Histopathological Features of Cancer-Associated Venous Thromboembolism: Presence of Intrathrombus Cancer Cells and Prothrombotic Factors

Abstract

Background: Cancer-associated venous thromboembolism (VTE) is a critical complication in patients with cancer. However, the pathological findings of VTE are limited. Here, we investigated the histopathological features of cancer-associated VTE in human autopsy cases. Methods: We clinically examined the autopsy cases of VTE with (n=114) and without cancer (n=66) and immunohistochemically analyzed the expression of prothrombotic factors in intrathrombus cancer cells, the thrombus contents of erythrocytes, fibrin, platelets, citrullinated histone H3, and degree of organization. Results: Vascular wall invasion or small cell clusters of cancer cells was observed in thrombi in 27.5% of deep vein thrombosis and 25.9% of pulmonary embolism cases. The majority of the cancer cells in deep vein thrombi appeared to be invading the vessel wall, whereas the majority of pulmonary thrombi had cancer cell clusters, consistent with embolization via blood flow. These cancer cells were immunohistochemically positive for TF (tissue factors) or podoplanin in up to 88% of VTE cases. The frequency of TF-positive monocyte/macrophages in thrombi was higher in cancer-associated VTE than that in VTE without cancer. Citrullinated histone H3 was predominantly observed in the early stages of organizing thrombi. There was no significant difference in thrombus components between VTE with cancer and without cancer groups. Conclusions: Vascular wall invasion or cancer cell clusters in thrombi might influence thrombogenesis of cancer-associated VTE. TF and podoplanin in cancer cells and in monocyte/macrophages may induce coagulation reactions and platelet aggregation. Neutrophil extracellular traps may play a role in the early stages of VTE, regardless of cancer status.

Circulating Tumor Cells and Cancer-Associated Venous Thrombosis: A Missing Link

“…In conclusion, the study by Gi et al 1 demonstrates that a high number of thrombi in patients with cancer contain cancer cell clusters. One can speculate that TF expression by the cancer cell triggered formation of thrombi.…”

“…Gi et al 1 analyzed thrombi from autopsy cases of VTE with (n=114) or without cancer (n=66). There was a frequent use of chemotherapy (55.3%) or radiation therapy 24.6%) in the patients with cancer, which may damage the endothelium.…”

“…Similar levels of cancer cells were observed in DVT and PE from patients with cancer. Gi et al 1 identified 2 patterns of thrombi: cancer cells invading the venous or pulmonary artery wall and clusters of cancer cells without invasion. Some of the thrombi in the inferior vena cava may be tumor thrombi as described above.…”

“…In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Gi et al 1 characterized thrombi collected postmortem from patients with venous thromboembolism (VTE) with or without cancer. Surprisingly, despite many postmortem studies, there are no studies to date analyzing the composition of thrombi from patients with cancer.…”

“…Next, Gi et al 1 compared thrombi from patients with or without cancer. Cancer-associated DVT areas but not PE areas were significantly larger (>2.5-fold) than those without cancer.…”