Dermatology

Polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome(osteosclerotic myeloma, Crowe-Fukase syndrome, Takatsuki syndrome, Plasma cell dyscrasia, endocrinopathy, polneuropathy [PEP])

Polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome( osteosclerotic myeloma, Crowe-Fukase syndrome, Takatsuki syndrome, Plasma cell dyscrasia, endocrinopathy, polneuropathy (PEP)

Are You Confident of the Diagnosis?

POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) is a paraneoplastic syndrome that is associated with an underlying plasma cell dyscrasia. It typically presents with an initially distal but progressive ascending symmetric sensory and motor neuropathy, accompanied by a variety of other systemic signs and symptoms, and laboratory abnormalities, including an increase in levels of vascular endothelial growth factor (VEGF), which parallels disease activity. Since the first reported case by Crowe in 1938 and coining of the POEMS term in 1980, additional features have been reported; thus, one should not be restricted to the acronym in assessing a patient for the possibility of POEMS. An expanded version of this acronym and additional features that characterize POEMS is listed in Table I.

What you should be alert for in the history

The clinical history should be detailed, and thorough, and should include investigation for sensorimotor abnormalities, sexual dysfunction and menstrual abnormalities, symptoms of volume overload, skin or nail changes, and respiratory dysfunction.

Peripheral neuropathy is the dominant and frequently presenting feature in patients with POEMS. The neuropathy initially presents as a sensory neuropathy with dysesthesias and sensory abnormalities, but it is later predominated by progressive motor neuropathy with substantial debilitating weakness in around half of the cases. Patients may report inability to climb stairs, rise from a chair, or grip objects. Some may be wheelchair bound. Except for erectile dysfunction, history of autonomic dysfunction is not reported.

Nearly all patients with POEMS have a lambda light chain monoclonal plasma cell proliferative disorder, although rare cases with heavy chain disease have been reported. Most patients have osteosclerotic myeloma or history of monoclonal gammopathy of undetermined significance (MGUS). Some may present with known history of a specific monoclonal gammopathy, while in others, boney lesions of osteomyeloma or other evidence of a plasma cell dyscrasia are detected during workup for POEMS in patients with neuropathy.

Castleman’s disease (angiofollicular lymph node hyperplaisa) has been reported to be associated with POEMS in 11-25% of patients, but this number may be under-represented, since POEMS-related lymphadenopathy is not always biopsied. The relationship of POEMS and Castleman’s disease (CD) is not fully understood. Although some consider multicentric CD with peripheral neuropathy to be a distinct entity, a history of CD and neuropathy, should prompt and extensive endocrinologic, dermatologic, and pulmonary evaluation to exclude POEMS.

Endocrinopathy is also central to a diagnosis of POEMS. Hypogonadism is one of the most frequently encountered endocrinologic disorders in men. This may present with complaints of erectile dysfunction or gynecomastia, or may not be apparent in the history, but is discovered as a low testosterone level during work-up for POEMS. Other endocrinologic disorders that may be extracted in the clinical history of patients with POEMS include: hypothyroidism, diabetes mellitus or abnormal glucose metabolism, hyperestrogenemia, amenorrhea, breast engorgement in women, hyperprolactinemia, and hypocalcemia. Patients may have adrenal insufficiency, but this is more often noted during work up as an abnormal response to synthetic adrenocorticotropic hormone (ACTH).

Complaints related to volume overload, especially pedal edema, are common presenting features of POEMS. The volume overload is non-cardiogenic, although some patients may have cardiomyopathy or history of congestive heart failure.

Respiratory symptoms, seen in around 28% of patients, include dyspnea, chest pain, cough, and orthopnea. Patients may present with a known history of pulmonary hypertension, pleural effusion, and/or restrictive lung disease.

Patients may report dermatologic changes, including diffuse or localized hyperpigmentation, hypertrichosis, sweating, skin tightening or thickening, Raynaud’s phenomenon, or white nail changes.

Constitutional symptoms frequently include fatigue and weight loss. Reports of diarrhea or bone pain are less common. The medical history may also include arterial or venous thromotic events or renal disease.

Characteristic findings on physical examination

The physical examination in patients suspected to have POEMS syndrome should be thorough, incorporating a complete sensory and motor neurologic evaluation, evaluation of the fundus, and assessment for organomegaly, lymphadenopathy, and volume overload, as well as a complete cardiac, pulmonary, skin and nail evaluation. The findings will vary, depending on the stage of evolution and presenting features of POEMS.

Nearly all patients will show evidence of peripheral neuropathy. Neurologic examination will reveal signs of sensory neuropathy, including impaired joint position, vibration, and touch sensation in a stocking and glove distribution. This is more prominent in the lower extremities. Loss or blunting of deep tendon reflexes is also common. There is frequently a Romberg’s sign.

Muscle weakness varies with the disease progression, and is initially more prominent in the distal muscle groups and lower extremities. Atrophy may be noted in advanced cases. Cranial nerve abnormalities are not seen, with the exception of papilledema, which is present in at least half the patients, especially if there is volume overload.

Evidence of endocrinopathy is usually detected with laboratory evaluation. Gynecomastia and testicular atrophy reflecting hypogonadism are often detected.

Dermatologic findings are seen in nearly 90% of patients with POEMS, especially hyperpigmentation, which may be localized or generalized. The hyperpigmentation may be related to underlying adrenal insufficiency. This may involve the areola. Hypertrichosis may present as coarse dark hairs on the extremities, or may be localized to chest or face. It has been reported to arise on sclerodermatous hyperpigmented areas, or may be generalized. The skin thickening may be associated with contractures, simulating scleroderma or may be localized.

One of the characteristic skin findings in POEMS is the presence of numerous small vascular papules, representing cherry angiomas and/or glomeruloid hemangiomas, the latter of which are unique to POEMS. These clinically present as multiple 0.5mm-15mm red or plum-colored dome-shaped papules on the trunk and proximal extremities (Figure 1). Lesions may be sessile or polypoid. The acquisition may be progressive or eruptive. Spontaneous resolution has been reported. Hyperhidrosis, flushing, plethora, fever, acrocyanosis, dependent rubor, and leukonychia are also frequently seen.

Organomegaly is present in up to around three quarters of patients, and hepatomegaly, splenomegaly, and lymphadenopathy are very often detectable on physical examination.

Figure 1.

Cherry angioma-like vascular lesions and glomeruloid hemangiomas in patient with POEMS syndrome. (Courtesy of Franco Rongioletti, MD)

Features of volume overload include pedal edema, ascites, and diminished breath sounds from pleural effusions.

Expected results of diagnostic studies

A diagnosis of POEMS relies heavily on the results of laboratory testing and radiologic imaging studies. Laboratory testing should include baseline nerve conduction studies, computed tomography (CT) scan, endocrinopathy workup (see bibliography), serum protein electropheresis and immunofixation, complete blood count, pulmonary function tests (PFTs), echocardiogram, skeletal radiographs or CT scan with bone windows or positron emission tomography (PET)/CT scan.

Electromyelographic and nerve conduction studies show prominent demyelination as well as axonal degeneration. A mixed picture is often seen.

Sural nerve biopsies reveal uncompacted myelin lamellae and variable degrees of chronic indolent demyelination and axonopathy. Prominent acute axonal and myelin degeneration is rare. Vascular proliferation forming tight clusters with perivascular lymphocytes are found in the epineurial and perineurial compartments. Amyloid depositions are not found. Narrowed lumina of endothelial vessels with thickened basement membranes and polyclonal immunoglobulin staining of endoneurium may be seen. There is lymphocytic inflammation with edema of the endoneurium, without vasculitis.

Plasma cell dyscrasias in POEMS are varied, and include MGUS, plasmacytoma, osteosclerotic myeloma, and mixed osteosclerotic and osteolytic myeloma. Documentation of the monoclonal plasma cellular proliferative disorder can be achieved by screening serum electrophoresis, but the size of the M-protein is small, rarely more than 3.0g/dL, with a median of 1.1g/dL; thus, in approximately 30% of cases, there is a false negative study. In these cases, immunofixation may document the M protein, which is usually IgG or IgA, and is nearly always lambda.

Bone marrow biopsies from the iliac crest may show plasmacytosis, but this is lower than that seen in multiple myeloma, usually less than 10%, ranging from around 5-10%. In around one-third of patients, the iliac bone marrow biopsy will be negative for a clonal plasma cell infiltrate, and considered “normal” or “reactive.” Common marrow findings include megakaryocyte hyperplasia and megakaryocyte clustering, changes of which may be interpreted as a myeloproliferative disorder. A helpful feature is the finding of lymphoid aggregates, rimmed by plasma cells (usually lambda).

Osteosclerotic lesions occur in nearly 95% of patients; thus, if no M spike is detected, biopsies from sclerotic bone lesions may document a clonal plasma cell population.

Skeletal imaging studies will show sclerotic or mixed lytic and sclerotic lesions. Lytic lesions often have a sclerotic rim. A mixed soap-bubble appearance has been described. Pure lytic lesions are rare. The boney lesions typically involve the spine, pelvis, ribs, and proximal extremities. These can be detected with skeletal radiograph, computerized tomography (CT), and/or bone scintigraphy, but false negative results may be seen, especially with bone scan.

Bone windows of CT imaging may be the best screening tool. Fluorodeoxyglucose positron emission tomography/computerized tomography (FDG PET/CT) has been shown to be positive in cases in which other imaging studies have been negative, but the results can be variable. This has the added advantage of documenting hypermetabolic lesions in the bone and in lymph nodes, enabling more effective selection and detection of clonal plasmacellular infitrates and Castleman’s disease (CD), respectively.

CT Imaging studies will reveal organomegaly, most commonly hepatomegaly, splenomegaly, and lymphadenopathy. Other manifestations of organomegaly have included gastric mucosa thickening, mimicking a gastric mucosal tumor.

Lymph node biopsy frequently shows CD, which is a distinct type of lymph node hyperplasia, characterized by two histomorphologic patterns. Hyaline vascular CD shows increased vascularity, numerous follicles with poorly formed germinal centers, and onion-skinning array of perivascular lymphocytes. Plasma cell type CD shows a predominance of plasma cells in the interfollicular zones, at times, with deposition of amorphous acidophilic material. There are solitary/unicentric and multicentric types. POEMS is associated with the multicentric CD. Hyaline vascular type, plasma cell type, and mixed hyaline plasma cell type may be seen.

Biopsies of hepatomegaly or splenomegaly usually show normal histology. Thickened gastric mucosa biopsies are reported to show an interstitial infiltrate of numerous plasma cells.

Vascular lesions show histologic features of cherry angioma, glomeruloid hemangioma, and/or tufted angioma. These features may all be present in a single lesion. Glomeruloid hemangiomas histologically are characterized by discrete dermal aggregates of capillaries surrounded by pericytes, residing within ectatic vascular spaces, morphologically resembling glomeruli (Figure 2, Figure 3).

Figure 2.

Glomeruloid hemangioma. In the dermis are multiple discrete lobules and tufts of small vascular channels, simulating glomeruli. Smalller tufts in the superficial dermis show clefting from the dilated vascular spaces in which they reside. (H&E, X10)

Figure 3.

Glomeruloid hemangioma. High-power view of a lobule demonstrates an intravascular conglomerate of capillaries lined by round to slightly plump endothelial cells. There are cells with abundant cytoplasm in the stroma, some of which contain eosinophilic homogenous globules. (H&E, X40)

Periodic acid-Schiff (PAS)-positive diastase-resistant globules can be seen in the cytoplasm of endothelial cells, and are felt to represent deposition of circulating immunoglobulin. Polytypic kappa and lambda staining can be demonstrated in eosinophilic globules. HHV8 staining has been reported in CD and in some cases of glomeruloid hemagioma, but this is not a universal finding.

Skin biopsies are usually non-specific. The pigmented areas show hyperpigmentation of the basal layer with a dermal chronic inflammatory infiltrate. Fibrosis has been reported, but the eccrine glands are not compressed by thickened collagen bundles typical of scleroderma. Clinically normal skin overlying nerve biopsy sites may show small clusters of vessels cuffed by lymphocytes and plasma cells. Complex subpapillary dilated and anastomosing vessels with thromboses have been described.

Abnormalities in endocrinologic function are common in patients with POEMS, and around half of these patients have evidence of multiple endocrinopathies in the four major endocrine axes (gonadal, thyroid, glucose, and adrenal). In men, total testosterone levels may be low in 79% of cases, and 96% have low free testosterone. Abnormalities in glucose metabolism, including fasting glucose levels, and diabetes requiring oral agents or insulin may be seen in 48% of cases. Elevated thyrotropin concentrations may be seen in around 58% of patients, half of whom have overt hypothyroidism, and half with mild increases in thyrotropin (>5 but <10 mIU/L; reference range, 0.3-5.0 mIU/L), often with normal free thyroxine levels, suggesting subclinical hypothyroidism.

Thyroglobin and thyroid microsomal antibody levels are not detected. An abnormal am cortisol level may be detected, but this may be normal, despite the presence of adrenal insufficiency. 67% may have an abnormal cortisol ACTH stimulation test. Hypocalcemia may be seen in 27% of patients. This may be accompanied by increased parathyroid hormone levels. Mild hyperprolactinemia may be seen in around 29% of cases. Hyperestrogenemia is also reported to occur frequently.

Hematologic evaluation will often reveal thrombocytosis (>450 x 103 / μL) and polycythemia (>15 g/dL in women, 17 g/dL in men). The erythrocyte sedimentation rate is usually normal but may be elevated. Significant cytopenias are not seen, although some with CD may have anemia.

There is a marked elevation of plasma and serum vascular endothelial growth factor (VEGF) which has been noted to correlate with disease activity and normalize with treatment response. Levels of acute pro-inflammatory cytokines (interleukin-6 (IL-6), IL-1 beta, and tumor necrosis factor (TNF) alpha) are increased, but measurement of these is predominantly for research purposes.

PFT frequently shows evidence of restrictive lung disease, impaired neuromuscular respiratory function or impaired diffuse capacity of carbon monoxide (DLCO). Chest radiographs may show pleural effusions, cardiomegaly, enlarged pulmonary vessels, elevated diaphragm, mediastinal adenopathy, or fibrosis.

Renal evaluation does not commonly show significant abnormalities. In one study, fewer than 6% of patients had serum creatinine greater than or equal to 1.5mg/dl, and fewer than 10% had evidence of proteinuria. Renal involvement may be more common in patients with CD. Renal biopsies show a variety of features, most commonly membranoproliferative changes and evidence of endothelial injury. Plasmacellular infiltration may be seen. Immunofluorescence is negative.

Cerebral spinal fluid analysis may reveal proetin, possibly with a monoclonal band.

Diagnosis confirmation

A diagnosis of POEMS can only be achieved if one is aware of the protean features with which it may present. It is important to have a through investigation of the history and physical examination, with assessment of endocrinologic status and VEGF levels. Aggressive pursuit for an underlying clone, with careful evaluation of bone marrow results and radiologic studies for boney lesions is critical.

The diagnosis may be elusive, prompting authors to propose and later modify criteria to allow one to more confidently make the diagnosis. These are outlined in Table II. According to these criteria, polyneuropathy and monoclonal plasma cell disorder must be present, plus at least one other major criterion and one minor criterion to make a diagnosis. These criteria have been challenged, as an undetectable monoclonal protein may be seen in up to 25% of cases otherwise typical of POEMS. Additionally, the M spike may clear in response to empiric steroid treatment.

Replacement of M protein with “lymphoproliferative disorder” has been suggested, allowing capture of cases of Castleman’s-associated POEMS. Rare cases, such as those without neuropathy, have been referred to as a typical POEMS. Patients with other disorders such as essential mixed cryoglobulinemia, inflammatory demyelinating polyneuropathy, and polyarteritis nodosa have erroneously qualified for a diagnosis of POEMS under the suggested criteria. Sclerotic bone lesions and lambda light chain monoclonal gammopathy appeared to be more specific to POEMS, in this series. The authors suggest exclusionary criteria such as absence of vasculitic neuronal changes, cryoglobulins, and kappa monoclonal gammopathy to avoid a misdiagnosis of POEMS in early presentations.

Screening for an M protein with serum protein electrophoresis alone is not adequate. In patients presenting with an unexplained symmetric peripheral neuropathy, especially if accompanied by papilledema, volume overload, and thrombocytosis, one should perform serum and urine immunofixation, along with a bone survey in search of a monoclonal gammapathy. Documentation of a lambda light chain gammopathy should prompt a thorough endocrinologic work up to confirm POEMS.

In cases of smoldering multiple myeloma or monoclonal gammopathy of undetermined significance, it is critical to exclude POEMS in order to direct therapy towards the clone and avoid progression of the associated paraneoplastic disorders. Since the full blown syndrome may not be apparent on initial presentation, it is important to follow patients closely if the criteria are not met, as delayed diagnoses have been made years after presentation of the incomplete syndrome.

Multiple myeloma may enter the differential diagnosis, but this is not associated with POEMS. Differentiating features that favor POEMS over multiple myeloma include younger age (peak incidence in 5th to 6th decade vs 7th decade), more consistent presence of organomegaly, without significant histologic or biologic abnormalities, the presence of osteosclerotic bone lesions, (in >95% in POEMS and 3% of multiple myeloma), lambda light chain gammopathy (>90%), more prominent thrombocytosis, volume overload, and endocrinologic dysfunction, less bone pain and renal failure, less marrow infiltration by plasma cells, and absence of significant elevation of the erythrocyte sedimentation rate (ESR). A markedly elevated VEGF will also help differentiate POEMS from MM.

Numerous and progressive development of cherry type and glomeruloid hemangiomas are strongly associated with POEMS, but isolated glomeruloid hemangiomas without the syndrome have rarely been reported. Nonetheless, abrupt or new onset of angiomas should prompt work up and close follow-up for additional diagnostic features of POEMS. At least one of the reported isolated glomeruloid hemangiomas has histologic and clinical features of papillary hemangioma, a simulator of glomeruloid hemangioma. Papillary hemangioma has a more papillary pericyte architecture, and tends to occur on the head and neck, in contrast to trunk and extremities for glomeruloid hemangioma.

The main differential diagnosis of the neurological symptoms is that of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) , amyloidosis, and possibly Guillain-Barre. Nerve biopsy can help differentiate these. Macrophage-associated demyelination seen in CIDP is not present in POEMS. IgM neuropathy and amyloidosis may enter in the differential, but nerve biopsy showing an absence of significant deposition of immunoglobulin and/or amyloid supports POEMS. A marked elevation of VEGF will also help differentiate POEMS from other neurologic disorders, as it was found to only be elevated in POEMS.

If the pathologist is not aware of the bone marrow features of POEMS, 5% clonal plasma cells may be misinterpreted as non-diagnostic. Close inspection of the architecture for lymphoid aggregates rimmed by clonal plasma cells is more helpful than flow cytometry. This finding also helps differentiate POEMS from MGUS, multiple myeloma, and amyoidosis.

The differential diagnosis of the osteosclerotic lesions include benign boney islands, aneurysmal bone cysts, non-ossifying fibromas, and fibrous dysplasia. Other disorders that POEMS may simulate include scleroderma or mixed connective tissue disease, but attention to the additional POEMS criteria should allow differentiation of these rheumatologic disorders.

Who is at Risk for Developing this Disease?

POEMS typically presents in adulthood, usually between the ages of 40 to 50 years, but the syndrome has been reported as young as 15 years of age. The full-blown syndrome may not be present in the pediatric age-group. An isolated glomeruloid hemangioma is not necessarily associated with POEMS, but patients with this diagnosis should be followed and carefully evaluated for development of the full blown syndrome. Patients with POEMS are over-represented in the Japanese literature, but there does not appear to be a true genetic or epidemiologic predisposition.

What is the Cause of the Disease?

Etiology

Pathophysiology

The exact pathogenesis is not known, but there is evidence that VEGF may be the dominant force in a network of proangiogenic and pro inflammatory cytokines (IL6, IL-1 beta, TNF-alpha) that are increased in patients with POEMS syndrome. Marked elevations of VEGF in plasma and serum, as well as increased levels of VEGF in ascites and CSF have been documented.

VEGF, which is expressed by osteoclasts, macrophages, plasma cells and platelets, promotes vascular permeability and angiogenesis, qualities of which have been implicated to account for edema, organomegaly, and skin lesions. VEGF secreted by the boney lesions may play a role, as radiation of these often results in reduced serum levels and cure of the syndrome. Glomeruloid hemangiomas are thought to represent reactive vascular proliferations, possibly to angiogenic stimuli such as VEGF.

Systemic Implications and Complications

Making an early diagnosis of POEMS is critical. Left untreated, at least half the patients may progress to a severe debilitating polyneuropathy, leaving them wheelchair bound, often succumbing to the consequences of multiorgan failure. Other significant consequences of the syndrome include pulmonary dysfunction, cardiomyopathy with congestive heart failure, and arterial or venous thrombosis resulting in gangrene, myocardial , cerebral, and/or splenic infarctions. Patients with POEMS-associated pulmonary hypertension may also develop non-cardiogenic acute pulmonary edema. Renal failure may be seen in some, in particular, those with CD.

Pulmonary involvement is common and may occur in the absence of significant respiratory symptoms. The neuromuscular symptoms may be so severe as to override symptoms of pulmonary dysfunction. Thus, pulmonary function testing is suggested as a screen as well as a tool to monitor for additional pulmonary involvement in patients diagnosed with POEMS. 48% of patients screened with echocardiogram within 2 years of presentation were found to have pulmonary hypertension. Echocardiography as a screening tool upon diagnosis of POEMS is also suggested to evaluate for the diagnosis and degree of cardiomyopathy.

Hypothyroidism has been associated with extravascular volume overload, which frequently resolves with thyroxine supplementary treatment ( 50-150 µg/day).

The median survival is approximately 13.7 years. The cause of death in POEMS has been attributed to cardiorespiratory failure, myocardial infarction, infection, capillary leak syndrome, renal failure, and in some, stroke and myocardial infarction. The prognosis is unrelated to the number of features of the syndrome. Respiratory symptoms, clubbing, and volume overload have been identified as poor prognostic indicators.

In patients with clubbing and extravascular volume accumulation, the medial survival has been reported to be 2.6 and 6.6 years, respectively. Cough and respiratory weakness are also poor prognostic indicators, with decreased survival time from 139 months to 87 months in patients with respiratory weakness. Co-existing CD may be associated with decreased survival compared to those without.

Patients who are candidates for radiation therapy and those who have received therapy with a good response have a better prognosis, so early identification and diagnosis is critical. Lower VEGF may predict a better therapeutic response, with resolution of features associated with increased vascular permeability, skin, and neurologic abnormalities.

Because it is common to develop additional symptoms and signs of POEMS beyond the initial time of diagnosis, close follow-up is recommended. Multidisciplinary care is crucial. Attention to pulmonary dysfunction with PFTs is important, with application of nocturnal oxygen or continuous positive airway pressure (CPAP) for supportive care as needed. Restrictive lung disease have been reported to occur up to 16 years after a diagnosis of POEMS, so PFT monitoring beyond the initial diagnostic and therapeutic time-frame is recommended.

One should monitor for consequences of neurologic complications. Occupational and physical therapists should be involved early in the disease course to prevent contractions and ulcers, and to assist with activities of daily living.

Echocardiogram at baseline is recommended, and should be repeated for any signs or symptoms of cardiomyopathy. Cases of delayed onset pulmonary hypertension have also been reported to have been detected with echocardiography. There should be ongoing monitoring for thrombotic events, which have been reported in 20% of patients. Risk factors for a cerebrovascular event include thrombocytosis and bone marrow plasmacytosis. Rare cases of calciphylaxis, unrelated to parathyroid/calcium disturbances, renal failure, or clotting disorder, suggesting POEMS as an independent risk factor.

Treatment Options

Physical Modalities

  • Local irradiation to bone lesions (3 or less)

  • Surgical excision alone or in conjunction with radiotherapy

  • Radioisotope

  • Phototherapy ( limited to treatment of persistent sclerodermatous lesions)

Medical Options (>3 skeletal lesions or (+) iliac bone marrow biopsy)

  • Alkylating agents: Melphalan, cyclophosphamide

  • Autologous peripheral blood stem cell transplantation following high dose chemotherapy

  • Systemic corticosteroids in combination with other agents

  • Lanalidomide

  • Thalidomide

  • Bevacizumab

  • Bortezomib

  • Interferon-alpha

  • Tamoxifen

  • Azathioprine

  • Ticlopidine

  • All-trans-retinoic acid

Optimal Therapeutic Approach for this Disease

General Considerations in the Algorithmic Treatment of POEM:

Randomized control trials of treatment for POEMS are lacking, and most of the medical therapies represent small series or case reports.

Since most of the symptoms and complications are paraneoplastic in nature, the key element of therapy is targeting of the clonal plasma cell dyscrasia, with similar regimens as that used for multiple myeloma. The approach to treatment of POEMS is determined by the presence or absence of bone marrow involvement and by the number of boney lesions.

For patients with isolated skeletal lesions numbering three or less, and without bone marrow involvement, as determined by careful evaluation of iliac crest marrow biopsy, irradiation is the treatment of choice. For disseminated skeletal plasmacytomas (>3) or bone marrow involvement, systemic treatment is indicated. The mainstays of systemic treatment have included chemotherapy with aklylated agents, in particular, melphalan, and autologous peripheral blood stem cell transplantation (APBSCT) following melphalan or other regimens, but treatment with immunomodulating agents alone and in combination has yielded promising results.

Avoidance of agents with neurotoxicity should be considered, but the risk benefit ratio may be worth the cautious use of medicines such as thalidomide. Intravenous immunoglobulin (IVIG) and plasmaphereis have not proven to offer significant benefit as isolated treatments.

It is important to tell the patients that there is a lag in therapeutic response. Some of the features, such as the skin disorders and volume overload may respond as early as a month into treatment, but neurologic disturbances may not begin to improve for 3-6 months. Improvment in POEMS features may continue up to 2-3 years after completion of therapy.

Physical modalities

Radiation therapy:

Irradiation of the boney lesions is the first line of treatment for non-disseminated disease. Eradication of lesions may result is complete cure, and at least half of the patients will note some improvement of symptoms up to 36 months after treatment. Adjuvant radiation may be used in patients with large bone lesions who have been treated with systemic agents, but this should not be considered until at least 6 months after treatment. Remissions may last for years. Symptoms and signs of POEMS recur with recurrence of bone lesions.

Strontium 89, a beta particle emitter used in palliation of patients with diffuse osterosclerotic metastases from adenocarcinomas, was used to treat a patient with disseminate osterosclerotic myeloma, resulting in resolution of debilitating neuropathy and other features of his POEMS syndrome. Strontium is physiochemically related to calcium, and tends to concentrate in areas where calcium accumulates, in particular, in areas of increased bone turnover seen in osteosclerotic metastases.

Short-distance radiotherapy is analogous to radioiodine treatment in thyroid disease. The main side effect is mild bone marrow suppression after 3-4 weeks. 150 MBq of Sr89 was administered as a slow intravenous push 3 to 6 monthly for five doses, resulting in marked improvement of neurologic symptoms, reversal of organomegaly, and normalization of platelets. This patient also received alternate day prednisone 45mg, which likely contributed to modification of proinflammatory cytokines.

Additional investigations are needed to confirm the benefit of Stontium-89, but in patients with diffuse lesions of osteosclerotic myeloma and co-morbidities that limit alkylating agents and/or stem cell transplantation, this may offer an alternative treatment.

Surgical excision

There are few detailed reports of surgical excision in patients with POEMS. This intervention has been reported for lesions in the thoracic and sacral spine, rib, and humerus, have resulted in improvement. Surgical treatment has been used in conjunction with radiation, chemotherapy, and/or stem cell transplantation. Surgery alone does not appear to play a role in definitive treatment of POEMS.

Phototherapy

In general, there is no role for ultraviolet (UV) light therapy in the treatment of POEMS syndrome. However in patients who have residual sclerodermatous plaques, UVA1 may offer some benefit. In a single case report, a patient with debilitating acral scleroderma-like changes associated with POEMS that did not respond to chemotherapy was treated with UVA1, commencing 3 months after completion of chemotherapy for 2 months. The regimen was 30J/cm2, for total of 35 treatments and a cumulative UVA1 dose of 1050J/cm2. There was marked improvement of sclerodactyly, reduction of the skin thickness, and improvement of mobility, lasting for more that 6 months. This therapeutic choice is not indicated as a treatment of the other symptoms or signs of POEMS.

Systemic Therapy

Alkylating agents

Melphalan is one of the mainstays of systemic treatment of POEMS. It is often used in conjunction with systemic corticosteroids, with doses ranging from 140mg/m2 to 200mg/m2. In one of the few prospective clinical trials in the treatment of POEMS, 31 patients with newly diagnosed POEMS were treated with 12 cycles of oral melphalan (10mg/m2 body surface area) in conjunction with oral dexamethasone 40mg/day, with improvement in neurologic disturbances and VEGF in 100% of patients. The initial neurological response was at 3 months after treatment, and the median time to maximal neurologic response was 12 months (range of around 3 to 15 months). Organomegaly, volume overload, pulmonary hypertension, and hematologic status also substantially improved.

This regimen is well tolerated, and should be considered early in the systemic treatment of POEMS, especially in patients who cannot undergo stem cell transplantation. Prolonged use of melphalan should be avoided, due to the possibility of secondary myelodysplastic syndrome.

Cyclophosphamide-based therapy may be of benefit, but this medicine is less well studied than melphalan. Benefit of cyclophosphamide in combination with immunomodulatory agents has been reported.

Autologous peripheral blood stem cell transplanation following high dose chemotherapy (APBST)

APBSCT is first-line therapy in some institutions, for selected individuals. This is been reported to have up to 100% response rate in neurologic symptoms. Morbidity is not insignificant, and early studies report a mortality rate of 7.4% versus 2% for multiple myeloma. Engraftment syndrome, characterized by fever, diarrhea, weight gain, respiratory symptoms and rash, between days 7 and 15 after stem cell infusion is common, especially in patients with splenomegaly.

Immunomodulatory drugs

There is a growing number of agents targeting specific cytokines, such as TNF-alpha and VEGF. In addition to diminishing levels of VEGF, some of these have apoptotic properties, that also allow anti-tumor cell properties. There are only a handful of case reports, with conflicting data regarding adverse events and clinical benefit, but the addition of these agents to the armamentarium of POEMS therapy is promising. Combination of these agents with one another and with alkylating agents and/or autologous stem cell transplant has also been beneficial in some patients.

Thalidomide: Thalidomide, which has anti-VEGF and anti-TNF properties, has been used alone and in conjunction with other medications or with APBSTC with encouraging results. Neurotoxicity is a significant side effect, so this medicine should be used with caution; however, the benefits of therapy may outweigh the risk of this potential side effect. Venous thromboembolism has been seen in patients treated with thalidomide-dexamethasone, so thromboembolism prophylaxis is recommended.

Lenalidomide: Lenalidomide, an analog of thalidomide, is a powerful anti-TNF immunomodultory drug that also is cytotoxic to malignant plasma cells. It has a different and less adverse side effect profile than thalidomide, which gives it the potential advantage in the treatment of POEMS. It is both immunomodulatory and cytotoxic to malignant plasma cells. This has been used at a dose of 25mg (initially starting dose of 15 mg) for 21 days of a 28-day cycle, in conjunciton with weekly dexamethasone 40mg, with successful results. There is also a risk of venous thromboembolism similar to thalidomide.

Bortezomib: Bortezomib, an anti-TNF, anti-VEGF drug, has been used in combination with dexamethasone and with supplementation by thalidomide, resulting in complete remission is a small handful of patients. This is associated with neurotoxicity, but the risk-benefit ratio appears to be in favor of the use of this agent, at least for limited courses.

Bevacizumab: Bevacizumab, a selective antibody to VEGF, is effective in decreasing serum levels of VEGF, and has been shown to relieve neurologic and volume overload symptoms of POEMS, allowing subsequent treatment with alkylating agents and/or stem cell transplant. It has had variable response rates in other situations, and its use has been associated with mortality from multiorgan failure and capillary leak syndrome. The acute alteration in the cytokine network may lead to these untoward complications, but the cause of potential demise is unclear. Because becacizumab does not target the clone, it may be more beneficial to use in combination with other agents.

Good response has been reported with the use of bevacizumab (300mg infusion times two), dexamethasone (40mg four times daily) and 1 g cyclophosphamide, and also with bevacizumab 5mg/kg plus thalidomide 100mg/day followed by autologous stem cell transplant. Bevacizamab may cautiously be considered a candidate for POEMS therapy, possibly playing a role in tuning up patient’s extra-vascular volume and performance status prior to consideration for transplantation. Further studies are needed to determine those at risk for adverse events such as capillary leak syndrome and multiorgan failure.

Additional miscellaneous agents

A single patient with POEMS was treated with all trans-retinoic acid, with a drop in levels of IL-6, TNF-alpha, and IL-1 beta, with a parallel response of platelet count and gammopathy. Progression of the neuropathy limits the desirability of this agent, but this is one isolated report. Isolated cases and/or inclusion in series with minimal treatment details have been reported with the used of interferon alpha, tamoxifen, ticlopidine, and argatroban, but these do not appear to offer an advantage over the regimens outlined above.

Patient Management

Management of patients with POEMS will be determined by the features of the syndrome. Supportive care during treatment is critical, and rehabilitation after treatment is also important. For instance, pedal edema should be addressed with pressure stockings. Neurologic disabilities should be accommodated until they are resolved.

It will be comforting for the patients to know that POEMS syndrome does not progress to multiple myeloma.

Since POEMS is a paraneoplastic syndrome, patients should be instructed to alert the physician of recurrent symptoms. Additionally, it is not uncommon to continue accumulating features of POEMS a decade or more after initial presentation. In a multivariate analysis, urinary monoclonal protein was predictive of the development of additional features.

The dermatologic conditions typically clear with systemic therapy, but in rare cases of residual sclerodermatous plaques, UVA1 may be considered.

Unusual Clinical Scenarios to Consider in Patient Management

Rare cases purported to represent atypical POEMS, in which polyneuropathy was lacking, have been reported. In the absence of debilitating neurologic symptoms and poor prognostic signs of POEMS, the authors suggest close monitoring, without therapeutic intervention.

What is the Evidence?

Dispenzieri, A, Kyle, RA, Lacy, MQ. "POEMS syndrome: definitions and long term outcome". Blood. vol. 101. 2003. pp. 2496-2506.

(A diagnosis of POEMS may be elusive, if limited to features of the acronym. In an attempt to clarify the diagnostic, therapeutic, and prognostic features of POEMS, 99 patients seen at the Mayo clinic with peripheral neuropathy and MGUS were assessed, and compared to previously published cases and case series. It was revealed that the medial survival was independent of the number of POEMS features, but potentially related to clubbing and extra-vascular volume overload. Pulmonary hypertension, restrictive lung disease, cardiomyopathy, and thromboses (arterial and venous) were identified as additional features of POEMS.This study was one of the most comprehensive analyses of this syndrome. Diagnostic criteria were extracted from the data, and although the criteria have been criticized, they capture most patients. The authors also confirmed that additional features of POEMS continue to develop, and they documented the value of radiation therapy. This article is a good reference for detailed descriptions of features noted before and after diagnosis, and the natural history of POEMS.)

Dispenzieri, A. "POEMS syndrome". Blood Rev. vol. 21. 2007. pp. 285-99.

(This article reviews and updates the clinical and laboratory features of POEMS, incorporating findings reported in the 2003 Mayo article, along with two large series from Japan and a French series. A revised version of the diagnostic criteria is offered. The role of VEGF, IL-1 beta, TNF-alpha, IL-6, and other cytokines, as well as other pathogenetic contributing factors are reviewed. An updated review of therapeutic interventions supports radiation and alkylating agents with or without PBSCT. This article also offers an extensive discussion of the role of Castleman's disease in POEMS, outlining differentiating features).

Soubrier, MJ, Dubost, JJ, Sauvezie, BJ. "French study group on POEMS syndrome: a study of 25 cases and a review of the literature". Am J Med. vol. 97. 1994. pp. 543-553.

(This article offers a detailed retrospective review of the clinical and laboratory abnormalities of POEMS in a French cohort, comparing the patients with the Asian and non-Asian literature. The findings highlight the central role the clone plays in the syndrome, and the authors stress the need for a rigorous search for an M protein [especially lambda] and boney lesion[s].).

Ghandi, GY, Basu, R, Dispenzieri, A, Basu, A, Montori, V, Brennan, MD. "Endocrinopathy in POEMS syndrome: The Mayo Clinic Experience". Mayo Clin Proc. vol. 82. 2007. pp. 836-42.

(This retrospective review of 64 patients followed at the Mayo clinic with POEMS, most of whom had undergone extensive endocrine evaluation,regardless of symptoms, found a high percent of endocrinopathy (84%), with the most common being hypogonadism. Over 50% had multiple endocrinopathies in the four major endocrine axes. [gonad, thyroid, glucose, adrenal] The authors suggest the endocrinolgic screening studies to include thyrotropin, free thyroxine, fasting am glucose, total and bioavailable testosterone, follicle stimulating hormone, lutenizing hormone, estradiol [women], prolactin, screening am cortisol, and calcium.)

Allam, JS, Kennedy, CC, Aksamit, TR, Dispenzieri, A. "Pulmonary manifestations in patients with POEMS syndrome: a retrospective review of 137 patients". Chest. vol. 133. Apr 2008. pp. 969-74.

(This retrospective review of 137 patients defined the pulmonary features of POEMS to incude pulmonary hypertension, restrictive lung disease, isolated diminished diffusing lung capacity, and respiratory muscle weakness, the latter of which was associated with decreased medial survival. Some of the disturbances were picked up on pulmonary PFT, in the absence of clinical symptoms. The article discusses features of PFTs and imaging studies in POEMS, and stresses the need for awareness of the relationship of pulmonary disease in POEMS.)

Chan, JKC, Fletcher, CDM, Hicklin, GA, Rosai, J. "Glomeruloid hemangioma. A distinctive cutaneous lesion of multicentric Castleman's disease associated with POEMS syndrome". Am J Surg Pathol. vol. 14. 1990. pp. 1036-46.

(Distinct vascular lesions are described in two patients with POEMS and Castleman's disease, the changes of which have been termed glomeruloid hemangioma. The tufts of glomeruli-like capillaries that characterize these proliferations were also noted in cherry-hemangioma-like lesions. The multiple and progressive presentation, together with the characteristic histologic features of these vascular proliferations were felt to be unique to POEMS, but subsequent to this article, solitary or isolated glomeruloid hemangiomas have been described. Follow up had not been sufficient to exclude POEMS in one case, and at least one of these have been re-diagnosed by a different author as a papillary hemangioma.)

Ofran, Y, Elinav, E. "POEMS syndrome: failure of newly suggested diagnostic criteria to anticipate the development of the syndrome". Am J Hematol. vol. 79. 2005. pp. 316-8.

(A retrospective review of 12 patients extracted from a database of 629 patients with plasma cell dyscrasias and MGUS who had unexplained polyneuropathy [fulfilling two major POEMS criteria] were evaluated for additional minor criteria. Impotence and hepatosplenomegaly developed, fulfilling the proposed criteria for POEMS, yet only five developed full-blown POEMS. The authors suggest including exclusionary criteria, such as vasculitis or kappa light chain clonality, elimination of common disorders, such as hepatosplenomegaly, and replacing M protein with lymphoproliferative disorders may avoid misdiagnoses. Other authors have offered cases of atypical POEMS, in which the neuropathy or M protein were undetectable. When sufficient criteria cannot be established, follow-up for acquisition of additional diagnostic features is imperative.

Kulkarni, GB, Mahadevan, A, Taly, AB, Yasha, TC, Seshagiri, KS, Nalini, A. "Clinicopathological profile of polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes (POEMS) syndrome". J Clin Neurosci. 2011. pp. 356-60.

(This retrospective review of 29 patients with POEMS offers an additional discussion of the clinical and laboratory features in a different cohort (Indian). Details of nerve conduction studies and nerve biopsy are discussed.)

Sternberg, AJ, Davies, P, Macmillan, C, Abdul-Cader, A, Swart, S. "Strontium-89: a novel treatment for a case of osteosclerotic myeloma associated with life-threatening neuropathy". Br J Haematol. vol. 118. 2002. pp. 821-4.

(This artice decribes details of a novel treatment of POEMS, in patients who have too many lesions to directly irradiate. The treatment works in a fashion analogous to radioiodine. There have been no further reports of this intervention, although the results were promising.)

Dispenzieri, A. "POEMS Syndrome:2011 Update on diagnosis, risk-stratification, and management". Am J Hematol. vol. 86. 2011. pp. 592-601.

(This updated review summarizes the frequencies of POEMS findings, based on review of the author's experience and review of several large series. There is a good discussion of risk-stratification and risk-adapted therapy , along with an updated summary of treatment, that includes immunomodulatory agents.)

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