Feasibility and efficacy of ultrasound-guided high-intensity focused ultrasound of breast fibroadenoma

Abstract

Objective

This nonrandomized prospective clinical trial aimed to assess the efficacy, safety and follow-up outcomes of ultrasound-guided high-intensity focused ultrasound (USgHIFU) surgery in patients with breast fibroadenoma.

Methods

With the approval of the institutional ethics committee and written informed consent, a total of 113 patients diagnosed with breast fibroadenoma by core-needle biopsy in our hospital were recruited. USgHIFU surgery was performed under local anesthesia. Contrast-enhanced ultrasound (CEUS) or contrast-enhanced MRI (CEMRI) was performed to evaluate the nonperfused volume (NPV). The patients were followed up with physical examination and ultrasound imaging.

Results

The clinical outcome of 85 patients with 147 fibroadenomas with a follow-up time of more than 3 months was analyzed in this study. Fifty-two patients had one lesion, twenty-one patients had two lesions and twelve patients had more than two lesions. During USgHIFU, the median localization time for all fibroadenomas was 3 (interquartile range: 1, 5) min, and the median treatment time was 9 (interquartile range: 5, 15) min. Under local anesthesia, all the patients tolerated the treatment well. No serious epidermal burns were observed in any of the patients. Based on CEUS or CEMRI imaging evaluation, the median NPV ratio was 100% (interquartile range: 79.2%, 116.8%). The VRR were 26.77 ± 50.05%, 50.22 ± 42.01% and 72.74 ± 35.39% at 3–6 months, 6–12 months and >12 months, respectively, which showed significant statistical difference (p < .001).

Conclusion

Ultrasound-guided HIFU surgery is an effective and safe noninvasive alternative technique for the treatment of breast fibroadenoma.

Keywords:

• High-intensity focused ultrasound (HIFU)
• breast fibroadenoma
• ablative technique
• minimally invasive surgery
• benign breast tumor

Introduction

Benign breast masses are the most common complaints in females and attack more frequently than malignant ones do. Fibroadenoma, which consists of both fibrous and glandular tissue, is the most common benign tumor which usually occurs in young women [1]. The growth of fibroadenoma is usually slow and the probability of malignant transformation has been reported as rare as 0.02–0.125% [2,3]. Hormone-related changes could cause a slight increase in size during pregnancy [2].

The majority of the patients presenting with benign breast messes intend to choose surgery resection rather than serial observation because of bothersome prominence, intermittent growth, physical discomfort and anxiety [4,5]. Common treatments for tumor resection are surgical excision and vacuum or endoscopy-assisted minimal invasive surgery [2,6]. Although the tumor can be removed entirely, young patients may face a surgical scar with the potential for keloids and breast volume loss resulting in a cosmesis defect and effects on breastfeeding. Moreover, residuals and significant hematoma were reported in vacuum-assisted surgery of breast tumors larger than 2 cm in diameter [7,8]. In the past two decades, the advent of ablation techniques provides an office-based minimal invasive treatment that may reduce discomfort, shorten healing time and has limited scarring [4,5,9–14].

High-intensity focused ultrasound (HIFU) is the only noninvasive transcutaneous ablative therapy that has been reported to treat various kinds of solid tumors [15]. During HIFU, multiple beams of high-intensity ultrasound are generated by a transducer and focused on the target area. The energy within the area can be quickly accumulated to induce coagulative necrosis and ablate the target lesion. Ultrasound beams can penetrate through surrounding tissues. Hence, compared with minimally invasive thermal ablation techniques relying on an inserted ablative probe, such as radiofrequency ablation (RFA), microwave ablation (MVA) and laser ablation (LA), HIFU is a more conformal ablation technique [16]. HIFU has been effectively used in treating benign and malignant breast tumors [17,18]. Wu et al. firstly reported the successful treatment of ultrasound-guided HIFU (USgHIFU) for breast cancer in a randomized clinical trial [19]. Several studies with small sample sizes (9–42 cases) demonstrated the feasibility and safety of HIFU for breast fibroadenoma. Tumor volume reduced significantly after HIFU treatment [20–24].

This prospective clinical trial aimed to assess the application principle and the clinical outcome of USgHIFU for treating breast fibroadenoma with a relatively large sample.

Materials and methods

Patient enrollment

This prospective study has been registered in Clinical-Trials.gov (ChiCTR2100050068) and approved by the institutional ethics committee of the First Affiliated Hospital with Nanjing Medical University (2020-SR-130). A written informed consent was obtained from each patient. From January 2021 to November 2022, a total of 113 patients diagnosed with breast fibroadenoma by core-needle biopsy in our hospital were recruited and underwent USgHIFU at our department. And the clinical outcome of 85 patients with a follow-up time of more than 3 months was analyzed in this study. The inclusion criterion included the following: (a) patients were older than 18 years; (b) the Breast Imaging Recording and Data System (BI-RADS) score ≤3 by ultrasound and mammography in addition for women older than 35 years; (c) breast fibroadenoma proved by core-needle biopsy; (d) the maximum diameter of lesion was between 5 and 40 mm; and (e) fibroadenomas with a safe acoustic pathway and the focus can reach the target. The exclusion criteria were as follows: (a) pathological diagnosis of breast cancer; (b) BI-RADS score ≥4; (c) pregnant or lactating women; (d) patients with evidence of coagulopathy, chronic liver diseases or renal failure; and (e) patients with breast implants.

Pre-HIFU treatment ultrasonography

All patients underwent pre-HIFU ultrasonography before biopsy using a real-time ultrasound system (DC-80S, Mindray, Shenzhen, China) with a 7.5 MHz linear array probe. Patients lay supine on the examination bed with arms outstretched. The locations of all the targeted tumors were recorded through a full breast scan from the nipple to the edge of the breast. The three orthogonal diameters (the longest diameter and two other perpendicular ones) and the Alder grade of each targeted tumor was observed and recorded. The volume was calculated according to the formula: V = πabc/6. Then, in order to evaluate the USgHIFU acoustic pathway, especially the near field, we define the near field as three types (mainly mammary glandular type, mixed type and mainly fat type) according to the composition of the organization, which has been described in detail in our previous studies [25].

USgHIFU therapeutic procedure

The procedure of USgHIFU was performed with a HIFU therapeutic system (Model JCQ-B, High Intensity Focused Ultrasound Ablation Therapeutic System for Breast, Chongqing Haifu Medical Technology Co. Ltd., China). After local anesthesia, patients were positioned prone on the HIFU therapeutic system bed with the skin overlaying to the lesion in contact with degassed water. Dynamic real-time ultrasound imaging (L9-3E, Mindray Medical, Shenzhen, China) was applied to observe the whole targeted lesion and the adjacent tissues, thus monitoring the HIFU ablation procedure (Figure 1). Before treatment, distance between the shallow margin of fibroadenoma to the skin and distance between the deep margin of fibroadenoma to the pectoralis major were measured. For pretreatment planning, the whole fibroadenoma was divided to slices of 3 mm separation. Then, the focus began from the deep side to the shallow side of each slice with treatment power started from 100 W. The treatment power was adjusted according to the hyperechoic grayscale change on the real-time ultrasonographic imaging or the feedback from patients. Once the hyperechoic grayscale completely encompassed the planned ablation area, the procedure was terminated [19,25]. Technical parameters including treatment duration, sonication duration, mean power and sonication energy were recorded.

Figure 1. Typical change in the gray scale of fibroadenoma on the dynamic realtime ultrasound image during HIFU treatment. (a) Before treatment, ultrasound image showed a hypoechoic breast fibroadenoma. The distance from the shallow margin of the fibroadenoma to the skin and the distance from the deep margin of the fibroadenoma to the pectoralis major were measured. (b) During HIFU, a significant gray scale changes was observed (white arrow). (c) Once the significant gray scale changed area covered the whole fibroadenoma, the procedure was terminated.

After the procedure, patients were monitored in the observation room with an ice pack placed on the treated breast for 0.5–2 h.

Safety assessment

Complaints from patients during and after HIFU were recorded in detail. A visual analogue scale (VAS) was used to evaluate the pain during HIFU. Any adverse events, such as severe pain, skin redness, skin burns and subcutaneous edema, were monitored within 72 h after HIFU.

Contrast-enhanced ultrasound and contrast-enhanced MRI

To evaluate the therapeutic response, contrast-enhanced ultrasound (CEUS) or contrast-enhanced MRI (CEMRI) was performed within 2 days after the HIFU procedure (Figure 2). For patients with one or two fibroadenomas, CEUS was performed using a contrast agent (SonoVue, Bracco Imaging, Milan, Italy). And for patients with three or more tumors, CEMRI was performed with a 3.0 T system (MAGNETOM Trio, Siemens, Germany) using a bilateral eight-channel phased-array breast coil. Contrast agent bolus injection consisted of 0.1 mmol gadopentetate dimeglumine (Magnevist, BayerSchering, Germany) per kilogram of body weight was administered at an injection rate of 3.0 ml/s, which was followed by a 20 ml saline solution. The ablated fibroadenoma was defined as a nonperfused volume (NPV) after contrast material administration and measured in 3 dimensions. NPV was calculated according to the formula: V = πabc/6. The NPV ratio was defined as NPV/fibroadenoma volume × 100%.

Figure 2. CEMRI images of a 27-year-old woman with bilateral breast fibroadenomas. Before HIFU, T1-weighted fat-suppressed CEMRI images showed hyperintensity masses in the right breast (a) and the left breast (c). The day after HIFU, CEMRI images showed nonperfused ablated zones in the right breast (b, white arrow) and the left breast (d, white arrow). A rim of enhancing tumor in the bottom section of one fibroadenoma in the left breast was shown in the CEMRI images (d, red arrow).

Follow-up and imaging analysis

At 1 month, 3, 6, 12 and 18 months after USgHIFU, follow-up was performed by physical examination and US imaging. Clinical symptoms and cosmetic outcomes, including pain, skin pigmentation, nipple discharge, and tumor palpability, were also recorded. The tumor was measured by US examination and its volume was calculated by the same formula used in the pre-ablation evaluation (Figure 3). According to the change of tumor volume during follow-up, we divided the therapeutic effect into the following four categories: (1) enlargement: the volume increased by more than 10%; (2) stable: the volume increased or decreased by no more than 10%; (3) reduction: the volume decreased by more than 10%; and (4) complete disappeared: completely disappeared under ultrasound examination. The volume reduction ratio (VRR) was calculated by the following formula: VRR (%) = [(initial volume – final volume) × 100]/initial volume.

Figure 3. Before HIFU, ultrasound images showed fibroadenomas with clear boundary (A(a), B(a)). (A(b)) Six months after treatment, US images showed an enlarged hypoechoic zone without blood flow signal, suggesting a postoperative change. (B(b)) Six months after treatment, US images showed a typical reduced hypoechoic ablation zone.

Statistical analysis

Categorical variables are presented as frequency or percentage and compared using the chi-square test or Fisher’s exact test. Continuous data with normal distribution were reported as mean ± SD and analyzed by an independent sample T-test; and data with skew distribution were reported as median and inter-quartile range (P25, P75) and analyzed by the Wilcoxon rank-sum test. Data were analyzed using SPSS 24.0 software (SPSS, IBM Company, USA) and the significance was set at 0.05.

Results

Baseline characteristics

A total of 85 patients with 147 fibroadenomas were included in this study and underwent USgHIFU with at least 3 months of follow-up. Five patients who developed new lesions after their initial HIFU treatment opted for HIFU treatment again. The baseline characteristics of enrolled patients are summarized in Table 1. Fifty-two patients had one lesion, twenty-one patients had two lesions and twelve patients had more than two lesions. Among them, the patient with the largest number of treated lesions has treated a total of nine lesions in bilateral breasts. The mean age of these 85 patients was 27.1 years ± 7.1. Nine patients had a history of previous breast surgery, and eight of them had a skin scar on the affected breast.

Table 1. Basic characteristics of patients (n = 85).

Variables	Data
Age (years)	27.1 ± 7.1
BMI (kg/m^2)	20.49 ± 2.32
No. of patients	85
With single lesion	52 (61.18%)
With two lesions	21 (24.70%)
With three or more lesions	12 (14.12%)
With history of breast surgery*	9 (10.59%)
Surgical excision	8 (88.89%)
Vacuum-assisted surgery	1 (11.11%)

*These are all for benign breast tumors.

The median longest diameter of these 147 tumors was 17 mm assessed by using US, with a range of 5.5–32 mm. Of these 147 tumors, the median distance between the shallow margin of the fibroadenoma and skin was 12 mm, with a range of 1–34 mm; the median distance between the deep margin of the fibroadenoma and pectoralis major was 3 mm, with a range of 0–25.3 mm. Before treatment, 100 (68.03%) tumors could be palpable. For the types of near field of acoustic pathway, 27 tumors with mainly mammary glandular type, 84 with mainly fat type and 36 with mixed type. The baseline characteristics of these tumors are summarized in Table 2.

Table 2. Basic characteristics of breast fibroadenomas (n = 147).

Variables	Data
Longest diameter of fibroadenoma (mm)	17 (13.8, 21.4)
Fibroadenoma volume (mm^3)	1109.13 (511.06, 2214.16)
Distance between the shallow margin of the fibroadenoma and skin (mm)	12 (7.85, 15.85)
Distance between the deep margin of the fibroadenoma and pectoralis major (mm)	3 (1, 6.9)
Lesion appearance
Palpable	100 (68.03%)
Impalpable	47 (31.97%)
Types of near field of acoustic pathway
Mainly mammary glandular	27 (18.37%)
Mixed	36 (24.49%)
Mainly fat	84 (57.14%)
Adler blood flow classification of ultrasound
0	50 (34.01%)
I	62 (42.18%)
II	33 (22.45%)
III	2 (1.36%)

Therapeutic response

As shown in Table 3, the median localization time for all lesions was 3 min, ranging from 0.1 to 35 min, and the median treatment time was 9 min, ranging from 1 to 63 min. A treatment power of 100–400 W was used for different lesions. The median sonication energy used was 10,400 J, and the median sonication time was 53 s. Overall, the safety profile appears very good. Under local anesthesia, all the patients tolerated the treatment well. The average VAS score during the treatment was 4.6 ± 2.54 points, whereas, no one claimed the procedure to stop. Two patients with hypertrophic scars on the skin directly above the lesion reported moderate pain at the site of their scars during ablation. Approximately one-quarter of the patients experienced slight skin redness and subcutaneous edema after surgery. No serious epidermal burns were observed in any of the patients. Based on CEUS or CEMRI imaging evaluation, the median NPV ratio was 100% (Interquartile range: 79.2%, 116.8%).

Table 3. USgHIFU treatment results for breast fibroadenomas (n = 147).

Variables	Data
Localization time (min)	3 (1, 5)
Treatment time (min)	9 (5, 15)
Sonication time (s)	53 (30, 98)
Sonication energy (J)	10,400 (5375, 18,425)
EEF (J/mm^3)	8.8 (6, 16.5)
NPV ratio (%)	100 (79.2, 116.8)

Follow-up imaging and volume reduction

The median follow-up was 12 months, ranging from 3 to 22 months. The observation period was 3–6 months for 12 patients (14.12%, 12/85), 6–12 months for 29 patients (34.12%, 29/85) and more than 12 months for 44 patients (51.76%, 44/85). At 3–6 months after ablation, 16 tumors enlarged, 9 tumors stabilized, 81 tumors shrunk and 3 disappeared completely. At 6–12 months, 2 tumors were enlarged, 8 tumors were stable, 89 tumors were shrunk and 7 were disappeared completely. At >12 months of follow-up, 2 tumors enlarged, 1 tumor stabilized, 58 tumors shrunk and 21 disappeared completely. The percentages of the four states of tumors at 3–6 months, 6–12 months and >12 months were summarized in Figure 4. After ablation, the proportion of enlarged and stable tumors decreased, while the proportion of tumors that shrunk and disappeared completely increased with the follow-up time. Based on the ultrasound images of the lesions and their ablation rates, among the four lesions with increased volume after more than 6 months of follow-up after treatment, one should be considered a postoperative change, while the remaining three were residual due to incomplete ablation. The VRR were 26.77 ± 50.05%, 50.22 ± 42.01% and 72.74 ± 35.39% at 3–6 months, 6–12 months and >12 months, respectively, which showed significant statistical difference (p < .001). Moreover, at 6–12 months, 57/106 (53.77%) lesions were palpable, and at >12 months, only 14/82 (17.07%) lesions could be palpable. Among the total 147 lesions, 99 lesions were less than 2 cm in diameter and 48 lesions were larger than or equal to 2 cm. And no differences were found in VRR at the follow-ups between two subgroups of lesions <2 cm and lesions ≥2.0 cm in size (p > .05, Figure 5).

Figure 4. Percentages and exact numbers of the four states of fibroadenomas at 3–6 months, 6–12 months and >12 months post-ablation, including complete disappeared, reduction, stability and enlargement.

Figure 5. VRR of fibroadenomas at 3–6 months, 6–12 months and >12 months post-ablation. (a) VRR of all the fibroadenomas during follow-up. ***p < .001. (b) No differences were found in VRR at the follow-ups between two subgroups of lesions <2 cm and lesions ≥2.0 cm in size. ns, p > .05.

Discussion

Breast fibroadenomas are commonly seen among young women worldwide. A number of patients experience repeated surgeries for breast fibroadenomas, resulting in substantial psychological burdens. Regarding the benign nature of FA, the surgeon constantly faces the dilemma whether to remove the tumor or to monitor it by means of regular follow-up examinations. Without the need for needle or probe insertion into the target, HIFU is the only noninvasive ablative technique and has been a promising image-guided technique in treating various kinds of solid tumors [15]. In the past two decades, HIFU was evaluated in several studies as an alternative treatment in the management of breast fibroadenomas. Studies demonstrated that HIFU was effective and safe in the treatment of breast fibroadenomas with better cosmetic outcomes. Hynynen et al. firstly reported the feasibility of magnetic resonance imaging (MRI) guided HIFU in the treatment of 11 breast fibroadenomas in 9 patients [20]. Six fibroadenomas showed complete response after ablation and mean volume decreased from 1.9 ± 1.5 to 1.3 ± 1.1 cm³ at 6 months posttreatment. Cavallo Marincola et al. evaluated the safety and efficacy of USgHIFU treatment using the model JC HIFU device in 10 patients with breast fibroadenomas [18]. The treatment time between the first and last sonication was 57.2 min (range 40–100 min) and a significant reduction of 50% in maximum diameter was seen at the 3-months follow-up. Kovatcheva et al. presented a prospective multicenter study in which 42 women with 51 breast fibroadenomas in one or both breasts were enrolled [24]. At the 12-months follow-up, a volume reduction of 72.5% was described and no serious adverse event was reported.

In this study, we reported a successful experience of USgHIFU ablation of 147 breast fibroadenomas in 85 patients with a median follow-up of 12 months. To the best of our knowledge, this study is the largest cohort of patients with breast fibroadenomas treated with USgHIFU. With a median treatment time between the first and last sonication of 9 min (range from 1 to 63 min), the median NPV was 100%. After 12 months of USgHIFU, the mean volume of lesions was reduced by 72.74% (SD 35.39%). More than a quarter of the lesions disappeared completely under ultrasound examination. During the physical examination, 82.93% of lesions were nonpalpable, compared to only 31.97% before ablation. Under local anesthesia, the pain and discomfort related to HIFU were well tolerated and no serious adverse events were seen. Therefore, five patients chose HIFU again when developed new breast fibroadenoma after their initial HIFU treatment.

Epidermal burns are the most common complication of thermal ablation techniques. In previous studies [19,20,22,24], the inclusion criteria generally consisted of tumors located at a distance of 5–15 mm or more from the skin. However, in this study, any distance from the tumor to the skin or chest wall was acceptable. The distance between the shallow margin of the fibroadenoma and the skin ranged from 1 to 34 mm and the distance between the deep margin of the fibroadenoma and pectoralis major ranged from 0 to 25.3 mm. A thorough local anesthesia of the subcutaneous and retromammary space effectively prevented adjacent tissue burns in this study. During HIFU treatment, multiple US beams generated from a transducer propagate through skin and subcutaneous tissue into the targeted area. At the interface between different types of tissues, deposition of ultrasound could be amplified, resulting in thermal damage to tissues beyond the target. Therefore, treatment for patients with skin abnormalities must be carried out with caution. This study included eight patients with skin scars resulting from previous breast surgeries. Although no serious complications related to the scar were seen, two patients with proliferative scars on the skin directly above the lesion reported pain at their scars during ablation, thus slowing down the treatment process. Therefore, patients with skin proliferative scars in the acoustic field, who tend to have a stronger inclination toward selecting noninvasive treatments, should be adequately informed. It may also be rational to divide the treatment into multiple sessions.

Minimally invasive thermal ablation techniques, such as RFA, MVA and LA, also play a role in the treatment of breast tumors [9–12]. During tumor ablation, an electrode or a probe is inserted into the center of the tumor and remained fixed to create a large round zone. In comparison, during HIFU treatment, the transducer is moved in three-dimensional directions to connect single ellipsoid-shaped coagulative necrosis to a volume necrosis, which is more conformal and flexible [15]. Without the need for multiple ablation insertions, HIFU has a more pronounced advantage in treating multiple lesions in bilateral breasts. In this study, 33 patients had two or more lesions and were treated under local anesthesia in the outpatient unit. HIFU ablation enabled the patients to undergo treatment without surgery and general anesthesia. Further advantages were an absence of scarring, no breast volume loss, therefore an improved cosmesis and reduced recovery time which could result in economic benefits. Meanwhile, HIFU can be reperformed noninvasively. Kovatcheva et al. reported an increased volume reduction with two sessions of HIFU ablation [22]. Additionally, the relatively flexible therapeutic strategy enables HIFU to have a greater variation of treatment modes. Peek et al. performed circumferential HIFU ablation in treatment of breast fibroadenomas that not only effectively reduced the volume of lesions but also shortened the treatment time [23].

Although FUS has been repeatedly shown to be feasible and promising, its widespread acceptance has been limited because of the relatively long ablation time and low complete ablation rate [9,20,26]. It is partially due to some technical factors such as the difficulty of precise target definition in the prone position and beam dosimetry. Patient movement can also increase the difficulty of intraoperative lesion localization [20]. Doctor training is a key to precise ablation. In our previous study [27], the cumulative summation technique was used to analyze the learning curve for HIFU treatment of breast fibroadenoma between two centers. It was reported that after 60–65 treatments, the training stage of the learning curve was finished. In the consolidation phase, the screening time, treatment time, sonication time and hyperechoic scale change emerging time were significantly shorter than that in initial phase. The ablation rate increased significantly in consolidation phase of both centers. Standardization of sonication energy deposited in the tumor could also aid in improving treatment efficacy and promoting the widespread application of HIFU. Previous study [25,28] demonstrated that clinical ultrasound characteristics, including fibroadenoma size, distance from the shallow margin of the fibroadenoma to skin and type of near field acoustic pathway, and ultrasound radiomics features could be used as predictors to evaluate the dosage delivery of USgHIFU treatment for breast fibroadenomas. And an optimal scaling regression model was established to quantitatively illustrate the dosimetry of HIFU.

There are some limitations existed in this study. First of all, a long follow-up period is warranted to assess the long-term results in the future, especially for these lesions suspicious of incomplete ablation. Secondly, the majority of the fibroadenomas included in this study had a diameter of less than 3 cm. The efficacy and safety of HIFU therapy for breast fibroadenomas larger than 3 cm are unclear. Lastly, prospective multi-center clinical trials with large sample size are expected to confirm our results.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data are fully available upon reasonable request. The corresponding authors should be contacted if someone wants to request the data.

Additional information

Funding

This study was supported by the Foundation of State Key Laboratory of Ultrasound in Medicine and Engineering [Grant No. 2021KFKT002, Grant No. 2021KFKT014 and Grant No. 2022KFKT009].