- Email: [email protected]
Lymph node wire localization post-chemotherapy: Towards improving the false negative sentinel lymph node biopsy rate in breast cancer patients
Clinical Imaging 48 (2018) 69–73
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: www.elsevier.com/locate/clinimag
Lymph node wire localization post-chemotherapy: Towards improving the false negative sentinel lymph node biopsy rate in breast cancer patients☆
MARK
Brittany Z. Dashevskya,⁎, Ashley Altmana, Hiroyuki Abea, Nora Jaskowiakb, Jean Baob, David V. Schachta, Deepa Shetha, Kirti Kulkarnia a b
University of Chicago Medical Center, Department of Radiology, Chicago, IL 60637, United States University of Chicago Medical Center, Department of Surgery, Chicago, IL 60637, United States
A R T I C L E I N F O
A B S T R A C T
Keywords: Lymph node localization Breast cancer Neoadjuvant chemotherapy
Purpose: To evaluate whether the disease status of the pre-neoadjuvant chemotherapy (NAC) core biopsied lymph node (preNACBxLN) in patients with node positive breast cancer corresponds to nodal status of all surgically retrieved lymph nodes (LNs) post-NAC and whether wire localization of this LN is feasible. Materials and methods: HIPPA compliant IRB approved retrospective study including breast cancer patients (a.) with preNACBxLN confirmed metastases, (b.) who received NAC, and (c.) underwent wire localization of the preNACBxLN. Electronic medical records were reviewed. Fisher's exact test was used to compare differences in residual disease post-NAC among breast cancer subtypes. Results: 28 women with node positive breast cancer underwent ultrasound guided wire localization of the preNACBxLN, without complication. There was no evidence of residual nodal disease for 16 patients, with mean 4.4 (median 4) LNs resected. 12 patients had residual nodal metastases, with mean 9.2 (median 7) LNs resected and mean 2.3 (median 2) LNs with tumor involvement. 11 patients had metastases detected within the localized LN. One patient had micrometastasis in a sentinel LN, despite no residual disease in the preNACBxLN. Patients with luminal A/B breast cancer more often had residual nodal metastases (86%) at pathology, as compared to patients with HER2 + (20%) and Triple Negative breast cancer (50%), though not quite achieving statistical significance (p = 0.055). Conclusion: Ultrasound guided wire localization of the preNACBxLN is feasible and may improve detection of residual tumor in patients post-NAC.
1. Introduction Management of the axilla in breast cancer patients has evolved greatly over the last few years. The American College of Surgical Oncology Group (ACOSOG) Z0011 trial recently found no survival benefit with axillary lymph node (LN) dissection (AxLND) over sentinel lymph node biopsy (SLNBx) alone for patients with stage 1 or stage 2 primary breast cancer with ≤ 2 axillary LN metastases, when undergoing breast conservation surgery with adjuvant whole breast radiotherapy and appropriate systemic therapy [1,2]. This may in part be accounted for by improvements in systemic therapy and inclusion of part of the axilla in the radiation field [3–6]. As a result conservative
surgical management of the axilla has been favored. Less extensive LN dissection reduces surgical morbidity by decreasing lymphedema, arm immobility and paresthesia [7–9]. However for patients with locally advanced node-positive breast cancer, who receive neoadjuvant chemotherapy (NAC), AxLND rather than SLNBx has been the mainstay for assessing nodal disease for many years. The SENTINA (SENTinel NeoAdjuvant) study found increased false negative SLNBx rate after neoadjuvant chemotherapy, as compared to prior to treatment [10]. Furthermore the ACOSOG Z1071 trial found a 12.6% false negative SLNBx rate post-NAC, placing the role of SLNBx in this population in question [11]. LN disease status is important for predicting patient prognosis and helps to determine the
Abbreviations: NAC, neoadjuvant chemotherapy; preNACBxLN, pre-neoadjuvant chemotherapy biopsied lymph node; LN, lymph node; AxLND, axillary lymph node dissection; SLNBxSentinel, lymph node biopsy ☆ Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ⁎ Corresponding author. E-mail addresses: [email protected] (B.Z. Dashevsky), [email protected] (A. Altman), [email protected] (H. Abe), [email protected] (N. Jaskowiak), [email protected] (J. Bao), [email protected] (D.V. Schacht), [email protected] (D. Sheth), [email protected] (K. Kulkarni). http://dx.doi.org/10.1016/j.clinimag.2017.10.003 Received 25 May 2017; Received in revised form 29 August 2017; Accepted 3 October 2017 0899-7071/ © 2017 Published by Elsevier Inc.
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extent of LN dissection and need for radiation therapy [10,12]. Thus, studies sought to better assess LN stage with improved LN mapping to allow more conservative management of the axilla [8,13–15]. In the Z1071 trial, the false negative SLNBx rate decreased to < 10% when ≥ 3 LNs were removed and two tracers were used for intra-operative LN mapping. LN staging is further improved when the preNACBxLN is removed at surgery [16,17]. Ultrasound-guided wire or radioactive seed localization may be used to assist retrieval of the preNACBxLN during surgery [16,17]. Preoperative LN localization is currently performed by many practices [18–20]. Here we identify patients with node positive locally-advanced breast cancer who received NAC, and evaluate whether the disease status of the retrieved preNACBxLN corresponds to the nodal status of all surgically retrieved LNs at SLNBx or AxLND. Lastly, we assess whether ultrasound-guided wire localization of the preNACBxLN is feasible.
Table 1 Patient characteristics. Nodal status Nodal disease at pathology Patient characteristics
LNs
Number of patients Age Total resected Residual tumor Wire-localized LN
No residual disease 16
Residual nodal disease 12
47 (range 27–87) 4.4 (median 4) 0 0
52 (range 39–79) 9.2 (median 7) 2.3 11
underwent post-NAC ultrasound-guided LN localization immediately prior to surgical resection. No complications were reported during or immediately post-wire localization. Seven patients underwent localization of the preNACBxLN with concomitant AxLND, with 5/7 found to have residual nodal metastases on pathology. All other patients (21) underwent SLNBx with dual tracer mapping, with 7/21 patients with residual nodal metastases at pathology. Definitive breast surgery was performed at the time of initial LN resection for all patients. Patients with residual nodal disease often had more LNs resected, since they had both more suspicious LNs and more often underwent AxLND (of 12 patients with residual nodal metastases, five underwent AxLND), as opposed to patients without residual nodal disease (of 16 patients without residual nodal metastases, two patients underwent AxLND). Median 4 LNs were removed at SLNBx, by utilizing dual tracer mapping, in accordance with ACOSOG Z1071 recommendations, to ensure appropriate excision of residual nodal disease. For 93% (26/28) of cases appropriate LN targeting was confirmed by identifying a biopsy clip or biopsy site changes within the wire-localized LN on pathology. For the two cases in which the preNACBxLN was not appropriately targeted, biopsy site change was identified on pathology in a different surgically retrieved LN. For these two cases the biopsy clip was difficult to identify on axillary ultrasound. One case had no evidence of nodal disease at pathology, while the other case had nodal metastases in the wire-localized LN, as well as in the preNACBxLN. HER2 + (ER/PR+ or −) and Triple Negative (HER2 −/ER −/ PR −) breast cancers more often responded to NAC, as compared to luminal A/B (HER2 −/ER+) breast cancers (Table 2). Post-NAC there was no pathologic evidence of invasive disease (ypN0 or N0i+ with ypT0 or Tis) in the breast or axilla for 73% (11/15) of HER2 +, 50% (3/ 6) of Triple Negative, and 14% (1/7) of luminal A/B breast cancer. Twenty percent (3/15) of patients with HER2 + breast cancer had residual nodal metastases, compared to 50% (3/6) and 86% (6/7) of patients with Triple Negative and luminal A/B breast cancer, respectively. However, among the breast cancer sub-types, differences in response to NAC for residual primary invasive and nodal disease were not statistically significant (p = 0.11 and 0.055, respectively), likely due to the small number of patients evaluated. For patients with no pathologic evidence of nodal disease (16), a median of 4 (mean 4.4; range 2–14) LNs were resected. For patients with residual nodal metastases (12), 67% had additional LNs with tumor involvement, with a median of 7 (mean 9.2; range 3–21) LNs resected and mean 2.3 LNs with tumor involvement (Table 1). Among patients with residual nodal disease, metastases were identified in the localized LN for 11/12 patients. Three patients had residual disease only within the wire-localized preNACBxLN. One patient had isolated tumor cells identified only in one non-localized sentinel LN; thus, for this case our localized LN was discordant with disease status among all resected LNs. This patient had luminal A (Ki67 15%) primary breast cancer, stage T3N1 and underwent NAC prior to mastectomy and
2. Materials and methods A HIPPA-compliant, IRB approved retrospective study was performed, including breast cancer patients with LN confirmed metastases, who subsequently received NAC and underwent wire localization of the preNACBxLN between January 2015 and December 2016. The health information system at our institution was reviewed for all breast cancer patients. Once breast cancer was confirmed, LN core biopsy was performed on the most suspicious LN identified on imaging for patient staging. Suspicious LN features included cortical thickening greater than 3 mm [21], cortical thickness equal to or greater than the width of the fatty hilum [22] and loss of the fatty hilum. At the time of the LN core biopsy, a marking clip was routinely placed, which allowed reidentification of the biopsied node after NAC and subsequent wire localization under ultrasound guidance. Patients were excluded if pathology was unavailable, if the LN was positive for a second primary cancer, or if the preNACBxLN was negative for metastatic disease. Post-NAC, patients went on to wire localization of the preNACBx LN. Dual tracer (blue dye and 99mTc activity) was used for LN mapping. Patients not in the ALLIANCE A011202 trial had a SLNBx after removal of the wire-localized LN; while patients in the ALLIANCE A011202 trial were randomized to SLNBx or AxLND which was also performed immediately after removal of the wire-localized LN. Upon surgical excision, resected biopsy clip and wire were immediately confirmed on specimen radiograph. The presence of the preNAC placed biopsy clip and biopsy site changes within the localized LN at pathology were used to confirm appropriate targeting. Both the targeted wire-localized LN and any additional resected LNs were identified. All LN specimens were evaluated by pathology with hematoxylin and eosin staining. Breast cancer staging post-NAC was performed at pathologic evaluation, in accordance with the American Joint Committee on Cancer Staging Manual, 7th edition. Treatment response and residual disease at pathology were recorded for both the resected axillary LNs and the primary breast cancer. Fisher's exact test was used to evaluate for significant differences in residual tumor within the breast or LNs among various breast cancer sub-types. Electronic medical records were reviewed for clinical, imaging and pathology findings. 3. Results Twenty-eight women with a mean age of 49 years (range: 28–87 years) with locally advanced breast cancer (27 IDC; 1 ILC) and LN involvement confirmed on pre-NAC core biopsy met inclusion/exclusion criteria (Table 1). Breast cancer stages of the 28 included women were as follows: 17 T2N1, 8 T3N1, 1 T2N2, 1 T3N2, and 1 T4N1. For all cases, a Hydromark (Biopsy Sciences, Clearwater, Florida) (Fig. 1) was placed post-core LN biopsy to facilitate detection of the core biopsied LN on ultrasound. Upon completion of NAC, patients were evaluated for treatment response and surgical planning. Patients 70
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Fig. 1. Workup of a 45 year old female with breast cancer. Upon identification of a primary breast cancer, the ipsilateral axilla was evaluated on ultrasound for suspicious LNs, and a LN with thickened cortex was identified (a). Patient underwent ultrasound guided core LN biopsy, with placement of a Hydromark clip (b), with nodal involvement confirmed on pathology. After NAC (c), the LN is no longer evident on ultrasound and only the Hydromark clip was visible. Ultrasound-guided wire localization of this LN (d) and mammography guided localization of the residual primary breast cancer was performed. Upon surgical resection, specimen imaging demonstrates the LN with traversing wire and biopsy clip present (e). Pathology results revealed residual nodal metastases within the wire-localized LN, and one additional sentinel LN, with the largest metastatic deposit measuring 0.7 mm.
SLNBx (stage ypT3N0i+).
Table 2 Residual breast cancer and nodal metastases by breast cancer sub-type. Type of breast cancer No. of patients LN status post NAC
Residual Primary breast Cancer
ypN0 ypN0i + N1 N2 ypT0 ypTis ypT1 ypT2 ypT3
HER2 +
Luminal A/B
Triple Neg
4. Discussion
15 80% (12) 0% (0) 13% (2) 7% (1) 40% (6) 33% (5) 20% (3) 0% (0) 7% (1)
7 14% (1) 14% (1) 57% (4) 14% (1) 0% (0) 14% (1) 29% (2) 29% (2) 29% (2)
6 50% (3) 33% (2) 17% (1) 0% (0) 50% (3) 17% (1) 33% (2) 0% (0) 0% (0)
We find wire localization of the preNACBxLN is feasible, with appropriate targeting obtained in 93% of cases. In agreement with prior work, patients with luminal A/B breast cancers were more likely to have residual breast or axillary nodal disease post-NAC, compared to patients with HER2 + or Triple Negative breast cancer [23,24]. For 3 patients in this study, the only residual tumor identified was located within the wire-localized preNACBxLN. Prior work found that post-NAC, the preNACBxLN may not be identified with blue dye or 99mTc mapping in 9–27% of cases [17,18,20]. Since this LN is the most likely to contain residual tumor, given presence of metastases prior to treatment, ultrasound-guided localization can be used to ensure removal and pathologic evaluation of this LN. Performing ultrasound71
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guided localization of the preNACBxLN in conjunction with SLNBx would be expected to decrease the FNR associated with SLNBx postNAC. We also identify a single case in which isolated tumor cells persist in an axillary LN, despite no residual tumor in the preNACBxLN. Thus, while localization of the preNACBxLN may provide a global assessment of nodal disease status, small residual tumor foci may be missed. Patients undergoing breast conservation surgery with T1 or T2 primary breast cancer and ≤ 2 involved LNs who received appropriate radiation and chemotherapy on the ACOSOG Z0011 trial did not benefit from AxLND [1,2]; nor did patients with micrometastases benefit from AxLND on the IBCSG 23-01 clinical trial [25]. This raises the question of which other patients, such as those undergoing NAC, may similarly benefit from more conservative nodal management. For patients who convert to cN0, the benefit of AxLND and radiation therapy is unclear [10,16,26]. Moreover, residual nodal micrometastases post-NAC are of uncertain significance and further work is needed to determine optimal management. Clinical trials are currently underway to determine the utility of AxLND among patients with node positive breast cancer who remain node-positive post-NAC (Alliance A011202) and the utility of radiation therapy among patients who convert to pathologically node-negative disease post-NAC (NSABP B51). In patients who respond to NAC, ensuring removal of the preNACBxLN can be particularly challenging due to reduction in size of the LN, as seen in Fig. 1c. Though the biopsied LN is marked with a biopsy clip, the clip is sometimes difficult to identify on ultrasound of the axilla. The HydroMARK clip was specifically designed for ultrasound detection and is comprised of a small echogenic titanium component surrounded by hypoechoic PEG based hydrogel, and appears as two small echogenic lines. This hydrogel can be seen for at least 3 months post-deployment in the untreated breast [27]. However, it was not always evident post-NAC in some of our cases. This may be due to absorption of the hydrogel fluid and difficulty detecting the echogenic titanium marker in the axilla or within the LN hilum which are both echogenic. The biopsy clip is better identified when placed within the cortex of the abnormal LN. The UltraCor TWIRL clip is another reasonable alternative for LN biopsies which consists of a larger echogenic metallic (Nitinol) component, which may be easier to detect on post-NAC ultrasound. The TWIRL clip is comprised of two concentric rings and is more echogenic than the HydroMARK. The rings are identified, rather than two short echogenic lines. However, the TWIRL clip causes more susceptibility artifact on MRI, as compared to HydroMARK. Localization of the preNACBxLN has only recently been implemented at some institutions. More data is needed to confirm these retrospective results and to optimize LN targeting. Other limitations of this study include the fact that not all patients went on to have AxLND. While unlikely, there may have been LNs with residual tumor that went undetected.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
5. Conclusion Nonetheless, we find ultrasound-guided wire localization of the preNACBxLN to be feasible. Wire localization of the preNACBxLN may improve detection of residual tumor in patients post-NAC, where dual tracer mapping is unable to identify this node. Among patients with residual nodal disease, wire localization of the preNACBxLN identified 11/12 patients. Complete NAC response of the wire-localized preNACBxLN may allow for more conservative LN surgery in patients receiving appropriate systemic therapy and radiation, possibly resulting in less morbidity for these patients.
[19]
[20]
[21]
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Contents lists available at ScienceDirect
Clinical Imaging journal homepage: www.elsevier.com/locate/clinimag
Lymph node wire localization post-chemotherapy: Towards improving the false negative sentinel lymph node biopsy rate in breast cancer patients☆
MARK
Brittany Z. Dashevskya,⁎, Ashley Altmana, Hiroyuki Abea, Nora Jaskowiakb, Jean Baob, David V. Schachta, Deepa Shetha, Kirti Kulkarnia a b
University of Chicago Medical Center, Department of Radiology, Chicago, IL 60637, United States University of Chicago Medical Center, Department of Surgery, Chicago, IL 60637, United States
A R T I C L E I N F O
A B S T R A C T
Keywords: Lymph node localization Breast cancer Neoadjuvant chemotherapy
Purpose: To evaluate whether the disease status of the pre-neoadjuvant chemotherapy (NAC) core biopsied lymph node (preNACBxLN) in patients with node positive breast cancer corresponds to nodal status of all surgically retrieved lymph nodes (LNs) post-NAC and whether wire localization of this LN is feasible. Materials and methods: HIPPA compliant IRB approved retrospective study including breast cancer patients (a.) with preNACBxLN confirmed metastases, (b.) who received NAC, and (c.) underwent wire localization of the preNACBxLN. Electronic medical records were reviewed. Fisher's exact test was used to compare differences in residual disease post-NAC among breast cancer subtypes. Results: 28 women with node positive breast cancer underwent ultrasound guided wire localization of the preNACBxLN, without complication. There was no evidence of residual nodal disease for 16 patients, with mean 4.4 (median 4) LNs resected. 12 patients had residual nodal metastases, with mean 9.2 (median 7) LNs resected and mean 2.3 (median 2) LNs with tumor involvement. 11 patients had metastases detected within the localized LN. One patient had micrometastasis in a sentinel LN, despite no residual disease in the preNACBxLN. Patients with luminal A/B breast cancer more often had residual nodal metastases (86%) at pathology, as compared to patients with HER2 + (20%) and Triple Negative breast cancer (50%), though not quite achieving statistical significance (p = 0.055). Conclusion: Ultrasound guided wire localization of the preNACBxLN is feasible and may improve detection of residual tumor in patients post-NAC.
1. Introduction Management of the axilla in breast cancer patients has evolved greatly over the last few years. The American College of Surgical Oncology Group (ACOSOG) Z0011 trial recently found no survival benefit with axillary lymph node (LN) dissection (AxLND) over sentinel lymph node biopsy (SLNBx) alone for patients with stage 1 or stage 2 primary breast cancer with ≤ 2 axillary LN metastases, when undergoing breast conservation surgery with adjuvant whole breast radiotherapy and appropriate systemic therapy [1,2]. This may in part be accounted for by improvements in systemic therapy and inclusion of part of the axilla in the radiation field [3–6]. As a result conservative
surgical management of the axilla has been favored. Less extensive LN dissection reduces surgical morbidity by decreasing lymphedema, arm immobility and paresthesia [7–9]. However for patients with locally advanced node-positive breast cancer, who receive neoadjuvant chemotherapy (NAC), AxLND rather than SLNBx has been the mainstay for assessing nodal disease for many years. The SENTINA (SENTinel NeoAdjuvant) study found increased false negative SLNBx rate after neoadjuvant chemotherapy, as compared to prior to treatment [10]. Furthermore the ACOSOG Z1071 trial found a 12.6% false negative SLNBx rate post-NAC, placing the role of SLNBx in this population in question [11]. LN disease status is important for predicting patient prognosis and helps to determine the
Abbreviations: NAC, neoadjuvant chemotherapy; preNACBxLN, pre-neoadjuvant chemotherapy biopsied lymph node; LN, lymph node; AxLND, axillary lymph node dissection; SLNBxSentinel, lymph node biopsy ☆ Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ⁎ Corresponding author. E-mail addresses: [email protected] (B.Z. Dashevsky), [email protected] (A. Altman), [email protected] (H. Abe), [email protected] (N. Jaskowiak), [email protected] (J. Bao), [email protected] (D.V. Schacht), [email protected] (D. Sheth), [email protected] (K. Kulkarni). http://dx.doi.org/10.1016/j.clinimag.2017.10.003 Received 25 May 2017; Received in revised form 29 August 2017; Accepted 3 October 2017 0899-7071/ © 2017 Published by Elsevier Inc.
Clinical Imaging 48 (2018) 69–73
B.Z. Dashevsky et al.
extent of LN dissection and need for radiation therapy [10,12]. Thus, studies sought to better assess LN stage with improved LN mapping to allow more conservative management of the axilla [8,13–15]. In the Z1071 trial, the false negative SLNBx rate decreased to < 10% when ≥ 3 LNs were removed and two tracers were used for intra-operative LN mapping. LN staging is further improved when the preNACBxLN is removed at surgery [16,17]. Ultrasound-guided wire or radioactive seed localization may be used to assist retrieval of the preNACBxLN during surgery [16,17]. Preoperative LN localization is currently performed by many practices [18–20]. Here we identify patients with node positive locally-advanced breast cancer who received NAC, and evaluate whether the disease status of the retrieved preNACBxLN corresponds to the nodal status of all surgically retrieved LNs at SLNBx or AxLND. Lastly, we assess whether ultrasound-guided wire localization of the preNACBxLN is feasible.
Table 1 Patient characteristics. Nodal status Nodal disease at pathology Patient characteristics
LNs
Number of patients Age Total resected Residual tumor Wire-localized LN
No residual disease 16
Residual nodal disease 12
47 (range 27–87) 4.4 (median 4) 0 0
52 (range 39–79) 9.2 (median 7) 2.3 11
underwent post-NAC ultrasound-guided LN localization immediately prior to surgical resection. No complications were reported during or immediately post-wire localization. Seven patients underwent localization of the preNACBxLN with concomitant AxLND, with 5/7 found to have residual nodal metastases on pathology. All other patients (21) underwent SLNBx with dual tracer mapping, with 7/21 patients with residual nodal metastases at pathology. Definitive breast surgery was performed at the time of initial LN resection for all patients. Patients with residual nodal disease often had more LNs resected, since they had both more suspicious LNs and more often underwent AxLND (of 12 patients with residual nodal metastases, five underwent AxLND), as opposed to patients without residual nodal disease (of 16 patients without residual nodal metastases, two patients underwent AxLND). Median 4 LNs were removed at SLNBx, by utilizing dual tracer mapping, in accordance with ACOSOG Z1071 recommendations, to ensure appropriate excision of residual nodal disease. For 93% (26/28) of cases appropriate LN targeting was confirmed by identifying a biopsy clip or biopsy site changes within the wire-localized LN on pathology. For the two cases in which the preNACBxLN was not appropriately targeted, biopsy site change was identified on pathology in a different surgically retrieved LN. For these two cases the biopsy clip was difficult to identify on axillary ultrasound. One case had no evidence of nodal disease at pathology, while the other case had nodal metastases in the wire-localized LN, as well as in the preNACBxLN. HER2 + (ER/PR+ or −) and Triple Negative (HER2 −/ER −/ PR −) breast cancers more often responded to NAC, as compared to luminal A/B (HER2 −/ER+) breast cancers (Table 2). Post-NAC there was no pathologic evidence of invasive disease (ypN0 or N0i+ with ypT0 or Tis) in the breast or axilla for 73% (11/15) of HER2 +, 50% (3/ 6) of Triple Negative, and 14% (1/7) of luminal A/B breast cancer. Twenty percent (3/15) of patients with HER2 + breast cancer had residual nodal metastases, compared to 50% (3/6) and 86% (6/7) of patients with Triple Negative and luminal A/B breast cancer, respectively. However, among the breast cancer sub-types, differences in response to NAC for residual primary invasive and nodal disease were not statistically significant (p = 0.11 and 0.055, respectively), likely due to the small number of patients evaluated. For patients with no pathologic evidence of nodal disease (16), a median of 4 (mean 4.4; range 2–14) LNs were resected. For patients with residual nodal metastases (12), 67% had additional LNs with tumor involvement, with a median of 7 (mean 9.2; range 3–21) LNs resected and mean 2.3 LNs with tumor involvement (Table 1). Among patients with residual nodal disease, metastases were identified in the localized LN for 11/12 patients. Three patients had residual disease only within the wire-localized preNACBxLN. One patient had isolated tumor cells identified only in one non-localized sentinel LN; thus, for this case our localized LN was discordant with disease status among all resected LNs. This patient had luminal A (Ki67 15%) primary breast cancer, stage T3N1 and underwent NAC prior to mastectomy and
2. Materials and methods A HIPPA-compliant, IRB approved retrospective study was performed, including breast cancer patients with LN confirmed metastases, who subsequently received NAC and underwent wire localization of the preNACBxLN between January 2015 and December 2016. The health information system at our institution was reviewed for all breast cancer patients. Once breast cancer was confirmed, LN core biopsy was performed on the most suspicious LN identified on imaging for patient staging. Suspicious LN features included cortical thickening greater than 3 mm [21], cortical thickness equal to or greater than the width of the fatty hilum [22] and loss of the fatty hilum. At the time of the LN core biopsy, a marking clip was routinely placed, which allowed reidentification of the biopsied node after NAC and subsequent wire localization under ultrasound guidance. Patients were excluded if pathology was unavailable, if the LN was positive for a second primary cancer, or if the preNACBxLN was negative for metastatic disease. Post-NAC, patients went on to wire localization of the preNACBx LN. Dual tracer (blue dye and 99mTc activity) was used for LN mapping. Patients not in the ALLIANCE A011202 trial had a SLNBx after removal of the wire-localized LN; while patients in the ALLIANCE A011202 trial were randomized to SLNBx or AxLND which was also performed immediately after removal of the wire-localized LN. Upon surgical excision, resected biopsy clip and wire were immediately confirmed on specimen radiograph. The presence of the preNAC placed biopsy clip and biopsy site changes within the localized LN at pathology were used to confirm appropriate targeting. Both the targeted wire-localized LN and any additional resected LNs were identified. All LN specimens were evaluated by pathology with hematoxylin and eosin staining. Breast cancer staging post-NAC was performed at pathologic evaluation, in accordance with the American Joint Committee on Cancer Staging Manual, 7th edition. Treatment response and residual disease at pathology were recorded for both the resected axillary LNs and the primary breast cancer. Fisher's exact test was used to evaluate for significant differences in residual tumor within the breast or LNs among various breast cancer sub-types. Electronic medical records were reviewed for clinical, imaging and pathology findings. 3. Results Twenty-eight women with a mean age of 49 years (range: 28–87 years) with locally advanced breast cancer (27 IDC; 1 ILC) and LN involvement confirmed on pre-NAC core biopsy met inclusion/exclusion criteria (Table 1). Breast cancer stages of the 28 included women were as follows: 17 T2N1, 8 T3N1, 1 T2N2, 1 T3N2, and 1 T4N1. For all cases, a Hydromark (Biopsy Sciences, Clearwater, Florida) (Fig. 1) was placed post-core LN biopsy to facilitate detection of the core biopsied LN on ultrasound. Upon completion of NAC, patients were evaluated for treatment response and surgical planning. Patients 70
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Fig. 1. Workup of a 45 year old female with breast cancer. Upon identification of a primary breast cancer, the ipsilateral axilla was evaluated on ultrasound for suspicious LNs, and a LN with thickened cortex was identified (a). Patient underwent ultrasound guided core LN biopsy, with placement of a Hydromark clip (b), with nodal involvement confirmed on pathology. After NAC (c), the LN is no longer evident on ultrasound and only the Hydromark clip was visible. Ultrasound-guided wire localization of this LN (d) and mammography guided localization of the residual primary breast cancer was performed. Upon surgical resection, specimen imaging demonstrates the LN with traversing wire and biopsy clip present (e). Pathology results revealed residual nodal metastases within the wire-localized LN, and one additional sentinel LN, with the largest metastatic deposit measuring 0.7 mm.
SLNBx (stage ypT3N0i+).
Table 2 Residual breast cancer and nodal metastases by breast cancer sub-type. Type of breast cancer No. of patients LN status post NAC
Residual Primary breast Cancer
ypN0 ypN0i + N1 N2 ypT0 ypTis ypT1 ypT2 ypT3
HER2 +
Luminal A/B
Triple Neg
4. Discussion
15 80% (12) 0% (0) 13% (2) 7% (1) 40% (6) 33% (5) 20% (3) 0% (0) 7% (1)
7 14% (1) 14% (1) 57% (4) 14% (1) 0% (0) 14% (1) 29% (2) 29% (2) 29% (2)
6 50% (3) 33% (2) 17% (1) 0% (0) 50% (3) 17% (1) 33% (2) 0% (0) 0% (0)
We find wire localization of the preNACBxLN is feasible, with appropriate targeting obtained in 93% of cases. In agreement with prior work, patients with luminal A/B breast cancers were more likely to have residual breast or axillary nodal disease post-NAC, compared to patients with HER2 + or Triple Negative breast cancer [23,24]. For 3 patients in this study, the only residual tumor identified was located within the wire-localized preNACBxLN. Prior work found that post-NAC, the preNACBxLN may not be identified with blue dye or 99mTc mapping in 9–27% of cases [17,18,20]. Since this LN is the most likely to contain residual tumor, given presence of metastases prior to treatment, ultrasound-guided localization can be used to ensure removal and pathologic evaluation of this LN. Performing ultrasound71
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guided localization of the preNACBxLN in conjunction with SLNBx would be expected to decrease the FNR associated with SLNBx postNAC. We also identify a single case in which isolated tumor cells persist in an axillary LN, despite no residual tumor in the preNACBxLN. Thus, while localization of the preNACBxLN may provide a global assessment of nodal disease status, small residual tumor foci may be missed. Patients undergoing breast conservation surgery with T1 or T2 primary breast cancer and ≤ 2 involved LNs who received appropriate radiation and chemotherapy on the ACOSOG Z0011 trial did not benefit from AxLND [1,2]; nor did patients with micrometastases benefit from AxLND on the IBCSG 23-01 clinical trial [25]. This raises the question of which other patients, such as those undergoing NAC, may similarly benefit from more conservative nodal management. For patients who convert to cN0, the benefit of AxLND and radiation therapy is unclear [10,16,26]. Moreover, residual nodal micrometastases post-NAC are of uncertain significance and further work is needed to determine optimal management. Clinical trials are currently underway to determine the utility of AxLND among patients with node positive breast cancer who remain node-positive post-NAC (Alliance A011202) and the utility of radiation therapy among patients who convert to pathologically node-negative disease post-NAC (NSABP B51). In patients who respond to NAC, ensuring removal of the preNACBxLN can be particularly challenging due to reduction in size of the LN, as seen in Fig. 1c. Though the biopsied LN is marked with a biopsy clip, the clip is sometimes difficult to identify on ultrasound of the axilla. The HydroMARK clip was specifically designed for ultrasound detection and is comprised of a small echogenic titanium component surrounded by hypoechoic PEG based hydrogel, and appears as two small echogenic lines. This hydrogel can be seen for at least 3 months post-deployment in the untreated breast [27]. However, it was not always evident post-NAC in some of our cases. This may be due to absorption of the hydrogel fluid and difficulty detecting the echogenic titanium marker in the axilla or within the LN hilum which are both echogenic. The biopsy clip is better identified when placed within the cortex of the abnormal LN. The UltraCor TWIRL clip is another reasonable alternative for LN biopsies which consists of a larger echogenic metallic (Nitinol) component, which may be easier to detect on post-NAC ultrasound. The TWIRL clip is comprised of two concentric rings and is more echogenic than the HydroMARK. The rings are identified, rather than two short echogenic lines. However, the TWIRL clip causes more susceptibility artifact on MRI, as compared to HydroMARK. Localization of the preNACBxLN has only recently been implemented at some institutions. More data is needed to confirm these retrospective results and to optimize LN targeting. Other limitations of this study include the fact that not all patients went on to have AxLND. While unlikely, there may have been LNs with residual tumor that went undetected.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
5. Conclusion Nonetheless, we find ultrasound-guided wire localization of the preNACBxLN to be feasible. Wire localization of the preNACBxLN may improve detection of residual tumor in patients post-NAC, where dual tracer mapping is unable to identify this node. Among patients with residual nodal disease, wire localization of the preNACBxLN identified 11/12 patients. Complete NAC response of the wire-localized preNACBxLN may allow for more conservative LN surgery in patients receiving appropriate systemic therapy and radiation, possibly resulting in less morbidity for these patients.
[19]
[20]
[21]
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