Iliac vein thrombectomy in a metastatic ovarian cancer patient: a case report and literature review


 BackgroundCirculating tumor cells (CTCs) is a major prognostic factor in both primary and metastatic tumor and associated with thrombosis,which may resulted in the formation of Venous thromboembolism (VTE) and the incidence of some adverse events. For the VTE, we can use anticoagulant treatment and Inferior vena cava filter (IVCF) to reduce the risk of pulmonary embolism (PE). However, For large vessels thrombus, These methods can’t solve the problem. So, innovative therapies can quickly and effectively alleviate symptoms and remove tumor thrombus, reducing the possibility of tumor hematogenous dissemination. External iliac venous thrombosis from metastatic ovarian cancer has rarely been reported, especially involving the mechanism that CTCs may lead to the formation of VTE. And little has been reported about the therapy of iliac vein thrombectomy to remove embolus. Here, we present a case of external iliac venous thrombosis and review relevant literature to provide a better recognition of this disease and relevant mechanism.Case presentationThe present case report describes a 60-year-old woman with the external iliac vein thrombosis. She received anticoagulant treatment and we inserted an IVCF to reduce the risk of PE. But it can’t alleviate symptoms and remove tumor thrombus. Finally, we incised external iliac vein to remove the embolus by open operation with the help of multiple disciplinary teamwork(MDT). The IVCF was retrieved on postoperative day nine. And the patient was discharged home on postoperative day twelve. She has good recovery after operation and has no recurrence. ConclusionsThe current report demonstrated that Preoperative IVCF insertion and iliac vein thrombectomy combined with MDT in the treatment of this metastatic cancer patient with deep venous thrombosis(DVT) is effective. And CTCs may involve in the formation of DVT of cancer patients, Exploring the mechanism of VTE that is associated with CTCs is vital important. In addition, Using innovative therapies such as iliac vein thrombectomy to remove embolus is also significant.

External iliac venous thrombosis from metastatic ovarian cancer has rarely been reported, especially involving the mechanism that CTCs may lead to the formation of VTE. And little has been reported about the therapy of iliac vein thrombectomy to remove embolus. Here, we present a case of external iliac venous thrombosis and review relevant literature to provide a better recognition of this disease and relevant mechanism.

Case presentation
The present case report describes a 60-year-old woman with the external iliac vein thrombosis. She received anticoagulant treatment and we inserted an IVCF to reduce the risk of PE. But it can't alleviate symptoms and remove tumor thrombus. Finally, we incised external iliac vein to remove the embolus by open operation with the help of multiple disciplinary teamwork(MDT). The IVCF was retrieved on postoperative day nine. And the patient was discharged home on postoperative day twelve. She has good recovery after operation and has no recurrence.

Conclusions
The current report demonstrated that Preoperative IVCF insertion and iliac vein thrombectomy combined with MDT in the treatment of this metastatic cancer patient with deep venous thrombosis(DVT) is effective. And CTCs may involve in the formation of DVT of cancer patients, Exploring the mechanism of VTE that is associated with CTCs is vital important. In addition, Using innovative therapies such as iliac vein thrombectomy to remove embolus is also signi cant.

Background
Trousseau described the clinical association between malignant tumor and venous thromboembolism (VTE) for the rst time in 1865 [1]. Women suffered from ovarian cancer are at a higher risk of VTE because a large pelvic tumor and massive ascites may compress intrapelvic veins. Up to 20% of women with ovarian cancer suffer from VTE [2]. Patients with colorectalcarcinoma, pancreatic neuroendocrine tumor or hepatocellular carcinoma may also suffer from VTE [3]. Studies found that ovarian cancer patients closely associate with intravascular thrombosis and the rate of its intravascular tumor thrombus is more than the VTE rate. What's more, study found that residual tumor increased the risk of thrombosis by more than 3-fold. However, the rate of intravascular tumor thrombus rate of other cancer is relatively low [4].With metastasis, the risk of thrombosis may be even higher [5,6]. High D-dimer levels are associated with a higher DVT risk, too [6]. Circulating tumor cells (CTCs), deriving from both primary and metastatic tumors, are believed to be involved in poor prognosis and metastasis [7,8]. CTCs could be involved in coagulation activation and eventually prompt numerous tumor types, e.g., breast cancer, pancreatic cancer, endometroid ovarian carcinoma to form the embolus, increasing the risk of VTE. CTCs are also a risk factor for VTE in metastatic cancers [9] However, CTCs' contribution to thrombosis in patients with metastatic ovarian cancer is rarely known.
We report a case of a 60-year-old patient with metastatic ovarian cancer presenting preoperatively with iliac venous thrombosis and our experience of external iliac vein thrombectomy intraoperatively.  The CEA, CA125 and CA19-9 tumor markers were measured and found to be elevated. What's more, platelets were found to be elevated and especially the level of D-dimer was found to be signi cantly elevated. Magnetic resonance imaging (MRI) showed a tumor mass of 67 × 77 × 85 mm occupying the right adnexal region, and an oval shaped lesion measuring approximately 4.0 cm in diameter seen next to the right common iliac artery above the mass with multiple swollen lymph nodes on both sides of the pelvic wall, suggesting possible metastatic malignant tumor ( Figure.    On March 13, the patient underwent laparoscopic exploration. A mass was seen in the right iliac vessel area with about 6 cm in diameter, and the right ovary was enlarged. Considering severe peritoneal adhesion, open operation was selected. After resecting the mass and the right adnexa, the distal segment of right external iliac vein was clipped temporarily by a bulldog clamp. Then the blood vessel was cut open with the length of 3 cm and the embolus was removed with gallbladder stone forceps. The vessel was suturedwith 3 − 0 Prolene and the bulldog clamp was taken off. The size of the embolus was about 4000 AXa IU of Low-molecular-weight heparinssodium injection (Clexane) was applied from 24 hours postoperatively, and was replaced with oral anticoagulant drugs at discharge.On postoperative day two, The patient can walk normally, and swelling and pain in the right lower extremity were relieved, and the circumference of the right thigh decreased to 52 cm ( Figure. 1) .The IVCF was retrieved on postoperative day nine. And the patient was discharged home on postoperative day twelve.

Discussion And Conclusions
VTE is a highly prevalent and potentially fatal disease, which can develop into the incidence of PE, causing higher mortality [10]. It is estimated that the annual incidence of VTE in patients with cancer is 0.5% compared to 0.1% in the general population. Active cancers account for 20% of the overall incidence of VTE and cancer-associated thrombosis (CAT) has worse survival among VTE patients, which is the second most prevalent cause of death from cancer, second only to cancer itself [10].In addtion, some therapeutic agents which targets tumor angiogenesis have been reported to be associated with venous and arterial thrombosis or tumor thrombus formation. For example,VEGF Inhibitors like the bevacizumab has been proven that increase the risk of arterial thrombosis. while the risk of VTE is uncertain. EGFR inhibitors like cetuximab and panitumumab have been tied to a signi cant increase in VTE [11]. Further research found that tumor cells can stimulate clotting and thrombosis in multiple approaches, which involves tissue factor (TF), platelets, tumor derived microparticles, CTCs, etc. In metastatic cancer, CTCs are particularly associated with tissue factor, platelets, and tumor derived microparticles in thrombosis [8]. Tissue factor (TF) is a transmembrane glycoprotein and primary initiator of blood coagulation. Circulating TF is mainly present as microparticles that are highly procoagulant, which contribute to venous thrombosis in cancer patients [12]. Phillips et al found that TF-positive CTCs and microparticles from primary tumors may serve as a trigger for cancer-associated thrombosis [13]. And TF can result in enhanced migration and upregulation of VEGF. In addition, TFs are overexpressed on cancer stem cells and on CTCs. It has been demonstrated that EGFR driven EMT in human carcinoma cells results in increased TF expression on these cells with high metastatic phenotype, nally promoting the thrombosis [9]. Platelets can protect tumor cells in circulation from immune response, contributing to metastasis. In addition, platelets can directly interact with tumor and enhance its growth, migration, and colonization through platelet-derived lysophosphatidic acid (LPA) and transforming growth factor β signaling pathway [14]. Mego et al found that CTC-positive patients had a signi cantly higher level of plasma D-dimer than CTC-negative patients. Plasma D-dimer and CTCs may play a part in coagulation cascade activation in early metastasis [15].
In this case, preoperative tests indicated elevated platelet and D-dimer levels, which is accord with mechanisms mentioned above. Considering the mechanism of CAT, the pathological examination, and the monism principle, we speculate this patient suffered metastasis after bladder tumor resection. The positive lymph nodes are likely to result from lymphatic metastasis. As for the origin of malignant cells in the thrombus, one scenario was that extranodal extension involving adjacent vascular wall and malignant cells entered circulation. The other scenarios were that the patient had hematogenous metastasis of primary bladder tumor. CTCs expressing TF promoted thrombosis by activating platelets and releasing micro particles, which explains the existence of malignant cells in the embolus.
Given the elevated risk of thrombosis in cancer patients, anticoagulation therapy is essential in preoperative management and anticoagulant therapy remains standard care protocol in patients with acute venous thromboembolism [16].And clinical guidelines recommend low-molecular-weight heparin (LMWH) as preferred anticoagulant for treatment in the rst 6 months in patients with proximal deep venous thrombosis(DVT) or PE and prevention of recurrent VTE in patients with advanced or metastatic cancer. If DVT exists before surgery, anticoagulation therapy might be ineffective or contraindicated or the proximal DVT, then IVCF insertion can be considered [15]. IVCF has been proven effective in preventing DVT and PE, as well as improving prognosis [17,18]. Nevertheless, lter penetration and fracture as well as the risk of DVT after IVCF insertion has raised concern [18,19]. As a preventive strategy, IVCF insertion cannot remove the thrombus directly. In this case, the patient missed the time window of thrombolytic therapy. The large emboli containing malignant cells in external iliac vein may not be resolved by conventional anticoagulation. With IVCF inserted to inhibit thrombus dissemination and PE, we performed right external iliac vein thrombectomy after mass resection to relieve the patient's symptoms in time. Postoperative pathology con rmed a cancer thrombus. External iliac vein incision and thrombectomy is relatively risky, but it can quickly and effectively alleviate symptoms and remove tumor thrombus, reducing the possibility of tumor hematogenous dissemination. In this case, the bene t of thrombectomy outweighed risks. It was reported that thrombectomy was effective to treat acute iliofemoral DVT and had advantages on reducing the length of hospital stay and major bleeding events [20].
Another characteristic of this case is the cooperation among gynecologists, radiologists, urologists, and pathologists, which highlights the role of MDT and makes it possible to obtain unique and innovative treatments for complex conditions. MDT is viewed as an additive where collaboration with other disciplines provides a new perspective to solving the problem and can create methodological innovations, knowledge, approaches, or paradigms [21].
In conclusion, Preoperative IVCF insertion and iliac vein thrombectomy combined with MDT in the treatment of this metastatic cancer patient with DVT is effective. Given involvement of CTCs in DVT, when treating DVT patients with malignant tumor history, we should alert to the possibility of tumor metastasis, and the thrombus should be handled appropriately in case of PE. In the future, we should further research the mechanism of thrombosis caused by CTCs, so that we can better prevent the formation of VTE.

Declarations
Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.  Magnetic resonance imaging (MRI) (a)-Arrowhead indicates a tumor mass of 67 × 77 × 85 mm occupying the right adnexal region (b)-Arrowhead indicates an oval shaped lesion whose diameter is about 4.0 cm that was seen next to the right common iliac artery.