Injection material/location

Considerable debate has surrounded the type of injection material used for sentinel node mapping. Some have advocated the use of blue dyes (such as patent blue V or Isosulphan blue) (Fig. 7.2) alone (severe hypersensitivity reactions with these drugs occur in approximately 1 in every 2000 patients), while others have preferred the use of radioactive tracers (such as technetium-99-labelled sulphur colloid or albumin). Still others have advocated the use of agents together. Numerous retrospective studies have found that while the false-negative rates are similar for the three techniques,^7,10,13–15 identification of sentinel nodes is improved with the use of a combined technique.¹⁶ A recent prospective trial found that identification rates were 99.1% when dual tracers were used, as opposed to 93.8–95.6% for blue dye and 96.0–96.2% for radioactive tracer.¹⁷ An approach that uses radioisotope in all patients and adds blue dye only in those patients where radioisotope uptake into sentinel lymph nodes is not apparent has appeal in that it reduces the number who require blue dye.

While originally many practitioners injected tracers at the site of the tumour, the concept of subareolar injection is appealing, particularly for non-palpable and/or multiple tumours, given the embryologic origins of the lymphatics in Sappey’s plexus. A number of authors have found that subareolar injection identifies the same sentinel node as a peritumoural technique,^18,19 has a high identification rate, and the same false-negative rate as other techniques.^17,20 Therefore, while the presence of multifocal/multicentric tumours had once been thought to be a relative contraindication to the use of sentinel node biopsy, more recent studies (many of which used a subareolar injection technique, although some utilised multiple peritumoural injections) have found the accuracy, identification and false-negative rates to be similar to smaller unifocal cancers.²¹

Use of lymphoscintigraphy

Lymphoscintigraphy is often used in melanoma, where drainage patterns can vary widely; however, in breast cancer, where 98–99% of lymphatics drain to the ipsilateral axilla, (Fig. 7.3) lymphoscintigraphy has not been found to be of significant value (uptake of sentinel nodes of radioisotope takes minutes only, allowing injection of isotope after induction of anaesthesia).^22,23 In cases of recurrent breast cancer, however, particularly if 10 or more lymph nodes have previously been removed, alternative drainage pathways may be encountered and lymphoscintigraphy is recommended.²⁴ Even in patients who have had prior complete axillary node dissections, Kaur et al. have demonstrated that lymphoscintigraphy can identify drainage in 29% of patients and, of these, drainage may be non-axillary (contralateral and/or internal mammary) in 38% of cases.²⁵ Furthermore, of the non-axillary sentinel nodes biopsied in the recurrent setting, 40% were positive and thus may alter management plans.²⁵

Intraoperative evaluation

Sentinel nodes may be sent for intraoperative pathological evaluation so as to minimise the possibility of the need for a subsequent completion axillary node dissection in node-positive patients. A number of techniques have been evaluated for intraoperative evaluation – most commonly, frozen section and touch imprint cytology.

Frozen section is the most common technique used, and is associated with a specificity of 99–100% and a sensitivity of 57–74%.²⁶ The sensitivity is far better for macrometastases (84–92%) than micrometastases (17–61%),²⁶ and may be particularly difficult to interpret in patients with invasive lobular carcinomas who have cytologically bland cells and an infiltrative growth pattern. Nonetheless, the overall accuracy of this technique is 83–91%.²⁶

Tew et al. conducted a meta-analysis of 31 studies of touch imprint cytology, and found that specificity and sensitivity of this technique were 94–100% and 34–95% respectively.²⁷ Pooled estimates from 11 studies comparing macro- and micrometastases found that the sensitivity for touch imprint cytology was significantly better for the larger deposits: 81% (95% confidence interval (CI) 74–86%) vs. 22% (95% CI 14–33%) for macro- and micrometastases, respectively.²⁷ On a more global level, the sensitivity of touch imprint cytology is lower than that of frozen section (62% (95% CI 53–70%) vs. 76% (95% CI 65–84%)), while specificity is comparable for both (99%).²⁷ Molecular techniques are available that detect cancer cells in sentinel nodes but these have not found widespread utility.

While intraoperative evaluation has long been advocated to avoid a second operative procedure, given that the majority of screen-detected breast cancer patients will be node negative, and that node-positive patients may not always require axillary node dissection (see ‘Is axillary node dissection necessary in node-positive patients?’ below), the value of intraoperative evaluation of sentinel nodes is under scrutiny.

Prophylactic mastectomy

For women at high risk who are undergoing prophylactic mastectomy, some have advocated sentinel node biopsy, as this avoids the need for subsequent axillary surgery if there is an occult breast cancer that is noted on final pathology, and the sentinel node is negative. Others, however, have argued that the risk of there being a cancer with associated lymph node metastasis is so low in the prophylactic setting that routine sentinel node biopsy, despite being of minimal additional morbidity, is not warranted. In a meta-analysis of six papers including 1251 patients who underwent 1343 prophylactic mastectomies, the rate of occult invasive cancer was 1.7% and the rate of positive sentinel nodes was 1.9%.²⁸ Patients with positive sentinel nodes in the prophylactic setting have often been found to have had a locally advanced breast cancer in the originally treated breast so, in these patients, sentinel node biopsy may be warranted when a prophylactic contralateral mastectomy is being performed.^28,29

Ductal carcinoma in situ (DCIS)

Some have argued that patients with DCIS who are at high risk of having concomitant invasive disease should have a sentinel node biopsy at the time of their excisional surgery to obviate the need to return to the operating room for a sentinel lymph node biopsy should an invasive focus be found on final pathology. The rate of DCIS on large core biopsy being upgraded to invasive disease on final pathology is reported to be up to 47%.^21,30–32 Fewer samples and the use of non-vacuum-assisted devices increase the rates of underestimation of invasive disease.³² Further, clinical factors such as young age, a palpable mass, large tumour size by imaging, high grade, and comedo necrosis are also associated with an increased risk of concomitant invasive disease in patients with core biopsy diagnosis of DCIS.^33,34

While some argue that such patients should have a sentinel lymph node biopsy, others prefer to confirm diagnosis of invasive disease before subjecting patients to a potentially unnecessary lymph node evaluation procedure. While sentinel node biopsy is minimally invasive and associated with few risks, it is not innocuous. It is well established that sentinel node biopsy can be performed after breast-conserving surgery has been performed. A recent meta-analysis comparing sentinel node identification and false-negative rates for patients who underwent surgical versus needle biopsy found that rates were comparable (sentinel node identification rates 91.3% vs. 92.8%; false-negative rates 12.3% vs. 9.9%).³⁵ Therefore, prior surgery does not affect the ability to perform this technique accurately and consensus guidelines have accepted that sentinel node biopsy should not be performed routinely in patients with DCIS undergoing breast-conserving surgery. It is accepted that for patients undergoing mastectomy for DCIS, a sentinel lymph node biopsy should be considered at the same time as the mastectomy,^36,37 as this technique cannot be performed once the breast is removed and an invasive focus is identified. In those with confirmed DCIS the node positivity rate is low at < 1%.

Neoadjuvant chemotherapy

Many patients with locally advanced or inflammatory breast cancers undergo neoadjuvant systemic therapy, and the use of preoperative chemotherapy is becoming increasingly popular even in patients with operable breast cancer, as a means to increase breast conservation rates as well as to evaluate in vivo tumour response to therapy. The burgeoning widespread use of neoadjuvant chemotherapy has led to a plethora of controversies regarding the accuracy and timing of sentinel node biopsy in this situation.

Some have argued that sentinel node biopsy should be performed prior to neoadjuvant systemic therapy. Studies have demonstrated a high identification (98–100%) and an exceedingly low false-negative rate (0%) in this situation.³⁸ Given that this technique is performed prior to any therapy, there can be no confounding of negative results as a result of therapy, which has resulted in false-negative rates as high as 39% in selected series³⁹ reported in patients who have a sentinel node biopsy following chemotherapy. Others, however, have argued that to do a sentinel node biopsy prior to chemotherapy eliminates the opportunity to spare the 2–35% of patients who have a pathologically complete response in the axilla the morbidity of an axillary dissection.³⁸ Furthermore, to evaluate sentinel nodes after neoadjuvant therapy, when surgery for the primary tumour is planned, may reduce the need for a second operative procedure.

A recent meta-analysis has demonstrated that sentinel node biopsy after neoadjuvant chemotherapy is associated with identification rates of between 71% and 100% (summary estimate 90.9%), false-negative rates between 0% and 39% (summary estimate 10.5%), and accuracy rates between 77% and 100% (summary estimate 94.4%).⁴⁰ Two groups have performed trials of sentinel lymph node biopsy (SLNB) in the neoadjuvant setting in women with node positive breast cancer whose nodes are cleared by chemotherapy. The issue these trials addressed is whether axillary dissection (AD) can be avoided in responding patients. The ACOSOG Z1071 trial was a single arm study of 756 women (T0-4, N1-2, M0) undergoing neoadjuvant chemotherapy (NAC) with axillary nodal involvement confirmed by ultrasound guided FNA or core biopsy.⁴¹ Some patients had the involved nodes clipped. Following completion of NAC, SLNB was performed and there had to be at least 2 SLNs removed before proceeding to AD. The primary endpoint was to determine if the false negative rate (FNR) was <10% in women with N1 disease who had at least 2 sentinel nodes biopsied after NAC. Of 643 patients with a SN identified, 40.3% had a complete pathological response in the axilla. SLNB correctly identified nodal status after NAC in 84% of 695 patients. There was a 12.6% false negative rate (higher than the primary endpoint of 10%). The false negative rate (FNR) was significantly lower (10.8%) if dual tracer with both radiolabelled colloid and blue dye was used, compared with blue dye (4/24 – 16.7%) or radioisotope alone (20/101 – 20%) (p=0.046). The FNR was lower if more than 2 nodes were examined, 9.8% for 3 sentinel nodes, 6.7% for 4 sentinel nodes, but 11% for 5 or more, p=0.004 for trend. Placement of a clip in the positive node at diagnosis also decreased the FNR to 7.4% vs 13.6% without clip placement. An apparent chemotherapy effect in the SNs removed as marked by greater fibrosis or other histopathological changes in the sentinel nodes was also associated with a lower FNR (10.8% vs 13.5% without). Avoiding a high rate of false negatives in patients with node positive disease is essential and the results of this study highlight that technical factors are important for accurate SLNB after NAC. Performance can be improved by the use of dual tracer, examination of a minimum of 2 sentinel lymph nodes and placement of clips in involved nodes at diagnosis. These are the requirements if this technique is to be used after NAC.

The German Breast Group addressed the issue of optimal timing for sentinel lymph node in the prospective German, multi-institutional SENTINA-trial.⁴² Of 1737 patients entered, 1022 women were clinically node negative and underwent SLNB prior to NAC. The SLN detection rate in this group of women was 99.1 % (1013/1022). Among these, 360 patients had histologically involved nodes and these women underwent a second SLNB followed by AD after NAC. The SLN detection rate in these patients undergoing their second SLNB after NAC was 60.8% (219/360). 592 patients, who presented initially with suspicious axillary nodes converted to a cN0 status after NAC and underwent SLNB, combined with AD. The SLN detection rate in these women was 80.1% (474/592). The difference between the detection rates of these three groups was highly statistically significant (p < 0.001).

The false negative rate in patients who had a repeat SLNB after NAC was very high at 51.6% and so performing 2 SLNB before and after NAC cannot be recommended. In patients who were down-staged with NAC from positive to negative axillary status, the false negative rate was 14.2%. There are many aspects of the SENTINA study which are unclear. There was no use of clips in nodes. Many sentinel nodes were visualised on scans but not removed. No information has so far been presented on false negative rates related to the number of nodes removed. The results from these two studies are not that different. SLNB after NAC is a difficult procedure. While SLNB before NAC is accurate, patients with involved nodes at diagnosis require AD but many will have their nodes cleared by NAC. For this reason SLNB after chemotherapy has started to be incorporated into clinical practice in selected N1 patients whose primary cancer and nodes respond to NAC. It can however only be recommended when strict criteria are adhered to.

Prediction models

Given that a significant proportion of patients with a positive sentinel node will have no further disease in their non-sentinel lymph nodes, a number of authors have developed nomograms and clinical prediction models in an effort to spare some patients with involved sentinel nodes the morbidity of axillary node dissection. Perhaps the best known of these is the Memorial Sloan-Kettering Nomogram developed by Kim van Zee and colleagues. This model predicts the probability of non-sentinel node status based on a number of factors, including pathological tumour size, grade, lymphovascular invasion, multifocality, oestrogen receptor status, the number of positive and negative sentinel lymph nodes, and the method used to identify sentinel lymph node metastases (either by immunohistochemistry, routine haematoxylin–eosin staining, serial sectioning with haematoxylin–eosin, or frozen section).⁴⁹ A number of other models have also been created, including the Cambridge nomogram,⁵⁰ the Mayo nomogram,⁵¹ the Tenon model,⁵² the MD Anderson score⁵³ and the Stanford nomogram.⁵⁴ All of these include some elements that are often available only after the sentinel nodes have been examined histologically, such as lymphovascular invasion and/or size of sentinel node metastases. These elements are clearly important in predicting non-sentinel node metastases, but in order to assist intraoperative decision-making, the Louisville clinical prediction model was developed as a simple clinical prediction model using variables that are available either pre- or intraoperatively, such as tumour size category, number of positive sentinel nodes and number of sentinel nodes removed.⁵⁵

A recent study by Chen et al. evaluated all of these models in a small independent cohort of 81 patients.⁵⁶ All models were similar, with areas under the curve ranging from 0.54 (95% CI 0.45–0.63) for the Stanford model to 0.73 (95% CI 0.65–0.81) for the Cambridge. Aside from these two outliers, all other models had areas under the curve ranging from 60% to 68%. The false-negative rate for the prediction models ranged from 0% in the Louisville model to 19.8% in the Tenon model. There is a trade-off, however, between the false-negative rate and the number of patients who fall below the threshold for avoiding axillary dissection – so that models such as the Louisville model that had a very low false-negative rate often were more stringent and allowed fewer patients to avoid an axillary dissection.

Is axillary node dissection necessary in node-positive patients?

While nomograms and models can help to define a cohort of node-positive patients who are at low risk of having non-sentinel node disease, the results of recent randomised controlled trials appear to have rendered such models irrelevant. The American College of Surgeons Oncology Group (ACOSOG) Z-0011 trial randomised 891 sentinel node-positive patients to complete axillary node dissection versus no axillary node dissection.⁵⁷ All patients received whole-breast tangential irradiation, which will have covered some of the lower two-thirds of the axilla, although no defined characteristics of the axillary radiation dose were specified in the trial and radiation fields used have yet to be reported. The median total number of nodes removed was 17 in the axillary lymph node dissection and two in the sentinel lymph node biopsy group alone. The median number of nodes with histologically demonstrated involvement was one in both groups; however, 27.3% of patients having a subsequent axillary dissection arm had non-sentinel node metastases.

With a median follow-up of 6.3 years, there was no significant difference in axillary recurrence between the patients who had a complete axillary node dissection (0.5%) and those who did not (0.9%). The adjusted hazard ratio for locoregional recurrence comparing complete dissection with sentinel node biopsy alone was 0.825 (95% CI 0.263–2.586, P = 0.7411).⁵⁵ Rates of locoregional recurrence did not differ between the two arms; local recurrence-free survival at 5 years was 96.7% (95% CI 94.7–98.6%) in the sentinel lymph node biopsy alone group, and 95.7% (95% CI 93.6–97.9%) in the axillary lymph node dissection group (P = 0.28). Disease-free survival did not differ significantly between the two treatment arms; the 5-year disease-free survival was 83.9% (95% CI 80.2–87.9%) for the sentinel lymph node biopsy alone group and 82.8% (95% CI 78.3–86.3%) for the axillary lymph node dissection group (Fig. 7.8). At a median follow-up of 6.3 years, there was no evidence that sentinel lymph node biopsy compared with axillary lymph node dissection resulted in a statistically significant inferior survival (Fig. 7.8). The unadjusted hazard ratio between the two groups was in favour of sentinel lymph node biopsy with a hazard ratio of 0.79 (90% CI 0.56–1.10). The hazard ratio for overall survival, adjusting for adjuvant therapy and age, was 0.87 (90% CI 0.63–1.23). The rates of wound infections, axillary seromas and paraesthesia were significantly higher for the axillary lymph node dissection group (70% vs. 25%, P < 0.001). Lymphoedema was also significantly more common in the axillary lymph node dissection group (P < 0.001), in accordance with other comparisons of sentinel lymph node biopsy and axillary lymph node clearance.

For many surgeons, this trial has been practice changing and has questioned the need for routine axillary dissection in the setting of a positive sentinel node. It should be noted, however, that this study had several important exclusion criteria. Patients who had locally advanced disease or who underwent neoadjuvant chemotherapy were not candidates for the trial. Further, only patients with fewer than three positive nodes were eligible. Patients must have had breast-conserving surgery with whole-breast irradiation (accelerated partial breast irradiation or brachytherapy was an exclusion factor), and most had systemic adjuvant therapy. There are also some other concerns about the trial, specifically the amount of missing data, the inclusion of a number of ineligible patients, the selective nature of the patients entered into the study and the large numbers lost to follow-up. Despite the numbers lost to follow-up, data were complete on survival so the primary end-point does appear secure. Furthermore, although the statistical end-point was achieved, it may be underpowered to show a small but potentially clinically significant effect on outcome. There are, however, large amounts of reassuring data on patients who have involved nodes treated by sentinel node biopsy alone, so the results of the Z-0011 study do not stand alone in indicating that it should no longer be routine practice to advise complete axillary dissection on all patients with a positive sentinel node.

The International Breast Cancer Study Group (IBCSG) 23-01 recently reported as yet unpublished results at the San Antonio Breast Cancer Symposium in December 2011. In this trial, 934 patients with sentinel nodes involved with micrometastases were randomised to complete axillary node dissection compared with no complete axillary node dissection.⁵⁸ Unlike the ACOSOG Z-0011 trial, only 75% of patients had breast-conserving surgery; 89% of patients in the group randomised to axillary node dissection received adjuvant breast or chest wall radiation therapy, and 92% of patients randomised to no complete axillary dissection received radiation. Five-year disease-free survival was 87.3% for the 464 patients who underwent axillary node dissection and 88.4% for the 467 patients who did not undergo this procedure, with low rates of axillary recurrence in both groups. Locoregional recurrences were seen in five patients (1.1%) of those having no axillary dissection: two in the axilla alone, one in the axilla together with internal mammary nodes, one in the breast and axilla, and one in the internal mammary nodes alone. There was only one patient in the axillary dissection group (0.2%) who developed locoregional recurrence and this was an isolated axillary recurrence. Overall survival was 98% at 5 years in both groups.

The European Organisation of Research and Treatment of Cancer (EORTC) 10981 ‘After Mapping of the Axilla, Radiotherapy or Surgery?’ (AMAROS) trial aims to assess whether surgery or radiation to the axilla produce similar outcomes in sentinel node-positive patients. Between 2001 and 2005, 2000 sentinel node-positive patients were enrolled in the trial, and were randomised to either complete axillary node dissection or axillary radiotherapy, and the trial continues.⁵⁹ Long-term recurrence and survival data are as yet unpublished, but this trial should provide valuable information regarding the relative utility of dedicated axillary radiation and axillary dissection in providing locoregional control as well as the relative rates of lymphoedema.

Ultrasound and fine-needle aspiration

Axillary ultrasound and fine-needle aspiration or core biopsy has been embraced as a means of staging the axilla to avoid sentinel node biopsy in node-positive patients, allowing them to proceed directly to axillary node dissection (Fig. 7.9). Given the findings from the Z-0011 trial, the value of this approach has been questioned as not all node-positive patients may need axillary dissection. Sentinel node biopsy in such patients may still be valuable to determine whether less than three sentinel nodes are involved. A number of studies have found the sensitivity of ultrasound with fine-needle aspiration to range from 21% to 86%, with higher rates being found in patients with more extensive lymph node involvement.⁷¹ A recent meta-analysis found the sensitivity and specificity of ultrasound in the detection of lymph node metastases to be 79.6% (95% CI 74.1–84.2) and 98.3% (95% CI 97.2–99.0), respectively.⁷² Furthermore, the rate of ultrasound-guided needle biopsy yielding an insufficient sample was 4.1% (interquartile range 0–10.9%).⁷² The role of ultrasound and fine-needle aspiration may therefore need to be redefined. While some may argue that patients who have a positive ultrasound-guided fine-needle aspiration should proceed directly to axillary node dissection given the propensity for extensive disease in this population, others have suggested that patients with limited nodal disease identified in this manner could be treated with sentinel node biopsy. This would give the option of avoiding axillary dissection in some, given the lack of survival benefit of removing lymph nodes, and the widespread use of adjuvant therapy, which may not change even as the number of positive nodes involved increases.

Positron emission tomography (PET)

PET has been explored as a potential means of detecting disease in the axilla, but to date results have been disappointing. In a meta-analysis of 26 studies, Cooper et al. found the sensitivity of PET to be 63% (range 20–100%; 95% CI 52–74%), with a specificity of 94% (range 75–100%; 95% CI 91–96%). The sensitivity was somewhat improved in studies evaluating PET-only (versus PET–computed tomography (CT); 66% vs. 56%, respectively); specificity, however, was improved by PET-CT (versus PET-only; 96% vs. 93%, respectively).⁷³ Sensitivity was 11% for micrometastases (based on five studies of 63 patients) and 57% for macrometastases (based on four studies of 111 patients).⁷³

Magnetic resonance imaging (MRI)

MRI has become popular as a breast imaging technique and its utility in evaluating axillary lymph nodes has also been investigated. In a meta-analysis of nine studies, Harnan et al. found that the ranges of sensitivity and specificity of this technique were 65–100% and 54–100%, respectively.⁷⁴ Pooled estimates for sensitivity and specificity were 90% for each, but these varied significantly by technique. Ultra-small superparamagnetic iron oxide-enhanced MRI had the highest sensitivity and specificity (98% and 96%, respectively), gadolinium-enhanced MRI performed less well (with a sensitivity and specificity of 88% and 73%, respectively) and magnetic resonance spectroscopy (based on only one study) had sensitivity and specificity of 65% and 100%, respectively.⁷³ At the moment, imaging (whether by ultrasound, PET or MRI) has limited utility without histological confirmation of lymph node metastases.

Complete decongestive therapy

Often considered the primary modality for managing lymphoedema, complete decongestive therapy consists of manual lymph drainage, compression garments/bandaging, lymphatic/decongestive exercises and self-care education.⁷⁵ Intermittent pneumatic compression is often used as an adjunct to manual drainage.⁷⁶

Pharmaceutical interventions

While pharmaceutical interventions with diuretics, benzopyrones and flavonoid derivatives have been investigated as potential therapies in the setting of lymphoedema, none have been found to be universally efficacious, and these modalities have been largely abandoned.⁷⁷

Surgical therapies for lymphoedema

Historic operations, described by Sistrunk⁷⁸ and Thompson,⁷⁹ aimed to create a connection between the superficial and deep lymphatic collection systems by resecting subcutaneous soft tissue and deep fascia. While these procedures may have reduced the size of lymphoedematous extremities, they also caused extensive scarring and morbidity without any objective evidence that new lymphatic pathways were created. Hence, these procedures have been abandoned and are of historic interest only. Liposuction has also been proposed as a technique that could reduce the volume of lymphoedematous extremities;⁸⁰ however, given the risk of injury to residual lymphatics, this technique may actually exacerbate this condition. It is effective in arms with non-pitting swelling with significant excess of fat in the subcutaneous tissue.

Other procedures, aimed at draining excess lymphatic fluid into other lymphatic or venous vessels, have also been described. In particular, some have advocated placing greater omental flaps into the upper extremity while maintaining continuity with the ipsilateral gastroepiploic vessels through a subcutaneous tunnel in the chest.⁸¹ The concept behind this procedure is that the omentum has more lymphatic vessels and that excess lymph fluid may be drained through the omental graft, although there is no objective evidence for this. Some have had success with lymphaticolymphatic bypass using lymphatic vessels of the medial thigh as a free composite graft to bypass routes between the upper arm and the supraclavicular region.⁸² Others have similarly found significant prolonged improvement in lymphoedema using a lymphaticovenular bypass;⁸³ however, these procedures are still anecdotal and not widely adopted.

Finally, microvascular lymph node transfer in which inguinal lymph nodes are transplanted into the axilla as part of a composite soft tissue graft has been suggested.⁸⁴ Although the hypothesis is that this procedure would sprout new lymphatics that would allow improved lymphatic drainage, there are no data to demonstrate that lymphatics regenerate from these nodes. Therefore, surgical management of lymphoedema remains investigational.

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