Mediterranean Journal of Hematology and Infectious Diseases Review Articles POEMS SYNDROME: an Update Andrea Nozza Department of Medical Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Hospital IRCCS, Rozzano, Milan, Italy Competing interests: The authors have declared that no competing interests exist. Abstract. POEMS syndrome is a rare, chronic and disabling condition. The causes of this condition remain unknown; however, chronic overproduction of proinflammatory cytokines appears to be a major contributor. Early diagnosis is essential to start treatment before the clinical state of the patient becomes compromised. A complete evaluation of the disease at its onset is critical to the treatment decision. In localized disease, curative doses of radiation (50 Gy) is the recommended therapy. On the other hand, patients with disseminated disease should be given systemic therapy. Treatment-related morbidity can be minimized by an efficient induction therapy that modifies the cytokine status, improving clinical condition and control disease severity before mobilization and transplantation. Patients not suitable for hematopoietic stem cell transplantation (HSCT) are usually treated with alkylator-based therapy. Novel agents may also offer benefits to patients with a poor performance status or renal dysfunction, and induce transplantation eligibility. Given the biological characteristics of POEMS, immunomodulatory effects and the absence of neurotoxicity, lenalidomide appears to be an effective therapy for the treatment of POEMS, both as short induction therapy before PBSCT and in non-transplant eligible patients, as it showed high response rate and durable responses. At present, however, guidelines for the diagnosis and treatment of POEMS are not available and appear advocated. Keywords: POEMS, Plasma Cell Dyscrasia, Osteosclerosis, Neuropathy. Citation: Nozza A. POEMS SYNDROME: an Update. Mediterr J Hematol Infect Dis 2017, 9(1): e2017051, DOI: http://dx.doi.org/10.4084/MJHID.2017.051 Published: September 1, 2017 Received: May 26, 2017 Accepted: August 5, 2017 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Correspondence to: Andrea Nozza. E-mail: [email protected] Introduction. POEMS syndrome is a ascites and effusions, pulmonary hypertension, multisystemic disease secondary to a plasma cell Castleman' disease (CD), thrombocytosis and dyscrasia. POEMS is an acronym for a range of erythrocytosis, and increased of serum vascular distinct features [peripheral neuropathy (P), endothelial growth factor (VEGF).1,2 POEMS organomegaly (O), endocrinopathy (E) SYNDROME has also been called osteosclerotic monoclonal plasma-cells proliferative disorder myeloma, Crow-Fukase syndrome, PEP syndrome (M) and skin changes (S)], even if the diagnosis (plasma cell dyscrasia, endocrinopathy, does not require that all these symptoms are polyneuropathy), or Takatsuki syndrome. POEMS present. Furthermore, many others clinical signs syndrome is a rare disease, but it is often under- are not included in the definition of POEMS, such recognized. as sclerotic bone lesions, papilledema, edema www.mjhid.org Mediterr J Hematol Infect Dis 2017; 9; e2017051 Pag. 1 / 13 The primary clinical features of this syndrome mutations of the V-region of the Ig lambda gene is a progressive polyneuropathy with a could produce excess cytokines (primarily, VEGF) predominant motor disability. The disease is through an yet undiscovered mechanism, leading potentially fatal, and patient’s quality of life to the clinical manifestations of POEMS.8 deteriorates due to a progressive neuropathy, massive peripheral edema, pleural effusion, and Diagnostic Criteria. POEMS syndrome is a rare ascites. Serious complications such as multiorgan disease, with diverse clinical manifestations, failure due to capillary leak syndrome, restrictive which lead the patient on a diagnostic “Odyssey” lung disease, and pulmonary hypertension result in across multiple specialists, without a correct and an adverse prognosis. definitive diagnosis. Moreover, the clinical Despite its seriousness, at present no guidelines features of POEMS widely differ from patient to or standardized criteria for the diagnosis and patient, and all symptoms are not always present. treatment of POEMS syndrome are available. This Therefore, patients may experience a delay in the narrative review provides an update of the current initiation of appropriate treatment. evidence on this condition. Literature research was Early diagnosis is critical to reduce the last updated in May 2017. morbidity rate and increase survival. However, the median time from onset of diagnosis is 13-18 Pathogenesis. Although significant progress has months.9 achieved in the diagnosis, management, and Diagnostic criteria for POEMS were first treatment of POEMS syndrome, its proposed in 200310 and were revised in 2007 after physiopathology remains unknown. Up-regulation the diagnostic relevance of VEGF level was of various pro-inflammatory cytokines and growth confirmed.11 In more details, clinical features have factors (tumor necrosis factor-alpha (TNF-alpha), been divided into mandatory criteria, major interleukin-1 (IL1), interleukin-6 (IL6) and above criteria, and minor criteria, in line with the all vascular endothelial growth factor (VEGF) play indications of The International Myeloma a crucial role in the pathogenesis of the POEMS Working Group (Table 1).12 The presence of both syndrome, contributing to vascular leak and "mandatory criteria," at least one major criteria polyneuropathy.3-5 In particular, VEGF is and at least one minor criteria are needed for the markedly elevated in POEMS patients and diagnosis of POEMS syndrome. correlates with the activity of the disease. Unfortunately, VEGF inhibition with specific Mandatory Criteria. inhibitors (e.g., bevacizumab) did not result in an Polyneuropathy. Patients in the early stage of effective treatment thus suggesting that VEGF POEMS are frequently misdiagnosed with CIDP may be only one component of a much more (chronic inflammatory demyelinating complex cytokine network.6,7 It has also been polyneuropathy), as both conditions involve the proposed that clonal B/plasma cells with genetic peripheral nerves and may present with albumin- Table 1. Diagnosis criteria for POEMS syndrome. Mandatory criteria Polineuropathy Monoclonal plasmacells disorder Major criteria Osteosclerotic or mixed sclerotic/lytic lesions Castleman’s Disease Elevated serum or plasma vascular endothelial growth factor (VEGF) Minor criteria Organomegaly (splenomegaly, hepatomegaly or lymphadenopathy Vascular volume overload (peripheral edema, ascites, pleural effusion) Endocrinopathy (adrenal, thyroid, pituitary, gonadal,parathyroid, pancreatic disorders excluding diabetess mellitus and hypothyroidism) Skin changes (Hyperpigmentation, hypertricosis, glomeruloid hemangiomata, phletora, acrocyanosis, flushing, white nails) Papilledema Thrombocytosis, Polycitemia Others signs or Clubbing, weight loss, hyperhidrosis, pulmonary hypertension/restrictive lung disease, thrombotic diathesis, symptoms diarrhea, low B12 value www.mjhid.org Mediterr J Hematol Infect Dis 2017; 9; e2017051 Pag. 2 / 13 cytologic dissociation in the cerebrospinal fluid.13 translocations were more likely to exhibit Moreover, nerve conduction studies and papilledema. electrophysiological examination can be used to distinguish POEMS from other polyneuropathies Major Criteria. with more prominent sign of axonal degeneration Bone lesions. Osteosclerotic lesions are reported and more neurogenic injury in lower limbs approximately in 95% of patients11 even if several muscles.14,15 reports from China showed a lower rate of bone Symptoms of peripheral neuropathy are usually lesions (27-41%) which may suggest ethnic particularly evident, and consist in tingling, differences. 9,21 paresthesia, and coldness; motor involvement Bone lesions could be sclerotic, lytic with follows sensory symptoms. Cranial nerves are not sclerotic rims or mixed sclerotic/lytic lesions with involved except for papilledema. Severe weakness soup-bubble appearance. Lytic lesions without is frequently reported, and patients experience an sclerotic rims are uncommon. In about half of inability to climb stairs, rise from a chair or to patients, a single bone lesion is found, while in the hold a firm grip. Over time, muscle weakness others lesions are multiple. The pelvis, spine, ribs becomes more marked than the sensory loss. and proximal extremity are the most common sites Peripheral neuropathy is due to endothelial of bone lesions. Hypercalcemia is not usually injury, caused directly or indirectly by abnormal reported at diagnosis; bone pain and fractures are activation of endothelial cells by VEGF expressed sporadic. in the nerves.5 Imaging approaches used for evaluation of bone involvement in POEMS are simple skeletal Monoclonal plasma cells proliferative disorder. radiograph and computed tomography of bone. All patients have a monoclonal protein (M-protein, (Figure 1) Bone uptake in bone scintigraphy has lambda-type chain), which can be detected either been described, although false negatives are in serum and/or urine with immunofixation tests.8 possible.22,23 Lesions have variable FDG uptake, The concentration