Intramedullary leukocytoclastic vasculitis and neutrophil extracellular trap (NET) formation in POEMS syndrome

POEMS syndrome [1] is a rare paraneoplastic syndrome caused by clonal plasma cells or lymphoplasmacytic cells causing polyneuropathy, organomegaly, endocrinopathy/ edema

POEMS syndrome [1] is a rare paraneoplastic syndrome caused by clonal plasma cells or lymphoplasmacytic cells causing polyneuropathy, organomegaly, endocrinopathy/ edema, and monoclonal-paraprotein.Most clinical and histopathologic findings can be explained by massive vascular endothelial growth factor (VEGF) secretion [2].NETosis is a program for formation of neutrophil extracellular traps (NETs), which consist of release of decondensed chromatin and granular contents extracellularly from granulocytes and monocytes.Here, we demonstrate leukocytoclastic vasculitis and NETosis in the bone marrow of an 80-year-old patient with POEMS syndrome.This report represents, to the best of our knowledge, the first published case of leukocytoclastic vasculitis and NETosis in POEMS syndrome and supports the role of VEGF in this phenomenon.
The patient presented with lower back pain, fatigue, and monoclonal gammopathy of undetermined significance; IgA lambda type (MGUS) was noted.
Polyneuropathy, MGUS, sclerotic bone lesions, and elevated VEGF levels were defined as major, endocrinopathy, thrombocytosis, and lymphadenopathy as minor criteria according to the IWMG [1] for POEMS syndrome.Therapy composed of dexamethasone p.o. and bortezomib s.c. for six cycles led to a significant reduction of VEGF levels to 705 pg/ml, normalization of platelet counts and CRP, and reduced metabolic activity of the bone lesions, weight gain, and less fatigue.
Leukocytoclastic vasculitis is a hypersensitivity vasculitis.It occurs as a complex series of endothelial/leukocyte interactions, vascular dilation, and leakage.Deposition of immune complexes and C3 around blood vessels is involved in the damage to endothelial cell membranes [3].Interestingly, in patients with vasculitis in the skin, VEGF serum levels are also elevated [4].One explanation for degranulation of mature neutrophils, NETosis, and leukocytoclastic vasculitis in POEMS may be via phosphorylation of ERK (extracellular-signal regulated kinases) downstream of VEGF receptor 1/flt1 in neutrophils [5,6].
While in vitro NETosis is a broadly studied effect and has been demonstrated to play a pivotal role in severe COVID-19 [7], few studies have shown NETosis occurring in vivo [8].Further studies are needed to investigate the exact mechanism of leukocytoclastic vasculitis and NETosis and whether anti-VEGF inhibition may be of therapeutic use in a subset of patients.