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Abstract
Objective To analyse the risk factors for post-operative recurrence or progression of intravenous leiomyomatosis and explore the impact of different treatment strategies on patient prognosis.
Methods Patients with intravenous leiomyomatosis who underwent surgery from January 2011 to December 2020 and who were followed for ≥3 months were included. The primary endpoint was recurrence (for patients with complete resection) or progression (for patients with incomplete resection). Kaplan-Meier survival analysis was used to analyse the factors affecting recurrence.
Results A total of 114 patients were included. The median age was 45 years old (range 24–58). The tumors were confined to the uterus and para-uterine vessels in 48 cases (42.1%), while in 66 cases (57.9%) it involved large vessels (iliac vein or genital vein and/or proximal large veins). The median follow-up time was 24 months (range 3–132). Twenty-nine patients (25.4%) had recurrence or progression. The median recurrence or progression time was 16 months (range 3–60). Incomplete tumor resection (p=0.019), involvement of the iliac vein or genital vein (p=0.042), involvement of the inferior vena cava (p=0.025), and size of the pelvic tumor ≥15 cm (p=0.034) were risk factors for recurrence and progression. For intravenous leiomyomatosis confined to the uterus or para-uterine vessels, no post-operative recurrence after hysterectomy and bilateral oophorectomy occurred in this cohort. Compared with hysterectomy and bilateral oophorectomy, the risk of recurrence after tumorectomy (with the uterus and ovaries retained) was significantly greater (p=0.009), while the risk of recurrence after hysterectomy was not significantly increased (p=0.058). For intravenous leiomyomatosis involving the iliac vein/genital vein and the proximal veins, post-operative aromatase inhibitor treatment (p=0.89) and two-stage surgery (p=0.86) were not related to recurrence in patients with complete tumor resection.
Conclusion Incomplete tumor resection, extent of tumor lesions and size of the pelvic tumor were risk factors for post-operative recurrence and progression of intravenous leiomyomatosis.
- Uterine Neoplasms
- Surgery
Data availability statement
Data are available upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Intravenous leiomyomatosis is rare. For patients with tumors confined to the uterus and para-uterine vessels, controversy remains as to whether retention of the uterus or ovaries has an impact on prognosis. Moreover, there is no clinical evidence on the prognosis of patients receiving anti-estrogen therapy after bilateral oophorectomy among patients with intravenous leiomyomatosis involving large vessels.
WHAT THIS STUDY ADDS
Incomplete tumor resection, involvement of the iliac vein or genital vein, involvement of the inferior vena cava, and size of the pelvic tumor ≥15 cm were risk factors for recurrence and progression. For intravenous leiomyomatosis confined to the uterus and para-uterine vessels, the recurrence rate after hysterectomy and bilateral oophorectomy was low. For intravenous leiomyomatosis involving the iliac vein/genital vein and proximal veins, aromatase inhibitor treatment after complete tumor resection and bilateral oophorectomy did not reduce recurrence.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Optimal surgical approach should be determined by patient’s age, desire for fertility, and risk of recurrence. For intravenous leiomyomatosis involving the iliac vein/genital vein, anti-estrogen therapy after complete resection and bilateral oophorectomy did not reduce recurrence. Aromatase inhibitor therapy is not recommended after complete tumor resection and bilateral oophorectomy.
Introduction
Intravenous leiomyomatosis features histologically benign smooth muscle tumors growing within vascular spaces outside the confines of a leiomyoma, which are free floating within the lumen or adherent to the vessel wall. It is a rare type of leiomyoma with a special pattern of growing along vascular wall; however, its incidence remains unknown. Some studies have suggested that the incidence of intravenous leiomyomatosis was estimated at 0.4–1.97% of uterine leiomyoma.1 The hypothetical origins are Knauer’s theory, which states that they originate from the vein wall,2 and Sitzendry’s theory, which states that it originates from uterine leiomyoma and thereafter invades blood vessels.3 These tumors originate from the uterus, spread along the uterine vein or genital vein toward the proximal end, and can involve the right atrium, right ventricle, or even the pulmonary artery. A diagnosis is made in cases where worm-like growth of smooth muscles is observed grossly.
Surgery is the primary treatment, but the post-operative recurrence rate can reach 14–31.0%.1 4–6 Complete tumor resection is the main factor influencing prognosis.7 For patients with tumors confined to the uterus and para-uterine vessels, controversy remains as to whether the retention of the uterus or ovaries has an impact on the prognosis.8 Moreover, there is no clinical evidence on the prognosis of patients receiving anti-estrogen therapy after bilateral oophorectomy when involving large vessels.9 Therefore, we retrospectively summarized the treatment strategies and prognosis of patients in a single center to assess risk factors impacting post-operative recurrence or progression, and explored the impact of different treatment strategies on prognosis.
Methods
Patient Inclusion
This was a single-center retrospective observational study with an analytical component. Patients diagnosed at Peking Union Medical College Hospital between January 2011 and December 2020 were retrospectively included. The inclusion criteria were as follows:
intravenous leiomyomatosis confirmed by pathological diagnosis
undergoing surgery
post-operative follow-up ≥3 months.
The exclusion criteria were:
not having surgery
no post-operative follow-up or post-operative follow-up <3 months.
All patients underwent surgery. The pre-operative estimated tumor size was determined by pelvic ultrasonography, venous ultrasonography, CT venous imaging, or echocardiography.
During the operation, the extent and size of the tumor lesions were recorded. The scope of the operation was comprehensively formulated according to the patient’s age, tumor range, fertility desire, and willingness for uterus preservation (in patients with lesions restricted within the uterus). The surgical approach was determined based on the size and location of the pelvic mass combined with the surgeon’s judgment. Two-stage surgery was performed in some patients with extensive lesions or poor performance status. During the two-stage surgery, intracardiac and inferior vena cava tumors above the level of the renal vein were removed during first-stage surgery, and hysterectomy, oophorectomy, and resection of tumors in the vascular lumens below the renal vein were performed during second-stage surgery.
Complete resection was defined as the absence of visible residual tumor. Post-operative pathological diagnosis was made by two experienced pathologists. When the diagnosis of two pathologists was inconsistent, a third pathologist was consulted. This study was approved by the Institutional Review Board of Peking Union Medical College Hospital, and informed consent for clinical data collection was obtained from all enrolled patients.
Follow-Up and Endpoints
All enrolled patients were followed up after surgery. The primary endpoint was recurrence (for patients with complete resection) or progression (for patients with incomplete resection). The follow-up intervals were 3–6 months within 3 years after surgery, 6–12 months from 3 to 5 years after surgery, and 12 months after 5 years. Follow-up ended on June 30, 2023. At each follow-up visit, pelvic physical examination and imaging tests, including pelvic ultrasonography, vascular sonography, CT, and echocardiography were performed when necessary. Pelvic ultrasonography was usually recommended every 3–6 months within 2 years after surgery, and once a year thereafter for 8 years, while CT and echocardiography were usually performed when abnormalities were detected during pelvic physical examination or ultrasonography.
For patients who underwent complete resection, recurrence was defined as the detection of a tumor larger than 1 cm in diameter on imaging. For patients with incomplete resection, progression was defined as a ≥20% increase in the maximum tumor diameter on imaging, according to the response evaluation criteria in solid tumors (RECIST) 1.1. Stable disease was defined as the absence of new lesions in patients who underwent complete resection, or for whom the maximum diameter of the residual lesion remained stable, decreased, or increased by less than 20%. When recurrence or progression in images was suspected, confirmation was made with repeated imaging examinations 1 month later.
Data Analysis
SPSS 20.0 software was used for the data analysis. Kaplan-Meier univariate survival analysis with the log-rank test was performed to test the associations between the endpoint and various factors, with recurrence or progression as the endpoint. The end of follow-up was December 2022. Censors were defined as no recurrence or progression at the last follow-up, or loss to follow-up. Possible variables of interest included age <45 years, menstruation status, incomplete resection, size of the pelvic tumor ≥15 cm, involvement of the iliac vein or the genital vein, involvement of the inferior vena cava, right atrium involvement, and pulmonary artery involvement. From the perspective of clinical practice, intravenous leiomyomatosis limited to the uterus and para-uterine vessels and tumor involving the iliac or genital veins had significantly different diagnostic clues and treatment methods. Therefore, we conducted a stratified analysis to explore the impact of hysterectomy, bilateral oophorectomy, and post-operative aromatase inhibitor therapy on patient prognosis. A two-tailed p value of 0.05 was considered to indicate statistical significance.
Results
General Conditions of the Enrolled Patients
A total of 135 patients were diagnosed with intravenous leiomyomatosis during the research period. Two patients were excluded because they did not undergo surgery, and 19 patients because they were lost to follow-up or had a follow-up period <3 months. A total of 114 patients were included (Figure 1), with a median age of 45 years (range 24–58), 58 (50.9%) of whom were older than 45 years. The median gravidity was 2 (range 0–7), and the median parity was 1 (range 0–4). In terms of menstruation status, 77 patients (67.5%) were pre-menopausal, nine patients (7.9%) were naturally post-menopausal, and 28 patients (24.6%) were no longer menstruating because of previous hysterectomy without an ovarian function test. Fifty-eight patients (50.9%) had a history of uterine surgery, of whom 35 (30.7%) had undergone myomectomy, and 28 patients (24.6%) had undergone hysterectomy (among whom five had undergone multiple surgical treatments, including previous myomectomy and later hysterectomy).
Flowchart of patients enrollment. IVL, intravenous leiomyomatosis.
Laparoscopic surgery was performed in six patients, and lesions in those six patients were restricted to the uterus. The extent of tumors was as follows: 48 patients (42.1%) confined to the uterus or para-uterine vessels, and the large vessels (iliac vein or genital vein and proximal large veins) in 66 patients (57.9%). The distal end of the tumor was located in the iliac vein or genital vein in six patients (9.1%), in the inferior vena cava in 16 patients (24.2%), in the right atrium or ventricle in 40 patients (60.6%), and in the pulmonary artery in four patients (6.1%). Among the 60 patients with involvement of the inferior vena cava, lesions in the inferior vena cava lumen were removed by incising the wall of the inferior vena cava. Among the 44 patients with cardiac involvement, intracardiac lesions in 42 patients were removed through incisions on the atrial or ventricular wall, and intracardiac lesions in two patients (with tumors involving the right atrium but not the right ventricle) were pulled out through inferior vena cava incisions under transesophageal ultrasound monitoring (without making incisions on the atrial wall). Figure 2 shows a tumor that originated in the uterus and spread along the right genital vein to the inferior vena cava and right atrium.
Images of a patient with intravenous leiomyomatosis involving the right atrium. A patient in her 40s presented with a huge mass in the pelvic and abdominal cavity (yellow arrow in A) that was 13.8 * 12.8 cm in size. The tumor lesion spread along the right genital vein (red arrows in A), entered the inferior vena cava in front of the right renal hilum (B), and extended upward into the right atrium (blue arrows in A). The size of the filling defect in the right atrium was approximately 3.2 * 2.8 cm (C).
The scope of the operation was as follows: seven patients (6.1%) had their uterus retained for young age and small tumor size; 79 patients (69.3%) had hysterectomy (28 patients had previously had hysterectomy); 93 patients (81.6%) had bilateral oophorectomy; and 21 patients (18.4%) had at least one ovary retained for young age. During the operation, tumors in 108 patients (94.7%) were completely resected without residual visible lesions, and residual tumors were recorded in six patients (5.3%). In terms of post-operative adjuvant therapy, 34 patients received aromatase inhibitor therapy for a median duration of 6 months (range 3–36).
Recurrence and Progression
The median follow-up time of all patients was 24 months (range 3–132), and 25 patients (21.9%) were followed for ≥60 months. During the follow-up period, recurrence or progression occurred in 29 patients (25.4%), with a median recurrence or progression time of 16 months (range 3–60). Sites of recurrence were as follows: pelvic cavity in 27 patients, iliac vessel in one patient, and pelvic cavity plus the iliac vessel in one patient.
The general characteristics of patients in the recurrence or progression group and the stable disease group are shown in Table 1. The results showed that all patients in the recurrence or progression group were pre-menopausal. Compared with those in the stable disease group, the proportions of patients younger than 45 years were greater (65.5% vs 43.5%, p=0.041) in the recurrence or progression group. Pelvic tumors were larger in the recurrence or progression group, with average diameters of 10.8±6.4 cm and 8.7±4.3 cm, respectively. In the recurrence or progression group, the proportion of patients with a pelvic tumor diameter ≥15 cm was greater (28.0% vs 8.7%, p=0.017), the proportion of patients with inferior vena cava involvement was greater (69.0% vs 47.1%, p=0.041), and the proportion of patients who underwent incomplete tumor resection was greater (13.8% vs 2.4%, p=0.036).
Characteristics of patients in the recurrence or progression group and the stable disease group.
Risk Factors for Recurrence and Progression
Survival analysis of all patients (Figure 3) revealed that incomplete tumor resection was a risk factor for recurrence and progression (p=0.019). Among 108 patients who underwent complete resection, 25 recurred (23.1%), while among the six patients who underwent incomplete resection, progression occurred in four patients (66.7%).
Risk factors for post-operative recurrence or progression in all patients. Kaplan-Meier survival analysis with the log-rank test showed that incomplete tumor resection (A), involvement of the iliac vein or genital vein (B), involvement of the inferior vena cava (C), and a pelvic tumor size ≥15 cm (D) were risk factors for post-operative recurrence or progression, whereas involvement of the right atrium (E) and pulmonary artery (F), menstrual status (G), age <45 years old (H), and history of uterine surgery (I) were not related to prognosis.
The extent and size of the tumor were significantly related to the prognosis. Involvement of the iliac vein or genital vein (p=0.042), inferior vena cava (p=0.025), or size of the pelvic tumor ≥15 cm (p=0.034) were risk factors for post-operative recurrence or progression. Among the 66 patients with involvement of the iliac vein or genital vein, 21 had recurrence or progression (31.8%), while eight (16.7%) had recurrence or progression out of the 48 patients with tumors confined to the uterus or para-uterine vessels. Among the 60 patients with involvement of the inferior vena cava, 20 had recurrence or progression (33.3%), while out of 54 patients without inferior vena cava involvement, nine (16.7%) had recurrence or progression. Among the 13 patients with a pelvic tumor ≥15 cm in size, recurrence or progression occurred in seven patients (53.8%), while of 81 patients with a pelvic tumor size <15 cm, 18 (22.2%) experienced recurrence or progression. However, right atrium involvement (p=0.53) and pulmonary artery involvement (p=0.55) were not factors affecting the prognosis.
In this study, none of the nine post-menopausal patients experienced recurrence or progression. Among the 56 patients aged <45 years, 19 had recurrence or progression (33.9%), while out of 58 patients aged ≥45 years, 10 (17.2%) had recurrence or progression.
Treatment and Prognosis in Disease Confined to Uterus and Para-Uterine Vessels
Among the 48 patients with tumors confined to the uterus and para-uterine vessels, two did not undergo complete resection because of large tumor size. Survival analysis of 46 patients who underwent complete resection was performed to explore the impact of different surgical regimens on patient prognosis (Figure 4).
Risk factors for post-operative recurrence or progression in subgroup analysis. Kaplan-Meier survival analysis with the log-rank test showed that for intravenous leiomyomatosis confined to the uterus and para-uterine vessels, the risk of recurrence after hysterectomy and bilateral oophorectomy was the lowest (A), and the risk of recurrence after tumorectomy was significantly higher (A) (P value refers to comparison between hysterectomy and bilateral oophorectomy and tumorectomy; P* value refers to comparison between hysterectomy and bilateral oophorectomy and hysterectomy). Para-uterine vessel involvement was not associated with recurrence (B). For intravenous leiomyomatosis involving the iliac vein, genital vein, and proximal veins, aromatase inhibitor therapy (C) and two-stage surgery (D) were not related to post-operative recurrence.
The recurrence risk after hysterectomy and bilateral oophorectomy was the lowest, and 28 patients who underwent hysterectomy and bilateral oophorectomy experienced no recurrence (seven patients received aromatase inhibitor). Comparatively, the risk of recurrence after disease resection (with the uterus and ovaries retained) was significantly greater (p=0.009), and three of six patients (50%) in this group had recurrence. The recurrence risk after hysterectomy was not significantly increased (p=0.058), and two of the 12 patients (16.7%) in this group experienced recurrence.
Treatment and Prognosis in Disease Involving Pelvic Veins
Among the 66 patients with tumors involving the iliac vein, genital vein, or proximal vein, four did not have complete resection due to the large size of the tumor. Survival analysis was also conducted for 62 patients who underwent complete resection to explore the impact of different treatment strategies on patient prognosis. All 62 patients in this group underwent hysterectomy and bilateral oophorectomy.
The univariate analysis (Figure 4) revealed that aromatase inhibitor therapy (p=0.89) and two-stage surgery (p=0.86) were not related to post-operative recurrence. Of the 27 patients who received aromatase inhibitors, eight (29.6%) had a recurrence, while 11 of the 35 (31.4%) patients who did not receive aromatase inhibitors had a recurrence. Among the 46 patients who underwent one-stage surgery, 14 (30.4%) experienced recurrence, while five of 16 (31.3%) patients who underwent two-stage surgery experienced recurrence.
Discussion
Summary of Main Results
We found that the risk factors for post-operative recurrence or progression of intravenous leiomyomatosis included incomplete tumor resection, involvement of the iliac vein or genital vein, involvement of the inferior vena cava, and size of the pelvic tumor ≥15 cm. For disease confined to the uterus and para-uterine vessels, the recurrence risk after hysterectomy and bilateral oophorectomy was the lowest. For disease involving the iliac vein, genital vein, and proximal vein, aromatase inhibitor therapy after complete resection and bilateral oophorectomy did not reduce the recurrence risk.
Results in the Context of Published Literature
Intravenous leiomyomatosis is a rare clinical condition, and its clinical symptoms mainly include symptoms similar to those of uterine fibroids and symptoms related to right heart dysfunction.9 It may lead to heart failure and sudden death in a minority of patients.9 Intravenous leiomyomatosis restricted to the uterus is usually diagnosed after post-operative pathology, whereas when involving large blood vessels it is usually diagnosed with imaging examination by chance or after the presentation of symptoms related to right heart dysfunction.10 Pathologically, it features benign smooth muscle tissue growing within the blood vessels. Worm-like growth of smooth muscles is observed grossly, and under a microscope, benign smooth muscle tissue could be observed without atypia or mitotic images.1 Surgery is the main treatment, and the goal of surgery is complete resection.7 Anti-estrogen treatment is currently the common post-operative adjuvant therapy.11 Incomplete tumor resection is the main risk factor for recurrence or progression,12 and thus, complete resection of the tumor is the goal of surgery.13
Hysterectomy and bilateral oophorectomy are recommended for disease confined to the uterus and para-uterine vessels, and the post-operative recurrence rate is very low. Yu et al14 reported 10 patients with disease confined to the uterus who underwent hysterectomy and bilateral oophorectomy and had no recurrence during a median follow-up time of 49 months. Peng et al15 reported 86 cases confined to the uterus who underwent hysterectomy with bilateral oophorectomy; only two patients experienced recurrence during a median follow-up of 26 months.
However, disease resection with preservation of the uterus was a risk factor for post-operative recurrence. In a previous report, Peng et al15 performed a single center-based retrospective study of 161 patients with disease confined to the uterus, and reported that 11 of 34 (32.4%) patients who retained their uterus had a recurrence during a follow-up of 45.3±7.4 months. Uterus preservation was a risk factor for recurrence (OR 20.09, 95% CI 4.16 to 97.10).
Due to the (low) risk of estrogen-related complications caused by bilateral oophorectomy, Du et al1 suggested preserving at least one ovary in young patients. In this study, compared with hysterectomy with bilateral oophorectomy, hysterectomy did not significantly increase the risk of recurrence, while Peng and colleagues’ study15 showed that retaining one ovary did not increase recurrence rate.
Anti-estrogen therapy after complete resection did not reduce recurrence rate. Traditionally, intravenous leiomyomatosis is believed to be a sex-hormone-dependent tumor16 that originates from the uterus and presents with sex hormone receptor characteristics similar to those of uterine myometrium and uterine leiomyoma, presenting as ER/PR positive by immunohistochemical staining.5 11 In clinical practice, anti-estrogen therapy is usually the preferred choice.17 A small amount of low-quality evidence from previous studies supported that post-operative anti-estrogen treatment did not affect patient prognosis.6 9 This study showed that for disease involving the iliac vein or genital vein, aromatase inhibitor treatment after bilateral oophorectomy did not reduce the post-operative recurrence rate.
Strengths and Weaknesses
The strengths of this study include the size of the cohort, complete clinical data and follow-up information of the single-center. This retrospective study has several limitations. Among the limitations we must recognize the short median follow-up of the patients, the small number of patients after stratification to grouping by risk factors, the lack of data on true extent of disease (as often imaging studies or intraoperative assessment may underestimate the extent of disease), the limited information that we can provide based on a one-step versus two-step procedure, and the fact that we cannot determine based on these data whether age and menopausal status truly impacts disease recurrence. Lastly, the impact that aromatase inhibitors or progestational agents might have on natural progression of disease remains unknown.
Implications for Practice and Future Research
We recommend that for young patients with intravenous leiomyomatosis, the scope of surgery should be determined with full consideration of the patient’s age, fertility desire, and risk of recurrence. For intravenous leiomyomatosis involving the iliac vein/genital vein, aromatase inhibitor therapy may not be required after complete tumor resection and bilateral oophorectomy.
Conclusion
Incomplete resection, extent of tumor, and pelvic mass size were risk factors impacting post-operative recurrence. For intravenous leiomyomatosis confined to the uterus and para-uterine vessels, the risk of recurrence after hysterectomy and bilateral oophorectomy was low. For disease involving the iliac vein or genital vein, aromatase inhibitor therapy after complete tumor resection did not reduce the risk of recurrence.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the Institutional Review Board of Peking Union Medical College Hospital. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We are thankful for the contributions of the study participants and research teams.
Footnotes
Contributors Conception and design: GRZ, XY, JHL; administrative support: JHL, BL, DCZ; provision of study materials or patients: GRZ, XY, BL, DCZ; data analysis and interpretation: GRZ, XY, JHL; manuscript writing: all authors; guarantor: XY. All authors have read and agreed to the final version of the paper.
Funding The study was funded by National High Level Hospital Clinical Research Funding, No. 2022-PUMCH-A-232 and National High Level Hospital Clinical Research Funding, No. 2022-PUMCH-C-046.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.