cancer o ganglio cent

American Society of Clinical Oncology GuidelineRecommendations for Sentinel Lymph Node Biopsy inEarly-Stage Breast CancerGary H. Lyman, Armando E. Giuliano, Mark R. Somerfield, Al B. Benson III, Diane C. Bodurka,Harold J. Burstein, Alistair J. Cochran, Hiram S. Cody III, Stephen B. Edge, Sharon Galper,James A. Hayman, Theodore Y. Kim, Cheryl L. Perkins, Donald A. Podoloff,Visa Haran Sivasubramaniam, Roderick R. Turner, Richard Wahl, Donald L. Weaver, Antonio C. Wolff,and Eric P. Winer

A B S T R A C T

PurposeTo develop a guideline for the use of sentinel node biopsy (SNB) in early stage breast cancer.

MethodsAn American Society of Clinical Oncology (ASCO) Expert Panel conducted a systematicreview of the literature available through February 2004 on the use of SNB in early-stagebreast cancer. The panel developed a guideline for clinicians and patients regarding theappropriate use of a sentinel lymph node identification and sampling procedure from hereonreferred to as SNB. The guideline was reviewed by selected experts in the field and theASCO Health Services Committee and was approved by the ASCO Board of Directors.

ResultsThe literature review identified one published prospective randomized controlled trial in whichSNB was compared with axillary lymph node dissection (ALND), four limited meta-analyses, and69 published single-institution and multicenter trials in which the test performance of SNB wasevaluatedwith respect to the results of ALND (completion axillary dissection). There are currentlyno data on the effect of SLN biopsy on long-term survival of patients with breast cancer.However, a review of the available evidence demonstrates that, when performed by experi-enced clinicians, SNB appears to be a safe and acceptably accurate method for identifyingearly-stage breast cancer without involvement of the axillary lymph nodes.

ConclusionSNB is an appropriate initial alternative to routine staging ALND for patients with early-stagebreast cancer with clinically negative axillary nodes. Completion ALND remains standardtreatment for patients with axillary metastases identified on SNB. Appropriately identifiedpatients with negative results of SNB, when done under the direction of an experiencedsurgeon, need not have completion ALND. Isolated cancer cells detected by pathologicexamination of the SLN with use of specialized techniques are currently of unknown clinicalsignificance. Although such specialized techniques are often used, they are not a requiredpart of SLN evaluation for breast cancer at this time. Data suggest that SNB is associatedwith less morbidity than ALND, but the comparative effects of these two approaches ontumor recurrence or patient survival are unknown.

J Clin Oncol 23. 2005 by American Society of Clinical Oncology

INTRODUCTION

The disease status of the axillary lymphnodes is the most significant prognostic fac-

tor for patients with early-stage breast can-cer. Predictors of node metastases includetumor size, lymphovascular invasion, tumorgrade, and patient age. Receptor status,

From the University of RochesterSchool of Medicine and Dentistry,Rochester, NY; John Wayne CancerInstitute, Santa Monica, CA; Northwest-ern University, Evanston, IL; TheUniversity of Texas M.D. AndersonCancer Center, Houston, TX; Dana-Farber Cancer Institute, Boston, MA;David Geffen School of Medicine,University of California, Los Angeles,Los Angeles, CA; Memorial Sloan-Kettering Cancer Center, New York,NY; Roswell Park Cancer Institute,Buffalo, NY; Brigham and WomensHospital, Boston, MA; University ofMichigan, Ann Arbor, MI; Tufts-NewEngland Medical Center, Boston, MA;the Susan G. Komen Breast CancerFoundation, Dallas, TX; The Universityof Texas M.D. Anderson CancerCenter, Houston, TX; University ofKentucky, Lexington, KY; St JohnsHealth Center, Santa Monica, CA; TheJohns Hopkins University, Baltimore,MD; University of Vermont College ofMedicine, Burlington, VT; Dana-FarberCancer Institute, Boston, MA; SidneyKimmel Comprehensive Cancer Centerat Johns Hopkins, Baltimore, MD.

Submitted August 3, 2005; acceptedAugust 4, 2005.

Authors disclosures of potential con-flicts of interest are found at the end ofthis article.

Address reprint requests to AmericanSociety of Clinical Oncology, CancerPolicy and Clinical Affairs, 1900 DukeSt, Suite 200, Alexandria, VA 22314;e-mail: [email protected].

2005 by American Society of ClinicalOncology

0732-183X/05/2330-1/$20.00

DOI: 10.1200/JCO.2005.08.001

JOURNAL OF CLINICAL ONCOLOGY A S C O S P E C I A L A R T I C L E

VOLUME 23 NUMBER 30 OCTOBER 20 2005

1Journal of Clinical Oncology, Vol 23, No 30 (October 20), 2005: pp 000-000DOI: 10.1200/JCO.2005.08.001

Published Ahead of Print on September 12, 2005 as 10.1200/JCO.2005.08.001

Copyright 2005 by American Society of Clinical OncologyCopyright 2005 by the American Society of Clinical Oncology. All rights reserved. Downloaded from www.jco.org on November 8, 2005 . For personal use only. No other uses without permission.

DNA content (ploidy), tumor location, method of detec-tion, and presence of casting-type calcifications on mam-mography have some predictive value.1-6 However, nocombination of predictors of axillary node status has re-placed surgical resection and histopathologic examinationof the lymph nodes.7 The use of mammography and in-creased public awareness of breast cancer have resulted inwomen having smaller tumors at the time of initial presen-tation, a lower risk of involved nodes, and fewer involvednodes.8,9 Similarly, while advances in computed tomogra-phy (CT), magnetic resonance imaging (MRI), positronemission tomography (PET), and ultrasonography canoften identify suspicious nodes in the axilla, false-negativefindings and failure to detect small metastases are common.Thus, reliance onhistologic examination of removed lymphnodes at the time of axillary lymph node dissection (ALND)is thought to be the most accurate method for assessingspread of disease to the lymph nodes. Accurate assessmentof the nodes is important not only for staging and progno-sis, but also for guiding treatment selection.

However, the anatomic disruption caused by ALNDmay also result in lymphedema, nerve injury, shoulder dys-function, and other complications that may compromisefunctionality and quality of life. Systematic studies in breastcancer have shown that breast cancer spreads to one or a fewlymph nodes, the sentinel lymph node(s) (SLNs), before itspreads to other axillary nodes and that these SLNs can beidentified by using vital blue dye, a radiolabeled colloid, orboth.10,11 The findings of these early studies suggested thatthe use of a sentinel lymph node identification and sam-pling procedure referred to here as sentinel node biopsy(SNB) could be reliably performed in selected patients withearly stage breast cancer by a carefully trained multidisci-plinary team (surgeon, pathologist, nuclear medicine tech-nician), thus reducing the need for ALND and avoiding theassociated morbidity.10-22 Despite few controlled clinicalstudies of SNB, this procedure has become widely practicedin the United States, Europe, and Australia. Currently, atmost major cancer centers in the United States, SNB isperformed without ALND if no disease is found in theSLN.23 The American Society of Clinical Oncology (ASCO)convened an Expert Panel to develop recommendations forthe use of SNB in oncology practice and to determine itssuitability in the staging and management of early stagebreast cancer.

GUIDELINE QUESTIONS

This guideline addresses four principal questions regardingthe appropriateness of SNB for the management of earlystage breast cancer:

1. How should the results of SNB be utilized in clinicalpractice?

a. Can full ALND be avoided in patients who havenegative findings on SNB?

b. Is full ALND necessary for all patients with positivefindings on SNB?

2. What is the role of SNB in special circumstances inclinical practice? (These special circumstances include largeand locally advanced invasive tumors, multicentric tumors,inflammatorybreast cancer, ductal carcinoma-in-situ [DCIS],older age [65 years or more], obesity, male breast cancer,pregnancy, evaluation of the internal mammary nodes, pres-ence of suspicious palpable axillary nodes, prior breast or axil-lary surgery, and preoperative systemic therapy.)

3.What factors affect the success of SNB (including lowrates of complications and false-negative results)?

4.What are the potential benefits and harms associatedwith SNB?

PRACTICE GUIDELINES

Practice guidelines are systematically developed statements toassist practitioners and patients in making decisions aboutappropriate health care for specific clinical circumstances. At-tributes of good guidelines include validity, reliability, repro-ducibility, clinical applicability, clinical flexibility, clarity,multidisciplinary process, review of evidence, and documen-tation. Guidelines may be useful in producing better care anddecreasing cost. Specifically, utilization of clinical guidelinesmay provide the following:

1. Improvement in outcomes2. Improvement in medical practice3. Means forminimizing inappropriate practice variation4. Decision support tools for practitioners5. Points of reference for medical orientation and

education6. Criteria for self-evaluation7. Indicators and criteria for external quality review8. Assistance with reimbursement and coverage

decisions9. Criteria for use in credentialing decisions

10. Identification of areas where further research isneeded

In formulating recommendations for the appropriateuse of the SNB in the management of early stage breastcancer, ASCO considered these tenets of guideline develop-ment, emphasizing review of data from appropriately con-ducted and analyzed clinical trials. However, it is importantto note that guidelines cannot always account for individualvariation among patients. Guidelines are not intended tosupplant physician judgment with respect to particular pa-tients or special clinical situations and cannot be consideredinclusive of all proper methods of care or exclusive of othertreatments reasonably directed at obtaining the same result.

Lyman et al

2 JOURNAL OF CLINICAL ONCOLOGY

Copyright 2005 by the American Society of Clinical Oncology. All rights reserved. Downloaded from www.jco.org on November 8, 2005 . For personal use only. No other uses without permission.

Accordingly, ASCO considers adherence to these guide-lines to be voluntary, with the ultimate determination regard-ing their application to be made by the physician in light ofeach patients individual circumstances. In addition, theseguidelines describe the use of procedures and therapies inclinical practice; they cannot be assumed to apply to the use ofthese interventions performed in the context of clinical trials,given that clinical studies are designed to evaluate or validateinnovative approaches in adisease forwhich improved stagingand treatment is needed. In that guideline development in-volves a review and synthesis of the latest literature, a practiceguideline also serves to identify important questions and set-tings for further research.

METHODS

Panel CompositionThe ASCO Health Services Committee (HSC) convened an

Expert Panel consisting of experts in clinical medicine and re-search relevant to breast cancer management, including surgicaloncology, pathology, radiation oncology, and medical oncology.Academic and community practitioners, an oncology fellow, and apatient representative were also part of the Panel. The Panelmem-bers are listed in Appendix 1.

Literature Review and AnalysisThe SNB is primarily a staging procedure and, in numerous

studies, its test accuracy has been based on comparisonwith comple-tion ALND dissection as the gold standard. As such, randomizedcontrolled trials (RCTs)havenotbeen thoughtnecessary todefine thestaging accuracy of SNB. RCTs are necessary, however, to determinethe effect of SNB compared with that of axillary dissection on subse-quent clinical management and long-term benefits and harms, in-cluding the clinical, quality-of-life, and economic impact on patientswith early-stage breast cancer. While ASCO awaits the results ofRCTs, the complexities, limitations, and variability of SNB perfor-mance prompted the Societys current effort to develop a ClinicalPractice Guideline for the interpretation and application of this pro-cedure in clinical oncology.

Three systematic reviewswith formal statisticalmeta-analysishave been published previously.24-26 Each of these reviews wasbased on data from a limited and selected number of existingstudies. In an effort to evaluate more fully the published results ofSNB, an expanded systematic review of published literature ofSNB test performance has been conducted by members of theASCO Guidelines Panel.24,27 This review utilized electronic tech-niques (Medline, the Cochrane Library, Best Evidence [ACP Jour-nal Club and Evidence-Based Medicine], DARE [Database ofAbstract of Reviews of Effectiveness], Dissertation Abstracts) andhand-searching techniques. Only studies incorporating full lymphnode dissection, regardless of the results of SNB were included. Be-tween 1994 and 2004, 69 trials that met eligibility criteria were re-ported. Study quality was evaluated by two blinded observers on a5-point modified scale with factors of description of patient char-acteristics, reason for study withdrawal, test performance mea-sures, measures of variability, and a description of the SNBtechnique. The relationships of the rate of false-negative findings,predictive value, and the proportion of successful lymphatic map-

pings to study size, the proportion of patients with positive lymphnodes, the technique used, and study quality were evaluated.

Consensus Development Based on EvidenceThe entire Panel met twice; additional work on the guideline

was completed through teleconferences of a steering group of thePanel. The purposes of the Panel meetings were to refine thequestions addressed by the guideline and to make writing assign-ments for the respective sections. All members of the Panel partic-ipated in the preparation of the draft guideline, which was thendisseminated for review by the entire Panel. Feedback from exter-nal reviewers was also solicited. The content of the guideline andthe manuscript were reviewed and approved by the HSC and bythe ASCO Board of Directors before dissemination.

Guideline and Conflict of InterestAll members of the Expert Panel complied with ASCO policy

on conflicts of interest, which requires disclosure of any financialor other interest that might be construed as constituting an actual,potential, or apparent conflict. Members of the Expert Panel com-pleted ASCOs disclosure form and were asked to identify ties tocompanies developing products thatmight be affected by promul-gation of the guideline. Information was requested regarding em-ployment, consultancies, stock ownership, honoraria, researchfunding, expert testimony, andmembership on company advisorycommittees. The Panel made decisions on a case-by-case basis asto whether an individuals role should be limited as a result of aconflict. No limiting conflicts were identified.

Revision DatesAt annual intervals, the Panel Co-Chairs and two Panel

members designated by the Co-Chairs will determine the need forrevisions to the guideline based on an examination of currentliterature. If necessary, the entire Panel will be reconvened todiscuss potential changes. When appropriate, the Panel will rec-ommend revision of the guideline to the HSC and the ASCOBoard for review and approval.

Definition of TermsAxillary lymph node dissection (ALND): surgical resection and

histopathologic examinationof lymphnodes contained in theaxillarybasin. In current practice, this routinely includes axillary level I and IInodes; level III nodes are optionally removed after intraoperativepalpation of the region. (Also referred to as axillary dissection.)

Lymphaticmapping: the use of blue dye, radiolabeled colloid,or both, to identify the drainage pattern of the breast, generallywith the intent of identifying the SLN(s).

Sentinel lymph node (SLN): the first lymph node or group oflymph nodes encountered in the lymphatic drainage of the breast,generally identified by lymphatic mapping. Some consider suspi-cious nodes found at the time of SNB as SLNs as well.

Sentinel node biopsy (SNB): the surgical removal and his-topathologic examination of the SLN.

Summary of Outcomes AssessedImportant measures for assessing SNB include the following:1. The percentage of patients for whom lymphatic mapping

is successful. When lymphatic mapping is not successful (failedsampling), full ALND is generally necessary to assess the status ofthe nodes.

2. The false-negative rate represents the proportion of pa-tients with negative findings on SNB who are subsequently foundto have disease in the axillary lymph nodes on ALND. An intraop-erative false-negative finding represents a SLN that is found to be

SNB in Early-Stage Breast Cancer

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negative for disease on intraoperative evaluation of frozen sectionor touch prep but metastasis is detected on evaluation of thepermanent section. An axillary false-negative finding is the ab-sence of evident metastasis on evaluation of a permanent sectionof the SLN but findings of metastases by full ALND.

3. The negative predictive value is the proportion of individ-uals with negative findings of SNB in whomno involvement of theaxillary lymph nodes is found on ALND.

4. Accuracy is the proportion of all patients (positive ornegative findings of SNB) for whom the SNB correctly predicts theresults of ALND.

RESULTS

Literature SearchThe 69 identified studies in which SNB was compared

with completion ALND included 10,454 patients, 8,059 ofwhom completed study. The sensitivity of SNB for node in-volvement ranged from 71% to 100%, and the false-negativerate averaged 8.4%, ranging from 0% to 29% across all trials.The rate of false-negative findings varied according to thenumber of patients; the proportion of successful mappings;inclusion of patient characteristics, measures of test perfor-mance, and measures of variability; and whether blue dye orradiolabeled colloid, or both, was used (Table 1). The propor-tion of successful mappings was significantly higher and thefalse-negative rate was significantly lower in studies in which aradiolabeled colloid was used for mapping.

In summary, this systematic review demonstrates thatreportedmeasures of SNB test performance vary dependingon sample size, risk, mapping technique (radioisotope, bluedye, or both) andmeasures of study quality. While many ofthese reports represent the investigators early experiencewith this procedure, as a whole the findings suggest thatSNB is a reasonably accuratemethod for assessing the statusof the axillary lymph nodes in many women with early-stage breast cancer. The overall false-negative rate in thereview of nonrandomized studies of test performance isvirtually identical to the rate found thus far in RCTs.

Previous Consensus StatementsConsensus statements have also been developed by

some professional societies, including the American Society

of Breast Surgeons; the Institute for Clinical Systemic Im-provement; theCanadian SteeringCommittee; theConsen-sus Conference Committee, Philadelphia; and the GermanSociety of Senology.28-32Whereas the Philadelphia Consen-sus Conference put more emphasis on the input from ex-perts and pioneers of the field, the other societies based theirstatements on a panel review of the existing literature. ThePhiladelphia Consensus Conference concluded that SNBcould replace routine ALND for patients with no disease inthe SLN, with no further axillary treatment necessary.30

HOW SHOULD THE RESULTS OF SNB BE UTILIZEDIN CLINICAL PRACTICE?

Can Full ALND Be Avoided in Patients WithNegative Findings on SNB?

Summary and recommendations. The reported testperformance characteristics of SNB varywidely across stud-ies reported in the medical literature.24 However, whencarried out by an experienced team, negative findings ap-pear to be predictive of negative axillary nodes for mostpatients with breast cancer.24 Significant predictors of post-test probability include the percentage of patients in thestudy population with positive axillary nodes and the pro-portion of successful lymphatic mappings. In addition, theincidence of axillary recurrence after negative findings onSNB is comparable to that following ALND.10,33 On thebasis of the available evidence, the Panel supports the use ofSNB for staging disease in most women with clinically neg-ative axillary lymph nodes. The concept of SNB has been soappealing to physicians and patients that the identificationand biopsy of SLNs has largely replaced ALND for patientswith clinically and histologically tumor-free lymph nodes.The Panel recommends that suspicious palpable nodesshould also be submitted as SLNs, and that, in this context,the surgeon should have a low threshold for default toALND, particularly for patients whose clinical presentationsuggests a high risk of axillary metastasis. SNB works well,with a comparable false-negative rate in the setting of bothmastectomy and breast-conserving surgery.34,35 Neverthe-less, the Panel concluded that, on the basis of the available

Table 1. False Negative Rates in Trials in Which Sentinel Lymph Node Biopsy Is Compared With Axillary Lymph Node Dissection

False-Negative Rate (%) P

All trials 8.4 (0-29)Trials with 100 patients v trials with 100 patients 6.7 v 9.0 .02Successful mapping in 90% v 90% 6.3 v 11.1 .003Patient characteristics (given v not given) 7.8 v 11.6 .009Measures of test performance (given v not given) 7.0 v 10.3 .009Measures of variability (given v not given) 6.2 v 9.0 .01Use of both dye and radiolabeled colloid v use of only one 7.0 v 9.9 .07

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literature, there are compelling reasons for the operating sur-geon to default to ALND, including a failed or technicallyunsatisfactory SNB procedure, and the presence of clinicallysuspicious nodes in the axilla after the removal of all SLNs.Abouthalf of patients inwhomthe identifiedSLNproves tobefalsely negativewill have had clinically suspicious nodes palpa-ble at surgery, because gross tumor involvementmay interferewith the uptake of both radiolabeled colloid and dye and devi-ate lymph flow to a node other than the true SLN.36,37

Evidence from RCTs. To date, only one prospectiverandomized trial has been published in which SNB wascompared with formal axillary dissection.10 Veronesi et alrandomly assigned 516 patients with tumors of 2 cm or lessto either SNB and ALND or SNB followed by axillary dis-section only if the SLN contained metastases. If lymphaticmapping failed, the patient was excluded from the study.For the patients who had SNB andALND, the false-negativerate was 8.8% (95%CI, 3.9 to 16.6) and the negative predic-tive value was 95.4% (95%CI, 91.1 to 98.0). There were feweraxillary complications and lessmorbidity in thegroup thathadALND only if the SLN was positive for disease. For patientswho did not have ALND, there were no axillary recurrencesand the short-term survival was the same as for patients withtumor-free nodes who had an ALND. However, the medianfollow-upwas only 46months, and the study lacked thepowerto detect small differences in survival.

Several RCTs are ongoing at multiple centers in theUnited States and Europe. In National Surgical AdjuvantBreast and Bowel Project (NSABP) B-32, as in the study byVeronesi et al, SNB followed by ALND is being comparedwith SNB andALNDonly if tumor is found in the SLN. Thislarge multi-institutional study is designed to examine thelong-term survival effect of SNB alone and its morbiditycompared with axillary dissection. This study has com-pleted accrual, with 5,611 randomly assigned patients whowill be evaluated over the next several years. Since comple-tion of the planned literature review for the present guide-line, the early results of NSABP B-32 were presented at amajor meeting (27th Annual San Antonio Breast CancerSymposium, December 8-11, 2004). For patients who hadSNB followed by ALND, lymphatic mapping was successfulin 97.1% (95% CI, 96.5 to 97.8), the false-negative rate was9.7% (95% CI, 7.6 to 11.9), and the negative predictivevalue was 96.1% (95% CI, 95.2 to 97.0).38

While awaiting long-term follow-up from RCTs, sur-geons continued to validate the test performance of SNB byperforming it with an axillary dissection in the samepatient.Currently, most trained and experienced surgeons at majorcancer centers in the United States and Europe performSNB alone when the SLN is found to be tumor-free byroutine analysis and perform completion ALND only whenthe findings of SNB indicate axillary metastases.23 Never-theless, while the diagnostic accuracy of SNB has been dem-onstrated to the satisfaction of most clinicians, further

RCTs are needed to evaluate the therapeutic impact andlong-term outcomes associated with the procedure.

Is Full ALND Necessary for All Patients WithPositive Findings on SNB?

Summary and recommendations. The recently re-ported meta-analysis demonstrates that, among patientswith a positive SLN, 48.3% (95%CI, 35 to 62)were found tohave additional node disease on ALND.24 Thus, the Panelrecommends routine ALND for patients with a positiveSLN according to routine histopathologic examination.More problematic is the management of patients for whomthe SLN is positive onlywith use of special studies, primarilyimmunohistochemical (IHC) analysis with antibodies tocytokeratin. IHC evaluation can upstage disease for approx-imately 10% of patients who have a negative SLN, butwhether this conversion to a higher stage is relevant remainsunknown at this time.39-42 In the new American Joint Can-cer Commission (AJCC) staging system, the node classifi-cation (pN0) is not altered by clusters of isolated tumor cellsof 0.2 mm or less, regardless of the staining technique usedto identify them.43,44

It remains unclear whether isolated tumor cells or mi-crometastases (lymph node metastases larger than 0.2 mmbut not larger than 2 mm) detected with hematoxylin andeosin (H&E) staining or special stains represents an adverseprognostic indicator and whether ALND should be carriedout in all such cases. Likewise, there are insufficient data todetermine whether the presence of isolated tumor cells ormicrometastases should be a factor in treatment decisions.However, metastasis is found in nonsentinel nodes in ap-proximately 10% of patients with isolated tumor cells in theSLN and in 20% to 35%of patients withmicrometastases inthe SLN.45 Until further studies addressing the clinical rel-evance of isolated tumor cells or micrometastases in theSLN are complete, the Panel recommends routine ALNDfor patients withmicrometastases (0.2 2mm) found onSNB, regardless of the method of detection. Regarding thequestion of which patients with a positive SLN may beappropriately treated with breast or axillary radiation andwhich patients should have completion ALND, relevantstudies have included short follow-up and small numbers ofpatients in retrospective series, and no results from RCTsare available. Therefore, the Panel concluded that there areinsufficient data to answer this question.

Predictive models. Treatment decisions may be aidedby knowing which patients with a positive SLN are likelyto have additional metastatic disease found at ALND. Inmultivariate analysis, three pathologic factors have beenidentified as being significantly associatedwith an increasedlikelihood of residual involvement of a nonsentinel node inthe presence of a positive SLN: size of the metastasis in theSLN (detected only by IHC analysis, micrometastasis [0.2 2.0 mm], or macrometastases), primary tumor size, and


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the presence of lymphovascular invasion.46-52 By combin-ing all three factors, involvement of a nonsentinel node canbe more accurately estimated for an individual patient.Turner et al generated detailed estimates of the likelihood ofinvolvement of a nonsentinel node in patients who had apositive SLN node for a broad range of clinical situations;these estimates may be useful in predicting the risk of resid-ual disease in the axilla for an individual patient with apositive SLN.48 Alternatively, Van Zee et al created a multi-variate model to predict the likelihood of additional metas-tases that incorporates nine variables based on data from702 patients who had a positive SLN and completionALND. This nomogram was then prospectively validatedon a subsequent population of 373 patients.53

Micrometastases and isolated tumor cells. Some studieshave demonstrated that micrometastasis has an adverseeffect on survival, whereas others have shown no effect onsurvival.41,54-61 The definition of micrometastasis used inthe literature has been variable and the mode of detectionhas been different, ranging from simple H&E staining to re-verse transcriptase polymerase chain reaction, with IHC anal-ysis used in most studies. There is only one relatively smallstudy in which no early adverse outcome was found at a me-dian follow-up of 38 months for patients with micrometasta-ses detected by either H&E staining or IHC analysis.41

Radiation therapy compared with ALND. There havebeen few studies concerning which patients with a positiveSLN will benefit from radiation therapy rather than com-pletion ALND. In NSABP B-04, 818 patients with clinicallynode-negative disease were randomly assigned to modifiedradical mastectomy, total mastectomy plus radiation therapyto the axilla, or totalmastectomyalone.At 10years, the axillaryrecurrence rate was 3.1% for patients treated with radiationcompared with 1.4% for patients treated with axillary dissec-tion.46 The Joint Center for Radiation Therapy reported re-gional node failure at 8 years in 7.1% of 42 patients withclinically node-negative disease who were found to have in-volved axillary nodes on pathologic evaluation and who had alimiteddissection (removal of one tofivenodes) and radiationtherapy to the breast and regional nodes.47

Determining which patients with a positive SLN maybenefit from radiation rather than completion ALND iscomplicated by the frequent use of breast tangential radia-tion and systemic therapy. Several small nonrandomizedseries with limited power have been designed to address thecomparative value of radiation therapy to the regionallymph nodes. In a series from Northwestern University, 63patients with a positive SLN who did not have ALND weretreatedwith adjuvant radiation therapy to the breast with orwithout radiation directed to the regional lymph nodes.62

At a median follow-up of 31.2 months, none of the 44patients who had radiation to only the breast had recur-rence in the axilla despite the fact that 87% of the patientshad a positive SLN on IHC analysis. Among the 20 patients

treatedwith radiation to the breast and regional nodes, all ofwhomhad a positive SLN onH&E staining, one patient hadrecurrence in the axilla. In a second series from Baylor, noaxillary recurrences were found at a mean follow-up of 30months among 31 patients who had a positive SLN andrefused axillary dissection.63 All patients received systemictherapy and either breast tangential or chest wall radiation.In a third study, there were no axillary recurrences at amedian follow-up of 32months among 46 womenwho hada positive SLN, did not haveALND, andhad radiation to thebreast.64 Therefore, radiation to the breast, with or withoutradiation directed specifically to the axilla, may be consid-ered for patients with clinically negative nodes in the axillaand a positive SLN who are a poor risk for surgery or areunwilling to have additional surgery. No data exist regard-ing the long-term benefits and harms associated with thesetreatment approaches.

Ongoing studies. The NSABP B-32 trial will also deter-mine the false-negative rate associatedwith SNB, as well as therate of recurrence in the axilla and the clinical significance ofoccultmicrometastases in SLNs classified as negative on initialevaluation but positive on more comprehensive evaluationwith step sections and IHCanalysis. InEuropeanOrganisationfor Research and Treatment of Cancer (EORTC) 10981,ALND is compared with radiation to the nodes for patientswith a positive SLN. In the American College of Surgeons(ACOSOG) trial Z0011, patients with a positive SLN onH&Estaining were randomly assigned to radiation to the breastonly, without specific treatment to the axillary nodes, or toradiation to the breast plus axillary dissection. This study isdesigned to compare the efficacy of tangential radiation aloneversus axillary dissection following positive results on SNB.Patients participating in this trial will be followed up, but thetrial has been suspendedbecause of lowaccrual andwill not beable to address the original study questions.

What Is the Role of SNB in SpecialCircumstances in Clinical Practice?

Summary and recommendations. On the basis of theavailable literature, the Panel concluded that SNB is notrecommended for large or locally advanced invasive breastcancers (T3 and T4); inflammatory breast cancer; DCIS,when breast-conserving surgery is to be done; pregnancy, inthe setting of prior nononcologic breast surgery or axillarysurgery; and in the presence of suspicious palpable axillarylymph nodes. Data are available to support the use of SNBfor smaller tumors (T1 andT2);multicentric tumors;DCIS,whenmastectomy or immediate reconstruction is planned;for older or obese patients; in male breast cancer; and priorexcisional or diagnostic biopsy. The recommendations andlevels of evidence are provided in Table 2.

Large and locally advanced invasive breast cancers.Most early studies limited the use of SNB to T1 tumors ( 2cm) or T2 tumors ( 2 but 5 cm); the Panel, therefore,

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recommends consideration of the use of SNB for womenwithtumors smaller than 5 cm. The Panel concluded that there arecurrently insufficient data on SNB for women with largertumors (T4 tumors, noninflammatory breast cancers) to sug-gest that the procedure is accurate in these situations. There-fore, the Panel does not recommend the routine use of SNB inthese settings until more data are available. As always, clinicaljudgment should be used to weigh the associated benefits andrisks for an individual patient and to select patients appropri-ate for surgical procedures.

Inflammatory breast cancer. There are insufficient dataon women with inflammatory breast cancer to recommendthe use of SNB in this situation. Because the subdermal lym-phatics arepartially obstructed, contain tumor emboli, andarefunctionally abnormal, the false-negative rate for SNB for thispopulation may be unacceptably high.65 Similarly, there areinsufficient data to recommend the use of SNB for womenwith otherT4 lesions (skin invasion and/or chestwall invasion).

Multicentric tumors. Multicentric cancer in the samebreast occurs in approximately 10%of cases and is generallydefined as distinct cancers occurring in separate quadrantsof the breast, or at a distance of more than 2 to 5 cm fromeach other. Most investigators have excluded patients withmulticentric lesions from SNB. More recently, several pro-posed techniques for performing SNB may address thisissue. Initial reports of SNB in breast cancer were based on atechnique involving peritumoral injection of either radio-labeled colloid66 or blue dye.67 Subsequent experience hasshown that subdermal,68 intradermal,37,69 and subareo-

lar70,71 routes of injection are associated with greater suc-cess and a comparable false-negative rate to that associatedwith the peritumoral route. If indeed the same SLN is sen-tinel for the entire breast, then this SLN or SLNs can beidentified in cases of multicentric cancer by subareolar orintradermal injection. Several small nonrandomized seriesin which such an approach was evaluated have demon-strated that the test performance of SNB is similar to that forwomen with unifocal disease, suggesting that the techniquecan be applied in this setting.72-74

Ductal carcinoma in situ. Axillary staging is generallynot necessary for patients with DCIS as determined bybiopsy results, but in certain clinical circumstances, axillarystaging may be important in order to avoid a second oper-ation. Several studies of DCIS have shown a 5% to 15%incidence of involved SLNs on the basis of IHC analysis, butthe clinical significance of suchmetastases remains unclear.

The Panel recommends considering SNB for patientswith DCIS when a mastectomy is indicated or when imme-diate reconstruction is planned, as axillary staging by SNB isessentially impossible if an invasive tumor is found. Al-though invasive cancer will be subsequently found in 10%to 20% of patients who have DCIS diagnosed by core bi-opsy, the Panel does not recommend routine use of SNB inpatients with DCIS who are to have breast-conserving sur-gery. Some Panel members recommend SNB for patientswith large or high-grade DCIS who are to have breast-conserving surgery or mastectomy, so as to avoid a secondoperation on the axilla if invasive cancer is found.

Table 2. Recommendations and Levels of Evidence

Clinical Circumstance Recommendation for Use of Sentinel Node Biopsy Level of Evidence

T1 or T2 tumors Acceptable GoodT3 or T4 tumors Not recommended InsufficientMulticentric tumors Acceptable LimitedInflammatory breast cancer Not recommended InsufficientDCIS with mastectomy Acceptable LimitedDCIS without mastectomy Not recommended except for large DCIS ( 5 cm)

on core biopsy or with suspected or provenmicroinvasion

Insufficient

Suspicious, palpable axillary nodes Not recommended GoodOlder age Acceptable LimitedObesity Acceptable LimitedMale breast cancer Acceptable LimitedPregnancy Not recommended InsufficientEvaluation of internal mammary lymph nodes Acceptable LimitedPrior diagnostic or excisional breast biopsy Acceptable LimitedPrior axillary surgery Not recommended LimitedPrior non-oncologic breast surgery (reduction or augmentationmammoplasty, breast reconstruction, etc)

Not recommended Insufficient

After preoperative systemic therapy Not recommended InsufficientBefore preoperative systemic therapy Acceptable Limited

Abbreviations: DCIS, ductal carcinoma-in-situ; SNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection.Levels of evidence: Good, multiple studies of SNB test performancebased on findings on completion ALND; Limited, few studies of SNB test performancebased on findings on completion ALND or multiple studies of mapping success without test performance assessed; and Insufficient, no studies of SNB testperformance based on findings on completion ALND and few if any studies of mapping success.


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Older age and obesity. Several studies have shown thataccurate identification of the SLN decreases with increasingage and bodymass. The findings of a study of 1,356 patientssuggested that for every increase of 1 unit of body massindex and for every increase of 1 year of age, the odds ofsuccessful SNB decreased by 0.05.75 This trial also demon-strated that the radioactive node count of a SLN is inverselyproportional to age (P .001). Another study of 966 pa-tients included a multivariate analysis that suggested thatsuccess of the SNB was greatest for women who were 60years or younger when a combination of dye and isotopewas used (P .033).34 These findings, however, do notsupport any contraindication for SNB in obese or olderindividuals.75 As always, clinical judgment should be usedto select appropriate patients for surgical procedures.

Male breast cancer. Male breast cancer is uncommon,with approximately 1,700 new cases expected annually inthe United States.76 Although the diagnosis in men is oftendelayed and patients often present with larger tumors, sur-vival is similar to that for women when controlled for com-mon prognostic factors.77,78 Modified radical mastectomy,often followed by radiation therapy, is the procedure mostcommonly recommended.79-81 The risk of local complica-tions (eg, hematoma and seroma) is greater for men,82 butthe risk of lymphedema following axillary node dissection issimilar to that for women. Data on the use of SNB in menwith breast cancer are limited, except for a few anecdotalreports82-84 and small institutional series.85,86 Port et alreported that the SLN was identified in 15 of 16 men withearly-stage breast cancer who had SNB at Memorial Sloan-Kettering Cancer Center between 1996 and 1999.85 Albo etal reported that the SLNwas identified in all 7menwho hadthe procedure at M.D. Anderson Cancer Center betweenOctober 1999 and 2000.86 Lymphedema developed in oneof the four patients who also had an ALND. Therefore,although the data are limited, the treatment of male breastcancer has paralleled that of female breast cancer, and thePanel believes that it is unlikely that SNB will be any lessaccurate in men than it is in women. The Panel concludesthat there are limited data to make categoric recommenda-tions about the use of SNB for men with breast cancer.

Pregnancy. The safety and test performance of SNBduring pregnancy has not been fully evaluated. Vital dyesshould not be administered to pregnant women; however,radiolabeled colloids are most likely safe because of therapid uptake into the reticuloendothelial system of anymaterial that enters circulation. Recent data demonstratethat the dose of radiation to the fetus is minimal, allowingreasonable consideration of SNB during pregnancy.87 Nev-ertheless, the Panel concludes that there are insufficientdata at this time to recommend the use of SNB in pregnantwomen with breast cancer.

Evaluation of internal mammary lymph nodes. Radicalresection of the internal mammary lymph nodes offers no

survival advantage over conventional surgery, and un-treated internal mammary nodes are rarely a source of localrecurrence in patients with early stage breast cancer.88 Thesignificance of internal mammary node involvement istherefore largely prognostic and comparable to that of pos-itive axillary nodes.89,90 The discovery of a positive internalmammary node benefits only those patients who are nototherwise candidates for adjuvant systemic therapy. Thelikelihood of internal mammary lymph node involvementin such patients is approximately 10%whether the tumor islocatedmedially or laterally.91 Two studies documented thepresence of nonaxillary SLNs in 19% to 25% of all patientswith breast cancer, butmetastasis was limited to the internalmammary nodes in only 1.3% of the women.92,93 AlthoughSNB of internal mammary nodes may be useful in someinstances, the decision to perform the procedure shouldbe determined on the basis of the clinical judgment ofthe treating physicians. The Panel concludes that there arelimited data on the use of SNB to evaluate internal mam-mary nodes.

Prior breast or axillary surgery. The impact of priorbreast or axillary surgery on the successful identification ofSLNs has not been well characterized. Many of the seminalreports on SNB excluded patients with previous excisionalbiopsy10,15,68,94 and/or previous axillary surgery.7,95 Lim-ited data suggest that the biopsy method, in particular,excisional biopsy, does not affect the success of SNB.96 In aretrospective study of 181 patients who were evaluated at asingle cancer center, excision done at some time before SNBdid not affect the subsequent identification rate of SLNs.Similarly, neither the volume of the excisional biopsy spec-imen nor the interval from the biopsy to the SNB affectedthe identification rate. On the basis of these data and accu-mulated clinical experience, the Panel concluded that priordiagnostic or excisional breast biopsy is not a contraindica-tion to SNB.30,97

However, the feasibility of SNB has not been evaluatedfor women who have had another, nononcologic breast sur-gery, such as reduction or augmentation mammoplasty, orbreast reconstruction. It is likely that more extensive breastand/or axillary surgerywouldbe associatedwith ahigher false-negative rate and technical failure of SNB. Lymphatic drain-age from the lateral and upper portions of the breast to theaxilla should be intact after breast reduction surgery orcosmetic breast implants in the submammary or subpec-toral position, particularly when the surgery was performedmore than 6 to 12 months previously. However, the Panelbelieves that there are insufficient data at this time andmorestudies of SNB in this setting are needed before it can berecommended. If SNB is conducted in this setting, it maybest be performed with preoperative lymphoscintigraphy(Appendix 2).

Similarly, SNB after axillary surgery has not beenwidely studied. Although data suggest that SNB may be

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attempted in women who have had axillary surgery, thesuccess rate is likely to be lower. In a retrospective analysis,32 cases of attempted SNB were identified among womenwith prior axillary surgery. Repeat SNB failed in 25% ofsuch women compared with less than 5% among womenwho had not had prior axillary surgery.97 Therefore, thePanel does not recommend SNB in the setting of prioraxillary surgery.

Suspicious palpable axillary lymph nodes. Most studiesof SNB excluded patients with clinically positive nodes inthe axilla. Previous studies have suggested that approxi-mately 25% of clinical axillary examinations yield false-positive findings, and recent experience with SNB supportsthis observation.98 Until further data are available, SNB isnot recommended in the setting of clinically palpable axil-lary nodes. If SNB is undertaken in the setting of clinicallysuspicious nodes, these nodes must be removed regardlessof whether they take up dye or radiolabeled colloid.

Preoperative systemic therapy. Several investigatorshave studied the feasibility of delaying assessment of theaxillary lymph nodes in patients who fulfill criteria for SNBuntil after the completion of preoperative systemic therapy;however, there are some concerns that this strategy maydecrease the likelihood of accurate identification of the SLNand increase the chance of a false-negative finding.99,100

Thus far, a comparison of ALND and SNB after preopera-tive chemotherapy has not been undertaken in a prospec-tive study. In small institutional case series, the rate of SLNidentification has ranged from 85% to 96% and the false-negative rate has ranged from 0% to 33%.101-107 Data col-lected at M.D. Anderson Cancer Center between 1994 and1999 showed that the identification rate improved withexperience, whereas the false-negative rate remained sta-ble.65 The largest study is a retrospective chart review of2,411 patients with operable breast cancer enrolled in theNSABP B-27 trial of preoperative chemotherapy.108 Ofthese patients, 420 (18%) had SNB; at least one SLN wasidentified in 85% of the 420 patients, and the false-negativerate was 11% for the 340 patients who also had ALND. Theloss of pretreatment node staging data to help plan addi-tional postoperative therapy (eg, the extent of radiationfields) has led some to recommend SNB before primarysystemic therapy, with ALND performed after chemother-apy if disease is present in the SLN.109

In summary, SNB after preoperative systemic chemo-therapy is technically feasible. However, because such treat-ment may eradicate foci of disease in axillary lymph nodes,the long-term clinical significance of negative findings onSNB after preoperative treatment is less clear. This potentialloss of prognostic information may complicate clinical de-cision making for local treatment, such as whether comple-tion axillary dissection is indicated, whether radiation isindicated after mastectomy, or what regions should be irradi-ated after lumpectomy. If such informationwould be valuable

in planning the local-regional treatment for a given patient,SNB should be considered before systemic therapy is started.The Panel concludes that there are insufficient data to recom-mend SNB or to suggest appropriate timing of SNB for pa-tients receiving preoperative systemic chemotherapy. ThePanel also emphasizes that whether in the preoperative orpostoperative setting, a SNB should only be performed in thesetting of clinically negative axillary lymph nodes.

What Factors Affect the Success of SNB(including low rates of complications and false-negative findings)?

Summary and recommendations. The ability to evalu-ate individual or institutional accuracy with SNB on thebasis of the proportion of successful mappings and thefalse-negative rate has enabled the procedure to gain wide-spread acceptance without prospective randomized trials.As SNB continues to replace ALND for staging of breastcancer, the Panel believes that appropriate training in theprocedure and issues of quality control are very important.The strongest predictor of the false-negative rate acrosstrials appears to be the proportion of patients for whommapping is successful.24 In addition, the greatest propor-tion of successful mappings and the lowest false-negativerates were associated with studies in which both blue dyeand radiolabeled colloid were used.24 While the Panel doesnot believe that ASCO should present separate guidelinesfor surgeons or institutions about the performance of thisprocedure, the Panel strongly supports the Guidelines forPerformance of Sentinel Lymphadenectomy for BreastCancer developed and updated in 2003 by the AmericanSociety of Breast Surgeons (http://www.breastsurgeons.org/officialstmts/sentinel.shtml). The American Society of BreastSurgeons recommends a rate of SLN identification of 85%with a false-negative rate of 5% or less in order to abandonaxillary dissection. This Societymaintains that performanceof a minimum of 20 SNB procedures in combination withaxillary dissection or with mentoring is necessary to mini-mize the risk of false-negative results.111 The Panel alsorecommends that surgeons (a) take a formal course on thetechnique, with didactic and hands-on training compo-nents; (b) have an experienced mentor; (c) keep track ofindividual results, including the proportion of successfulmappings, false-negative rates, and complication rates; and(d) maintain follow-up on all patients over time. The Panelbelieves that these issues are important quality controlmea-sures as they could meaningfully impact on false-negativerates. While awaiting further results from RCTs, the Panelbelieves that high false-negative rates may have a directadverse impact on patient care including accurate staging,treatment decision making and long-term outcomes in-cluding survival. Clearly, the potential for both local as wellas systemic undertreatment of patients increases as thefalse-negative rate increases. Case volume and experience


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are clearly important determinants of success, but there areinsufficient data to recommend specific volume levels tomaintain proficiency. However, the systematic review indi-cates that the proportion successfully mapped representsthe strongest predictor of false-negative rate and may serveas a reasonable quality indicator for this procedure. Inaddition, the review demonstrates the anticipated reduc-tion in the predictive value of a negative SNB with anincreasing lymph nodepositive rate in the populationstudied. Therefore, caution is required when applying theSNBprocedure in patients at considerably increased risk forlymph node-positive disease.

Finally, the SNB procedure is very much a team effortwith active skilled involvement of multiple disciplines includ-ing surgery, pathology, radiology, nuclear medicine, nursingand pharmacy among others. In addition to the individualtrainingandexperience requiredof all teammembers, optimalresults with the SNB requires the integrated and highly coor-dinated effort that comes with experience and frequent appli-cation of the procedure. Importantly, pathologists evaluatingSNB specimens should be trained and experienced in the de-tection of the minimal amount of disease that is characteristi-cally found in SLNs (Appendix 3).

Review of relevant literature. A survey of randomlyselected fellows of the American College of Surgeons in2001 indicated that 77% perform SNB without ALND and90% use a combination of blue dye and radiolabeled col-loid. Of these surgeons, 35% learned to perform the proce-dure through courses, 31% by observation of colleagues,26% through a surgical oncology fellowship training pro-gram, and 26% by self-instruction. Respondents were di-rected to indicate all that apply to their situation.110 Manystudies have sought to determine the optimal technique forSNB.Most research has shown that for beginning surgeons,the combinations of radiolabeled colloid, lymphoscintigra-phy, and blue dye afford the highest success rates with thelowest false-negative rates.111-113 A small prospective ran-domized study in which the use of blue dye alone was com-paredwith a combination of blue dye and radiolabeled colloidshowed that surgeons achieved equal results with either tech-nique when initially learning the procedure.114 Clearly SNBaccuracy and the identification rate improve with experi-ence.112 In one controlled environment, surgeons achieved a90% rate of SLN identificationwith a false-negative rate of lessthan 5%after performing 30 cases. Less successwas seenwhenpatients were older than 50 years and when the surgeons hadperformed 10 or fewer SLN biopsies.41

What Are the Potential Benefits and Harmsof SNB?

Summary and recommendations. The reported inci-dence of lymphedema following ALND varies widely and isdependent on many variables, including definition oflymphedema, the extent of surgery, use of radiation ther-

apy, and length of follow-up, among others.115 SNB isthought to be associated with fewer complications such asinfection (cellulitis) of the chest wall and arm, sensorychanges, and lymphedema than conventional ALND.18 ThePanel recommends that, as with any medical procedure,written informed consent be obtained from all patientsbefore SNB. The benefits and harms of the procedure, in-cluding the potential for a false-negative result should beexplained to the patient. Written patient educational mate-rials should provide accurate information on the risk ofcomplications, contraindications for the procedure, theneed for a multidisciplinary team (surgeon, nuclear medi-cine technician, and pathologist), the potential costs (whichmay be offset by fewer complications and less follow-upcare), the lack of long-term survival data, the risk of radia-tion exposure, and the follow-up protocols for each proce-dure. A comparison of the data in anunderstandable formatwill help to clarify some of the issues for patients makingtreatment choices.

Review of relevant literature. Several studies clearlyshow that SNB reduces but does not completely eliminatethe risk of lymphedema.18,115,116 Veronesi et al demon-strated a marked diminution of complications associatedwith SNB when compared with ALND.10 A recent RCTsimilarly found significant reductions in both physical andpsychological morbidity, including reductions in postoper-ative arm swelling, rate of seroma formation, loss of sensi-tivity to light touch and pinprick, and psychologicalmorbidity.117 In addition, the two trials reported at recentmeetings confirm the expected decreased complication rateof SNB compared with ALND. Early results from a largetrial (Axillary Lymphatic Mapping Against Nodal Clear-ance) in which the morbidity associated with SNB wascompared with that associated with conventional ALNDwere recently presented.118 Interim analysis at 18 monthsshowed that less lymphedema, shoulder discomfort, sen-sory deficits, and infections were associated with SNB thanwith ALND. Quality of life was found to be superior andarm-relatedmorbidity was lower for patients who had SNB.The adverse effects of each procedure diminish markedlyover the first 3 months postoperatively, and 5% to 10% ofpatients who have SNB will describe persistent severe sen-sory phenomena beyond that time, less than the percent-age of women who have the phenomena after ALND.18

Axillary web syndrome, the transient developmentof tender lymphatic cords along the upper inner arm, is along-observed but only recently described sequellum toALND and it appears to occur after SNB as well.115,119

Allergic reactions to the dye occur in no more than 1% to2% of patients who have SNB; most of these reactions arehives, which are often strikingly blue and respond to anti-histamines. True anaphylactic reactions are rare, occurringin approximately 0.25% to 0.5% of patients.120 Radiationexposure to the patient, family and friends, surgeon, staff,

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and pathologist appears to be small. For mapping witha radiolabeled colloid, an injected dose of technetium(99mTc) in the range of 0.1 to 1.0 mCi (3.7 to 37 MBq) isapproximately 4% of that administered for a conventionalbone scan.121 No isolation, precautions, or special radiationmonitoring are required.

There is little in the literature about educational mate-rials for patients and informed consent for SNB for breastcancer.122,123 More than 4,000 cases of SNB have been re-ported in the literature, and patients should know that theprocedure is widely used and accepted even though it hasbeen compared with ALND in only one recently publishedRCT.10 A review of the quality-of-life outcomes commonlyseen with each procedure will allow realistic expectations ofthe outcome of the chosen procedure.10,123 It should beexplained that outcomes improve with greater experienceof the surgeon and pathologist, and referrals to qualifiedteams should be routinely offered. While the quality-of-lifeadvantages to SNB in the short-term may be obvious, thepatient should be told that there are limited data fromcontrolled clinical trials in which the two proceduresare compared.

Interpretive SummaryThe Panel emphasizes that, despite the widespread ap-

plication of SNB for early-stage breast cancer, it is a rela-tively new procedure with wide variation in reported testperformance characteristics that are dependent on studyvolume,mapping technique, and the proportion of success-ful mappings. There are little data on other important clin-ical outcomes and only one published RCT. The Panelrecognizes that SNB is a potentially valuable diagnostic andstaging test and believes that studies in which SNB is com-pared with completion ALND are adequate to determinethe diagnostic accuracy of this new procedure. This guide-line characterizes the utility of SNB in accurately determin-ing whether axillary metastases are present; related clinicalissues of surgical experience, pathologic staging, and appro-priate patient selection can provide confidence in a negative

SNB result. The range of rates for false-negative findingsand SLN identification serve to emphasize the variabilityand learning curve of this technical procedure in differentcenters. Nevertheless, once a multidisciplinary team is ex-perienced with the procedure, reasonable levels of accuracyare achieved, with reported identification rates of morethan 95%. The Panel considers the findings from SNB asbeing an acceptably accurate assessment of the axillary sta-tus, thus permitting rational treatment decisions for a widerange of patients with early stage breast cancer. The role ofroutine IHC and/or molecular biologic analysis of the SLNremains unclear. For patients who have a positive SNB andfor patients in whom a SLN is not identified intraopera-tively, ALND should be considered standard practice untilthe results of ongoing clinical trials are evaluated. Appro-priately identified patients, successfully mapped, with anegative SNB do not require a level I or II ALND. SNB isunlikely to be appropriate for patients who have large tu-mors, and clinicians should use an individual assessment ofparticular circumstances before recommending the proce-dure in these situations. Limitations in understanding thefull role of this procedure in the management of womenwith early-stage breast cancer will not be addressed until theresults of ongoing randomized trials are available. Untilthen, it seems reasonable that SNB be performed by expe-rienced teams at properly equipped centers. Cliniciansmust continue to use their best judgment for applyingand interpreting the results of the SNB based on individ-ual patient and institutional considerations.

AcknowledgmentThe Expert Panel wishes to express its gratitude to

Charles M. Balch, MD, Andrea Eisen, MD, Frederick L.Greene, MD, Gabriel N. Hortobagyi, MD, Clifford Hudis,MD, Kevin S. Hughes, MD,MonicaMorrow, MD, CarolynD. Runowicz, MD, Lee Schwartzberg, MD, Vered Stearns,MD, and David J. Winchester, MD, for their thoughtfulreviews of earlier drafts.


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Appendix 2Lymphoscintigraphic imaging for detection of sentinel

lymph nodes. In some medical centers, lymphoscinti-graphic imaging using a gamma camera is routinely per-formed before intraoperative probe detection of radioactivityin sentinel nodes at surgery for axillary staging of breast can-cer.137 Arguments for using imaging instead of simply usinga gamma probe over the axilla at the time of surgery includethe ability of lymphoscintigraphy to define whether theradiocolloid has drained to the axilla or to other possiblesites of drainage, such as the internalmammary, intramam-mary, contralateralaxillary or supraclavicular nodes.138-140

In addition, the position of the imaged draining nodes canbe marked on the skin at the time of gamma camera imag-ing, potentially facilitating the detection of sentinel nodes atthe time of surgery with a gamma probe. Frequency ofvisualization of axillary sentinel nodes is typically in the60% to 90% range inmost centers, withmore recent studiestypically in the higher part of this range.141-143 There isconsiderable variability in the type of radiocolloid used indifferent parts of the world. Using very small particles mayresult in a higher frequency of visualization of nodes, butthis is somewhat controversial, as some studies have sug-gested larger colloids are preferable. Clearly, many colloidalpreparations can be effective in lymphoscintigraphy, and inthe United States both unfiltered and filtered 99mTc sulfurcolloid agents are normally used.137,141,144 An area of somecontroversy is whether injections for lymphoscintigraphic im-aging should only be perilesional, or whether injections in thesubdermal skin overlying the tumor, or in the periareolar area,aremost appropriate.142,145 A concern with perilesional injec-tions only is that there appears to be a significantly higher

frequency of nonvisualization of sentinel nodes versus injec-tions in the skin or periareolar region.137,142,145 In some cen-ters, injections in more than one area of the breast are given,peritumoral and periareolar, for example.141,145 Obese andelderly patients tend to have a higher frequency of false-negative lymphoscintigraphy than thinner, younger patientsin some series.142 In addition, imaging done soon after injec-tion (eg, 2 hours) will generally detect fewer positive lymphnodes than imaging done 6 to 18 hours after injection. If laterimaging, which can be performed by injections the afternoonbefore the surgery is planned, is performed, adequate dosesof 99mTc colloid must be given, typically at least 10 mBq andoften more.141-143 In general, delayed imaging detects morenodes than does early imaging.

There is substantial variability in the frequency of im-aging visualization of internal mammary nodes, rangingfromunder 10% to nearly 40% in some series. It is clear thatalthough medial breast cancers are more likely to drain tointernal mammary nodes than laterally situated tumors,there can be drainage to internal mammary nodes fromtumors located in almost any location in the breast tis-sue.140,141 The frequency of internal mammary nodal visu-alization may be dependent on the type of colloid used androute of injection as well as the time from imaging untilinjection. In most series, the use of an intraoperativegamma probe system is more sensitive than use of thegamma camera for detecting axillary sentinel nodes (ie,more sentinel nodes are identified with the probe than byimaging), as there are substantial geometric and physicalconsiderations favoring high sensitivity when a detector isplaced immediately over a focus of radioactivity, ratherthan imaging with a gamma camera from a distance

Appendix 1.

Investigator Institution

Gary H. Lyman, M.D., M.P.H. Co-Chair University of Rochester School of Medicine and DentistryArmando E. Giuliano, M.D., Co-Chair John Wayne Cancer InstituteAl B. Benson III, M.D. Northwestern UniversityDiane C. Bodurka, M.D. UT MD Anderson Cancer CenterHarold J. Burstein, M.D., Ph.D. Dana-Farber Cancer InstituteAlistair J. Cochran, M.D. David Geffen School of Medicine at UCLAHiram S. Cody III, M.D. Memorial-Sloan Kettering Cancer CenterStephen B. Edge, M.D. Roswell Park Cancer InstituteSharon Galper, M.D. Brigham and Womens HospitalJames A. Hayman, M.D. University of MichiganTheodore Y. Kim, D.O. Tufts New England Medical CenterCheryl L. Perkins, M.D., RPH The Susan G. Komen Breast Cancer FoundationDonald A. Podoloff, M.D. UT MD Anderson Cancer CenterVisaharan Sivasubramaniam, M.D. University of KentuckyRoderick R. Turner, M.D. Saint Johns Health CenterRichard Wahl, M.D. Johns Hopkins UniversityDonald L. Weaver, M.D. University of Vermont College of MedicineEric P. Winer, M.D. Dana-Farber Cancer InstituteAntonio C. Wolff, M.D. Sidney Kimmel Cancer Center at Johns Hopkins

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through a great deal of body tissue.137,141 Given the lowersensitivity of the gamma camera for detection of nodes,longer periods of time from injection until imaging areoften used than in studies using a gamma probe alone andsome imaging protocols involve injection the afternoonbefore planned surgery. Even if no lymph nodes are visual-ized on lymphoscintigraphy, probe-based detection of sen-tinel nodes should be performed as sentinel nodes can befound in the majority of cases even when negative on exter-nal gamma camera imaging. While data are limited, nonvi-sualization with a gamma camera and nondetection ofsentinel nodes by probe is a situation associated with arelatively higher frequency of tumor involvement in lymphnodes and axillary dissection may be indicated in suchcases.140,142,143,146 Small handheld gamma cameras, whichprovide an image rather than probe counts, may provideunique advantages over probe detectors alone, but are notyet in widespread use.147

Thus, lymphoscintigraphic imaging can be useful indemonstrating unexpected draining nodes, especially in theinternal mammary region and may guide probe-based sur-gery. The clinical significance of such findings may includeadditional invasive procedures to determine the nodal his-tology or the use of external-beam irradiation of internalmammary nodesdepending on the therapeutic intent. Itis clear that lymphoscintigraphy is not a substitute forprobe-based surgery but is adjunctive. Lymphoscintigraphyis, however, a routine part of the practice pattern in manycenters where it precedes and can direct the performance ofthe radionuclide guided probe-based sentinel node surgery.

Appendix 3Pathologic Evaluation of Sentinel Lymph NodesIntroduction. Sentinel node procedures are increasingly

used in the management and staging of various malignantdiseases, including breast cancer.124 For the approach to beeffective, surgeons must identify and remove all true SLNsand pathologists must carefully and systematically examinethem.Clinicians, pathologists, and patients should be awareof the significance of identifyingmetastases in lymphnodes,as well as the possibility that small metastases may bemissed. Accurate identification of node metastases is thefirm basis on which appropriate treatment decisions aremade.125 Pathologists, as part of their standard analysis,must quantify tumor burden in the nodes. This assessmentwill be increasingly important as SLN-derived informationbecomes better understood. Consistent categoric reporting,using the American Joint Commission on Cancer (AJCC)/International Union Against Cancer (UICC) staging sys-tem, facilitates uniform communication with cliniciansand, as national databases mature, analysis of outcomes.

Management of the gross specimen. Pathologists receiveeither single lymph nodes dissected free of fat or axillary fatcontaining one or more lymph nodes. Fatty nodules are

carefully dissected to identify all lymph nodes. Lymphnodes are inspected for blue color, measured, and cut intosections no thicker than 2.0 mm through and parallel to thelongest meridian. Each SLN is submitted in a separate cas-sette or identified by colored ink to permit accurate assess-ment of the total number of lymph nodes and number ofinvolved lymph nodes; all node sections are submitted formicroscopic examination. Because of the short half-life andlimited penetration of technetium, health risks to thosehandling SLNs are negligible.126

Intraoperative assessment of SLNs. Intraoperativeassessment of SLNs was used in the development of themodern SNB technique.12 It allows immediate axillary dis-section when metastasis is found in the SLN. An under-standing of the strengths and limitations of intraoperativeexamination of SLNs is critical. Approximately 75% of pa-tients considered for SNB have tumor-free lymph nodes inpermanent sections. In the 25% of patients with positivenodes, disease will not be detected intraoperatively becauseof sampling limitations and the challenge of detecting mi-crometastases. For every 100 patients who have SLNs eval-uated intraoperatively, 16 to 17 will have positive nodes and8 to 9 will have false-negative results. Each institution mustestablish a policy on intraoperative assessment or deferral topermanent sections. Both approaches are legitimate, pro-vided that patients are informed of the possibility and risksof a second surgery for completion axillary dissection. In-traoperative assessment may be by gross inspection, im-print cytology, evaluation of cells scraped from the cutsurface of the node, or frozen section. SLNs that are positiveon gross examination are most likely to be associated withpositive nonsentinel nodes. It is therefore of real value toidentify this category of SLNs early in surgicalmanagement.Immediate cytologic evaluation or frozen section can con-firm suspicious gross appearances. Cut surfaces of SLNstouched to glass slides provide cellular imprints and cell-rich scrapes of the SLN surfaces may be smeared onto aslide. A positive imprint/smear is of immediate practicalassistance, but negative imprints/smears are not definitiveevidence that a node is tumor free. Suspicious findingsshould be reported as not diagnostic for tumor and deferredto paraffin section. Intraoperative frozen sections carry therisk of significant destruction of potentially diagnostic tis-sue. However, with experienced clinicians, frozen sectionmay be the most desirable intraoperative assessment forsome surgeon/pathologist teams, providing slightly highersensitivity for detection of metastases than immediate cy-tology alone.127 The quality of frozen tissue preparations isseldom as good as those prepared from well-fixed tissue,and incomplete sections may exclude the critical subcapsu-lar sinus. Prior freezing may compromise the quality ofparaffin section histology.

Sampling SLNs. Most SLNs with macrometastases ormicrometastases are readily identified by examination of


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H&E-stained sections, an approach endorsed by leadingpathology organizations.128,129 Limited step sections fromthe block (top level plus one or two sections cut at 200- to500-m intervals into the block) enhance detection of micro-metastases by allowing evaluation of more of the subcapsularsinus, the location in which micrometastases are most oftenfound. Superficial serial sections limit sampling to the upperlevels of the block. If the SLN has been grossly sectioned asrecommended, virtually all macrometastases ( 2.0mm) andmostmicrometastases ( 0.2mm to 2.0mm)will be detectedon limitedH&E-stained step sections.130-132 In some patients,isolated tumor cells and clusters ( 0.2 mm) will also bedetected with use of this sectioning technique, particularly ifimmunohistochemical analysis (IHC) is utilized.

IHC analysis. IHC analysis may facilitate screening ofSLN sections, but the significance and practical relevance ofsmall clusters of breast cancer cells detected by this methodare debated. The use of antibodies to cytokeratin is of valuein lobular carcinoma, where tumor cells may be extensiveand closely resemble lymphoid cells. Antibodies to cytoker-atins often disclose small numbers of tumor cells not readilyvisible on H&E-stained sections.42,133 The biologic relevanceof small numbers of tumor cells is unknown, and it is hopedthat the relevance will be determined by careful analysis ofresults from ongoing clinical trials. Another guideline panelhas recommended against the use of routine IHC screen-ing134,135 The decision to utilize IHC analysis and act on theresults remains for now amatter of discussion among individ-ual surgeons, oncologists, and pathologists, based on a deter-mination of the best course for their patients, assessed fromtheir own experience and review of the available literature. IfIHC analysis is to be performed, patients should be informedof the uncertain significance of any positive results. Regardlessof the institutional decision on utilization of IHC analysis, thepathologic findings should be reported in accordance withAJCC/UICC guidelines.

Pathology reporting of SLNs. Pathologists must providesufficient information in their pathology reports to facili-tate accurate cancer staging using the criteria of the currentAJCC/UICC system.44 This information includes docu-mentation of tumor burden in the nodes. If any node me-tastasis is larger than 2.0 mm, the total number of tumor-positive nodes determines the N category. Special rulesapply if internal mammary, supraclavicular, or infraclavic-ular nodes contain tumor. Micrometastases now have anupper and lower size limit and are individual tumor depos-its larger than 0.2 mm but not larger than 2.0 mm. Thelower limit accommodates the frequency of small tumordeposit identified in SLNs.When the largest confluent focusof node tumor is no larger than 0.2 mm, regardless of themethod of detection, deposits are referred to as isolatedtumor cells or tumor cell clusters (ITC). Micrometastasesare classified as pN1mi. Isolated tumor cells or cell clustersare classified pN0 (i). A recentmodification of the staging

guidelines extends the use of the (i)modifier beyond detec-tion by IHC analysis to any metastasis of 0.2 mm or less,regardless of the method of detection.136 Careful attentionmust be given to accurately reporting the correct number oftumor-positive nodes. Bisected, trisected, or serially sectionedpositive SLNs may be over-recorded without coordinationbetween the dissector of the gross specimen and the attendingpathologist. This underscores the need to separately identifySLNs and carefully document the manner in which they aresectioned before microscopic examination.

Molecular biology. Sophisticated molecular biology ap-proaches such as the reverse transcriptase polymerase chainreaction are under active investigation for their potentialapplicability to evaluation of SLNs. These approaches arehighly sensitive and, if required, permit the evaluation ofrelatively large amounts of tissue. However, during prepa-rations for analysis, the tissues are destroyed and it is there-fore not possible to determine the cell from which anaugmented signal for tumor marker mRNA originates. Forthis reason, it is likely that such approaches will be used inparallel with histologic evaluation. For the present, suchtechniques should be evaluated within controlled studiesand are not ready to be applied in routine management.

Pathology Summary Recommendations. All true SLNsand incidental nonsentinel nodes require special attention.

1. All submitted nodes should be counted and mea-sured, with notations on the coloration and the relativeradioactive uptake reported by the surgeon.

2. Intraoperative evaluation of sentinel nodes may in-volve inspection of cut faces of the node, cytology of nodeimprints, or cell smears or frozen sections. Evaluation of theSLN is likely to be more accurate on the basis of paraffinsections.

3. Nodes are to be cut into perimeridianal (longitudi-nal) slices no thicker than 2 mm. At a minimum, full cross-sections of each SLN slice should be prepared and examinedwith H&E staining. Additional micrometastases are morelikely to be detected with step sections at 200- to 500-mintervals than with superficial serial sections alone.

4. IHC analysis with antibodies to cytokeratins facili-tates the detection of small tumor deposits. There is insuf-ficient evidence at present to recommend that IHC tocytokeratin be performed routinely. Routine IHC is notcurrently recommended for the evaluation of sentinelnodes from patients with breast cancer.

5. Reports should indicate the category of metastasisidentified and the patterns (single cells or clusters, micro-metastases, macrometastases, and so on) of tumor presentusing current AJCC/UICC criteria. The maximal size of thelargest tumor cell cluster should be recorded.

6. Molecular approaches remain investigational, andtissue potentially required for histologic diagnosis shouldnot be utilized for investigational purposes until the diag-nosis is secure.

Lyman et al



Authors Disclosures of Potential Conflicts of InterestAlthough all authors completed the disclosure declaration, the following authors or their immediate family members

indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of theinvestigation. For a detailed description of the disclosure categories, or formore information aboutASCOs conflict of interestpolicy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section inInformation for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other

Alistair J. Cochran HIH/John WayneCancer Institute (C)

Donald A. Podoloff GE Healthcare (A);IDEC (A); Bexxar

(A)

GE Healthcare (A);IDEC (A); Bexxar

(A)

GE Healthcare (A);Bexxar (A)

Richard Wahl Cardinal Health(A); GE Healthcare

(A); PhilipsMedical (A)

GE Healthcare (C)

Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

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