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{{POEMS syndrome}}
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==Overview==
== 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 [[Paraneoplastic syndrome|para-neoplastic syndrome]] characterized by multi-organ system dysfunction, [[Monoclonal antibody|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 antibody|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-1]], [[Interleukin 6|interleukin-6]], [[interleukin-12]], [[vascular endothelial growth factor]] ([[VEGF]]) and [[TNF-alpha|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]] ([[C-reactive protein|CRP]]) and [[thrombocytosis]]. The [[Mesangial cell|mesangial]] proliferation and [[membranoproliferative glomerulonephritis]] ([[MPGN]]) seen in POEMS syndrome is thought to be secondary to increased production of [[platelet-derived growth factor]] ([[Platelet-derived growth factor|PDGF]]) and [[fibroblast growth factor]] beta (FGF-β) have been implicated in [[Mesangial cell|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]] ([[Monoclonal gammopathy of undetermined significance|MGUS]]), [[pulmonary hypertension]], [[restrictive lung disease]], [[thrombophilia]], [[cardiac amyloidosis]] and [[papilledema]].


==Pathophysiology==
==Pathophysiology==
While the main features of the disease have been described, the exact mechanism of the disease has remained elusive. The paraprotein alone is insufficient to explain the multi-organ features, and various [[cytokine]]s produced by plasmacytoma cells have therefore been linked with the features of POEMS syndrome, specifically [[IL1B|interleukin 1β]], [[interleukin 6]] and [[TNFα]]. There also seems to be a role of [[vascular endothelial growth factor]], given the [[angiogenesis|angiogenetic]] changes in many tissues.<ref name=Dispenzieri />
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 [[Paraneoplastic syndrome|para-neoplastic syndrome]] characterized by multi-organ system dysfunction, [[Monoclonal antibody|monoclonal]] [[plasma cell]] proliferation and [[demyelinating]] [[inflammatory]] [[polyneuropathy]].<ref name="pmid2115264">{{cite journal |vauthors=Aggarwal S, Goulatia RK, Sood A, Prasad K, Ahuja GK, Mitchell MJ, Kumar A |title=POEMS syndrome: a rare variety of plasma cell dyscrasia |journal=AJR Am J Roentgenol |volume=155 |issue=2 |pages=339–41 |date=August 1990 |pmid=2115264 |doi=10.2214/ajr.155.2.2115264 |url=}}</ref>
 
=== Pathogenesis ===
'''Monoclonal Plasma Cell Proliferation'''
* POEMS syndrome is associated with [[plasma cell dyscrasia]] in which there is [[monoclonal]] proliferation of [[Plasma cell|plasma cells]]. The [[Plasma cell|plasma cells]] are involved in [[antibody]] production under physiological conditions via reorganization of [[immunoglobulin]] [[Heavy chains|heavy]] and [[Light chain|light chains]].
* The lambda component of [[immunoglobulin light chains]] is thought to be overproduced in POEMS syndrome secondary to [[Monoclonal antibody|monoclonal]] [[plasma cell]] proliferation.<ref name="pmid24482101">{{cite journal |vauthors=Wang C, Su W, Zhang W, Di Q, Duan MH, Ji W, Cao XX, Zhou DB, Li J |title=Serum immunoglobulin free light chain and heavy/light chain measurements in POEMS syndrome |journal=Ann. Hematol. |volume=93 |issue=7 |pages=1201–6 |date=July 2014 |pmid=24482101 |doi=10.1007/s00277-014-2019-y |url=}}</ref>
* [[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 cell|plasma cells]] leads to development of predominantly sclerotic [[bone]] lesions. This is in contrast with [[Multiple myeloma|myeloma]] patients where there is a predominance of [[lytic]] [[bone]] lesions. The bony lesions are primarily restricted to the [[Axial skeleton|axial]] and proximal appendicular skeleton.<ref name="pmid6248720">{{cite journal |vauthors=Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL |title=Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature |journal=Medicine (Baltimore) |volume=59 |issue=4 |pages=311–22 |date=July 1980 |pmid=6248720 |doi= |url=}}</ref><ref name="pmid6539431">{{cite journal |vauthors=Nakanishi T, Sobue I, Toyokura Y, Nishitani H, Kuroiwa Y, Satoyoshi E, Tsubaki T, Igata A, Ozaki Y |title=The Crow-Fukase syndrome: a study of 102 cases in Japan |journal=Neurology |volume=34 |issue=6 |pages=712–20 |date=June 1984 |pmid=6539431 |doi= |url=}}</ref><ref name="pmid7244223">{{cite journal |vauthors=Resnick D, Greenway GD, Bardwick PA, Zvaifler NJ, Gill GN, Newman DR |title=Plasma-cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes: the POEMS syndrome. Distinctive radiographic abnormalities |journal=Radiology |volume=140 |issue=1 |pages=17–22 |date=July 1981 |pmid=7244223 |doi=10.1148/radiology.140.1.7244223 |url=}}</ref>
* 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:<ref name="urlElevated levels of interleukin-1 beta (IL-1 beta) and IL-6 in serum and increased production of IL-1 beta mRNA in lymph nodes of patients with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome | Blood Journal">{{cite web |url=http://www.bloodjournal.org/content/83/9/2587.short?sso-checked=true |title=Elevated levels of interleukin-1 beta (IL-1 beta) and IL-6 in serum and increased production of IL-1 beta mRNA in lymph nodes of patients with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome &#124; Blood Journal |format= |work= |accessdate=}}</ref>
** [[Interleukin 1 beta]] ([[Interleukin 1 beta|IL-1b]])
** [[Interleukin 6]] ([[Interleukin 6|IL-6]])<ref name="pmid15719002">{{cite journal |vauthors=Mandler RN, Kerrigan DP, Smart J, Kuis W, Villiger P, Lotz M |title=Castleman's disease in POEMS syndrome with elevated interleukin-6 |journal=Cancer |volume=69 |issue=11 |pages=2697–703 |date=June 1992 |pmid=1571900 |doi= |url=}}</ref>
** [[Interleukin 12]] (IL-12)<ref name="pmid22843279">{{cite journal |vauthors=Kanai K, Sawai S, Sogawa K, Mori M, Misawa S, Shibuya K, Isose S, Fujimaki Y, Noto Y, Sekiguchi Y, Nasu S, Nakaseko C, Takano S, Yoshitomi H, Miyazaki M, Nomura F, Kuwabara S |title=Markedly upregulated serum interleukin-12 as a novel biomarker in POEMS syndrome |journal=Neurology |volume=79 |issue=6 |pages=575–82 |date=August 2012 |pmid=22843279 |doi=10.1212/WNL.0b013e318263c42b |url=}}</ref>
** [[Tumor necrosis factor alpha]] ([[Tumor necrosis factors|TNF-Alpha]])<ref name="pmid18356256">{{cite journal |vauthors=Koike H, Iijima M, Mori K, Yamamoto M, Hattori N, Watanabe H, Tanaka F, Doyu M, Sobue G |title=Neuropathic pain correlates with myelinated fibre loss and cytokine profile in POEMS syndrome |journal=J. Neurol. Neurosurg. Psychiatry |volume=79 |issue=10 |pages=1171–9 |date=October 2008 |pmid=18356256 |doi=10.1136/jnnp.2007.135681 |url=}}</ref>
** [[Vascular endothelial growth factor]] ([[Vascular endothelial growth factor|VEGF]])<ref name="pmid8596427">{{cite journal |vauthors=Watanabe O, Arimura K, Kitajima I, Osame M, Maruyama I |title=Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome |journal=Lancet |volume=347 |issue=9002 |pages=702 |date=March 1996 |pmid=8596427 |doi= |url=}}</ref>
'''Role of Interleukin-6 , Interleukin-12 and TNF-Alpha'''
* [[Interleukin 6|Interleukin- 6]] is overproduced in patients with POEMS syndrome. [[Interleukin 6|IL-6]] is a pro-inflammatory [[cytokine]] involved in maturation of [[B-cells]] into [[antibody]] producing [[Plasma cell|plasma cells]], induction of [[Acute phase reactant|acute phase reactants]] and thrombopoeisis.<ref name="pmid6799573">{{cite journal |vauthors=Yoshizaki K, Nakagawa T, Kaieda T, Muraguchi A, Yamamura Y, Kishimoto T |title=Induction of proliferation and Ig production in human B leukemic cells by anti-immunoglobulins and T cell factors |journal=J. Immunol. |volume=128 |issue=3 |pages=1296–301 |date=March 1982 |pmid=6799573 |doi= |url=}}</ref><ref name="pmid3258006">{{cite journal |vauthors=Muraguchi A, Hirano T, Tang B, Matsuda T, Horii Y, Nakajima K, Kishimoto T |title=The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells |journal=J. Exp. Med. |volume=167 |issue=2 |pages=332–44 |date=February 1988 |pmid=3258006 |pmc=2188837 |doi= |url=}}</ref><ref name="pmid2444978">{{cite journal |vauthors=Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H |title=Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue=20 |pages=7251–5 |date=October 1987 |pmid=2444978 |pmc=299269 |doi= |url=}}</ref> 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|C-Reactive protein]] ([[C-reactive protein|CRP]]) and [[thrombocytosis]].<ref name="pmid1786657">{{cite journal |vauthors=Hitoshi S, Okazawa H, Shimizu J, Suzuki K, Sakuta M |title=[A case of Crow-Fukase syndrome with increased serum interleukin-6] |language=Japanese |journal=Rinsho Shinkeigaku |volume=31 |issue=7 |pages=730–3 |date=July 1991 |pmid=1786657 |doi= |url=}}</ref><ref name="pmid1571900">{{cite journal |vauthors=Mandler RN, Kerrigan DP, Smart J, Kuis W, Villiger P, Lotz M |title=Castleman's disease in POEMS syndrome with elevated interleukin-6 |journal=Cancer |volume=69 |issue=11 |pages=2697–703 |date=June 1992 |pmid=1571900 |doi= |url=}}</ref>
* [[Interleukin 1 beta|Interleukin-1 beta]] and [[interleukin-6]] both are also involved in increased production of [[VEGF]] in POEMS syndrome.<ref name="SoubrierDubost1997">{{cite journal|last1=Soubrier|first1=Martin|last2=Dubost|first2=Jean-Jacques|last3=Serre|first3=Anne Françhise|last4=Ristori|first4=Jean-Michel|last5=Sauvezie|first5=Bernard|last6=Cathebras|first6=Pascal|last7=Piette|first7=Jean-Charles|last8=Chapman|first8=Antoine|last9=Authier|first9=François-Jérôme|last10=Gherardi|first10=Romain K.|title=Growth factors in POEMS syndrome: Evidence for a marked increase in circulating vascular endothelial growth factor|journal=Arthritis & Rheumatism|volume=40|issue=4|year=1997|pages=786–787|issn=00043591|doi=10.1002/art.1780400430}}</ref>
'''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]], [[Macrophage|macrophages]], [[Tumor cell|tumor cells]] (including [[Plasma cell|plasma cells]]) and [[Megakaryocyte|megakaryocytes]].
* [[Vascular endothelial growth factor|VEGF]]165 is the isoform of [[Vascular endothelial growth factor|VEGF]] that is overexpressed in POEMS syndrome.
* Increased [[Vascular endothelial growth factor|VEGF]] could account for the [[organomegaly]], [[edema]], [[Hemangioma|skin hemangiomata]], and possibly the occasional [[Glomerular disease|mesangioproliferative]] changes found on renal biopsy.
* Since [[VEGF]] is expressed by [[osteoblasts]] and has a role in [[Osteoblast|osteoblastic]] differentiation, the [[bone]] condensation (sclerosis) seen in POEMS syndrome may also be partly attributed to increased circulating [[VEGF]] levels.<ref name="urlVascular Endothelial Growth Factor, a Potent and Selective Angiogenic Agent">{{cite web |url=http://www.jbc.org/content/271/2/603.full |title=Vascular Endothelial Growth Factor, a Potent and Selective Angiogenic Agent |format= |work= |accessdate=}}</ref>
* The [[Mesangial cell|mesangial]] proliferation and [[membranoproliferative glomerulonephritis]] ([[MPGN]]) seen in POEMS syndrome is thought to be secondary to increased production of [[platelet-derived growth factor]] ([[Platelet-derived growth factor|PDGF]]), [[transforming growth factor beta]] ([[TGF-β]]), and [[fibroblast growth factor]] beta (FGF-β) have been implicated in [[Mesangial cell|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.<ref name="urlHarvardKey Login">{{cite web |url=https://www-sciencedirect-com.ezp-prod1.hul.harvard.edu/science/article/pii/S0272638699703860#bib21 |title=HarvardKey Login |format= |work= |accessdate=}}</ref>
'''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]] ([[Peripheral nervous system|PNS]]), which subsequently results in endoneural [[edema]]. The [[edema]] compresses the nerves and eventually leads to secondary [[Axon|axonal]] degeneration.
 
== Associated Conditions ==
POEMS syndrome is known to be associated with the following conditions:<ref name="pmid26346518">{{cite journal |vauthors=Pei G, Yang D, Sun J, Luo Y, Yan J, Chen Y |title=Cardiac Involvement in a Patient With POEMS Syndrome Detected Using Cardiac Magnetic Resonance Imaging |journal=Int Heart J |volume=56 |issue=5 |pages=571–3 |date=2015 |pmid=26346518 |doi=10.1536/ihj.15-038 |url=}}</ref>
* [[Multiple myeloma]] (osteosclerotic type)
* [[Castleman's disease]]
* P[[plasmacytoma|lasmacytoma]]
* [[Monoclonal gammopathy of undetermined significance]] ([[MGUS]]).
* [[Pulmonary hypertension]]
* [[Restrictive lung disease]]
* [[Thrombophilia]]
* [[Cardiac amyloidosis]]
* [[Papilledema]]
* Necrotizing autoimmune myopathy<ref name="pmid29088446">{{cite journal |vauthors=Gremain V, Litrowski N, Boulard C, Marguet F, Courville P, Zarnitsky C, Langlois V |title=Necrotizing autoimmune myopathy associated with POEMS syndrome report |journal=QJM |volume=111 |issue=1 |pages=49–50 |date=January 2018 |pmid=29088446 |doi=10.1093/qjmed/hcx197 |url=}}</ref>
 
== 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.<ref name="pmid475535">{{cite journal| author=Sapira JD, Williamson DL| title=How big is the normal liver? | journal=Arch Intern Med | year= 1979 | volume= 139 | issue= 9 | pages= 971-3 | pmid=475535 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=475535  }} </ref><ref name="pmid6622701">{{cite journal| author=Niederau C, Sonnenberg A, Müller JE, Erckenbrecht JF, Scholten T, Fritsch WP| title=Sonographic measurements of the normal liver, spleen, pancreas, and portal vein. | journal=Radiology | year= 1983 | volume= 149 | issue= 2 | pages= 537-40 | pmid=6622701 | doi=10.1148/radiology.149.2.6622701 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6622701  }} </ref>
[[Image:Hepatomegaly.jpg|300px|left|thumb|''Hepatomegaly''Source:https://commons.wikimedia.org]]
<br style="clear:left">
 
== Microscopic Pathology ==
* POEMS syndrome is most often associated with [[multiple myeloma]].
* On microscopic histopathological analysis, multiple myeloma is characterized by the following:<ref name="patho">Multiple myeloma. Librepathology (2015)http://www.wikidoc.org/index.php?title=Multiple_myeloma_pathophysiology&action=edit&section=1 Accessed on September, 20th 2015</ref>
:*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:
 
<gallery>
Image:Bone marrow aspiration in multiple myeloma 0001.jpg|Bone marrow aspiration in multiple myeloma. <br> (Image courtesy of Melih Aktan M.D.)
Image:Bone marrow biopsy in multiple myeloma 0001.jpg|Bone marrow biopsy in multiple myeloma.  <br> (Image courtesy of Melih Aktan M.D.)
Image:Bone marrow in multiple myeloma 0001.jpg|Bone marrow in multiple myeloma.  <br> (Image courtesy of Melih Aktan M.D.)
Image:Bone marrow in multiple myeloma 0002.jpg|Bone marrow in multiple myeloma.  <br> (Image courtesy of Melih Aktan M.D.)
File:Multiple myeloma intermed mag.jpg|Multiple myeloma slide with intermediate magnification<ref name="patho">Multiple myeloma. Librepathology (2015)http://www.wikidoc.org/index.php?title=Multiple_myeloma_pathophysiology&action=edit&section=1 Accessed on September, 20th 2015</ref>
File:Multiple myeloma.jpg|Multiple myeloma slide with high magnification<ref name="patho">Multiple myeloma. Librepathology (2015)http://www.wikidoc.org/index.php?title=Multiple_myeloma_pathophysiology&action=edit&section=1 Accessed on September, 20th 2015</ref>
Russell bodies.jpg|Multiple myeloma slide with russell bodies<ref name="patho">Multiple myeloma. Librepathology (2015)http://www.wikidoc.org/index.php?title=Multiple_myeloma_pathophysiology&action=edit&section=1 Accessed on September, 20th 2015</ref>
</gallery>


==References==
==References==
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[[Category:Rare diseases]]
[[Category:Rare diseases]]
[[Category:Syndromes]]
[[Category:Syndromes]]
[[Category:Diseases]]
[[Category:Disease]]


[[es:Síndrome POEMS]]
[[es:Síndrome POEMS]]

Latest revision as of 06:00, 11 February 2019

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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.[1]

Pathogenesis

Monoclonal Plasma Cell Proliferation

Cytokine Storm

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

Upregulation of VEGF production

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

Associated Conditions

POEMS syndrome is known to be associated with the following conditions:[19]

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.[21][22]
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:[23]
  • 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 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 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.)

  • 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[23]

    Multiple myeloma slide with intermediate magnification[23]

  • Multiple myeloma slide with high magnification[23]

    Multiple myeloma slide with high magnification[23]

  • Multiple myeloma slide with russell bodies[23]

    Multiple myeloma slide with russell bodies[23]

References

  1. ↑ Aggarwal S, Goulatia RK, Sood A, Prasad K, Ahuja GK, Mitchell MJ, Kumar A (August 1990). "POEMS syndrome: a rare variety of plasma cell dyscrasia". AJR Am J Roentgenol. 155 (2): 339–41. doi:10.2214/ajr.155.2.2115264. PMID 2115264.
  2. ↑ Wang C, Su W, Zhang W, Di Q, Duan MH, Ji W, Cao XX, Zhou DB, Li J (July 2014). "Serum immunoglobulin free light chain and heavy/light chain measurements in POEMS syndrome". Ann. Hematol. 93 (7): 1201–6. doi:10.1007/s00277-014-2019-y. PMID 24482101.
  3. ↑ Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL (July 1980). "Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature". Medicine (Baltimore). 59 (4): 311–22. PMID 6248720.
  4. ↑ Nakanishi T, Sobue I, Toyokura Y, Nishitani H, Kuroiwa Y, Satoyoshi E, Tsubaki T, Igata A, Ozaki Y (June 1984). "The Crow-Fukase syndrome: a study of 102 cases in Japan". Neurology. 34 (6): 712–20. PMID 6539431.
  5. ↑ Resnick D, Greenway GD, Bardwick PA, Zvaifler NJ, Gill GN, Newman DR (July 1981). "Plasma-cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes: the POEMS syndrome. Distinctive radiographic abnormalities". Radiology. 140 (1): 17–22. doi:10.1148/radiology.140.1.7244223. PMID 7244223.
  6. ↑ "Elevated levels of interleukin-1 beta (IL-1 beta) and IL-6 in serum and increased production of IL-1 beta mRNA in lymph nodes of patients with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome | Blood Journal".
  7. ↑ Mandler RN, Kerrigan DP, Smart J, Kuis W, Villiger P, Lotz M (June 1992). "Castleman's disease in POEMS syndrome with elevated interleukin-6". Cancer. 69 (11): 2697–703. PMID 1571900.
  8. ↑ Kanai K, Sawai S, Sogawa K, Mori M, Misawa S, Shibuya K, Isose S, Fujimaki Y, Noto Y, Sekiguchi Y, Nasu S, Nakaseko C, Takano S, Yoshitomi H, Miyazaki M, Nomura F, Kuwabara S (August 2012). "Markedly upregulated serum interleukin-12 as a novel biomarker in POEMS syndrome". Neurology. 79 (6): 575–82. doi:10.1212/WNL.0b013e318263c42b. PMID 22843279.
  9. ↑ Koike H, Iijima M, Mori K, Yamamoto M, Hattori N, Watanabe H, Tanaka F, Doyu M, Sobue G (October 2008). "Neuropathic pain correlates with myelinated fibre loss and cytokine profile in POEMS syndrome". J. Neurol. Neurosurg. Psychiatry. 79 (10): 1171–9. doi:10.1136/jnnp.2007.135681. PMID 18356256.
  10. ↑ Watanabe O, Arimura K, Kitajima I, Osame M, Maruyama I (March 1996). "Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome". Lancet. 347 (9002): 702. PMID 8596427.
  11. ↑ Yoshizaki K, Nakagawa T, Kaieda T, Muraguchi A, Yamamura Y, Kishimoto T (March 1982). "Induction of proliferation and Ig production in human B leukemic cells by anti-immunoglobulins and T cell factors". J. Immunol. 128 (3): 1296–301. PMID 6799573.
  12. ↑ Muraguchi A, Hirano T, Tang B, Matsuda T, Horii Y, Nakajima K, Kishimoto T (February 1988). "The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells". J. Exp. Med. 167 (2): 332–44. PMC 2188837. PMID 3258006.
  13. ↑ Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H (October 1987). "Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells". Proc. Natl. Acad. Sci. U.S.A. 84 (20): 7251–5. PMC 299269. PMID 2444978.
  14. ↑ Hitoshi S, Okazawa H, Shimizu J, Suzuki K, Sakuta M (July 1991). "[A case of Crow-Fukase syndrome with increased serum interleukin-6]". Rinsho Shinkeigaku (in Japanese). 31 (7): 730–3. PMID 1786657.
  15. ↑ Mandler RN, Kerrigan DP, Smart J, Kuis W, Villiger P, Lotz M (June 1992). "Castleman's disease in POEMS syndrome with elevated interleukin-6". Cancer. 69 (11): 2697–703. PMID 1571900.
  16. ↑ Soubrier, Martin; Dubost, Jean-Jacques; Serre, Anne Françhise; Ristori, Jean-Michel; Sauvezie, Bernard; Cathebras, Pascal; Piette, Jean-Charles; Chapman, Antoine; Authier, François-Jérôme; Gherardi, Romain K. (1997). "Growth factors in POEMS syndrome: Evidence for a marked increase in circulating vascular endothelial growth factor". Arthritis & Rheumatism. 40 (4): 786–787. doi:10.1002/art.1780400430. ISSN 0004-3591.
  17. ↑ "Vascular Endothelial Growth Factor, a Potent and Selective Angiogenic Agent".
  18. ↑ "HarvardKey Login".
  19. ↑ Pei G, Yang D, Sun J, Luo Y, Yan J, Chen Y (2015). "Cardiac Involvement in a Patient With POEMS Syndrome Detected Using Cardiac Magnetic Resonance Imaging". Int Heart J. 56 (5): 571–3. doi:10.1536/ihj.15-038. PMID 26346518.
  20. ↑ Gremain V, Litrowski N, Boulard C, Marguet F, Courville P, Zarnitsky C, Langlois V (January 2018). "Necrotizing autoimmune myopathy associated with POEMS syndrome report". QJM. 111 (1): 49–50. doi:10.1093/qjmed/hcx197. PMID 29088446.
  21. ↑ Sapira JD, Williamson DL (1979). "How big is the normal liver?". Arch Intern Med. 139 (9): 971–3. PMID 475535.
  22. ↑ Niederau C, Sonnenberg A, Müller JE, Erckenbrecht JF, Scholten T, Fritsch WP (1983). "Sonographic measurements of the normal liver, spleen, pancreas, and portal vein". Radiology. 149 (2): 537–40. doi:10.1148/radiology.149.2.6622701. PMID 6622701.
  23. ↑ 23.0 23.1 23.2 23.3 Multiple myeloma. Librepathology (2015)http://www.wikidoc.org/index.php?title=Multiple_myeloma_pathophysiology&action=edit&section=1 Accessed on September, 20th 2015

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