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Clinical role of sentinel-lymph-node biopsy in breast cancer
Review
Sentinel-lymph-node biopsy
Clinical role of sentinel-lymph-node biopsy in breast cancer Mohammed RS Keshtgar and Peter J Ell
The introduction of sentinel-lymph-node biopsy has brought new impetus to the early staging of cancer in general, and breast cancer in particular. This technique has rekindled the discussion on the present role and routine practice of axillary-lymph-node dissection in early breast cancer, the methods available for the histopathological assessment of lymph nodes, and the current thoughts about best surgical practice in the management of breast cancer. Sentinel-lymph-node biopsy has spread so rapidly that surgeons, pathologists, and patients are no longer willing or able to ignore the possible consequences of its implementation. A vast amount of data (over 1150 publications in the peer-reviewed literature on this subject to date) attests to the explosive interest in the past 5 years. In this article we review our own experience and discuss recommendations for clinical practice. Lancet Oncol 2002; 3: 105–10
The surgical management of primary breast carcinoma has become less aggressive in recent years. There is a tendency to use breast-conserving surgery without compromising local control or long-term survival. The histological status of axillary lymph nodes is still regarded as the most powerful predictor of survival in patients with breast cancer. As far as the management of the axilla is concerned, axillary-lymphnode dissection (ALND) has been the standard treatment for most of the past century, because it has a well-established role in staging, prognosis, and securing regional disease control. ALND is also said to help with rational decisionmaking on adjuvant therapy, but such therapy is also being used without reference to lymph-node status. The 1998 world overview of the Early Breast Cancer Trialists’ Collaborative Group1 on adjuvant polychemotherapy shows that the proportional risk reduction for recurrence and mortality seems to be the same for women with nodenegative and node-positive breast cancer. Nevertheless, in terms of 10-year survival, the absolute benefit is 7% for patients with node-negative disease and 11% for those with node-positive disease. Until recently, there was consensus that for small invasive breast cancers, patients would not benefit from the routine use of adjuvant chemotherapy in the absence of axillary-nodal disease. In a recent publication, Bernard Fisher and colleagues2 argue to the contrary. After analysing data from five National Surgical Breast and Bowel projects, they concluded that chemotherapy and/or tamoxifen should be considered for the treatment of women with oestrogen receptor (ER)-negative or ER-positive tumors of 1 cm or less and negative axillary lymph nodes. In THE LANCET Oncology Vol 3 February 2002
Figure 1. Sentinel-lymph-node mapping and biopsy.
light of this report, one could argue that knowledge of the axillary nodal status is not important for deciding on adjuvant systemic therapy. Since almost two thirds of patients present with an axilla that is free from disease, a less invasive approach in the staging of the axilla has been sought. Techniques such as computed tomography and ultrasonography scanning, Technetium-99m-Sestamibi scintigraphy, positron-emission tomography (PET), and magnetic resonance imaging have all been tested. There is no evidence that any of these imaging techniques can reliably reflect the true status of axillary lymph nodes in a patient with breast cancer. Patients with breast cancer now present with smaller tumours than in the past. This change reflects increased awareness by patients and the widespread use of highquality screening by mammography. The incidence of axillary nodal involvement is, therefore, also lower than before. It is difficult to justify exposing patients with breast cancer to the risk of axillary dissection, which carries significant morbidity, just to satisfy rigid criteria for staging, especially if a large proportion of patients have no axillary MRSK and PJE are both at the Department of Surgery and the Institute of Nuclear Medicine, Royal Free and University College Medical School, University College London, London, UK. Correspondence: Mr MRS Keshtgar, Department of Surgery, Middlesex Hospital, Mortimer Street, London W1T 3AA, UK. Tel: +44 (0) 20 7380 9426. Fax: +44 (0) 20 7436 0603. Email: [email protected]
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Review
Sentinel-lymph-node biopsy
Sentinel node biopsy
Selective lymphadenectomy
Figure 2. New concept of selective lymphadenectomy based on the histological status of the SLN.
involvement. When ALND is done, patients must stay in hospital for longer with significant cost implications. Lymphatic mapping and sentinel-lymph-node (SLN) biopsy represent an exciting development in surgical oncology. Successful SLN mapping and biopsy require a concerted team effort between nuclear medicine physicians, surgeons, and histopathologists. The process involves the administration of a radiopharmaceutical in the breast followed by lymphoscintigraphy. Intraoperative detection of the SLN involves a combination of blue-dye lymphatic mapping and the use of a detection probe (Figure 1). This technique introduces a new concept, namely that of selective lymphadenectomy in breast cancer on the basis of the histological status of the SLN (Figure 2). This procedure would enable the surgeon to stratify patients for appropriate surgery without exposing those without SLN metastases to unnecessary regional lymphnode dissection. The concept was pioneered by Donald Morton and colleagues3 from the John Wayne Cancer Center in Santa Monica, USA. Blue dye was used to identify the SLNs in patients with malignant melanoma. On the basis of the hypothesis that lymph flow is orderly and predictable and that tumour cells disseminate sequentially, Morton and co-workers defined the SLN as ‘any lymph node which receives direct drainage from the primary tumour’. The histological status of the SLN would reflect the status of the distant lymph-node basin, for example, in the case of the breast, this mainly reflects the status of the axilla. Giuliano and co-workers4 used this technique in earlystage breast cancer with blue dye only. Krag and associates5 used a radiopharmaceutical (radiolabelled colloid) to identify the SLN and introduced -probe-guided surgery in the operating room. Albertini and colleagues6 were the first group to use a combination of blue dye and probe-guided surgery, showing that these two techniques complement each other. SLN biopsy holds promise in the following areas: ● the investigation of the SLN will accurately predict the status of the distant lymph-node basins; ● it will allow for selection of patients before invasive axillary or internal mammary surgery; ● a large proportion of patients will be spared extensive surgery (morbidity and cost savings); and, ● it will optimise the surgical approach. 106
The SLN approach also improves staging accuracy by allowing the pathologist to do a more detailed examination of the lymph nodes that have the highest chance of harbouring metastatic disease. However, the significance of micrometastases detected by immunohistochemistry remains unclear, although analysis of the results from patients enrolled in the International (Ludwig) Breast Cancer Study7 showed significantly worse disease-free survival and overall survival of patients with nodal micrometastatic disease. The investigators concluded that the pathological examination of a single section stained with haematoxylin and eosin is ‘probably no longer clinically tenable’. They also acknowledged that processing of the specimen is an enormous task. Modern molecular-based techniques lend credence to the SLN concept. Van Trappen and colleagues8 showed that the highest copy-numbers of cytokeratin 19 occur in those lymph nodes that are nearest to the primary cancer (in this case, cervical cancer). A detailed analysis of the SLN undoubtedly increases the sensitivity of the staging procedure and allows improved detection of micrometastases. Although patients with node-negative breast cancer have relapse rates of up to 30%,9 this node negativity is based only on histology stained with haematoxylin and eosin of the ALND specimen. SLN biopsy should stimulate a more detailed examination of the SLN by serial sectioning and immunohistochemistry. Detection of micrometastases by these techniques can potentially identify this group of patients. Turner and colleagues10 provided further histological support for the SLN concept. They used cytokeratin immunohistochemistry to examine the sentinel and non-sentinel nodes in 103 patients with breast cancer. In 60 patients whose SLNs were metastases-free by haematoxylin and eosin staining and immunohistochemistry, only one additional tumour-positive lymph node was identified in 1087 non-sentinel nodes. In this series, if the sentinel node is free of tumour, as judged by haematoxylin and eosin staining and immunohistochemistry, then the probability of non-SLN involvement (assessed in the same way) is less than 0.1%. The false-negative rate was 0.97%, equating to one patient in 103. Schrenk and co-workers11 studied morbidity after SLN biopsy or ALND for patients with breast carcinoma and concluded that SLN biopsy is associated with negligible morbidity compared with complete ALND. The other potential advantages of SLN biopsy include smaller axillary incision size and improved postoperative function of the Table 1. Patient selection for sentinel-lymph-node biopsy High Risk DCIS/DCISM Non-palpable breast carcinoma T1, T2 carcinomas Special good-prognosis tumours Mucinous Papillary Colloid Adenoid cystic DCIS, ductal carcinoma in situ; DCISM, ductal carcinoma in situ with microinvasion
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Review
Sentinel-lymph-node biopsy
arm and shoulder with elimination of chronic lymphoedema. Moreover, the surgeon would be able to identify non-axillary lymphatic drainage if present. Several factors need to be taken into account when discussing the appropriateness and relevance of this technique for patients with early breast cancer. The following deserve special consideration.
Directional flow changes
False-negative SLNB
Selection of patients In a study by Silverstein and colleagues,12 which examined axillary-node positivity in 2282 patients with breast carcinoma, the frequency of nodal involvement was 0.8% in ductal carcinoma in situ (DCIS), 5% in T1a carcinoma (1.1–5.0 mm), 16% in T1b carcinoma (5.1–10.00 mm), and 28% in T1c carcinoma (10.1–20 mm). The incidence of axillary-nodal disease in T2 breast carcinoma was 47%; this proportion was substantially increased in T3 and T4 carcinoma at 68% and 86%, respectively. The study also confirmed that with widespread use of high-quality mammography and ultrasonography more non-palpable breast cancers are detected. This feature indicates a good prognosis with a considerably lower rate of axillary disease, than with palpable tumours of the same T category. DCIS represents about 20% of all breast cancers and the risk of axillary-node involvement is less than 1% based on haematoxylin and eosin staining. This risk is increased to 5% in the presence of microinvasion. Exposure of these patients to the risk of morbidity that is associated with ALND is difficult to justify. Klauber-Demore and colleagues13 performed SLN biopsy in 76 patients with DCIS. They discovered SLN involvement in nine patients (12%). In seven of these patients, there was evidence of micrometastases detected by immunohistochemical staining alone. In another group of 31 patients with DCIS and microinvasion, three patients had positive SLNs, two of which were positive for micrometastases only. Patients with tumours of a favourable histological type such as medullary, mucinous, papillary, and adenoid cystic carcinomas also have a low rate of nodal disease, and would therefore benefit from SLN biopsy. Table 1 summarises the groups of patients that are suitable for SLN biopsy. The only remaining reason for excluding patients from SLN biopsy for breast cancer is evidence of clinical involvement of the axillary nodes. Involvement of axillary nodes with metastatic carcinoma leads to mechanical obstruction of lymphatic sinuses, which in turn leads to directional flow changes and transport of radiocolloid and blue dye to a non-sentinel node. This will give a falsenegative result (Figure 3). Patients who had previously undergone excision biopsy used to be excluded from SLN biopsy, but several studies have now confirmed that these patients can safely have this procedure.14 Opinions are also changing for patients with multicentric breast carcinoma. Early trials showed a high false-negative rate. Schrenk and colleagues15 did SLN biopsy followed by ALND in 19 patients with multicentric breast carcinoma and reported a 100% concordance rate with no false-negative cases. They therefore proposed that multicentric carcinomas should not be excluded from SLN biopsy. THE LANCET Oncology Vol 3 February 2002
Figure 3. Pathophysiology of a flase negative result of sentinel-lymphnode biopsy (SLNB) due to involvement of true sentinel lymph nodes with metastatic deposits.
Technical aspects There have been variations in every step of the procedure between different groups and yet most encouraging results are reported. The tracer or radiopharmaceutical for SLN biopsy should ideally migrate from the injection site rapidly and accumulate within the SLN without substantial spill over. Most of the labelled ligands in use today are colloids, with varying particle sizes that are labelled with the standard radionuclide 99mTc. There has been some progress in the field of tracer development and work by Stadalnik and Vera16 with a synthetic macromolecule (99mTc-DTPA-mannosyldextran) deserves a particular mention. Preliminary data from animal experiments are encouraging and show that this molecule has the desired properties of rapid injectionsite clearance and high accumulation in the SLN with low distal-node accumulation. With regard to the most appropriate injection technique, there is no consensus between research groups. The most common routes of administration are peritumoral, intratumoral, and intradermal (Figure 4). In a multicentre study involving more than 2200 patients by McMasters and colleagues,17 peritumoral, subdermal, and intradermal injection techniques were compared. The investigators concluded that SLN detection was improved by intradermal injection of radiotracer. This effect was attributed to an increase in SLN radioactivity of five to seven fold. Despite differences in the success rates, there was no significant difference in the false-negative rate. A frequently voiced criticism of the intradermal injection technique is that the detection rate of internal mammary drainage is low. In a recent survey of surgical practice in the USA, only 28% of surgeons who responded said they would harvest the internal mammary SLN.18 This practice is not presently common in the UK either, although the SLN concept may change this approach in future. Most researchers advocate massaging the injection site after delivery of the radiopharmaceutical. This action encourages the migration of radioactive colloid into the
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Sentinel-lymph-node biopsy
Table 2. Potential advantages of preoperative lymphoscintigraphy Unusual sentinel location Intramammary Subscapular SLN in different lymphatic basin Internal mammary Supra/infraclavicular lymphatic basin Contralateral axilla Helps to differentiate the SLN from 2nd ecchelon Figure 4. Various techniques for delivery of the radiopharmaceutical.
Predicts success of SLN-node procedure SLN, sentinel lymph node
lymphatic system. Rosser19 has questioned the safety of SLN biopsy and has attributed an increased positive result on immunohistochemical examination of the SLN to mechanical or traumatic dislodgement of malignant epithelial cells during massage. Preoperative lymphoscintigraphy is an important part of the lymphatic mapping procedure (Table 2). Dynamic imaging is considered an essential feature of lymphoscintigraphy in malignant melanoma. In breast carcinoma there is no established role for the dynamic acquisition of the data, because of the slow particle kinetics after intraparenchymal injection of the radiotracer.20 We investigated the role of dynamic imaging in 73 patients with breast carcinoma after intradermal injection of the radiotracer and established that dynamic imaging offers little additional benefit during lymphoscintigraphy21 and therefore is not necessary. As far as intraoperative detection of the SLN is concerned, there is overwhelming evidence to support better results when both detection methods (blue dye and probe guided radionuclide SLN detection) are combined, compared with use of these techniques alone. In a study of 1000 patients from the Memorial Sloan-Kettering Cancer Center (NY, USA), Cody and colleagues22 confirm that the success of SLN identification is optimised by using dye and radionuclide methods in combination. The initial definition of a SLN was very strict and implied that only one or two nodes could be identified in patients as true SLNs. With experience, this definition is changing and the discussion between “harvesting” and “sampling” has been rekindled. McCarter and colleagues23 investigated 1561 patients and discovered that 449 of them had positive nodes. Of these 449, 440 (98%) had positive nodes within the first three SLN sites. They encountered 241 patients (15%) with more than three SLNs. In nine (2%) of the 449 node-positive patients, a positive SLN was detected at site four or more. The researchers concluded that there should be no absolute upper threshold for the number of the SLNs that need to undergo biopsy. They argued that sampling of additional nodes carries only a small increased risk of morbidity, but may alter treatment decisions considerably. Wong and colleagues24 studied the relation between the number of SLNs that had undergone biopsy and the false-negative detection rate in 1436 patients. They noted a significantly higher falsenegative rate (14.3%) in patients with a single SLN than in those who had several SLNs biopsied (4.3%). They concluded that the ability to identify multiple SLNs, when they exist, improves diagnostic accuracy of SLN biopsy. 108
There are reports on four-node sampling as a method of axillary staging. This technique has been evaluated in a randomised trial comparing axillary-node sampling with level 3 axillary clearance.25 The findings indicate that fournode sampling is a reliable procedure for staging of the axilla. The drawback is that, unlike SLN biopsy, there is no lymph node to target. Four-node sampling may be a valuable procedure in developing countries. There is no doubt that successful mapping and biopsy of the SLN are directly related to the surgeon’s experience. The American College of Surgeons Oncology Group and American Society of Breast Surgeons recommend a study of 30 patients as a minimum learning phase for accreditation. The critical issue in SLN biopsy is the false-negative detection rate as this can lead to incorrect treatment decisions in patients with early breast cancer who will mostly benefit from adjuvant therapy in the presence of axillary disease. We need to weigh up the benefit of less invasive staging against the risk of a false-negative result. Debate will continue about what might be an acceptable false-negative rate . A frequently quoted figure is 5%,26–29 although there are many variations. In a multicentre validation study involving 443 patients, Krag and co-workers30 reported a false-negative rate of 11%. Meta-analysis of the data from 6855 patients who had SLN biopsy for breast cancer shows that the falsenegative rate ranges between 5.1% and 7.6% (Table 4). In a recent national survey, Lucci and colleagues18 gave a 27-point questionnaire to 1000 randomly selected members of the American College of Surgeons (ACS). 41% of surgeons returned the questionnaires and the data are Table 3. Results of a survey* on the national practice patterns of sentinel-lymph-node biopsy in breast carcinoma18 Surgical practice
Frequency of occurrence (percentage of surgeons)
Response rate
41
Surgeons performing SLN
77
Part of clinical trials
51
Lymphoscintigraphy
60
Internal mammary
28
Combined technique
90
Immunohistochemistry
80
High grade DCIS
28
*All 1000 respondents were fellows of the American College of Surgeons. SLN, sentinel lymph node; DCIS, ductal carcinoma in situ.
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Review
Sentinel-lymph-node biopsy
Table 4. Meta-analysis of the sentinel-node studies in breast carcinoma Study lead author
Ref
Year
No. of patients
Success rate (%)
Sensitivity (%)
Specificity PPV (%)
NPV
Accuracy (%)
SLN only site False-negative of disease (%) rate (%)
McMasters
25
1998
1385
86
94
100
100
97
98
48
6.2
Miltenburg
26
1999
912
84
95
100
100
97
98
51
5.1
Martins
27
2000
758
89
94
100
100
97
98
-
5.8
Gemignani
28
2001
3800
88
93
100
100
96
97
45
7.6
PPV, positive predictive value; NPV, negative predictive value; SLN, sentinel lymph node
summarised in Table 3. When questioned about an trials that are addressing issues such as regional control, acceptable rate of false-negative results, 44% of surgeons long-term survival, morbidity, and quality of life. said that 2% false negativity was acceptable, although Whether SLN biopsy is ready to replace conventional another 2% quoted a rate of 5%. ALND is also associated ALND in breast cancer remains unclear, but there is no with a false-negative rate of up to 3%. Only 2% of surgeons doubt that the conventional thoughts in respect to ALND thought that a false-negative rate greater than 10% was have now been seriously challenged. We need to await the acceptable. It is also interesting to note that 80% of results of current trials with long-term follow-up before responders used routine immunohistochemistry, 15% accepting SLN biopsy in breast cancer as standard of care. As performed RT-PCR, and only 51% of these surgeons far as staging is concerned, there is enough evidence to were participating in clinical trials. Despite clear guidelines support the idea that this technique is a reliable staging from the ACS, 26% of surgeons abandoned ALND after investigation. Encouraging results are also emerging for having done 10 or fewer SLN biopsies during their regional control. Giuliano and colleagues32 reported on 67 patients with negative SLNs who did not have completion learning phase. At present, there are conflicting data on the prognostic ALND, and who had no regional recurrence at the median significance of detecting micrometastatic disease in the SLN, follow-up of 39 months. These results need to be validated by immunohistochemistry, how this information could be in large multicentre randomised trials. There are insufficient used in clinical practice is unclear. Should these patients be data at present for long-term survival effects to be assessed. subjected to the toxicity of adjuvant chemotherapy? Should The challenge that we face now is to ensure that patients there be further management of the axilla? The effects on with positive SLNs have their nodes removed and receive regional disease control and long-term survival are also appropriate adjuvant treatment and those with negative unclear. The outcomes of randomised multicentre trials are nodes have least disturbance of the axilla. eagerly awaited and should help to clarify some of these issues. Management algorithm Although the results of SLN biopsy studies in breast On the basis of current evidence for axillary management carcinoma are promising, there is still a need to take a strategy, we propose that patients with high-risk DCIS and cautious approach in implementing this technique as best DCIS with microinvasion, T1a, T1b invasive carcinoma, and practice. Braun and colleagues31 studied the effect of good-prognosis histological carcinoma, should proceed with cytokeratin-positive cells in the bone marrow on survival of SLN biopsy only, and further axillary management should patients with breast cancer. They obtained bone-marrow be decided on the basis of the SLN histology. In T1c and T2 aspirates from the iliac crests of 552 patients and found that carcinoma it is important to ensure that SLN biopsy is done in 199 (36%) there was evidence of occult metastases. There in a clinical trial setting because this technique is still not was no association between the lymph-node histological status and the presence of micrometstases in the High risk DCIS/DCISM T1c & T2 invasive bone marrow. Patients were followedGood prognosis tumours carcinoma up for 4 years, and those who had (mucinous, papillary, colloid) (1·0–5·0 cm) T1a & T1b invasive carcinoma (< 1·0 cm) occult metastatic cells in their bone marrow had worse prognosis than the group without micrometastasis. In this study, the axillary nodes were not scrutinised in as much detail as bone marrow and a comparison was not SLN biopsy SLN biopsy alone drawn with the SLN. A trial of the Proceed with ALND within randomised American College of Surgeons only if SLN positive controlled trials. If SLN positive: Oncology Group (AZ001) is investproceed with ALND. igating bone-marrow and SLN If SLN negative: analyses and their effect on long-term observe. survival. There are other multicentre randomised trials underway, includ- Figure 5. Management algorithm. DCIS, ductal carcinoma in situ; DCISM, ductal carcinoma in situ ing ALMANAC, NSABP, and EORTC with microinvasion; ALND, axillary-lymph-node dissection; SLN, sentinel lymph node. THE LANCET Oncology Vol 3 February 2002
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Review
Sentinel-lymph-node biopsy
Search strategy and selection criteria Referenced papers were identified through searches of MEDLINE and PubMed up to July 2001. Search terms included ‘sentinel node’, ‘breast cancer’, and ‘axilla’. Additional references were selected from the retrieved papers. From this search, we cite the 32 most relevant peer-reviewed studies with statistical power, meta-analysis studies, and data published in mainstream surgical, clinical, and oncological journals. The review also reflects the 5-year experience of the authors in this field.
considered the standard of care. The decision on axillary management should be based on the histological status of the SLN (Figure 5). Surgeons need to ensure that they gain experience of completion lymphadenectomy during the learning phase and carefully audit their results. References
1 Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. The Lancet 1998; 352: 930–42. 2 Fisher B, Dignam J, Tan-Chiu E et al. Prognosis and treatment of patients with breast tumours of one centimeter or less and negative axillary nodes. J Natl Cancer Inst 2001; 93: 112–20. 3 Morton D, Wen D, Wong J, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127: 392–99. 4 Giuliano AE, Kirgan DM, Guenther JM, et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994; 220: 391–98. 5 Krag DN, Weaver DL, Alex JC, et al. Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surgl Oncol 1993; 2: 335–40. 6 Albertini JJ, Lyman GH, Cox C, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 1996; 276: 1818–22. 7 Ludwig Breast Cancer Study Group. Prognostic importance of occult axillary-lymph-node micrometastases from breast cancers. The Lancet 1990; 335: 1565–58. 8 van Trappen PO, Gyselman VG, Lowe DG et al. Molecular quantification and mapping of lymph node micrometastases in cervical cancer. Lancet 2001; 357: 15–20. 9 Rosen PP, Groshen S, Saigo PE, et al. A long term follow up study of survival in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma. J Clin Oncol 1989; 7: 355–66. 10 Turner RR, Ollila DW, Krasne DL et al. Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg 1997; 226: 271–78. 11 Schrenk P, Shamiyeh A, Wayand W. Sentinel lymph node biopsy compared to axillary lymph-node dissection for axillary staging in breast cancer patients. Eur J Surg Oncol 2001; 27: 378–82. 12 Silverstein MJ, Skinner KA, Lomis TJ. Predicting axillary nodal positivity in 2282 patients with breast cancer World J Surg 2001; 25: 767–72.
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13 Klauber-Demore N, Tan LK, Liberman L et al. Sentinel lymph node biopsy: is it indicated in patients with high risk ductal-carcinomain-situ and ductal-carcinoma-in-situ with microinvasion? Ann Surg Oncol 2000; 7: 636–42. 14 Miner TJ, Shriver CD, Jacques DP et al. Sentinel lymph node biopsy for breast cancer: the role of previous biopsy on patient eligibility. Am Surg 1999; 65: 493–39. 15 Schrenk P, Wayand W. Sentinel-node biopsy in axillary lymphnode staging for patients with multicentric breast cancer. Lancet 2001; 357: 122. 16 Stadalnik RC, Vera DR. The evolution of Tc-99m-NGA as a clinically useful receptor-binding radiopharmaceutical. Nucl Med Biol 2001; 28: 499–503. 17 McMasters KM, Wong SL, Martin RC, et al. Dermal injection of radioactive colloid is superior to peritumoral injection for breast cancer sentinel lymph node biopsy: results of a multiinstitutional study. Ann Surg 2001; 233: 676–87. 18 Lucci A, Kelemen PR, Miller III C, et al. National practice patterns of sentinel lymph node dissection for breast carcinoma. J Am Coll Surg 2001; 192: 453–58. 19 Rosser RJ. Safety of sentinel lymph node dissection and significance of cytokeratin micrometatases. J Clin Oncol 2001; 19: 1882–83. 20 Keshtgar MRS, Ell PJ. Sentinel node detection and imaging. Eur J Nuc Med 1999; 26: 57–67. 21 Keshtgar M, Waddington W, Ell PJ, et al. The role of dynamic imaging in sentinel node biopsy in breast cancer. Eur J Cancer 2001; 37: 17–18. 22 Cody HS, Fey J, Akhurst T, et al. Complementarity of blue dye and isotope in sentinel node localization for breast cancer: univariate and multivariate analysis of 966 procedures. Ann Surg Oncol 2001; 8: 13–19. 23 McCarter MD, Yeung H, Fey J, Borgen PI, et al. The breast cancer patient with multiple sentinel nodes: when to stop? J Am Coll Surg 2001; 192: 692–27. 24 Wong SL, Edwards MJ, Chao C, et al. Sentinel lymph node biopsy for breast cancer: impact of number of sentinel nodes removed on false negative rate. J Am Coll Surg 2001; 192: 684–89. 25 Forrest APM, Everington D, McDonald CC, et al. The Edinburgh randomised trial of axillary sample or clearance after mastectomy. Br J Surg 1995; 82: 1504. 26 McMasters KM, Giuliano AE, Ross MI, et al. Sentinel-lymph-node biopsy for breast cancer-not yet the standard of care. N Engl J Med 1998; 339: 990–95. 27 Miltenburg DM, Miller C, Karamlou TB, et al. Meta-analysis of sentinel node biopsy in breast cancer. J Surg Res 1999; 84: 138–42. 28 Martin RCG, Edwards MJ, Wong SL, et al. Practical guidelines for optimal gamma probe detection of sentinel lymph nodes in breast cancer: results of multi-institutional study. Surgery 2000; 128: 139–44. 29 Gemignani ML, Borgen PI. Is there a role for selective lymph node dissection in breast cancer? World J Surg 2001; 25: 809–18. 30 Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer–a multicenter validation study. N Engl J Med 1998; 339: 941–46. 31 Braun S, Pantel K, Muller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000; 342: 525–33. 32 Giuliano AE, Haigh PI, Brennab MB, et al. Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer. J Clin Oncol 2000; 18: 2553–59.
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Sentinel-lymph-node biopsy
Clinical role of sentinel-lymph-node biopsy in breast cancer Mohammed RS Keshtgar and Peter J Ell
The introduction of sentinel-lymph-node biopsy has brought new impetus to the early staging of cancer in general, and breast cancer in particular. This technique has rekindled the discussion on the present role and routine practice of axillary-lymph-node dissection in early breast cancer, the methods available for the histopathological assessment of lymph nodes, and the current thoughts about best surgical practice in the management of breast cancer. Sentinel-lymph-node biopsy has spread so rapidly that surgeons, pathologists, and patients are no longer willing or able to ignore the possible consequences of its implementation. A vast amount of data (over 1150 publications in the peer-reviewed literature on this subject to date) attests to the explosive interest in the past 5 years. In this article we review our own experience and discuss recommendations for clinical practice. Lancet Oncol 2002; 3: 105–10
The surgical management of primary breast carcinoma has become less aggressive in recent years. There is a tendency to use breast-conserving surgery without compromising local control or long-term survival. The histological status of axillary lymph nodes is still regarded as the most powerful predictor of survival in patients with breast cancer. As far as the management of the axilla is concerned, axillary-lymphnode dissection (ALND) has been the standard treatment for most of the past century, because it has a well-established role in staging, prognosis, and securing regional disease control. ALND is also said to help with rational decisionmaking on adjuvant therapy, but such therapy is also being used without reference to lymph-node status. The 1998 world overview of the Early Breast Cancer Trialists’ Collaborative Group1 on adjuvant polychemotherapy shows that the proportional risk reduction for recurrence and mortality seems to be the same for women with nodenegative and node-positive breast cancer. Nevertheless, in terms of 10-year survival, the absolute benefit is 7% for patients with node-negative disease and 11% for those with node-positive disease. Until recently, there was consensus that for small invasive breast cancers, patients would not benefit from the routine use of adjuvant chemotherapy in the absence of axillary-nodal disease. In a recent publication, Bernard Fisher and colleagues2 argue to the contrary. After analysing data from five National Surgical Breast and Bowel projects, they concluded that chemotherapy and/or tamoxifen should be considered for the treatment of women with oestrogen receptor (ER)-negative or ER-positive tumors of 1 cm or less and negative axillary lymph nodes. In THE LANCET Oncology Vol 3 February 2002
Figure 1. Sentinel-lymph-node mapping and biopsy.
light of this report, one could argue that knowledge of the axillary nodal status is not important for deciding on adjuvant systemic therapy. Since almost two thirds of patients present with an axilla that is free from disease, a less invasive approach in the staging of the axilla has been sought. Techniques such as computed tomography and ultrasonography scanning, Technetium-99m-Sestamibi scintigraphy, positron-emission tomography (PET), and magnetic resonance imaging have all been tested. There is no evidence that any of these imaging techniques can reliably reflect the true status of axillary lymph nodes in a patient with breast cancer. Patients with breast cancer now present with smaller tumours than in the past. This change reflects increased awareness by patients and the widespread use of highquality screening by mammography. The incidence of axillary nodal involvement is, therefore, also lower than before. It is difficult to justify exposing patients with breast cancer to the risk of axillary dissection, which carries significant morbidity, just to satisfy rigid criteria for staging, especially if a large proportion of patients have no axillary MRSK and PJE are both at the Department of Surgery and the Institute of Nuclear Medicine, Royal Free and University College Medical School, University College London, London, UK. Correspondence: Mr MRS Keshtgar, Department of Surgery, Middlesex Hospital, Mortimer Street, London W1T 3AA, UK. Tel: +44 (0) 20 7380 9426. Fax: +44 (0) 20 7436 0603. Email: [email protected]
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Sentinel-lymph-node biopsy
Sentinel node biopsy
Selective lymphadenectomy
Figure 2. New concept of selective lymphadenectomy based on the histological status of the SLN.
involvement. When ALND is done, patients must stay in hospital for longer with significant cost implications. Lymphatic mapping and sentinel-lymph-node (SLN) biopsy represent an exciting development in surgical oncology. Successful SLN mapping and biopsy require a concerted team effort between nuclear medicine physicians, surgeons, and histopathologists. The process involves the administration of a radiopharmaceutical in the breast followed by lymphoscintigraphy. Intraoperative detection of the SLN involves a combination of blue-dye lymphatic mapping and the use of a detection probe (Figure 1). This technique introduces a new concept, namely that of selective lymphadenectomy in breast cancer on the basis of the histological status of the SLN (Figure 2). This procedure would enable the surgeon to stratify patients for appropriate surgery without exposing those without SLN metastases to unnecessary regional lymphnode dissection. The concept was pioneered by Donald Morton and colleagues3 from the John Wayne Cancer Center in Santa Monica, USA. Blue dye was used to identify the SLNs in patients with malignant melanoma. On the basis of the hypothesis that lymph flow is orderly and predictable and that tumour cells disseminate sequentially, Morton and co-workers defined the SLN as ‘any lymph node which receives direct drainage from the primary tumour’. The histological status of the SLN would reflect the status of the distant lymph-node basin, for example, in the case of the breast, this mainly reflects the status of the axilla. Giuliano and co-workers4 used this technique in earlystage breast cancer with blue dye only. Krag and associates5 used a radiopharmaceutical (radiolabelled colloid) to identify the SLN and introduced -probe-guided surgery in the operating room. Albertini and colleagues6 were the first group to use a combination of blue dye and probe-guided surgery, showing that these two techniques complement each other. SLN biopsy holds promise in the following areas: ● the investigation of the SLN will accurately predict the status of the distant lymph-node basins; ● it will allow for selection of patients before invasive axillary or internal mammary surgery; ● a large proportion of patients will be spared extensive surgery (morbidity and cost savings); and, ● it will optimise the surgical approach. 106
The SLN approach also improves staging accuracy by allowing the pathologist to do a more detailed examination of the lymph nodes that have the highest chance of harbouring metastatic disease. However, the significance of micrometastases detected by immunohistochemistry remains unclear, although analysis of the results from patients enrolled in the International (Ludwig) Breast Cancer Study7 showed significantly worse disease-free survival and overall survival of patients with nodal micrometastatic disease. The investigators concluded that the pathological examination of a single section stained with haematoxylin and eosin is ‘probably no longer clinically tenable’. They also acknowledged that processing of the specimen is an enormous task. Modern molecular-based techniques lend credence to the SLN concept. Van Trappen and colleagues8 showed that the highest copy-numbers of cytokeratin 19 occur in those lymph nodes that are nearest to the primary cancer (in this case, cervical cancer). A detailed analysis of the SLN undoubtedly increases the sensitivity of the staging procedure and allows improved detection of micrometastases. Although patients with node-negative breast cancer have relapse rates of up to 30%,9 this node negativity is based only on histology stained with haematoxylin and eosin of the ALND specimen. SLN biopsy should stimulate a more detailed examination of the SLN by serial sectioning and immunohistochemistry. Detection of micrometastases by these techniques can potentially identify this group of patients. Turner and colleagues10 provided further histological support for the SLN concept. They used cytokeratin immunohistochemistry to examine the sentinel and non-sentinel nodes in 103 patients with breast cancer. In 60 patients whose SLNs were metastases-free by haematoxylin and eosin staining and immunohistochemistry, only one additional tumour-positive lymph node was identified in 1087 non-sentinel nodes. In this series, if the sentinel node is free of tumour, as judged by haematoxylin and eosin staining and immunohistochemistry, then the probability of non-SLN involvement (assessed in the same way) is less than 0.1%. The false-negative rate was 0.97%, equating to one patient in 103. Schrenk and co-workers11 studied morbidity after SLN biopsy or ALND for patients with breast carcinoma and concluded that SLN biopsy is associated with negligible morbidity compared with complete ALND. The other potential advantages of SLN biopsy include smaller axillary incision size and improved postoperative function of the Table 1. Patient selection for sentinel-lymph-node biopsy High Risk DCIS/DCISM Non-palpable breast carcinoma T1, T2 carcinomas Special good-prognosis tumours Mucinous Papillary Colloid Adenoid cystic DCIS, ductal carcinoma in situ; DCISM, ductal carcinoma in situ with microinvasion
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arm and shoulder with elimination of chronic lymphoedema. Moreover, the surgeon would be able to identify non-axillary lymphatic drainage if present. Several factors need to be taken into account when discussing the appropriateness and relevance of this technique for patients with early breast cancer. The following deserve special consideration.
Directional flow changes
False-negative SLNB
Selection of patients In a study by Silverstein and colleagues,12 which examined axillary-node positivity in 2282 patients with breast carcinoma, the frequency of nodal involvement was 0.8% in ductal carcinoma in situ (DCIS), 5% in T1a carcinoma (1.1–5.0 mm), 16% in T1b carcinoma (5.1–10.00 mm), and 28% in T1c carcinoma (10.1–20 mm). The incidence of axillary-nodal disease in T2 breast carcinoma was 47%; this proportion was substantially increased in T3 and T4 carcinoma at 68% and 86%, respectively. The study also confirmed that with widespread use of high-quality mammography and ultrasonography more non-palpable breast cancers are detected. This feature indicates a good prognosis with a considerably lower rate of axillary disease, than with palpable tumours of the same T category. DCIS represents about 20% of all breast cancers and the risk of axillary-node involvement is less than 1% based on haematoxylin and eosin staining. This risk is increased to 5% in the presence of microinvasion. Exposure of these patients to the risk of morbidity that is associated with ALND is difficult to justify. Klauber-Demore and colleagues13 performed SLN biopsy in 76 patients with DCIS. They discovered SLN involvement in nine patients (12%). In seven of these patients, there was evidence of micrometastases detected by immunohistochemical staining alone. In another group of 31 patients with DCIS and microinvasion, three patients had positive SLNs, two of which were positive for micrometastases only. Patients with tumours of a favourable histological type such as medullary, mucinous, papillary, and adenoid cystic carcinomas also have a low rate of nodal disease, and would therefore benefit from SLN biopsy. Table 1 summarises the groups of patients that are suitable for SLN biopsy. The only remaining reason for excluding patients from SLN biopsy for breast cancer is evidence of clinical involvement of the axillary nodes. Involvement of axillary nodes with metastatic carcinoma leads to mechanical obstruction of lymphatic sinuses, which in turn leads to directional flow changes and transport of radiocolloid and blue dye to a non-sentinel node. This will give a falsenegative result (Figure 3). Patients who had previously undergone excision biopsy used to be excluded from SLN biopsy, but several studies have now confirmed that these patients can safely have this procedure.14 Opinions are also changing for patients with multicentric breast carcinoma. Early trials showed a high false-negative rate. Schrenk and colleagues15 did SLN biopsy followed by ALND in 19 patients with multicentric breast carcinoma and reported a 100% concordance rate with no false-negative cases. They therefore proposed that multicentric carcinomas should not be excluded from SLN biopsy. THE LANCET Oncology Vol 3 February 2002
Figure 3. Pathophysiology of a flase negative result of sentinel-lymphnode biopsy (SLNB) due to involvement of true sentinel lymph nodes with metastatic deposits.
Technical aspects There have been variations in every step of the procedure between different groups and yet most encouraging results are reported. The tracer or radiopharmaceutical for SLN biopsy should ideally migrate from the injection site rapidly and accumulate within the SLN without substantial spill over. Most of the labelled ligands in use today are colloids, with varying particle sizes that are labelled with the standard radionuclide 99mTc. There has been some progress in the field of tracer development and work by Stadalnik and Vera16 with a synthetic macromolecule (99mTc-DTPA-mannosyldextran) deserves a particular mention. Preliminary data from animal experiments are encouraging and show that this molecule has the desired properties of rapid injectionsite clearance and high accumulation in the SLN with low distal-node accumulation. With regard to the most appropriate injection technique, there is no consensus between research groups. The most common routes of administration are peritumoral, intratumoral, and intradermal (Figure 4). In a multicentre study involving more than 2200 patients by McMasters and colleagues,17 peritumoral, subdermal, and intradermal injection techniques were compared. The investigators concluded that SLN detection was improved by intradermal injection of radiotracer. This effect was attributed to an increase in SLN radioactivity of five to seven fold. Despite differences in the success rates, there was no significant difference in the false-negative rate. A frequently voiced criticism of the intradermal injection technique is that the detection rate of internal mammary drainage is low. In a recent survey of surgical practice in the USA, only 28% of surgeons who responded said they would harvest the internal mammary SLN.18 This practice is not presently common in the UK either, although the SLN concept may change this approach in future. Most researchers advocate massaging the injection site after delivery of the radiopharmaceutical. This action encourages the migration of radioactive colloid into the
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Table 2. Potential advantages of preoperative lymphoscintigraphy Unusual sentinel location Intramammary Subscapular SLN in different lymphatic basin Internal mammary Supra/infraclavicular lymphatic basin Contralateral axilla Helps to differentiate the SLN from 2nd ecchelon Figure 4. Various techniques for delivery of the radiopharmaceutical.
Predicts success of SLN-node procedure SLN, sentinel lymph node
lymphatic system. Rosser19 has questioned the safety of SLN biopsy and has attributed an increased positive result on immunohistochemical examination of the SLN to mechanical or traumatic dislodgement of malignant epithelial cells during massage. Preoperative lymphoscintigraphy is an important part of the lymphatic mapping procedure (Table 2). Dynamic imaging is considered an essential feature of lymphoscintigraphy in malignant melanoma. In breast carcinoma there is no established role for the dynamic acquisition of the data, because of the slow particle kinetics after intraparenchymal injection of the radiotracer.20 We investigated the role of dynamic imaging in 73 patients with breast carcinoma after intradermal injection of the radiotracer and established that dynamic imaging offers little additional benefit during lymphoscintigraphy21 and therefore is not necessary. As far as intraoperative detection of the SLN is concerned, there is overwhelming evidence to support better results when both detection methods (blue dye and probe guided radionuclide SLN detection) are combined, compared with use of these techniques alone. In a study of 1000 patients from the Memorial Sloan-Kettering Cancer Center (NY, USA), Cody and colleagues22 confirm that the success of SLN identification is optimised by using dye and radionuclide methods in combination. The initial definition of a SLN was very strict and implied that only one or two nodes could be identified in patients as true SLNs. With experience, this definition is changing and the discussion between “harvesting” and “sampling” has been rekindled. McCarter and colleagues23 investigated 1561 patients and discovered that 449 of them had positive nodes. Of these 449, 440 (98%) had positive nodes within the first three SLN sites. They encountered 241 patients (15%) with more than three SLNs. In nine (2%) of the 449 node-positive patients, a positive SLN was detected at site four or more. The researchers concluded that there should be no absolute upper threshold for the number of the SLNs that need to undergo biopsy. They argued that sampling of additional nodes carries only a small increased risk of morbidity, but may alter treatment decisions considerably. Wong and colleagues24 studied the relation between the number of SLNs that had undergone biopsy and the false-negative detection rate in 1436 patients. They noted a significantly higher falsenegative rate (14.3%) in patients with a single SLN than in those who had several SLNs biopsied (4.3%). They concluded that the ability to identify multiple SLNs, when they exist, improves diagnostic accuracy of SLN biopsy. 108
There are reports on four-node sampling as a method of axillary staging. This technique has been evaluated in a randomised trial comparing axillary-node sampling with level 3 axillary clearance.25 The findings indicate that fournode sampling is a reliable procedure for staging of the axilla. The drawback is that, unlike SLN biopsy, there is no lymph node to target. Four-node sampling may be a valuable procedure in developing countries. There is no doubt that successful mapping and biopsy of the SLN are directly related to the surgeon’s experience. The American College of Surgeons Oncology Group and American Society of Breast Surgeons recommend a study of 30 patients as a minimum learning phase for accreditation. The critical issue in SLN biopsy is the false-negative detection rate as this can lead to incorrect treatment decisions in patients with early breast cancer who will mostly benefit from adjuvant therapy in the presence of axillary disease. We need to weigh up the benefit of less invasive staging against the risk of a false-negative result. Debate will continue about what might be an acceptable false-negative rate . A frequently quoted figure is 5%,26–29 although there are many variations. In a multicentre validation study involving 443 patients, Krag and co-workers30 reported a false-negative rate of 11%. Meta-analysis of the data from 6855 patients who had SLN biopsy for breast cancer shows that the falsenegative rate ranges between 5.1% and 7.6% (Table 4). In a recent national survey, Lucci and colleagues18 gave a 27-point questionnaire to 1000 randomly selected members of the American College of Surgeons (ACS). 41% of surgeons returned the questionnaires and the data are Table 3. Results of a survey* on the national practice patterns of sentinel-lymph-node biopsy in breast carcinoma18 Surgical practice
Frequency of occurrence (percentage of surgeons)
Response rate
41
Surgeons performing SLN
77
Part of clinical trials
51
Lymphoscintigraphy
60
Internal mammary
28
Combined technique
90
Immunohistochemistry
80
High grade DCIS
28
*All 1000 respondents were fellows of the American College of Surgeons. SLN, sentinel lymph node; DCIS, ductal carcinoma in situ.
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Table 4. Meta-analysis of the sentinel-node studies in breast carcinoma Study lead author
Ref
Year
No. of patients
Success rate (%)
Sensitivity (%)
Specificity PPV (%)
NPV
Accuracy (%)
SLN only site False-negative of disease (%) rate (%)
McMasters
25
1998
1385
86
94
100
100
97
98
48
6.2
Miltenburg
26
1999
912
84
95
100
100
97
98
51
5.1
Martins
27
2000
758
89
94
100
100
97
98
-
5.8
Gemignani
28
2001
3800
88
93
100
100
96
97
45
7.6
PPV, positive predictive value; NPV, negative predictive value; SLN, sentinel lymph node
summarised in Table 3. When questioned about an trials that are addressing issues such as regional control, acceptable rate of false-negative results, 44% of surgeons long-term survival, morbidity, and quality of life. said that 2% false negativity was acceptable, although Whether SLN biopsy is ready to replace conventional another 2% quoted a rate of 5%. ALND is also associated ALND in breast cancer remains unclear, but there is no with a false-negative rate of up to 3%. Only 2% of surgeons doubt that the conventional thoughts in respect to ALND thought that a false-negative rate greater than 10% was have now been seriously challenged. We need to await the acceptable. It is also interesting to note that 80% of results of current trials with long-term follow-up before responders used routine immunohistochemistry, 15% accepting SLN biopsy in breast cancer as standard of care. As performed RT-PCR, and only 51% of these surgeons far as staging is concerned, there is enough evidence to were participating in clinical trials. Despite clear guidelines support the idea that this technique is a reliable staging from the ACS, 26% of surgeons abandoned ALND after investigation. Encouraging results are also emerging for having done 10 or fewer SLN biopsies during their regional control. Giuliano and colleagues32 reported on 67 patients with negative SLNs who did not have completion learning phase. At present, there are conflicting data on the prognostic ALND, and who had no regional recurrence at the median significance of detecting micrometastatic disease in the SLN, follow-up of 39 months. These results need to be validated by immunohistochemistry, how this information could be in large multicentre randomised trials. There are insufficient used in clinical practice is unclear. Should these patients be data at present for long-term survival effects to be assessed. subjected to the toxicity of adjuvant chemotherapy? Should The challenge that we face now is to ensure that patients there be further management of the axilla? The effects on with positive SLNs have their nodes removed and receive regional disease control and long-term survival are also appropriate adjuvant treatment and those with negative unclear. The outcomes of randomised multicentre trials are nodes have least disturbance of the axilla. eagerly awaited and should help to clarify some of these issues. Management algorithm Although the results of SLN biopsy studies in breast On the basis of current evidence for axillary management carcinoma are promising, there is still a need to take a strategy, we propose that patients with high-risk DCIS and cautious approach in implementing this technique as best DCIS with microinvasion, T1a, T1b invasive carcinoma, and practice. Braun and colleagues31 studied the effect of good-prognosis histological carcinoma, should proceed with cytokeratin-positive cells in the bone marrow on survival of SLN biopsy only, and further axillary management should patients with breast cancer. They obtained bone-marrow be decided on the basis of the SLN histology. In T1c and T2 aspirates from the iliac crests of 552 patients and found that carcinoma it is important to ensure that SLN biopsy is done in 199 (36%) there was evidence of occult metastases. There in a clinical trial setting because this technique is still not was no association between the lymph-node histological status and the presence of micrometstases in the High risk DCIS/DCISM T1c & T2 invasive bone marrow. Patients were followedGood prognosis tumours carcinoma up for 4 years, and those who had (mucinous, papillary, colloid) (1·0–5·0 cm) T1a & T1b invasive carcinoma (< 1·0 cm) occult metastatic cells in their bone marrow had worse prognosis than the group without micrometastasis. In this study, the axillary nodes were not scrutinised in as much detail as bone marrow and a comparison was not SLN biopsy SLN biopsy alone drawn with the SLN. A trial of the Proceed with ALND within randomised American College of Surgeons only if SLN positive controlled trials. If SLN positive: Oncology Group (AZ001) is investproceed with ALND. igating bone-marrow and SLN If SLN negative: analyses and their effect on long-term observe. survival. There are other multicentre randomised trials underway, includ- Figure 5. Management algorithm. DCIS, ductal carcinoma in situ; DCISM, ductal carcinoma in situ ing ALMANAC, NSABP, and EORTC with microinvasion; ALND, axillary-lymph-node dissection; SLN, sentinel lymph node. THE LANCET Oncology Vol 3 February 2002
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Search strategy and selection criteria Referenced papers were identified through searches of MEDLINE and PubMed up to July 2001. Search terms included ‘sentinel node’, ‘breast cancer’, and ‘axilla’. Additional references were selected from the retrieved papers. From this search, we cite the 32 most relevant peer-reviewed studies with statistical power, meta-analysis studies, and data published in mainstream surgical, clinical, and oncological journals. The review also reflects the 5-year experience of the authors in this field.
considered the standard of care. The decision on axillary management should be based on the histological status of the SLN (Figure 5). Surgeons need to ensure that they gain experience of completion lymphadenectomy during the learning phase and carefully audit their results. References
1 Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. The Lancet 1998; 352: 930–42. 2 Fisher B, Dignam J, Tan-Chiu E et al. Prognosis and treatment of patients with breast tumours of one centimeter or less and negative axillary nodes. J Natl Cancer Inst 2001; 93: 112–20. 3 Morton D, Wen D, Wong J, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127: 392–99. 4 Giuliano AE, Kirgan DM, Guenther JM, et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994; 220: 391–98. 5 Krag DN, Weaver DL, Alex JC, et al. Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surgl Oncol 1993; 2: 335–40. 6 Albertini JJ, Lyman GH, Cox C, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 1996; 276: 1818–22. 7 Ludwig Breast Cancer Study Group. Prognostic importance of occult axillary-lymph-node micrometastases from breast cancers. The Lancet 1990; 335: 1565–58. 8 van Trappen PO, Gyselman VG, Lowe DG et al. Molecular quantification and mapping of lymph node micrometastases in cervical cancer. Lancet 2001; 357: 15–20. 9 Rosen PP, Groshen S, Saigo PE, et al. A long term follow up study of survival in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma. J Clin Oncol 1989; 7: 355–66. 10 Turner RR, Ollila DW, Krasne DL et al. Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg 1997; 226: 271–78. 11 Schrenk P, Shamiyeh A, Wayand W. Sentinel lymph node biopsy compared to axillary lymph-node dissection for axillary staging in breast cancer patients. Eur J Surg Oncol 2001; 27: 378–82. 12 Silverstein MJ, Skinner KA, Lomis TJ. Predicting axillary nodal positivity in 2282 patients with breast cancer World J Surg 2001; 25: 767–72.
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13 Klauber-Demore N, Tan LK, Liberman L et al. Sentinel lymph node biopsy: is it indicated in patients with high risk ductal-carcinomain-situ and ductal-carcinoma-in-situ with microinvasion? Ann Surg Oncol 2000; 7: 636–42. 14 Miner TJ, Shriver CD, Jacques DP et al. Sentinel lymph node biopsy for breast cancer: the role of previous biopsy on patient eligibility. Am Surg 1999; 65: 493–39. 15 Schrenk P, Wayand W. Sentinel-node biopsy in axillary lymphnode staging for patients with multicentric breast cancer. Lancet 2001; 357: 122. 16 Stadalnik RC, Vera DR. The evolution of Tc-99m-NGA as a clinically useful receptor-binding radiopharmaceutical. Nucl Med Biol 2001; 28: 499–503. 17 McMasters KM, Wong SL, Martin RC, et al. Dermal injection of radioactive colloid is superior to peritumoral injection for breast cancer sentinel lymph node biopsy: results of a multiinstitutional study. Ann Surg 2001; 233: 676–87. 18 Lucci A, Kelemen PR, Miller III C, et al. National practice patterns of sentinel lymph node dissection for breast carcinoma. J Am Coll Surg 2001; 192: 453–58. 19 Rosser RJ. Safety of sentinel lymph node dissection and significance of cytokeratin micrometatases. J Clin Oncol 2001; 19: 1882–83. 20 Keshtgar MRS, Ell PJ. Sentinel node detection and imaging. Eur J Nuc Med 1999; 26: 57–67. 21 Keshtgar M, Waddington W, Ell PJ, et al. The role of dynamic imaging in sentinel node biopsy in breast cancer. Eur J Cancer 2001; 37: 17–18. 22 Cody HS, Fey J, Akhurst T, et al. Complementarity of blue dye and isotope in sentinel node localization for breast cancer: univariate and multivariate analysis of 966 procedures. Ann Surg Oncol 2001; 8: 13–19. 23 McCarter MD, Yeung H, Fey J, Borgen PI, et al. The breast cancer patient with multiple sentinel nodes: when to stop? J Am Coll Surg 2001; 192: 692–27. 24 Wong SL, Edwards MJ, Chao C, et al. Sentinel lymph node biopsy for breast cancer: impact of number of sentinel nodes removed on false negative rate. J Am Coll Surg 2001; 192: 684–89. 25 Forrest APM, Everington D, McDonald CC, et al. The Edinburgh randomised trial of axillary sample or clearance after mastectomy. Br J Surg 1995; 82: 1504. 26 McMasters KM, Giuliano AE, Ross MI, et al. Sentinel-lymph-node biopsy for breast cancer-not yet the standard of care. N Engl J Med 1998; 339: 990–95. 27 Miltenburg DM, Miller C, Karamlou TB, et al. Meta-analysis of sentinel node biopsy in breast cancer. J Surg Res 1999; 84: 138–42. 28 Martin RCG, Edwards MJ, Wong SL, et al. Practical guidelines for optimal gamma probe detection of sentinel lymph nodes in breast cancer: results of multi-institutional study. Surgery 2000; 128: 139–44. 29 Gemignani ML, Borgen PI. Is there a role for selective lymph node dissection in breast cancer? World J Surg 2001; 25: 809–18. 30 Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer–a multicenter validation study. N Engl J Med 1998; 339: 941–46. 31 Braun S, Pantel K, Muller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000; 342: 525–33. 32 Giuliano AE, Haigh PI, Brennab MB, et al. Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer. J Clin Oncol 2000; 18: 2553–59.
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