POEMS Syndrome-Clinical Picture and Management

Artur Jurczyszyn; Magdalena Olszewska-Szopa; David Vesole

Review Article

Austin J Anat. 2022; 9(1): 1108.

POEMS Syndrome-Clinical Picture and Management

Artur Jurczyszyn¹, Magdalena Olszewska-Szopa²* and David Vesole³

¹Department of Hematology, Jagiellonian University Medical College, 31-501 Kraków, Poland

²Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland

³Hackensack University Medical Center, New Jersey Medical School, Rutgers University, Hackensack, NJ, USA

*Corresponding author: Magdalena Olszewska-Szopa, Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland

Received: September 27, 2022; Accepted: October 26, 2022; Published: November 02, 2022

Introduction

The term ‘POEMS syndrome’ was created in 1980 [1]. The acronym derived from words: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes, does not cover the variety of symptoms that can be observed in this disease.

Keywords: POEMS, plasma cell dyscrasia, therapy

Pathophysiology and Epidemiology

One of the most important factors in POEMS mechanism seems to be overproduction of pro inflammatory cytokines eg. Vascular Endothelial Growth Factor (VEGF), tumor necrosis factor-a (TNF- -a) and interleukin -6 (IL-6). High levels of these cytokines are responsible for symptoms like edema and effusions in the mechanism of endothelial permeability increase. The disease is actually considered a paraneoplastic phenomenon secondary to plasma cell dyscrasia [2]. Little is known about cytogenetic aspect of the disease. Presence of a small plasmacytic clone makes research problematic [3]. Chen at al analyzed the genetic profile of bone marrow cells in 42 POEMS patients, finding high mutational heterogeneity [4]. In an earlier publication by Nagao et al., based on the molecular analysis of 20 patients, the authors suggested a distinct genetic POEMS plasma cells profile from MGUS and MM cells [5]. The differences in the clinical characteristics of the studied patients and the diagnostic methods do not allow for easy comparison of the two above-mentioned reports.

Although the exact incidence and prevalence is unknown, POEMS is declared to be a rare condition. The first and major challenge in making the diagnosis is coming up with an idea that POEMS might be the explanation of patients problems.

Diagnostic criteria are listed in Table 1.

Table 1: POEMS syndrome diagnostic criteria according to Barwick, 1980 [1].




  
    MANDATORY

      (both required)
    
      Clonal plasma cell dyscrasia
      Polyneuropathy
    
       
  
  
    MAJOR

      (1 of 3 required)
    
      Castleman disease
      VEGF elevation
      Osteosclerotic lesions
    
       
  
  
    MINOR

      (1 of 6 required)
    
      Organomegaly: spleno/hepatomegaly,    lymphadenopathy
      EndocrinoptahyA
      Extravascular volume overload: oedema, pleural    effusion, ascites
      Skin changes: hyperpigmentation,hypertrichosis,    glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails
      Papilledema
      Polycythemia/Thrombocytosis
    
  
  
    A: Diabetes mellitus or thyroid abnormality    alone-does not fulfill minor criterion, VEGF: Vascular Endothelial Growth Factor.



Table 1: POEMS syndrome diagnostic criteria according to Barwick, 1980 [1].

Mandatory Criteria

Monoclonal Plasma Cell Disorder (PCD) detection is essential for crucial role of monoclonal plasma cells in the disease pathophysiology. Plasma Cell Myeloma (PCM) or Waldenstrom Macroglobulinemia are revealed occasionally, although the criteria for these diseases are not fulfilled in many cases. Blood and/or urine tests should reveal monoclonal protein presence. Trephine biopsy, more sensitive than bone marrow smear, shows plasma cells in two thirds of patients, at least 95% of which are lambda restricted [6,7]. The average plasma cell percentage does not exceed 5% [2].

Another mandatory criterion is peripheral neuropathy. Ascending symmetric sensory or less often motor symptoms usually occur primarily in distal parts of extremities. They might not be prominent. If POEMS is suspected, whereas neuropathy symptoms are not evident, neurological tests should be conducted. Electromyography reveals an abated nerve conduction, delayed distal latencies and compound muscle action potential [8]. Nerve biopsy, rarely performed, shows demyelination, often with axonal loss, and uncompacted myelin lamellae [9]. The mechanism of POEMS neuropathy is still not well understood though some assumptions about potential mechanisms were published [10].

Major Criteria

Castleman disease. POEMS associated multicentric Castleman disease (POEMS associated MCD -multicentric disease) is distinguished from other MCDs [11]. Histologically often mixed or plasmacytic variant are observed. Castleman variant of POEMS is characterized by a milder neuropathy than in typical form of the disease [12].

VEGF is a sensitive and specific marker in POEMS diagnosis [13]. Although probably not a driving force in POEMS, VEGF is considered the best prognostic marker [14]. The growth of VEGF correlates best with the activity of the disease [15]. This cytokine affects endothelial cells which lead to an increase in its permeability [2]. It is worth mentioning serum levels are 10-50 times higher than plasma levels [16]. When assessing VEGF level one should be aware of the fact, that corticosteroid therapy might profoundly lower the result [2]. Other cytokines, eg Il-12, Il-6, IL-1β, have been shown to play a role in POEMS pathogenesis [2,17]. A correlation between Il- 12 level and disease activity was also observed [18].

Novel markers for POEMS have been reported in recent years. Wang et al, in 2014, proposed N-terminal propeptide of type I collagen (P1NP)[19]. In 2020 Isshiki et al described osteopontin, encoded by SPP1 gene, elevation in POEMS patients [20].

Osteosclerotic lesions are revealed in 95% patients in plain radiological tests. However additional presence of osteolysis is often observed. In more than 50% cases the lesions are numerous [8]. Variable fluorodeoxyglucose uptake is seen in PET-CT [21,22], however PET-CT and low dose CT give the benefit of visualizing possible organomegaly and as cites [2].

Minor Criteria

Skinchanges. A wide range of abnormalities are considered POEMS syndrome connected: hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, clubbing, white nails. Even in normal appearing skin biopsy might reveal vascular abnormalities in histopathological examination [23].

Extravascular overload. Peripheral oedemas are most characteristic, but fluid might accumulate in peritoneum, pleura and pericardium.

Endocrine disturbances apply to thyroid, parathyroid, adrenal functioning, diabetes mellitus and hypogonadism. Thyroid function abnormalities and diabetes mellitus due to its high prevalence cannot be considered criteria for POEMS [2]. Gonadal axis abnormalities are most commonly observed endocrine symptoms [2,24].

Papilledema. Elevated cytokine production leads to increased vascular permeability and optic disc swelling. On the basis of 94 patients analysis Cui et al considered papilledema an independent negative prognostic factor in POEMS [25].

Organomegaly. Hepatomegalyas well as splenomegaly might be present. Lymphadenopathy, usually mild, may be a part of Castleman disease [26].

Polycythemia/Thrombocytosis. Increased number of platelets and/or hemoglobin level is describeda common laboratory feature in POEMS syndrome. However 26% POEMS patients were anemicin Li study [27].

Diagnostic and clinical features with differences in frequencies given by distinct authors are listed in Table 2.

Table 2: Clinical and laboratory features in POEMS. Differences in frequencies given by distinct authors.




  
    Feature
    Dispenzieri

      2019[12]
    Zhao

      2019[48]
    Wang

      2017[70]
    Jurczyszyn

      2022[46]
  
  
    Number of patients
    metaanalysis
    347
    362
    108
  
  
    Age
    -
    >50 y - 40%
    >50y -40%
    median age 51
  
  
    Male sex (%)
    -
    65,7
    62
    72
  
  
    Polycythemia (%)
    12-19
     
    15
     
  
  
    Thrombocytosis (%)
    54-88
     
    51
    38
  
  
    M protein on serum electrophoresis
    24-54
     
     
     
  
  
    BMPC >10% (%)
    -
    3,7
    3
     
  
  
    Castleman disease (%)
    11-25
    61,5
    64
    23
  
  
    Splenomegaly (%)

      Hepatomegaly (%)

      Lymphadenopathy (%)
    22-70

      24-78

      26-74
    59

      38

      64
    67

      47

      65
    44

      47

      46
  
  
    Any endocrinopathy (%)

      Gonadal axis abnonrmalities
    67-84

      55-89
     
    >68
    58

      31
  
  
    Bone lesions present (%)
    27-97
     
    =>55
     
  
  
    Skin lesions (%)
    68-89
     
    >87
    69
  
  
    Extravascular volume overload (%)
    29-87
    84
    >87
    62
  
  
    Papilledema
    29-64
     
     
    39
  
  
    Weight loss (%)
    37
     
     
    50
  
  
    Fatigue (%)
    31
     
     
    67
  
  
    BMPC: Bone Marrow Plasma Cell Percentage



Table 2: Clinical and laboratory features in POEMS. Differences in frequencies given by distinct authors.

In more than 90% patients creatinine level is within normal limits and significant proteinuria is present in less than 10% cases. But cystatin-C is elevated in 71% patients [2]. Pulmonary involvement may vary in severity in POEMS: restrictive lung disease, pulmonary hypertension, reduced diffusion capacity of carbon monoxide. Pulmonary hypertension was diagnosed in 25 [28] to 27% [29] POEMS patients.

Thrombotic Complications

Based on small studies arterial and venous thrombosis is claimed to appear in 20% of POEMS patients [12]. Therapy regimens used in POEMS, adapted from plasma cell myeloma, such as immunomodulating drugs have prothrombotic effect [2]. However, thrombotic risk in myeloma seems to be lower than in POEMS [30]. Sayar et al analyzed retrospectively data from 83 patients from UK POEMS registry. They revealed that 30% of POEMS cohort experienced arterial and/or venous thrombotic event. According to their observations arterial thrombosis was more common than venous (16 vs 18 cases respectively), and the highest risk period preceded therapy beginning [31]. Based on these results University College London Hospitals (UCLH) recommend concurrently prophylactic LMWH and single antiplatelet drug until serum VEGF drops below 1000 pg/mL. If immunomodulating agent is used USLH advises to maintain prophylactic LMWH [31]. Mellors et al analyzed retrospectively the data of 230 POEMS patients. The rate of thrombotic complications was 27% and, as in the report by Sayar et al, the predominance of arterial thrombosis was observed. Among the risk factors for arterial thrombosis, the authors mentioned thrombocytosis, high hematocrit, extravascular volume overload and splenomegaly, and for venous thrombosis hyperprolactinemia only. Recurrent disease was observed in 21% of thrombotic patients [32].

Feng et al analyzed retrospectively 510 POEMS patients. Up to 8% of them suffered from Ischemic Stroke (IS), which occurred mainly within the first three months after the diagnosis. Furthermore recurrent IS were documented in 37% of ischemic patients, but not in those in haematological remission [33]. Mellors at al reported similar IS rates (7%) [32].

Prognosis and Risk Factors

The number of clinical features present at diagnosis does not determine survival in POEMS [8].

Kourelis et al based on the retrospective analysis of 291 POEMS patients, determined younger age (RR 0.98 [0.96-1.00]), albumin greater than 3.2 g/dL (RR 0.5 [0.32-0.89]) and attainment ofcomplete hematologic response (RR 0.4 [0.2-0.9]) good prognostic factors. These parameters affect RR (relapse rate) and OS (overall survival) [39].

According to Yang observations based on 383 POEMS cases retrospective analysis, baseline hypothyroidism is an independent prognostic factor for OS (82.8 vs. 92.8%) and PFS (68.9 vs. 82.5%) [40].

Extravascular volume overload [8], pulmonary disorders [41] and ischemic complications [Feng et al] are associated with unfavorable prognosis in POEMS.

Castleman disease presence might negatively influence OS in POEMS patients [2, 31].

Prognostic factors of potential value are listed in Table 3.

MANDATORY (both required)	Clonal plasma cell dyscrasia Polyneuropathy
MAJOR (1 of 3 required)	Castleman disease VEGF elevation Osteosclerotic lesions
MINOR (1 of 6 required)	Organomegaly: spleno/hepatomegaly, lymphadenopathy EndocrinoptahyA Extravascular volume overload: oedema, pleural effusion, ascites Skin changes: hyperpigmentation,hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails Papilledema Polycythemia/Thrombocytosis
A: Diabetes mellitus or thyroid abnormality alone-does not fulfill minor criterion, VEGF: Vascular Endothelial Growth Factor.

Negative prognostic factor	author	Positive prognostic factor	author
Age >50	Wang 2017[70]	Complete hematological response	Kourelis 2016[34]
Pleural effusion	Wang 2017[70]	Albumin >=3,2 g/dl	Kourelis 2016[34]
eGFR < 30 mL/min/1.73 m2	Wang 2017[70]	Low VEGF level	Scarlato 2005[10]
Pulmonary hypertension	Wang 2017[70]
Ischemic stroke	Feng 2020[33]; Fu 2017[71]
Thrombosis	Mellors 2022[32]
Early relapse	Kourelis 2016[34]
Baseline hypothyroidism	Yang 2020[72]
Castleman disease presence	Dispenzieri 2019[12] Li 2011[27]
Papilledema	Cui 2014[25]
eGFR: Glomerular Filtration Rate; VEGF: Vascular Endothelial Cell Growth Factor.

feature/aspect	Complete response	Improvement	Progression
Heamotologic	Negative: immunofixation of blood and urine; bone marrow assesment	= 50% M-spike reduction	= 25% M-spike increase from the lowest level (at least 0,5 g/dl)
VEGF	Negative	= 50% reduction	= 50% increase from the lowest level
PET-CT	Negative	= 50% reduction in uptake value	= 30% increase in uptake value
2021 Update on diagnosis, risk-stratification, and management [2]. M-spike - monoclonal protein spike; VEGF - vascular endothelial growth factor; PET-CT-positron emission tomography - computed tomography

POEMS Syndrome-Clinical Picture and Management

Introduction

Pathophysiology and Epidemiology

Mandatory Criteria

Major Criteria

Minor Criteria

Thrombotic Complications

Prognosis and Risk Factors

Therapy

Limited Stage Disease

Advanced Disease

Future Therapies

Response Criteria and Monitoring

References