High intensity focused ultrasound treatment for adenomyosis: comparison of efficacy based on MRI features

Abstract Objective To compare the clinical efficacy of High intensity-focused ultrasound(HIFU) for different types of adenomyosis classified by magnetic resonance imaging (MRI). Methods A total of 227 patients with adenomyosis who underwent HIFU treatment in Suining Central Hospital from January 2014 to December 2019 were included. Based on the preoperative pelvic MRI examination and Kishi isometric classification method, the patients were divided into 4 types according to the location of lesions. There were 82 cases of type I (endogenous type), 75 cases of type II (exogenous type), 34 cases of type III (nodular type), and 36 cases of type IV (heterogeneous type). The results of HIFU treatment for four types of adenomyosis and intraoperative adverse effects were analyzed. The changes of lesion size, dysmenorrhea, and menstrual volume were analyzed at 3 and 6 months after the operation. Result (1) adverse effects: All patients successfully accepted HIFU treatment under sedation and analgesia. Grade A adverse effects occurred in 51 cases (22.47%) and grade B adverse effects in 3 cases (1.32%). The incidence of adverse effects in type I–IV patients was 21.95%, 22.66%, 23.53%, and 30.56%, respectively. There was no significant difference in the incidence of grade A and B adverse effects in all types, and no grade C–F adverse effects occurred. (2) Ablation effect: The ablation rate of type III(nodular type)patients was (74.7 ± 20.3) %, which was significantly higher than that of the other three types (p < .05). (3) Changes in lesion size: the lesion size of all patients decreased after treatment and the reduction rate gradually increased with time. At 6 months after the operation, the lesion reduction rate of type III patients was (70.8 ± 14.8) %, higher than that of the other three types patients (p < .05). There was no significant difference in the reduction rate of type I, type II and type IV. (4) Remission of menorrhagia: At 6 months after the operation, the total remission rate of type III patients was 100%, while the total remission rate of type IV patients (65.4%, 17/26) that was lower than that of type I, II and III patients(p < .05). (5) Dysmenorrhea relief: At 6 months after the operation, the total dysmenorrhea relief rate of type III patients was 100% and the complete relief rate (28.1%, 18/31) was higher than that of the other three types, which was significant differences (p < .05). Conclusions HIFU is safe and effective in the treatment of different types of adenomyosis, the therapeutic effect of HIFU in patients with type III adenomyosis is better than that of the other three types.


Introduction
Adenomyosis is a common benign gynecological disease characterized by ectopic endometrial glands and stroma in the myometrium [1], with a prevalence of 7%-23%.The main clinical symptoms include increased menstruation, severe dysmenorrhea and infertility, which seriously endanger the health of women of childbearing age [2].Currently, hysterectomy is still the only curative treatment for adenomyosis.However, it is not suitable for patients who are unwilling to remove the uterus or have fertility requirements.Therefore, it has been a hot spot in clinical research to explore new and less invasive modality to treat adenomyosis.High-intensity focused ultrasound (HIFU) is a noninvasive thermal ablation technique, which has been widely used in the treatment of adenomyosis due to its advantages such as accurate ablation of lesions, small side effects, and repeated treatment under ultrasound guidance [3][4][5].Several studies have shown that the treatment efficacy and recurrence rate after HIFU are related to the type of adenomyosis and HIFU treatment for focal adenomyosis is superior to diffuse adenomyosis [6].Since the size of diffuse adenomyosis is large and the boundary is unclear, the postoperative recurrence rate and re-intervention rate are high [7][8].Recently, MRI classification is widely recognized, but only a few studies investigated the efficacy of HIFU treatment based on the MRI classification of adenomyosis.In this study, the patients with adenomyosis were divided into four types based on the relationship between the adenomyotic lesion and endometrium and myometrium according to Kishi's classification of adenomyosis [9], aiming to retrospectively analyze the efficacy of HIFU ablation in different types of adenomyosis.

Materials and methods
This study was approved by the Medical Research Ethics Review Committee of Suining Central Hospital.The reference number of the committee is LLSLH20210068.We conformed to the principles of the Helsinki Declaration, and all methods were carried out in accordance with relevant guidelines.Because of the retrospective study design, informed consent was waived by the Medical Research Ethics Review Committee of Suining Central Hospital.

Subjects
A total of 227 patients who received HIFU treatment in Suining Central Hospital from January 2014 to December 2019 were enrolled in the study according to the following inclusion and exclusion criteria.

MRI classification
According to the characteristics of the adenomyotic lesion, the enrolled patients were divided into four groups by Kishi classification.The MRI images were reviewed jointly by two senior radiologists and gynecologists.If there was any ambiguity in classification, the images were read and classified again by the third physician.
Type I (intrinsic type): the lesion invaded the endometrium and junctional zone, but the myometrium and serosa are normal; Type II (external type): the lesion invaded the serosa and myometrium, but the endometrium and junctional zone are normal; Type III (intermural type): the lesion is confined to the myometrium, and the whole structure of the uterus is intact; Type IV (heterogeneous type): adenomyosis foci that do not meet the diagnostic criteria of the above three types.As shown in Figure 1.

High intensity focused ultrasound treatment
HIFU treatment was performed under conscious sedation.A JC 200 HIFU tumor therapeutic system (Chongqing Haifu Medical Technology) was used for the procedure.This system contains an ultrasound imaging device (MyLab 70, Esaote, Genova, Italy) situated in the center of the transducer, to provide real-time imaging for monitoring the treatment.The patients were placed in a prone position, with the abdominal wall immersed in degassed water.The treatment began on the inferior surface of the adenomyotic lesion, moved toward the superior surface, and then from the posterior area to the anterior area of the adenomyotic lesion.The focus was kept at least 1.5 cm away from the endometrium and boundary of the adenomyotic lesion.During the procedure, the sonication power was regulated according to the feedback from the patient and the changing grayscale on the ultrasound imaging.The treatment was terminated when the hyperechoic area covered the entire lesion, or the contrast-enhanced ultrasound showed no blood flow in the treated adenomyotic lesion.The lesion volume and NPV (Non-perfused Volume) were calculated according to the elliptic volume formula V ¼ 0.523 Â abc (a: upper and lower diameter; b: left and right diameter; c: anterior and posterior diameter), and the non-perfused volume ratio (NPVR) was calculated as NPV/lesion volume Â 100%.The average power and sonication time of HIFU were recorded, and the total ablation dose (kJ) was calculated as P Â t, where P was the acoustic power (W) and t was the sonication time (s).
The adverse effects after HIFU treatment included sacrococcygeal pain, lower abdominal pain, groin pain, skin injury, lower limb motor sensory dysfunction, vaginal discharge, hematuria, etc. were evaluated according to the complication grading system of the International Society of Interventional (SIR) [10].As shown in Table 1.

Follow-up
A total of 227 patients completed follow-up at 3 months and 6 months after HIFU.The relief of dysmenorrhea or menstrual volume was analyzed.The volume of the adenomyotic lesion was compared before and after treatment, and the volume reduction rate was calculated.Reduction rate (%) ¼ (V before treatment À V at follow-up)/V before treatment Â 100%.Visual analogue scale (VAS) was used to quantitatively score the degree of dysmenorrhea (before treatment, 3 months, and 6 months after treatment): 0 point (no pain); 1-3 points: mild pain, tolerable; 4-6 points: pain affects sleep, tolerable; 7-10 points: the pain is unbearable [11].The 5-level scoring method was used to evaluate the menstrual volume of patients before HIFU, 3 months, and 6 months after HIFU [12]: 1 point: no increase; 2 points: slight increase; 3 points: moderate increase; 4 points: severe severe; 5 points: very severe increase.Complete relief: the score was the minimum; Obvious relief: the score was reduced by 2 points or more; Partial relief: the score was reduced by 1 point; Ineffective: the score did not change or increased compared with that before HIFU [13].Response rate ¼ number of clinical responses/the number of patients at follow-up Â100%.

Statistical analysis
The data was analyzed using SPSS software (SPSS21.0,IBM Company, Chicago IL).The normally distributed data is reported using mean ± standard deviation; the skewed data distribution was reported using the median and the interquartile range.Kruskal-wails H test was used for comparison among groups, and the test level was adjusted according to Bonferroni correction for further pairwise comparison.Pearson chi-square test or Fisher Criterion was used for comparison between groups for percentage, and p < .05 was considered as statistically significant.

Baseline characteristics
The median age of patients was 43 (19-52) years, the median disease course (with typical clinical symptom duration) was 3 years (1-27 years), and the median body mass index (BMI) was 22.7 (17.2-33.7)kg/m 2 .There were no significant differences in preoperative age, BMI, course of the disease, frequency of abortion and childbirth, menstrual volume score, and dysmenorrhea score of all types of patients (p > .05),and there were no significant differences in the number of lesions and the distribution of symptoms (p > .05),which were comparable, as shown in Tables 2  and 3.

HIFU ablation evaluation
Contrast-enhanced ultrasound showed no perfusion area in all treated lesions after HIFU treatment.A significant difference was observed in NPV and NPVR among the four groups (p ¼ .021,p ¼ .018).Further pairwise comparison showed that the NPV and NPVR of type III were significantly higher than those of the other three types patients (p < .05)while there was no significant difference in NPV and NPVR among type I, II, and IV (p > .05).There was no significant difference in power, treatment time, sonication time and total used energy dose among the four groups (p > .05).As shown in Table 4.

Symptom score and adenomyotic volume changes
The menstrual volume score and dysmenorrhea score in patients with all types of adenomyosis decreased at 3-and 6-month after HIFU.The lesion volume in patients with different types of adenomyosis shrank respectively, compared with their pre-HIFU lesion volume, which was statistically ).As for type I, II, IV patients, lesion reduction rates compared between each other groups, there were no significant differences, as shown in Table 5.

Follow-up results
At 6 months after HIFU, typeIIIpatients menorrhagia symptom improved dramatically, and the complete reduction rate of menstrual volume was significantly higher than that of the other three types, and the differences were statistically significant (p < .05).There was no significant difference in type I, type II and type IV (p > .05).The menstrual volume reduction rate of type IVpatients was less than that of other three types patients, which was statistically significant (p < .05),asshown in Table 6.

Dysmenorrhea
A total of 207 patients had dysmenorrhea symptoms before the operation.At 6 months after the operation, the complete remission rate of dysmenorrhea in four types was 20.5%, 18.8%, 58.1% and 20.6% respectively.In type III patients was higher than that of the other three types, and the differences were statistically significant (p < .05).While there was no significant difference in types I, II, and IV (p > .05),also were no significant differences in the effective rate of dysmenorrhea relief among different types (p > .05),as shown in Table 7.
All patients successfully completed HIFU treatment in one session under conscious sedation.Among the 227 patients, 51 (22.47%) had grade A. The main symptoms were lower abdominal pain, sacrococcygeal pain, lower limb The sample sizes of each group were the same as in Table 3.
a Compared with type III patients the NPV and NPVR of the other three types patients had a significant difference, p < .05.The sample size of each group was the same as Table 3.
a Compared with before operation, p < .05;b Compared with 3 months after operation, p < .05;c p < .0083,compared with type III at this time point (Bonferronin method adjusted level of 0.05).sensorimotor dysfunction, vaginal discharge, first-degree scald injuries, nausea and vomiting, and hematuria, with the corresponding incidence of 11.45%, 3.08%, 1.76%, 1.76%, 2.2%, 2.2%, and 0.88%, respectively.No special treatments were given for the above symptoms which gradually improved until disappeared.3 cases (1.32%) had grade B adverse effects, of which 2 cases (0.88%) had neurotoxicity and 1 case (0.44%) had pelvic inflammation and other related symptoms occurred 1 week after the operation.disappeared after 2-7 d of symptomatic treatment such as antiinflammatory and neurotrophic treatment, and 1 case (0.44%) of pelvic inflammation and other related symptoms occurred 1 week after the operation, and the symptoms completely disappeared after 11 d of symptomatic treatment such as anti-inflammatory fluid replacement, as shown in Tables 8 and 9.

Discussion
In 2007, ultrasound-guided HIFU was first used in the treatment of adenomyosis [14].Since then, reports on HIFU treatment of adenomyosis have gradually increased, and tens of thousands of patients with adenomyosis have been treated in nearly 100 hospitals in China.Studies have shown that the NPV of the lesion is a marker of tissue necrosis and is correlated with lesion volume reduction and symptom relief [3].This study showed that the non-perfused areas appeared in all treated lesions, and the median NPV ratio was 66%, which was similar to the results achieved in previous studies [4].In this study, we found that the NPV ratio of type III adenomyotic lesion was larger than that of the other three types.We also observed that the lesion size in patients with type III adenomyosis was significantly reduced at 6 months after HIFU, and the lesion reduction rate was greater than that of type I, II, and IV, indicating that the ablative effect for type III adenomyosis was better than other types.This phenomenon can be explained by that type III lesions do not invade the endometrium and serosa, type III lesions thus can be completely ablated [7].
Adenomyosis causes menorrhagia which is mainly manifested as a large menstrual volume with blood clots, a prolonged menstrual period, or bleeding during ovulation, and even leads to severe anemia in patients [15].This study found that there was no statistically significant difference in the menstrual volume score of patients with different types before HIFU treatment.The overall remission rate of menstrual volume at 3 and 6 months after HIFU was 86.5% and 82.7%, which was similar to the results from a previous study [8].Among them, the remission rate of type III patients reached 100%, and the complete remission rate (61.1%) was significantly higher than that of the other three types of patients at 6 months after HIFU.However, the overall remission rate of type IV patients (65.4%) was significantly lower than that of the other three types, and the proportion of invalid treatment cases was the largest.Studies have shown [10] that type IV is defined as a special type distinct from the other three types, the causes of this lesion formation are complex, and a single treatment may be difficult to relieve clinical symptoms.Therefore, similar to endometriosis, patients with adenomyosis also need long-term management [16].
Progressive dysmenorrhea is the main clinical symptom of adenomyosis, which affects the quality of life of patients.Therefore, dysmenorrhea relief is an important indicator to evaluate its clinical effect after treatment [17].This study showed that there was no significant difference among the four groups in dysmenorrhea score before HIFU.After HIFU ablation, the average dysmenorrhea score decreased in patients with four types of adenomyosis.The remission rates at 3 and 6 months after HIFU were 95.2% and 88.9%, respectively, which were slightly higher than the results from Shui et al. [13].At 6 months after HIFU, every patients with type III adenomyosis reported dysmenorrhea improved, the total remission rate reached 100%, and the complete remission rate (58.1%) was significantly higher than that of the patients with the other three types adenomyosis.Although a significant difference was observed in NPV ratio in the four groups of patients, no significant difference was observed among them in the total relief rate of dysmenorrhea between 3 and 6 months after HIFU.A study have shown that dysmenorrhea was caused by specific inflammatory mediators, such as IL-6, IL-8, TNF-a, and PGE2, and its pathogenesis is very complex [18].Even if the NPV ratio was not satisfactory, the thermal and mechanical effects of HIFU may change the internal environment of the uterus or the level of pro-inflammatory factors to alleviate dysmenorrhea [19].Safety is always a main concern of HIFU treatment.In this study, 229 patients successfully completed HIFU treatment, and the incidence of was 23.79%.All were classified as grade A-B based on SIR classification.No significant difference was observed in the incidence of grade A and grade B among different groups.No serious of grade C-F occurred.The incidence of grade A was 22.47%, among which the incidence of lower abdominal pain was 11.45%, sacrococcygeal pain was 3.08%, and vaginal discharge was 2.2%.The incidence of grade B was 1.32%, which was lower than the results of Lee et al. [5].In this study, leg pain occurred in two patients after HIFU who had a large lesion and located in the posterior wall of the uterus.Their treatment time and dose were greater than the median level.After HIFU, mecobalamin and vitamin B 12 was administered, and the symptoms gradually improved in 2 weeks.One patient with type I adenomyosis developed fever, chills, lower abdominal pain after HIFU, and the highest body temperature was 39.3 C. Combined with specialized physical examination and auxiliary examination, the inflammatory reaction caused by the necrotic lesion tissue in the absorption was considered, and the patient was given anti-inflammatory rehydration and other treatments.On the 11th day after the operation, the above symptoms were completely relieved.
This study is limited because it is a retrospective study, thus bias may have occurred.In addition, the sample size of each group was not large enough, which may cause a certain degree of bias.Finally, the follow-up time (6 months) is short, and the difference in long-term efficacy after treatment in types cannot be determined.
Based on the results from this study, we concluded that HIFU is safe and effective in the treatment of different types of adenomyosis.However, we found a significant difference in the efficacy of HIFU treatment for different types of adenomyosis.HIFU treatment for patients with type III adenomyosis seems better than that for patients with the other three types.Since this is a single-center retrospective study with a small sample size in each type of adenomyosis, a future multi-center prospective study with a large-sample size is necessary to verify the findings of this study.

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

( 1 )
diagnosis of adenomyosis patients was confirmed by color ultrasound and MRI; (2) all patients had different degrees of dysmenorrhea and/or increased menstrual volume; (3) patients didn't receive other treatment; (4) Complete follow-up information and imaging data were obtained at 3 months and 6 months after HIFU.

Figure 1 .
Figure 1.Classification of adenomyosis based on MRI.(A) Type I: the lesion invaded the endometrium layer, and the serosal layer (arrow) was intact; (B) Type II: the lesion invaded the outer uterine layer, the endometrium and the junctional zone (arrow) were intact; (C) Type III: lesions (arrows) confined to the myometrium with intact uterine structure; (D) Type IV: lesion (arrow) invaded the whole uterus.

Table 1 .
SIR classification system for complications by the outcome.

Table 2 .
Baseline characteristics of patients with adenomyosis in four groups.

Table 4 .
The conditions required of individuals who completed the HIFU ablation in four groups (x ± s).

Table 5 .
Lesion size and menstruation volume before and after HIFU ablation in four groups (x ± s).

Table 3 .
Lesion characteristics and symptoms of the patients with adenomyosis in four groups [n(%)].

Table 6 .
The constituent ration of menorrhagia remission at 6 month after HIFU ablation in four groups [n(%)].¼ 17.789, p < .001) was used for the constituent ratio of the remission of the menorrhagia in each group.Pearson chi-square test was used for remission rate between each two groups: a Complete remission rate of other three types patients compared with type III patients respectively, p < .05;b effective rate of other three types patients compared with type IV patients respectively, p < .05.

Table 7 .
The constituent ratio of dysmenorrhea relief at 6 month after HIFU ablation in four groups [n(%)].The constituent ratio of dysmenorrhea relief in each group was analyzed by Kruskal-Wails H test (H ¼ 18.113, p < .001).The Pearson chi-square test for response between each two groups.
a Complete remission of other three types patients compared with type III patients respectively, p < .05.

Table 8 .
The constituent ratio of SIR scale after HIFU ablation in four groups [n(%)].

Table 9 .
The constituent ratio of after HIFU ablation in 227 patients.