POEMS Syndrome

Synonyms: osteosclerotic myeloma, Crow-Fukase syndrome, Takatsuki syndrome.

POEMS syndrome is defined as the presence of a peripheral neuropathy, a monoclonal plasma cell disorder, and other paraneoplastic features.¹ The acronym stands for:

• P - peripheral neuropathy: the main symptom
• O - organomegaly
• E - endocrinopathy
• M - M protein (or monoclonal gammopathy)
• S - skin changes

Not all these features are required for diagnosis.

Other possible features not represented in the acronym are: sclerotic bone lesions, papilloedema, pleural effusion, oedema, ascites, thrombocytosis and Castleman's disease (giant lymph node hyperplasia).

Both major criteria and at least 1 minor criterion are required for diagnosis²:

• Major criteria
  • Polyneuropathy
  • Monoclonal plasmaproliferative disorder
• Minor criteria
  • Sclerotic bone lesions
  • Castleman's disease
  • Organomegaly (splenomegaly, hepatomegaly or lymphadenopathy)
  • Oedema (peripheral oedema, pleural effusion or ascites)
  • Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid or pancreatic - but diabetes mellitus or hypothyroidism alone are insufficient, as they are common in the general population)
  • Skin changes (hyperpigmentation, hypertrichosis, plethora, haemangiomata, white nails)
  • Papilloedema

• POEMS is probably rare (of the order of hundreds of cases are reported) but may be under-diagnosed and the incidence is unknown.
• Peak incidence is age 40-60.

The cause is unknown. Increased levels of cytokines, particularly vascular endothelial growth factor (VEGF), may play a role.

These are listed in order of the commonest at diagnosis:

• The defining symptom is a chronic peripheral neuropathy, with motor features predominating:
  • It starts in the feet with paraesthesia.
  • There is symmetrical and proximal spread.
  • Progression is usually gradual but can be rapid.
  • Respiratory muscles may be affected.
  • Some patients also have pain.
• Osteosclerotic lesions:
  • Occur in 95% of patients.
  • May be solitary or multiple; there may be mixed sclerotic and lytic lesions.
• Skin changes:
  • Hyperpigmentation and hypertrichosis are common; coarse black hair may occur on the extremities.
  • Other skin changes are: thickening, haemangiomata, plethora, clubbing, white nails.
• Endocrinopathy:⁴
  • Most commonly hypogonadism.
  • Diabetes and hypothyroidism are also common.
  • Adrenal insufficiency and hypocalcaemia can occur.
  • There may be multiple endocrine axes affected.
• Thrombocytosis.
• Organomegaly - may be:
  • Hepatomegaly.
  • Splenomegaly.
  • Lymphadenopathy.
  • Castleman's disease.
• Papilloedema:
  • Affects up to half of patients.
  • May be asymptomatic, or may cause headache and visual symptoms.
• Extravascular volume overload - pitting oedema, ascites or pleural effusions.
• Uncommon features or complications are:
  • Respiratory - pulmonary hypertension, restrictive lung disease.
  • Thrombosis - arterial or venous.
  • Renal impairment (rare).
  • Congestive cardiac failure.
  • A capillary leak-like syndrome.

Blood tests:

• Serum proteins investigations:¹
  • By definition all patients have a monoclonal plasma-proliferative disorder.
  • The monoclonal protein is typically small; it may be missed on electrophoresis unless immunofixation is done on both serum and 24-hour urine.
• VEGF levels are nearly always raised in patients with active POEMS. Other cytokine levels may be raised.
• Full blood count: there may be thrombocytosis with or without polycythaemia.
• Liver and renal function.
• A full endocrine assessment is advised if POEMS is strongly suspected.⁴

Radiology:

• Skeletal survey may show sclerotic or lytic bone lesions.
• Chest X-ray if cardiovascular/respiratory symptoms.

Other tests:

• Nerve conduction studies and electromyelography.
• ECG, echocardiogram and lung function tests for cardiorespiratory symptoms.

Biopsy:

• Biopsy of bone marrow or an osteosclerotic lesion - may show marrow monoclonal plasma cells.
• Lymph node biopsy - if lymphadenopathy; may demonstrate Castleman's disease.
• Nerve biopsies - usually reveal evidence of axonal degeneration and demyelination.

• Chronic inflammatory demyelinating polyneuropathy.
• Monoclonal gammopathy of undetermined significance with associated peripheral neuropathy.
• Multiple myeloma - may have polyneuropathy and rarely, can present with diffuse osteosclerotic bone lesions.
• Solitary plasmacytoma of bone - may have small amount of monoclonal protein in serum or urine.
• Waldenström's macroglobulinemia.

• The interconnections between POEMS syndrome, osteosclerotic myeloma, and Castleman's disease are still under investigation².
• Possible associations include pulmonary hypertension, restrictive lung disease, thrombotic diatheses, arthralgias, cardiomyopathy and low vitamin B12².

• Supportive care as required for neurological and respiratory problems - e.g. physiotherapy, occupational therapy, respiratory support or multidisciplinary care.
• Radiotherapy - if the osteosclerotic lesions are single or restricted to a limited area.
• If osteosclerotic lesions are widespread - chemotherapy or autologous stem cell transplantation.⁵. Possible treatments (from small series and case reports) are:
  • Melphalan and prednisolone.
  • Cyclophosphamide ± prednisolone.
  • Corticosteroids alone may help stabilise the disease.¹
  • High-dose chemotherapy with stem cell transplantation - though this carries significant risks.⁶
  • Lenalidomide or thalidomide. There are concerns that thalidomide also causes peripheral neuropathy and fluid retention.¹ Lenalidomide was helpful in one reported case.⁷
  • Bevacizumab therapy has been reported as beneficial in some cases^8,9 but fatal in another.¹⁰

• As an overview, POEMS is generally progressive with a chronic course. However, symptoms (including neuropathy) may remit or stabilise if they respond to treatment.
• Average survival after presentation (in one review) was nearly 14 years.
• Cardiorespiratory problems and infection were the commonest causes of death.