POEMS syndrome

POEMS syndrome is a symptom complex that occurs in patients suffering from oncological diseases, primarily monoclonal gammapathies. The main clinical symptoms are presented in the first letters of the abbreviation in English transcription: P – polyneuropathy, O – organomegaly, E – endocrinopathy, M – the presence of M-protein in the blood, S – skin changes. The diagnosis is established on the basis of clinical and laboratory confirmation of the main components of the syndrome. The treatment is complex, includes cytostatics, immunomodulatory drugs, monoclonal antibodies. Radiation therapy and stem cell transplantation are used.

ICD 10

63.1 Polyneuropathy in neoplasms

Meaning

POEMS syndrome (Crowe-Fukaza syndrome, Takatsuki disease, Japanese systemic disease) was first described by the English physician R. Crowe in 1956. The peculiarity of pathology is the early debut of neurological symptoms, so patients usually turn to neurologists. There is no exact information about the prevalence, according to Japanese researchers, the occurrence is 0.3 per 100,000. People aged 40-60 years are more likely to suffer. No gender differences were found. Often there is a combination with Castleman’s disease.

Causes

The etiological factor remains unknown. The role of long–term persistence of viruses, namely, chronic antigenic stimulation of herpesvirus type 8, was assumed in the occurrence of the syndrome, but convincing data in favor of this theory was not obtained. There is a clear link with oncological diseases (ovarian cancer, breast cancer).

In the vast majority of cases, POEMS syndrome is associated with oncohematological pathologies, especially with paraproteinemias – osteosclerotic myeloma, Waldenstrom’s macroglobulinemia, monoclonal gammapathies of unclear etiology. Therefore, some authors regard this nosology as a manifestation of the paraneoplastic process.

Pathogenesis

The exact pathophysiological mechanisms of POEMS syndrome have not yet been sufficiently studied. In the course of studies, a correlation was found between mediators such as vascular endothelial growth factor (VEGF), interleukin-6 and tumor necrosis factor-alpha with the activity of the pathological process – the severity of hepatosplenomegaly, generalized edematous syndrome and the formation of cutaneous hemangiomas.

Neurological symptoms in the form of polyneuropathy are explained by the deposition of immune complexes in the perineurium and nerve vessels, which causes the release of pro-inflammatory cytokines, activation of the monocyte-macrophage system and penetration through the hemato-neural barrier of metalloproteinases that destroy the myelin sheath of nerve fibers.

Symptoms

The leading symptom in the clinical picture, which comes to the fore in terms of intensity and time of occurrence, is chronic progressive sensorimotor polyneuropathy of the “ascending type”. At first, there are tingling sensations, a feeling of chilliness in the legs, a decrease in tactile sensitivity. Temperature and pain sensitivity are preserved.

After a few months, muscle weakness joins with gradual atrophy, which is why gait is disturbed. Then similar symptoms develop on the upper extremities. Dermatological signs of POEMS syndrome include hyperpigmentation resembling Addison’s disease, coarsening and darkening of the hair, pronounced pallor of the nail plates, thickening and compaction of the skin.

Changes in the endocrine system are diverse, most often manifested by hypogonadism. Men have erectile dysfunction, decreased or no libido, gynecomastia, and women have menstrual cycle disorders of the type of oligo- or amenorrhea. Diabetes mellitus, hypothyroidism, and adrenal insufficiency may be diagnosed.

Approximately half of the patients have aching or dull pains, heaviness in the right and left hypochondria caused by hepatosplenomegaly. Due to increased vascular permeability and proteinuria, edematous syndrome is often found – ascites, hydrothorax, hydropericardium. Due to muscular atrophy and thinning of subcutaneous fat, patients lose weight significantly.

Complications

POEMS syndrome is characterized by a wide range of adverse effects. The most common complication is sluggish tetraparesis due to polyneuropathy, which causes restriction of active movements of the patient. The spread of the pathological process to the nerve fibers innervating the respiratory muscles can lead to respiratory arrest. Lung tissue is often affected with the development of pneumofibrosis and pulmonary hypertension.

Arterial thrombosis of various localization is diagnosed in 20% of patients. Since paraproteinemia is characterized by signs of osteolysis, patients with POEMS syndrome have a risk of pathological fractures. Due to hypogonadism, primary infertility occurs. With a prolonged course of the disease, chronic renal failure develops.

Diagnostics

There are diagnostic criteria for POEMS syndrome. To make a diagnosis, the patient must have at least three large criteria and one small one.

The big criteria include:

• Polyneuropathy
• Monoclonal plasma cell proliferation
• Sclerotic bone changes
• Increasing VEGF
• Castleman’s disease

Small criteria are:

• Organomegaly
• Endocrinopathy
• Edematous syndrome
• Skin changes
• Edema of the optic disc
• Thrombocytosis

Patients are supervised by neurologists and hematologists. During the examination, attention is paid to the atrophy of the muscles of the upper and lower extremities, the color of the skin, lymphadenopathy (sometimes generalized). The signs of edematous syndrome are determined – peripheral edema, a positive symptom of fluctuation, dulling of percussion sound and weakening of respiratory noises on the lower border of the lungs. Additional laboratory and instrumental examination is aimed at diagnosing the components of the syndrome:

• Laboratory tests. In the blood test, there is an increase in ESR, thrombocytosis, sometimes erythrocytosis and leukocytosis, in the biochemical blood test – hypoalbuminemia, hypergammaglobulinemia. In the analysis of urine, proteinuria is detected.
• Hormonal studies. It is often possible to detect a decrease in the concentration of sex hormones – androgens, estrogens, FSH, LH, less often – thyroxine and TSH. If adrenal insufficiency is suspected, a test with ACTH is performed.
• Immunochemical studies. With serum electrophoresis with immunofixation, a high M-gradient and paraprotein secretion occurs only in the late stages of the disease. The Bence-Jones protein is found in the urine. Immunohistochemical analysis reveals the expression of abnormal proteins and tumor CD markers.
• Instrumental research. On ultrasound of the abdominal organs, an increase in the liver and spleen, an effusion into the abdominal cavity is determined, on echocardiography – an effusion into the pericardial cavity. On the chest X–ray – pleural effusion, on the skull X–ray – osteolytic foci. Electromyography shows signs of demyelination and axonal degeneration (slowing down, blocking the nerve impulse).
• Histological studies. The histological picture of the bone marrow punctate usually includes nonspecific reactive changes – lymphoid hyperplasia, clusters of plasma cells, rarely – lymphoplasmophytic infiltration. A nerve biopsy reveals lymphocytic infiltration, perineurial edema.

Differential diagnosis is performed with chronic inflammatory demyelinating polyneuropathies (Guillain-Barre syndrome). POEMS syndrome should also be distinguished from multiple myeloma, amyloidosis, angiofollicular hyperplasia of lymph nodes, autoimmune polyglandular syndromes.

Treatment

Conservative therapy

All patients are subject to mandatory hospitalization in the hematology department. No specific treatment has been developed. Therapy is carried out according to general schemes, depending on the presence of certain components of the disease. There are the following conservative methods of treating POEMS syndrome:

• Chemotherapy. In case of bone marrow damage, various schemes of high-dose chemotherapy are used. Alkylating drugs (chlorambucil, cyclophosphamide), cytostatics (melphalan), antitumor antibiotics (doxorubicin) are prescribed.
• Anti-inflammatory therapy. Glucocorticosteroids (prednisone, dexamethasone) are used as part of complex chemotherapy, for pathogenetic control of polyneuropathy (suppression of inflammation) and to reduce the severity of proteinuria.
• Immunomodulatory therapy. Medications such as thalidomide, levalinomide and monoclonal antibodies effectively reduce the level of VEGF and, as a result, reduce the activity of the pathological process.
• Hormone replacement therapy. If a deficiency of a hormone is detected, a lifetime intake of hormonal medications is prescribed – L-thyroxine, hydrocortisone, fludrocortisone, oral contraceptives, etc.
• Elimination of edematous syndrome. Loop (furosemide, torasemide) and thiazide (hydrochlorothiazide) diuretics are used to remove excess extravascular fluid.
• Radiation therapy. In patients with isolated osteosclerotic foci, local radiation therapy is successfully used.

Surgical treatment

High-dose chemotherapy is often supplemented with autologous bone marrow transplantation, that is, transplantation of the patient’s own stem cells. This method avoids a large number of complications of chemotherapy (severe anemia, massive bleeding, the addition of severe bacterial, fungal or viral infections) due to a faster restoration of the hematopoietic function of the bone marrow.

Experimental treatment

Work is still underway to find an effective drug for the treatment of this syndrome. Some authors report that in some patients, against the background of tamoxifen and interferon, clinical and hematological regression of the disease was observed – a decrease in the severity of polyneuropathy and organomegaly, normalization of the level of proinflammatory cytokines.

Prognosis and prevention

POEMS-syndrome is a severe pathology with a chronic course and a high mortality rate. The average life expectancy of patients after diagnosis is 10-15 years. The main causes of death are respiratory failure due to paralysis of the respiratory muscles or pneumofibrosis, infectious complications.

Effective methods of primary prevention have not been developed. There are only recommendations to reduce the likelihood of complications of tumor treatment, for example, regular monitoring of clinical blood tests during a course of chemotherapy. The use of medications with neurotoxicity in their side effects (bortezomib) should be avoided as much as possible.

Literature

1. Dispenzieri A. POEMS Syndrome: 2019 Update on diagnosis, risk-stratification, and management. Am J Hematol. 2019;94(7):812–827. link
2. Pihan M., Lunn M., D’Sa S. et al. Raised VEGF: usefulness in the diagnosis of POEMS syndrome. J Neurol Neurosurg Psychiatry 2014;85(10):e4. link
3. Nasu S., Misawa S., Sekiguchi Y. et al. Different neurological and physiological profiles in POEMS syndrome and chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry. 2012;83(5):476–479.
4. Mauermann M.L. The Peripheral Neuropathies of POEMS Syndrome and Castleman Disease. Hematol Oncol Clin North Am. 2018;32(1):153–163. link
5. Lehmann H.C., Burke D., Kuwabara S. Chronic inflammatory demyelinating polyneuropathy: update on diagnosis, immunopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2019;90(9):981–987.