Image-guided cryoablation for uterine diseases: a systematic review

Uterine myoma, endometriosis and adenomyosis are some of the most common chronic gynecological disorders that can cause symptoms such as dysmenorrhea, heavy menstrual flow, infertility, urinary frequency, etc., leading to reduced quality of life ( 1 - 3 ). Conventional treatments include surgical treatment (uterine conservation or hysterectomy) and medical treatment such as non-steroidal anti-inflammatory drugs (NSAIDs), gonadotropin-releasing hormone analogues (GnRH-a) and progesterone ( 3 - 5 ). Interventional therapy represents an innovative, low-risk, and minimally invasive surgical technique that demonstrates rapid symptom alleviation and expedited recovery in eligible patients with specific indications. Currently, uterine artery embolization (UAE), radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), and microwave ablation (MWA) have been widely used. UAE and MWA are considered as the primary treatment options of myoma, while thermal ablations are also employed for adenomyosis ( 6 - 11 ). Nevertheless, these minimally invasive interventions exhibit clinical limitations. UAE carries risks of myometrial necrosis, post-embolization syndrome requiring hospitalization, and potential ovarian insufficiency impacting reproductive outcomes ( 6 , 12 ). RFA demonstrates efficacy but is associated with procedure-related pain and uterine perforation rates ( 8 , 13 ). HIFU shows minimally invasive advantages yet correlates with transient vaginal discharge or bleeding, skin burn incidence, and rare but severe deep venous thrombosis ( 10 , 14 , 15 ). MWA similarly induces lower abdominal pain or vaginal secretions in 21.1% of cases ( 7 ). These safety profiles underscore the need for optimized ablation modalities. Cryoablation merits investigation due to its distinct ice ball visualization advantage and theoretical reduction of thermal injury risks to adjacent tissues. Cryoablation is an innovative, minimally invasive interventional therapy designed to induce cellular damage and death by direct mechanisms, which cause intracellular ice crystals, and indirect mechanisms, which cause changes in the cellular microenvironment and impair tissue viability while reducing tissue damage by preserving collagen and other fibrous structures. The refrigeration of tissues and nerves has an anesthetic effect, leading to less pain than heat-based ablation techniques, such as MWA or RFA ( 16 ). With the development of the technology, the effectiveness of cryoablation for the treatment of soft-tissue tumors has also become widely accepted ( 17 - 19 ). Nevertheless, the number of studies evaluating image-guided cryoablation for aforementioned gynecologic conditions is limited. To facilitate novel research perspectives, this article reviews the safety and efficacy of cryoablation for uterine myoma, abdominal wall endometriosis (AWE) and uterine adenomyomas. We present this article in accordance with the PRISMA reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2816/rc ).

The protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42024587962, can be retrieved at https://www.crd.york.ac.uk/prospero/ ), and was amended to updated the quality assessment. The literature search of Medline (using PubMed as the search engine), EMBASE, and Web of Science was performed based on the combinations of Medical Subject Heading terms, EMtree terms, and free terms to identify eligible studies updated to December 8, 2024. The bibliographies of the retrieved articles were manually searched. The full search strategy was listed in the Table S1 . The study selection and data extraction were conducted independently by 2 reviewers after initial screening of the retrieved titles. Any disagreement was resolved by consensus. Abstracts and full articles were acquired for detailed assessment. All prospective and retrospective studies focused on the safety and efficacy of image-guided cryoablation for the treatment of symptomatic uterine myoma, endometriosis, or uterine adenomyosis were included. The exclusion criteria were as follows: (I) the studies that evaluated other treatment rather than cryoablation; (II) the studies that reported overlapped or repeated data; (III) reviews, case reports, abstracts, and letters; (IV) the studies that were not written in English. The summary of study eligibility criteria was listed in the Table S2 . Safety: the frequency and severity of post-operative adverse events which was assessed according to the grading system used by each included study. Technical efficacy: the reduction rate of myoma or adenomyoma volume on MRI which was calculated as [( the volume before treatment – the volume after treatment ) /the volume before treatment ] × 100%, and the post-initial-ablation efficiency of AWE which was defined as the percentage of patients with complete relief of pain in the total population or that of AWE lesions with the absence of residual endometriosis nodules on MRI after the initial treatment. Clinical efficacy: the relief of subjective symptoms and the enhancement of life quality, including the reduction rate in symptom severity score (SSS), the improvement rate in health-related quality of life (HRQL) scores, VAS (from 0/no pain to 10/maximum pain) at baseline and follow-up, and pain-free survival rate (the percentage of patients who were completely free of pain until the longest follow-up). Pregnancy process and outcomes after cryoablation: the pregnancy course, abortion, mode of delivery, health status of newborns and complications during the follow-up. Residual symptom and lesion recurrence of each disease: patients who exhibited no evidence of lesions, yet continued to experience symptoms were considered to suffer from a residual symptom. In contrast, those whose lesions were confirmed through imaging examination after treatment were identified as having lesion recurrence. Extraction of the following data from each included study was carried out by 2 independent researchers: author, year of publication, country of origin, disease studied, study duration, number of centers, prospective or retrospective design, age, sample size, and number of lesions. Quantitative data such as lesion volume reduction rate, the post-initial-ablation efficiency, SSS, HRQL, VAS, and pain-free survival rate were also extracted. Additionally, the relevant data on pregnancy outcomes (such as the number of patients with successful pregnancy and childbirth, age at delivery, the proportion of vaginal delivery or cesarean section) and the data on treatment process (such as operation time, the proportion of complications after operation, etc.) were also extracted. The assessments of risk-of-bias and evidence quality for the included studies were accomplished by 2 independent researchers, using the JBI Critical Appraisal Checklist for Case Series, which is widely used to assess the quality of single-arm studies, as a foundation. Data analysis was conducted without meta-analysis owing to the limited data, different lengths of follow-up times and especially the considerable discrepancy in measurement indicators across studies. The statistical analysis applied IBM SPSS Statistics 26.0 software (IBM, USA). Categorical variables were reported as numbers and percentages, and continuous variables were presented as means and standard deviation (SD), or medians and interquartile ranges (IQRs), depending on whether they were normally distributed or not. The normality of data distribution was checked by Kolmogorov-Smirnov test. Continuous variables with homogeneous variance and normal distribution were analyzed using the independent samples t -test for comparison between groups, whereas the Mann-Whitney U test was employed for skewed data or those with heterogeneous variance. Categorical variables were examined using the two-way unordered R×C Fisher exact probability method and chi-square test. P<0.05 was defined as statistically significant.

The search strategy initially identified 338 potential records. 92 duplicates citations were removed and 200 irrelevant records were excluded after reviewing the titles. The remaining 46 references were further evaluated. Twenty-four references were excluded from the abstract review for reasons which were shown in the flow diagram of the study selection process ( Figure 1 ). After an in-depth review by full-text appraisal, 4 studies out of 22 were excluded, leaving 18 studies that were accorded with the inclusion criteria. The exclusion reasons by full-text appraisal were run than can be included in the article. Interested readers can find them in Table S3 . Flow diagram of the study selection process. The included studies were published between 1998 and 2024. The analyzed sample totally contained 338 participants with their age ranged from 24–55 years. Except for 1 study that did not report study design, 9 of the included studies were prospective and the rest were retrospective. Eight studies evaluated the role of cryoablation in uterine myoma ( 20 - 27 ). Eight studies were conducted for AWE ( 28 - 35 ), 1 of which directly compared cryoablation with conventional surgery ( 32 ). One study reported on the efficacy and safety of cryoablation for the treatment of adenomyomas ( 36 ). Another study reported the outcomes of pregnancies during follow-up ( 37 ) ( Table 1 ). When analyzing the age of patients included in each study, the variables were presented as mean ± standard deviation, or median [interquartile range], depending on whether they were normally distributed or not. In instances where the included studies did not provide the age of each patient, the mean or median age reported in the study was used directly. AM, adenomyoma; AWE, abdominal wall endometriosis; CT, computed tomography; L, laparoscopy; MRI, magnetic resonance imaging; NR, not reported; P, prospective; R, retrospective; UM, uterine myoma; US, ultrasound. The quality of included studies ranged from low to medium ( Table 2 ). The potential problems were as follows: (I) lack of comparability: the mostly included studies were single-arm studies; (II) unclear inclusion/exclusion criteria in some studies; (III) lack of representativeness of participants and extrapolation of results; and (IV) loss of follow-up and different follow-up periods among these studies. Q1. Were there clear criteria for inclusion in the case series? Q2. Was the condition measured in a standard, reliable way for all participants included in the case series? Q3. Were valid methods used for identification of the condition for all participants included in the case series? Q4. Did the case series have consecutive inclusion of participants? Q5. Did the case series have complete inclusion of participants? Q6. Was there clear reporting of the demographics of the participants in the study? Q7. Was there clear reporting of clinical information of the participants? Q8. Were the outcomes or follow up results of cases clearly reported? Q9. Was there clear reporting of the presenting site(s)/clinic(s) demographic information? Q10. Was statistical analysis appropriate? L, low; M, medium; N, no; NA, not applicable; Y, yes; UC, unclear. Uterine myoma are solid, spherical masses and are currently the most common benign uterine tumor ( 2 ); AWE is the ectopic implantation of endometrium and glands in the superficial tissues of the abdominal wall, and the majority of patients have undergone gynecological or obstetric surgery, with the lesions situated close to the surgical scar ( 38 ); and uterine adenomyosis is caused by implantation of the uterine endometrium into the myometrium, which is classified into diffuse adenomyosis and focal adenomyoma based on the characteristics of the distribution of the lesions ( 39 ), as the latter is relatively limited and easy to implement cryoablation, it has become a focus of research and evaluation. Tables 3-8 provide detailed calculation results for the assessments of the safety and efficacy of cryoablation for gynecologic conditions. Data are presented as mean ± standard deviation. AWE, abdominal wall endometriosis; UM, uterine myoma. Last follow-up, data on the longest follow-up reported in each study. AWE, abdominal wall endometriosis; BL, baseline; M, months; PFSR, pain-free survival rate; VAS, visual analogue score. The variables were presented as median [interquartile range], depending on the skewed distribution. EHP-5, endometriosis health profile 5 questionnaire; PBAC, pictorial blood loss assessment chart (abnormal uterine bleeding >100); VAS, visual analogue score. AWE, abdominal wall endometriosis. BL, baseline; M, month; PFSR, pain-free survival rate; VAS, visual analogue score. Conditions of complications were described in Table 3 . Following the treatment of uterine myoma, the complications were mild and had no significant impact on patients’ recovery ( 23 , 24 ). Cryoablation has demonstrated substantial technical and clinical efficacy in the treatment of uterine myomas. The mean volume reduction rate was 69.8%±22.4% at the longest follow-up ( 20 ). Among the included studies that focused on uterine myomas, one study reported that the median reduction rate in SSS scores and the median improvement rate in HRQL scores of patients were 61.9% and 43.3%, respectively, at the 6 th month, and 66.7% and 55.8% at the 12 th month ( 23 ). The remaining studies provided textual descriptions or subjective evaluations by patients, corroborating the improvement of clinical symptoms. Among the studies focused on AWE, only 2 studies reported serious complications ( 33 , 34 ), which were properly handled and did not cause long-term adverse effects ( Table 3 ). Studies on AWE showed that the median post-initial-ablation efficiency was 82% for each patient, and 93.6% for each AWE lesion, respectively. A second cryoablation can further improve efficacy ( 28 , 33 ). Cryoablation for AWE has demonstrated not only significant technical efficacy but also favorable clinical efficacy. The VAS for dysmenorrhea also showed a significant reduction after treatment (P<0.05), and the median pain-free survival rates at 1, 3, 6, 12, and 36 months were maintained at high levels. The study reported only incomplete intrauterine adhesions in 2/5 cases while no major complications following cryoablation of adenomyoma ( 36 ). A mean volume reduction rate of 65.8% was seen in uterine adenomyoma patients after a year of follow-up ( 36 ). After cryoablation, patients with uterine adenomyoma experienced effective relief of pain, bleeding, and other symptoms ( Table 5 ). The variability in technical efficacy across studies may be attributed to the differences in baseline characteristics and procedural protocols. For studies focusing on uterine myomas, the broad standard deviation in volume reduction (SD ±22.4%) suggests heterogeneity in lesion size (range 2–13 cm across studies). Additionally, studies employing MRI-guided ablation reported higher consistency (SD ±16.3%) at the longest follow-up than laparoscopic approaches, potentially due to improved targeting accuracy ( 24 ). In the trials regarding AWE, factors such as baseline lesion sizes, the intended ablation margin, hormone therapy before or after cryoablation (gonadotropin-releasing hormone, oral contraceptives, progesterone, or danazol), and different image guidance techniques might all impact efficacy. Cryoablation can effectively relieve symptoms, but subsequent changes to the intrauterine environment, especially intrauterine adhesions, must be considered. The study reported that after cryoablation for adenomyoma, two of the five participants had suffered from incomplete intrauterine adhesion indicated by hysterosonography, which may have an adverse impact on the fertility ( 36 ). An observational study explored the pregnancy process and outcome of patients after cryomyolysis ( 37 ). Nine of the 61 uterine myoma patients became pregnant. The study identified 11 cases of fibroids in these 9 patients across locations including the subserosal, subserosal/intramural, and intramural. The average interval between cryomyolysis and the starting of pregnancy was 18.6 months with a range from 7 to 39 months. The mean and median age of patients at delivery were 33.6 and 33 years respectively, with a range from 27 to 41 years. At the beginning of pregnancy, the mean reduction rate of the uterine myoma volume was as high as 83.17%, with a median reduction rate of 87.2%, reflecting the efficacy of cryoablation. However, two patients experienced early abortion at 9 and 11 weeks, respectively. Particularly, the second patient had two large fibroids at the beginning of pregnancy, with volumes of 124.7 and 8.8 mL, which may increase the risk of abortion. Among the 7 patients who completed pregnancies, 4 (57.1%) achieved vaginal delivery, while 3 (42.9%) required cesarean section for various reasons: dystocia, non-reassuring fetal heart rate (FHR), and ovarian cysts. The birth weights and the Apgar scores of all newborns were within the normal range, and no complications were detected during the postpartum and puerperium. These results might serve as an additional basis to support the safety of cryoablation. This systematic review was conducted on the residual or recurrent clinical symptoms reported in 12 studies. The mean proportions of residual symptoms and lesion recurrence for uterine myoma patients ( Table 6 ), as well as for AWE patients ( Table 7 ) were all lower than 10%. As the study reported, there was no residual or recurrent uterine adenomyoma ( 36 ). One study set up surgery group and cryoablation group respectively, and the data were presented in Table 8 to contrast the efficacy and safety of the two ( 32 ). A total of 20 patients were included in the study, with 13 undergoing surgery and 7 cryoablation. Only the differences in procedure time and hospital stay between groups were statistically significant (P<0.05). VAS at 1 month and 6 months follow-up in both groups showed significant declines (P<0.05 vs. baseline). From an aesthetic viewpoint, cryoablation avoids large tissue defects, maintaining patient appearance.

Post-operative complications are key indicators for evaluating the safety of cryoablation. Although complications were observed in approximately 25% of patients, the mild conditions of complications (serious cases are all less than 5%) confirmed the reliability of cryoablation. The main minor adverse events were fever, skin anesthesia and inflammation, which can be self-limiting, suggesting the outstanding safety profile of cryoablation. This is highly consistent with the data reported by recent studies on treating soft tissue tumors with cryoablation ( 18 , 19 , 40 ). In the evaluation of both technical and clinical efficacy, cryoablation has exhibited significant therapeutic outcomes across a spectrum of uterine pathologies, including uterine myomas, AWE, and adenomyosis. In patients with uterine myomas, cryoablation has demonstrated a substantial capacity to reduce myoma size. Follow-up patient questionnaires have revealed improvements in subjective symptoms. For individuals with AWE, the initial cryoablation succeeded in eliminating about 95% of lesions, with a subsequent cryoablation further enhancing efficacy. Moreover, the VAS for dysmenorrhea decreased significantly from baseline during the follow-up period; however, the pain-free survival rate began to decline by the 24th month, which may be associated with disease recurrence or loss of follow-up. Another study also indicated that patients with adenomyosis who underwent cryoablation experienced a significant reduction in lesion size, along with notable improvements in symptoms such as dysmenorrhea, painful intercourse, abnormal uterine bleeding, and heavy menstrual flow. Despite various studies consistently showing cryoablation is effective for aforementioned gynecologic conditions, results still have subtle differences. One of the included studies showed that 17 months after cryoablation, the average reduction in fibroid volume was only 12% ( 26 ), which differed from other studies. This may be attributed to the pre-treatment of patients with GnRH, which changed hormone status. Furthermore, the image information obtained from laparoscopy may have been blurred, potentially leading to the discrepancy ( 20 , 21 ). Other studies also pointed out the differences among image guidance. Real time ultrasound (US) guidance avoids radiation exposure, but may be affected by shadow occlusion ( 30 ). Computed tomography (CT) scanning performs well in the treatment of superficial lesions with its visualization ability, while magnetic resonance imaging (MRI) shows higher value in precise control of the treatment edge, especially when dealing with complex or deep lesions ( 32 - 34 ). In addition, another study proposed that with the aggravation of the severity of the disease, clinicians may refer patients more frequently to gynecologists for treatment after initial screening ( 33 ). Although this phenomenon reflects the timely attention and intervention of the medical system to the patient’s condition, it may also introduce selection bias. Following cryoablation, the pregnancy process and outcome were generally safe and normal. Of the 64 subjects who were followed up, 9 successfully became pregnant. The interval between cryotherapy and the beginning of pregnancy was relatively long, with an average of 18.6 months, suggesting the necessity for detailed fertility planning after treatment. Despite 2 cases of early abortion, the remaining 7 women delivered without complications, and all the neonates were in the normal range for indicators such as weight and Apgar score. However, the presence of large uterine myomas at the beginning of pregnancy may be a risk factor for early abortion. This article also investigated the occurrence of residual symptom or recurrence disease. For patients with uterine myomas, the incidence of residual symptoms and disease recurrence was less than 10% during the follow-up period, which spanned a minimum of two years. The same outcome was observed in patients with AWE. In the study on adenomyosis, no residual or recurrent uterine adenomyoma was observed. As previously reported, suspicious risk factors for AWE recurrence include the size of the lesion, the extent of invasion in specific tissues (such as some muscles or peritoneum) ( 41 ) and inadequate treatment of deep lesions in the umbilicus ( 32 ). These findings further emphasized the necessity of accurate and comprehensive treatment for preventing recurrence. Other ablation techniques have also been used in the treatment of uterine diseases. A critical advantage of cryoablation over HIFU and RFA, which have been commonly used in recent years, is the ability to avoid coagulative necrosis usually observed with heat-based ablation and to prevent tissue granulation, resulting in improved aesthetic outcomes ( 32 , 42 ). Another advantage of cryoablation is that the ice ball is visible under real-time US, CT, and MRI ( 16 , 18 ) guidance while delivering tissue ablation at freezing temperatures ( 43 ), with precise ablation coverage. Moreover, compared with surgical resection, which has been a well-established treatment, cryoablation has a lower incidence of adverse events and lower time and economic costs. Percutaneous cryoablation is a potentially superior first-line treatment for focal AWE, reducing hospitalization duration and complications. However, this approach may not be suitable for larger lesions. In such cases, a combination of cryoablation and hormonal or surgical treatment may be necessary. There are a few limitations to our study: (I) most of the included studies were single-center and single-arm studies that lacked a control group, the geographic and demographic specificity may have affected the results; (II) owing to the limited sample size and the considerable discrepancy in measurement indicators among studies, meta-analysis was not applicable, and we cannot provide conclusive evidence; (III) the follow-up periods varied among the studies, and the short follow-up periods in some studies could preclude the assessment of long-term efficacy and underestimate the risk of recurrence and long-term complications; (IV) we only included studies written in English. To address these potential issues, future research may need to conduct randomized controlled trials (RCTs), calculate appropriate sample sizes, extend the follow-up period, and implement comparison with other therapies.

Cryoablation can effectively reduce the volume of uterine myoma or adenomyoma, eliminate AWE nodes, relieve clinical symptoms and improve quality of life. It prevents major complications with less affect to the tissues, indicating its safety profile, although a few cases of post-procedural uterine adhesions have been reported. This systematic review contributes to a further understanding and definitely provides supplementary evidence to support clinical practice. While current evidence supports cryoablation’s therapeutic potential for benign uterine conditions, rigorous RCTs with extended follow-up periods remain essential to validate safety and efficacy.

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