Feasibility trial for selective surgical localization of axillary lymph nodes containing metastases in breast cancer patients

Abstract

Importance

Nodal ultrasound with needle biopsy of abnormal nodes helps to define the extent of disease prior to neoadjuvant chemotherapy. A clip can be placed to designate nodes with documented metastases. Targeted axillary dissection (TAD), or selective removal of lymph nodes known to contain metastases (clipped nodes) as well as sentinel lymph nodes, may provide more accurate assessment of pathologic response after neoadjuvant chemotherapy.

Objective

The goal of this prospective study was to determine the feasibility of image-guided localization and resection of lymph nodes containing known metastases.

Design, Setting, and Participants

This IRB approved feasibility trial included patients with axillary nodal metastases confirmed by fine needle aspiration biopsy who had a clip placed in the node targeted for biopsy.

Intervention

The clipped lymph node was targeted preoperatively under ultrasound guidance by wire-localization or I¹²⁵ radioactive seed placement. Surgeons removed the localized node before completion axillary node dissection and radiographed the specimen to confirm removal of the clipped node/seed.

Results

Twelve patients were enrolled: 2 had wire localization, and 10 had I¹²⁵ seed placement. Image-guided localization and selective removal was successful in all patients. Five patients underwent sentinel lymph node (SLN) dissection in addition to removal of the clipped lymph node. I¹²⁵ seed placement did not interfere with lymphoscintigraphy or intraoperative identification of SLNs. In 4 (80%) patients, the clipped node was one of the SLNs. Ten patients completed neoadjuvant chemotherapy before surgery. Of the nine patients who underwent node dissection, 4 (44%) had residual nodal disease after chemotherapy; all had disease identified in the clipped lymph node.

Conclusions

Axillary nodes marked with a clip can be localized and selectively removed to accomplish targeted axillary dissection. This is technically possible after chemotherapy and is easily performed with other axillary surgery such as SLN dissection. The ability to add selective removal of clip-containing lymph nodes to SLN dissection has the potential to identify patients for limited nodal surgery after chemotherapy with increased accuracy for determining residual disease over SLN alone.

The presence of lymph node metastases in patients with breast cancer is an important prognostic feature used to guide systemic and locoregional therapies. Neoadjuvant chemotherapy is often used in these patients to downsize the primary tumor, which increases the ability to perform breast conserving therapy (BCT) and also allows for a smaller volume of breast tissue to be resected. Similarly, there is considerable interest in avoiding extensive axillary surgery when chemotherapy eradicates metastatic disease in lymph nodes. Currently, there is no clear consensus on a reliable mode of restaging the axilla after chemotherapy to confirm conversion to negative lymph node status.[1, 2] While sentinel lymph node (SLN) dissection reliably identifies nodal metastases in clinically node negative women,[3-5] this technique alone has had mixed results when performed in clinically node-positive women who receive neoadjuvant chemotherapy.[6-8] The recently published American College of Surgeons Oncology Group (ACOSOG) Z1071 trial was designed to determine if SLN dissection was accurate in staging the axilla after chemotherapy in patients presenting with node-positive disease. The trial had a prespecified false negative rate (FNR) of 10% as the success benchmark. The overall FNR was 12.6% which has sparked considerable conversation about how to improve this to a more acceptable rate. The ultimate goal is to provide optimal oncologic locoregional control with limited morbidity.[1]

On subgroup analysis of ACOSOG Z1071, patients who had a clip placed in nodes after needle biopsy and who had documented removal of the clip-containing SLN had a lower FNR.[9] Thus, perhaps SLN dissection with removal of the lymph node known to contain metastases (clipped node) may improve axillary staging after chemotherapy. In fact, the NCCN recently revised their guidelines to recommend placement of clips in lymph nodes with biopsy-confirmed metastases. The guidelines also mandate that the marked node be removed during surgery.[10] The ability to selectively remove these clip-containing nodes has enormous clinical potential to improve the ability for assessing residual disease and spare patients the considerable morbidity associated with ALND.

We hypothesize that targeted axillary dissection (TAD) which includes not only removing the SLNs, but also removing the clip-containing nodes that contained disease at presentation may be a more reliable approach to restaging the axillary nodal basin after chemotherapy. The goal of this study was to determine the feasibility of localizing clip-containing lymph nodes in patients with known axillary metastases. A secondary endpoint was to determine the feasibility of performing this in conjunction with dual-tracer SLN dissection.

Methods

This is a single-institution prospective IRB approved feasibility study designed to determine methods for localizing and selectively removing axillary lymph nodes containing clips in breast cancer patients. All patients underwent surgery between December 2012 and November 2013. Patients with confirmed axillary metastases and a clip in the sampled node were offered participation in the trial. Patients were eligible if they had surgery after neoadjuvant chemotherapy or if they underwent surgery first. Clinicopathologic data were prospectively obtained from source documentation in the electronic medical record (clinic notes, radiologic and pathology reports).

Nodal Ultrasound and Clip Placement

Per our institutional practice, real-time ultrasound of the ipsilateral regional nodal basins to include the axillary, infraclavicular and internal mammary nodal basins was performed in patients with a diagnosis of breast cancer. Abnormal axillary lymph nodes (eccentric cortical thickening, hilar compression, displacement, or effacement, and irregular margins of the node) were identified, and patients underwent ultrasound-guided FNA using a 21-gauge needle.[11] Immediate cytological evaluation was performed and when this demonstrated metastasis, a clip marker (HydroMark T3) was placed within the cortex of the sampled node under ultrasound guidance. (See Figure 1)

Figure 1.

Ultrasound image of clip in lymph node after neoadjuvant chemotherapy

Radiologic Localization

Prior to surgery, the clipped node was re-identified using gray scale ultrasound. A standard radioactive I¹²⁵ titanium seed with activities ranging 0.100-0.300 mCi or a hook wire was used to target the clipped node, and confirmed on post-procedural mammograms. The I¹²⁵ seed has a half-life of 60 days, and was placed within 5 days of the planned surgery (usually the day before).

Surgical Procedure

In patients who had wire localization (n=2), an axillary incision was made in accordance with the planned ALND. The lymph node localized was then removed separately and x-rayed to confirm that the node contained the clip. In the 10 patients with I¹²⁵ seed localization of the clipped node, the planned axillary incision was made and the axilla explored using a handheld gamma probe optimized to I¹²⁵, which is distinct from the activity setting used for SLN identification. The clipped lymph node was identified using the probe and removed. Intra-operative x-ray confirmed that the excised node contained the clip and seed. After the localized lymph node was removed, the remaining axillary contents were removed per standard surgical technique.

A proportion of patients also underwent SLN dissection at the same operation. This was added after we determined that selective removal of the clipped node was safe and feasible.

Pathologic Handling

Upon arrival to the Pathology laboratory for intra-operative assessment, the specimen was accessioned and taken for gross pathological examination in a separate section of the lab that is designated for handling specimens containing radioactive materials. Prior to sectioning, a gamma probe was used to identify the location of the radioactive seed in the specimen. The specimen was then radiographed to confirm and document the presence of the seed and clip in the specimen. The radioactive seed was removed and stored in a dedicated lead shielded container for storing and subsequent disposal. The removal and storage of the explanted seed was recorded in an inventory log. The lymph node with the marker clip was serially sectioned and placed in a separate cassette for routine processing similar to the non-clipped lymph nodes. Formalin fixed and paraffin embedded tissue blocks of the lymph nodes were cut at 5 micron thickness and stained with hematoxylin and eosin (H&E) for histopathological examination by a dedicated breast pathologist. The histopathological changes in the clipped node, including the presence or absence of residual metastatic carcinoma, was reported in the final pathology report

Results

Twelve patients with node positive disease at diagnosis were included in this study meeting the study’s planned accrual. Clinicopathologic characteristics of the trial participants are summarized in Table 1. Two patients had wire localization and ten patients had localization using I¹²⁵ radioactive seed placement in the clipped node under ultrasound guidance. All cases had successful radiologic localization of the clipped node as well as surgical removal with x-ray confirmation that the clip-containing lymph node was removed (Figure 2).

Table 1.

Clinicopathologic features of trial participants

	N= 12
Mean Age (years)	55 (range 35-69)
Gender:  Female  Male	11 (92%) 1 (8%)
Clinical Tumor Size – mean	3.8 cm (range 1.7-7.5)
Clinical T Stage  T1  T2  T3	2 (67%) 8 (17%) 2 (17%)
Number of suspicious nodes seen on US  1  2  ≥3	8 (67%) 2 (17%) 2 (17%)
Size of sampled lymph node - mean	2.1 cm (range 0.6 – 5)
Tumor Histology:  Ductal  Mixed	11 (92%) 1 (8%)
ER Positive	8 (67%)
PR Positive	8 (67%)
HER2 Positive	2 (17%)
Received Neoadjuvant Chemotherapy:	10 (83%)
Type of breast surgery:  Breast Conserving Therapy  Mastectomy	6 (50%) 6 (50%)
Pathologic Tumor Size - mean	2 cm (range 0-6.7)
SLND performed  Number of SLNs removed - mean  Clip identified in SLN	5 (42%) 2.4 (range 1-6) 4/5 (80%)
ALND performed	11 (92%)
Total number of nodes removed – mean	20 (range 2-34)

Figure 2.

Images of node localization

Figure 2A- Images of wire-localization of lymph node as well as intra-operative radiograph confirming that the clip-containing lymph node was removed.

Figure 2B: Post-localization mammogram of I¹²⁵ localization as well as intra-operative radiograph confirming removal

Five patients had a SLN dissection at the same operation. Presence of the I¹²⁵ seed in the lymph node did not interfere with preoperative lymphoscintigraphy (demonstrated in Figure 3). I¹²⁵ has a gamma emission at 35 keV compared to 140 keV seen with technetium. Lymphoscintigraphy cameras capture 120-150 keV, thus not detecting the I¹²⁵ emission.[12, 13] SLNs were able to be identified in all patients where SLN dissection was attempted. The mean number of SLNs retrieved was 2.4 (range 1-6). The clipped node was also a SLN in 80% (4/5) of cases.

Figure 3.

Lymphoscintigraphy performed after I¹²⁵ seed placed in an axillary node (clipped node). These early images show no axillary radioisotope drainage at that point. However, since the I¹²⁵ seed had already been placed, this demonstrates no interference in radioisotope imaging with the I¹²⁵ seed.

A variety of techniques were used in order to resect the seed-containing lymph node and SLNs. One approach was to start with the gamma probe on the technetium setting to identify SLNs with increased radioisotope count. When “hot” nodes were removed, the gamma probe was then changed to the I¹²⁵ setting to determine if the node contained the radioactive seed. Some surgeons started with the I¹²⁵ setting and identified the clip-containing node first, then changed the probe setting to assess the technetium counts. Both techniques were equally successful. Selective removal of the clipped lymph node did not interfere with the planned completion ALND.

Ten patients had chemotherapy before their axillary surgery and 2 had surgery first. One patient refused ALND, and had only the clipped node (which was also a SLN) as well as one additional SLN removed – no residual disease was identified in the nodes. In the remaining 9 patients who had NCT and completion ALND, four had residual disease identified in the clipped node and 5 had no residual disease. All patients with residual axillary metastases had disease identified in the clipped lymph node.

There were no adverse events reported intraoperatively. Two patients had post-operative complications that were not attributable to the specific removal of the clipped lymph node. One patient had a skin-sparing mastectomy with tissue expander placement at the same operation as the axillary operation. She presented with a hematoma on post-operative day 5 and had surgical exploration which revealed a source of bleeding on the pectoralis muscle. One patient underwent total mastectomy at the time of axillary surgery and was noticed to have post-operative cellulitis which was managed with oral antibiotics as an outpatient.

Discussion

We present a novel surgical technique to localize clip-containing lymph nodes in breast cancer patients with documented axillary metastasis at initial presentation. The technique was successful in a variety of patients, was easily performed by multiple surgeons, and could be performed in conjunction with any breast or axillary surgery. We propose that the selective removal of lymph nodes with confirmed metastases in addition to SLN dissection, targeted axillary dissection, may improve the ability to accurately stage the axilla after chemotherapy. This study was designed to explore the feasibility of localizing clipped lymph nodes, and was not designed to assess the false negative rate of TAD, although prospective studies to assess this are now ongoing.

In the first 2 patients we used wire-localization to identify the clipped node but then transitioned to I¹²⁵ seed localization as this technique became more common for localization of breast lesions. There are several advantages to using the I¹²⁵ seed including patient comfort, increased ease of surgical scheduling, decreased risk of displacement, and potential for decreased risk of injury to surrounding vascular structures in the time between localization and surgery. The seeds are made of titanium and contain I¹²⁵ which emits 35 keV of gamma radiation and has a half-life of 60 days.[12, 13] Our institution has limited the number of seeds inserted in a patient to 4 to limit excess radiation exposure – this allows for placement of the seed in axillary nodes even when multiple seeds are needed to localize breast lesions. Standard handheld gamma probes used for SLN detection can be used to localize both the I¹²⁵ seed as well as radioisotope-containing SLNs by changing the energy mode. Several institutions have now reported on their initial experience with using I¹²⁵ seeds in breast localization showing it to be a safe and oncologically successful approach.[14-17]

The surgical technique for removing seed-containing lymph nodes is straightforward for surgeons experienced with SLN dissections. In fact, participating surgeons felt identifying the seed-containing node was easier since the expected count was >10,000 with no background counts. In a trial from the Netherlands describing the use of radioactive I¹²⁵ seeds to mark lymph nodes for selective removal, the authors reported similar technical success. [18] There were 15 patients who had I¹²⁵ seeds placed in sampled lymph nodes after the initial diagnostic biopsy. Patients then completed chemotherapy with the seed in place, and had selective removal after completion of chemotherapy. Similar to our preliminary results, they found that the clipped lymph node correctly identified patients with residual nodal disease in all cases. Our trial has the added advantage of showing that the localization and removal of the clipped lymph node can be done with SLN dissection. We also show that the seed can be placed in the perioperative period instead of prior to chemotherapy which limits radiation exposure to the patient.

Two recent trials evaluated the accuracy of SLN dissection to stage the axilla after chemotherapy in patients who present with clinically node-positive disease. The ACOSOG Z1071 trial[1] required pathologic confirmation of axillary metastasis by FNA or core biopsy before chemotherapy. While the trial did not meet the prespecified FNR endpoint, it did identify technical aspects that could improve the accuracy of SLN dissection. For instance, the use of dual tracers (radioisotope and blue dye) improved the FNR to 10.8% compared to 20.3% when a single tracer was used (p=0.05). The removal of more SLNs also improved the accuracy from a FNR of 31.5% when 1 SLN was examined to 21.1% if 2 SLNs were examined, to 9.1% if ≥3 SLNs were removed (p=0.007). This is not surprising as one would expect that sensitivity would increase with a larger number of sampled nodes. One preliminary subgroup analysis presented at the 2012 AACR San Antonio Breast Symposium revealed that 96 patients had a clip placed in the lymph node after their initial needle biopsy. When the clipped node was identified in one of the SLNs, the FNR was reduced to 7.4% (95% CI 2-17.9%).[9] This led to revisions to the NCCN guidelines which now recommend marking biopsied nodes with clips when metastases are confirmed and removing all clipped nodes during surgery.[10]

The European SENTInel neoAdjuvant (SENTINA) study[2] also examined the use of SLN dissection in clinically node-positive patients after neoadjuvant chemotherapy. The trial did not require pathologic confirmation of axillary metastases at presentation with only 149/592 patients undergoing needle biopsy of suspicious lymph nodes. Similar to ACOSOG Z1071, they reported an overall FNR of 14.2% (95% CI 9.9-19.4) which improved from 24.3% with a single SLN removed to <10% if ≥3 SLNs were removed. They also reported a trend towards an improved FNR when dual tracers were used versus a single mapping agent (8.6% vs. 16%). Investigators from both trials hypothesize that SLN dissection could accurately stage the axilla after chemotherapy in select patients if technical aspects are optimized.

TAD requires a multidisciplinary team that works together from the first diagnostic nodal ultrasound to the completion of pathology after surgical removal. First, radiologists must place a clip in axillary lymph nodes when metastases are confirmed by needle biopsy. Additionally, radiologists must be available and able to accurately place a wire or I¹²⁵ seed in the clipped node pre-operatively. Surgeons comfortable using gamma probes to identify radioisotope-containing SLNs should be able to accurately identify the seed-containing node intra-operatively, although precautions must be in place because of the radioactive material similar to those used when I¹²⁵ seeds are used to guide segmental mastectomy.[12, 13] Removal of the clipped node is confirmed by intra-operative x-ray which requires a participating pathologist and radiologist. Similar to intra-operative assessment for breast localization, handling and disposing of the I¹²⁵ seed must also be performed in concordance with radioactive safety guidelines.[12, 13]

There are limitations to this pilot feasibility trial. While the small number of patients enrolled established feasibility of the technique, we are unable to evaluate its efficacy in identifying patients with residual nodal disease. Trials to assess this are currently accruing at our institution. Also, while there may be potential for this technique in patients who are not receiving neoadjuvant chemotherapy and otherwise fit ACOSOG Z0011 eligibity criteria but have a single suspicious lymph node seen on US if removal of the clipped node as well as evaluation of sentinel nodes reveals only 1-2 positive nodes, the application of the Z0011 criteria in this case is unclear and will need further investigation. Lastly, placing an I¹²⁵ seed preoperatively involves an added procedure for patients that involves added risk and extra radiation exposure, and should only be implemented into practice if there is a potential benefit.

In conclusion, documented axillary lymph nodes containing metastases marked with a clip can safely be localized and removed at the time of breast surgery. This procedure can be done with wire localization or by placement of a radioactive I¹²⁵ seed and can be performed with other axillary surgery, including SLN dissection and ALND. While ongoing studies must be completed to determine if adding this targeted surgical technique to SLN dissection improves our ability to identify patients whose nodal disease is eradicated by chemotherapy, there is exciting potential for its use in breast cancer and possibly other disease sites as well.