DISCUSSION:
The major focus of this study was to review the role of anticoagulation in the treatment of tumor thrombus. Our study showed that a minority (20%) of patients with tumor thrombus at a large tertiary center received anticoagulation with the purpose of preventing bland thrombus formation and/or embolization. Furthermore, there was no significant difference in the rate of bland thrombus formation and/or embolization or in overall survival in pediatric patients with intravascular extension of a solid tumor or tumor thrombus treated with or without anticoagulation. Patients who received anticoagulation experienced a statistically significant increase in bleeding events.
Tumor thrombus is overall an uncommon clinical entity. However, its presence can complicate the management plan. Hence, early and accurate detection is helpful in surgical planning and in some cases, tumor staging 9,10. Imaging is critical for early detection and differentiation from bland thrombus 11. In adults, renal cell carcinoma, hepatocellular carcinoma, and adrenocortical carcinoma are the malignancies most frequently associated with tumor thrombus12; while in children, Wilms tumor has a tendency for vascular invasion 3,13. In Wilms tumor, 20-35% patients have renal vein involvement, while extension into the IVC is reported in 4-10% of patients 4,13. There are isolated case reports reporting vascular invasion and tumor thrombus in patients with Ewing sarcoma, osteosarcoma, neuroblastoma, and hepatoblastoma 14–17. In our study, the most common malignancy associated with tumor thrombus was hepatoblastoma, followed by osteosarcoma and Wilms tumor.
Most of the patients were asymptomatic and tumor thrombus was detected on routine imaging, similar to the observation in previous studies5,13. However, two of our patients presented with PE and one with lower extremity pain and swelling. PE has been previously reported as a presenting sign of primary or relapsed osteosarcoma associated with tumor thrombus 18,19. Yeduluri et al speculated that this could be attributable to the predilection of metastatic spread by vascular invasion in osteosarcoma20. Our patient with Ewing sarcoma had tumor thrombus-related PE, similar to a report by Dotson et al describing a patient with Ewing sarcoma who developed systemic emboli and myocardial infarction from tumor thrombus located in the left atrium21.
Although chemotherapy, surgery, and/or radiation form the backbone of management of primary tumor and potentially, tumor thrombus, there is a risk of tumor rupture or spread with potential complications such as PE or systemic emboli of bland thrombus components. This risk is particularly high in cases where tumor thrombus is located in the IVC or extending to the heart. Hence considering anticoagulation, either by prophylactic or therapeutic dosing, is not unreasonable. However, the use of anticoagulation for patients with tumor thrombus is inconsistent. While all Wilms tumor patients with intracardiac extension of the tumor received anticoagulation post-resection for a minimum of 3 months in a study by Cox et al 22, anticoagulation was not attempted in some other similar studies 4,13,23 and the results were comparable in terms of survival and response to treatment. In a review assessing OS patients with cardiovascular involvement, the authors reported one patient was on anticoagulation before the diagnosis of tumor thrombus was correctly established, but otherwise almost all patients received chemotherapy and/or surgery with no adjuvant anticoagulation with good outcomes 20. In a study of patients with renal cell carcinoma, the most common tumor associated with tumor thrombus in adults, presenting with PE, 5 of the 7 patients received anticoagulation with either unfractionated heparin or enoxaparin; anticoagulation was held in the remaining two patients due to bleeding 24. The authors’ rationale was that patients with malignancy are already at a high risk for thrombosis and in the presence of an IVC tumor thrombus, there is additional disturbance of flow through the IVC, further increasing their risk of bland thrombosis or thromboembolism. In our patient cohort, we noted a similar approach by the providers in that most of patients did not receive anticoagulation, but it was initiated in 20% of the patients for management of signs or symptoms and/or to prevent further complications from progression of bland components of the tumor thrombus or thromboembolism. However, we want to emphasize that although anticoagulation could be helpful, the backbone of treatment of tumor thrombus is surgical with or without chemotherapy and radiation (when indicated) for the underlying malignancy 3. This is supported by findings in our patient cohort. Our patient with relapsed osteosarcoma continued to have worsening tumor thrombus despite therapeutic anticoagulation until thrombectomy was performed, and despite initial improvement, had another episode of PE in the absence of cancer-directed therapy. In contrast, our patient with Ewing sarcoma received anticoagulation in conjunction with chemotherapy and surgery and had a complete resolution of the tumor thrombus. The underlying characteristics of tumor thrombus are different than bland thrombus making it more likely to resolve with chemotherapy and respond minimally to anticoagulation.
The benefits of anticoagulation must be weighed against the risks of bleeding. Malignancy itself places patients at a high risk of bleeding and thrombosis. In our dataset, 40% patients on anticoagulation developed bleeding, while this percentage was only 5% for the group not on anticoagulation. This difference in bleeding was statistically significant, which is not surprising given the use of anticoagulation in one group, but further underscores the importance of considering anticoagulation on a case-by-case basis.
There are some limitations of this study. The design is retrospective with subjects being identified by reported imaging findings. It is possible that some patients may not have been included if tumor thrombus was diagnosed intra-operatively but not appreciated on imaging, leading to underreporting of the finding in our study. This could possibly explain why there was a lower proportion of Wilms tumor thrombus in our study compared to other pediatric reports. Pathological confirmation was not made for all the suspected tumor thrombus cases, raising the possibility that some tumor thrombi may have a component of bland thrombus and hence, may have responded in part to anticoagulation. As a single center study, our sample size is small, limiting the statistical power to draw conclusions. Hence, further larger multi-center studies are to needed to confirm these findings.
In conclusion, this study reports the largest case series of pediatric tumor thrombus treated with or without anticoagulation in combination with cancer-directed therapy. An important advantage of our study over previous reports is that we focused on the role of anticoagulation in lessening the potential risk of bland thrombus formation and/or embolization in this cohort of patients since data is limited on this subject. We found no difference in rate of bland thrombus formation and/or embolization or survival in patients who did or did not receive anticoagulation. However, we did find a significantly higher rate of bleeding events in the anticoagulation group. Our study provides some practical information and guidance for clinicians considering the use of anticoagulation in these complicated patients both at risk for bleeding and clotting. While we found no clear evidence that anticoagulation administered in conjunction with cancer-directed therapies improves outcomes in pediatric patients with tumor thrombus, further studies are indicated to identify subgroups that may benefit from thromboprophylaxis.
Conflict of Interest: Authors have no conflict of interest to disclose.