POEMS syndrome
(Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes)

Article written and reviewed by Dr Luca Moretti

POEMS syndrome is a rare hematologic disease characterized by a distinctive combination of polyneuropathy, organomegaly, endocrinopathies, monoclonal gammopathy, generally lambda, and skin changes.

The acronym POEMS summarizes the main clinical manifestations, Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes, but the syndrome is distinguished by multisystem involvement and the wide range of paraneoplastic manifestations that accompany it.

First described in the 1950s and more precisely defined in subsequent decades, this entity accounts for less than 1% of plasma cell dyscrasias and is among the most complex disorders to recognize and diagnose, often because of the multiplicity of symptoms and their subtle presentation.

The estimated annual incidence is below 1 case per million inhabitants, with a slight male predominance and a mean age at onset between the fifth and sixth decades of life. Despite its rarity, POEMS syndrome is receiving increasing clinical and scientific attention, both because of its distinctive pathophysiology, in which abnormal production of VEGF, Vascular Endothelial Growth Factor, plays a central role, and because of therapeutic opportunities associated with newer treatment strategies.

The clinical course is extremely variable: without early recognition and targeted treatment the prognosis may be poor, whereas timely treatment often leads to substantial regression of symptoms and improvement in quality of life.

Etiology, pathogenesis and pathophysiology

POEMS syndrome is one of the most enigmatic rare plasma cell dyscrasias, with pathophysiology combining a monoclonal plasma cell clone and a cascade of systemic paraneoplastic events. The starting point is plasma cell proliferation, almost always limited to a small tumor burden and often localized to the marrow or peripheral osteosclerotic lesions. In more than 95% of cases, these plasma cells produce a lambda monoclonal gammopathy, a feature that distinguishes POEMS from other disorders in the same family.

Although POEMS differs from classic multiple myeloma in its clinical picture and low tumor burden, cytogenetic abnormalities of the plasma cell clone have been documented, including IgH locus translocations and deletions or monosomy of chromosome 13; their pathogenetic and prognostic significance is not fully defined.

The etiology of the syndrome therefore remains largely obscure. No specific risk factors are known: there are no documented associations with viral infections, environmental toxins, autoimmune diseases or immunodeficiency states. The disease mainly affects adults in the fifth and sixth decades of life, with a slight male predominance.

From a pathogenetic standpoint, abnormal cytokine production is central. POEMS syndrome is associated with very high levels of proangiogenic and proinflammatory factors; in particular, VEGF, Vascular Endothelial Growth Factor, whose cellular source has not been definitively established, is markedly elevated in serum or plasma in most patients. VEGF plays a central role in increasing vascular permeability, pathologic neoangiogenesis and fluid leakage from intravascular compartments into interstitial tissues.
In addition to VEGF, abnormalities of molecules such as interleukin-6, TNF-α, FGF and PDGF have been found and may contribute to a chronic inflammatory microenvironment and endothelial dysfunction; however, their causal role and relationship with survival of the plasma cell clone are not fully defined.

The pathophysiology of POEMS syndrome is characterized by the often striking discrepancy between the limited extent of plasma cell proliferation and the severity of the systemic manifestations. The mechanisms of polyneuropathy are incompletely defined; demyelination, axonal damage, endoneurial edema and blood-nerve barrier abnormalities may all contribute. Organomegaly, particularly hepatosplenomegaly and lymphadenopathy, also has a multifactorial pathogenesis and cannot be explained solely by fluid retention or proliferation of lymphoid tissues.

The mechanisms of the endocrinopathies accompanying the syndrome, such as hypothyroidism, hypogonadism or diabetes mellitus, are incompletely defined and cannot generically be attributed to direct cytokine-mediated gland injury. Typical skin changes, including thickening, hyperpigmentation, multiple angiomas and erythromelalgia, are associated with pathologic neoangiogenesis, fibroblast stimulation and microcirculatory dysfunction.

Finally, generalized edema and serous cavity effusions are associated, at least in part, with VEGF-mediated increased vascular permeability; pulmonary hypertension instead has multifactorial and incompletely defined mechanisms. The multisystem and paraneoplastic nature of POEMS syndrome therefore requires an interpretive approach that goes well beyond simple marrow proliferation and takes account of the molecular and cellular dynamics that, despite a relatively small neoplastic clone, can cause severe multiorgan impairment.

Clinical manifestations

POEMS syndrome is distinguished by the abundance and variety of clinical manifestations involving numerous organs and systems, often developing subtly and progressively. The typical presentation is multisystemic, with a constellation of symptoms reflecting its paraneoplastic nature and cytokine-driven pathophysiology.

The cardinal symptom, present in almost all patients, is polyneuropathy, which is often the first sign of disease and the main cause of disability. It presents as a symmetric sensorimotor neuropathy, initially distal, predominantly affecting the lower limbs and progressively also involving the upper limbs. Symptoms include paresthesias, burning pain, hypoesthesia, muscle weakness, loss of deep tendon reflexes and, in advanced cases, marked muscle atrophy and difficulty walking.
Progression is generally slow, but functional impairment may become severe within months or a few years, leading to complete loss of independent mobility.

Another major component of the clinical picture is organomegaly, most commonly hepatosplenomegaly and generalized lymphadenopathy. Organ enlargement, often detected on physical examination or imaging, is typically asymptomatic but may cause compressive symptoms or abdominal pain when marked.

Endocrinopathies are a distinctive feature and may affect several hormonal axes. Common abnormalities include hypothyroidism, hypogonadism, which may present as amenorrhea in women and impotence or infertility in men, diabetes mellitus or glucose intolerance, adrenal insufficiency and, less often, growth or somatotropic axis disorders. Endocrine dysfunction is frequently subclinical and requires specific testing to be recognized.

The monoclonal component, generally a lambda immunoglobulin, is almost always present, although its level may be very low. The monoclonal gammopathy can be detected by serum or urine immunofixation, often without overt hypergammaglobulinemia on standard electrophoresis.

Skin manifestations are among the most suggestive features and include hyperpigmentation, skin thickening, hypertrichosis, multiple angiomas, especially cherry or glomeruloid angiomas, erythromelalgia and, less often, digital clubbing, localized scleroderma and atypical vascular manifestations.
These skin findings may precede neurologic symptoms by years or, conversely, appear in advanced stages of disease.

Another common feature, often underestimated in early stages, is generalized edema, which may manifest as peripheral edema of the lower limbs, pleural and pericardial effusions, ascites and soft-tissue thickening. These manifestations reflect the effect of VEGF on vascular permeability and represent a marker of disease activity.

Less frequent but clinically important manifestations include focal osteosclerosis, seen on radiography or CT as hyperdense lesions that are often multiple, pulmonary hypertension, ranging clinically from exertional dyspnea to overt right-sided heart failure, thrombocytosis and cachexia in advanced cases.

Because of its extraordinary heterogeneity and the variability of symptoms among patients, the clinical picture of POEMS syndrome requires a comprehensive and careful assessment, with a detailed history, complete physical examination and awareness of atypical presentations that often cause substantial diagnostic delay.

Investigations and diagnosis

Diagnosis of POEMS syndrome requires a particularly careful clinical and instrumental work-up and close attention to correlations among the different symptoms, which are often nonspecific and subtle at onset. Suspicion most commonly arises in a patient with progressive sensorimotor polyneuropathy not attributable to common causes, especially when accompanied by systemic findings such as organomegaly, edema, endocrinopathies or skin manifestations.

The first step consists of routine laboratory tests, which may show mild anemia, modest thrombocytosis or a slight increase in inflammatory markers but are often nonspecific. It is essential to search for a lambda monoclonal component using serum and urine immunofixation: in POEMS, the quantity may be very low and escape detection by standard electrophoresis, making sensitive methods necessary.

Serum VEGF measurement is crucial because it is elevated in almost all patients and constitutes an important marker of disease activity.
In parallel, assessment of endocrine function, including TSH, FT4, cortisol, glucose and sex hormones, allows recognition of dysfunction that is often subclinical but extremely frequent in the syndrome. A complete blood count, liver and kidney function tests and evaluation for coagulation abnormalities should also always be performed, both for differential diagnosis and assessment of general status.

Instrumentally, electromyography (EMG) almost invariably documents a demyelinating polyneuropathy with evidence of secondary axonal injury. Abdominal imaging, including ultrasound and CT, demonstrates organomegaly and often lymphadenopathy. Skeletal radiography, CT and magnetic resonance imaging allow identification of typical osteosclerotic lesions, a distinctive feature that may be present even without skeletal symptoms.
Cardiologic evaluation with echocardiography and chest CT is indicated in patients with respiratory symptoms or suspected pulmonary hypertension, whereas skin findings and the presence of edema or effusions should be documented on physical examination and, when necessary, evaluated further with ultrasonography.

Bone marrow biopsy shows, in most cases, a small monoclonal lambda plasma cell clone, often involving less than 10% of nucleated cells, and may reveal focal sclerosis of bone tissue.
Integration of these findings directs clinical reasoning toward POEMS syndrome while excluding alternative diagnoses such as chronic inflammatory polyneuropathies, AL amyloidosis, atypical multiple myeloma or other paraneoplastic syndromes.

Internationally accepted criteria are used for the diagnosis of POEMS syndrome, allowing this disorder to be distinguished from other plasma cell dyscrasias and other causes of multisystem polyneuropathy. The criteria are divided as follows:

• Mandatory criteria (both required):
  • Presence of an acquired polyneuropathy, typically sensorimotor, symmetric and with a subacute or chronic course.
  • Evidence of monoclonal plasma cell proliferation, almost always lambda, demonstrated by serum and/or urine immunofixation or bone marrow biopsy.
• Major criteria (at least one required):
  • Bone sclerosis, meaning single or multiple osteosclerotic lesions demonstrated by skeletal imaging;
  • Elevated serum VEGF levels, Vascular Endothelial Growth Factor;
  • Castleman disease;
• Minor criteria (at least one required):
  • Organomegaly, including hepatomegaly, splenomegaly or lymphadenopathy;
  • Generalized edema, pleural or pericardial effusions, or ascites;
  • Endocrine abnormalities, including hypogonadism, adrenal insufficiency or other documented endocrine dysfunction; isolated diabetes and thyroid abnormalities are not sufficient as a minor criterion;
  • Skin changes, including hyperpigmentation, thickening, multiple angiomas, erythromelalgia and digital clubbing;
  • Papilledema;
  • Thrombocytosis or polycythemia.

POEMS syndrome is diagnosed in the presence of both mandatory criteria, at least one major criterion and at least one minor criterion

This structure provides a rigorous and reproducible framework for assessing the patient, facilitates distinction from the principal differential diagnoses and guides the diagnostic and therapeutic pathway.

Finally, a multidisciplinary approach and consultation with referral centers are important for managing atypical presentations, reducing diagnostic errors and promoting timely targeted treatment.

Treatment and prognosis

Management of POEMS syndrome requires an individualized multidisciplinary approach because of multisystem involvement and the complexity of its pathogenetic mechanisms. The fundamental objective of therapy is control of the monoclonal plasma cell clone and reduction of VEGF levels in order to prevent disease progression and improve quality of life.

The first therapeutic distinction concerns the location and extent of disease. In patients with an isolated sclerotic bone lesion, representing a solitary plasmacytoma, and no evidence of aggressive systemic disease, the treatment of choice is targeted radiotherapy to the pathologic focus. This approach often provides durable clinical control with regression of paraneoplastic symptoms, particularly when systemic involvement is mild.

When disease is multifocal or clinically significant systemic manifestations are present, such as severe polyneuropathy, marked organomegaly, major endocrinopathies or generalized edema, systemic therapy is required.
Autologous hematopoietic stem cell transplantation is a reference option for eligible patients with systemic disease. Induction therapy may be used in patients with active disease or to improve transplant eligibility, but it is not mandatory in every case; lenalidomide plus dexamethasone is a common choice, whereas bortezomib requires caution because of neuropathy. Autologous transplantation can produce durable complete or partial remissions with significant improvement in polyneuropathy and systemic manifestations.

For patients who are not transplant candidates because of advanced age or relevant comorbidities, systemic therapies include immunomodulatory regimens, such as lenalidomide or thalidomide with corticosteroids, proteasome inhibitors such as bortezomib, and less commonly alkylating agents such as cyclophosphamide. Choice depends on disease extent, tolerability and comorbidities.
Bevacizumab is not recommended in routine POEMS practice: despite the VEGF rationale, inconsistent results, treatment failures and a possible increase in mortality have been observed.

Throughout treatment, supportive management of systemic manifestations and complications is essential: physiotherapy and neuromuscular rehabilitation for polyneuropathy, symptomatic treatment of endocrinopathies with targeted hormone replacement, monitoring and management of edema, prevention of treatment-related infections and surveillance for possible cardiovascular and respiratory complications.

The prognosis of POEMS syndrome has improved substantially over recent decades because of increased clinical awareness, highly effective therapies and better management of complications. In promptly and adequately treated disease, 5-year survival may exceed 80%, with a good probability of remission of neurologic and systemic manifestations. Prognosis nevertheless remains closely related to speed of diagnosis, extent of systemic involvement and response of the plasma cell clone to treatment.
In untreated cases or when diagnosis is delayed, disease progression may cause severe multiorgan impairment, permanent neurologic disability and a risk of fatal vascular, infectious or respiratory events.

Research is exploring new therapeutic targets, such as selective inhibitors of the bone marrow microenvironment or anticytokine agents, and the future management of POEMS syndrome is likely to become increasingly personalized through better understanding of the underlying molecular mechanisms and ever earlier diagnosis.

Complications

Because of its multisystem nature and the complexity of the pathogenetic mechanisms involved, POEMS syndrome may cause numerous complications, some of which are major causes of morbidity and mortality. Prevention, early diagnosis and prompt treatment of these complications are essential to improve prognosis and quality of life.

The most important functional complication is progression of polyneuropathy. In untreated disease or when treatment response is inadequate, neuropathy may progress to loss of independent mobility, with severe disability, risk of falls and secondary complications such as pressure ulcers, skin infections and muscle-tendon contractures.

Among systemic complications, generalized edema and serous cavity effusions, including pleural, pericardial and ascitic fluid, are particularly important and, when large, may cause respiratory failure and hemodynamic impairment.
Pulmonary hypertension is one of the most serious and feared complications: it can arise at any stage of the disease and present with progressive dyspnea, right-sided heart failure and, in advanced cases, refractory cardiac failure, sometimes leading to fatal outcomes.

Inadequately managed endocrinopathies may cause specific complications: untreated hypothyroidism worsens muscle weakness and general condition; hypogonadism contributes to loss of muscle mass and bone fragility; diabetes or glucose intolerance increases the risk of infection and vascular complications.

A distinctive and often underestimated risk is thromboembolic complications, including deep-vein thrombosis, pulmonary embolism and ischemic cerebrovascular events, promoted by thrombocytosis, endothelial dysfunction and factors related to the disease or its treatments. This risk may be accentuated by immunomodulatory therapy and requires careful surveillance.

Other complications include treatment-related opportunistic infections, especially in patients receiving corticosteroids, immunosuppressants or transplantation, and cachexia in advanced cases, related to the chronic inflammatory syndrome.

Finally, the psychological and social burden accompanying the course of the disease should not be overlooked: anxiety, depression, social isolation and loss of autonomy are additional challenges requiring specific support for both patients and families.
Early recognition and integrated management of all these complications are fundamental aspects of care for patients with POEMS syndrome and have a major impact on long-term prognosis.

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