2.1.1. Research Participants

Using convenience sampling based on age, we retrospectively analysed 480 cases of patients with IGM treated in the Breast Surgery Department of our hospital between January 2020 and December 2021. All patients were diagnosed with IGM by core needle biopsy prior to hospitalisation. The random number table method was used to group the patients according to the treatment method. The operation steps were as follows: (1) the patients were numbered by drawing lots; (2) starting from any number in the random number table, a random number was obtained for each experimental unit in the same direction; and (3) for grouping, the random numbers were arranged from small to large (if the numbers were the same, the first number was placed in front). The patients corresponding to the first 160 random numbers were included in the CHQGT combination group (CHQGT + MWA), the patients corresponding to the middle 160 random numbers were included in the glucocorticoid combined group (glucocorticoids + MVA) and the last 160 patients were included in the control group (glucocorticoids).

IGM was diagnosed by combining the patient’s clinical manifestations, physical examination, breast ultrasonography and histopathological findings (Figure 1). Most of the clinical manifestations of these patients were painful masses on one side of the breast, and there was no obvious abnormality in local skin colour and temperature at the beginning of the disease. As the disease progresses, more than 50% of patients have inflammatory changes in the affected side of the breast, such as erythema and swelling. Other symptoms include sunken nipples, fistulas and ulcers, and around 37% of patients develop abscesses. Lesions can occur in any quadrant of the breast, mostly from the peripheral quadrant, gradually spreading to the areola area and even to the entire breast in a short time. Some patients may be accompanied by fever, chills, rash and other systemic symptoms [27]. The typical ultrasonographic manifestations of IGM are multiple adjacent hypoechoic masses with posterior acoustic shadow or posterior acoustic shadow enhancement. Advanced cases show effusion, cavity or even strip hypoechoic (sinus); rich blood flow signals or signs of angiogenesis can be seen in the diseased area, and 15%–55% of cases can exhibit ipsilateral axillary reactive lymph node enlargement [28]. The final diagnosis of IGM depends on histopathology, and hollow needle biopsy is the first choice of method. The disease’s typical pathological feature is the formation of a noncaseous necrotic granuloma with breast lobule as the centre, accompanied by local infiltration of multinucleated giant cells, epithelioid cells, lymphocytes and plasma cells [29]. In traditional Chinese medicine, IGM belongs to the category of ‘acne mastitis’ (female nipple belongs to ‘liver’ and breast belongs to ‘stomach’), which is characterised by loss of liver qi and stagnation of qi. Stagnation of liver qi leads to obstruction of milk collaterals, stagnation of liver and stomach, phlegm and blood stasis, obstruction of breast collaterals, agglomeration, heat for long periods and meat rot resulting in abscess and fistula following ulceration [30].

This study was approved by the ethics committee of our hospital (Ethics No. 202044). All participants were informed and signed written consent forms. The inclusion criteria were as follows: patients with (1) signs of liver-qi depression, such as breast pain, dysmenorrhea chest tightness, ventosity, constipation and depression; (2) onset within 1 month, without undergoing hormone, antituberculosis drug, immunotherapy or surgical treatment (excluding simple abscess drainage surgery), and those requiring conservative drug treatment during the acute progression period; and (3) women aged between 18 and 60 years old (inclusive of both 18 and 60).

The exclusion criteria included (1) coexistence of malignant breast tumours, other endocrine diseases, autoimmune diseases or inflammatory diseases with symptoms similar or identical to those of IGM; (2) coexistence of other breast diseases, or patients taking medication that might influence the study results; (3) coexistence of severe cardiovascular diseases, primary diseases such as liver or kidney dysfunction, or mental disorders; (4) pregnant or lactating women; and (5) individuals with a predisposition to allergies or known allergies to the class of drugs or its components.

The elimination criteria were as follows: (1) pregnancy during treatment; (2) poor compliance, failing to attend follow-up visits or provide relevant case report information; and (3) discovery of other violations of the inclusion criteria or meeting the exclusion criteria during the study.

The termination criteria included (1) serious adverse reactions during the trial (mainly adverse reactions to the use of glucocorticoids, including osteoporosis, osteonecrosis, aggravated infection, induced or aggravated gastric and duodenal ulcers); (2) unexpected circumstances arose, making it challenging to evaluate the drug’s efficacy; and (3) treatment was forcibly terminated due to other diseases (mainly secondary diabetes and other diseases that could not be addressed in this study).

2.1.2. Research Methods

For the control group, prednisone was used for treatment, starting at a dose of 20 mg/d. Upon symptom relief, the dosage was gradually reduced every 1-2 weeks sequentially to 16, 12, 8, and 4 mg/d, and was maintained at 4 mg/d until the end of the treatment course. The judgment was made by clinicians based on expert consensus. The criteria for determining symptom relief are the disappearance of clinical symptoms, the inaccessibility of the original inflammatory lesions clinically and the healing of ulcers or sores, but the presence of scattered minor lesions is still visible on imaging [31]. The total duration of treatment was 3 months. Patients unresponsive to the treatment underwent surgical excision. The criteria for determining such patients are as follows: (1) clinical symptoms (breast lump size, redness, swelling and pain) are not relieved after 1 week of treatment; (2) imaging shows no response to treatment (stable or enlarged lesion range); and (3) the granulomatous lobular mastitis disease activity index remains unchanged or increases [31].

For the glucocorticoids combined group, MWA treatment was added to the regimen of the control group. The MWA device (KY-2000, Nanjing Canyon Medical Technology Co., Nanjing, China) operated at a frequency of 2450 MHz. The MWA needle had an outer diameter of 16G and a transmission tip length of 3 mm. Ultrasound examinations were performed using the American GE Logiq P9 ultrasound device (probe: 9–12 LMHz) and operated on an ultrasound imaging software platform equipped with an Italian Demetro 16G semiautomatic biopsy needle. Ultrasound was used to determine the lesion’s location, size, number, blood flow signals and echo characteristics. Local infiltration anaesthesia was administered to the patient’s breast skin and retromammary space prior to treatment. Physiological saline was injected into lesion areas close to the skin, areola and muscles to form a barrier to prevent thermal injury. Individualised ablation treatment plans were formulated based on ultrasound results of the lesion. The treatment plan included determining the needle insertion point, needle insertion depth, number of needle insertions, lesion fluid aspiration and duration of ablation. The microwave power was set to 25–30 W. Under ultrasound guidance, the active tip of the MWA needle was placed within the lesion, and the entire process was continuously observed under dynamic ultrasound in multiple sections. Dilated milk ducts were gradually ablated from deep to shallow along the duct wall. Micro-abscesses were treated with pinpoint ablation, and multipoint, multilevel mobile ablation was used for multiple lesions and larger lesions (maximum diameter: > 2 cm). Contrast-enhanced ultrasound was employed to determine whether the ablation was complete (intraoperative ultrasound monitoring with SonoVue infusion into the cubital vein [2.4 mL]). Ablation was considered complete when no contrast agent perfusion was observed in the ablation area. If the ablation was incomplete, the ablation process had to be repeated immediately. Following ablation, patients were treated with local dressings and ice packs and were discharged 4–6 h later. Patients unresponsive to the treatment underwent surgical excision.

For the CHQGT combination group, treatment was administered using CHQGT combined with MWA, with the MWA procedure being the same as described above. The prescription for CHQGT is as follows: 9 g of Bai Gui (Paeonia lactiflora), 9 g of Dang Gui (Angelica sinensis), 15 g of Bai Jian (ampelopsis japonica), 10 g of rhizome, 10 g of turmeric, 6 g of dried citrus peel, 5 g of licorice, 18 g of dandelion and 18 g of Shi Zi (Ardisia chinensis Benth). Following preparation, the patient took the decoction orally once a day, and continued this for a month, until the lesion completely disappeared or the treatment was ineffective. Patients unresponsive to the treatment underwent surgical excision.

2.1.3. Data Collection

We aimed to compare the overall treatment effect of the three groups, including the effect on reducing lump size, reducing patient pain and accelerating recovery. Data regarding the patient’s age, body mass index (BMI), number of lesions, size of lesions, distribution of lesions, marital and childbirth history, white blood cell count (WBC), percentage of neutrophils (NEUT%), C-reactive protein (CRP), efficacy at the end of the study and breast appearance following treatment were collected. After treatment, data from 1, 3 and 5 months were collected, including Visual Analog Scale (VAS), Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA) scores, and lump size. After the end of treatment, the patients were followed up for 2 years, and the patients were requested to undergo a follow-up every 3 months to investigate any recurrence and adverse reactions.

In terms of efficacy, with reference to the Standards of Diagnosis and Therapeutic Effect of TCM Diseases and Syndromes from 1994 in the People’s Republic of China, the outcomes were classified into the following: (1) cured: breast redness, swelling, heat and pain had disappeared, the fistula healed, no pseudo-healing and all systemic symptoms had disappeared; (2) improved: most of the lump had disappeared or most of the fistula had healed, with superficial wounds remaining unhealed; and (3) ineffective: the breast still exhibited redness, swelling, heat and pain, the fistula did not heal, or the lesion area had even expanded. The efficacy rate = (cured + improved)/N × 100% [32].

Based on the standards jointly established by the American Surgical Association, Radiological Society, Pathological Society and the Surgical Oncology Society, breast appearance was categorised as follows: (1) excellent: the size and shape of the breast after treatment are roughly the same as the contralateral breast; (2) good: retraction and skin changes of the breast involve less than 1/4 of the original; (3) fair: retraction and skin changes involve between 1/4 and 1/2 of the breast; (4) poor: breast deformity involves more than 1/2 of the breast. The good-to-excellent rate = (excellent + good)/total cases × 100% [33].

The VAS score was used to evaluate the pain situation before and after treatment in the three groups, with the score directly proportional to the level of pain. A score of 0 indicates no pain, with a maximum of 10. Scores of < 3 indicate mild pain, 4–6 represents moderate pain and > 7 indicates severe pain [34].

The HAMD was developed by Hamilton in 1960. The scale has 24 items across seven categories: anxiety/somatisation, weight, cognitive impairment, diurnal variation, retardation, sleep disturbances and feelings of despair. In terms of scoring criteria, a total score of > 35 indicates severe depression, 21–35 signifies mild-to-moderate depression, 8–20 represents borderline depression and < 8 means no depression [35].

The HAMA is used to evaluate patients anxiety symptoms before and after nursing. A score of < 7 indicates no anxiety symptoms and is psychologically normal; scores of > 7 but < 14 suggest possible anxiety symptoms; scores of > 14 but < 21 indicate definite anxiety symptoms; scores of > 21 but < 29 confirm significant anxiety symptoms; and scores of > 29 represent severe anxiety symptoms. The score is inversely proportional to the severity of anxiety symptoms; the lower the score is, the milder the symptoms [36].

2.1.4. Statistical Analysis

Statistical analysis was conducted using SPSS 26.0 software. Data conforming to a normal distribution were expressed in terms of means and standard deviation (x ± s). Intergroup comparisons were performed using analysis of variance (ANOVA), with pairwise comparisons utilising the least significant difference method. Count data were expressed as frequency and percentage, with the chi-square (χ²) test or Fisher’s exact test used for intergroup comparisons and the chi-square partition method for pairwise comparisons. A significance level of p < 0.05 indicated statistical significance.

2.2.1. Screening of Active Ingredients and Related Targets of Bupleurum Qinggan Decoction

In the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) (https://tcmspw.com/tcmsp.php/), the effective active ingredients of the formula were screened using 12 traditional Chinese medicines of Bupleurum Qinggan Tang as keywords, with oral bioavailability ≥ 30% and drug likeness ≥ 0.18 used as the limiting conditions. The target protein was converted into a standard name using the UniProt database (https://sparql.uniprot.org/).

2.2.2. Acquisition of IGM-Related Targets and Key Targets

The keyword ‘idiopathic granulomatous mastitis’ was searched in the Gene Cards (https://www.genecards.org/) database to obtain disease-related targets. The drug active ingredient targets and disease targets were introduced into Venny 2.1.0 to create a Wayne diagram, and the drug/disease key targets of the CHQGT decoction for the treatment of IGM were obtained.

2.2.3. Construction of Chai Hu Qinggan Decoction for the Treatment of IGM Target Network

The data on the drugs, active ingredients, disease-related targets and their attribute files were imported into Cytoscape 3.9.1, and the composition–disease–target network diagram of Bupleurum Qinggan decoction and IGM was plotted.

2.2.4. Protein–Protein Interaction (PPI) Network Construction of Intersecting Targets

The drug–disease intersection target was input into the STRING database (https://www.string-db.org). The species was selected as ‘Homo sapiens,’ the minimum interaction threshold was set to ‘medium confidence (0.4)’ and the PPI network was obtained. The results were imported into Cytoscape 3.9.1 for visualisation.

2.2.5. Gene Oncology (GO) Enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Enrichment Analysis

The intersection targets of the CHQGT decoction in the treatment of IGM were imported into the DAVID database (https://david.ncifcrf.gov/), and p < 0.05 was set. GO enrichment analysis was performed in terms of three modules: biological process (BP), cellular component (CC) and molecular function (MF). The entries of the enrichment results were plotted as bar charts and bubble charts using an online data analysis visualisation platform (https://www.bioinformatics.com.cn/).

2.2.6. Molecular Docking Verification of Key Targets

The top 5 core active ingredients were calculated according to the topological parameter Degree value, and the three-dimensional (3D) structure in Mol2 format was downloaded from the TCMSP database and the structure was imported into ChemBio3DUltra 14.0 for energy minimisation. The 3D structure of the core protein gene was downloaded from the Protein Data Bank database, and Pymol2.3.0 was used to remove protein crystal water and original ligands. AutoDock was used (v1.5.6) to hydrogenate the core active ingredients and key targets, calculate the charge, etc. and save them in PDBQT format. Then, POCASA 1.1 was used to predict the protein binding site and AutoDock Vina1.1.2 was used for docking. The PyMOL 2.3.0 and LigPlot V2.2.5 systems were used to analyse the interaction mode of the docking results. The binding activity of the compound and the core protein target was evaluated according to the binding energy, with the binding energy of < −5.0 kJ/mol selected as the screening condition to evaluate the docking effect of the two.

3.1.1. General Information

The results indicated that before treatment, there were no statistically significant differences among the three groups of patients in terms of age, BMI, smoking history, alcohol consumption history, number of lesions, size of lesions, distribution of lesions, marital and fertility history, WBC, NEUT% and CRP (all p > 0.05). This suggested that the three groups of patients were comparable, as shown in Table 1.

3.1.2. Changes in Patients’ Lump Size and Psychological Status After Treatment

Colour Doppler ultrasound was used to monitor changes in lesion volume during treatment (Figures 2(a) and 2(b)). Single-factor repeated-measures ANOVA was employed to investigate the effects of different treatment methods on VAS scores, HAMD scores, HAMA scores and lump sizes for the three patient groups. According to the Shapiro–Wilk test, the data of each group followed an approximate normal distribution (p > 0.05). According to Mauchly’s test of sphericity, the variance–covariance matrices of the groups were equal (p > 0.05). Data were presented as x ± s, as shown in Table 2. The results are summarised as follows. The interaction of time ∗ treatment was significant in VAS scores, HAMD scores, HAMA scores and lump sizes across the three groups (F_VAS score = 322.111, p < 0.001; F_HAMD score = 219.432, p < 0.001; F_HAMA score = 112.122, p < 0.001; F_lump size = 144.561, p < 0.001), indicating that the individual effect changes in VAS scores, HAMD scores, HAMA scores and lump sizes were different among the three groups. Moreover, with the extension of time, the scores and lump sizes in all three groups generally decreased (F_VAS score = 123.456, p < 0.001; F_HAMD score = 245.423, p < 0.001; F_HAMA score = 247.218, p < 0.001; F_lump size = 145.131, p < 0.001), indicating a significant change in the patients’ VAS scores, HAMD scores, HAMA scores and lump sizes over time. Lastly, the influence of different treatment methods on VAS scores, HAMD scores, HAMA scores and lump sizes varied across the three patient groups (F_VAS score = 145.423, p < 0.001; F_HAMD score = 144.393, p < 0.001; F_HAMA score = 145.642, p < 0.001; F_lump size = 287.328, p < 0.001).

Further pairwise comparisons were made in terms of VAS scores, HAMD scores, HAMA scores and lump sizes across the three patient groups at different time points. There were no statistically significant differences among the three groups in any of the metrics (all p > 0.05), suggesting good comparability across the groups. The descriptions of the metrics for the three groups at 1, 3, and 5 months are as follows. For VAS scores, at 1 and 3 months, the ranking was CHQGT combination group < corticosteroid combination group < control group; at 5 months, CHQGT combination group = corticosteroid combination group < control group. For HAMD and HAMA scores, the ranking at 1, 3, and 5 months were the same, with CHQGT combination group = corticosteroid combination group < control group. For lump size, at the first month, the ranking was CHQGT combination group = corticosteroid combination group < control group; at 3 and 5 months, it was CHQGT combination group < corticosteroid combination group < control group (Table 2).

3.1.3. Comparison of Treatment Efficacy Among the Three Groups

The overall effective rates were 91.88%, 87.50% and 67.50% in the CHQGT combination group, glucocorticoids combination group and control group, respectively. The comparison results of treatment efficacy showed a statistically significant difference in the overall effective rate among the three groups (χ² = 55.824, p < 0.001). Pairwise comparison revealed that the CHQGT combination group and glucocorticoids combination group had a better curative effect than the control group. However, there were no significant difference between the CHQGT combination group and the glucocorticoids combination group. In addition, the disease duration of the CHQGT, glucocorticoids and control groups were compared, with the durations 5.54 ± 3.03, 5.85 ± 3.04, 8.24 ± 3.21 months, respectively. There was a significant difference in the disease duration among the three groups (F = 11.360, p < 0.001). Following pairwise comparison, the difference of disease duration among the groups was statistically significant (Table 3).

3.1.4. Comparison of Adverse Reactions During Treatment

Within 2 years after treatment, 4 patients in the CHQGT combination group, 15 patients in the corticosteroid combination group and 34 patients in the control group experienced adverse reactions, with overall adverse reactions incidence rates of 2.50%, 9.38% and 21.25%, respectively, showing a statistical difference among the three groups (p < 0.001). The comparison of adverse reactions showed that the incidence rate of adverse reactions during treatment in the CHQGT combination group and glucocorticoids combination group was significantly lower than that in the control group (Table 4).

3.1.5. Comparison of Recurrence

The results showed that within 2 years after treatment, 30 patients in the combination group, 35 in the glucocorticoids group and 50 in the control group were readmitted to the hospital for relapse, with recurrence rates of 18.75%, 21.88% and 31.25%, respectively. The difference in recurrence rates between the three groups was statistically significant (χ² = 7.433, p = 0.024). Among them, the recurrence rate of the combination group and the glucocorticoids group was lower than that of the control group (p < 0.05), whereas there was no significant difference in the recurrence rate between the combination group and the glucocorticoids group (p > 0.05).

3.1.6. Comparison of Breast Appearance After Treatment

The comparison results of breast appearance post-treatment showed statistically significant differences in the good-to-excellent rate of breast appearance among the three groups (χ² = 45.366, p < 0.001), with 84.38% in the CHQGT combination group, 64.38% in the glucocorticoids combination group and 48.75% in the control group. Pairwise comparisons indicated that the good-to-excellent rate of breast appearance in the CHQGT combination group and glucocorticoids combination group was significantly higher than that in the control group (Table 5). Changes in the typical appearance of the breast after treatment are shown in Figure 3.

3.2.1. Target Network Analysis of Bupleurum Qinggan Decoction and IGM

A total of 199 active ingredients, 293 active ingredient targets and 79 IGM disease-related targets were obtained after screening, of which 23 were active ingredient and disease intersection targets (Figure 4). A total of 478 nodes and 4374 edges were obtained using Cytoscape 3.9.1 to construct the network of Bupleurum Qinggan decoction and IGM, and Network Analyser was used to analyse the topological parameters of PPI. Ranked by Degree value, the top 5 active pharmaceutical ingredients were quercetin (MOL000098, quercetin), kaempferol (MOL000422), β-sitosterol (MOL000358, beta-sitosterol), stigmasterol (MOL000449) and baicalein (MOL000173, wogonin) (Figure 5). It is speculated that the Bupleurum Qinggan decoction may play a key role in the treatment of IGM through the above active ingredients.

3.2.2. Analysis of Core Targets of Bupleurum Qinggan Decoction in the Treatment of IGM and Construction of PPI Network

A total of 23 intersecting targets were imported into the STRING database for PPI network analysis, and 23 nodes and 163 edges were obtained after screening (Figure 6). The results were imported into Cytoscape 3.9.1, and the PPI topological parameters were analysed using Network Analyzer. The top 10 nodes were selected as the core targets, namely interleukin (IL)-6, tumour necrosis factor (TNF), albumin, IL-1β, C-X-C motif chemokine ligand 8 (CXCL8), signal transducer and activator of transcription 3 (STAT3), C-C motif chemokine ligand 2, IL-4, interferon gamma and CRP, and the visual network diagram was created (Figure 7). It is speculated that the Bupleurum Qinggan decoction acts on the above targets and plays a role in the treatment of IGM.

3.2.3. GO Enrichment Analysis and KEGG Pathway Enrichment Analysis

A total of 23 drug-disease intersection targets were imported into the DAVID database for GO enrichment analysis, and p < 0.05 was used as the screening condition, with a total of 129 items for BP enrichment, 9 items for CC enrichment and 13 items for MF enrichment. The results showed that BP mainly included inflammatory response, positive regulation of gene expression, cellular response to lipopolysaccharide and positive regulation of DNA transcription. Moreover, CC mainly includes extracellular space, extracellular region, exosomes and plasma membrane, and MF mainly includes protein binding, identical protein binding, cytokine activity, enzyme binding and receptor binding. We constructed a KEGG functional enrichment map based on the count of disease-related genes or proteins (Figure 8), which primarily included 15 core signaling pathways such as IL-17, toll-like receptors, cytokine receptor interactions, nuclear factor kappa B (NF-κB), and TNF.

3.2.4. Connection Between the Main Active Ingredients of Bupleurum Qinggan Decoction and the Molecules of Key Targets

According to the results of network pharmacology analysis, the top 5 active ingredients with the highest degree value were quercetin (MOL000098), kaempferol (MOL000422), β-sitosterol (MOL000358, beta-sitosterol), stigmasterol (MOL000449) and baicalein (MOL000173, wogonin), along with IL-6 (PDBID: 1ALU), TNF (PDBID: 2E7A), IL-1β (PDBID: 6I8Y), CXCL8 (PDBID: 6N2U), STAT3 (PDBID: 6NJ2) and IL-4 (PDBID: 2D48). The binding energy of the key active ingredients and the core target was ≤ −5.0 kJ/mol.