The diagnosis of<unk>  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. These criteria are: * Mandatory major criteria * Plasma cell dyscrasia: This is evidenced by 1) the presence of a serum myeloma protein, typically an IgG or IgA isotype (occurs in nearly 100% of cases; in >95% of instances the myeloma proteins contain a λ chain that is restricted to either of two V lambda 1 subfamily members viz., IGLV1-40*01 and IGLV1-44*01 (see V lambda family); 2) any, but often a small, increase above the normal value of <1.5% in the percentage of nucleated bone marrow cells that are clonal plasma cells (occurs ~67% of cases); and/or 3) presence of a plasma cell tumor (i.e. plasmacytoma) usually in bone (occurs in ~33% of cases). * Polyneuropathy: The nerve damage is usually symmetrical, located in distal extremities, and due to the nerve losing its fatty myelin coating and axonal damage. Neurons of the Sensory, motor and autonomic nervous systems are all affected. The typical symptoms are therefore numbness, tingling, and weakness in the feet, later affecting the legs and hands. Pain is unusual, but the weakness may eventually become severe and disabling. The autonomic neuropathy may cause excessive sweating and erectile dysfunction; hormonal changes may also contribute to the latter. It is usually the symptoms of neuropathy which prompt a person with<unk>  to seek medical attention. * Other major criteria * Castleman disease: The lymphoproliferative disorder Castleman disease associated with<unk>  is multicentric and occurs in ~15 of cases. It is characterized by a morphology in lymph nodes termed angiofollicular lymph node hyperplasia; an overly activate immune system; excessive production of cytokines including particularly IL-6 and to lesser extents, proliferation of immune B cells and T cells, enlarged lymph nodes, enlarged liver and spleen, capillary leak<unk> , anasarca, evidence of extravascular fluid overload, and organ failure. Patients with Castleman disease without a plasma cell dyscrasia and peripheral neuropathy but having other signs and symptoms of<unk>  can be classified as a Castleman disease variant of<unk> . * Sclerotic bone lesions: These lesions consist of plasma cell tumors encased within or associated with abnormally dense bone structures; in different studies, they have been observed to occur in 27% to 97% of cases. * Elevated VEGF: VEGF is a cytokine that stimulates angiogenesis (i.e. capillary formation), increases capillary permeability, and contributes to polyneuropathy. It is elevated in almost all cases of<unk>  and has become a clinically useful marker for the<unk> 's presence, severity, and response to treatment. However, its role in mediating the symptoms of this disease are unclear. A second cytokine, IL-12, is similar to VEGF in being highly correlated with the disease activity level in<unk> . * Minor criteria * Organomegaly: Enlargement spleen, liver, and/or lymph nodes occurs in 45% to 85% of cases. * Extravascular volume overload: Ascites, pleural effusions, pericardial effusions, and/or lower extremity edema occur in 27% to 89% of cases. * Endocrinopathy: Gynecomastia occurs in 12% to 18% of cases; endocrine abnormalities involving the regulation of gonadotrophins, adrenal gland corticosteroids, and prolactin occur in 55% to 89%, 16% to 33%, and 55 to 20% of cases, respectively. Diabetes and hypothyroidism also occur in 3% to 36% and 9% to 67%, respectively, of cases but are not considered to be criteria for the presence of<unk>  because of their frequent occurrence in the general population. * Skin changes: Skin changes occur in 68% to 89% of<unk>  patients. These changes most commonly are hyperpigmentation and/or hypertrichosis (abnormal amount of hair growth over the body) but less commonly include glomeruloid hemangioma, signs or symptoms of Hypervolemia (e.g. edema and ascites), acrocyanosis (blue discoloration of the extremities due to blood flow abnormalities), flushing, and/or white nails. * Papilledema: Papilledema (swelling of retinal optical discs) occurs in 29% to 64% of cases. Papilledema in<unk>  patients may occur with or without visual disturbances, increased intracranial pressure, or changes in cerebral spinal fluid protein levels. * Thrombocytosis/polycythemia: Thrombocytosis (increase in blood platelet count) and polycythemia (increase in red blood cells) occurs 54% to 88% and 12% to 19%, respectively, of<unk>  patients and may be may underlying causes of these patients to experience thrombosis events. Laboratory findings In addition to tests corresponding to the above findings (such as EMG for neuropathy, CT scan, bone marrow biopsy to detect clonal plasma cells, plasma or serum protein electrophoresis to myeloma proteins, other tests can give abnormal results supporting the diagnosis of<unk> . These included raised blood levels of VEGF, thrombocytes, and/or erythrocyte parameters. Differential diagnosis Patients diagnosed as having Castleman disease but also exhibiting many of the symptoms and signs of<unk>  but lacking evidence of a peripheral neuropathy and/or clonal plasma cells should not be diagnosed as having<unk> . They are better classified as having Castleman disease variant of<unk> . These patients may exhibit high blood levels of the interleukin-6 cytokine and have an inferior overall survival compared to<unk>  patients. Treatment of patients with this<unk>  variant who have evidence of bone lesions and/or myeloma proteins are the same as those for<unk>  patients. In the absence of these features, treatment with rituximab, a monoclonal antibody preparation directed against B cells bearing the CD20 antigen, or siltuximab, a monoclonal antibody preparation directed against interleukin-6, may be justified.
POEMS syndrome
AL amyloidosis
Monoclonal gammopathy of undetermined significance
Waldenström macroglobulinemia
Smouldering myeloma
AA amyloidosis
Secondary systemic amyloidosis
Multiple myeloma