1 Division of Breast Surgery, European Institute of Oncology, Milan; 2 Postgraduate School of General Surgery, University of Perugia, Perugia; 3 Division of Breast Surgery, Fondazione Salvatore Maugeri, Pavia; 4 Division of Pathology, European Institute of Oncology, Milan; 5 University of Milan School of Medicine, Milan; 6 Division of Nuclear Medicine, European Institute of Oncology, Milan; 7 European Institute of Oncology, Milan, Italy
* Correspondence to: Dr A. Luini, Director, Division of Breast Surgery, European Institute of Oncology, via G. Ripamonti 435, 20 141 Milan, Italy. Tel: +39-0257-489725; Fax: +39-0257-489780; Email: alberto.luini{at}ieo.it
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Abstract |
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Key words: axillary surgery, breast cancer, sentinel node biopsy
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Introduction |
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Axillary staging is an important step in the treatment of breast carcinoma: axillary dissection has remained for years the standard technique for the majority of cases, and it is still useful in a significant number of patients affected by this disease. Axillary lymph node status is a significant prognostic pathologic variable in patients with operable primary breast cancer: it remains the most powerful predictor of recurrence and survival. The number of lymph nodes with metastasis also has prognostic importance [1, 2
].
The introduction of sentinel-node biopsy is revolutionizing the surgery of breast cancer: the information derived from the sentinel-node biopsy is valuable, with less discomfort for patients when compared with complete axillary dissection [3].
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Prediction of axillary metastasis |
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Currently, about 30% of patients come to treatment facilities with positive axillary lymph nodes; if the disease continues its improving course in terms of mean and median maximum diameter, we believe that the overall node-positive rate in invasive cancer will inevitably decrease further, probably to about 20%; moreover, many cases will be micrometastases.
Early diagnosis has led to an increased number of dissections in which axillary nodes are free of disease. In this situation, a surgical technique that reduces the extent of the removed tissue in the axilla without losing prognostic information may have a very good impact on quality of life.
Clinical examination of the axilla and available imagery are manifestly inaccurate for axillary staging. Among patients with non-palpable nodes in the axilla, the histopathological presence of metastasis was found in 3540%; palpation is therefore not accepted for assessing risk. The combination of tumor size and palpability was noted to be a more accurate predictor than either tumor category alone [4]. Other studies found an association between nuclear grade, size and lymph vascular invasion as predictors, whereas some others noted tumor size alone as the best predictor [5
, 6
]. There is a subset of favorable histological types which have low rates of axillary metastasis, including medullary, mucinous, papillary, tubular and adenoid cystic tumors.
Mammograms can only identify grossly involved nodes. The sensitivity of computed tomography (CT) for axillary metastasis is only 50%. At present, positron emission tomography (PET) has a high specificity, but the sensitivity is too low and the technique is not accurate enough to detect small and few nodal metastases [7].
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Surgical approach to axillary lymph nodes |
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A prospective non-randomized study on 401 patients [14] with early-stage breast cancer (
2 cm) evaluated the impact of surgery without axillary dissection on axillary and distant relapses. The 5-year follow-up revealed a low rate of nodal and distant relapses for T1a and T1b patients. Avoidance of axillary dissection has a negligible effect on the outcome of T1 patients, conversely in the T2 group the high rate of relapses represents a limit for avoiding axillary dissection. The question is whether lymph node removal is always necessary in patients with a clinically negative axilla. In fact, following the development of imaging techniques that detect small, early-stage primary carcinomas, it is increasingly noted that axillary dissection finds only healthy lymphatic nodes [15
, 16
].
In our trial on the complete avoidance of axillary dissection in T1aT1b breast cancer patients, which randomized 435 women into two arms with simple follow-up or radiotherapy to the axilla [17], we observed a very low rate of axillary relapse after a mean follow-up of 42 months.
Sentinel-node biopsy
Sentinel-node biopsy has been developed for the axillary staging of breast carcinoma. This technique provides surgeons with information that allows axillary dissection to be avoided if the sentinel node is negative. Anatomically, the sentinel node is the first lymph node which receives lymph from the anatomic site of the primary breast tumor. The rationale for the adoption of sentinel-node biopsy is that, due to the progressive involvement of axillary nodes by tumor cells, the histology of this first lymph node would be representative of all the other axillary nodes.
Initial results on sentinel-node biopsy in breast carcinoma [1826
] and many later studies indicated this is a reliable axillary staging technique, although a limited number of false-negative results are a feature of all the published experience.
Three large randomized trials on sentinel-node biopsy are now ongoing.
The ALMANAC [22, 23
] trial begun in November 1999, is a randomized, multicenter trial in the UK comparing sentinel-node biopsy with conventional axillary treatment in clinically node-negative patients. In total, 1031 patients have been randomized and first results were presented at the 2004 ASCO meeting. The authors concluded that sentinel-node biopsy is associated with less arm morbidity and better quality of life and is cost-effective compared with standard axillary treatment.
The NSABP-32 [24] trial is a phase III, randomized trial comparing axillary resection with sentinel node dissection and involving more than 5000 patients in 73 institutions in North America. It began in January 1999 and no preliminary results have been published as yet.
The third trial, RACS SNAC [25], is a multicenter randomized trial of the Royal Australian College of Surgeons. From May 2001 to November 2003, 789 women have been randomized and analysis of the first 150 women indicates good compliance with study treatment and acceptable surgical technique.
Our experience with sentinel-node biopsy is being validated with a randomized trial which compared sentinel-node biopsy with complete axillary dissection in the identification of axillary metastases, and evaluated the incidence of axillary relapse in patients who underwent sentinel-node biopsy [3]. The enrollment of patients in this clinical trial was concluded in December 1999 (516 patients): women between 40 and 75 years of age affected by unifocal breast carcinoma with maximum diameter 2 cm and clinically negative axillary nodes had been considered candidates for the trial. Patients received conservative surgery and were randomized for complete axillary dissection or sentinel-node biopsy: in this latter case, axillary dissection was carried out in the case of sentinel-node involvement by tumor cells.
A sentinel node was positive in 83 of the 257 patients in the axillary-dissection group (32.3%), and in 92 of the 259 patients in the sentinel-node group (35.5%). At a median follow-up of 46 months, among the 167 patients who did not undergo axillary dissection, there were no cases of overt axillary metastasis. Post-operative side-effects were much less frequent in patients who underwent sentinel-node biopsy only compared with those who underwent complete axillary dissection.
The follow-up is ongoing, adding evidence to the effectiveness of sentinel-node biopsy as an effective procedure in breast cancer staging. During follow-up, we are checking the axillary situation both with clinical examination and by ultrasound.
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Discussion |
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In the 18th century, the German surgeon Lorenz Heister was the first to advocate axillary dissection as part of the treatment of invasive breast cancer [27]. In 1875, Richard von Volkman observed the communication of the mammary lymphatic vessels with the axillary nodes [28
]. In 1867, Moore of the Middlesex Hospital in London proposed that complete removal of the breast (total mastectomy) and the diseased glands [29
] was the treatment of choice for lesions in any area of the breast. In 1882, Banks agreeing with Moore stated that "the axillary nodes should be removed even when they were not clinically involved" [30
]. In 1891, William Halsted described the theory of centrifugal spread of breast cancer [31
]: preserving the main continuity with the primary tumor, he overemphasized the role of lymphatic permeation as a major mechanism of tumor dissemination in breast cancer. He proposed that a radical surgical approach to breast cancer was the key to successful treatment of the disease. Halsted reported local and regional recurrence rates of 6% and 16%, respectively.
In 1948, Patey and Dyson [32] described a less radical approach to surgery and introduced a modified radical mastectomy as a less mutilating operation with an outcome similar to that seen with radical mastectomy. The pectoralis major was preserved but the extent of axillary surgery remained the same.
The first milestone in the conservative surgery for breast cancer was the introduction of quadrantectomy and lumpectomy. In the early 1970s, Veronesi and colleagues started randomized trials aimed to demonstrate that a combination of local surgery and radiotherapy achieved the same results as those of radical mastectomy. After a median follow-up of 20 years, the overall and breast specific survival rates were similar [4, 33
]. Total axillary clearance remained an integral part of this procedure.
Lumpectomy and quadrantectomy are conservative approaches which have received validation in the treatment of breast carcinoma.
Complete axillary dissection is still a powerful staging method in several cases of breast carcinoma: patients with multi-centric tumors, with tumor diameter larger than 2.5 cm, and patients with clinical involvement of axillary nodes should receive axillary dissection. In most cases, lymphatic spread from the breast within the axilla is orderlyfrom the first to the third Berg levelsand skip metastases are infrequent [3436
]. These findings encouraged investigations of sentinel-node biopsy in breast cancer, a procedure which is effective in melanoma [37
]. Several studies investigated sentinel-node biopsy, which is appearing as a reliable and safe technique to stage the axilla. The impact of sentinel-node biopsy on quality of life is good: the arm mobility is improved when compared with the results of complete axillary dissection, and also the risk of arm edema is lower.
Sentinel-node biopsy is currently indicated in unifocal breast carcinoma up to 2.5 cm diameter, with no clinical involvement of axillary lymph nodes by the disease. The indication to sentinel-node biopsy is also under evaluation in the case of neo-adjuvant chemotherapy and multi-focal or multi-centric tumors [3840
]. Moreover, sentinel-node biopsy can be carried out after previous breast biopsy [41
] and under local anesthesia; this last technique allows a better organization of the treatments and also extension of the technique to centers which cannot organize intraoperative examination of the sentinel node [42
, 43
].
The next stages in axillary surgery will probably be the extension of the indications for sentinel node, together with research on diagnostic tests which could be substituted for sentinel-node biopsy in the staging of breast cancer (e.g. PET).
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Conclusion |
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The use of sentinel-node biopsy is a powerful staging method, but it should be tested in different settings to give surgeons the knowledge of the benefits and limits of the technique.
Even if sentinel-node biopsy represents a surgical approach of growing importance in the majority of patients affected by breast carcinoma, complete axillary dissection is still a valid approach for breast cancer. In cases of positive sentinel node, clinically involved axillary lymph nodes, multicentric breast tumors or large tumors, axillary dissection remains a very important technique to obtain the oncological information needed for the prescription of adjuvant therapy.
Received for publication July 30, 2004. Revision received September 8, 2004. Accepted for publication September 18, 2004.
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References |
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