LG-ESS is a rare uterine tumor that commonly spreads to the vagina, pelvis, and peritoneal cavity(4). In this study, we reviewed the demographics, clinicopathological characteristics, treatments and outcomes of 8 LG-ESS patients with intracaval or intracardiac extension, constituting the largest case series collected to date.
Intracaval or intracardiac extension of LG-ESS has rarely been reported, so the pathophysiology is still unclear. Based on previous studies reported in the literature, we hypothesize that the possible underlying mechanisms are as follows: 1) ESS exhibited hematogenous spread to the lung and thereafter to the pulmonary veins and direct extension from the pulmonary veins into the heart(5, 6). At this point, intracardiac and lung metastases could be detected without concurrent abdominal or caval metastasis. 2) Tumor thrombi directly spread through the venous system, stretching through the IVC from the iliac vein to the heart(7–10). Most cases reported, including ours, spread in this way. LG-ESS typically develops in premenopausal and perimenopausal women, with a mean age of 46 (range 18–83) years(11). Older age was thought to be an independent risk factor for OS in some studies(4, 12). In our study, the median age was 44 years, ranging from 28 to 56 years. Most of them were premenopausal or perimenopausal, similar to previous study results.
The clinical presentation of these lesions depends on the localization of the tumor. The typical clinical presentation in more than 90% of cases is abnormal uterine bleeding, which also presents with dysmenorrhea and pelvic pain. Patients with extrauterine spread tend to present with progressive dyspnea, abdominal pain, and lower limb edema. The diagnosis is usually confirmed by imaging modalities such as echocardiography or CT(13). In our study, abnormal uterine bleeding was the most common intimal symptom, and other clinical presentations, including abdominal pain, low back discomfort, edema of the lower limbs and dyspnea, were also observed. Due to the atypical presentation, this tumor is susceptible to misdiagnosis before tumor resection(14). In view of tumor invasion into the major cardiovascular channels, clinical behaviors are similar to those of intravenous leiomyomatosis (IVL), a very rare smooth muscle tumor. IVL is characterized by worm-like extensions into the uterine veins or into other pelvic veins. Tumor growth involving the inferior vena cava in more than 10% of patients with IVL and even cardiac involvement is occasionally seen. Indeed, all cases in our series had a preoperative diagnosis of IVL at the initial treatment. We suggest that the spread pattern of our cases may resemble IVL. The histological diagnosis of LG-ESS was confirmed both in primary tumors and in metastatic sites in all cases. In addition, tumor infiltrations to adjacent organs were observed in our series, while such invasion is seldom seen in IVL.
Many investigators have agreed that imaging examination should be regarded as a diagnostic technique for the preoperative assessment of the extent of neoplastic caval thrombus. Generally, uneven density or low density filling defects are seen in the iliac vein, IVC or heart. In our case, CT or CTV delineated the extent of the thrombus and visualized any residual caval flow (Fig. 1). Thus, imaging could help to guide the scope of surgery. However, differentiation between LG-ESS and IVL according to their enhancement of the characteristics upon imaging modalities is unreliable, and there is no suitable tumor marker for this disease(15). An accurate diagnosis can only be made utilizing histological evaluation(16). Immunohistochemical detection of markers such as CD10, SMA, and desmin can have very good auxiliary use(17). In our research, the positivity rate of CD10 was 87.5%, that of desmin was 50%, and that of SMA was 71.4%, showing value in differentiating ESS from uterine smooth muscle tumors. Therefore, a high suspicion index is required not only to predict the disease but also to monitor recurrence. In addition, a multidisciplinary team consisting of a cardiac surgeon, radiologist and oncologist should be involved(18).
Given the rarity of this kind of disease, the optimal treatment for this condition is still a matter of debate. Surgery represents the most important procedure for the management of patients with ESS. In cases with intracaval or intracardiac extension, the disease condition is particularly complicated and associated with high mortality and postoperative recurrence rates. Herein, surgery for such tumors requires the participation of clinicians from various disciplines. The role of lymphadenectomy in the surgical management of ESS patients is not conclusive. Lymph node involvement among these patients was uncommon, and no differences were found either in recurrence-free survival or in overall survival after performing lymphadenectomy(19–21). In our cohort, all the patients underwent surgery without lymphadenectomy under the direction of gynecologic, vascular and cardiac surgeons. All patients recovered well after surgery, and no recurrence was found after treatment during the follow-up period. Complete resection of the intravascular and extravascular portions of the tumor is mandatory to relieve symptoms and prevent recurrence(22). Whenever possible, radical tumor resection should be attempted. Considering the longer surgical duration and higher risk of massive hemorrhage in a one-stage procedure, two-stage operations were also recommended (23).
In addition to surgery, hormone therapy, radiotherapy and chemotherapy are important adjuvant treatments for LG-ESS, but their effects need to be identified and discussed. Hormonal therapy with progestins, aromatase inhibitors, and gonadotropin-releasing hormone analogs has been considered an effective adjuvant treatment, especially for recurrent tumors, and their use should be guided by the hormone receptor status of the tumor concerned(24, 25). On the one hand, aromatase inhibitors are associated with longer RFS in patients with advanced LGESS, which is better tolerated than progestins and can be primary HT for LG-ESS(26). ER and PR were found in 87.5% of our cases; therefore, letrozole was used in 4 patients. However, the optimal dose, regimen and duration are not well established(27). On the other hand, a recent meta-analysis concluded that HT could only reduce the risk of recurrence in patients with FIGO stage I-II but without conferring any benefit in terms of overall survival(28). Moreover, adjuvant radiotherapy alone appears to improve local control, but the impact on survival is unclear(29). Adjuvant chemotherapy with anthracyclines and ifosfamide may be beneficial in patients with advanced or recurrent hormone-unresponsive tumors(30). Nevertheless, most studies have failed to show a clear survival benefit from adjuvant radiotherapy or chemotherapy, and no standardized or validated guidelines for adjuvant radiotherapy and chemotherapy exist as of yet(31). In our report, four patients received adjuvant radiotherapy, and 3 of them received letrozole maintenance treatment. In addition, one patient was treated with letrozole alone, and one patient received medroxyprogesterone. No patients have relapsed to date. The best combination, providing the best long-term survival, may be complete surgical resection and postoperative adjuvant therapy. However, we still need to expand the sample size for further study to investigate the optimal adjuvant treatment.
The 5-year survival rate for ESS is 54–100% at stage I and 30% at stage II, followed by a dramatic decrease to 11% at stages III and IV(2). However, patients in our study seemed to have a relatively good prognosis even in stage III or IV compared with previous studies. Most patients underwent radical resection of the tumor though a multidisciplinary team and received adjuvant therapy, which may prolong the overall survival time. In addition, the age in our patients was relatively young, and the oldest patient was only 56 years old, which may be associated with a better prognosis. According to a previous study, the risk of recurrence in LG-ESS is 10–20%, and 37–60% of patients show late tumor recurrence(3). Approximately 40% of recurrences were limited to the pelvis, and 60% occurred as distant metastases or as a combination of all forms of dissemination(32). The median period until the appearance of recurrence is 5.4–9.3 years in stages I and II and only 9 months in stages III and IV(32). Although the patients in our research were in an advanced stage, no patients showed a sign of recurrence during the follow-up period. The possible reason may be that most patients were followed up within 5 years, while late recurrence after more than 10–30 years are characteristic of this disease(11). Thus, long-term follow-up is crucial because of the high rate of late recurrence.
In conclusion, LG-ESS with intracaval or intracardiac extension is an uncommon type of tumor. Due to the lack of effective detection methods, it can easily be misdiagnosed as IVL, and accurate diagnosis can only be made by means of histological evaluation postoperatively. Complete tumoral excision followed by adjuvant hormone therapy provides relatively long-term survival in most patients. Multidisciplinary treatment and regular follow-up for 10 or 20 years after initial diagnosis are necessary due to the high rate of late recurrence.