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