The sentinel node in breast cancer.

Biopsy of the sentinel lymph node now forms part of routine management in many centres dealing with early stage breast cancer. This article seeks to discuss developments over the past number of years and to summarise current practice.

Introduction

The prognosis of breast cancer is determined primarily by axillary lymph node status[. Axillary lymph node dissection (ALND) surgery carries a significant morbidity with complications such as lymphoedema, pain, numbness and limited shoulder movement[. The sentinel node is the first draining node on the direct drainage pathway from the primary tumour site[. If the sentinel node is positive there is a 40% risk that higher order nodes may also be involved with metastatic disease[. Moreover, the frequency of patients with metastatic disease increases significantly if a sentinel lymph node policy is in place[. Sentinel lymph node biopsy (SLNB) is a minimally invasive alternative to ALND for nodal staging in breast cancer, which is associated with low post-operative long-term morbidity[. The technique assumes orderly progression of tumour spread to the regional nodes and biopsy of the first node in the lymphatic chain at risk for metastasis should therefore reflect involvement of the remaining nodes. Early prospective studies validated the concept13–16. Subsequent studies have shown that comparing the results of SLNB to ALND indicate that the sentinel node is representative of the presence or absence of metastases in the remainder of the nodal basin (with a false negative rate of less than 2% in most series)[. Current practice is to perform a completion ALND for breast cancer patients although <50% will have non-sentinel node metastases. New models using just three variables have been developed to predict the accuracy of non-sentinel lymph node status[. Introduction of SLNB has led to stage migration as is reflected by the small but significant increase in the proportion of patients with positive axillary lymph nodes after adjustment for tumour size and age[. In a recent analysis of over 35,000 breast cancer patients diagnosed with T1–T2 tumours, clinically negative nodes and without distant metastases, 70% underwent the procedure and for 65% it was the final axillary treatment[.

Technical issues

Lymphoscintigraphy

A large choice of dyes and radiopharmaceuticals (usually 99mTc sulphur colloid) are available. Isosulfan blue dye is safe with anaphylaxis occurring only rarely[28,29]; likewise, with the radiolabelled colloid[. The colloid employed should be of a size to be taken up efficiently and retained within the sentinel node. It has been shown that the highest counts in recovered sentinel nodes were from 100 to 200 nm albumin colloid particles[. Filtered 99mTc-sulphur colloid (100 nm filtered) has a faster transport rate to the regional nodes and lower radiation dosimetry. As a result it is the preferred choice if performing surgery within 2 h of injection[. The sentinel node is more successfully identified with radiopharmaceuticals than with dyes but a combined technique using both maximises the potential of accurate staging[. Increasing body mass, tumour location outside the upper outer quadrant and non-visualisation of nodes on preoperative lymphscintigram adversely affect the accuracy of the procedure[. Combining the technique of dye, isotope and axillary node sampling improves accuracy further.

A recently published study reviewing 434 patients in a single centre demonstrated a positive axillary node in 13/36 patients with a negative sentinel node[. Work performed elsewhere has shown that removal of more than the first four hottest sentinel nodes does not improve staging accuracy[. Preoperative lymphoscintigraphy enables faster location of radioactive nodes at surgery and the combined approach results in identification and harvesting of more nodes[. However, this view is not universally accepted[.

The injection technique seems to matter little as axillary nodes stained blue by intradermal, peritumoural, subdermal, periareolar and subareolar injections identify the same nodes[. It also appears that there is often more than one sentinel lymph node and using dual agents will assist in identifying all sentinel nodes. In a prospective multi-institutional study of 1436 patients, the false negative rate was 14.3% if a single sentinel lymph node was removed compared with 4.3% if multiple sentinel lymph nodes were removed indicating that there is often more than one sentinel node[.

Despite variation in mapping techniques results have been similar worldwide with sensitivity and diagnostic accuracy rates greater than 95% and false negative rates ranging from 0 to 10%[. Some breast cancer programmes do not routinely utilize preoperative lymphoscintigraphy because of the added time, expense and the fact that the surgical decision making can be performed intraoperatively[. Others advocate the concept of the triple-technique comprising preoperative lymphoscintigraphy, injection of radiotracer with use of hand probe and blue dye[. Variables such as availability of resources, patient numbers, level of competence and local working practices mean that no standard protocol exists. Nonetheless, it is recognised that identification of the sentinel node in greater than 96% patients and a false negative rate of less than 5% is a desirable outcome[.

Using lymphoscintigraphy the surface location of the sentinel node can be marked with some centres marking all sentinel nodes visualised[. Although high resolution collimators should be used, a medium energy collimator will suffice[. The camera is placed as close to the patient as possible and images should be acquired in at least two planes. If the site of injection is close to the nodes, shielding may be necessary to visualise the sentinel node. In one centre analysing the results of 640 patients, 94% demonstrated a sentinel node in the ipsilateral axilla but 46% also had sentinel nodes outside the axilla[. The most important site of extra-axillary drainage was to the internal mammary nodal chain and 40% of patients demonstrated a sentinel node in this area[. In 5% of patients drainage was exclusively to extra-axillary sentinel nodes. Preoperative lymphoscintigraphy enables these nodes to be identified. In another study comprising 1201 patients lymphoscintigraphy demonstrated extraaxillary lymph node drainage in almost 25% of patients[. SPECT CT improves pre-operative localisation of draining nodes by detecting nodes missed by planar imaging, excluding non-nodal false positive sites of uptake and accurately localising axillary and extra-axillary nodes particularly in those who are overweight[. Upright imaging may also be advantageous[. Recent work has also shown the potential of the portable gamma camera in theatre over the hand-held probe[.

Site of injection

Several theories exist concerning lymph node drainage in the human breast[. Although Sappey described flow to the subareolar plexus and then to the axilla, this view was not universally accepted[. An alternative drainage pattern proposed direct drainage to the ipsilateral axilla avoiding the subareolar plexus[. A study of 145 dynamic lymphoscintigrams using both intraparenchymal and subdermal injections was unable to visualise the subareolar plexus indicating that it may not act as a conduit to the ipsilateral axilla[. Recently published work on breast lymphatic anatomy (24 breasts, 14 patients) demonstrated no significant difference between female and male breasts[. Perforating lymphatic tracts tracking internal mammary vessels draining internal mammary lymphatics were identified. In some breasts one sentinel node in the axilla drained almost the entire breast but in the majority more than one sentinel node was represented.

The findings are discordant with current understanding of lymphatic drainage and may account for a percentage of false negative studies. They also support peritumoural injection as the preferred technique. Variable drainage patterns from injections of localising agents into the subareolar plexus, subdermal breast tissue and the deep breast parenchyma has been demonstrated by several groups64–67. Seven sites of injection have been described (peritumoural, subdermal, periareolar, intratumoural, intradermal, subareolar and subtumoural) and one of the factors dictating choice is the intention to locate internal mammary nodes in addition to axillary nodes[. Peritumoural injections were the first type of injection used[. Some groups claim better success with intradermal or subdermal injections than with peritumoural technique when sulphur colloid and blue dye are used[. Internal mammary node drainage occurs in a significant proportion after peritumoural injection but not after intradermal injection[. However, the intradermal technique has been shown to identify the SLN in the axilla with a frequency of 98% compared with 90% for peritumoural parenchymal technique[.

A recent study evaluating the success rate of 5 different injection techniques in 192 patients demonstrated that the highest detection rate for the axilla (98%) was obtained with an intradermal-periareolar injection[. The highest detection rate for internal mammary nodes (22%) was achieved using a peritumoural injection. Combining the two injection sites may optimise results. Periareolar injections are made just outside the areolar border at four equally spaced sites. The injections are subdermal although a single subareolar injection lined up with the tumour can also be used[. This technique militates against extra-axillary node identification but is easy and efficient[.

Using a combination of radioisotope and blue dye, the SLN was identified successfully in 98% with no false negative results[. Subareolar injection of blue dye alone has been shown to demonstrate a sentinel lymph node in 98% of cases with no false negative sentinel nodes[. Likewise, it has been shown that subareolar injection of technetium is equivalent to peritumoural injection of blue dye[. One centre uses the combined intraparenchymal and subdermal injection technique because it more accurately reflects all lymphatic flow from breast tumour[. Intraparenchymal injections consistently visualise a more diverse pattern of lymph flow. In particular, the internal mammary chains and supraclavicular nodes are commonly seen after intraparenchymal injection but rarely after subareolar or subdermal injections. Peritumoural and subdermal injection of 99mTc sulphur colloid combined with periareolar injection of isosulphan blue dye is advocated by another group with extensive experience[. In a recent review of 1019 patients a low overall recurrence (0.5%) and overall false negative rate (1.4%) was shown for the intratumoural injection technique[.

When should injection be performed?

Comparable accuracies have been shown for same day and day before surgery radioisotope injections[. After injection, breast massage may be performed to augment lymphatic flow[. However, concern exists that tumour cells might be transported from the primary tumour into the lymphatics. Pressure within the lymphatics can increase up to 22-fold following external massage and transport of tumour cells to the lymphatic spaces has been demonstrated93–95. However, isolated tumour cells are not true metastases and do not have malignant potential. Intraoperative injection is little used as it requires transfer of radioisotope to the operating theatre, is not as reliable and is complicated by radiation safety issues.

Radiation safety

Several papers have discussed various aspects of radiation safety associated with the sentinel node in detail96–102. Radiation doses are low and no additional procedures are required for the protection of staff. The procedure can be performed safely during pregnancy as the foetal dose is very low.

Clinical issues

In a study comparing complete ALND with a two-step procedure in 83 patients there was similar morbidity in terms of lymphoedema, sensory loss, intercostobrachial nerve division rates, impairment of shoulder movement, infection rate or time to resumption of normal day to day activity[. The second surgery was associated with increased axillary operative time and total hospital stay. Contrary to some opinions SNLB is not contraindicated in patients with clinically palpable axillary nodes, multicentric breast cancer or who have undergone previous breast cancer surgery103–105. Relative contraindications include prior axillary surgery, subglandular breast implants and previous breast irradiation[. In one centre, more than 50 patients with subpectoral implants have been associated with 100% SLN identification success rate and no clinically detected recurrences in patients with negative SLN biopsy[. Guide wire localisation may adversely influence visualisation of the sentinel node[.

ALND is the standard treatment for patients with SN metastasis but most of these patients have negative non-sentinel nodes. In a retrospective study of 400 consecutive patients the SLN contained metastases in 148 patients (38.5%)[. In this patient group those with T2 tumours, micrometastases in SLNs and extracapsular node extension were more likely to have non-SLN metastases in both univariate and multivariate analyses. Others have devised scoring systems to help identify a subgroup of patients who have a low risk of having non-sentinel node metastases, obviating the need for ALND[.

For patients with a primary tumour greater than 3 cm the success of SLNB shows little difference to those with smaller tumours[. In patients with multifocal breast cancer sentinel node identification has been reported in 94% and is an accurate predictor of nodal status[. This type of cancer favours a periareolar or subareolar injection protocol. Recent published work involving 213 patients found that although patients with large and/or multifocal tumours were more likely to have a positive sentinel node, the findings provide some indication that SNLB may be reliable for staging the axilla in these patients[. SLNB performed following excisional biopsy demonstrates satisfactory results[.

Patients with ductal carcinoma-in-situ (DCIS) have an excellent long term prognosis (98% survival) but 10–29% of these patients will have invasive cancer at definitive surgery115–121. Analysis of resected nodes from patients who had negative axillary surgery previously demonstrated micrometastases in 13% of nodes but none in patients who had disease recurrence[. In a study of 470 high risk patients with DCIS, 43 (9%) had SLN metastases with 21% of this group being upstaged[. A recent review of 179 patients who underwent mastectomy with SNLB for DCIS were found to have invasive cancer on final pathology in 11%[. The use of SNLB during mastectomy for DCIS allowed nearly all such patients to avoid axillary dissection. A larger study involving 854 patients with pure DCIS identified SLN metastases in 1.4% of patients[. Based on this finding SNLB could not be considered a standard procedure. The sole criteria should be when any uncertainty exists regarding the presence of invasive foci at definitive histology[.

False negative rate

The false negative rate is the percentage of node positive patients who are missed by mapping[. In one centre there has been no axillary recurrence (mean 5 years) following a negative node biopsy in 1914 patients[. A more recent study involving 842 patients demonstrated a false negative rate of 9.6% with grade 3 tumours compared with 4.7% in patients with grade 2 tumours (p = 0.022)[. The false negative rate in patients who had one sentinel node harvested was 10.1% compared with 1.1% in those who had three or more sentinel nodes removed (p = 0.010).

Data from case–control studies to date indicate SLN biopsy to be highly predictive of axillary node status with a false negative rate of less than 5%[. Reasons for false negative results are attributed to changes in surgical personnel, difficult lymph node location and absence of a thorough histological study[. As stated previously factors militating against sentinel node identification are increasing age, increasing body mass index, tumour outside the upper outer quadrant and failure of visualisation on preoperative lymphoscintigraphy[.

A review of 10 large observational studies revealed just 10 axillary recurrences in 2664 patients (0.4%) who did not undergo ALND following negative SLN biopsy[. A large study comprising 4008 patients and a median follow-up of 31 months had an overall axillary recurrence rate of 0.25%[. A further study in 234 patients (median follow-up 42 months) did not find an increased rate of axillary recurrence in patients with negative SLN or SLN micrometastases[. As the axillary recurrence rate should not exceed that seen after conventional axillary clearance surgery (1.0–2.3%), the figures quoted above compare favourably with other work published elsewhere133–135. In a study involving 335 patients with a median follow-up of 33 months, 15 patients (4.5%) who had negative SLNB and who did not undergo completion axillary dissection developed a cancer recurrence. Only 2 patients (0.6%) had an axillary recurrence. A further study following 95 patients (for up to 5 years) with a negative sentinel node without ALND demonstrated that <1% patients developed nodal extraaxillary recurrence[. A multicentre study involving specialised institutions and small community hospitals examined 3534 patients with a median follow-up of 37 months demonstrated that the axilla was the sole site of recurrence in 13 patients (0.6%)[. In 7 patients axillary relapse occurred after or concurrently with a local recurrence in the breast and in a further 7 cases it coincided with distant or extra-axillary lymphatic metastases. The overall recurrence rate was 27 (1.2%), overall 5-year survival rate was 91.6% and disease-free survival rate 92.1%. A recent study by Chetty et al. involving 434 patients demonstrated a false negative rate of 2.4% with pathological analysis indicating that blockage of the lymphatic tracts was the principal cause[.A large multicentre randomised trial comparing SLN with ALND in 749 patients revealed a false negative rate of 16.7% in the ALND arm[. At a median follow-up of 56 months there were more locoregional recurrences in the SLN arm. The 5-year disease free interval was 89.8% in the ALND arm compared with 87.6% in the SLN arm. Unfortunately, the number enrolled was insufficient to make a definitive conclusion.

Internal mammary nodes

Internal mammary nodes with metastases have been documented as independent predictors of poor outcome for patients with breast cancer[. In one centre analysing the results of 640 patients, 94% demonstrated a sentinel node in the ipsilateral axilla and 46% also had sentinel nodes outside the axilla[. In 5% of patients drainage was exclusively to non-axillary sentinel nodes. The most important non-axillary drainage was to the internal mammary nodal chain and 40% of patients demonstrated a sentinel node in this area[. Sentinel lymph node biopsy of internal mammary nodes is associated with a low morbidity and has been shown to improve staging and change treatment strategy[. Proponents of evaluating internal mammary nodes argue that this supports lymphatic mapping as it provides more accurate staging although its impact on outcome is less clear[. Nonetheless, it has been demonstrated that metastases in the internal mammary nodes influence survival in a manner comparable to that of metastases in axillary lymph nodes[. A review with 30-year results demonstrated that patients with isolated IMN disease have a prognosis equivalent to that of patients with isolated axillary metastases[. Combination of metastatic disease in both axillary and internal mammary nodal chains has an especially poor prognosis with a 10 year survival of 37%[. Internal mammary nodes identified on preoperative lymphoscintigraphy require histopathological confirmation of disease before therapy is commenced[. Internal mammary nodes are best identified when peritumoural, intratumoural or subtumoural injections are made with some reports visualising these nodes in 10–30% of patients, whereas subdermal, intradermal, periareolar or subareolar injections result in much less frequent visualisation of these nodes[. A recently published prospective study involving 604 patients demonstrated drainage to internal mammary nodes in 17% resulting in a reduced overall 5-year survival and recurrence free survival[. Internal mammary nodal drainage predicted a nearly three-fold increased mortality risk in node positive patients.

Micrometastases

Micrometastases are defined as tumour deposits in nodes ranging from 0.2 to 2 mm with cells less than 0.2 mm, known as isolated tumour cells[. Despite the evidence of some retrospective studies there is controversy regarding the prognostic significance of micrometastases found only by immunohistochemistry staining, particularly when only isolated tumour cells are found[. A literature review on the clinical significance of micrometastases concluded that they were associated with a poorer prognosis than that associated with no axillary involvement[. In a study involving a 15-year follow-up on almost 100 patients and 1539 axillary lymph nodes with pT1 breast cancer, half of the patients developed distant metastases[. However, studies involving 234 patients and 84 patients (median follow-up 42 and 40 months respectively) showed that micrometastases were not associated with an increased risk of axillary recurrence or that outcome was significantly affected by the presence of micrometastases[. A study involving 2150 patients found micrometastases in 23% of involved sentinel nodes and submicrometastases in 16%[. Additional macrometastases were found in 15% and 4%, respectively, resulting in altered treatment in 7% of patients. In a recently published study involving 2408 patients detection of micrometastatic carcinoma was a major indicator of poorer survival[. In addition, 9.3% of these patients had additional axillary nodal disease on axillary dissection and decreased survival when axillary dissection was omitted. A further study involving the re-examination of axillary node specimens (using modern pathological techniques) obtained surgically 20 years ago revealed that 83 of 368 patients (23%) were converted to node positive[. Univariate and multivariate analysis revealed a significant relationship with disease free survival and disease free death.

Neoadjuvant therapy

In published work to date the SLN identification rate has ranged from 84 to 97% implying that the accuracy of sentinel node biopsy is not influenced by neoadjuvant therapy154–165. A recent prospective study involving 129 patients with infiltrating breast carcinoma and clinically negative axillary nodal disease demonstrated identification of the sentinel node in 94% following neoadjuvant therapy[. Fifty-six of these patients had tumour in the sentinel node with eight having no tumour giving a false negative rate of 14.3%. The false negative patients were correlated with larger tumours and positive nodal status. It would appear therefore that performing SNLB after neoadjuvant therapy can predict axillary lymph nodal status with high accuracy in patients who are clinically node negative at presentation. Questions remain as to whether all nodes respond equally to therapy and a high false negative rate (up to 33%) has been reported in some of these series. Despite recent data, the preferred practice remains performing SLNB prior to commencement of neoadjuvant therapy.

Summary

Lymphatic mapping for early breast cancer has become the standard of care but there is as yet no single study that demonstrates conclusively which particular sentinel node protocol is best for a specific patient.