it provides excellent local control of disease in the axilla. Data from recent randomized clinical trials suggest that effective local-regional control of the tumour can affect long-term survival (level I evidence).6,7,8 Axillary dissection, however, comes with recognized morbidity: wound infection, restriction of shoulder movement, arm problems (stiffness, loss of sensation), pain and lymphedema (see guideline 11).9

Sentinel lymph node biopsy

Lymphatic mapping with SLN biopsy is a new procedure that aims to replace total axillary node dissection as a staging procedure for operable invasive breast cancer. Radioactive material or a blue dye, or both, is injected locally in the breast tissue that surrounds the tumour or biopsy cavity. This material is then taken up by the lymphatic system, and the surgeon traces it with a handheld gamma probe, or follows the blue dye, until the first 1 or 2 nodes draining the peritumoural breast tissue are detected. The sentinel node(s) is (are) then removed and examined histologically for the presence of tumour cells.

The histologic status of the SLN is thought to represent the histologic status of the whole lymphatic basin from which it has been removed; that is, a negative SLN suggests that other nodes in the axilla are also negative, and a positive SLN suggests that additional nodes may be positive.

Benefits and challenges of SLN biopsy

· If a patient requests or is offered SLN biopsy, the benefits and risks as well as what is and is not known about the procedure should be outlined.

· Patients should be informed of the number of SLN biopsies performed by the surgeon and the surgeon's success rate with the procedure, as determined by the identification of the SLN and the false-positive rate (the presence of tumour cells in the axillary nodes when the SLN biopsy result is negative).

Benefits

There are several reasons for the current widespread interest in SLN biopsy. First, with the removal of only 1 or 2 lymph nodes, morbidity is substantially less than the morbidity resulting from axillary dissection.10 Second, with the increasing use of screening mammography, smaller tumours are being detected, and these are less likely to be associated with axillary metastases.11 In such circumstances, patients receive no proven benefit from axillary dissection in the absence of positive nodes, yet they are still left with its associated morbidity. Third, staging by SLN biopsy may be more accurate: because only 1 or 2 nodes are removed, more sections per node can be made and studied by the pathologist than can routinely be examined from the whole axillary dissection specimen. Immunohistochemical studies can be performed on the SLN that would be too impractical and expensive to do on the many nodes removed by axillary dissection; however, this potential benefit remains unproven because the significance of immunohistochemical studies has yet to be determined.

Challenges

Although the concept of SLN biopsy is simple, the performance of the procedure to accurately locate, harvest and analyze the SLN in breast cancer is complex and challenging. It requires a team of members from nuclear medicine, surgery and pathology, and is only mastered after a substantial learning period.

Surgical volume appears to be an important factor in the success rate of identifying the SLN. Giuliano and colleagues12,13 reported that the SLN was identified in 52% of their first case series of 124, in 70% of their second case series of 50 and in 94% of their third case series of 100. In their last 160 cases, there was only 1 failure. In a study by Morrow and associates,14 the likelihood of finding the SLN was 73% in the first 10 cases performed by a surgeon and 91% after 30 cases. And finally, Cox and collaborators15 reported that surgeons performing 1 to 2 SLN biopsies per month had a success rate of 82%, those performing 3 to 6 per month had a success rate of 90%, and surgeons performing more than 6 per month had a 97% success rate.

A literature search from January 1991 to December 2000 for studies in which both SLN biopsy and axillary dissection were performed identified 53 studies, involving a total of 9303 patients.12,14,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66 There were no randomized trials. The studies were all case series, some prospective and some retrospective (level IV and V evidence). In all of these studies patients first had SLN biopsy and then axillary dissection. In the analyses of these studies the SLN was considered the “diagnostic test” and the status of the lymph nodes (i.e., the presence or absence of disease) the “gold standard.” It is of interest that a positive SLN was always counted as both a positive test result and a positive gold standard. Hence the positive predictive value and specificity were always 100% (i.e., there were never any false-positive results). In one study, the SLN was the only positive node in 9% of cases,25 whereas in another study it was the only positive node in as many as 77% of cases.63 Because the results of the SLN biopsy are used to decide on adjuvant therapy, the false-negative rate should be as near to 0 as possible. The false-negative rate, calculated as the number of cases in which the biopsy result was negative divided by the total number of patients in whom the axillary status was positive, ranged from 0% to 22.2%.

The potential effect of SLN biopsy on local disease control in the axilla and on overall patient survival needs to be considered. It has been reported that, without axillary dissection, the recurrence rate in the axilla is as high as 28% after a 10-year follow-up.5 Although SLN biopsy is not the equivalent of no treatment of the axilla (as positive cases are generally submitted to axillary dissection) there are no data on long-term local recurrence rates among patients with a negative SLN biopsy result. In addition, eradication of axillary disease, as may occur with axillary dissection, may affect long-term survival. This concept is supported by the results of recent clinical trials demonstrating that effective local-regional control (i.e., radiation to the chest wall, axilla and internal mammary areas after axillary dissection) in women receiving adjuvant systemic therapy can improve survival (level I evidence).6,7,8

In summary, the technique for identifying the SLN has been well studied. In experienced hands, the rate of identifying the SLN is high and the false-negative rate low. What is unknown is whether or not control in the axilla or long-term survival will be as good as that with a level 1 and 2 axillary dissection. (Note: The axilla is commonly divided into 3 levels: level 1 is inferior and lateral to the pectoralis minor muscle, level 2 is beneath the pectoralis minor muscle, and level 3 is superior and medial to the pectoralis minor muscle. The standard axillary dissection removes the level 1 and level 2 nodes.) Women facing this decision must be made aware of this uncertainty.

Making treatment decisions

Adoption of procedure

· Before surgeons replace axillary dissection by SLN biopsy as the staging procedure at their institution, they should (a) familiarize themselves with the literature on the topic and the techniques needed to perform the procedure, (b) follow a defined protocol for all 3 aspects of the procedure (nuclear medicine, surgery, pathology) and (c) perform backup axillary dissection until an acceptable success rate (determined by the identification of the SLN and the false-negative rate) is achieved.

· A surgeon who performs breast cancer surgery infrequently should not perform SLN biopsy.

· A positive SLN biopsy result or failure to identify an SLN should prompt full axillary dissection.

· SLN biopsy is contraindicated in women who have clinically palpable nodes, locally advanced breast cancer, multifocal tumours, previous breast surgery or previous irradiation of the breast.

Surgeons who wish to use SLN biopsy as the only surgical staging procedure for invasive breast cancer should satisfy the following 3 requirements:

· Surgeons should thoroughly familiarize themselves with the literature on the topic and the technique needed to perform successful SLN biopsy. One way of doing this is to attend a continuing medical education course or workshop featuring SLN biopsy. A visiting surgeon experienced in SLN biopsy may be very helpful.

· Surgeons should follow a defined protocol for each of the 3 aspects of the procedure (nuclear medicine, surgery and pathology). While the technique remains under development at their institution, the procedure might be designated “investigational” and could be placed under the surveillance of their institutional review board.67

· Initially, surgeons should always perform backup axillary dissection when doing an SLN biopsy. There is no gold standard on the number of cases that should be done with backup axillary dissection. The steering committee felt that the criteria first put forward by the American Society of Breast Surgeons and endorsed by the American College of Surgeons Oncology Group68 are reasonable: performance of 30 SLN biopsies followed by complete axillary dissection, with an 85% success rate in identifying the SLN and a 5% or lower false-negative rate. Of these 30 cases, at least 10 should have metastatic disease in the axilla. (Note: Even with 30 cases, the confidence limits around an observed rate are very wide.) Performance of fewer than 30 SLN biopsies could be considered in the context of a randomized controlled trial in which quality control is monitored by an external agency.

The performance of SLN biopsy requires a dedicated and experienced team from surgery, pathology and nuclear medicine. There are data from case series that show that the success rate in identifying the SLN is related to surgical volume,12,13,14,15 and there are some data from health services research that show a relation between surgical volume and outcome (level V evidence).69,70,71 On the basis of these considerations the steering committee felt it was reasonable to recommend that a surgeon who performs breast cancer surgery infrequently should not perform SLN biopsy.

Histologic staining

· Staining of tissue sections with hematoxylin and eosin, and not immunohistochemical analysis for cytokeratin, should determine adjuvant therapy.

Serial sectioning of the 1 or 2 SLNs analyzed immunohistochemically for cytokeratin has yielded larger numbers of “metastases” than has routine staining with hematoxylin and eosin. The increased frequency of metastases in the nodes does not correspond to the natural history of the tumours studied. For example, in one study, 5 of 6 patients with tumours less than 0.5 cm in diameter had positive results of staining for cytokeratin in the SLN, substantially greater than the incidence of positive SLNs detected with hematoxylin and eosin staining in tumours greater than 0.5 cm in diameter (level V evidence).72 Cytokeratin-positive cells deserve caution in interpretation because they have been found in bone marrow samples of 23% of patients with tumours less than 0.5 cm in diameter and in 35% of patients with tumours between 0.5 cm and 1.0 cm in diameter (level V evidence).73 The majority of these cells may not be clinically significant. They may in fact not be malignant.74,75 At this juncture the independent prognostic significance of isolated tumour cells identified by immunohistochemistry in axillary nodes is unclear.76 It is important to realize that the clinical trials that have provided the data supporting the effectiveness of adjuvant systemic therapy (chemotherapy or tamoxifen therapy, or both) enrolled patients whose nodes removed by axillary dissection underwent traditional hematoxylin and eosin staining. Hence, there are insufficient data available on the natural history of breast tumours when metastases to sentinel axillary nodes are identified only by immunohistochemical stains for cytokeratin.

Trials underway

· Participation in randomized trials is encouraged.

Many questions remain unanswered about SLN biopsy. What is its effect on survival and on local control of cancer in the axilla? Is a full axillary dissection or systemic adjuvant therapy necessary with a positive SLN node detected by means of immunohistochemical staining only? What should be done with SLNs in the internal mammary chain?

Randomized trials that will look at these and other issues are underway. In the National Surgical Adjuvant Breast and Bowel Project B-32 trial, 4000 women with operable breast cancer will be assigned to undergo either SLN biopsy followed by axillary dissection or SLN examination followed by axillary node dissection only if the SLN is positive or if it is not identified. In 2 trials conducted by the American College of Surgeons Oncology Group (Z0010 and Z0011), 7600 women will be enlisted to undergo SLN biopsy. Patients with a negative biopsy result or those whose SLN is positive only by immunohistochemistry will be followed. Patients with a positive SLN biopsy result (estimated to be 1900 patients) will be randomly assigned to full axillary dissection or no further axillary intervention. Participation in such trials is encouraged.

While these trials are underway and outstanding questions are being answered, SLN biopsy needs to be introduced into medical practice in a safe and organized manner.

Appendix 1.

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Appendix 1. Continued.

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Footnotes

The steering committee is part of Health Canada's Canadian Breast Cancer Initiative. A list of the committee members appears at the end of the article.

A patient version of these guidelines appears in Appendix 1.

A patient guide to sentinel lymph node biopsy appears on page 172.

This article has been peer reviewed.

Competing interests: None declared.

Correspondence to: Dr. Mark Levine, c/o Ms. Humaira Khan, Faculty of Health Sciences, McMaster University Health Sciences Centre, Rm. 2C6, 1200 Main St. W, Hamilton ON L8N 3Z5; fax 905 577-0017.

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