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Axillary dissection in breast cancer
Critical Reviews in Oncology/Hematology 30 (1999) 63 – 70
Axillary dissection in breast cancer Alberto Luini *, Stefano Zurrida, Viviana Galimberti, Gisela Andreoni Senology Department, Istituto Europeo di Oncologia, 6ia G. Ripamonti 435, 20141 Milano Italy Accepted 31 July 1998
Contents 1. Complete axillary dissection versus partial emptying . . . . . . . . . . . . . . . . . . . . . . . .
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2. Can axillary dissection be avoided? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3. Newer developments and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. No axillary dissection and the role of axillary radiotherapy . . . . . . . . . . . . . . . . . 3.2. The role of the sentinel node . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4. Surgical techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Axillary lymph node dissection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Sentinel node biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Biography. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Our knowledge of the natural history of breast cancer has come a long way since Halsted’s initial attempts to approach the disease, and its treatment, in a scientific manner. The incidence of breast cancer has increased since Halsted’s time and today it is the most frequent cancer in women [1]. Important early discoveries concerning the natural history of the disease were that it is not systemic at onset, and that metastatic spread does not occur exclusively via the lymphatic system, but also through the circulation. Thus, the excessively aggressive approaches to the disease, by early surgeons, did not improve patients’ survival but only worsened the quality of their lives. This was demonstrated by randomized trials that compared the classic Halsted mastectomy with enlarged mastectomies that included removal of the internal mammary chain [2] and supraclavicular nodes [3]. * Corresponding author. Tel.: +39 02 57489718; fax: +39 02 57489725; e-mail:[email protected]
From the beginning the size of the primary was recognized as a major determinant of disease prognosis. Later, tumour diameter was shown to correlate statistically with the risk of axillary metastases and the axilla emerged as a key area in strategies to control breast cancer. After adequate local treatment of the primary, the problem was to find the best way of dealing with the axilla, that involved neither undertreatment nor overtreatment. Today, as breast cancer is diagnosed earlier, the average size of the tumour is smaller and the probability of axillary involvement has decreased. It is not surprising therefore that many surgeons question the need for axillary dissection, so that the debate concerning axillary treatment continues to be controversial, with no sign of a consenus emerging. While some authorities maintain that the axilla should be a ‘no-go zone’ [4], others believe a clinically negative axilla should only be treated in some instances but not others. Among those who believe the axilla should generally be treated, there is argument about the
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level of aggressiveness required to ensure local control and adequate staging. Some authors believe that upper arm lymphedema is such a severe complication of complete axillary dissection that they prefer to remove the first level only (partial axillary lymphadenectomy) [5] or to perform a random biopsy (sampling) [6,7]. Others maintain that simple lymph node biopsy can give sufficient information on the state of the axilla [8]. There is also controversy concerning the morbidity of the various treatments, including adjuvant treatment with radiotherapy [9]. The debate has also involved non-surgeons. One statistical study applied a mathematical model to a large series of our patients in whom number of axillary nodes and level of involvement had been recorded [10]; the model estimated how many nodes should be sampled in order to be sure of removing all involved nodes. Paradoxically this number varied according to the actual number of involved nodes [11]. On one point most are agreed: non-surgical staging of the axilla is inadequate. Neither ultrasonic examination, lymphangiography [12] nor lymphoscintigraphy [13] are able to reliably reveal the real extent of lymph node involvement; while PET and MRI are still experimental techniques as far as the diagnosis of axillary metastases is concerned [14]. Clinical examination is recognised as notoriously unreliable for detecting pathological nodes [15]. The questions that are perhaps at the heart of the controversies seem to be the following: Do we always need the staging information provided by axillary dissection? If the nodes are clinically negative, do they need to be treated? Are there particular histological subtypes of breast cancer in which dissection of a clinically clear axilla is not necessary? Are there valid alternatives to axillary dissection as a way of treating the axilla? The rest of this article will examine the problem of axillary dissection in breast cancer, in an attempt to provide answers to these questions, but more importantly, will discuss significant new developments in the area which may help resolve the controversies that have raged for so long.
1. Complete axillary dissection versus partial emptying In our study on 1446 patients with breast cancer [10] we found that axillary lymphatic spread is orderly, involving the first level initially and successively the second and then the third level. Only exceptionally are lower levels skipped. Moreover the risk of metastases at higher levels is proportional to the number of involved nodes at the first level, as well as the size of the primary carcinoma. Finally, the number of nodes removed bears no relation to the extent or type of surgery on the
breast (Halsted or Patey mastectomy, quadrantectomy, with en bloc axillary dissection or separate incision, according to Veronesi). Based on these findings we believe it is reasonable to conclude that when axillary dissection is performed, it must be complete [16], that is it must include the three Berg levels [7]: the first level comprising all lymph nodes lateral to the lateral margin of the pectoralis minor muscle, the second level comprising the nodes behind the pectoralis minor muscle, and the third level comprising the nodes medial to the medial margin of the muscle, in the space commonly defined as the apex of the axilla. When axillary dissection of the first and second levels is partial, or if nodes are sampled, the risk is to leave in situ metastatic foci. With sampling, there is also the problem of not finding any lymphatic tissue in 10% of cases sampled [5] so that no prognostic information is obtained. It should not be forgotten either that metastatic nodes at the 3rd level and interpectorally are present in 16–58% of patients with a clinically involved axilla. Removal of all three levels, with exploration, and if necessary removal of Rotter’s nodes requires little extra operating time, is not technically difficult, and, in addition to providing the maximum possible information for staging, ensures oncological radicality of the region draining the breast. The risk of axillary recurrence is inversely related to the number of nodes resected per axilla as shown by Fisher in the NSABP B-04 study [17] and by the Danish Breast Cancer Co-Operative Group [18]. In addition, axillary recurrence in an incompletely emptied axilla seems to be a negative prognostic event [19]. Special problems arise when disease recurs in a partially emptied axilla, particularly one that has been irradiated. In such cases the anatomical structure of the area has been considerably altered, not least by the growth of scar and granulomatous tissue formed after the first operation; it therefore becomes very difficult to find and remove all residual disease. However, the most important problem connected with partial emptying is that post-operation consolidation renders it difficult to identify recurrence at an early stage by clinical means. Thus, when re-operation is performed, the nodes often involve the axillary vein; they may be fixed to it, infiltrate it or completely surround it; and removal of all macroscopic disease may be impossible.
2. Can axillary dissection be avoided? In 1997 Haffy et al. [20] reported on the long-term follow-up of a series of breast cancer patients, 565 of whom received axillary dissection and 390 did not; all had a clinically negative axilla. Those who did not receive surgical treatment to the axilla received radio-
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therapy to the internal mammary, supraclavicular and axillary nodes. Local, regional, and distant metastasis rates, as well as long term outcome, were closely similar in the two groups. In a subset analysis of patients older than 50 years, overall survival, disease free survival, and distant and loco-regional failure rates were independent of whether or not patients underwent axillary node dissection. This was true also considering differences in the two populations in terms of primary tumour size, clinical stage, type of radiation treatment or outcome measures. On the other hand Cabanes [21] randomized patients with tumours less than 3 cm and no clinically positive axillary nodes, to treatment with either lumpectomy alone followed by radiation to axillary and internal mammary nodes, or to lumpectomy plus axillary dissection followed by irradiation of the internal mammary nodes. There was a significant survival advantage for patients who received axillary dissection. In a recent publication, Fein et al. [22] reported on a series of 1598 stage I and II patients and concluded that axillary dissection should be foregone in mammographically-detected tumours up to 5 mm, mammographically-detected tumours of size 6 – 10 mm age 5 40 years, tubular carcinoma 5 10 mm. Earlier (1996), in a retrospective study, Greco et al. [23] reached similar conclusions concerning the risk of axillary metastases in elderly patients, finding that of 401 patients (81% postmenopausal, mean age 62.9 years) who did not receive axillary dissection or radiotherapy, only 19 cases (4.7%) required delayed full dissection for histologically confirmed metastases. From these data it seems clear that axillary dissection can be foregone in some cases, however many variables were involved in these studies (RT, lumpectomy vs. mastectomy, mammographic detection), so that it would be difficult if not impossible to draw up consensus guidelines as to when and when not to perform axillary dissection. Large-scale prospective studies with long term follow up are required to resolve this problem.
3. Newer developments and future prospects In the past, when large size and locally advanced tumours were the rule, the great majority of patients had involved axillary nodes. Today this situation has changed radically and tumours are smaller, frequently clinically occult and rarely accompanied by clinically palpable axillary lymph nodes. Such early stage tumours are biologically less aggressive than more advanced cancers, and there is only a limited risk of spread to the axillary nodes. According to Tabar [24] who studied 238 patients with tumours of diameter less than 1 cm, this risk is around 2 – 5% while Veronesi et
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al. [25] found about 3% axillary involvement in tumours up to 5 mm. With findings such as these it is no wonder that more and more surgeons are doubting the necessity of axillary dissection in the absence of clinically palpable lymph nodes, particularly since axillary dissection can produce unpleasant sequelae including sensory loss, paresthesia, hypofunctionality of the scapula-humeral articulation, impaired lymphatic drainage and increased susceptibility to infection. Moreover, it is now possible to obtain consistent prognostic information by determining a series of biological properties on the primary tumour. Various biological properties are known to be related to prognosis, even when there are no axillary metastases; these include histological grade, hormonal receptor status, proliferation index and presence of peritumoral and/or lymphatic invasion. Today, more N0 patients are receiving adjuvant therapy when factors determined on their primary, or menopausal status, indicate a poorer prognosis [26]. Even in the absence of the information provided by these modern parameters, it is possible to safely avoid axillary dissection under certain circumstances. Thus a randomized study by Fisher [17] compared total mastectomy plus axillary dissection with mastectomy only (with axillary clearance in the event of metastatic lymphadenopathy). The long-term results demonstrated that overall survival was the same in both groups. However, ‘as required’ axillary dissection can be problematic. The lack of secure methods to diagnose early axillary involvement mean that follow-up must be regular and thorough. As well as being costly, this approach may place the patient under considerable psychological strain. Nevertheless as our understanding of the natural history of breast cancer has increased it has become clear that disease aggressiveness varies considerably with histotype, and this has convinced us that axillary dissection can be avoided in certain cases. Such cases would be mucinous carcinoma, Paget’s disease, tubular carcinoma, intracystic carcinoma, papillary carcinoma and colloidal carcinoma, in all of which, if the size is 5 1 cm (T1a–b) the percentage of axillary involvement is around 1%. We also believe that axillary dissection can be safely forgone in elderly women, as the results of the consecutive retrospective analysis of Greco et al. [23] indicated. Furthermore, in view of the increasing frequency of radiologically-detected non-palpable lesions which turn out to be in situ, perhaps DCIS should also be included in this category. The risk of axillary metastases in DCIS correlates with the presence of infiltrating microinvasion. About 1% of patients with axillary lymph node metastases have no evidence of stromal invasion on light microscope examination of the primary [27]. In
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such cases invasion is probably present but not recognized or undetected because of sampling error. Incidence rates for axillary involvement in patients diagnosed with DCIS in the pre-mammographic era range from 0.8 to 4% (Table 1) when most patients presented with a palpable mass. In more recent series of DCIS patients detected mammographically, as a small lesion and confirmed histologically, axillary involvement was zero. We therefore tend to consider that axillary dissection is not necessary in intraductal carcinoma cases. A number of ongoing studies are investigating the consequences of avoiding axillary emptying in N0 patients. One approach is to not perform axillary dissection at all, except in patients who develop metastatic lymphadenopathy during follow up. A second approach involves use of the sentinel node. This is the first lymph node to receive lymph from the breast area containing the tumour. The idea is that this node is identified, removed and examined histologically (and immunohistologically if necessary). If it contains no metastases it is reasonable to conclude that the entire axilla is free of metastases.
tute of Oncology (IEO), in which nine other Italian centres are participating. Adjuvant therapy is decided according to the results of biological tests performed on the primary tumour. According to hormonal receptor status, tumour grade and proliferative index (Ki-67) patients receive no further adjuvant treatment, tamoxifen 20 mg/day for 5 years, or six cycles of CMF. At the end of December 1997, 381 patients had been randomized, 188 to the group treated by breast radiation, and 193 to the group treated by radiation to the breast and axilla. A total of 159 cases have been enrolled at IEO and 222 at the other centres. The 363 patients for whom all data was available have been analysed. Tamoxifen was given 264 cases, 78 patients received no adjuvant treatment and 21 received CMF. The breakdown is T5 1cm in 73%, G1 in 42%, G2 in 86%, ER+ in 80% PgG+ in 68% and Ki-67 5 20% in 77%. These data indicate that the great majority of patients so far randomized have favourable prognostic factors; only three patients have developed metastatic axillary nodes. Recruitment will be closed at 400 cases and initial results are expected in 1999.
3.2. The role of the sentinel node 3.1. No axillary dissection and the role of axillary radiotherapy The idea of performing radiotherapy on the axilla instead of axillary dissection was proposed by McWirther [28] based on the results of a randomized study that compared Halsted mastectomy with total mastectomy plus radiotherapy to the axilla. Radiotherapy to the intact axilla does not produce the same side effects as when it is performed after partial axillary dissection. In 1995 a randomized study began to assess the role of axillary radiotherapy in reducing the risk of lymph node metastases in patients older than 45 years and undergoing conservative breast surgery for invasive carcinoma of size not more than 1.2 cm. The objective is to determine whether radiotherapy to the axilla can reduce risk of axillary metastases from the expected 10% without axillary treatment to around 3%. This is a multicentric study, coordinated by the European InstiTable 1 Literature review of DCIS patients who underwent axillary dissection Author
No. of patients
No. of axillary dis- N+cases sections
Ashikary Fisher Lagios Rosner Silverstein Sunshine
112 78 53 210 100 70
113 78 53 210 100 61
1 0 1 8 0 0
The sentinel node technique was first used by Morton with blue dye [29] and van der Veen [30] with radioactive tracer and lymphoscintigraphy to select melanoma patients for regional node dissection. The technique of identification, excision biopsy and histological examination of the sentinel node promises to radically alter the clinical approach to breast cancer and axillary node treatment. Studies published on a large series of patients by Giuliano [31] using the blue dye method, and by our group [32] using 99mtechnetium-labelled albumin and a gamma-ray detecting probe, showed that the accuracy of axillary staging by these techniques can be around 98%. Even greater staging accuracy (close to 100%) is obtained for small unifocal tumours (51.2 cm) located in the upper outer quadrant. The study by our group [32] had three objectives. First to assess the reliability of external-body lymphoscintigraphy as a means of identifying the node receiving lymph from the region of the primary carcinoma; second to assess the utility of g-ray detecting probe to identify and remove the sentinel node during surgery; third to evaluate by histological analysis of all axillary nodes, the predictive value of the sentinel node. The sentinel node was identified with the probe in all but three (98%) of the 163 cases (T1–T3). In 65% of the 160 evaluated cases one sentinel node was detected by the probe, in 25% two nodes were detected and in 9% three nodes were radioactive. The predictive value of the sentinel node or nodes was 97.5%. The sentinel node was the only metastatic node in 40% of cases with an involved axilla, supporting the biological validity of the sentinel
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Table 2 Axillary node metastases according to pathological variables [31] Size of primary (maximum diameter, cm)
No. with positive axillary nodes
%
94 66
45 40
47.8 60.6
117 43
59 26
50.4 60.5
Proliferati6e rate (Ki67) B20 ]20
97 63
47 38
48.4 60.3
Grading a G1 G2 G3
25 72 58
10 36 36
41.6 50.0 62.0
Peritumoral 6ascular in6asion PVI− PVI+
92 68
32 53
35.2 77.9
B2.0 ]2.0 Estrogen receptors ER+ ER−
a
No. of cases
In five cases grading was not available.
node concept. False negative sentinel nodes were observed in four cases (2.5% of all cases and 5.4% of negative cases). In fact lack of reliability of sentinel node diagnosis on standard frozen section examination proved to be a weakness of the method. Frozen sections were examined in the last 107 cases of the series; in 18 cases (17%) the intraoperative diagnosis was falsely negative, as micrometastasic foci were found in the permanent histological sections. This percentage is high and could represent a limiting factor for the technique, since the surgeon must decide whether to empty the axilla in the operating theatre. In the second phase of the study, at least 15 regularly-spaced pairs of sections from the entire sentinel node were examined, with conventional staining and, if negative, immunohistochemical staining. The results in 54 patients showed a 100% concordance between frozen section and permanent section results. This phase of the study also identified pathologic variables predicting metastatic spread to the axillary nodes. Perivascular invasion seems to have the strongest correlation with axillary involvement (Table 2). The third phase of our sentinel node project is now in course. This is a prospective randomized trial to evaluate overall and disease-free survival in patients with unifocal invasive breast carcinoma of size up to 2 cm, without clinically involved lymph nodes. One arm will receive conservative breast surgery plus axillary dissection, the other arm will receive conservative surgery and sentinel lymph node biopsy only — if the histology of the sentinel node proves benign; those with an involved sentinel lymph node will undergo complete axillary dissection. Patients without axillary node involvement, either clinically in the first arm, or those with a negative sentinel node in the second, may receive
systemic therapy depending on prognostic factors determined on the primary (Fig. 1). It remains our opinion that complete axillary dissection must be performed in all patients with a clinically positive axilla. For the near future we envisage four treatment options for the axilla in women with breast cancer and a clinically negative axilla. For tumours up to 1 cm. axillary dissection can probably be avoided; however before this can be adopted as general policy, the results of the clinical trial comparing the axillary radiotherapy and no treatment must be assessed. For tumours up to 2 cm. sentinel node biopsy is likely to be a reliable predictor of axillary status. However it is important that lymphoscintigraphy to identify the sentinel node is performed correctly [33]; that surgeons are trained to isolate the sentinel node with precision; and that the intraoperative histological examination considers an adequate number of
Fig. 1. Design of prospective study to determine long-term validity of the sentinel node biopsy in small size breast cancer.
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sections, perhaps also using immunohistochemical methods. Again, however, the results of the randomized study to verify the reliability of the technique, in terms of its effect on overall and disease-free survival, must be available before sentinel node biopsy can be adopted as a basis for decision-making. For tumours of diameter greater than 1.5 cm. we believe that axillary dissection must always be performed. For certain histotypes and elderly patients, as discussed earlier, axillary dissection can also be avoided.
4. Surgical techniques
4.1. Axillary lymph node dissection This is performed in continuity with the breast incision when the tumour is in the upper-outer quadrant and, normally, by separate incision when the tumour is elsewhere. In the latter case, the incision may follow the lateral margin of the pectoralis major muscle, slightly below it, or cross the axillary skin along natural skin creases. Once the incision has been made, a small lateral cutaneous flap is prepared to allow access to the lateral margin of the latissimus dorsi, its insertion in the humerus, the coracobrachial muscle and the lateral portion of the vasculo – nervous tract. The margin of the latissimus dorsi is isolated along its length so as to identify and prepare the blood vessels and the thoracodorsal nerve. The adipose tissue between the internal fascia of the latissimus dorsi and the surface of the chest wall is detached. At this point the long thoracic nerve (Bell’s nerve) adherent to the chest wall may be observed under the muscle fascia and whose pathway runs from the high portion of the latissimus dorsi nervous – vascular tract to the lower part of the serratus muscle. The medial cutaneous flap is now prepared to access the lateral margin of the pectoralis major and to identify the surface between this and the underlying pectoralis minor. By introducing a retractor the pectoralis minor may be accessed. The adipose tissue between the two muscles, which includes the Rotter lymph nodes, is thus carefully explored and if nodes are palpable they are removed, sparing always the thoracic acromial peduncle and the interpectoralis vessels. The coracoclavicular pectoralis ligament is now located and is displaced medial to the vasculo– nervous thoracic acromial fascia. The margins of the pectoralis minor muscle are identified, and, medially and laterally to the coracoclavicular pectoralis fascia, the index finger is introduced
under the venter musculi. Dissection of the adipose tissue continues by uncovering the plexus brachialis and the axillary vein—the anterior surface of which is isolated. By following the vein medially, the tendon of the subclavius muscle becomes visible; thus reaching the apex of the axilla (3rd level) where the highest axillary lymph nodes and lymphatic vessels are located. These should be isolated carefully, excising the adipose tissue from the tendon of the subclavius muscle and pulling it downwards. The lateral limit of each lymph node level should always be marked by metal discs or different coloured threads to facilitate pathological examination. Performed in this way, so as to spare all vascular and nervous tracts of the muscles, including the intercostal nerves, axillary clearance causes side effects (arm lymphedema, pain and paresthesia) in less than 6% of cases, yet provides maximum possible prognostic information. By contrast random biopsy of one axillary node, sampling, or removal of the first level only, do not ensure disease removal, do not completely obviate the risk of lymphedema and completely overlook the risk of skip metastases, which in our experience is quite rare [10], but is reported to occur in up to 12% of cases by some authors. Complete dissection is not a particularly difficult procedure and extends operating time by only about 10–15 min. Furthermore it eliminates the risk of axillary recurrence and allows an accurate prognosis based on both number of involved nodes and their level.
4.2. Sentinel node biopsy A total of seven MBq of 99mtechnetium-labelled human albumin of size between 200 and 1000 nm (Albu-res, Sorin Biomedica) is administered subdermally above the tumour or peritumorally the day before surgery. After 30 min these particles have entered the lymphatic capillary system and reached the regional lymph-nodes where they are held. Preliminary studies identified albumin nanocolloid in the size range specified as the most suitable non-specific tracer, particularly when the operation is delayed. Whereas sulphide colloid moves faster and is more suitable for patients operated on a few hours later. An incision of 2–3 cm. in the axillary fossa is sufficient to permit removal of the sentinel node under guidance of the gamma ray detecting probe.
Reviewer This paper was reviewed by Professor Luigi Cataliotti, Universita` Degli Studi di Firenze, Instituto di Clinica Chirurgica Generale E Terapia Chirurgica, Italia.
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References [1] Boring CC, Squires TS, Tong T. Cancer statistics. CA Cancer J Clin 1993;43:7 – 26. [2] Veronesi U, Cascinelli N, Bufalino R, et al. Risk of internal mammary lymph-node metastases and its relevance on prognosis of breast cancer patients. Ann Surg 1983;198(6):681–4. [3] Veronesi U, Zingo L. Extended mastectomy for cancer of the breast. Cancer 1967;20:677–80. [4] Fentiman IS, Mansel RE. The axilla: not a no go zone. Lancet 1991;337:221 – 3. [5] Steel RJC, Forrest APM, Gibson T, et al. The efficacy of lower axillary sampling in obtaining lymph node status in breast cancer: a controlled randomized trial. Br J Surg 1985;72:368 – 9. [6] Kissin MW, Price AB, Thompson EM, et al. The inadequacy of axillary sampling in breast cancer. Lancet 1982;1:1210–2. [7] Berg JW. The significance of axillary node levels in the study of breast carcinoma. Cancer 1955;8:776–8. [8] Christensen SB, Jansson C. Axillary biopsy compared with dissection in the staging of lymph nodes in operable breast cancer. A randomised trial. Eur J Surg 1993;159:159–62. [9] Dewar JA, Sarrazin D, Benhamou E, et al. Management of the axilla in conservatively treated breast cancer: 592 patients treated at Institut Gustave-Roussy. Int J Radiat Oncol Biol Phys 1987;13:475 – 81. [10] Veronesi U, Luini A, Galimberti V, et al. Extent of metastatic axillary involvement in 1446 cases of breast cancer. Eur J Surg Oncol 1990;16:127 – 33. [11] Kirikuta IC, Warszawski N, Tausch J, et al. Incomplete axillary dissection in early breast cancer and the risk of erroneous staging. Oncol Reports 1994;1:661–6. [12] Musumeci R, Tesoro Tess JD, Costa A, et al. Indirect lymphography of the breast with iotasul: a vanishing hope? Lymphology 1984;17:118 – 23. [13] Tjandra JJ, Russel IS, Collins JP, et al. Immuno-lymphoscintigraphy for the detection of lymph node metastases from breast cancer. Cancer Res 1989;49:1600–8. [14] Nieweg OE, Kim EE, Wong WH, et al. Positron emission tomography with fluorine-18-deoxyglucose in the detection and staging of breast cancer. Cancer 1989;71:3920–5. [15] Fisher B, Wolmark N, Bauer M, et al. The accuracy of clinical nodal staging and of limited axillary dissection as a determinant of histological nodal status in carcinoma of the breast. Surg Gynecol Obstet 1981;152:765–72. [16] Veronesi U, Galimberti V, Zurrida S, Merson M, Greco M, Luini A. Prognostic significance of number and level of axillary node metastases in breast cancer. Breast 1993;2:224–8. [17] Fisher B, Redmond C, Fisher ER, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. New Engl J Med 1985;312:674 – 81. [18] Axelsson CK, Mouridsen HT, Zedeler K. Axillary dissection of level I and II lymph nodes is important in breast cancer classification. The Danish Breast Cancer Cooperative Group (DBCG). Eur J Cancer 1992;28A:1415–8. [19] Deckers PJ. Axillary dissection in breast cancer: when, why, how much and for how long? Another operation soon to be extinct? J Surg Oncol 1991;48:217–9. [20] Huffty BG, Ward B, Pathare P, et al. Reappraisal of the role of axillary lymph node dissection in the conservative treatment of breast cancer. J Clin Oncol 1997;15:691–700. [21] Cabanes PA, Salmon RJ, Vilcoq JR, et al. Value of axillary dissection in addition to lumpectomy and radiotherapy in early breast cancer. Lancet 1992;339:1245–8. [22] Fein DA, Fowble BL, Hanlon AL, et al. Identification of women with T1 – T2 breast cancer at low risk of positive axillary nodes. J Surg Oncol 1997;65:34–9.
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[23] Greco M, Agresti R, Raselli R, et al. Axillary dissection can be avoided in selected breast cancer patients: Analysis of 401 cases. Anticancer Res 1996;16:3913 – 8. [24] Tabar L, Fagerberg C, Duffy SW, et al. Update of the Swedish two-country program of mammographic screening for breast cancer. Radiol Clin North Am 1992;30:187 – 210. [25] Veronesi U, Salvadori B, Luini A, et al. Breast conservation is a safe method in patients with small cancer of the breast. Longterm results of three randomized trials on 1,973 patients. Eur J Cancer 1995;31(10):1574– 9. [26] Goldhirsch A, Gelber RD, Castiglione M, et al. Present and future projects of the International Breast Cancer Study Group. Cancer 1994;74(1):3. [27] Fowble B. In situ breast cancer. In: Fowble B, Goodman RL, Glick JH, et al., editors. Breast Cancer Treatment: a Comprehensive Guide to Management. St Louis, Mosby-Year book, 1991. [28] McWhirter R. Simple mastectomy and radiotherapy in the treatment of breast cancer. Br J Radiol 1955;28:128 – 39. [29] Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392 – 9. [30] van der Veen H, Hoekstra OS, Paul MA, et al. Gamma probe guided sentinel node biopsy to select patients with melanoma for lymphadenectomy. Br J Surg 1994;8(1):1769– 70. [31] Giuliano AE, Dale P, Turner R, et al. Improved axillary staging of breast cancer with sentinel lymphadenectomy. Ann Surg 1995;222:394 – 401. [32] Veronesi U, Paganelli G, Galimberti V, et al. Sentinel node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. Lancet 1997;349:1864 – 7. [33] De Cicco C, Paganelli G, Cremonesi M, et al. Gamma Probe guided resection of the sentinel node in breast cancer. Eur J Nucl Med 1997;24(8):893.
Biography Dr Alberto Luini graduated in Medicine at Milan University in July 1973. In June 1976, he received a postgraduate degree in Oncology from the University of Genova. From October 1975 until April 1994 he worked as an assistant at the National Cancer Institute, Milan. From 1983 until 1988 he was the National Secretary of the National Research Council (CNR) with the responsibility for organising the activities concerned with the ‘Oncology’ project regarding the guidelines for colon, ovarian, melanoma and head and neck tumours for specialists and general practitioners. Since 1980 Dr Luini is National Secretary of the Task Force for Breast cancer, with responsibility for developing and distributing diagnostic and treatment protocols. In 1996 he was a team member for the development of the guidelines for breast cancer of the CNR ‘ACRO’ project. He forms part of the teaching staff of the Italian School of Senology and the European School of Oncology. He is a member of the editorial board of the ‘Attualita` in Senologia’ magazine, edited by the Italian School of Senology and Medical Radiology Society. He is a member of the European Society of Mastology (Eusoma) and of the board of directors of the Italian
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Society of Senology. His main area of research interest concerns the conservative treatment of breast carcinoma; he has participated in protocol elaboration, patient accrual, follow-up and data evaluation in several randomised clinical studies in this field. His selected publications include: (a) Veronesi U, Saccozzi R, Del Vecchio M, Banfi, Clemente C, De Lena M, Gallus, G, Greco M, Luini A, Marubini E, Muscolino G, Rilke F, Salvadori B, Zecchini A, Zucali R. Comparing
.
radical mastectomy with quadrantectomy, axillary dissection and radiotherapy in patients with small cancer of the breast. New Engl J Med 1981;305:6–11; (b) Veronesi U, Luini A, Del Vecchio M, et al. Radiotherapy after breast-preserving surgery in woman with localized cancer of the breast. New Engl J Med 1993;328:1587 –1591; and (c) Luini A, Zurrida S, Galimberti V, Paganelli G. Radioguided surgery of occult breast lesions. Eur J Cancer 1998;34-1:204–205.
Axillary dissection in breast cancer Alberto Luini *, Stefano Zurrida, Viviana Galimberti, Gisela Andreoni Senology Department, Istituto Europeo di Oncologia, 6ia G. Ripamonti 435, 20141 Milano Italy Accepted 31 July 1998
Contents 1. Complete axillary dissection versus partial emptying . . . . . . . . . . . . . . . . . . . . . . . .
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2. Can axillary dissection be avoided? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3. Newer developments and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. No axillary dissection and the role of axillary radiotherapy . . . . . . . . . . . . . . . . . 3.2. The role of the sentinel node . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4. Surgical techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Axillary lymph node dissection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Sentinel node biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Biography. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Our knowledge of the natural history of breast cancer has come a long way since Halsted’s initial attempts to approach the disease, and its treatment, in a scientific manner. The incidence of breast cancer has increased since Halsted’s time and today it is the most frequent cancer in women [1]. Important early discoveries concerning the natural history of the disease were that it is not systemic at onset, and that metastatic spread does not occur exclusively via the lymphatic system, but also through the circulation. Thus, the excessively aggressive approaches to the disease, by early surgeons, did not improve patients’ survival but only worsened the quality of their lives. This was demonstrated by randomized trials that compared the classic Halsted mastectomy with enlarged mastectomies that included removal of the internal mammary chain [2] and supraclavicular nodes [3]. * Corresponding author. Tel.: +39 02 57489718; fax: +39 02 57489725; e-mail:[email protected]
From the beginning the size of the primary was recognized as a major determinant of disease prognosis. Later, tumour diameter was shown to correlate statistically with the risk of axillary metastases and the axilla emerged as a key area in strategies to control breast cancer. After adequate local treatment of the primary, the problem was to find the best way of dealing with the axilla, that involved neither undertreatment nor overtreatment. Today, as breast cancer is diagnosed earlier, the average size of the tumour is smaller and the probability of axillary involvement has decreased. It is not surprising therefore that many surgeons question the need for axillary dissection, so that the debate concerning axillary treatment continues to be controversial, with no sign of a consenus emerging. While some authorities maintain that the axilla should be a ‘no-go zone’ [4], others believe a clinically negative axilla should only be treated in some instances but not others. Among those who believe the axilla should generally be treated, there is argument about the
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level of aggressiveness required to ensure local control and adequate staging. Some authors believe that upper arm lymphedema is such a severe complication of complete axillary dissection that they prefer to remove the first level only (partial axillary lymphadenectomy) [5] or to perform a random biopsy (sampling) [6,7]. Others maintain that simple lymph node biopsy can give sufficient information on the state of the axilla [8]. There is also controversy concerning the morbidity of the various treatments, including adjuvant treatment with radiotherapy [9]. The debate has also involved non-surgeons. One statistical study applied a mathematical model to a large series of our patients in whom number of axillary nodes and level of involvement had been recorded [10]; the model estimated how many nodes should be sampled in order to be sure of removing all involved nodes. Paradoxically this number varied according to the actual number of involved nodes [11]. On one point most are agreed: non-surgical staging of the axilla is inadequate. Neither ultrasonic examination, lymphangiography [12] nor lymphoscintigraphy [13] are able to reliably reveal the real extent of lymph node involvement; while PET and MRI are still experimental techniques as far as the diagnosis of axillary metastases is concerned [14]. Clinical examination is recognised as notoriously unreliable for detecting pathological nodes [15]. The questions that are perhaps at the heart of the controversies seem to be the following: Do we always need the staging information provided by axillary dissection? If the nodes are clinically negative, do they need to be treated? Are there particular histological subtypes of breast cancer in which dissection of a clinically clear axilla is not necessary? Are there valid alternatives to axillary dissection as a way of treating the axilla? The rest of this article will examine the problem of axillary dissection in breast cancer, in an attempt to provide answers to these questions, but more importantly, will discuss significant new developments in the area which may help resolve the controversies that have raged for so long.
1. Complete axillary dissection versus partial emptying In our study on 1446 patients with breast cancer [10] we found that axillary lymphatic spread is orderly, involving the first level initially and successively the second and then the third level. Only exceptionally are lower levels skipped. Moreover the risk of metastases at higher levels is proportional to the number of involved nodes at the first level, as well as the size of the primary carcinoma. Finally, the number of nodes removed bears no relation to the extent or type of surgery on the
breast (Halsted or Patey mastectomy, quadrantectomy, with en bloc axillary dissection or separate incision, according to Veronesi). Based on these findings we believe it is reasonable to conclude that when axillary dissection is performed, it must be complete [16], that is it must include the three Berg levels [7]: the first level comprising all lymph nodes lateral to the lateral margin of the pectoralis minor muscle, the second level comprising the nodes behind the pectoralis minor muscle, and the third level comprising the nodes medial to the medial margin of the muscle, in the space commonly defined as the apex of the axilla. When axillary dissection of the first and second levels is partial, or if nodes are sampled, the risk is to leave in situ metastatic foci. With sampling, there is also the problem of not finding any lymphatic tissue in 10% of cases sampled [5] so that no prognostic information is obtained. It should not be forgotten either that metastatic nodes at the 3rd level and interpectorally are present in 16–58% of patients with a clinically involved axilla. Removal of all three levels, with exploration, and if necessary removal of Rotter’s nodes requires little extra operating time, is not technically difficult, and, in addition to providing the maximum possible information for staging, ensures oncological radicality of the region draining the breast. The risk of axillary recurrence is inversely related to the number of nodes resected per axilla as shown by Fisher in the NSABP B-04 study [17] and by the Danish Breast Cancer Co-Operative Group [18]. In addition, axillary recurrence in an incompletely emptied axilla seems to be a negative prognostic event [19]. Special problems arise when disease recurs in a partially emptied axilla, particularly one that has been irradiated. In such cases the anatomical structure of the area has been considerably altered, not least by the growth of scar and granulomatous tissue formed after the first operation; it therefore becomes very difficult to find and remove all residual disease. However, the most important problem connected with partial emptying is that post-operation consolidation renders it difficult to identify recurrence at an early stage by clinical means. Thus, when re-operation is performed, the nodes often involve the axillary vein; they may be fixed to it, infiltrate it or completely surround it; and removal of all macroscopic disease may be impossible.
2. Can axillary dissection be avoided? In 1997 Haffy et al. [20] reported on the long-term follow-up of a series of breast cancer patients, 565 of whom received axillary dissection and 390 did not; all had a clinically negative axilla. Those who did not receive surgical treatment to the axilla received radio-
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therapy to the internal mammary, supraclavicular and axillary nodes. Local, regional, and distant metastasis rates, as well as long term outcome, were closely similar in the two groups. In a subset analysis of patients older than 50 years, overall survival, disease free survival, and distant and loco-regional failure rates were independent of whether or not patients underwent axillary node dissection. This was true also considering differences in the two populations in terms of primary tumour size, clinical stage, type of radiation treatment or outcome measures. On the other hand Cabanes [21] randomized patients with tumours less than 3 cm and no clinically positive axillary nodes, to treatment with either lumpectomy alone followed by radiation to axillary and internal mammary nodes, or to lumpectomy plus axillary dissection followed by irradiation of the internal mammary nodes. There was a significant survival advantage for patients who received axillary dissection. In a recent publication, Fein et al. [22] reported on a series of 1598 stage I and II patients and concluded that axillary dissection should be foregone in mammographically-detected tumours up to 5 mm, mammographically-detected tumours of size 6 – 10 mm age 5 40 years, tubular carcinoma 5 10 mm. Earlier (1996), in a retrospective study, Greco et al. [23] reached similar conclusions concerning the risk of axillary metastases in elderly patients, finding that of 401 patients (81% postmenopausal, mean age 62.9 years) who did not receive axillary dissection or radiotherapy, only 19 cases (4.7%) required delayed full dissection for histologically confirmed metastases. From these data it seems clear that axillary dissection can be foregone in some cases, however many variables were involved in these studies (RT, lumpectomy vs. mastectomy, mammographic detection), so that it would be difficult if not impossible to draw up consensus guidelines as to when and when not to perform axillary dissection. Large-scale prospective studies with long term follow up are required to resolve this problem.
3. Newer developments and future prospects In the past, when large size and locally advanced tumours were the rule, the great majority of patients had involved axillary nodes. Today this situation has changed radically and tumours are smaller, frequently clinically occult and rarely accompanied by clinically palpable axillary lymph nodes. Such early stage tumours are biologically less aggressive than more advanced cancers, and there is only a limited risk of spread to the axillary nodes. According to Tabar [24] who studied 238 patients with tumours of diameter less than 1 cm, this risk is around 2 – 5% while Veronesi et
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al. [25] found about 3% axillary involvement in tumours up to 5 mm. With findings such as these it is no wonder that more and more surgeons are doubting the necessity of axillary dissection in the absence of clinically palpable lymph nodes, particularly since axillary dissection can produce unpleasant sequelae including sensory loss, paresthesia, hypofunctionality of the scapula-humeral articulation, impaired lymphatic drainage and increased susceptibility to infection. Moreover, it is now possible to obtain consistent prognostic information by determining a series of biological properties on the primary tumour. Various biological properties are known to be related to prognosis, even when there are no axillary metastases; these include histological grade, hormonal receptor status, proliferation index and presence of peritumoral and/or lymphatic invasion. Today, more N0 patients are receiving adjuvant therapy when factors determined on their primary, or menopausal status, indicate a poorer prognosis [26]. Even in the absence of the information provided by these modern parameters, it is possible to safely avoid axillary dissection under certain circumstances. Thus a randomized study by Fisher [17] compared total mastectomy plus axillary dissection with mastectomy only (with axillary clearance in the event of metastatic lymphadenopathy). The long-term results demonstrated that overall survival was the same in both groups. However, ‘as required’ axillary dissection can be problematic. The lack of secure methods to diagnose early axillary involvement mean that follow-up must be regular and thorough. As well as being costly, this approach may place the patient under considerable psychological strain. Nevertheless as our understanding of the natural history of breast cancer has increased it has become clear that disease aggressiveness varies considerably with histotype, and this has convinced us that axillary dissection can be avoided in certain cases. Such cases would be mucinous carcinoma, Paget’s disease, tubular carcinoma, intracystic carcinoma, papillary carcinoma and colloidal carcinoma, in all of which, if the size is 5 1 cm (T1a–b) the percentage of axillary involvement is around 1%. We also believe that axillary dissection can be safely forgone in elderly women, as the results of the consecutive retrospective analysis of Greco et al. [23] indicated. Furthermore, in view of the increasing frequency of radiologically-detected non-palpable lesions which turn out to be in situ, perhaps DCIS should also be included in this category. The risk of axillary metastases in DCIS correlates with the presence of infiltrating microinvasion. About 1% of patients with axillary lymph node metastases have no evidence of stromal invasion on light microscope examination of the primary [27]. In
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such cases invasion is probably present but not recognized or undetected because of sampling error. Incidence rates for axillary involvement in patients diagnosed with DCIS in the pre-mammographic era range from 0.8 to 4% (Table 1) when most patients presented with a palpable mass. In more recent series of DCIS patients detected mammographically, as a small lesion and confirmed histologically, axillary involvement was zero. We therefore tend to consider that axillary dissection is not necessary in intraductal carcinoma cases. A number of ongoing studies are investigating the consequences of avoiding axillary emptying in N0 patients. One approach is to not perform axillary dissection at all, except in patients who develop metastatic lymphadenopathy during follow up. A second approach involves use of the sentinel node. This is the first lymph node to receive lymph from the breast area containing the tumour. The idea is that this node is identified, removed and examined histologically (and immunohistologically if necessary). If it contains no metastases it is reasonable to conclude that the entire axilla is free of metastases.
tute of Oncology (IEO), in which nine other Italian centres are participating. Adjuvant therapy is decided according to the results of biological tests performed on the primary tumour. According to hormonal receptor status, tumour grade and proliferative index (Ki-67) patients receive no further adjuvant treatment, tamoxifen 20 mg/day for 5 years, or six cycles of CMF. At the end of December 1997, 381 patients had been randomized, 188 to the group treated by breast radiation, and 193 to the group treated by radiation to the breast and axilla. A total of 159 cases have been enrolled at IEO and 222 at the other centres. The 363 patients for whom all data was available have been analysed. Tamoxifen was given 264 cases, 78 patients received no adjuvant treatment and 21 received CMF. The breakdown is T5 1cm in 73%, G1 in 42%, G2 in 86%, ER+ in 80% PgG+ in 68% and Ki-67 5 20% in 77%. These data indicate that the great majority of patients so far randomized have favourable prognostic factors; only three patients have developed metastatic axillary nodes. Recruitment will be closed at 400 cases and initial results are expected in 1999.
3.2. The role of the sentinel node 3.1. No axillary dissection and the role of axillary radiotherapy The idea of performing radiotherapy on the axilla instead of axillary dissection was proposed by McWirther [28] based on the results of a randomized study that compared Halsted mastectomy with total mastectomy plus radiotherapy to the axilla. Radiotherapy to the intact axilla does not produce the same side effects as when it is performed after partial axillary dissection. In 1995 a randomized study began to assess the role of axillary radiotherapy in reducing the risk of lymph node metastases in patients older than 45 years and undergoing conservative breast surgery for invasive carcinoma of size not more than 1.2 cm. The objective is to determine whether radiotherapy to the axilla can reduce risk of axillary metastases from the expected 10% without axillary treatment to around 3%. This is a multicentric study, coordinated by the European InstiTable 1 Literature review of DCIS patients who underwent axillary dissection Author
No. of patients
No. of axillary dis- N+cases sections
Ashikary Fisher Lagios Rosner Silverstein Sunshine
112 78 53 210 100 70
113 78 53 210 100 61
1 0 1 8 0 0
The sentinel node technique was first used by Morton with blue dye [29] and van der Veen [30] with radioactive tracer and lymphoscintigraphy to select melanoma patients for regional node dissection. The technique of identification, excision biopsy and histological examination of the sentinel node promises to radically alter the clinical approach to breast cancer and axillary node treatment. Studies published on a large series of patients by Giuliano [31] using the blue dye method, and by our group [32] using 99mtechnetium-labelled albumin and a gamma-ray detecting probe, showed that the accuracy of axillary staging by these techniques can be around 98%. Even greater staging accuracy (close to 100%) is obtained for small unifocal tumours (51.2 cm) located in the upper outer quadrant. The study by our group [32] had three objectives. First to assess the reliability of external-body lymphoscintigraphy as a means of identifying the node receiving lymph from the region of the primary carcinoma; second to assess the utility of g-ray detecting probe to identify and remove the sentinel node during surgery; third to evaluate by histological analysis of all axillary nodes, the predictive value of the sentinel node. The sentinel node was identified with the probe in all but three (98%) of the 163 cases (T1–T3). In 65% of the 160 evaluated cases one sentinel node was detected by the probe, in 25% two nodes were detected and in 9% three nodes were radioactive. The predictive value of the sentinel node or nodes was 97.5%. The sentinel node was the only metastatic node in 40% of cases with an involved axilla, supporting the biological validity of the sentinel
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Table 2 Axillary node metastases according to pathological variables [31] Size of primary (maximum diameter, cm)
No. with positive axillary nodes
%
94 66
45 40
47.8 60.6
117 43
59 26
50.4 60.5
Proliferati6e rate (Ki67) B20 ]20
97 63
47 38
48.4 60.3
Grading a G1 G2 G3
25 72 58
10 36 36
41.6 50.0 62.0
Peritumoral 6ascular in6asion PVI− PVI+
92 68
32 53
35.2 77.9
B2.0 ]2.0 Estrogen receptors ER+ ER−
a
No. of cases
In five cases grading was not available.
node concept. False negative sentinel nodes were observed in four cases (2.5% of all cases and 5.4% of negative cases). In fact lack of reliability of sentinel node diagnosis on standard frozen section examination proved to be a weakness of the method. Frozen sections were examined in the last 107 cases of the series; in 18 cases (17%) the intraoperative diagnosis was falsely negative, as micrometastasic foci were found in the permanent histological sections. This percentage is high and could represent a limiting factor for the technique, since the surgeon must decide whether to empty the axilla in the operating theatre. In the second phase of the study, at least 15 regularly-spaced pairs of sections from the entire sentinel node were examined, with conventional staining and, if negative, immunohistochemical staining. The results in 54 patients showed a 100% concordance between frozen section and permanent section results. This phase of the study also identified pathologic variables predicting metastatic spread to the axillary nodes. Perivascular invasion seems to have the strongest correlation with axillary involvement (Table 2). The third phase of our sentinel node project is now in course. This is a prospective randomized trial to evaluate overall and disease-free survival in patients with unifocal invasive breast carcinoma of size up to 2 cm, without clinically involved lymph nodes. One arm will receive conservative breast surgery plus axillary dissection, the other arm will receive conservative surgery and sentinel lymph node biopsy only — if the histology of the sentinel node proves benign; those with an involved sentinel lymph node will undergo complete axillary dissection. Patients without axillary node involvement, either clinically in the first arm, or those with a negative sentinel node in the second, may receive
systemic therapy depending on prognostic factors determined on the primary (Fig. 1). It remains our opinion that complete axillary dissection must be performed in all patients with a clinically positive axilla. For the near future we envisage four treatment options for the axilla in women with breast cancer and a clinically negative axilla. For tumours up to 1 cm. axillary dissection can probably be avoided; however before this can be adopted as general policy, the results of the clinical trial comparing the axillary radiotherapy and no treatment must be assessed. For tumours up to 2 cm. sentinel node biopsy is likely to be a reliable predictor of axillary status. However it is important that lymphoscintigraphy to identify the sentinel node is performed correctly [33]; that surgeons are trained to isolate the sentinel node with precision; and that the intraoperative histological examination considers an adequate number of
Fig. 1. Design of prospective study to determine long-term validity of the sentinel node biopsy in small size breast cancer.
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sections, perhaps also using immunohistochemical methods. Again, however, the results of the randomized study to verify the reliability of the technique, in terms of its effect on overall and disease-free survival, must be available before sentinel node biopsy can be adopted as a basis for decision-making. For tumours of diameter greater than 1.5 cm. we believe that axillary dissection must always be performed. For certain histotypes and elderly patients, as discussed earlier, axillary dissection can also be avoided.
4. Surgical techniques
4.1. Axillary lymph node dissection This is performed in continuity with the breast incision when the tumour is in the upper-outer quadrant and, normally, by separate incision when the tumour is elsewhere. In the latter case, the incision may follow the lateral margin of the pectoralis major muscle, slightly below it, or cross the axillary skin along natural skin creases. Once the incision has been made, a small lateral cutaneous flap is prepared to allow access to the lateral margin of the latissimus dorsi, its insertion in the humerus, the coracobrachial muscle and the lateral portion of the vasculo – nervous tract. The margin of the latissimus dorsi is isolated along its length so as to identify and prepare the blood vessels and the thoracodorsal nerve. The adipose tissue between the internal fascia of the latissimus dorsi and the surface of the chest wall is detached. At this point the long thoracic nerve (Bell’s nerve) adherent to the chest wall may be observed under the muscle fascia and whose pathway runs from the high portion of the latissimus dorsi nervous – vascular tract to the lower part of the serratus muscle. The medial cutaneous flap is now prepared to access the lateral margin of the pectoralis major and to identify the surface between this and the underlying pectoralis minor. By introducing a retractor the pectoralis minor may be accessed. The adipose tissue between the two muscles, which includes the Rotter lymph nodes, is thus carefully explored and if nodes are palpable they are removed, sparing always the thoracic acromial peduncle and the interpectoralis vessels. The coracoclavicular pectoralis ligament is now located and is displaced medial to the vasculo– nervous thoracic acromial fascia. The margins of the pectoralis minor muscle are identified, and, medially and laterally to the coracoclavicular pectoralis fascia, the index finger is introduced
under the venter musculi. Dissection of the adipose tissue continues by uncovering the plexus brachialis and the axillary vein—the anterior surface of which is isolated. By following the vein medially, the tendon of the subclavius muscle becomes visible; thus reaching the apex of the axilla (3rd level) where the highest axillary lymph nodes and lymphatic vessels are located. These should be isolated carefully, excising the adipose tissue from the tendon of the subclavius muscle and pulling it downwards. The lateral limit of each lymph node level should always be marked by metal discs or different coloured threads to facilitate pathological examination. Performed in this way, so as to spare all vascular and nervous tracts of the muscles, including the intercostal nerves, axillary clearance causes side effects (arm lymphedema, pain and paresthesia) in less than 6% of cases, yet provides maximum possible prognostic information. By contrast random biopsy of one axillary node, sampling, or removal of the first level only, do not ensure disease removal, do not completely obviate the risk of lymphedema and completely overlook the risk of skip metastases, which in our experience is quite rare [10], but is reported to occur in up to 12% of cases by some authors. Complete dissection is not a particularly difficult procedure and extends operating time by only about 10–15 min. Furthermore it eliminates the risk of axillary recurrence and allows an accurate prognosis based on both number of involved nodes and their level.
4.2. Sentinel node biopsy A total of seven MBq of 99mtechnetium-labelled human albumin of size between 200 and 1000 nm (Albu-res, Sorin Biomedica) is administered subdermally above the tumour or peritumorally the day before surgery. After 30 min these particles have entered the lymphatic capillary system and reached the regional lymph-nodes where they are held. Preliminary studies identified albumin nanocolloid in the size range specified as the most suitable non-specific tracer, particularly when the operation is delayed. Whereas sulphide colloid moves faster and is more suitable for patients operated on a few hours later. An incision of 2–3 cm. in the axillary fossa is sufficient to permit removal of the sentinel node under guidance of the gamma ray detecting probe.
Reviewer This paper was reviewed by Professor Luigi Cataliotti, Universita` Degli Studi di Firenze, Instituto di Clinica Chirurgica Generale E Terapia Chirurgica, Italia.
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References [1] Boring CC, Squires TS, Tong T. Cancer statistics. CA Cancer J Clin 1993;43:7 – 26. [2] Veronesi U, Cascinelli N, Bufalino R, et al. Risk of internal mammary lymph-node metastases and its relevance on prognosis of breast cancer patients. Ann Surg 1983;198(6):681–4. [3] Veronesi U, Zingo L. Extended mastectomy for cancer of the breast. Cancer 1967;20:677–80. [4] Fentiman IS, Mansel RE. The axilla: not a no go zone. Lancet 1991;337:221 – 3. [5] Steel RJC, Forrest APM, Gibson T, et al. The efficacy of lower axillary sampling in obtaining lymph node status in breast cancer: a controlled randomized trial. Br J Surg 1985;72:368 – 9. [6] Kissin MW, Price AB, Thompson EM, et al. The inadequacy of axillary sampling in breast cancer. Lancet 1982;1:1210–2. [7] Berg JW. The significance of axillary node levels in the study of breast carcinoma. Cancer 1955;8:776–8. [8] Christensen SB, Jansson C. Axillary biopsy compared with dissection in the staging of lymph nodes in operable breast cancer. A randomised trial. Eur J Surg 1993;159:159–62. [9] Dewar JA, Sarrazin D, Benhamou E, et al. Management of the axilla in conservatively treated breast cancer: 592 patients treated at Institut Gustave-Roussy. Int J Radiat Oncol Biol Phys 1987;13:475 – 81. [10] Veronesi U, Luini A, Galimberti V, et al. Extent of metastatic axillary involvement in 1446 cases of breast cancer. Eur J Surg Oncol 1990;16:127 – 33. [11] Kirikuta IC, Warszawski N, Tausch J, et al. Incomplete axillary dissection in early breast cancer and the risk of erroneous staging. Oncol Reports 1994;1:661–6. [12] Musumeci R, Tesoro Tess JD, Costa A, et al. Indirect lymphography of the breast with iotasul: a vanishing hope? Lymphology 1984;17:118 – 23. [13] Tjandra JJ, Russel IS, Collins JP, et al. Immuno-lymphoscintigraphy for the detection of lymph node metastases from breast cancer. Cancer Res 1989;49:1600–8. [14] Nieweg OE, Kim EE, Wong WH, et al. Positron emission tomography with fluorine-18-deoxyglucose in the detection and staging of breast cancer. Cancer 1989;71:3920–5. [15] Fisher B, Wolmark N, Bauer M, et al. The accuracy of clinical nodal staging and of limited axillary dissection as a determinant of histological nodal status in carcinoma of the breast. Surg Gynecol Obstet 1981;152:765–72. [16] Veronesi U, Galimberti V, Zurrida S, Merson M, Greco M, Luini A. Prognostic significance of number and level of axillary node metastases in breast cancer. Breast 1993;2:224–8. [17] Fisher B, Redmond C, Fisher ER, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. New Engl J Med 1985;312:674 – 81. [18] Axelsson CK, Mouridsen HT, Zedeler K. Axillary dissection of level I and II lymph nodes is important in breast cancer classification. The Danish Breast Cancer Cooperative Group (DBCG). Eur J Cancer 1992;28A:1415–8. [19] Deckers PJ. Axillary dissection in breast cancer: when, why, how much and for how long? Another operation soon to be extinct? J Surg Oncol 1991;48:217–9. [20] Huffty BG, Ward B, Pathare P, et al. Reappraisal of the role of axillary lymph node dissection in the conservative treatment of breast cancer. J Clin Oncol 1997;15:691–700. [21] Cabanes PA, Salmon RJ, Vilcoq JR, et al. Value of axillary dissection in addition to lumpectomy and radiotherapy in early breast cancer. Lancet 1992;339:1245–8. [22] Fein DA, Fowble BL, Hanlon AL, et al. Identification of women with T1 – T2 breast cancer at low risk of positive axillary nodes. J Surg Oncol 1997;65:34–9.
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[23] Greco M, Agresti R, Raselli R, et al. Axillary dissection can be avoided in selected breast cancer patients: Analysis of 401 cases. Anticancer Res 1996;16:3913 – 8. [24] Tabar L, Fagerberg C, Duffy SW, et al. Update of the Swedish two-country program of mammographic screening for breast cancer. Radiol Clin North Am 1992;30:187 – 210. [25] Veronesi U, Salvadori B, Luini A, et al. Breast conservation is a safe method in patients with small cancer of the breast. Longterm results of three randomized trials on 1,973 patients. Eur J Cancer 1995;31(10):1574– 9. [26] Goldhirsch A, Gelber RD, Castiglione M, et al. Present and future projects of the International Breast Cancer Study Group. Cancer 1994;74(1):3. [27] Fowble B. In situ breast cancer. In: Fowble B, Goodman RL, Glick JH, et al., editors. Breast Cancer Treatment: a Comprehensive Guide to Management. St Louis, Mosby-Year book, 1991. [28] McWhirter R. Simple mastectomy and radiotherapy in the treatment of breast cancer. Br J Radiol 1955;28:128 – 39. [29] Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392 – 9. [30] van der Veen H, Hoekstra OS, Paul MA, et al. Gamma probe guided sentinel node biopsy to select patients with melanoma for lymphadenectomy. Br J Surg 1994;8(1):1769– 70. [31] Giuliano AE, Dale P, Turner R, et al. Improved axillary staging of breast cancer with sentinel lymphadenectomy. Ann Surg 1995;222:394 – 401. [32] Veronesi U, Paganelli G, Galimberti V, et al. Sentinel node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. Lancet 1997;349:1864 – 7. [33] De Cicco C, Paganelli G, Cremonesi M, et al. Gamma Probe guided resection of the sentinel node in breast cancer. Eur J Nucl Med 1997;24(8):893.
Biography Dr Alberto Luini graduated in Medicine at Milan University in July 1973. In June 1976, he received a postgraduate degree in Oncology from the University of Genova. From October 1975 until April 1994 he worked as an assistant at the National Cancer Institute, Milan. From 1983 until 1988 he was the National Secretary of the National Research Council (CNR) with the responsibility for organising the activities concerned with the ‘Oncology’ project regarding the guidelines for colon, ovarian, melanoma and head and neck tumours for specialists and general practitioners. Since 1980 Dr Luini is National Secretary of the Task Force for Breast cancer, with responsibility for developing and distributing diagnostic and treatment protocols. In 1996 he was a team member for the development of the guidelines for breast cancer of the CNR ‘ACRO’ project. He forms part of the teaching staff of the Italian School of Senology and the European School of Oncology. He is a member of the editorial board of the ‘Attualita` in Senologia’ magazine, edited by the Italian School of Senology and Medical Radiology Society. He is a member of the European Society of Mastology (Eusoma) and of the board of directors of the Italian
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Society of Senology. His main area of research interest concerns the conservative treatment of breast carcinoma; he has participated in protocol elaboration, patient accrual, follow-up and data evaluation in several randomised clinical studies in this field. His selected publications include: (a) Veronesi U, Saccozzi R, Del Vecchio M, Banfi, Clemente C, De Lena M, Gallus, G, Greco M, Luini A, Marubini E, Muscolino G, Rilke F, Salvadori B, Zecchini A, Zucali R. Comparing
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radical mastectomy with quadrantectomy, axillary dissection and radiotherapy in patients with small cancer of the breast. New Engl J Med 1981;305:6–11; (b) Veronesi U, Luini A, Del Vecchio M, et al. Radiotherapy after breast-preserving surgery in woman with localized cancer of the breast. New Engl J Med 1993;328:1587 –1591; and (c) Luini A, Zurrida S, Galimberti V, Paganelli G. Radioguided surgery of occult breast lesions. Eur J Cancer 1998;34-1:204–205.