Correlations of ultrasound features and immunohistochemical indicators with axillary lymph node metastasis in invasive breast cancer

Introduction

Breast cancer is the leading type of cancer and a major cause of cancer-related deaths among women globally, representing approximately 23% of all new cancer diagnoses and contributing to an estimated 14% of cancer fatalities (1). In China, breast cancer is also the most prevalent malignancy among women, with incidence and mortality rates steadily increasing in recent years (2). While breast cancer predominantly affects middle-aged and elderly women, there has been a notable increase in incidence among younger women starting from the age of 20 years (3). In Western countries, the incidence rate among women under 30 years is around 1%, whereas in Asian countries, it exceeds 3% (4). Given China’s large population, the total number of female breast cancer cases is the highest in the world (3).

Breast cancer is a group of malignant tumours occurring in the breast duct and epithelium with a high heterogeneity (5), and can be divided into many subtypes. Progesterone receptor (PR), oestrogen receptor (OR), human epidermal growth factor receptor 2 (HER2), the proliferating cell nuclear antigen, and Kiel-67 (Ki-67) are common molecular markers for breast cancer. OR and PR are expressed on the surface of normal breast cells and can promote their growth and proliferation after oestrogen and progesterone bind to corresponding receptors. When breast tissue undergoes a cancerous transformation, OR and PR expression may be lost to varying degrees, which can be used to predict the prognosis of patients with breast cancer and determine the selection of treatment strategies. For example, in both OR- and PR-positive cases, the therapeutic effect on endocrine disorders is more reliable, and the prognosis is better (6). HER2 is a type of epidermal growth factor receptor expressed by a gene sequence located on chromosome 17q12, directly involved in the occurrence and development of various human cancers (7). HER2 has been shown to be one of the factors predicting the prognosis of breast cancer, and its overexpression is correlated with poor prognosis (8). Ki-67 is a nuclear protein that is associated with cell division and proliferation, present in the active phases (G1, S, G2, and M) of proliferating cells, but not expressed in the quiescent phase (G0) (9). The protein can well reflect the proliferation of cells (10), and it is widely used as an effective indicator to evaluate the proliferative and metastatic potentials of tumour cells.

The St. Gallen international expert consensus on the primary therapy of early breast cancer (11) suggests that breast cancer should be classified into luminal type, HER2-overexpression type and triple-negative type according to different expression of its molecular markers. The luminal type includes A and B subtypes, and the luminal B subtype can be further subdivided into HER2-negative and HER2-positive types. Luminal A breast cancer, characterised by positive expression of OR and PR with low Ki-67 proliferation index, typically has a lower metastasis rate and better prognosis. Luminal B, which can be either OR⁺/PR⁺ with high Ki-67 or OR⁺/HER2⁺, tends to have a higher recurrence and metastasis rate compared with luminal A. The HER2-overexpression breast cancer type, defined by HER2 positivity and OR/PR negativity, is more aggressive and has a higher propensity for metastasis, although targeted therapies have markedly enhanced outcomes. Triple-negative breast cancer, lacking expression of OR, PR and HER2, is often associated with a higher risk of recurrence and metastasis within the first few years of diagnosis, due to its lack of targeted treatment options and aggressive biological behaviour. The exact metastasis rates for each subtype can vary depending on individual patient characteristics, disease stage and treatment response.

The China Anti-Cancer Association (CACA) guidelines and specifications for diagnosis and treatment of breast cancer (2021 edition) (12) clearly point out that for patients with suspected breast lumps, sentinel lymph node biopsy (SLNB) should be performed prior to axillary lymph node dissection (ALND), which is conducted or not based on result evaluation and can be avoided in patients who are SLNB-negative. ALND is prone to axillary venous and brachial plexus injuries, as well as complications such as upper limb lymphedema, sensory disturbance and axillary deformities, which can seriously affect the quality of life of patients (13,14). In addition, a considerable proportion of patients with breast cancer undergoing ALND clinically do not have axillary lymph node metastases, highlighting the importance of non-metastatic lymph node chains in impeding the proliferation and dissemination of tumour cells (15). At present, the guidelines and standards for diagnostic accuracy of breast cancer, optimal tracer selection and micrometastasis determination during SLNB have not been unified. Moreover, SLNB is expensive and invasive, requiring precise preoperative localisation and accurate pathological diagnosis, which is likely to yield false-negative results. Furthermore, tracer allergy is inevitable in some patients (16). Therefore, exploring a non-invasive method to accurately assess the preoperative status of axillary lymph nodes in patients with breast cancer is urgently needed.

Axillary lymph node ultrasound is an important imaging method for determining the benignity or malignancy of lymph nodes. Currently, there is no unified standard for diagnosing axillary lymph node metastasis, but previous studies (17,18) have demonstrated that metastatic lymph nodes have their unique features on ultrasound images compared with normal lymph nodes. For example, metastatic lymph nodes are spherical with the disappearance of hilar structures, eccentric thickening of the cortex, and the appearance of calcified lesions. It has been reported that the threshold of 3 mm as the maximum thickness of the lymph node cortex has a high predictive value for the diagnosis of metastatic lymph nodes (19). On this basis, the present study explores the correlations of breast ultrasound and immunohistochemistry with axillary lymph node metastasis in patients with invasive breast cancer (IBC). We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1002/rc).

Methods

Participants

Using a convenience sampling approach, we retrospectively identified 125 patients with IBC who underwent surgical resection at The Affiliated Hospital of Yangzhou University between January 2019 and December 2022, following either a preoperative core-needle biopsy or an intraoperative pathological diagnosis. The inclusion criteria were as follows: (I) female patients with primary IBC; (II) no evidence of metastasis to distant organs such as the liver, kidneys, lungs, brain or bones; (III) no prior treatment (including chemotherapy or radiotherapy); and (IV) the clinician found palpable axillary lymph nodes during palpation, SLNB before breast cancer or ALND during breast cancer surgery. Patients were excluded if they had (I) recurrence or metastasis following previous breast cancer surgery; (II) bilateral breast cancer or multiple breast lesions; or (III) incomplete relevant clinical data. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Committee of The Affiliated Hospital of Yangzhou University (No. 2024-YKL09-009). Due to the retrospective nature of the study and anonymised patient information, informed consent was waived by the ethics committee. All methods were performed in accordance with relevant guidelines and regulations.

Research methods

Ultrasound examination

A Siemens ACUSON S3000 ultrasonic diagnostic apparatus with an L9-4 probe (frequency range: 4–9 MHz; Siemens Medical Solutions USA, Inc., Malvern, PA, USA) and a GE LOGIQ E9 ultrasonic diagnostic apparatus with an L11-9 probe (frequency range: 9–11 MHz; GE Medical Systems Ultrasound & Primary Care Diagnostics, LLC, Wauwatosa, WI, USA) were used. The optimal ultrasound images were obtained using a high-frequency (4–11 MHz) linear array probe by adjusting the scanners based on the patients’ actual conditions in the preset breast mode. During the examination, the patients were positioned lying flat on the examination bed, with both upper arms raised and the head held by both hands, which were abducted as much as possible to fully expose the breast and bilateral axillae. The entire breast was continuously scanned with the probe in a clockwise and radial pattern from the edge of the lateral upper quadrant. Each anatomical layer of the breast was carefully observed, and suspicious lesions were subjected to repeated multi-sectional scans. The contralateral breast was examined using the same approach. The morphology, internal structure, echogenicity, and adhesions to surrounding tissues of the lesions were recorded. Following this, the colour Doppler mode was used to observe the characteristics of blood flow within the lesions. The distribution and abundance of blood flow were classified into four grades according to Adler’s grading criteria: grade 0, no blood flow; grade I, a small amount of blood flow, with up to two visible punctate blood flow signals; grade II, a moderate amount of blood flow, with multiple visible punctate blood flow signals and a blood vessel with a thick wall; and grade III, abundant blood flow, with multiple small blood vessels (>4) or a vascular network.

In the axillary examination, suspicious lymph nodes were explored carefully within each axillary subregion (lateral lymph nodes, subscapular lymph nodes, pectoral lymph nodes, central lymph nodes, and apical lymph nodes), referring to the position of major blood vessels of the axillary fossa. The following ultrasound signs were recorded: (I) lymph node morphology (morphological changes, measurement of the ratio of long/short diameter); (II) lymphatic hilum (twisted deformation, disappearance or not); (III) cortex (thickening, maximum thickness ≥3 mm or not); (IV) calcification in lymph nodes; and (V) blood flow in lymph nodes (portal blood flow, abundance). Abnormal lymph nodes were determined as follows: (I) displacement or disappearance of lymphatic hilum; and (II) spherical or circular lymph nodes, or changed long/short diameter ratio.

The results were analysed blindly by two senior physicians with more than 5 years of experience in ultrasound diagnosis of breast diseases, without interference from other imaging results. When their diagnostic results were inconsistent, a consensus was reached through joint consultation. The stored ultrasound images were analysed, and image features, including the sizes, echogenicity, morphology, boundaries, anteroposterior/transverse diameter (A/T) ratios, internal calcifications, border morphology, and blood flow signals of colour Doppler flow imaging of the lesions were recorded and classified.

Pathological examination

The breast cancer specimens obtained intraoperatively were fixed with 10% formaldehyde. Following immersion in formalin solution, the specimens were dehydrated with gradient ethanol, cleared in fresh xylene solution, embedded in paraffin, and sliced into thin sections using a slicer. The sections were then routinely stained with haematoxylin-eosin and carefully observed under a microscope. The pathological classification of tumours was determined based on observed results. The pathological subtypes of breast cancer are classified as luminal A, luminal B, HER2 overexpressing, and triple-negative.

Immunohistochemistry

The paraffin-embedded sections were first immersed in xylene solution and then dehydrated with gradient ethanol. Following antigen retrieval, the area to be detected was circled with a grease pencil, and endogenous peroxidase blocking solution was added, followed by incubation at room temperature for 10 min. After washing, a primary antibody was added to the sections and incubated at room temperature for 60 min before enzyme-labelled sheep anti-mouse/rabbit immunoglobulin G was added and incubated at room temperature for 15 min. After removing excess liquid, the sections were developed with diaminobenzidine. Subsequently, the sections were incubated with haematoxylin for 10–30 s and re-stained, followed by blue coloration with phosphate-buffer saline (PBS) solution, dehydration, clearing, and mounting; PBS was used instead of the primary antibody as a negative control, and known positive specimens were used as positive controls.

Evaluation criteria for immunohistochemical indicators: based on the evaluation criteria for Ki-67 expression in the CACA guidelines and specifications for diagnosis and treatment of breast cancer (2015 edition) (20), Ki-67 ≥14% was defined as high expression, and Ki-67 <14% as low expression. In addition, based on the above criteria, a percentage of OR- and PR-positive cells ≥1% was defined as positive, and that <1% as negative.

Evaluation criteria for HER2: HER2-positive cells were defined by brownish-yellow staining of their cell membrane, with unstained cells as (−) and 30% stained cells as (+++). In this study, (−) and (+) were evaluated as HER2-negative, and (+++) as HER2-positive. When the result was (++), further fluorescence in situ hybridisation of the HER2 gene was needed to determine whether it was positive (21).

Molecular typing

Luminal A type was classified by OR-positive, PR ≥20%, HER2-negative, and Ki-67 <14%; luminal B type by OR-positive, PR <20%, HER2-positive, and/or Ki-67 ≥14%; HER2-overexpression type by OR-negative, PR-negative, and HER2-positive; and triple-negative type by OR-negative, PR-negative, and HER2-negative.

Statistical analysis

All statistical processing was performed using SPSS 26.0. The Kolmogorov-Smirnov test was utilized to evaluate the normality of data. The measurement data satisfying normality were expressed as mean ± standard deviation and analysed using the independent sample t-test. Enumeration data were described by frequency (n) or rate (%), and analysed using the Chi-squared (χ²) test. Logistic regression analysis was conducted to identify suspected risk factors. A two-tailed P<0.05 was considered as statistically significant.

Results

Molecular type distribution of IBC

The results showed that among the 125 patients, there were 26 (21%) patients of luminal A type, 58 (46%) of luminal B type, 20 (16%) of HER2-overexpression type, and 21 (17%) of triple-negative type, as shown in Figure 1.

Figure 1 Constituent ratios of all molecular types in this study (%). HER2, human epidermal growth factor receptor 2.

Univariate analysis

There were statistically significant differences between the two groups (P<0.05) in terms of the proportions of tumour blood flow grades, axillary lymph node ultrasound, tumour sizes, and Ki-67-positive. However, no statistically significant differences were found between the two groups in terms of age, tumour morphology, tumour boundary, and A/T ratio (P>0.05), as shown in Table 1.

Multivariate analysis

A logistic regression model was constructed with the occurrence of axillary lymph node metastasis as the dependent variable (occurrence =1, non-occurrence =0) and statistically significant factors in the univariate analysis as independent variables. The variables and codes are listed in Table 2. According to regression analysis, large tumour [odds ratio (OR) =9.776; 95% confidence interval (CI): 2.111–45.266] and abnormal ultrasound diagnosis of axillary lymph nodes (OR =35.800; 95% CI: 7.637–167.846) were risk factors for axillary lymph node metastasis in IBC (Table 3). To further illustrate these differences, Figure 2 presents representative ultrasound images from patients in the metastatic group, highlighting the distinct features associated with axillary lymph node metastasis.

Figure 2 Representative ultrasound images of breast cancer patients in the metastatic group. (A) Irregular tumour morphology; (B) unclear tumour boundary; (C) tumour A/T ratio ≥1; (D) presence of microcalcifications in the tumour; (E) tumour blood flow grade 2–3; (F) suspected lymph node on ultrasound; (G) maximum diameter ≥20 mm. A/T, anteroposterior/transverse diameter.

Discussion

At present, SLNB is mostly used to assess the status of axillary lymph nodes in patients with early breast cancer. Nevertheless, SLNB is an invasive procedure that cannot avoid postoperative complications and is unsuitable for patients with surgical contraindications or other accompanying syndromes (22), greatly reducing its scope of application. Therefore, it is necessary to explore appropriate indicators to assess the status of axillary lymph nodes in patients with early breast cancer.

Unlike with the age of onset of breast cancer, data (23) show that age is an independent risk factor for poor prognosis of breast cancer, and younger patients with breast cancer are more prone to axillary lymph node metastasis, which may be related to poor differentiation of tumour cells in young patients. Fu’s study (24) demonstrated that with the age of 40 years as a boundary, young patients with breast cancer exhibit poorer differentiation and a higher proportion of lymph node metastasis. The present study’s results showed no significant correlation between age and axillary lymph node metastasis (P>0.05) (Table 1), which may be because the included patients were generally older, thereby leading to deviations from previous research results.

The tumour size of primary breast cancer is generally defined as its maximum diameter, which reflects the proliferation rate and invasive capability of tumour cells. As the tumour size continues to increase, the risk of tumour cell metastasis via lymphatic vessels to axillary lymph nodes increases. According to Li et al. (25), tumour size is an independent risk factor for axillary lymph node metastasis (OR =3.526; 95% CI: 1.104–11.259). In the present study, with 20 mm as the threshold of the maximum tumour diameter, the difference in tumour size between the metastatic group and the non-metastatic group was statistically significant (P<0.001) (Table 1). Multivariate analysis showed that a large maximum tumour diameter was a risk factor for axillary lymph node metastasis, which is consistent with the above findings (Table 3) and is also why this tumour size cutoff is assigned to a higher disease stage.

The morphology of breast lesions reflects tumour growth. It has been shown that the ’spiculation sign’ of breast cancer is correlated with axillary lymph node metastasis (26). In the present study, the results revealed no significant correlations between the boundary and morphology of breast lesions and axillary lymph node metastasis (P>0.05) (Table 1). This may be because the boundary and morphology of masses are good indicators for determining the benignity or malignancy of breast lesions, but their predictive value for axillary lymph node metastasis is limited. The A/T ratio is also one of the morphological characteristics reflecting tumour growth. Malignant tumours generally exhibit invasive growth, with actively proliferating tumour cells in the vertical direction exceeding those in other directions and an A/T ratio >1 (27). However, in this study, no significant correlation was found between the A/T ratio and axillary lymph node metastasis (P>0.05) (Table 1), which may be a result of the fact that our selected patients already had masses that had existed for a long time at the examination, and the growth in all directions tended to be balanced.

It has been previously shown that there is a significant correlation between the abundance of blood flow in breast masses and axillary lymph node metastasis, and that a higher blood flow grade is correlated with a greater likelihood of metastasis (P<0.05) (26,27), indicating that blood flow grades II–III of primary lesions are factors relevant to axillary lymph node metastasis. Microcalcifications are defined as punctate or clustered calcifications with diameters mostly <1 mm in breast lesions, while some researchers also utilise 0.5 mm as the standard (28). Microcalcifications, mainly composed of hydroxyapatite, often occur in ductal carcinoma in situ, and their detection in IBC usually indicates a high possibility of metastasis. Some scholars believe that microcalcification is a type of dystrophic calcification formed by cell necrosis and calcium salt deposition during rapid tumour growth due to ischemia, which often indicates high malignancy, growth rate, and invasiveness of tumours (29). In the present study, there was no statistically significant difference in microcalcification detection between the metastatic group and the non-metastatic group (P>0.05) (Table 1), which may be related to the different defining standards for microcalcifications, as well as ultrasound image display and operational level.

Our results showed that the sensitivity, specificity, and accuracy of ultrasound in diagnosing lymph nodes were 88.9%, 80.0%, and 78.3%, respectively, which are similar to the results of a large-sample clinical study (90.4%, 68.2%, and 71.9%, respectively) (30). In ultrasound results of patients with IBC, axillary lymph node metastasis typically manifests as cortical thickening (either localised or diffuse, >3 mm), altered lymph node morphology (becoming round or oval with a length-to-width ratio <2), disrupted or shifted lymph node hilum echogenicity, and chaotic blood flow signals with increased resistance. In this study, the ultrasound diagnosis of axillary lymph nodes exhibited statistically significant differences among different statuses of lymph nodes (P<0.05) (Table 1), suggesting that suspected axillary lymph node ultrasound is a factor relevant to lymph node metastasis. According to logistic regression analysis, suspected axillary lymph node ultrasound is a risk factor for axillary lymph node metastasis and a good indicator for its prediction.

Breast cancer has a high degree of heterogeneity, essentially due to different gene expressions. Compared with luminal A type, luminal B type exhibits a higher grade and poorer prognosis (31). The HER2-overexpression type, characterised by the overexpression of HER2/HER2 signalling-related genes and HER2 amplicon located on chromosome 17q12, is highly malignant and invasive, and has high applicability for molecular targeted therapy with trastuzumab (32). The basal-like/triple-negative type is characterised by the lack of expression of OR, PR, and HER2 on the surface of tumour cells, presenting a triple-negative phenotype, and is insensitive to hormone therapy, with high tumour cell proliferation and poor prognosis.

In the present study, the expressions of OR, PR, and HER2 were not correlated with axillary lymph node metastasis (P>0.05), whereas Ki-67 was a factor relevant to axillary lymph node metastasis (P<0.05) (Table 1). It has been shown that the positive rates of PR and OR in patients with non-lymph node metastasis are significantly higher than those in patients with lymph node metastasis, and are protective factors for breast cancer (33). Leehy et al. (34) hold that the co-expression of PR and OR promotes the progression of breast cancer. The present study revealed no significant correlations between PR and OR with axillary lymph node metastasis, which may be related to PR and OR being hormone receptors in the breast and the sensitivity of cancer cells to oestrogen and progesterone. Overexpression of HER2 can inhibit the apoptosis of tumour cells and promote their distant metastasis. A previous study (33) revealed that the HER2-positive rate in patients with breast cancer and axillary lymph node metastasis is higher than that in those without lymph node metastasis. In the present study, no significant differences were found in the HER2-positive rate among different statuses of axillary lymph nodes. One reason for this is that different researchers have different defining standards for HER2 positivity, and another is that there may be experimental errors in the detection and counting of HER2-positive cells. A previous study reported Ki-67 as a high-molecular-weight proliferating cell nuclear antigen that plays an important role in the occurrence and development of tumours (35), consistent with the results of the present study.

There are some limitations in this study. First, all patients included were from the same hospital, with regional and source restrictions. There are issues related to the small sample size, short research time, and limited sample source. It is necessary to conduct deeper observations through increasing the number and range of samples and extending the research time. Furthermore, this study adopted a retrospective design. Given its reliance on existing cases, there is a potential for selection bias as certain cases may have been omitted from the records or were otherwise unavailable due to various reasons. The inherently observational nature of retrospective studies limits the ability to establish causality. Additionally, the absence of a prospective follow-up complicates the control for other confounding variables that might affect the outcomes.

Conclusions

In conclusion, tumour size, blood flow grade, Ki-67 expression, and axillary lymph node ultrasound diagnosis are correlated with axillary lymph node metastasis in IBC. Moreover, the maximum tumour diameter ≥20 mm and abnormal ultrasound diagnosis of axillary lymph nodes are risk factors for axillary lymph node metastasis in patients with IBC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1002/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1002/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1002/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Committee of The Affiliated Hospital of Yangzhou University (No. 2024-YKL09-009). Due to the retrospective nature of the study and anonymized patient information, informed consent was waived by the ethics committee.

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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