- Author: Joanna L Chan, MD; Chief Editor: Dirk M Elston, MD more...
Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystemic disease that occurs in the setting of a plasma cell dyscrasia. The pathophysiologic link between the constellation of symptoms and the underlying disease is not well understood, but the link may be related to changes in the levels of a cytokine or a growth factor. POEMS syndrome was first described by Crow in 1956 and then by Fukase in 1968. The syndrome was termed Crow-Fukase syndrome (by which it is known in Japan) by Nakanishi in a study of 102 cases in Japan.
In 1980, the acronym POEMS was coined by Bardwick et al based on the 5 main features of the disease, namely, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.
No specific case definition exists for POEMS syndrome; however, most authors agree that patients with POEMS syndrome should have 3 or more of the 5 features. Some authors have proposed that the presence of 2 major criteria, including a monoclonal plasma-proliferative disorder and polyneuropathy, in addition to the existence of 1 minor criterion, is sufficient for diagnosis. The suggested minor criteria include sclerotic bone lesions, organomegaly, edema, endocrinopathy, papilledema, and skin changes. However, the findings of a retrospective analysis of 629 patients using these criteria suggest that this approach may be inadequate for excluding other disease processes that may account for symptoms and that atypical presentations of POEMS may be misdiagnosed.[1, 2]
The polyneuropathy associated with POEMS syndrome is a bilateral symmetric disturbance. It involves both motor and sensory nerves, begins distally, and has a progressive proximal spread. Associated cranial or autonomic nerves are not involved. Both demyelination and axonal degeneration are noted.
The liver, the lymph nodes, and the spleen are the organs most frequently involved. Enlargement of the lymph nodes and spleen is secondary to changes consistent with Castleman disease (giant angiofollicular hyperplasia, multicentric plasma cell variant) in most patients. Approximately 15% of patients with POEMS syndrome have concomitant evidence of Castleman disease. Hepatomegaly is not associated with any defined histologic or pathophysiologic changes.
Multiple endocrinopathies have been associated with POEMS syndrome, and most patients have more than 1 endocrine abnormality. Many of the abnormalities noted can be explained by elevations in estrogen levels. Impotence and gynecomastia are common among men. Amenorrhea is common among women. Diabetes mellitus and glucose intolerance are also noted in many patients. Other associated endocrinopathies include hypothyroidism, hyperprolactinemia, and hypoparathyroidism.
POEMS syndrome is seen in the setting of a plasma cell dyscrasia. Although many plasma cell disorders have been reported in patients with POEMS syndrome, most patients are seen with osteosclerotic myeloma or monoclonal gammopathy of unknown significance.
The M proteins most frequently found are the immunoglobulin A (IgA)–gamma and immunoglobulin G (IgG)–gamma light chains. In a case report of one patient with POEMS syndrome, serum electrophoresis demonstrated an M-band with isolated IgA heavy chain but no abnormal light chain, which could suggest abnormal secretion of monoclonal protein or the rare possibility of coincidental heavy-chain disease in association with POEMS syndrome. A single case of POEMS syndrome in association with Waldenström macroglobulinemia, characterized by immunoglobulin M–kappa paraproteinemia, has been reported. Classic multiple myeloma has not been associated with the disease. The type of plasma cell disorder has not been shown to be correlated with the constellation of symptoms noted in patients with POEMS syndrome.
Multiple dermatologic changes have been associated with POEMS syndrome. The most common changes include hyperpigmentation, skin thickening, sclerodermoid changes, and hypertrichosis. Other skin changes, including whitening of the proximal nail (Terry nails), peripheral edema, hyperhidrosis, clubbing of the fingers, Raynaud phenomenon, and angiomas, have been observed.
Other signs and symptoms associated with POEMS syndrome include papilledema, anasarca, pleural effusions, ascites, fever, thrombosis, renal insufficiency, and diarrhea.
The pathophysiology of POEMS syndrome is not well understood. In all patients, a plasma cell disorder underlies the development of the syndrome; however, the mechanism by which this occurs is unknown. Elevations of cytokines, such as interleukin (IL)–1beta, IL-6, and tumor necrosis factor (TNF)–alpha, have all been noted.
Most recently, significant elevations in vascular endothelial growth factor (VEGF) levels have been noted. Increases in VEGF levels have been postulated to lead to enhanced vascular permeability, leading to the associated edema, increased endoneural pressure, and deposition of plasma cell–derived material. As myelin is exposed to serum cytokines and complement, demyelination can occur. In one case report of a patient with POEMS syndrome and bilateral cystoid macular edema, macular thickness varied with serum VEGF levels. After vitrectomy and an intraocular triamcinolone injection, decreased macular thickness was associated with lower intraocular VEGF levels. The authors proposed that elevated VEGF levels may be causally related to cystoid macular edema in persons with POEMS syndrome. Stimulated vascular proliferation has also been postulated to result in some of the skin changes associated with the disease.
VEGF may also play a role in bone metabolism, as suggested by a study of 2 patients who received high-dose therapy (HDT) with autologous stem cell transplantation. In this study by Kastritis et al, decreasing VEGF levels corresponded with both clinical improvement and the normalization of bone metabolism as measured by multiple remodeling indices.
In a study of 22 patients with POEMS, hyperalgesia was correlated with an elevation of proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), in addition to the electrophysiologic reduction of sensory nerve action potentials and the histopathologic loss of myelinated fibers. Serum levels of other growth factors, including epidermal growth factor, fibroblast growth factor, and platelet-derived growth factor, are not increased in patients with POEMS syndrome. Because POEMS syndrome is associated with Castleman disease and angioma formation, a role for human herpesvirus 8 (HHV-8) has been postulated; however, early studies have not demonstrated an association.
POEMS syndrome is rare. Several hundred cases have been described in the literature; however, the incidence may be underreported because the syndrome may go unrecognized.
No specific racial association has been identified, although a preponderance of cases have been reported in the Japanese literature.
POEMS syndrome is slightly more prevalent among men than women, with a male-to-female ratio of 2.5:1.
The onset of POEMS syndrome occurs most frequently in the fifth or sixth decade of life, with a mean patient age at onset of 48 years for men and 59 years for women. In 2007 and 2008, however, POEMS syndrome has been reported to occur in two 15-year old patients.[8, 9]
Ofran Y, Yishay O, Elinav E, Eran E. POEMS syndrome: failure of newly suggested diagnostic criteria to anticipate the development of the syndrome. Am J Hematol. 2005 Aug. 79(4):316-8. [Medline].
Morizane R, Sasamura H, Minakuchi H, Takae Y, Kikuchi H, Yoshiya N, et al. A case of atypical POEMS syndrome without polyneuropathy. Eur J Haematol. 2008 May. 80(5):452-5. [Medline].
Min JH, Hong YH, Lee KW. Electrophysiological features of patients with POEMS syndrome. Clin Neurophysiol. 2005 Apr. 116(4):965-8. [Medline].
Pavord SR, Murphy PT, Mitchell VE. POEMS syndrome and Waldenström's macroglobulinaemia. J Clin Pathol. 1996 Feb. 49(2):181-2. [Medline].
Watanabe O, Arimura K, Kitajima I, Osame M, Maruyama I. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome. Lancet. 1996 Mar 9. 347(9002):702. [Medline].
Kastritis E, Terpos E, Anagnostopoulos A, Xilouri I, Dimopoulos MA. Angiogenetic factors and biochemical markers of bone metabolism in POEMS syndrome treated with high-dose therapy and autologous stem cell support. Clin Lymphoma Myeloma. 2006 Jul. 7(1):73-6. [Medline].
Koike H, Iijima M, Mori K, Yamamoto M, Hattori N, Watanabe H, et al. Neuropathic pain correlates with myelinated fiber loss and cytokine profile in POEMS syndrome. J Neurol Neurosurg Psychiatry. 2008 Apr 3. [Medline].
Lanza C, Misericordia M, Fabrizzi G. POEMS syndrome in a 15-year-old boy: radiological findings. Pediatr Radiol. 2007 Nov. 37(11):1147-50. [Medline].
Sevketoglu E, Hatipoglu S, Ayan I, Dogan O, Salihoglu B. Case report: POEMS syndrome in childhood. J Pediatr Hematol Oncol. 2008 Mar. 30(3):235-8. [Medline].
Miralles GD, O'Fallon JR, Talley NJ. Plasma-cell dyscrasia with polyneuropathy. The spectrum of POEMS syndrome. N Engl J Med. 1992 Dec 31. 327(27):1919-23. [Medline].
Pei G, Yang D, Sun J, Luo Y, Yan J, Chen Y. Cardiac Involvement in a Patient With POEMS Syndrome Detected Using Cardiac Magnetic Resonance Imaging. Int Heart J. 2015 Sep 29. 56 (5):571-3. [Medline].
Gandhi GY, Basu R, Dispenzieri A, Basu A, Montori VM, Brennan MD. Endocrinopathy in POEMS syndrome: the Mayo Clinic experience. Mayo Clin Proc. 2007 Jul. 82(7):836-42. [Medline].
Allam JS, Kennedy CC, Aksamit TR, Dispenzieri A. Pulmonary manifestations in patients with POEMS syndrome: a retrospective review of 137 patients. Chest. 2008 Apr. 133(4):969-74. [Medline].
Garcia T, Dafer R, Hocker S, Schneck M, Barton K, Biller J. Recurrent strokes in two patients with POEMS syndrome and Castleman's disease. J Stroke Cerebrovasc Dis. 2007 Nov-Dec. 16(6):278-84. [Medline].
Wiaux C, Landau K, Borruat FX. Unusual cause of bilateral optic disc swelling: POEMS syndrome. Klin Monatsbl Augenheilkd. 2007 Apr. 224(4):334-6. [Medline].
Chong DY, Comer GM, Trobe JD. Optic disc edema, cystoid macular edema, and elevated vascular endothelial growth factor in a patient with POEMS syndrome. J Neuroophthalmol. 2007 Sep. 27(3):180-3. [Medline].
Bourgeault E, Dahl A, Thibeault MM, Dupéré A, Drolet AM, Mathieu J. POEMS Syndrome Complicated by Extensive Calciphylaxis: A Remarkable Recovery. J Cutan Med Surg. 2015 May-Jun. 19 (3):309-12. [Medline].
Hudnall SD, Chen T, Brown K, Angel T, Schwartz MR, Tyring SK. Human herpesvirus-8-positive microvenular hemangioma in POEMS syndrome. Arch Pathol Lab Med. 2003 Aug. 127(8):1034-6. [Medline].
Papo T, Soubrier M, Marcelin AG, Calvez V, Wechsler B, Huraux JM, et al. Human herpesvirus 8 infection, Castleman's disease and POEMS syndrome. Br J Haematol. 1999 Mar. 104(4):932-3. [Medline].
Obermoser G, Larcher C, Sheldon JA, Sepp N, Zelger B. Absence of human herpesvirus-8 in glomeruloid haemangiomas associated with POEMS syndrome and Castleman's disease. Br J Dermatol. 2003 Jun. 148(6):1276-8. [Medline].
Colaco SM, Miller T, Ruben BS, Fogarty PF, Fox LP. IgM-lambda paraproteinemia with associated cutaneous lymphoplasmacytic infiltrate in a patient who meets diagnostic criteria for POEMS syndrome. J Am Acad Dermatol. 2008 Apr. 58(4):671-5. [Medline].
Dao LN, Hanson CA, Dispenzieri A, Morice WG, Kurtin PJ, Hoyer JD. Bone marrow histopathology in POEMS syndrome: a distinctive combination of plasma cell, lymphoid and myeloid findings in 87 patients. Blood. 2011 Mar 8. [Medline].
Li J, Zhang W, Jiao L, Duan MH, Guan HZ, Zhu WG, et al. Combination of melphalan and dexamethasone for patients with newly diagnosed POEMS syndrome. Blood. 2011 Mar 10. [Medline].
Ganti AK, Pipinos I, Culcea E, Armitage JO, Tarantolo S. Successful hematopoietic stem-cell transplantation in multicentric Castleman disease complicated by POEMS syndrome. Am J Hematol. 2005 Jul. 79(3):206-10. [Medline].
Imai H, Kusuhara S, Nakanishi Y, Teraoka Escaño MF, Yamamoto H, Tsukahara Y, et al. A case of POEMS syndrome with cystoid macular edema. Am J Ophthalmol. 2005 Mar. 139(3):563-6. [Medline].
Giglia F, Chiapparini L, Fariselli L, Barbui T, Ciano C, Scarlato M. POEMS syndrome: relapse after successful autologous peripheral blood stem cell transplantation. Neuromuscul Disord. 2007 Dec. 17(11-12):980-2. [Medline].
Nakaseko C. Autologous stem cell transplantation for POEMS syndrome. Clin Lymphoma Myeloma Leuk. 2014 Feb. 14 (1):21-3. [Medline].
Dispenzieri A, Lacy MQ, Hayman SR, Kumar SK, Buadi F, Dingli D, et al. Peripheral blood stem cell transplant for POEMS syndrome is associated with high rates of engraftment syndrome. Eur J Haematol. 2008 May. 80(5):397-406. [Medline].
Kojima H, Katsuoka Y, Katsura Y, Suzuki S, Suzukawa K, Hasegawa Y, et al. Successful treatment of a patient with POEMS syndrome by tandem high-dose chemotherapy with autologous CD34+ purged stem cell rescue. Int J Hematol. 2006 Aug. 84(2):182-5. [Medline].
Sinisalo M, Hietaharju A, Sauranen J, Wirta O. Thalidomide in POEMS syndrome: case report. Am J Hematol. 2004 May. 76(1):66-8. [Medline].
Badros A, Porter N, Zimrin A. Bevacizumab therapy for POEMS syndrome. Blood. 2005 Aug 1. 106(3):1135. [Medline].
Dietrich PY, Duchosal MA. Bevacizumab therapy before autologous stem-cell transplantation for POEMS syndrome. Ann Oncol. 2008 Mar. 19(3):595. [Medline].
Kanai K, Kuwabara S, Misawa S, Hattori T. Failure of treatment with anti-VEGF monoclonal antibody for long-standing POEMS syndrome. Intern Med. 2007. 46(6):311-3. [Medline].
Straume O, Bergheim J, Ernst P. Bevacizumab therapy for POEMS syndrome. Blood. 2006 Jun 15. 107(12):4972-3; author reply 4973-4. [Medline].
Dispenzieri A, Klein CJ, Mauermann ML. Lenalidomide therapy in a patient with POEMS syndrome. Blood. 2007 Aug 1. 110(3):1075-6. [Medline].
Sethi S, Tageja N, Arabi H, Penumetcha R. Lenalidomide Therapy in a Rare Case of POEMS Syndrome with Kappa Restriction. South Med J. 2009 Sep 4. [Medline].
Jaccard A, Danielou-Lazareth A, Karlin L, Choquet S, Frenzel L, Garderet L. A Prospective Phase II Trial of Lenalidomide and Dexamethasone (Len-Dex) in POEMS Syndrome. Clinical Lymphoma Myeloma and Leukemia. 2015 Sep 27. 15(3):e57. [Full Text].
Sanada S, Ookawara S, Karube H, Shindo T, Goto T, Nakamichi T, et al. Marked recovery of severe renal lesions in POEMS syndrome with high-dose melphalan therapy supported by autologous blood stem cell transplantation. Am J Kidney Dis. 2006 Apr. 47(4):672-9. [Medline].
Authier FJ, Belec L, Levy Y, Lefaucheur JP, Defer GL, Degos JD, et al. All-trans-retinoic acid in POEMS syndrome. Therapeutic effect associated with decreased circulating levels of proinflammatory cytokines. Arthritis Rheum. 1996 Aug. 39(8):1423-6. [Medline].
Tang X, Shi X, Sun A, et al. Successful bortezomib-based treatment in POEMS syndrome. Eur J Haematol. 2009 Aug 6. [Medline].
Kaygusuz I, Tezcan H, Cetiner M, Kocakaya O, Uzay A, Bayik M. Bortezomib: A New Therapeutic Option for POEMS Syndrome. Eur J Haematol. 2009 Sep 3. [Medline].
Jouve P, Humbert M, Chauveheid MP, Jaïs X, Papo T. POEMS syndrome-related pulmonary hypertension is steroid-responsive. Respir Med. 2007 Feb. 101(2):353-5. [Medline].
Rached S, Athanazio RA, Dias SA Jr, Jardim C, Souza R. Systemic corticosteroids as first-line treatment in pulmonary hypertension associated with POEMS syndrome. J Bras Pneumol. 2009 Aug. 35(8):804-8. [Medline].