Background
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare multisystemic disease that occurs in the setting of a plasma cell dyscrasia. [1] 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.
Described first by Crow in 1956 and then by Fukase in 1968, the syndrome was given the name 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 on the basis of the aforementioned five main features of the disease.
Although no specific case definition has been established for POEMS syndrome, it has generally been agreed that patients with the syndrome should have three or more of the five main features.
In another approach to establishing the diagnosis, it was proposed that the presence of two major criteria (monoclonal plasma-proliferative disorder and polyneuropathy) along with at least one of seven minor criteria (sclerotic bone lesions, Castleman disease, organomegaly, edema, endocrinopathy, skin changes, and papilledema) is sufficient for diagnosis. [2] However, the findings of a retrospective analysis of 629 patients suggested 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. [3, 4]
A refinement of this approach specified that three of five major criteria (the two mandatory ones and one of the three nonmandatory ones) plus at least one of six minor criteria are required. [5] The major criteria are as follows:
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Polyneuropathy, typically demyelinating (mandatory)
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Monoclonal plasma cell-proliferative disorder (mandatory)
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Castleman disease
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Sclerotic bone lesions
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Vascular endothelial growth factor (VEGF) elevation
The minor criteria are as follows [5] :
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Organomegaly (splenomegaly, hepatomegaly, lymphadenopathy)
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Extravascular volume overload (edema, pleural effusion, ascites)
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Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)
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Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails)
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Papilledema
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Thrombocytosis/polycythemia
The polyneuropathy associated with POEMS syndrome is bilateral and symmetric. 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. [6]
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, and both may be associated with glomeruloid hemangioma. [7] 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 one 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 this 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)-γ and immunoglobulin G (IgG)-γ light chains. In a case report of one patient with POEMS syndrome, [8] 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 case of POEMS syndrome in association with Waldenström macroglobulinemia, [9] characterized by immunoglobulin M (IgM)-κ paraproteinemia, has been reported.
Classic multiple myeloma has not been associated with the disease. This plasma cell disorder has not been shown to be correlated with the constellation of symptoms noted in patients with POEMS syndrome.
POEMS syndrome has been associated with multiple dermatologic changes, the most common of which are hyperpigmentation, skin thickening, sclerodermoid changes, and hypertrichosis. Whitening of the proximal nail (Terry nails), peripheral edema, hyperhidrosis, clubbing of the fingers, Raynaud phenomenon, and angiomas have also been observed.
Additional signs and symptoms associated with POEMS syndrome include papilledema, anasarca, pleural effusions, ascites, fever, thrombosis, renal insufficiency, and diarrhea.
Pathophysiology
The pathophysiology of POEMS syndrome has not been well defined. It is known that in all patients, a plasma cell disorder underlies the development of the syndrome; however, the mechanism by which this occurs is not known. Elevations of cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, have been noted.
In addition, significant elevations in vascular endothelial growth factor (VEGF) levels have been noted. Increased VEGF levels have been postulated to lead to enhanced vascular permeability, resulting in 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. [10] 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 report of two patients who received high-dose therapy (HDT) with autologous stem cell transplantation. [11] In a study by Kastritis et al, [12] decreasing VEGF levels corresponded with both clinical improvement and 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-1β, IL-6, and TNF-α), in addition to the electrophysiologic reduction of sensory nerve action potentials and the histopathologic loss of myelinated fibers. [13] Serum levels of epidermal growth factor (EGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) have not been found to be increased in patients with POEMS syndrome.
The association of POEMS syndrome with Castleman disease and angioma formation led some to propose a role for human herpesvirus 8 (HHV-8); however, early studies did not confirm this role.
Etiology
All cases of POEMS syndrome are associated with a plasma cell disorder. The syndrome has been seen in association with osteosclerotic myeloma, monoclonal gammopathy of unknown significance, and Waldenström macroglobulinemia, but not with classic multiple myeloma. It is not clear why plasma cells in some dyscrasias produce factors that cause POEMS syndrome and those in others do not. The mechanism by which plasma cells lead to POEMS syndrome is not understood; however, elevations in IL-1β, IL-6, TNF-α, and VEGF levels have been implicated.
Epidemiology
POEMS syndrome is rare, with several hundred cases described in the literature; however, the incidence may be underreported because the syndrome may go unrecognized.
The onset of POEMS syndrome occurs most frequently in the fifth or sixth decade of life (mean age at onset, 48 y for men and 59 y for women). In 2007 and 2008, however, POEMS syndrome was reported to occur in two 15-year old patients. [14, 15] POEMS syndrome is slightly more prevalent among men than women, with a male-to-female ratio of 2.5:1. No specific racial association has been identified, though a preponderance of cases have been reported in the Japanese literature.
Prognosis
The prognosis depends on the extent of the underlying plasma cell disorder and its response to treatment. The prognosis is best for patients with a single lytic lesion, worst for those with a plasma cell disorder involving the bone marrow, [16] and intermediate for those with multiple lytic bone lesions. When the plasma cell disorder responds to treatment, all other symptoms usually improve or resolve completely. The morbidity associated with POEMS syndrome depends on the systems involved and can range from skin pigment alteration to debilitating weakness and loss of function.
The natural course of POEMS syndrome is chronic, with a reported median survival of approximately a decade (8-13.8 y). Miralles et al reported a 5-year survival rate of 60%. [17] Cardiorespiratory failure, renal failure, infection, and progressive inanition are among the most common causes of death. Overall shorter survival has been associated with extravascular volume overload (eg, effusions, edema, or ascites) and fingernail clubbing. Reduced survival times have been associated with the presence of cough, and in one study, respiratory weakness decreased the mean survival time from 139 months to 87 months. [18]
In a study (N = 49) of known deaths from POEMS syndrome at the Mayo Clinic during the period 2000-2022, Lee et al described a "capillary leak phenotype" (characterized by refractory ascites, effusions, and/or anasarca that ultimately resulted in hypotension, renal failure and cardiopulmonary arrest) that was found to be the cause of 19 of the 49 deaths (39%). [19]
Central and peripheral nervous system involvement can lead to significant morbidity and mortality. [20, 21, 22, 23] The neurologic sequelae of POEMS syndrome cause approximately 50% of patients with POEMS syndrome to become bedridden. Death may also occur as a consequence of decubitus ulcers and thromboses due to inactivity, organomegaly, and endocrinopathy, rather than as a consequence of the aggressiveness of the monoclonal protein.
