Vascular disorders preceding diagnosis of cancer: Distinguishing the causal relationship based on Bradford-Hill guidelines

The literature investigating the association between vascular disorders and malignant neoplasms does not comprehensively review the full spectrum of vascular disorders associated with cancer, or provide proof that cancer is an etiologic factor in the development of these disorders. This paper investigates the causal role of cancer in the pathogenesis of vascular disorders, based on the Bradford-Hill criteria of causation. The Medline database was searched for articles on vascular disorders preceding the diagnosis of cancer (VDPCD). Included in the analysis were vascular disorders caused either by direct tumoral involvement of vessels or by paraneoplastic mechanisms. Vascular disorders caused by adverse reactions to anticancer therapy were excluded from analysis. Seven categories of VDPCDs were recognized: venous thromboembolism, arterial thrombosis and embolism, nonbacterial thrombotic endocarditis, migratory superficial thrombophlebitis, vasculitis, thrombotic microangiopathy, and leukothrombosis. To establish causality of the association between VDPCDs and malignancy, the degree of fulfillment of the Bradford-Hill criteria was assessed. A strong association was found in the literature between venous thromboembolism and cancer (OR 2.3-14.9 and SIR 1.3-4.4). Consistency and temporality of the association were confirmed in all VDPCD variants. Seven Bradford-Hill criteria were fulfilled for cancer associated with venous thromboembolism, six criteria for superficial phlebitis and cancer, and five criteria for each of the other VDPCDs. In conclusion, these data support the causal role of cancer in the pathogenesis of all seven categories of VDPCDs. Recognition of such a causal link between cancer and various vascular disorders may promote an earlier cancer diagnosis.