POEMS syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

POEMS syndrome is an acronym, where the 'P' stands for polyneuropathy, 'O' for organomegaly (specifically of the liver and spleen), 'E' for endocrinopathy, 'M' for immunoglobulin (para-protein or M-protein) and 'S' for skin changes. POEMS syndrome is a para-neoplastic syndrome characterized by multi-organ system dysfunction, monoclonal plasma cell proliferation and demyelinating inflammatory polyneuropathy. The lambda component of immunoglobulin light chains is thought to be overproduced in POEMS syndrome secondary to monoclonal plasma cell proliferation. Bone marrow studies of patients suffering from POEMS syndrome shows lymphoid aggregates rimmed by monotypic or polytypic plasma cells. The monoclonal gammopathy or overproduction of lambda light chain stimulates the monocyte/macrophage system to produce various proinflammatory cytokines. such as interleukin-1, interleukin-6, interleukin-12, vascular endothelial growth factor (VEGF) and TNF-Alpha. Transforming growth factor beta (TGF-beta), an inhbitory cytokine is thought to be underproduced in patients suffering from POEMS syndrome leading to a storm of proinflammatory cytokines which drive the disease process. The overproduction of this IL-6 may be related to some of the clinical features seen in POEMS syndrome such as gammopathy, elevated C-Reactive protein (CRP) and thrombocytosis. The mesangial proliferation and membranoproliferative glomerulonephritis (MPGN) seen in POEMS syndrome is thought to be secondary to increased production of platelet-derived growth factor (PDGF) and fibroblast growth factor beta (FGF-β) have been implicated in mesangial cell proliferation. The neovascularization induced by VEGF leads to increased vascular permeability. Since the increased production of VEGF is unchecked due to the plasma cell dyscrasia, the consequence is an unregulated extravasation of intravascular fluid into the extravascular compartment. resulting in edema. POEMS syndrome is known to be associated multiple myeloma (osteosclerotic type), Castleman's disease, plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), pulmonary hypertension, restrictive lung disease, thrombophilia, cardiac amyloidosis and papilledema.

Pathophysiology

POEMS syndrome is an acronym, where the 'P' stands for polyneuropathy, 'O' for organomegaly, 'E' for endocrinopathy, 'M' for immunoglobulin (para-protein or M-protein) and 'S' for skin changes. POEMS syndrome is a para-neoplastic syndrome characterized by multi-organ system dysfunction, monoclonal plasma cell proliferation and demyelinating inflammatory polyneuropathy.

Pathogenesis

Monoclonal Plasma Cell Proliferation

• POEMS syndrome is associated with plasma cell dyscrasia in which there is monoclonal proliferation of plasma cells. The plasma cells are involved in antibody production under physiological conditions via reorganization of immunoglobulin heavy and light chains.
• The lambda component of immunoglobulin light chains is thought to be overproduced in POEMS syndrome secondary to monoclonal plasma cell proliferation.
• Bone marrow studies of patients suffering from POEMS syndrome shows lymphoid aggregates rimmed by monotypic or polytypic plasma cells.
• Diffuse infiltration of light chain restricted plasma cells leads to development of predominantly sclerotic bone lesions. This is in contrast with myeloma patients where there is a predominance of lytic bone lesions. The bony lesions are primarily restricted to the axial and proximal appendicular skeleton.
• The monoclonal gammopathy or overproduction of lambda light chain stimulates the monocyte/macrophage system to produce various proinflammatory cytokines.

Cytokine Storm

• The monoclonal plasma cell proliferation in POEMS syndrome is thought to play a major role in overproduction of numerous pro-angiogenic and pro-inflammatory cytokines.
• The hypercytokinetic state induced in patients of POEMS syndrome is thought to drive the disease process. The following cytokines are overproduced:
  • Interleukin 1 beta (IL-1b)
  • Interleukin 6 (IL-6)
  • Interleukin 12 (IL-12)
  • Tumor necrosis factor alpha (TNF-Alpha)
  • Vascular endothelial growth factor (VEGF)

Role of Interleukin-6 , Interleukin-12 and TNF-Alpha

• Interleukin- 6 is overproduced in patients with POEMS syndrome. IL-6 is a pro-inflammatory cytokine involved in maturation of B-cells into antibody producing plasma cells, induction of acute phase reactants and thrombopoeisis. The overproduction of this cytokine may be related to some of the clinical features seen in POEMS syndrome such as gammopathy, elevated C-Reactive protein (CRP) and thrombocytosis.
• Interleukin-1 beta and interleukin-6 both are also involved in increased production of VEGF in POEMS syndrome.

Upregulation of VEGF production

• VEGF is a pro-angiogenic cytokine that promotes neovascularization. It is thought to be overproduced in POEMS syndrome and can serve as a marker of disease activity in these patients.
• VEGF is expressed by osteoblasts, chondrocytes, macrophages, tumor cells (including plasma cells) and megakaryocytes.
• VEGF165 is the isoform of VEGF that is overexpressed in POEMS syndrome.
• Increased VEGF could account for the organomegaly, edema, skin hemangiomata, and possibly the occasional mesangioproliferative changes found on renal biopsy.
• Since VEGF is expressed by osteoblasts and has a role in osteoblastic differentiation, the bone condensation (sclerosis) seen in POEMS syndrome may also be partly attributed to increased circulating VEGF levels.
• The mesangial proliferation and membranoproliferative glomerulonephritis (MPGN) seen in POEMS syndrome is thought to be secondary to increased production of platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β), and fibroblast growth factor beta (FGF-β) have been implicated in mesangial cell proliferation. It has been suggested that FGF-β participates in the initiation, PDGF in the maintenance, and TGF-β (an inhibitory cytokine) in the resolution of the proliferation.

Neovascularization and Edema

• The neovascularization induced by VEGF leads to increased vascular permeability. Since the increased production of VEGF is unchecked due to the plasma cell dyscrasia, the consequence is an unregulated extravasation of intravascular fluid into the extravascular compartment.
• As a result, there is accumulation of fluid in the extracellular compartment and the resultant edema seen in patients of POEMS syndrome.

Alteration of Blood-Nerve Barrier and Secondary Axonal Degenration

• Unregulated neovascularization also leads to disruption of the blood-nerve barrier in the peripheral nervous system (PNS), which subsequently results in endoneural edema. The edema compresses the nerves and eventually leads to secondary axonal degeneration.

Associated Conditions

POEMS syndrome is known to be associated with the following conditions:

• Multiple myeloma (osteosclerotic type)
• Castleman's disease
• Plasmacytoma
• Monoclonal gammopathy of undetermined significance (MGUS).
• Pulmonary hypertension
• Restrictive lung disease
• Thrombophilia
• Cardiac amyloidosis
• Papilledema
• Necrotizing autoimmune myopathy

Gross Pathology

• POEMS syndrome is known to cause organomegaly, specially of the liver and spleen.
• A normal liver is less than 16 cm on ultrasound evaluation. Hepatomegaly may be found during physical examination or on imaging studies. Imaging is more accurate in determining liver size.

HepatomegalySource:https://commons.wikimedia.org

Microscopic Pathology

• POEMS syndrome is most often associated with multiple myeloma.
• On microscopic histopathological analysis, multiple myeloma is characterized by the following:

• Abundant eosinophilic cytoplasm
• Eccentrically placed nucleus
• Clock face morphology of the nucleus due to chromatin clumps around the edges
• Russell bodies which are eosinophilic, large (10-15 micrometres), homogenous immunoglobulin-containing inclusions
• Dutcher bodies which are PAS stain +ve intranuclear crystalline rods

• Shown below is a series of microscopic images seen in multiple myeloma:

• 

  Bone marrow aspiration in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)

• 

  Bone marrow biopsy in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)

• 

  Bone marrow in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)

• 

  Bone marrow in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)

• 

  Multiple myeloma slide with intermediate magnification

• 

  Multiple myeloma slide with high magnification

• 

  Multiple myeloma slide with russell bodies