POEMS syndrome (P = polyneuropathy, O = organomegaly, E = endocrinopathy, M = monoclonal gammopathy, S = skin changes) is a rare clinical unit belonging to plasma cell dyscrasias [1Dispenzieri A, Rajkumar SV, Kyle RA. Diagnosis and treatment of POEMS syndrome Treatment of multiple myeloma and related disorders 2009; 182-95.]. Unlike multiple myeloma (MM), it is usually manifested in younger patients, and its course is less aggressive [2Rajkumar SV, Kyle RA, Suarez GA, Gertz MA, Greipp PR. Neuropathy associated with plasma cell proliferative disorders.Multiple myeloma and related plasma cell disorders Mayo Foundation for medical education and research 2004; 35-52.].

The presenting symptoms include obligatory chronic progressive polyneuropathy and the presence of monoclonal immunoglobulin (almost exclusively with lambda light chain). The other characteristic features of the acronyme (organomegaly, endocrinopathy, skin changes) are variably present and sometimes difficult to unreveal, and many of the patients are treated as other (usually neurological) disorders.

The previously used diagnostic criteria were too vague and enabled the inclusion of different unrelated conditions solely on the coincidence of the symptoms [3Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome definitions and long-term outcome Blood 2003; 101: 496-506.]. The current opinion on this disease has recently changed the criteria into a more coherent panel (Table 1) [4Dispenzieri A. Mayo Clinic Criteria for the Diagnosis of Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes Syndrome. Note. From "POEMS Syndrome Blood Rev 2007; 21: 287.]. Interestingly, one of the major molecules which is thought to be responsible for the pathogenesis of the disease, the vascular endothelial growth factor (VEGF), is nowadays being regarded as one of the major criteria in POEMS syndrome diagnostics [5Watanabe O, Maruyama I, Arimura K, et al. Overproduction of vascular endothelial growth factor/vascular permeability factor is causative in Crow-Fukase (POEMS) syndrome Muscle Nerve 1998; 21: 1390-7.,6Dispenzieri A. POEMS Syndrome Blood Rev 2007; 21: 285-99.].

Table 1

Criteria of POEMS Syndrome – Mayo Clinic Criteria from 2003 [3Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome definitions and long-term outcome Blood 2003; 101: 496-506.] and 2007 [4Dispenzieri A. Mayo Clinic Criteria for the Diagnosis of Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes Syndrome. Note. From "POEMS Syndrome Blood Rev 2007; 21: 287.]

We present three different manifestations of the disease with stress placed on the role of VEGF (measured by quantitative sandwich enzyme immunoassay) as an emerging diagnostic tool as well as a possible parameter of the activity of the disease.

POEMS syndrome represents a very complex disease with variable presence of accompanying symptoms. Except for characteristic polyneuropathy and monoclonal gammopathy, the other associated symptoms might not be evident at the onset of the disease. Or, similarly as in the case report 2, they might be obscure and related to other concomitant diseases. It is therefore necessary, that the assessment is carried out by an experienced physician, and every polyneuropathy associated with monoclonal gammopathy (especially with the presence of light chain lamda) should be investigated for the signs of POEMS syndrome. Recent studies aim at the biology of the disease with the expectation of possible molecules specific for the disease.

The pathogenesis of POEMS syndrome has been intensively studied. It is supposed to be caused by the imbalance between pro-inflammatory cytokines, IL-1β, IL-6 and TNFα. The actual impulse responsible for the onset of the disease is thought to be the elevation of vascular endothelial growth factor - VEGF.

VEGF is reckoned to be responsible for majority of the symptoms. Increasing microvascular permeability leads to edema of neural tissue, increased endoneural pressure and exposure of myelin to serum cytokines which cause demyelination[7Watanabe O, Arimura K, Kitajima I, et al. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome Lancet 1996; 347: 702.,8Hayashi T. POEMS syndrome and VEGF Intern Med 2004; 43: 1014.].Increased vascular permeability and angiogenesis are thought to cause organomegaly, edema and skin hemangiomas,as seen in our patients[7Watanabe O, Arimura K, Kitajima I, et al. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome Lancet 1996; 347: 702.]. The pathogenesis, on the other hand, is more complex as the symptoms might not be present in all patients. Even our small cohort showed different manifestations from nearly physiological findings (except of peripheral neuropathy) in case report 2, to the „wet form” of POEMS syndrome with severe edema of the limbs, pleural and cardiac effusions and ascites.

VEGF is highly expressed in blood vessels and some nonmyelin forming Schwann cells [9Scarlato M, Previtali SC, Carpo M, et al. Polyneuropathy in POEMS syndrome role of angiogenic factors in the pathogenesis Brain 2005; 128: 1911-20.]. One of the major sources are thought to be the platelets [10Hashiguchi T, Arimura K, Matsumuro K, et al. Highly concentrated vascular endothelial growth factor in platelets in Crow Fukase syndrome Muscle Nerve 2000; 23: 1051-6.]. This idea is in accordance with increased levels of thrombocytes in majority of patients, and thrombocytopenia might be the reason for the lack of VEGF elevation in some patients [11Kuwabara S. Relapse of POEMS syndrome without increased level of VEGF Neuromuscular Disord 2009; 19: 740-1.]. On the other hand, even patients with low platelet count present elevated VEGF levels. The possible other sources of VEGF are osteosclerotic lesions, plasma cells, tumor cells and endothelial cells [12Nakajima H, Ishida S, Furutama D, et al. Expression of vascular endothelial growth factor by plasma cells in the sclerotic bone lesions of a patient with POEMS syndrome J Neurol 2007; 254: 531-3.,13Nobile-Orazio E, Terenghi F, Giannotta C, et al. Serum VEGF levels in POEMS syndrome and immune mediated neuropathies Neurology 2009; 72: 1024-6.].

The levels of VEGF in POEMS syndrome are usually higher than in patients with other plasma cell dyscrasias such as MGUS and multiple myeloma [1Dispenzieri A, Rajkumar SV, Kyle RA. Diagnosis and treatment of POEMS syndrome Treatment of multiple myeloma and related disorders 2009; 182-95.,14Soubrier M, Dubost JJ, Serre AF, et al. Growth factors in POEMS syndrome: evidence for a marked increase in circulating vascular endothelial growth factor Arhritis Rheum 1997; 40: 786-.,15Gherardi RK, Belec L, Soubrier M, et al. Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome Blood 1996; 87: 1458-65.]. On the other hand, they might be affected by other conditions, such as the presence of solid tumor, inflammation, estrogen levels, hepatic disorders or even some reparative physiological processes, which make VEGF less specific for differential diagnosis. The complicated role of VEGF in the pathogenesis of POEMS syndrome has been underlined by several reports on the treatment of the disease using an anti-VEGF antibody, bevacizumab [16Badros A, Porter N, Zimrin A. Bevacizumab therapy for POEMS syndrome Blood 2005; 106: 1135.-18Samaras P, Bauer S, Stenner-Liewen F, et al. Treatment of POEMS syndrome with bevacizumab Haematologica 2007; 92: 1438-9.]. In the study of Badros et al., a patient with POEMS syndrome was sucessfully treated with bevacizumab with the decrease of VEGF, resolution of edema and vanishing of the neuropathy pain [16Badros A, Porter N, Zimrin A. Bevacizumab therapy for POEMS syndrome Blood 2005; 106: 1135.]. Contrary to this experience, in the report of Strasume et al. and Samaras et al., the patients after short-term improvement developed refractory edema and died, suggesting the impact of increased apoptosis of motor neurons and endothelial cells due to rapid decrease of VEGF [17Straume O, Bergheim J, Ernst P. Bevacizumab therapy for POEMS syndrome Blood 2006; 107: 4972-3.,18Samaras P, Bauer S, Stenner-Liewen F, et al. Treatment of POEMS syndrome with bevacizumab Haematologica 2007; 92: 1438-9.]. Nevertheless, the investigation of VEGF in POEMS syndrome has a great potential to unreveal the actual causes of the disease and to choose the optimal treatment target.

Evaluation of the course of POEMS syndrome is often very not easy and dependent on subjective assessment of the physician. There are no standard means of remission or progression of the disease, and even the values of paraprotein might not be always helpful. Remission and/or progression are therefore usually defined as the normalization or re-appearance of clinical symptoms (edema, skin lesions, lymph nodes, worsening of neuropathy) together with laboratory abnormalities (endocrine spectrum, hemoglobin levels, etc.). Our findings suggest VEGF as an emerging tool for routine assessment of the course of POEMS syndrome. There have not been many studies monitoring VEGF in the course of the disease. Kuwabara reported the normalization of VEGF levels in 4 patients with POEMS syndrome treated by autologous stem cell transplantation [19Kuwabara S, Misawa S, Kanai K, et al. Autologous peripheral blood stem cell transplantation for POEMS syndrome Neurology 2006; 66: 105-7.], some other authors described recently case reports with sequential VEGF monitoring [20Mineta M, Hatori M, Sano H, et al. Recurrent Crow–Fukase syndrome associated with increased serum levels of vascular endothelial growth factor: a case report and review of the literature Tohoku J Exp Med 2006; 210: 269-77.-22Imai N, Taguchi J, Nobuyasu Y, et al. Relapse of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS syndrome) without increased level of vascular endothelial growth factor following successful autologous peripheral blood stem cell transplantation Neuromuscul Disord 2009; 19: 363-5.], still, there has not been a larger cohort study which would confirm the presented findings.

We acknowledge the limitations in the retrospective analysis, and the small number of patients precludes statistical analysis. The levels of VEGF were not evaluated in standardized intervals, and the time between drawing of the sample and the analysis of VEGF levels differed. All of the samples were first frozen and then analyzed together, usually in 2-3 month interval so the degradation as well as other external influences might have affected the final result. Studies with longer follow-up and larger number of patients will be needed to determine whether the role of VEGF in POEMS syndrome maintains only its diagnostic value or might have the potential to predict the course of the disease and become the marker of the stability and/or the activity of the disease.

Our paper contributes to the assessment of POEMS syndrome by the suggestion of longitudinal monitoring of VEGF levels in the course of the disease. The levels of VEGF behaved in accord with the activity of the disease and predicted the course of the disease better than the evaluation of paraprotein and subjective symptoms. If confirmed by larger studies, VEGF has the potential to become a pivotal marker of the disease activity and a predictor of its behavior or, at least as a surrogate marker of successful treatment of this rare disease.

The study was supported by the grant MZ CR NR 9489-3.