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INTRODUCTION
Uterine leiomyomas are the most common gynecological tumors, and approximately 50% of patients with these tumors experience symptoms (1). The American College of Obstetricians and Gynecologists has recommended uterine artery embolization (UAE) as a treatment option for selected women who wish to retain their uteri (2). Since the introduction of UAE for the treatment of symptomatic leiomyomas and adenomyosis, many studies have been published on the topic; some of the conclusions deserve further study, whereas other important outcomes do not shed much light on the topic. This review focuses on general knowledge regarding UAE but also highlights UAE-related concepts that are often not addressed, poorly understood, or rarely published.
This review discusses difficulties that are frequently encountered during UAE procedures and their solutions. Furthermore, recent trends in medication for pain control and updates regarding UAE for leiomyoma and adenomyosis are also presented.
Pre-Procedural
UAE for Pedunculated Subserosal Leiomyomas
According to the Society of Interventional Radiology guidelines, UAE is not contraindicated in patients with a pedunculated subserosal leiomyoma (3). In contrast, the Cardiovascular and Interventional Radiological Society of Europe guidelines consider a pedunculated subserosal leiomyoma as a relative contraindication due to the potential risks of detachment, infection, and sepsis (4). In a previous study of 1069 patients who underwent UAE, 55 patients with pedunculated subserosal leiomyomas, including 11 patients with high-risk pedunculated subserosal leiomyomas (stalk diameter < 25% of the leiomyoma diameter), showed no adverse events after UAE (5).
UAE for Cervical Leiomyomas
Most uterine leiomyomas (≥ 95%) develop in the uterine corpus, but a few (< 5%) occur in the uterine cervix. The location of a leiomyoma in the cervix increases the difficulty of surgery due to the limited access for suturing and increased blood loss (67). One study reported that the cervix always shows perfusion immediately after embolization, which may influence the results of UAE in cervical leiomyomas (8). Only 50% of cervical leiomyomas were successfully treated with UAE in a previous study (9). In the author's experience, the outcome depends on the vascularity of the leiomyoma during embolization (Fig. 1). Because cervical leiomyomas frequently show poor vascularity, the results of UAE were disappointing (9). Therefore, caution is required in the selection and pre-surgical counseling of patients, especially for those who are symptomatic only due to cervical leiomyomas.
UAE for Leiomyomas with High Signal Intensity (SI) on T2-Weighted Imaging (T2WI)
High signal intensity (SI) of a leiomyoma on T2-weighted imaging (T2WI) may indicate high cellularity, proliferative activity, and increased vascularity (10). Cellular leiomyomas, which are composed of compact smooth muscle cells, have a relatively higher SI on T2WI and may demonstrate good enhancement on contrast-enhanced magnetic resonance (MR) imaging (MRI). Extensive edema in interstitial spaces may also result in high SI on T2WI. Burn et al. (11) reported that a high SI of leiomyomas on T2WI was a good prognostic factor. In a previous study (12), the mean volume reduction rate of leiomyomas in the T2-high group at three months after UAE was 61.7%, which was significantly higher than that in the control group (42.1%).
UAE for Malignant Tumors Misdiagnosed as Leiomyomas
A few reports have discussed UAE for malignant tumors that were misdiagnosed as leiomyomas (1415). The US Food and Drug Administration has estimated that 1 in 350 women who undergo a hysterectomy or a myomectomy for presumptive leiomyoma have a uterine sarcoma, with an incidence between 0.24% and 1.4%. In our experience, among 1300 patients, two patients had a misdiagnosed malignancy, with an incidence of 0.15%.
The SI of a leiomyoma may vary on T2WI, making it difficult to differentiate a leiomyoma from a malignant tumor. Therefore, eliciting a detailed clinical history in addition to careful evaluation of the MR images is mandatory, even when a prior biopsy report is available (Fig. 3).
Gonadotropin-Releasing Hormone (GnRH) Agonists for Large Leiomyomas Prior to UAE
Controversy persists regarding the use of UAE for large leiomyomas (1617). Some authors insist that UAE for leiomyomas ≥ 10 cm in diameter should be avoided because of a higher incidence of complications such as infection, sepsis, uterine necrosis, and death, whereas others have reported no significant increase in complications for such large leiomyomas. One serious issue is the large leiomyoma becoming endocavitary after UAE, causing cramping abdominal pain with or without infection.
Gonadotropin-releasing hormone (GnRH) agonists are widely used preoperatively to reduce the size of leiomyomas. The common protocol involves subcutaneous administration of 3.75 mg of leuprolide acetate once a month for 2 to 6 months before UAE. Patients were monitored using ultrasound every month to determine the relative decrease in the size of leiomyomas. Because GnRH agonists tend to make the uterine arteries smaller and more spastic, radiologists might have some difficulty selecting the uterine arteries due to arterial spasm. However, although the uterine arteries in most patients who are treated with GnRH agonists shrink in comparison with their pre-treatment size, they are still sufficiently large to undergo UAE (18). Therefore, treatment with GnRH agonists does not preclude the use of UAE. Indeed, most of our patients treated with GnRH agonists demonstrated complete infarction of leiomyomas after the procedure (Fig. 4). Interestingly, patients who were treated with GnRH agonists experienced significantly less pain after the procedure compared with those who were not treated with GnRH agonists, according to the author's experience. Furthermore, fewer embolic materials were used in these patients.
UAE for Recurrent Leiomyomas after HiFU
HiFU is another option for non-surgical management of leiomyomas in selected patients. In contrast to UAE, which aims for complete infarction of leiomyomas in most patients, HiFU requires a peripheral, viable portion of the tumor to secure a safety margin. This could be the reason for the higher recurrence of leiomyomas following HiFU than that following UAE (Fig. 5). UAE can be considered a viable treatment option for recurrent or incompletely infarcted leiomyomas after HiFU.
UAE in Post-Menopausal Women
UAE is usually not recommended for the treatment of leiomyomas in post-menopausal women. Some post-menopausal women with leiomyomas who take hormone replacement therapy develop symptoms, which can be persistent, and some experience vaginal bleeding. In a previous article, the growth of pre-existing leiomyomas or even development of new leiomyomas has been reported (19). However, UAE can be effective even in post-menopausal women (20) after the possibility of endometrial cancer is ruled out using MRI or endometrial biopsy.
UAE and Deep Vein Thrombosis (DVT)
Although deep vein thrombosis (DVT) followed by a pulmonary embolism after UAE is extremely rare, it can be fatal (Fig. 6). Nikolic et al. (21) revealed that UAE induced hypercoagulability. To date, four cases of mortality following UAE due to pulmonary embolism have been reported (2223). Because many patients with leiomyomas take oral contraceptives to control uterine bleeding, an unknown number of UAE candidates may already have DVT before the procedure. Hidden malignancy-related coagulopathy may also contribute to the development of DVT (Fig. 7). Therefore, recording a detailed clinical history and performing a routine d-dimer test before UAE can increase patient safety, specifically in those taking oral contraceptives.
Procedure
Identification of Leiomyomas Using Uterine Arteriography
Identification of leiomyomas using uterine arteriography is very important because it can predict the success of UAE (Fig. 8). In general, leiomyomas larger than 3 cm in diameter can be easily detected on arteriography by interventional radiologists with some experience. If a leiomyoma is not identified on an arteriogram, the possibility of a collateral supply should be considered, especially for large leiomyomas in the uterine fundus. Comparison of a coronal T2W MR image of the uterus with the fluoroscopic image during or after UAE is a good method to verify the accuracy of an embolization.
Anatomically Complicated UAE
The uterine arteries may show some anatomical variations, such as a unilateral uterine artery supplying the entire uterus, duplicated uterine arteries, or an aplastic uterine artery replaced by an ovarian artery. Collaterals from the inferior mesenteric artery are identified at a significantly higher rate in patients with adenomyosis (24).
Highly tortuous uterine arteries can make it difficult for radiologists to select the arteries. In such cases, Robert's uterine catheter (Cook, Spencer, IN, USA) can be useful. In patients with a single uterine artery, the UAE outcome can be good if the leiomyoma receives its blood flow exclusively from the embolized uterine artery (Fig. 9).
Ovarian Artery Embolization (OAE)
A previous study demonstrated that 3.8% of patients who underwent UAE needed ovarian artery embolization (OAE) (25). OAE is required in patients with a Type II utero-ovarian anastomosis based on the utero-ovarian anastomosis classification (Fig. 10) (26), or with a hypoplastic or aplastic uterine artery functionally replaced by an ovarian artery (Fig. 11). Only patients with an ovarian artery entering the myometrium on aortography after UAE can be considered for OAE. MR angiography before UAE can be useful to predict the necessity of OAE (25). A Mickelson or Simmons Type II catheter (Cook) can be effective in selecting the ovarian artery.
Post-Procedural Steps
Pain Management
Several investigations have described analgesic and pain management techniques to control pain after UAE. The most common method is a patient-controlled analgesia pump containing fentanyl and non-steroidal anti-inflammatory drugs. A recent randomized study revealed the efficacy of dexmedetomidine, which has a fentanyl-sparing effect and induces sedation without respiratory depression (27).
Administration of steroids may relieve pain and inflammation because steroids have anti-inflammatory effects. One previous study showed that a 10-mg intravenous injection of dexamethasone 1 hour before UAE induced a post-procedure decrease in the release of acute inflammation mediators C-reactive protein and interleukin-6, along with a decreased level of the stress hormone cortisol (28). Intra-arterial injection of 5 mL of 1% lidocaine administered after UAE into each uterine artery is also effective for acute pain relief (29).
Complications of UAE
Endocavitary leiomyoma may occur following UAE (33), inducing serious complications such as secondary infection. Patients with endocavitary leiomyoma with or without infection may present with symptoms of cramping abdominal pain, vaginal discharge with a foul odor, and fever. In severe cases, hysteroscopic myomectomy with cervical dilation and curettage or, rarely, hysterectomy may be needed. When a necrotic leiomyoma cannot be completely excised the first time, cervical dilation and curettage or hysteroscopic resection can be attempted more than 2 or 3 times for complete removal (Fig. 12). However, endocavitary leiomyomas less than 6 cm in diameter are not generally considered clinically significant according to the author's experience.
Repeated UAE
In the author's limited experience, the outcome of repeated UAE was disappointing. On arteriography, some patients have uterine arteries that have recanalized or have several collaterals from pelvic branches or ovarian arteries, rendering repeat UAE inefficient (Fig. 13). Therefore, repeated UAE is not usually recommended.
Re-Intervention Risk after UAE
Previous randomized studies that compared the long-term effectiveness of UAE and surgery for leiomyomas revealed that the re-intervention rate at 5 years was significantly higher for UAE (32%) than for surgery (4%) (3435). However, these data included procedures performed during the early periods of UAE, when the technical success rates were low. The rate of complete necrosis of leiomyomas with UAE during early attempts was also low. However, previous studies did not address an essential query: what percentage of patients would need re-intervention in 5 years after UAE when complete necrosis of leiomyomas had been achieved as observed using MRI after UAE?
One recent study found that only approximately 10% of patients who underwent UAE, most of which showed complete necrosis of leiomyomas confirmed using MRI, required a re-intervention procedure such as myomectomy or hysterectomy at 5 years (36). We believe that this rate might be acceptable, indicating the sustainability of UAE.
Adenomyosis
Adenomyosis is characterized by the presence of endometrial glands and stroma scattered randomly deep within the myometrium, along with adjacent smooth muscle hyperplasia. Approximately one-third of women with adenomyosis experience symptoms such as menorrhagia, pelvic pain, and bulk-related symptoms. Adenomyosis is regarded as a difficult disease entity to treat, with hysterectomy considered the only curative treatment. The long-term efficacy of UAE as a treatment option for adenomyosis remains controversial and is lower than its efficacy for treating leiomyoma. Previous studies (37383940) have revealed that when small non-spherical polyvinyl alcohol (PVA) particles measuring 150–250 µm are used at the beginning of embolization, followed by 250–355-µm and 355–500-µm particles (the “1-2-3 protocol”), complete necrosis of adenomyosis was achieved in more than 80% of patients after UAE, with a low recurrence rate of symptoms (Fig. 14). Angiography usually shows a straight, dilated, and perifibroid plexus in leiomyomas, whereas only fine myometrial staining is seen in adenomyosis. Therefore, using medium-sized embolic particles (355–500 µm PVA, or 500–700 µm Tris-acryl gelatin microspheres) for UAE in adenomyosis might be less effective in achieving ischemia of the uterus. However, there could be concerns regarding the use of small PVA particles. In contrast to our expectation, however, the use of small 150- to 250-µm-sized particles during UAE was reported to be safe and effective for leiomyomas (41). In this study, only one patient experienced permanent amenorrhea due to endometrial atrophy with normal hormonal levels. Therefore, the use of small particles may be safe and effective. However, because endometrial atrophy causes infertility, small particles should not be recommended for women who desire a future pregnancy. A dark SI of adenomyosis on T2WI (similar to the SI of rectus muscle) or continuous junctional zone thickening from the endometrium with a homogeneously low SI were findings that predicted a favorable response to UAE. Conversely, a heterogeneous SI or an SI equal to that of the myometrium was an unfavorable predictor (37).
CONCLUSION
UAE can be an effective alternative treatment to surgery in most patients with symptomatic leiomyomas. Understanding the anatomy of a normal uterine artery and its variations is crucial. If patients are appropriately screened prior to UAE and the outcome is expected to be successful based on post-procedural imaging, the risk of re-intervention is low. Proper management of post-procedural pain and other complications is essential. GnRH agonists can be used as pre-UAE treatment for patients with large leiomyomas. In adenomyosis, achievement of complete necrosis with UAE is still challenging, but the use of small embolic particles can be safe and effective.
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