Axillary nodal evaluation in patients with breast cancer – When, why and how?

Mammography

The axilla is incompletely imaged on standard mammographic imaging due to limitations of positioning. While level I nodes are visible on the mediolateral oblique view in 50% of patients^[7] [Figure 2a], their visualization is dependent on positioning [Figure 2b]. A normal axillary node demonstrates a thin cortex, reniform shape, and a fatty hilum [Figure 2a]. An abnormal node demonstrates a thickened cortex, loss of reniform shape, and loss of the fatty hilum [Figure 2c]. Dedicated axillary views can be performed in certain cases to increase visualization of axillary tissue. Metastatic nodes can rarely show calcifications similar to those seen in the primary tumor.^[8] Differential diagnosis for abnormal axillary nodes includes reactive nodes, inflammatory diseases such as sarcoidosis, lymphoma, and metastases from breast and non-breast primaries. Calcifications within abnormal axillary nodes can also be seen in tuberculous lymphadenopathy. Tattoo pigmentation and silicone within nodes can mimic calcifications. Correlation with patient history can help distinguish between these entities.^[9,10]

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Figure 2:

Mammographic evaluation of the axilla. A 65-year-old patient underwent routine mammographic screening over multiple years. (a) Right mediolateral oblique (RMLO) view shows heterogeneously dense parenchyma. Multiple normal axillary nodes are seen in the axilla (yellow circle). The nodes demonstrate a reniform shape, thin cortex, and a preserved fatty hilum. (b) RMLO view from screening mammogram performed the next year does not show any axillary nodes due to positioning. (c) RMLO view from screening mammogram 2 years later shows an enlarged axillary node with cortical thickening, loss of reniform shape, and partial loss of the fatty hilum (yellow arrow). An irregular mass with spiculated margins is seen in the upper right breast (white circle). Ultrasound-guided biopsy of the mass and axillary node demonstrated ER/PR-positive invasive ductal carcinoma with metastatic nodal disease.

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Ultrasound (US)

US is an excellent modality for axillary imaging. If the patient has no impediment to raising their arm over their head, it provides for a detailed evaluation of the axilla. The patient is typically rolled onto their contralateral side until the ipsilateral axilla faces the ceiling and the arm is raised over the head [Figure 3]. Standard US probes suffice for evaluation. Normal axillary nodes demonstrate a uniform cortex <3 mm, a reniform shape, and a preserved fatty hilum [Figure 4]. Sonographic criteria for an abnormal node include diffuse or focal nodular (>3 mm) cortical thickening, cortical irregularity, loss of normal reniform shape, or obliteration of the fatty hilum [Table 1 and Figure 5].^[11–14] There is some variation in the criteria used for defining a thickened cortex. A cortical thickening of >2 mm yields a sensitivity of 94% and a specificity of 89% for detecting metastatic disease.^[15] If the threshold of 3 mm is applied for abnormal cortical thickness, then the sensitivity was found to be 56.3% and the specificity is 86.7%.^[16] Alvarez et al. performed a systematic review and found the sensitivity of axillary US for detection of nodal metastases in non-palpable nodes ranged from 48.8% to 87.1%, and specificity ranged from 55.6% to 97.3%.^[17] Multiple studies in this review used a criterion of cortical thickness >5 mm.

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Figure 3:

Patient position for sonographic evaluation of the axilla. The patient is rolled onto the contralateral side till the ipsilateral axilla faces the ceiling. The arm is raised over the head.

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Figure 4:

Normal structures seen on axillary ultrasound. (a) A transverse ultrasound image demonstrates a normal axillary node (white arrow) with a preserved fatty hilum (red arrow). Also marked is the skin (black arrow) and axillary adipose tissue (yellow arrow). (b) A color Doppler image of the same node demonstrates hilar vessels in a normal fatty hilum (yellow arrow).

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Figure 5:

Sonographic features of abnormal axillary nodes. (a) Focused ultrasound (US) evaluation of the axilla demonstrates an axillary node with a diffusely thickened cortex measuring 10 mm (calipers). (b) Focused US evaluation of the axilla demonstrates an axillary node with a round shape and loss of a fatty hilum. (c) Focused US evaluation of the axilla demonstrates an axillary node with a focal cortical bulge (yellow arrow). Reprinted with permission from Humphrey et al.^[11]

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Additional sonographic methods for evaluation of metastatic axillary lymphadenopathy, such as color Doppler and elastography, have also been investigated. For palpable nodes, Yang et al. demonstrated that while color flow was seen equally well in benign and malignant nodes, peripheral flow was significantly higher in malignant nodes, and central flow was significantly higher in benign nodes; no such difference was seen in non-palpable nodes.^[18] Other Doppler criteria, including pulsatility index, resistive index, and peak systolic velocity, showed overlap between benign and malignant lymphadenopathy and could not distinguish between the two.^[18] Contrast-enhanced US has also been studied and found to have a sensitivity of 82% and a specificity of 95.2% for identifying abnormal axillary nodes.^[19] In addition, malignant nodes demonstrated increased peripheral blood vessels and longer duration of enhancement on color power Doppler US after contrast administration.^[20]

Elastography has shown promise for evaluation of axillary nodes. A node is classified as abnormal on elastography if >50% of the node demonstrates increased stiffness.^[21,22] and strain values >0.65 are considered malignant.^[21] While some studies have shown that the addition of elastography increases sensitivity and specificity when combined with conventional US,^[22] others have not^[14] and its exact clinical value remains to be determined.

US-Guided Biopsy

Tissue sampling is often performed under sonographic guidance after identification of abnormal axillary nodes. Both fine needle aspiration (FNA) and core needle biopsy (CNB) can be performed under sonographic guidance. FNA is minimally invasive and very well tolerated. However, a cytopathologist must be available on-site to assess the adequacy of samples. Additionally, FNA has a high false negative rate.^[23,24] A CNB allows for larger samples and does not need an on-site cytopathologist. Pre-biopsy imaging should include the use of Doppler to identify axillary vessels [Figure 6a]. In cases where nodes are in close proximity to vascular structures, an open bowl, no-throw technique can be used to minimize risk of vascular injury [Figure 6b]. In this technique an introducer is first placed within or as close as possible to the targeted node. The biopsy device is advanced through the introducer with its bowl open [Figure 6c–e]. Once placed within the node, the device is deployed and the sample obtained. As there is no throw, it allows for better control of device placement and reduces the risk of vascular injury.

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Figure 6:

Ultrasound (US)-guided biopsy of an axillary node using the no-throw-open-bowl technique. (a) An anti-radial image of the axilla demonstrates an abnormal axillary node (yellow arrow) with increased cortical thickness. A color Doppler box is placed over the node prior to biopsy to identify surrounding vessels. The location of axillary vessels must be identified to decrease inadvertent vascular injury. (b) A biopsy device with an open bowl (white arrow) in conjunction with an introducer (red arrow) can be used for safe CNB of axillary nodes. (c) A 52-year-old patient with known right breast invasive ductal carcinoma presented for axillary sonographic evaluation. A sagittal US image of the axilla shows an abnormal node with increased cortical thickness (8 mm) and loss of fatty hilum (yellow arrow). (d) An US image of the axilla shows the biopsy device placed with an open bowl in the node (yellow arrow). (e) An US image shows the no-throw deployment and closed bowl within the node (yellow arrow), allowing for accurate placement of the biopsy device and reducing the risk of vascular injury. (f) The US image shows a post-biopsy marker clip (yellow arrow) placed within the biopsied node to allow for presurgical localization.

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It is recommended that a marker clip be placed in the biopsied node after CNB [Figure 6f]. A post-biopsy marker clip aids in pre-surgical localization of the biopsied node. This is particularly significant for the management of axillary nodes in patients undergoing surgical therapy after neoadjuvant chemotherapy (NAC).

Magnetic Resonance Imaging (MRI)

Breast MRI is utilized for the pre-treatment evaluation of many patients with newly diagnosed breast cancer and for response monitoring in patients undergoing NAC.^[25] While its primary indication is for evaluation of the breast parenchyma, it also allows for non-operator-dependent evaluation of the axilla. Patients lie prone on the breast coil within the scanner. They can be scanned either with their arms overhead or down by their sides. Scanning with arms down improves visualization of the axillary tissue by including more axillary tissue within the field of view. Nodes are hyperintense on T2-weighted imaging and demonstrate uniform enhancement on post-contrast T1-weighted imaging [Figure 7a]. Post biopsy clips within biopsied nodes can be seen secondary to their susceptibility artifact [Figure 7b]. The criteria used for identifying abnormal nodes on MRI are similar to those used in US [Table 1].^[26] However, the MRI scanner does not allow for tissue sampling. A second look US is often performed for abnormal nodes identified on MRI, and US-guided biopsy can be performed if clinically indicated. Internal mammary lymph nodes can also be evaluated on MRI.^[25]

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Figure 7:

Magnetic resonance imaging (MRI) imaging of axillary nodes. (a) Axial post-contrast T1-weighted fat-saturated image demonstrates a round node with a thickened cortex and loss of a normal fatty hilum in the right axilla (yellow arrow). The node demonstrates homogenous contrast enhancement. (b) Axial T1-weighted spoiled gradient recalled MRI image demonstrates an abnormal axillary node (yellow arrow) and susceptibility artifact secondary to a post-biopsy clip within the node (white arrow).

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Positron Emission Tomography/Computed Tomography (PET/CT)

Newer techniques such as PET/CT are not routinely utilized solely for axillary nodal evaluation. However, the axillae can be visualized on staging PET/CT. Abnormal nodes show increased uptake, but differentiation between reactive and metastatic nodes may be difficult. PET/CT can be useful in patients undergoing NAC. A study of 58 patients undergoing PET/CT after NAC found that 28% of patients had increased uptake in nodes that were not the sentinel nodes on lymphoscintigraphy prior to surgery. 40% of patients had excision of additional nodes based on the PET/CT findings.^[27]

Preoperative Marking of Clipped Axillary Lymph Nodes

Preoperative marking of clipped nodes is most commonly indicated in patients undergoing breast conservation surgery after completion of NAC. Multiple methods are available for localization axillary nodes. Most axillary nodes are localized using wireless localisation techniques such as radioactive iodine seeds, Radiofrequency identification (RFID) tags, or injection of carbon. Low axillary nodes can be excised using wire localization. The technique is similar to that used in localizing breast masses.

Practice Changing ACOSOG Z0011 Trial

Prior to the publication of the ACOSOG Z0011 trial^[4], almost every patient diagnosed with breast cancer underwent a sonographic axillary evaluation, and abnormal nodes were biopsied under US guidance. If there was biopsy-proven nodal metastatic disease prior to surgery, patients would skip SNB and proceed directly to ALND. Clips were typically not placed in biopsied nodes for two reasons. First, it didn’t matter which node was biopsied since an ALND would excise any node in the Level I and Level II lymph node basins, and second, wire localization was risky in the axilla, and wireless localization methods were not readily available at that time. This paradigm was challenged when the Z0011 trial results were incorporated into clinical practice. This trial evaluated 891 women with known breast cancer and non-palpable axillary nodes [Figure 9]. All patients underwent SNB and had 1–2 positive sentinel nodes. 445 patients were randomized to receive ALND, and 446 patients received SNB alone. In the final analysis, 420 patients were included in the ALND arm and 436 in the SNB-only arm. All patients under standard radiation therapy with neither arm receiving third-field axillary radiation. Patients were followed for 6.3 years, and 5-year overall survival was 91.8% with ALND and 92.5% with SNB alone. The 5-year disease-free survival was 82.2% with ALND and 83.9% with SLND alone. This trial demonstrated that if T1–T2 clinically node-negative patients undergoing breast conservation and radiation had 1–2 positive sentinel nodes, then ALND could be safely omitted. Long-term follow-up of 9.25 years reported that there was no significant difference in local recurrence-free survival between the two groups.^[5,29] This study did not incorporate any imaging evaluation of the axilla, so patients were considered node negative if no palpable nodes were found on clinical examination alone.

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Figure 9:

ACOSOG Z011 trial design. Adapted from Giuliano et al.^[4] SNB: Sentinel node biopsy, ALND: Axillary lymph node dissection, XRT: X-Ray radiotherapy.

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The clinical implementation of the Z0011 trial findings has been variable, resulting in a mosaic of approaches.^[31–35] Some surgeons interpreted the results as patients would be eligible to skip ALND only if no positive nodes were known prior to surgery. In other words, if the patient had a positive node established by US-guided biopsy, even if the node was not clinically palpable, the patient would be considered ineligible for the Z0011 algorithm, and ALND would be performed. Other surgeons ignored the positive US-guided biopsy results if the patient was clinically node negative and proceeded with SNB and treated the patient according to the Z0011 algorithm (i.e., if <3 nodes were positive, then they did not proceed to ALND). The negative impact of axillary US nodal evaluation and biopsy in these scenarios is that some patients eligible for the Z0011 algorithm underwent an ALND, which could have been avoided, and some patients underwent an unnecessary axillary node biopsy, which did not change their surgical management. As a result, radiologists had to rethink the sonographic evaluation of the axilla in patients with early-stage breast cancer to avoid harmful downstream consequences for some patients.

The approach to axillary nodal evaluation depends to a certain extent on the local surgical practice. A proposed algorithm is described in Figure 9. It incorporates the Z0011 eligibility criteria while allowing for differences in approaches between various treating physicians. In this algorithm, an up-front axillary US nodal evaluation should be performed in any patient with a primary tumor greater than T2 (>5 cm), suspicion of multifocal or multicentric disease, palpable axillary nodes, or suspicion of inflammatory breast cancer.

Patients Undergoing NAC

The ACOSOG Z1071 trial specifically looked at patients with known nodal metastatic disease who underwent axillary surgery after completion of NAC.^[36] It was demonstrated that if the biopsied and clipped node along with two other sentinel nodes showed complete pathologic response (PCR), then ALND can be eliminated in these patients.^[37] Resultant National Comprehensive Cancer Network (NCCN) guidelines recommend SNB alone in patients with PCR in the axilla (if the clipped node and two other nodes are excised and show no residual disease on pathology).^[38] Hence, patients who are deemed eligible for NAC are candidates for node evaluation prior to starting therapy, as abnormal nodes may become difficult to identify after therapy. The post-treatment decrease in size prevents their identification on US, and they have a higher than accepted false negative rate on SNB, likely secondary to treatment-related fibrosis.^[39] These patients should undergo a sonographic axillary evaluation to look for abnormal nodes prior to starting therapy. This can be done after consultation with the treating oncologist, either individually or in the multidisciplinary clinic setting. Any abnormal nodes are then biopsied and a clip placed. The clip serves as an important guide for presurgical localizing tags, which are placed adjacent to the biopsied nodes to aid the surgeon in targeted excision.

In certain patients the decision of whether to give NAC or which regimen to administer may be based on nodal evaluation. In patients with T1c tumors (tumors > 10 mm but ≤ 20 mm in greatest dimension), NAC may be recommended if there is biopsy-proven nodal disease.^[30] If the patient has comorbidities that increase the risks of specific chemotherapeutic drugs, then the regimen used may change based on their nodal status. In these patients sonographic axillary evaluation and biopsy of abnormal nodes may be indicated and should be performed in collaboration with the medical oncologist [Figure 10].

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Figure 10:

A 40-year-old patient presented with known left breast ER/PR-positive, HER2Neu-positive invasive ductal carcinoma, with the primary tumor measuring 2 cm. The patient had baseline thrombocytopenia. An abnormal axillary node with focal cortical thickening was seen on the initial mammogram. After consultation with the medical oncologist, the patient was deemed a candidate for NAC. Due to pre-existing thrombocytopenia, a decision was made to sample the axillary node to guide the choice of chemotherapy regimen. (a) The left mediolateral oblique (LMLO) view demonstrates an irregular, spiculated mass with pleomorphic calcifications in the central left breast (white arrow). A partially visualized level 1 axillary node demonstrated a mildly thickened cortex (yellow arrow). (b) Transverse ultrasound (US) image demonstrates an axillary node with a focally thickened cortex (yellow arrow) measuring 6 mm. (c) An US-guided CNB of the node was performed and a clip placed. A post-biopsy LMLO view demonstrates the post-biopsy clip in the axilla (yellow arrow). A ribbon clip is seen in the primary mass (green arrow). A displaced circular clip from a prior nondiagnostic biopsy is also seen in the axillary adipose tissue (red arrow). TRV: Tranverse, CNB: Core needle biopsy, NAC: Neoadjuvant chemotherapy, ER/PR: Estrogen receptor/Progesterone receptor.

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Patients Over 70

Patients diagnosed with breast cancer over the age of 70 form a unique subgroup due to two reasons. In 2004, Hughes et al. demonstrated that lumpectomy with adjuvant therapy alone was as effective as lumpectomy followed by tamoxifen plus radiation therapy in women over 70 with early ER-positive breast cancer.^[40] Pursuant to these findings, women over 70 with ER-positive tumors do not receive radiation following a lumpectomy. It is to be noted that in the Z0011 trial all patients received radiation therapy. Secondly, patients over 70 often do not get sentinel node biopsies. Martelli et al. evaluated 671 patients over 70 with clinically node-negative, early-stage, hormone-receptor-positive cancers. Of these, 172 received ALND and 499 did not. They showed that elderly patients with early breast cancer did not benefit in terms of breast cancer mortality from axillary clearance.^[41] Additionally, SNB could also be omitted, as the cumulative incidence of axillary disease was very low in this patient group.^[41] The Society of Surgical Oncology in its Choosing Wisely algorithm^[42] recommends surgeons not use SNB routinely in clinically node-negative women over 70 with hormone receptor-positive, Human epidermal growth factor receptor 2 (HER2)-negative early-stage tumors.

Hence, women over 70 do not get evaluated with SNB for axillary nodes and do not get treated with radiation therapy. Some practitioners may not apply Z0011 findings to patients over 70 who are not candidates for radiation therapy. Since these patients also do not undergo SNB, there may be a greater need to evaluate their axilla with imaging prior to treatment.

Emerging Role of Axillary US in Early-Stage Breast Cancer

The Sentinel Node vs Observation After Axillary Ultra-Sound (SOUND) trial was published in 2023 and is once again changing management of axillary nodes in breast cancer.^[43] This randomized phase 3 clinical trial demonstrated that in patients with a primary breast tumor ranging in size from 0.8 to 1.5 cm and negative axillary breast US prior to surgery, omission of axillary surgery was noninferior to SLN biopsy. Further studies are needed to validate these results, but as clinicians adopt these changes, the role of breast radiologist will once again evolve.