Revisiting Paraneoplastic Acral Vascular Syndrome

Paraneoplastic acral vascular syndrome (PAVS) is a rare entity that presents in the form of acrocyanosis and digital necrosis, secondary to an underlying malignancy [1]. It can also precede the detection of cancer, which may be of several histologic types. Though the etiology of PAVS is not yet fully understood, it may be associated with a number of features, including tumor microembolization or the release of tissue factors from cancer cells, which then promote a hypercoagulative state and hyperviscosity responsible for secondary thrombosis and subsequent digital ischemia [2]. Another mechanism of consideration may be that the localization of the tumor or its metastasized lymph nodes may directly compress the cervical plexus, causing the hyperstimulation of the sympathetic nervous system, thus resulting in vasoconstriction and acrocyanosis. Notably, however, patients who present with such clinical symptoms should also undergo screening for other possible causes, such as underlying thrombophilia, presence of lupus anticoagulants, anti-neutrophil cytoplasmic antibodies, cryoglobulins, and IgG4-associated disease; of these, the latter may also initially raise the suspicion of a malignancy before histopathological confirmation. Once no evidence of vascular or autoimmune condition or the use of vasoconstrictive drugs is apparent, patients with acral vascular syndrome—elderly individuals in particular—should be extensively examined for a neoplastic origin. The article by Nakayama et al. brings attention to the intercorrelation between the immune system and hemostasis in PAVS [3]. In their case report, the authors describe a 66-year-old female patient with pancreatic ductal adenocarcinoma, where the histopathology of the cutaneous biopsy displayed the coexistence of fibrinoid degeneration and intravascular thrombosis, suggesting an immune-mediated response triggered by the thrombotic event. From a clinical point of view, one might often contemplate whether inflammation of the blood vessel was the initiator for a secondary occlusion or vice versa. However, the evolution of this process might not be as black and white as one might think since the interplay between inflammation and coagulation is vastly intertwined. Over the years, as more research on the matter arose, this link between the two processes has also been termed immunothrombosis (Figure 1). Standing on the precipice of this conundrum are neutrophil extracellular traps, which have not only been shown to contribute to cancer-associated thrombosis but are also present in the thrombi of cancer patients [4]. Their role in PAVS remains to be determined thus far, though examining their presence (or lack thereof) in such cases would further contribute to the understanding of acral vascular syndrome in cancer patients, albeit it being such a rarely reported condition in the literature. The management of PAVS also proves challenging as therapeutic efficacies are difficult to assess. According to previous case reports, potential treatment modalities are comprised of vasodilators in the form of prostacyclin, prostaglandin E1 analogs or calcium-channel blockers, anticoagulants or antiplatelet medications, sympatholytics, and analgesics for pain management, but ultimately—as with all paraneoplastic phenomena—it is the treatment of the underlying malignancy which may yield the best therapeutic results regarding the resolution of the vascular involvement [5]. In conclusion, the interplay between the immune system and the coagulation cascade should always be considered, not just in autoimmune diseases but also in patients with an active malignancy. Though it seems like there are a multitude of factors to consider when it comes to PAVS, more research with an expansive view—with immunothrombosis of particular interest—may broaden the horizon and help us elucidate the full scope of the underlying pathomechanism at hand. The author declares no conflicts of interest.