Prediction of axillary nodal burden using preoperative magnetic resonance imaging scoring in patients with clinically node-negative breast cancer: a retrospective cohort study

Introduction

Background

Breast cancer is the most common cancer among women, accounting for 12.5% of all new annual cancer cases worldwide (1). Axillary lymph node metastasis (ALNM) strongly predicts overall patient survival and recurrence; therefore, an accurate assessment of ALNM is crucial in staging breast cancer (2).

Rational and knowledge gap

Since the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial was published, clinical paradigms for axilla treatment have been changed to a less aggressive approach. This trial demonstrated that sentinel lymph node biopsy (SLNB) without axillary lymph node (LN) dissection is appropriate in selected patients with clinically node-negative cancer having 1–2 nodal metastases at SLNB and undergoing breast-conserving surgery (3). Thus, the preoperative assessment of axillary nodal burden is essential to guide multidisciplinary treatment decisions and provide optimal patient treatment (4,5). Currently, there are several methods for assessing axillary nodal burden, such as ultrasound and positron emission tomography/computed tomography (PET/CT) (2,6-8). However, these methods continue to possess constraints. For instance, ultrasound exhibits variable sensitivity and specificity and is dependent on the operator (2), while magnetic resonance imaging (MRI) is a high-resolution imaging technique characterized by high sensitivity and a substantial negative predictive value (NPV), capable of evaluating LNs across all three levels (9-14). Diffusion-weighted imaging (DWI) is a technique that helps improve the identification of ALNM (15-18). However, the individual evaluation of LNs may not be stratified into extensive and nonextensive groups.

Objective

This study aimed to establish an MRI scoring system based on preoperative breast MRI to predict extensive ALNM in patients with clinically node-negative breast cancer. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-24-379/rc).

Methods

Study population

The study was approved by the ethics committee of the Faculty of Medicine, Chulalongkorn University (No. 0878/2022), and the requirement for informed consent was waived because of the retrospective nature of the study and confidentiality obligation on the patient’s identity. The study was conducted in accordance with the Declaration of Helsinki (revised in 2013). Information on patients who underwent breast MRI between January 1, 2010 and December 31, 2020 at King Chulalongkorn Memorial Hospital was initially retrieved (n=1,793). The Hospital Information System, Radiological Information System, and Picture Archiving and Communication System (PACS) were used to obtain data. The exclusion criteria were as follows: performing MRI for purposes other than preoperative breast cancer evaluation, final pathology showing no invasive primary breast cancer, unavailable axillary pathological data after MRI examination, palpable ALN, and receiving neoadjuvant chemotherapy or ipsilateral breast/axillary surgery for breast cancer before MRI examination. Finally, 226 patients with invasive primary breast cancer with nonpalpable ALNs were included in this study (Figure 1).

Figure 1 Flowchart of the study population. MRI, magnetic resonance imaging; KCMH, King Chulalongkorn Memorial Hospital; N, number of axillary nodal metastasis.

Data collection

Clinical and histopathological data, including age, family history of breast cancer, symptoms at presentation, breast cancer gene (BRCA) status, stage (T, N), histological type, tumor grade, molecular subtype, and surgical methods, were obtained from the medical records and retrospectively reviewed (Table 1).

The radiological data were reviewed via the PACS. The MRI images were obtained using a 1.5-Tesla MRI system with a dedicated breast coil and intravenous paramagnetic contrast. Apparent diffusion coefficient (ADC) maps were automatically created with b values of 0 and 800. The characteristics of breast tumors and axillary LNs were independently reviewed by two researchers. All clinical and histopathological data were blinded during the review to avoid bias. Any disagreement between the two researchers was resolved by consensus.

The most suspicious LN for metastasis or the largest LN in the ipsilateral axilla was chosen to assess our MRI scoring system’s imaging characteristics and score (Table 2). Regions of interest (ROIs) were manually drawn on LNs with a short diameter (SD) >5 mm on axial DWI images (at b value =800 s/mm²). The ROIs were marked as slightly smaller than the actual size of the nodes/primary breast tumors and included the most considerable solid portion possible. The identified ROIs were then copied and pasted onto the corresponding ADC map for quantitative analysis (Figure 2). The ADC values of the axillary LNs were averaged from three measurements. The results are presented as the mean ADC value. The ADC values of the primary breast tumors were also obtained. The ADC LN/tumor ratio was then calculated.

Figure 2 A 50-year-old patient with IDC: (A) contrast-enhanced T1-weighted image, (B) color-coded dynamic contrast material enhanced image, (C) DWI at b =800, and (D) ADC map showing the manually drawn ROI of the largest right axillary node. ROI, region of interest; IDC, invasive ductal carcinoma; DWI, diffusion-weighted imaging; ADC, apparent diffusion coefficient.

Statistical analysis

All statistical analyses were performed using Statistical Package for the Social Sciences (version 28.0; IBM Corp., Armonk, NY, USA) and STATA. All continuous variables are presented as means and standard deviations. All categorical variables are presented as frequencies and percentages and were analyzed using the chi-square test. P values <0.05 were used to denote statistical significance. The diagnostic performance of the MRI scoring system for predicting extensive ALNM was evaluated via validity (sensitivity and specificity), efficiency [positive predictive value (PPV) and NPV], and reliability (Cohen’s Kappa statistics). The receiver operating characteristic (ROC) curve was drawn, and the area under the ROC curve was used to determine the cutoff value of this MRI scoring system for differentiating between extensive and nonextensive ALNM. Extensive nodal metastasis was defined as ≥3 metastatic nodes. We aimed for the predictions to demonstrate high sensitivity and NPV, confirming that the patients do not have a significant nodal burden. We employed the threshold of approximately 80% for AUC and 90% for sensitivity.

Results

Patients’ demographic and pathological characteristics

The patients’ characteristics are summarized in Table 3. The mean age of the patients was 51.9±10.4 years and ranged from 27 to 81 years. The ALNs were derived from SLNB and axillary LN dissection. Of the 226 enrolled patients, 19 had a positive family history of breast cancer, of whom 2 had extensive nodal metastasis. Of the 195 patients with nonextensive nodal metastasis, 136 (69.7%) had symptoms at presentation, whereas 24 of the 31 patients with extensive nodal metastasis (77.4%) had symptoms at presentation. The most common histological type in the nonextensive and extensive nodal metastasis groups was invasive ductal carcinoma (IDC), accounting for 83.6% and 80.6%, respectively. The frequency of tumor grades in the nonextensive and extensive nodal metastasis groups was sorted in descending order as follows: grade 2, grade 3, and grade 1. Of the 195 patients with nonextensive nodal metastasis, 98 (50.3%) were luminal B, 48 (24.6%) were luminal A, 24 (12.3%) were HER2-enriched, and 24 (12.3%) were triple-negative molecular subtype.

Patients’ MRI characteristics

Table 4 shows the MRI characteristics of the axillary LNs and primary breast tumors in the nonextensive and extensive nodal metastasis groups. Of the 195 patients with nonextensive nodal metastasis, 75.4% showed no suspicious LN on MRI, 21.0% showed 1–2 questionable LNs, and 3.6% had ≥3 suspicious LNs, whereas of the 31 patients with extensive nodal metastasis, 48.4% had ≥3 suspicious LNs, 29.0% had 1–2 suspicious LNs, and 22.6% showed no suspicious LNs. The circumscribed margin was the most common in the nonextensive and extensive nodal metastasis groups (94.9% vs. 61.3%, respectively). The number, shape, and margin of axillary LNs are significant in differentiating axillary nodal burden (P<0.001). LN asymmetry in both axillae, ≥3 mm cortical thickening, asymmetrical cortical thickening, and the absence of fatty hilum were found more frequently in the extensive nodal metastasis group (P<0.001), accounting for approximately 77.4%, 80.6%, 71.0%, and 58.1%, respectively. In contrast, these characteristics were found in the nonextensive nodal metastasis group at approximately 19.0%, 24.6%, 22.6%, and 8.2%, respectively. Moreover, 93.3% of patients with nonextensive nodal metastasis had LNs with SDs <10 mm, whereas approximately 54.8% had LNs with SDs <10 mm. Furthermore, most patients with extensive nodal metastasis (71.0%) showed <2 long diameter (LD)/SD ratio, whereas most patients with nonextensive nodal metastasis (69.7%) showed ≥2 LD/SD ratio. No statistically significant difference in signal intensity (SI) on DWI was observed between the nonextensive and extensive nodal metastasis groups (P=0.18).

Most nonextensive and extensive nodal metastasis groups had spiculated or indistinct breast lesions (100% vs. 94.9%, respectively). The sizes of the breast lesions in the nonextensive nodal metastasis group were >2–5 cm in 48.7%, ≤2 cm in 45.1%, and >5 cm/chest wall or skin involvement in 6.2%. The sizes of the breast lesions in the extensive nodal metastasis group were >2–5 cm in 51.6%, >5 cm/chest wall or skin involvement in 32.3%, and ≤2 cm in 16.1%.

After analyzing the MRI characteristics of the LNs and breast lesions according to the ROC and Kappa statistics, the cutoff value for the MRI scoring system with available LN ADC value to predict extensive nodal metastasis was 14 (total 60 patients), showing sensitivity, specificity, PPV, and NPV of approximately 81%, 69.2%, 58.6%, and 87.1%, respectively. The ROC area was 0.751 [95% confidence interval (CI): 0.638–0.864], representing acceptable discrimination. The Kappa value was 0.461 (95% CI: 0.244–0.679), indicating moderate agreement (Figure 3).

Figure 3 ROC curve and cutoff value of the MRI scoring system with ADC value. MRI, magnetic resonance imaging; ADC, apparent diffusion coefficient; CI, confidence interval; PPV, positive predictive value; NPV, negative predictive value; ROC, receiver operating characteristic; Kappa, Cohen’s Kappa coefficient.

The cutoff value for the MRI scoring system without the ADC value to predict extensive nodal metastasis was 8 (total 226 patients), showing sensitivity, specificity, PPV, and NPV of approximately 77.4%, 81%, 39.3%, and 95.8%, respectively. The ROC area was 0.792 (95% CI: 0.712–0.872), representing acceptable discrimination. The Kappa value was 0.415 (95% CI: 0.280–0.551), indicating moderate agreement (Figure 4).

Figure 4 ROC curve and cutoff value of the MRI scoring system without ADC value. MRI, magnetic resonance imaging; ADC, apparent diffusion coefficient; CI, confidence interval; PPV, positive predictive value; NPV, negative predictive value; ROC, receiver operating characteristic; Kappa, Cohen’s Kappa coefficient.

Discussion

In patients with breast cancer, the preoperative evaluation of the axillary nodal status is essential for prognosis prediction and development of management strategies. Since the publication of ACOSOG Z0011, axillary nodal management in patients with nonextensive nodal metastasis has become less invasive.

Key findings

Our study demonstrated that the number of suspicious LNs and other MRI characteristics of the axillary LNs, including shape, margin, symmetry, cortical thickening, LN hilum, LN SD, and LN LD/SD ratio, and breast tumor size and margin, were associated with extensive nodal metastasis.

Strengths and limitations

Vasigh et al. and Keelan et al. found that ultrasonographic evaluation of the axilla of patients with early-stage, clinically node-negative breast cancer is not sensitive enough to differentiate nonextensive nodal metastasis from extensive nodal metastasis (19,20). Although some studies have demonstrated that extranodal extension in involved axillary nodes is associated with an extensive nodal burden, it is highly invasive (21-24). Therefore, a higher sensitivity modality, such as MRI, was chosen for stratification in this study.

In this study, we encountered several limitations. First, this was a retrospective study conducted at a single institution. Second, the number of patients with extensive nodal metastasis (31 of the 226 patients) and those who had measurable ADC values (60 of the 226 patients) was small, which might affect the reliability of the results; some findings were not statistically significant because of lack of power. This could be because of the exclusion of patients who received neoadjuvant therapy and were clinically nodal-positive. Third, we did not analyze all axillary LNs seen on MRI but chose only one LN per person with the most suspicious characteristics or the largest size. Fourth, we did not perform lesion-by-lesion comparisons between the most suspicious LN on MRI and pathological results. Finally, most patients had IDC histological subtypes; therefore, using this MRI scoring system in patients with other histological subtypes might have limitations.

Comparison with similar research

Similar to Caudle et al. and Ha et al., we showed that the number of suspicious LNs could be used to predict extensive nodal metastasis (10,25). Our analysis also demonstrated that other MRI characteristics of the axillary LNs, including shape, margin, symmetry, cortical thickening, LN hilum, LN SD, and LN LD/SD ratio, and breast tumor size and margin, were associated with extensive nodal metastasis, which was similar to the results reported by Li et al. (9).

Only a few studies have examined the DWI and ADC values of LNs. They found that these values could be used to discriminate between metastatic and nonmetastatic nodal metastases (17). He et al. demonstrated that their MRI scoring system, including SI on DWI and ADC value with a cutoff value of 6, had sensitivity and specificity of approximately 96% and 83%, respectively, for diagnosing metastatic nodes (26). No recent study has used the DWI and ADC values of LNs to discriminate between nonextensive and extensive nodal metastases. Our study included 60 patients with available ADC values but found no significant difference in SI on DWI and mean ADC values between the nonextensive and extensive nodal metastasis groups.

Explanations of the findings

Our study showed that the cutoff values of our MRI scoring system with and without ADC had high sensitivity, specificity, and NPV but had relatively low PPV. Compared with a previous study (27), which showed high NPV (approximately 99.6%) of breast MRI to exclude advanced nodal disease, the cutoff value of our MRI scoring system without ADC value also showed high NPV (approximately 95.8%).

Implications and actions needed

Song et al. suggested that patients with low probability scores from their clinical imaging nomogram accompanying negative axillary ultrasonography are candidates for the SLNB omission (28). This result emphasized our MRI scoring system’s ability to exclude extensive nodal metastasis, which may help avoid unnecessary axillary surgery. Xu et al. (29) revealed that MRI characteristics of breast edema were promising imaging features for predicting axillary nodal burden; therefore, further study with breast edema in the MRI scoring system increase the system accuracy.

Conclusions

The proposed preoperative MRI scoring system may help identify patients with extensive nodal metastasis in clinically node-negative breast cancer. This could assist clinicians and surgeons in considering less invasive axillary nodal treatment strategies to reduce morbidity.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-379/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-379/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-379/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-379/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work, ensuring that any questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (revised in 2013). The study was approved by the ethics committee of the Faculty of Medicine, Chulalongkorn University (No. 0878/2022). The requirement for informed consent was waived because of the retrospective nature of the study and the confidentiality obligations concerning patient identities.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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