Hysteroscopic excision of symptomatic myometrial adenomyosis: feasibility and effectiveness

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1 DOI: / Surgical technique Hysteroscopic excision of symptomatic myometrial adenomyosis: feasibility and effectiveness W Xia, a,b D Zhang, a,b Q Zhu, a,b H Zhang, a,b S Yang, a,b J Ma, a,b H Pan, a,b T Tong, a,b J Sun, c J Zhang a,b a Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China b Institute of Embryo-Fetal Original Adult Disease Affiliated to School of Medicine, Shanghai Jiaotong University, Shanghai, China c Department of Obstetrics and Gynaecology, Shanghai First Maternity and Infant Hospital, Tong Ji University School of Medicine, Shanghai, China Correspondence: Jian Zhang, Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. zhangjian_ipmch@sjtu.edu.cn and Jing Sun, Department of Obstetrics and Gynaecology, Shanghai First Maternity and Infant Hospital, Tong Ji University School of Medicine, Shanghai, China. sunjing61867@126.com Accepted 27 March Published Online 1 June Objective To explore the feasibility and efficacy of hysteroscopic excision of myometrial adenomyotic lesions. Design A case-series study. Setting A university medical centre. Population 51 women with myometrial adenomyosis completed the study. Methods The patients underwent hysteroscopic excision of myometrial adenomyosis and were followed up for 24 months. The degree of symptoms, uterine volume, and serum CA125 concentrations were recorded. The degrees of menorrhagia and dysmenorrhea were evaluated. Results The mean MVJ and VAS score significantly decreased from the baseline. The uterine volume and the serum CA125 significantly reduced. Conclusions Hysteroscopic excision of myometrial adenomyotic lesions is feasible and may be effective in improving symptoms. Keywords Adenomyosis, dysmenorrhoea, hysteroscope, menorrhagia. Tweetable abstract Hysteroscopic excision is feasible for patients with symptomatic adenomyosisis. Please cite this paper as: Xia W, Zhang D, Zhu Q, Zhang H, Yang S, Ma J, Pan H, Tong T, Sun J, Zhang J. Hysteroscopic excision of symptomatic myometrial adenomyosis: feasibility and effectiveness. BJOG 2017;124: Introduction Adenomyosis is a common gynaecological disease with a morbidity of 8 27% in women of reproductive age. 1,2 Hysterectomy has been the main mode of treatment for adenomyosis. 3 Recently, with decrease of onset age and the increasing desire to preserve the uterus even among older women, conservative surgery has emerged as a popular treatment. Hysteroscopy has replaced old and/or invasive techniques, and has become a standard in gynaecological practice and has considerable advantages, such as less postoperative pain, shorter hospital stay and shorter recovery WX and DZ contributed equally to this work. time. 4 Hysteroscopic surgery has a better ability to remove submucous myomas and partially intramural myomas, keeping the outer myometrium intact and preserving the uterus. 4,5 However, only a few case reports have described hysteroscopic excision of myometrial adenomyomas or the diagnosis of adenomyosis by biopsy Here, we introduced transcervical resection (TCR) of intramural adenomyosis. Materials and methods Participants From October 2012 to October 2014, patients with symptomatic adenomyosis who were willing to preserve their uterus and had no fertility desire were included in this ª 2017 Royal College of Obstetricians and Gynaecologists 1615

2 Xia et al. study. Adenomyosis was diagnosed on the basis of medical history, physical examination, diagnostic transvaginal ultrasound (TVS) scan, magnetic resonance imaging (MRI), and the diagnosis was confirmed by postoperative pathology (Figure S1). 11 The following exclusion criteria were applied: pregnancy, precancerous condition or malignant lesion in a productive organ, deep infiltrative endometriosis (DIE) or ovarian endometriosis, pelvic inflammatory disease, postmenopausal status, or the patient declined to participate. Additionally, patients treated with gonadotropin-releasing hormone (GnRHa), except those who stopped taking GnRHa and had at least one menstrual cycle before the surgery, were excluded from this study. Data collection Patient information, including sociodemographic characteristics, type of adenomyosis, final postoperative pathological diagnosis, intraoperative and postoperative parameters, and length of hospital stays, were collected. Menstrual blood loss was assessed using the Mansfield Voda Jorgensen menstrual bleeding scale (MVJ) ranging from 1 (spotting) to 6 (gushing). An MVJ score equal to or >5 is considered hypermenorrhoea. 12 A visual analogue scale (VAS) was used to evaluate the degree of menstrual pain (0, no pain; 1 3, mild pain; 4 6, moderate pain; 7 10, severe pain). 13 The uterine size was measured by TVS a[uterine volume (cm 3 ) = length (cm) 9 width (cm) 9 height (cm) ]. 14 Haemoglobin level <120 g/l was defined as anaemia. 15 The serum CA125 levels were determined by enzyme-linked immunosorbent assay (ELISA) using a sandwich ELISA kits (R&D Systems, Minneapolis, MN, USA) according to the manufacturer s instructions (normal CA125 level, 35 U/ml). Surgical procedure One skilled surgeon performed transabdominal ultrasound-guided resectoscopic adenomyomectomy. The operation was performed using a TCR resectoscope (Ch. 26 model WA22061 with a 12 optic 22001A) equipped with a 3-mm-deep and 5-mm-wide loop (Olympus, Germany), and 0.9% NaCl was used as the irrigant under 120 mmhg intrauterine pressure. After general anaesthesia, we used a cutting loop to resect the lesions repeatedly and progressively with the standard electroresection. Two-dimensional transabdominal ultrasound guidance was used to assist the hysteroscopic excision and was performed by a doctor. Bladder filling was performed with 300 ml of saline serum (9%) to optimize visualization. The surgical procedure is presented in Video S1. Under ultrasound guidance, the first step was to evaluate the features of the uterine cavity, such as irregular endometrium with endometrial defects (Figure S2A and B), hypervascularization (Figure S2C), strawberry pattern (Figure S2D) or cystic haemorrhagic lesions (Figure S2E) on the endometrial surface. Firm white intramural lesions or intramural endometriomas were exposed during resection and lacked typical myometrial structure (Figure S2F). Openings of endometriotic lesions opened and closed like the mouth of a fish with the pulsing change in distension pressure (Figure S2A and B). There were some differences between the opening of endometriotic lesions and the proximal opening of tubal ostia. Upon cutting the endometrium covering the adenomyotic lesions, pink ectopic endometrial lesions in the myometrium were exposed (Figure S3A). The ectopic endometrium and adenomyotic lesions in the myometrium were then gradually resected (Figure S3B and C). During the resection of lesions, several intramural microcysts with wide bases were revealed (Figure S3D and E). Opening the microcyst resulted in the outflow of a thick brownish fluid, mostly old blood (Figure S3F). We then resected the endometrium-like tissue and microcysts with the loop. During resection, the myometrial vessels were coagulated to avoid excessive fluid absorption (Figure S4A). During the procedure, several intramyometrial diverticula were discovered (Figure S4B), and blood came through the openings (Figure S4C). After fluid drainage, an internal view of the microcyst revealed the presence of pink ectopic endometrium-like tissue (Figure S4D). After fluid drainage, the lacunae were cut. The loop was used to gradually resect the ectopic endometrium and adenomyotic lesions. Thereafter, the distension fluid flowed into the defects that appeared on the posterior uterine wall. As shown in the figure, the defects gradually enlarged under ultrasonic monitoring (Figure S4E). Then the electric loop was used to excise the endometrium covering the adenomyosis lesions in the uterine wall. The endometrial covering was excised to reveal the adenomyotic lesions. Then the ectopic endometrium and adenomyotic lesions in the myometrium were gradually resected. During the resection of lesions, several intramural microcysts with wide base were revealed. The endometrium-like tissue and microcysts were resected with the electric loop. During resection, the myometrial vessels were coagulated to avoid excessive absorption of fluid. After fluid drainage, the lacunae were cut. The loop was used to gradually resect the ectopic endometrium and adenomyotic lesions. Thereafter, the distension fluid flowed into the defects that appeared on the posterior uterine wall. The operation was considered complete when the pink fasciculate structure of the myometrium appeared. To prevent perforation and determine the margin of the lesion, we took the resectoscope back to the cervix. The cavity was filled with distension solution, and we evaluated the margins of the uterus and the lesion by sonohysterography. The procedure would stop if any complications occurred or if the estimated fluid deficit was more than 1 l ª 2017 Royal College of Obstetricians and Gynaecologists

3 Hysteroscopic excision of adenomyosis Follow-up The surgical efficacy was evaluated according to the serum CA125 level, uterus size, and the severity of dysmenorrhoea and hypermenorrhoea before and at 3, 6, 12, 18 and 24 months after the surgery. MRI was used to perform a 12- month assessment of treatment response. The pre- and postsurgical VAS and MVJ scores were compared, and treatment response was classified into four categories (partial relief, obvious relief, complete relief, and aggravation). 16 The clinical remission rate was determined as the sum of the remission rate recorded at different visiting times. Postoperative amenorrhoea was defined as the absence of menstrual bleeding for at least 12 months after surgery. Statistical analysis Statistical analysis was performed using GraphPad Prism 6.0 (GraphPad Software, CA, USA). Data were presented as the means standard deviation and were compared using the unpaired t-test. A P-value of <0.05 was considered statistically significant. Results Baseline data In this study, we included a total of 55 women with myometrial adenomyosis. Finally, 51 women completed the Table 1. Baseline characteristics of all enrolled participants (n = 51) Age (years) (38 50)* Parity Symptoms Menorrhagia alone 11 Dysmenorrhoea alone 9 Both 31 Duration of symptoms (years) Menorrhagia (6 14)* Dysmenorrhoea (0 20)* Medication treatment failure None 15 Norethisterone 15 GnRH agonist 8 Oral contraceptive 13 Previous abdominal surgery** Caesarean section 20 Myomectomy 5 Appendectomy 4 Adnexal surgery 18 Endometriosis 17 GnRH, gonadotropin-releasing hormone. *Data were presented as mean standard deviation (range). **A patient may have undergone two or more abdominal surgeries, thus the sum is greater than the number of patients. study after excluding four patients due to incomplete information (Figure S5). The baseline characteristics of all participants are shown in Table 1. Thirty-six patients have had medication treatment failure. The mean menstrual period lasted days. Among the 51 patients, 42 suffered from menorrhagia. Of these, eight, 14 and nine patients had mild, moderate and severe anaemia, respectively, with the lowest haemoglobin concentration of 59 g/l. Surgical data Table 2 presents the results of the hysteroscopic resection. Endometrial excision was performed in 10 patients during the hysteroscopic procedure. The mean operation time was minutes and the mean blood loss was (15 70) ml. There were no severe intraoperative complications or hysteroscopic complications, such as water intoxication and gas embolism. Uterine perforation occurred in one case. In this case, intraoperatively, we found lesions in the posterior wall of the uterus and a defect with a diameter of 0.5 cm in the uterine serosal layer of the posterior wall, indicative of uterine perforation. At that time, as we had removed most of the lesions, we decided to withdraw instruments and stop the surgery. Thereafter, we conservatively treated the uterine perforation successfully. There were no postoperative complications in the 51 patients. None of the patients was given any antibiotics. The median weight of the resected tissue was g. Effectiveness of surgery The mean MVJ score decreased significantly after the surgery (Figure S6A; P < 0.001). Of the 42 women with Table 2. Surgical findings Types of adenomyosis Diffuse 13 Focal 35 Cystic 3 Lesion location Anterior wall (%) 15 Posterior wall (%) 25 Entire uterus (%) 11 Operation time (min) * Blood loss (ml) * Volume of the medium used (ml) * Intraoperative complications (n) 1 Conversion to other surgeries (n)** 0 Postoperative fever morbidity 1/51 Weight of specimen (g) * Hospital stay (days) * *Data were presented as mean standard deviation. **Other surgeries refers to operations performed by laparoscopy or laparotomy. ª 2017 Royal College of Obstetricians and Gynaecologists 1617

4 Xia et al. menorrhagia, the remission rate of menorrhagia was 100.0% (42/42), 88.1% (37/42), 88.1% (37/42), 87.2% (34/ 39) and 84.6% (33/39) at 3, 6, 12, 18 and 24 months after treatment, respectively, suggesting that there was a significant improvement in menorrhagia (Table 3). Among the 10 patients (mean age 46 years) who underwent endometrial resection during the same procedure, four had amenorrhoea and one patient, who was 50 years old, underwent hysterectomy because there was no improvement in her menorrhagia and MVJ score. The other five cases had less menstrual blood to different degrees. In general, there was no significant difference in the MVJ and VAS scores between patients who received endometrial resection and those who did not (P > 0.05, data not shown). For 40 women who suffered from dysmenorrhoea before treatment, the mean VAS score significantly decreased after the operation (Figure S6B; P < 0.001). The clinical effective rates among the patients with dysmenorrhoea were 95.0%, 92.5%, 87.5%, 86.8% and 86.8% at 3, 6, 12, 18 and 24 months after the operation, respectively (Table 4). Among the remaining 11 patients, six had mild dysmenorrhoea postoperatively with a VAS score ranging from 1 to 2, and no treatment was administered in these cases. The uterine volume (Figure S6C; P = 0.01) and serum CA125 (Figure S6D; P < 0.001) levels both significantly reduced after the surgery. However, the uterine volume and serum CA125 level at 3, 6 and 12 months after the operation remained the same as the preoperative levels, but significantly decreased at 18 and 24 months after the operation (P > 0.05). Four patients underwent another hysteroscopic resection because they experienced no improvement in symptoms. They all had diffuse lesions involving both the anterior and posterior uterine walls. After the second operation, two patients reported a significant reduction in the MVJ and VAS scores, while the VAS score of the other two patients dropped from 10 to 3 with an effective rate of 100% at 12 months after the second surgery. The clinical effective rate of menorrhagia at 12 months after the second surgery was 50%. Two patients who were younger than 40 years and had relatively large uteri (235.1 and cm 3 ) had diffuse lesions involving both the anterior and posterior uterine walls. Their serum CA125 concentrations were and U/ml, and their MVJ score and VAS score were 5 and 10 after operation. At 12 months after the operation, both patients underwent laparoscopic resection of adenomyotic lesion as the operation had resulted in only a slight decrease in the MVJ and VAS scores, and both women strongly wished to preserve the uterus. During the laparoscopic procedure, both were found to have concurrent DIE and severe pelvic adhesion. One of our study participants was a 50- year-old patient with menorrhagia with a haemoglobin concentration as low as 59.2 g/l before the first surgery and a uterine volume of cm 3. MRI showed diffuse lesions involving the whole uterus. The amount of menstrual bleeding had significantly decreased within 6 months of the operation, but it increased at 9 months to more than the preoperative amount. Therefore, we performed a hysterectomy 1 year after the hysteroscopic surgery. Discussion We demonstrated the clinical feasibility of hysteroscopic TCR to treat symptomatic myometrial adenomyosis. The intraoperative and postoperative safety and low recurrence rate of menorrhagia and dysmenorrhoea during the 2-year follow-up demonstrated the potential applications of Table 3. Efficacy of hysteroscopic treatment on menorrhagia* Time points Complete relief Obvious relief Partial relief No response Clinical effectiveness*** n** % n** % n** % n** % n** % 3rd month th month th month**** th month***** th month***** *The efficacy of hysteroscopic treatment on menorrhagia was measured among women who suffered from menorrhagia before the surgery (n = 42). Menorrhagia refers to MVJ score equal to or greater than 5. **The number of patients who got a relief in menorrhagia. ***The clinical effectiveness was calculated by adding complete/obvious/partial relief rate of certain time point up. ****There are four cases that had undergone another hysteroscopic resection at 6th, 9th, 12th month after the operation for unimprovement in MVJ score or VAS score, and we followed up their menstrual conditions after the second hysteroscopic surgery. *****There are two cases that had undergone adenomyotic lesion resection under laparoscopy and hysterectomy, respectively. We did not continue the follow-up after that. Thus, we visited 39 patients at 18th and 24th month after the first operation ª 2017 Royal College of Obstetricians and Gynaecologists

5 Hysteroscopic excision of adenomyosis Table 4. Efficacy of hysteroscopic treatment on dysmenorrhoea* Time points of evaluation Complete relief Obvious relief Partial relief No response Clinical effectiveness*** n** % n** % n** % n** % n** % 3rd month th month th month**** th month***** th month***** *The efficacy of hysteroscopic treatment on dysmenorrhoea was measured among women who suffered from menorrhagia before the surgery (n = 40). **The number of patients who got a relief in dysmenorrhoea. ***The clinical effectiveness was calculated by adding complete/obvious/partial relief rate of certain time point up. ****There are four cases who had undergone another hysteroscopic resection at 6th, 9th, 12th month after the operation for unimprovement in MVJ score or VAS score, and we followed up their menstrual conditions after the second hysteroscopic surgery. *****There are two cases who had undergone adenomyotic lesion resection under laparoscopy for aggravated symptoms. We did not continue the follow-up after that. Thus, we visited 38 patients at 18th and 24th month after the first operation. Another 50-year-old patient was treated by hysterectomy at the 12th month for aggravated symptoms, and she was not one of the 40 patients in this table because she did not suffer from dysmenorrhoea. hysteroscopy in treating adenomyosis, as reported previously. 1,3,5,17 However, hysteroscopic surgery is confined to the uterine cavity, and affords surgeons limited space and view. Moreover, muscular tissue is thin and easily perforated; therefore, it is vital to choose patients carefully and ensure that the surgery is performed by a skilled surgeon. Here, seven patients received another surgery due to unsatisfactory outcome. Four of these patients underwent a second hysteroscopic surgery and got 100% relief from dysmenorrhoea and 50% relief from menorrhagia. Therefore, a second hysteroscopy can be considered for patients who do not have a satisfactory result the first time. All seven patients were diagnosed with diffuse-type adenomyosis involving all muscular layers. The depth of the adenomyotic lesions limits the treatment outcome. As the ectopic endometrium invades the myometrium deeply and widely and even the adenomyotic structures are localized in the outer intramural third, it is more difficult to completely resect the deep ectopic endometrium, resulting in no improvement in the symptoms of menstrual pain and bleeding. The most obvious advantage of hysteroscopic resection of adenomyotic lesions compared with other surgeries is that it is especially appropriate for adenomyosis that adenomyotic lesions located in the inner muscular layer and the uterine are small. Adenomyotic lesions can be completely resected if the ectopic endometrium is well identified. However, adenomyotic lesions are often unclear and diffusely distributed. Thus, it is difficult to remove them completely and relieve symptoms. Although those who had pelvic DIE or ovarian endometriosis had been diagnosed by physical examination, diagnostic TVS scan or MRI were excluded preoperatively, three patients in this study underwent another non-hysteroscopic surgery after the initial operation due to unsatisfactory outcome. During laparotomy or laparoscopic surgery, we found severe adhesion and pelvic DIE in two cases, indicating that it is difficult to diagnose DIE preoperatively. Moreover, we recommended laparotomy or laparoscopic excision for patients with diffuse-type adenomyosis or concurrent DIE to improve the efficacy. Menorrhagia and dysmenorrhoea were significantly alleviated at every follow-up visit, while the decreases in uterine volume and CA125 were insignificant. This may be because few patients had extremely large uterus or abnormally increased CA125, and most lesions were located in the inner muscularis layer, making them easy to remove. Three cases underwent non-hysteroscopic surgery at 12 months after the initial operation, and we did not conclude the data after second surgery. The preoperative uterine volume and serum CA125 concentration of these three patients were higher than the mean values. At 3, 6 and 12 months after the surgery, the uterine volume and serum CA125 were almost unchanged. The clinical symptoms, uterine volume and serum CA125 concentration were improved after excluding the data of these three cases at 18 and 24 months. Conclusions Hysteroscopic excision of myometrial adenomyotic lesions is feasible, and may be effective in treating menorrhagia and dysmenorrhoea in women with adenomyosis. Larger studies with long-term follow-up are required to confirm the long-term effects. ª 2017 Royal College of Obstetricians and Gynaecologists 1619

6 Xia et al. Author contributions Jian Zhang and Jing Sun conceived and designed the experiments; Wei Xia and Duo Zhang performed the experiments and wrote the manuscript; Tong Tong and Siqin Yang contributed to data collection; Qian Zhu, Huiyu Zhang, Jue Ma and Hongjie Pan participated in statistical analysis and revision of the manuscript. All authors read and approved the final version of the manuscript. Declaration of interest None declared. Completed disclosure of interests form available to view online as supporting Information. Details of ethics approval This study was approved by the Institutional Review Board of the International Peace Maternity and Child Health Hospital, Shanghai, China: ref. no. (GKLW) (obtained in June 2012). Before every procedure, written informed consent was obtained from each patient after informing them of the possible effects of the treatment on dysmenorrhoea and menorrhagia, potential failure of the treatment, and recurrence of these symptoms. Funding This work was supported by grants from the Science and Technology Commission of Shanghai Municipality (grant numbers , ) and the Shanghai Hospital Development Center (grant number SHDC ). Supporting Information Additional Supporting Information may be found in the online version of this article: Figure S1. MRI imaging of adenomyosis. Figure S2. Surgical procedure. Figure S3. Surgical procedure. Figure S4. Surgical procedure. Figure S5. Flow chart. Figure S6. Effectiveness of the surgery. Video S1. Hysteroscopic excision of symptomatic myometrial adenomyosis. & References 1 Huang X, Huang Q, Chen S, Zhang J, Lin K, Zhang X. Efficacy of laparoscopic adenomyomectomy using double-flap method for diffuse uterine adenomyosis. BMC Womens Health 2015;15:24. 2 Leyendecker G, Wildt L, Mall G. The pathophysiology of endometriosis and adenomyosis: tissue injury and repair. Arch Gynecol Obstet 2009;280: Grimbizis GF, Mikos T, Tarlatzis B. Uterus-sparing operative treatment for adenomyosis. Fertil Steril 2014;101: Zayed M, Fouda UM, Zayed SM, Elsetohy KA, Hashem AT. Hysteroscopic myomectomy of large submucous myomas in a 1-step procedure using multiple slicing sessions technique. J Minim Invasive Gynecol 2015;22: Nishida M, Takano K, Arai Y, Ozone H, Ichikawa R. Conservative surgical management for diffuse uterine adenomyosis. Fertil Steril 2010;94: Gordts S, Campo R, Brosens I. Hysteroscopic diagnosis and excision of myometrial cystic adenomyosis. Gynecol Surg 2014;11: Molinas CR, Campo R. Office hysteroscopy and adenomyosis. Best Pract Res Clin Obstet Gynaecol 2006;20: Fernandez C, Ricci P, Fernandez E. Adenomyosis visualized during hysteroscopy. J Minim Invasive Gynecol 2007;14: McCausland AM. Hysteroscopic myometrial biopsy: its use in diagnosing adenomyosis and its clinical application. Am J Obstet Gynecol 1992;166: Kumar A1, Kumar A. Myometrial cyst. J Minim Invasive Gynecol 2007;14: Struble J, Reid S, Bedaiwy MA. Adenomyosis: a clinical review of a challenging gynecologic condition. J Minim Invasive Gynecol 2016;23: Mansfield PK, Voda A, Allison G. Validating a pencil-and-paper measure of perimenopausal menstrual blood loss. Women s Health Issues 2004;14: Gerlinger C, Schumacher U, Wentzeck R, Uhl-Hochgra ber K, Solomayer EF, Schmitz H, et al. How can we measure endometriosisassociated pelvic pain? J Endometriosis 2012b;4: Park DS, Kim ML, Song T, Yun BS, Kim MK, Jun HS, et al. Clinical experiences of the levonorgestrel-releasing intrauterine system in patients with large symptomatic adenomyosis. Taiwan J Obstet Gynecol 2015;54: Stoltzfus RJ. Rethinking anaemia surveillance. Lancet 1997;349: Shui L, Mao S, Wu Q, Huang G, Wang J, Zhang R, et al. Highintensity focused ultrasound (HIFU) for adenomyosis: two-year follow-up results. Ultrason Sonochem 2015;27: Pontis A, DAlterio MN, Pirarba S, de Angelis C, Tinelli R, Angioni S. Adenomyosis: a systematic review of medical treatment. Gynecol Endocrinol 2016;5: ª 2017 Royal College of Obstetricians and Gynaecologists