How to use routine examination data to judge SLN status in patients who have a suspicious ALN at ultrasound, but a negative clinical physical examination, is highly problematic. In this study, ALN-US was evaluated relative to pathological characteristics for differentiating patients with positive or negative SLNs, and a nomogram constructed for predicting SLN metastasis. It was found that patients who were SLN+ were more likely to demonstrate histological IDC, PR-positive status, and ALN-US with irregular shape, unclear CMD, and the presence of blood flow. We developed a nomogram based on the pathology and ALN-US characteristics to predict SLN metastasis, and it displays excellent ability to predict SLN metastasis, with an area under the C-statistic curve (AUC) of 0.714. The nomogram can be used to assist clinicians to predict SLN metastasis preoperatively, and thus may assist decisions regarding surgical strategy for patients with breast cancer. It is easy to generalize, simple to use, and more intuitive. The AUC values were verified in validation groups, internally and externally, as 0.816 and 0.942, respectively. The calibration curve of the nomogram shows that the nomogram prediction is consistent with the actual metastasis rate. Such a nomogram is rare, based as it is on ultrasound and pathological parameters, with complete survival data, and receiving multicenter validation.
Currently, the increasing need for SLN dissection has highlighted concern for a means to predict LN metastasis and aid the selection and treatment of these patients. Scientists have reported many clinical characteristics that are related to LN metastasis, including multifocality, LN palpability, histological type, and LN status determined via magnetic resonance imaging (9, 30-32). In addition, Bevilacqua et al. (30) found that patient age, tumor size, grade, and location, lymphovascular invasion, estrogen receptor (ER) and PR status are related to LN metastasis (33). Other nomograms to assist LN prediction in breast cancer have been published. For example, Huang et al. (34) constructed a nomogram based on carcinoembryonic antigen (CEA) status, radiomics signature, and LN status depicted on computed tomography. Xie et al.’s (35) nomogram incorporated risk factors (age, tumor size, tumor location, and ALN US-reported status) and miRNA signature. Some others have relied only on a single examination feature, without combining patients’ clinical data. The above predictive models, which rely on miRNAs, computed tomography, and magnetic resonance imaging, are not used widely by surgeons, and a nomogram based on ultrasound lacks detailed morphology. Most importantly, a preoperative nomogram hardly exists that was constructed specifically for patients with breast cancer who have a suspicious ALN on US, but a negative clinical physical examination.
In recent years, more and more nomograms have been built using imaging data, for example, predicting ALN in early breast cancer (36), or non-SLN metastasis in patients during neoadjuvant chemotherapy (37). These models share similarities with ours, but are also fundamentally different. The nomogram of the present study has successfully resolved the questions raised above. Its greatest advantage is that LNs can be evaluated preoperatively using only the pathology based on biopsy and ultrasound morphological status. Its practicability and value is not only reflected in its convenience and rapid application, but also avoids false negative results from SLN biopsy to some degree, which internationally ranges from 5.5% to 43% (38). What is more, this nomogram can assist decisions to conduct further ALND in some complicated cases of breast cancer.
According to the 2020 NCCN guidelines for breast cancer, further axillary surgery is not recommended for patients with T1 or T2 tumor with 1 or 2 positive SLNs, who did not receive preoperative systemic therapy, were treated with lumpectomy, or are prepared to receive whole breast radiation (18). However, there is no consideration of the total number of SLNs resected. For example, in a case in which the intraoperative frozen section of the SLN is 2/2, not 2/4, then the clinician is left with a cofounding decision whether to perform ALN dissection or administer continuous treatment. The present PUMCH-SLN nomogram provides a more detailed reference. Although the Tenon, MSKCC, MDA, Mayo, Cambridge, and Stanford models (39, 40) all assess the risk of non-SLN metastasis using SLN and pathology, they are not designed especially for this very situation, and do not incorporate imaging features. The novel feature of our nomogram is that morphological status is incorporated with ALN-US.
In addition to the convenience and easy operation of the present nomogram, to our best knowledge there is no reliable evaluation and reporting standard for ALN, and the overall accuracy of ALN-US remains controversial (35). Because the study of ALNs is subject to strong subjectivity, there is great variability in the judgements made by ultrasound doctors all over the world. In some studies (27, 28), LN size, or morphological findings, or both, were used as ultrasound criteria. However, recent studies (3, 26) show that the morphological criteria of LNs on ultrasound are more important, with total replacement or eccentric hilus of the LN and hypo-echoic cortex being the most important morphological ultrasound criteria. Bedi et al. (19, 41) emphasized that there is no difference between the size of benign and malignant LNs, and cortical morphological findings and hypoechoic cortex are more important than LN size. This is similar to the present results.
Whether the data is qualitative or quantitative, specific values among studies are not consistent. For example, cortical thickness >5 mm was identified as the cutoff for metastatic LNs, while diffuse cortical thickening >3 mm was reported as suspicious criteria with a specificity of 49% to 85%, and sensitivity of 96%, in predicting metastatic disease (28). For the present nomogram, diffuse cortical thickening >3 mm was considered suspicious criteria, while other morphological indicators are subjective.
We wondered if developing BI-RADS ALN criteria could be applied in breast cancer; such criteria could include detailed evaluation of the eccentric placement, complete anechoic or hypoechoic appearance of the LN, axillary and echogenic hilus obliteration, asymmetric cortical thickening, and other possible quantitative evaluations gained from ultrasound ALN-US. Meanwhile, our team is developing another artificial intelligence-assisted SLN prediction system. In this way metastatic LNs could be identified by ultrasonography with high sensitivity and positive predictive value, assisting in the stratification of patients with ALN metastasis, aiding in therapy planning and patient staging, and ultimately contributing to improvements in surgery strategy and survival rates.
T-staging must be discussed. First, the pathological T stage cannot be gained before surgery; only the tumor size may be determined by ultrasound. In the research of Fidan et al. (28), histopathological tumor size correlated with the primary tumor size measured. In the present study, we were not able to differentiate SLN positivity by the tumor size shown on ultrasound (Table 1). Here, it should be noted that although some DCIS are large in diameter, they have a lower risk of metastasis. Meanwhile, a subgroup analysis of patients with IDC was conducted in this study, using the chi-squared and Fisher’s exact tests. The results showed that, with χ2 = 6.333 and P = 0.032, there was a statistical difference. Yet, about 25% of women with seemingly pure DCIS on initial biopsy will be found with invasive breast cancer at the time of the definitive surgical procedure (42), and thus will ultimately require ALN staging (18). In any case, primary tumor size is an important factor affecting ALN metastasis (4, 5). In the present study the pathological T stages of all patients were compared, and there were statistical differences (χ2＝22.067, P < 0.001). However, statistics for the last two T stages are obtained at the postoperative detailed evaluation of pathological results, and therefore cannot be used as a reference before surgery at this time. Therefore, we can acknowledge that pathological T staging is related to LN metastasis in all patients with breast cancer, but the T parameter was not included in the nomogram for preoperative use developed in this study.
In the survival analysis, the DFS of the SLN+ patients was significantly shorter than that of the SNL– patients, and a similar trend has been reported in key clinical trials (43). The two groups are similar in overall survival, perhaps because of short follow-up time, and SLN dissection is performed in patients with relatively early stage breast cancer. In addition, in the present study p53 expression was associated with prognosis. This poses questions that warrant more basic research and large-scale clinical trials in all patients with breast cancer.