POEMS syndrome (also termed osteosclerotic myeloma, Crow–Fukase syndrome, Takatsuki disease, or PEP syndrome) is a rare paraneoplastic syndrome caused by a clone of aberrant plasma cells. The name POEMS is an acronym for some of the disease's major signs and symptoms (polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes), as is PEP (polyneuropathy, endocrinopathy, plasma cell dyscrasia). The signs and symptoms of most neoplasms (excessive, abnormal tissue growths) are due to their mass effects (compression of surrounding tissue by the mass of the growth) caused by the invasion and destruction of tissues by the neoplasms' cells. Signs and symptoms of a cancer causing a paraneoplastic syndrome result from the release of humoral factors such as hormones, cytokines, or immunoglobulins by the syndrome's neoplastic cells and/or the response of the immune system to the neoplasm. Many of the signs and symptoms in POEMS syndrome are due at least in part to the release of an aberrant immunoglobulin, i.e. a myeloma protein, as well as certain cytokines by the malignant plasma cells. POEMS syndrome typically begins in middle age – the average age at onset is 50 – and affects up to twice as many men as women.
Signs and symptoms The signs and symptoms of POEMS syndrome are highly variable. This often leads to long delays (e.g. 13–18 months) between the onset of initial symptoms and diagnosis. In addition to the signs and symptoms indicated by the POEMS acronym, the PEST acronym is used to describe some of the other signs and symptoms of the disease. PEST stands for Papilledema, evidence of Extravascular volume overload (ascites, pleural effusion, pericardial effusion, and lower extremity edema), Sclerotic bone lesions, and Thrombocytosis/erythrocytosis (i.e. increased in blood platelets and red blood cells). Other features of the disease include a tendency toward leukocytosis, blood clot formation, abnormal lung function (restrictive lung disease, pulmonary hypertension, and impaired lung diffusion capacity), very high blood levels of the cytokine vascular endothelial growth factor (VEGF), and an overlap with the signs and symptoms of multicentric Castleman disease.
Common features The more common features of the disease are summarized in the acronym POEMS: Papilledema (swelling of the optic disc) often but not always due to increased intracranial pressure) is the most common ocular sign of POEMS syndrome, occurring in ≥29% of cases. Less frequent ocular findings include cystoid macular edema, serous macular detachment, infiltrative orbitopathy, and venous sinus thrombosis. Some features have been observed in patients with POEMS syndrome but are not yet certain to form part of the syndrome itself. These include a predisposition to forming blood clots, joint pain, cardiomyopathy (systolic dysfunction), fever, low vitamin B12 levels, and diarrhea.
Pathogenesis While the main features of this paraneoplastic disease have been described, the exact mechanism behind its development, progression, and manifestations remain elusive. Overproduction of the myeloma protein and VEGF may underlie some, but are insufficient to explain all, of the multi-organ features of the disease. It is suggested that various other cytokines produced by the clonal plasma cells, perhaps working in concert with each other as well as with VEGF and the myeloma proteins, mediate many of the features of POEMS syndrome. The other cytokines detected in, and suspected of contributing to, POEMS syndrome include interleukin 1β, interleukin 6, and TNFα. Nonetheless, it seems likely that some of these paraneoplastic factors, operating individually, make a major contribution to certain features of the disease. For example, VEGF, given its ability to stimulate blood vessel formation, would seem likely to be the major contributor to the pathologic hyper-vascularization changes seem in many tissues, such as lymph nodes, affected by POEMS syndrome.
Diagnosis The diagnosis of POEMS syndrome is based on meeting its two mandatory criteria, meeting at least one of its 3 other major criteria, and meeting at least one of its 6 minor criteria.
Mandatory criteria
Polyneuropathy
Subacute, distal, symmetrical sensorimotor neuropathy with allodynia and hyperpathia is the most frequent presentation of POEMS syndrome. Neuropathy is often the first trait, and it may be the only initial symptom. Clinical examination may show distal wasting, weakness, and sensory impairment affecting both large and small fibre sensory modalities.
Plasma cell dyscrasia
Plasma cell dyscrasias are a group of monoclonal gammopathies in which normal plasma cells in the bone marrow and soft tissues become altered. POEMS syndrome is often associated with an IgA or IgG lambda limited plasma cell dysfunction. On iliac crest biopsies, patients with POEMS syndrome often have few monoclonal plasma cells. In patients with localized illness, iliac crest biopsies may be normal. Other common findings were megakaryocyte hyperplasia and clustering, as well as unusual megakaryocyte appearances. Atypical plasma cells invade normal marrow in osteosclerotic lesions, causing sclerosis of the bony lamellae.
Major criteria
Castleman's disease
Castleman's disease (CD) is a rare heterogeneous lymph node disorder characterized by elevated interleukin-6 levels. Neuropathy can occur in CD patients with or without POEMS syndrome. CD and POEMS tend to overlap, with roughly 15–24% of POEMS syndrome patients also having CD, with the majority having hyaline vascular type.
Sclerotic bone lesions Osteosclerotic lesions have been documented in around 95% of patients. Bone lesions can be sclerotic, lytic with sclerotic rims, or a mixture of the two with a soup-bubble look. About half of the patients have a single bone lesion, whereas the other half have several lesions. The most prevalent locations for bone lesions are the pelvis, spine, ribs, and proximal extremities.
Vascular endothelial growth factor
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