Uterine intravenous leiomyomatosis (IVL), a rare neoplasm defined by the intravascular proliferation of a histologically benign smooth muscle cell tumor, is an uncommon growth pattern of uterine leiomyoma (1). The clinical course varies depending on the severity of the condition. Vascular smooth muscle tumors can spread into the major veins and even the right atrium of the heart, obstructing blood flow and causing death (2–5).

Appropriate imaging examinations are required since IVLs could be misdiagnosed as intravascular thrombus, myxoma, or pancreatic tumors (6–8). Enhanced CT imaging can show the location, size, and full-scale extension pathway of IVL lesions, and it can be utilized in preoperative assessment (9). MRI could help with an accurate diagnosis, which is critical for deciding on a surgical plan and achieving a positive outcome (6). Echocardiography can be used to assess extension into the right atrium (10).

Pelvic arteriovenous fistula (AVF) is a rare vascular malformation that is most commonly congenital, post-traumatic, or iatrogenic (11, 12). Massive AV shunting causes high output cardiac failure. This malformation is hard to eradicate completely because of a high recurrence rate. Because of the significant hemorrhage, surgical resection is often challenging. Although transcatheter embolization has recently become the treatment of choice for pelvic AVF, full embolization to stop the shunt flow is equally challenging (11–13). The link between leiomyomatosis and AVF has only been mentioned rarely in the medical literature. Three definite cases have been recorded since the first description in 1993 (14–16). We provide four further examples of fistula associated with leiomyomatosis, review the literature on the topic, and speculate on possible pathophysiological causes for the cooccurrence.

For the literature review, PubMed, Embase, CNKI, and WanFang were utilized to conduct systematic searches of peer-reviewed literature published between 2000 and 2020. IBM SPSS was used to conduct the statistical analysis (IBM SPSS 26.0, SPSS Inc). For qualitative variables, Fisher's exact test and Pearson's chi-square test were utilized. All tests of statistical significance were two-sided, with p < 0.05.

The cause of AVFs formation in patients with IVL is unknown, and the association between AVF and IVL cannot be confirmed. Spontaneously developed pelvic vascular malformations are rare, and the most common causes include trauma, iatrogenic injury, aneurysm, and malignant tumor-related neovascularization (13, 17, 18). Vascular malformation induced by benign tumors, such as IVL, is seldom reported.

As demonstrated in cases 1 and 4, secondary vascular abnormalities developed around the tumor at the site of IVL invading the vein for unexplained reasons. The contrast agent in the vein appeared in advance under the angiography, indicating that the process of IVL invading the vein may promote local vascular malformation. Sometimes, this vascular malformation can even become the primary diagnosis in patients, masking IVL and leading to missed diagnosis and ignorant of the leiomyomatosis, resulting in tumor development (19).

There are several possible reasons why AVF would form in these patients with IVL. Six patients, including four cases from our center, who had leiomyomatosis complicated by pelvic AVF had received uterine surgery 7–15 years before. Thus, Iatrogenic AVF is to be suspected (15, 16). Furthermore, leiomyomatosis exhibits behaviors resembling malignant tumors; it invades blood vessels and induces angiogenesis. If the tumor invades and destroys both veins and arteries, fistulas could be formed during angiogenesis. AVF may originate from the nutritional artery of the tumor itself, and form AVFs as the tumor invades and grows into the vein. Such a process might be induced by iatrogenic injury during uterine surgery (20). The tumor inside the vein blocks the blood return, increasing local pressure, resulting in sphincter relaxation, and remodeling of the AVF. Some fistulas regressed after pressure relief (21, 22). The observation of pulmonary vascular malformation induced by benign metastasizing leiomyoma (BML) of the lungs increases the possibility of the hypotheses above.

Although pathological research provided evidence for AVF formation in the myometrium, such theories lack the support of long-term imaging surveillance (23, 24). Considering the risk of iatrogenic AVF, gynecologists are advised to avoid injury to arteries and veins during pelvic surgery. Among the reported cases and those reported by us, there were three patients [Case 2~3, and Mizuno et al. (16)] whose AVF and IVL occurred at different sites, which may have other reasons.

Magnetic resonance angiography (MRA) and DSA should be considered for the evaluation in IVL patients with heavy right cardiac load to exclude potential AVF. The advantage of MRA lies in its better ability to differentiate between soft tissue vascular malformations and soft tissue masses (25). Compared with CT, especially in patients with IVL, MRA can reduce the probability of misdiagnosing IVL as venous dissection or other hyper-vascular soft tissue tumors (19). The advantage of angiography is that it can clearly diagnose vascular malformations, which can be treated with coil embolization during the examination (11, 19). If a vascular malformation is found, it should be embolized from the arterial segment before the IVL surgery to reduce the blood flow in the vascular malformation and prevent bleeding during the IVL surgery, which contributes to a safe operation. If the vascular malformation is discovered during the operation, it is often difficult to remove due to tight adhesion and severe bleeding, as in Case 1. At this time, ligation of the artery supplying the AVF should be considered, as in Case 4.

Vascular malformation aggravates the symptoms of IVL and increases the risk of operation. High venous flow caused by vascular malformation increases the right ventricular pressure (Cases 2 and 3). Timely embolization may significantly improve the problem of right ventricular overload, reverse right heart failure, promote the recovery of right ventricular systolic pressure, and improve the blood supply of the lungs (Table 4). The rich blood supply of tumors caused by vascular malformations may promote IVL tumor growth in addition to increasing the risk of surgical bleeding. As in Case 4, the IVL significantly blocks IVC and reaches the heart.

According to statistics, the recurrence rate of intravascular tumor residue was much greater than that of patients with clean intravascular excision (Table 3). This discrepancy could be attributable to the bias introduced by the short sample size. Nevertheless, the ligation of the bilateral internal iliac vein and ovarian vein is helpful to prevent the recurrence or shedding of residual tumor embolus (26). Patients who have a pelvic tumor resection are more likely to experience complications than patients who do not have a pelvic tumor resection (Table 3), which could be owing to the abundance of the pelvic vascular bed, or possibly the creation of tumor-related arteriovenous malformations.

There is currently no consensus on the diagnosis and treatment of IVL, and only a few retrospective cohort studies in big centers with more cases were conducted (10, 27). Ma et al. presented an IVL staging system, categorizing IVLs into stages 1 through 4 based on the extent of intravenous tumor spread (28). Liu et al. categorized IVLs that enter the heart chambers into types 1–5 and discussed surgical plans for each type of IVLs (29). Further classification methods and surgical techniques were discussed by Li et al., although the surgical categorization differs from that suggested by Liu et al. According to the relative diameter between tumor and IVC, Li et al. recommended four types of surgery. Such classification agrees with Ma et al.'s method on stage 3 IVLs, including IVLs reaching and not reaching the right atrium. However, effective imaging tools are still needed to determine whether the tumor in the heart can be retrieved from the IVC in advance according to their reports. Therefore, different institutes should share their surgical experiences and promote diagnostic guidelines to decrease misdiagnosis and missed diagnoses, improve complication management, and decrease significant complications and recurrence.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

The study protocol was approved by the Research and Ethics Board of the Peking Union Medical College Hospital. The patients/participants provided their written informed consent to participate in this study and for the publication of any potentially identifiable data included in this article.

HK and YCa analyzed the patient data and were major contributors in writing the manuscript. YZ and YCh made substantial contributions to the study design and gave final approval to the version to be published. All authors read and approved the final manuscript.

This research was funded by CAMS Innovation Fund for Medical Sciences (CIFMS, numbers 2021-I2M-C&T-A-006 and 2021-I2M-1-016), the Major Research Program of Natural Science Foundation of China (51890892), the National Natural Science Foundation of China (NSFC, numbers 82070492, 81770481, and 82170516), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2021-JKCS-027).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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