Benign metastasizing leiomyoma: a systematic review of diagnosis, management, and outcomes

Introduction

Distant metastasis is characteristic for malignant tumors, when the vascular barrier is broken and cancer cells migrate from the primary tumor to the microvessels, and then develop in remote locations (1,2). Diagnosis metastatic cancer is associated with an unfavorable prognosis and is responsible for the majority of cancer-related deaths (3). A unique form of disseminated disease is benign metastasizing leiomyoma (BML). Although it spreads to distant locations, it originates from a benign primary lesion in the uterine. The etiology is not fully understood, and several theories of the development of this disease have been presented so far. One of them is that benign endometrial cells may inadvertently remain in the peritoneum after laparotomy or laparoscopic morcellation, implant, proliferate and spread to the organs via the bloodstream (4). Another suggestion is that they are leiomyosarcomas with low-grade malignant potential (5). A number of chromosomal abnormalities and gene mutations have been reported in BML. It includes terminal deletions in the long arms of chromosomes 19 and 22 as well as chromosomal abnormalities in chromosomes 1, 7, 13 and 14, chromosome translocations (Jeny12;14) (Jeny1;2). Gene mutations were identified in the BMP8B, MED12, ARID2 and NTRK1 and amplifications in BC11B and TCL1A (4,5).

Regardless of the mechanism of metastasis of BML, the management is a challenge for clinicians, mainly due to its rare incidence and the lack of guidelines/recommendations. Moreover, it is unclear which medical specialty should be responsible for managing patients with BML. Although gynecologists deal with the treatment of uterine fibroids, they may feel uncertain in the case of metastatic disease. On the other hand, medical oncologists and gynecologic oncologists reluctantly manage these patients due to the benign nature of the disease.

This systematic review analyzes case reports of patients diagnosed with BML focusing on the clinicopathological characteristics and treatment approaches. The aim of this study is to improve quality of care. It should be helpful to all clinicians, who are involved in management of patients with BML. We present this article in accordance with the PRISMA reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-40/rc).

Methods

The Google Scholar and PubMed databases were searched using the keyword “benign metastasizing leiomyoma”. Full text articles and conference abstracts published in English language from January 1, 2000 to March 31, 2024 were screened (Figure 1). The 778 selected articles, consisting of two separate databases of 468 articles from PubMed and 310 articles from Google Scholar, were checked for duplicate article titles, and duplicates were removed, giving 632 articles. The next step was to read the abstracts, as a result of the selection, 75 articles were not written in English, 344 articles were not relevant to the article topic. The next step was to evaluate the articles using the Joanna Briggs Institute (JBI) spreadsheet. JBI critical appraisal checklist for case report form was used to assess each article. Reviewers (K.K., N.S., E.B., K.P., M.P.) independently assessed each article. If at least 4 out of 5 authors qualified the article as relevant, it was included in the review, if 3/5, the senior author decides. If the article scored less than 3, it was excluded from the review. Review articles were excluded, 213 papers were included in this review. That leaves us with 213 articles that provided comprehensive data that were included in the final analysis. Analyzed data included patient’s demographics, menopausal status, time from first operation for myoma to notice changes, number of pregnant and birth, coexisting chronic conditions, symptoms, tumor characteristics, history of hysterectomy and myomectomy, imaging, tumor histopathology, genetic analysis, treatment methods and therapy outcomes, complications, recurrence and survival outcomes.

Figure 1 PRISMA diagram shows the details of our search and selection process used during the review.

Results

Overall, 277 patients were diagnosed with BML. The mean age was 47.8 (range, 20–77) years (Figures 2,3). Menopausal status was unreported for the majority of patients (n=193; 69.7%). Among the remaining 84 cases, 54 (19.5%) were postmenopausal and 30 (10.8%) were premenopausal. Ethnic origin was documented in 159 (57.4%) cases. BML was diagnosed mostly in Asian (n=74, 46.5%), followed by Caucasian (n=54, 34,0%), Latina (n=21, 13.2%), African (n=6, 3.8%), Arab (n=3, 1.9%), Caribbean (n=1, 0.6%).

Figure 2 Distribution of age at diagnosis in patients with BML. BML, benign metastasizing leiomyoma.

Figure 3 Age range of patients diagnosed with BML. The largest group consisted of patients aged 45–54 years (n=129; 46.6%), followed by those aged 35–44 years (n=82; 29.6%), 55–64 years (n=41; 14.8%), the over 64 years group accounted for 4.3% (n=12), and those under 35 years of age 4.7% (n=13). BML, benign metastasizing leiomyoma.

Obstetric data were missing for 196 cases (70.8%). Among 81 (29.2%) women with known obstetric history, 66 (81.5%) patients had been pregnant, and 15 (18.5%) were nulliparous. Of those with pregnancies, 53 (65.4%) patients gave birth naturally, 13 (16.1%) by cesarean section, 8 (9.9%) had experienced miscarriage and 11 (13.6%) were reported as pregnant without available delivery information. There were no reported cases of BML diagnosis during pregnancy.

Most patients (n=188, 67.9%) reported symptoms and the most commonly were: cough (n=55, 29.3%), dyspnea (n=52, 27.7%) and abdominal pain (n=42, 22.3%). Other symptoms included: chest pain (n=21, 11.2%) (6-15), vaginal pain/pruritus or uterine bleeding (n=21, 11.2%) (16-24), back pain (n=18, 9.6%) (25-35), leg pain (n=9, 4.8%) (29,36,37) and weight loss (n=7, 3.7%) (6,12,37-42). Among the 277 patients, 89 (32.1%) were asymptomatic and diagnosis of BML was incidentally during chest imaging (6-30). A total of 202 (72.9%) patients had no history of chronic conditions, while 75 (27.1%) women reported commorbidities. The most common were hypertension (n=16; 21.3%), asthma (n=8; 10.7%) and diabetes (n=7; 9.3%). Extrauterine lesions were diagnosed by computed tomography (CT) in 153 (55.2%) patients, X-ray in 101 (36.5%) patients, magnetic resonance imaging (MRI) in 53 (19.1%) patients and ultrasonography (USG) in 32 (11.6%) patients. In 82 (29.6%) patients positron emission tomography (PET) was performed. Mean standardized uptake value (SUV) was 3.6 (range, 1.3–18.8).

The most common pathological feature of BML was positive expression of estrogen receptor in 181 (65.3%), progesterone receptor in 178 (64.3%) and desmin in 129 (46.6%) patients. Detailed characteristics of histological examination were presented in Table 1. Genetic analysis was performed in 20 (7.2%) patients. Deletion in chromosome 19q13, 22q12 and 1p36 was found in 5 (25.0%), 3 (15.0%) and 1 (5.0%) patients, respectively. Simultaneous deletion of chromosome 19q13 and 22q12 was detected in 3 (15.0%) patients, in 1 (5.0%) isolated deletion of 19q13, in 1 (5.0%) simultaneous deletion of 19q13 with 1p36. Single mutations have also been found in various genes such as ALK, NI532D, JUN, BLMH and others. No genetic alterations were detected in 4 (20.0%) patients.

The most common site of BML metastasis was the lungs (n=235, 84.8%). Other metastatic locations included the peritoneum (n=40, 14.4%), vertebrae (n=17, 6.1%), heart (n=15, 5.4%), retroperitoneal space (n=9, 3.3%), vessels (n=8, 2.9%), and bones (n=7, 2.5%). Based on the available data, metastases confined to a single site occurred in 208 (75.1%) patients, while multiple site involvement was found in 69 (24.9%) patients. Regarding the most common site of metastasis—the lungs—fewer than 5 lesions were noted in 39 (16.6%) cases, 5–10 lesions in 28 (11.9%) cases, while more than 10 metastases in 168 (71.5%) cases. The mean size of the largest pulmonary metastasis was 47 mm × 38.7 mm (range, 4–300 mm × 1–260 mm).

The majority of patients (n=239; 86.3%) underwent surgical treatment. Surgery was performed in 200 (83.7%) patients prior to BML diagnosis, while in 39 (16.3%) cases it was performed after the diagnosis. Among them, 180 (75.3%) patients underwent upfront total hysterectomy, 26 (10.9%) had subtotal hysterectomy and 74 (31.0%) patients had myomectomy. Among patients who initially underwent myomectomy, 41 (55.4%) subsequently had a total hysterectomy. In 30 (73.2%) of these cases, hysterectomy was performed after the diagnosis of BML, and in 17 (41.5%) it was performed due to recurrence of myomas following prior myomectomy. In 4 (9.8%) cases, hysterectomy was performed due to suspected sarcoma.

The mean time between surgery and the first diagnosis of BML was 101 months (8.4 years).

The diagnosis of BML was established by biopsy in 141 (50.9%) cases, by resection in 134 (48.4%) cases and post mortem in 2 (0.7%) cases. The most common locations for biopsies outside the lungs were the vertebrae (n=16; 11.4%) (25,29,31-37), heart (n=11; 7.8%) (13,30,38-46) and peritoneal cavity (n=8; 5.7%), while resections were the lymph nodes (n=7, 5.2%) peritoneal cavity (n=6; 4.5%) (47,48) and vertebrae (n=4; 3.0%) (34,49-51).

A total of 38 (13.7%) patients did not undergo any prior uterine surgery and had only diagnostic biopsy of metastatic lesions. Metastatic lesions were surgically excised in 98 (35.4%) patients: 73 (74.5%) had metastasis in a single site, while 25 (25.5%) had metastases in 2 or more sites.

Data also indicate that 35 women underwent bilateral adnexectomy, with 11 patients undergoing adnexectomy combined with hysterectomy. Up to 24 (88.9%) patients noted stabilization or regression of lesions, likely due to reduced estrogen levels (52-56).

Data regarding adjuvant treatment were available for 109 (39.4%) patients. Hormonal agents were the most commonly used and included gonadotropin-releasing hormone (GnRH) analogues (n=39, 35.8%), anti-estrogen (n=34, 31.2%), gestagen (n=12, 11.0%) and anti-progesterone (Mifepriston) (n=1, 0.9%) (Table 2). A total of 18 (16.5%) patients received combination adjuvant treatment, which included: gestagen + anti-estrogen (n=9, 50.0%), GnRH analogues + anti-estrogen (n=6, 33.3%), GnRH analogues + anti-progesterone (n=1, 5.6%), anti-estrogen + anti-progesterone (n=1, 5.6%), gestagen + anti-estrogen + GnRH (n=1, 5.6%). In 63 (22.7%) patients no adjuvant treatment was used.

Chemotherapy was administered to 3 (3.8%) patients. This included MAID regimen (n=1, 33.33%) and therapy with several agents such as doxurubicin, gemtacibine, docetacel, epirubicin (n=2, 66.66%). Surveillance data were available in 214 (77.3%) patients. The mean follow-up was 22 (range, 2–192) months. Treatment outcomes showed improvement or reduction in symptoms or tumor size in 47 (17.0%) cases, stable disease in 149 (53.8%), and disease progression in 10 (3.6%).

Eight (2.9%) patients died due to BML progression. In 2 (25.0%) patients, BML was considered the direct cause of death (57,58). Reported reasons of death were also: pulmonary embolism with respiratory failure (n=2, 25.0%) (59,60), and Clostridium perfringens infection (n=1, 12.5%) (61) and no specific cause was available for 3 cases.

Discussion

This systematic review synthesizes data from 213 case studies involving 277 patients with BML, offering a comprehensive overview of this rare condition. Our analysis provides insights into the demographic characteristics, clinical presentations, diagnostic approaches, treatment modalities, and outcomes associated with BML.

BML predominantly affects perimenopausal women. Although it is less frequently diagnosed in young and old women, the clinical course is significantly different. In patients younger than 32 years (n=8) asymptomatic course is less frequent (12.5% vs. 32.1%) (62-69), while in patients over 70 years (n=6) asymptomatic patients constitute most cases (66.7% vs. 32.1%) (58,70-74).

The condition appears to be globally distributed, affecting women from various racial and regional backgrounds. Despite numerous data gaps, our review indicates that BML most commonly affects individuals of Asian descent, followed by those of European ancestry.

Clinically, many patients were asymptomatic (6,7,64,75-96), with BML often discovered incidentally during imaging for unrelated reasons. When symptoms were present, they frequently corresponded to the site of metastasis. Respiratory symptoms such as cough and dyspnea were common, reflecting the high incidence of pulmonary involvement (7,8,10,15,19,21-24,28,29,61,75,77,78,97-105) (Appendix 1). This reinforces the importance of considering BML in the differential diagnosis when women with a history of uterine leiomyomas present with respiratory complaints. There is no consensus on recommended tests in patients with suspected BML. They are performed according to the clinical symptoms that patients present at the time of admission (58). The vast majority of patients underwent CT imaging, which is considered the gold standard for detecting pulmonary lesions. BML-related lung metastases occur bilaterally in approximately 70.0% of cases, with an average of six nodules measuring around 18 mm each. Due to the variable size of pulmonary metastases, chest X-ray examination may not be sufficient, particularly for small lesions (106). Many patients undergoing surgery for leiomyomas have only preoperative chest X-rays rather than CT scans, potentially delaying or missing the diagnosis of BML. Other imaging modalities may be useful in diagnosing extrapulmonary metastases. MRI has the highest sensitivity for detecting spinal involvement, however such metastatic lesions are very rare (47).

For pulmonary lesions of uncertain significance, PET can help assess their malignant potential (107). Hagi et al. evaluated patients with soft-tissue sarcoma and found SUV values for metastatic pulmonary nodules of 2.4 (range, 0–19.5), and it was significantly higher than in benign nodules (0.1; range, 0–5) (93). In the present study, the mean SUV was 3.6 (range, 1.3–18.8), so it can exclude benign character of the lesion but is not sufficient for differentiating BML from sarcoma. Ultimately, the vast majority of patients will still require a biopsy of pulmonary lesions due to the lack of a histopathological diagnosis of malignant disease.

On the other hand, PET is mainly used in differentiating from malignant tumors when they are suspected (107). The use of different imaging techniques without a standardized protocol highlights a need for guidelines to optimize diagnostic accuracy.

In total, 239 (86.3%) patients had a history of hysterectomy or myomectomy before the diagnosis of BML, suggesting a potential link between prior uterine surgery and the development of metastatic lesions (5,108). This observation supports the hypothesis that uterine manipulation during surgical procedures such as myomectomy, hysterectomy or even caesarean section may facilitate intravascular dissemination of leiomyoma cells, subsequently manifesting as BML. However, the exact underlying mechanism remains unclear.

Surgery is a cornerstone in management of patients with BML. Although the majority of patients underwent total hysterectomy, there were 74 (26.7%) patients after myomectomy and 38 (13.7%) patients, who did not have any uterine surgery (26,109-116). There is no data that prognosis was influenced by uterine resection. BML may affect women in reproductive age. Although there was not any case of fertility-sparing treatment, myomectomy may be a safe method in women who desire childbearing.

Adjuvant treatment was not routinely administered. Only 29.6% of patients received adjuvant therapy. Endocrine treatment was mostly used, reflecting the high expression of estrogen and progesterone receptors in BML lesions (17). The responsiveness of BML to hormone therapy underscores the role of estrogen and progesterone in the pathogenesis and progression of the disease.

Our findings are consistent with previous reviews regarding the indolent nature of BML (4,55). Although prognosis is favorable, reported mortality rates vary. Barnaś et al. found no disease-related deaths in a series of 153 cases (4). Whereas, Liu et al. analysed 385 cases and observed disease-related mortality in 4.0% of patients (51). Our analysis showed that 2.9% of patients died due to disease progression. This may be attributable to variations in sample size and/or duration of follow-up. The median follow-up in our study was 18 months, compared to 60 months in the study by Liu et al. (51).

The review process used in this systematic review has several limitations that should be considered when interpreting the results. One of the most significant issues is missing data related to menopausal status (n=187), ethnicity (n=120) or reproductive status (n=134). This lack of complete demographic data limits the ability to draw definitive conclusions about how these factors might influence the outcomes observed in the review. The review also faces challenges related to the heterogeneity of the included studies.

Variability in population characteristics, interventions, and outcomes makes it difficult to synthesize results and draw uniform conclusions. This heterogeneity, coupled with differences in the methodologies of the included studies, could affect the overall quality and reliability of the review’s findings.

Language bias is another consideration, the review included only studies published in English. This could result in the exclusion of relevant studies published in other languages, limiting the comprehensiveness of the review.

Additionally, the limited follow-up data reported in some studies poses a challenge. The median follow-up time in the dataset is 18 months. Short follow-up periods may not be sufficient to observe long-term outcomes or late-onset side effects, which affects the ability to assess the long-term effectiveness of the interventions reviewed.

These limitations underscore the need for cautious interpretation and application of the findings in clinical practice, and they also point to areas where future research could improve the validity and applicability of the conclusions drawn.

The findings highlight the need for heightened clinical awareness of BML, particularly in women with a history of uterine leiomyomas who develop pulmonary or systemic symptoms. Given the hormone receptor positivity observed in many cases, hormonal therapies may offer effective treatment options and should be considered in management plans. The lack of standardized diagnostic and therapeutic protocols suggests that developing evidence-based guidelines could improve patient outcomes.

Further research is needed to clarify the mechanisms underlying BML, particularly the role of prior surgical interventions and the potential for genetic predispositions. Prospective studies with standardized data collection and reporting would enhance understanding of the disease and inform the development of clinical guidelines. Investigating the molecular and genetic profiles of BML lesions may uncover targets for novel therapies and provide insights into the transition from benign uterine leiomyomas to metastatic disease.

Conclusions

Our findings align with previous reviews highlighting the indolent nature of BML, with generally favorable prognosis, low mortality, and most patients experiencing stable disease or improvement. However, the variability in treatment approaches and outcomes underscores the lack of consensus on optimal management strategies. Clinicians should maintain awareness of BML, particularly in women with a history of uterine leiomyomas presenting with pulmonary or systemic symptoms. Given the frequent hormone receptor positivity, hormonal therapies may be effective and warrant consideration. The absence of standardized diagnostic and therapeutic protocols suggests a need for evidence-based guidelines to improve patient outcomes. Further research should investigate the role of prior surgical interventions, genetic predispositions, and molecular profiles to uncover novel therapeutic targets and enhance understanding of disease progression.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-25-40/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-40/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-40/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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