Unraveling unique features of plasma cell clones in POEMS syndrome with single-cell analysis.

POEMS syndrome is a rare monoclonal plasma cell disorder, with unique symptoms distinct from those of other plasma cell neoplasms, including high serum VEGF levels. Because the prospective isolation of POEMS clones has not yet been successful, their real nature remains unclear. Herein, we performed single-cell RNA-Seq of BM plasma cells from patients with POEMS syndrome and identified POEMS clones that had Ig λ light chain (IGL) sequences (IGLV1-36, -40, -44, and -47) with amino acid changes specific to POEMS syndrome. The proportions of POEMS clones in plasma cells were markedly smaller than in patients with multiple myeloma (MM) and patients with monoclonal gammopathy of undetermined significance (MGUS). Single-cell transcriptomes revealed that POEMS clones were CD19+, CD138+, and MHC class IIlo, which allowed for their prospective isolation. POEMS clones expressed significantly lower levels of c-MYC and CCND1 than MM clones, accounting for their small size. VEGF mRNA was not upregulated in POEMS clones, directly indicating that VEGF is not produced by POEMS clones. These results reveal unique features of POEMS clones and enhance our understanding of the pathogenesis of POEMS syndrome.

POEMS syndrome: A multisystem clonal disorder.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome is a rare condition defined by monoclonal plasma cell disorder, peripheral neuropathy, and other systemic symptoms. The pathophysiology of POEMS syndrome is unknown, but the overproduction of vascular endothelial growth factor (VEGF) appears to be an important contributory element. The diagnosis of POEMS syndrome requires the presence of both mandatory criteria (ie, polyneuropathy and a monoclonal plasma cell disorder), at least one major criterion (ie, osteosclerotic bone lesions, Castleman disease, or elevated serum or plasma levels of vascular endothelial growth factor), and at least one of the six minor criteria. POEMS syndrome lacks a standard treatment, but patients with limited sclerotic bone lesions are typically treated with radiation therapy. In contrast, those with widespread lesions receive chemotherapy and hematopoietic stem cell transplantation.

The Wide Spectrum of Pathophysiologic Mechanisms of Paraproteinemic Neuropathy.

Monoclonal gammopathy is encountered quite frequently in the general population. This type of hematologic abnormality may be mild, referred to as monoclonal gammopathy of undetermined significance or related to different types of hematologic malignancies. The association of a peripheral neuropathy with monoclonal gammopathy is also fairly common, and hemopathy may be discovered in an investigation of peripheral neuropathy. In such a situation, it is essential to determine the exact nature of the hematologic process in order not to miss a malignant disease and thus initiate the appropriate treatment (in conjunction with hematologists and oncologists). In this respect, nerve biopsy (discussed on a case-by-case basis) is of great value in the management of such patients. We therefore propose to present the objectives and main interests of nerve biopsy in this situation.

Distinctive patterns of peripheral neuropathy across the spectrum of plasma cell disorders.

Many patients with plasma cell disorders suffer from peripheral neuropathy, but differential diagnosis with chronic inflammatory demyelinating polyneuropathy (CIDP) is difficult. We aimed to (1) identify factors useful for differential diagnosis between peripheral neuropathy associated with plasma cell disorders versus CIDP and (2) determine whether neuropathy presentations and severity varied across the spectrum of different plasma cell disorders. A retrospective chart review of 18 monoclonal gammopathy of unknown significance (MGUS) patients, 15 POEMS syndrome patients and 34 CIDP patients between January 2005 and December 2016 was conducted. The peripheral neuropathy associated with plasma cell disorders seemed to be more sensory oriented compared to CIDP. MGUS patients were significantly older than CIDP patients (median age 70 vs. 59, respectively, p = 0.027). POEMS syndrome patients showed significantly higher platelet count at the time of neuropathy presentation compared to CIDP (p = 0.028). Lambda type MGUS patients were associated with less severe symptoms compared to POEMS syndrome patients despite harboring lambda monoclonal gammopathy as a common denominator. Kappa type MGUS patients showed predominantly axonal type neuropathy compared to its counterpart and POEMS syndrome. Careful inspection of clinical profiles and symptoms of patients presenting with neuropathy can help to discriminate those with underlying plasma cell disorders. The phenotype of neuropathy, platelet count and age at presentation seem to be the most useful indicators.

Paraneoplastic Syndromes in Neuro-ophthalmology.

PURPOSE OF REVIEW: This article discusses the varied types of paraneoplastic syndromes that commonly have neuro-ophthalmologic manifestations. Diagnostic considerations and therapeutic options for individual diseases are also discussed. RECENT FINDINGS: Paraneoplastic syndromes can affect the afferent and efferent visual systems. Paraneoplastic syndromes may result in reduced visual acuity from retinal degeneration, alterations in melanocyte proliferation and uveal thickening, or acquired nystagmus. Ocular motor abnormalities related to paraneoplastic syndromes may present with symptoms from opsoclonus or from neuromuscular junction disease. Diagnosis remains challenging, but serologic identification of some specific antibodies may be helpful or confirmatory. Treatment, in addition to directed therapies against the underlying cancer, often requires systemic corticosteroids, plasma exchange, or immunosuppression, but some specific syndromes improve with use of targeted pharmacologic therapy. SUMMARY: Diagnosis and therapy of paraneoplastic syndromes presenting with neuro-ophthalmic symptoms remain a challenge, but strategies are evolving and new approaches are on the horizon.

POEMS syndrome: A rare paraneoplastic presentation of spinal plasmacytoma.

The acronym POEMS syndrome was coined for a unique multisystem disorder characterised by peripheral neuropathy, organomegaly, endocrinopathies, monoclonal gammopathy and skin changes. We report a male patient presenting to us with spinal plasmacytoma complicated with paraplegia. He was subsequently diagnosed to have POEMS syndrome and successfully treated with thalidomide and dexamethasone. Post treatment, he is able to ambulate independently.

POEMS Syndrome: Indian Experience From a Tertiary-Care Institute.

INTRODUCTION: POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome is a rare multisystem paraneoplastic syndrome characterized by peripheral neuropathy and monoclonal plasmacytosis. Retrospective institutional experiences from the Mayo Clinic as well as Chinese, European, and Japanese series have provided important insights into the characteristics and treatment of this disease, but Indian data are extremely limited. We retrospectively analyzed 49 cases from our institute including 10 patients who underwent autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS: We analyzed clinical and laboratory characteristics, treatment details and outcome of all patients diagnosed with POEMS syndrome between 1993 and 2017. RESULTS: Complete medical records were available for 49 patients with a median age of 44 years. Male/female ratio was 38:11. Twenty patients (40.8%) had Eastern Cooperative Oncology Group performance status of 4. Before 2012, melphalan/prednisolone was the most common regimen provided, while bortezomib/dexamethasone and lenalidomide/dexamethasone were used later. Hematologic response was available for 40 patients, 15 (37.5%) of whom experienced complete response, 13 (32.5%) partial response, and 11 (27.5%) stable disease. The median modified Rankin score at baseline was 4 (range, 1-5), which improved to 3 (range, 1-5). Ten patients underwent consolidation ASCT after a median of 4 cycles of induction. Median melphalan dose was 140 mg/m2. Engraftment syndrome was observed in 4. After ASCT, all 10 patients experienced hematologic complete response and clinical improvement. CONCLUSION: This retrospective analysis provides important information on the clinical characteristics of POEMS syndrome in Indian patients, which will help the clinician's decision-making process.

An atypical presentation of POEMS syndrome with IgG kappa type M protein and normal VEGF level: Case report and review of literature.

POEMS syndrome is a multisystem disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. We present an atypical case of POEMS syndrome with subclinical polyneuropathy, splenomegaly, hypogonadism, and myeloma of immunoglobulin G kappa type. The typical osteosclerotic lesions and skin lesions were absent, and vascular endothelial growth factor (VEGF) level was normal. Our patient also had chronic kidney disease due to focal segmental glomerulosclerosis. The patient died due to multisystem complications nine months after presenting with acute on chronic renal failure. POEMS syndrome is an uncommon, potentially fatal paraneoplastic syndrome presenting with plasma cell neoplasm and multisystem involvement. Despite the normal VEGF level, our patient was diagnosed to have possible POEMS syndrome due to other clinical manifestations. It may be reasonable to expand the diagnostic criteria of POEMS syndrome if further atypical cases are reported in the future.

POEMS syndrome in a patient with rheumatoid arthritis.

Multiple myeloma has been reported to be associated with rheumatoid arthritis (RA). POEMS syndrome is a rare variant of multiple myeloma and is characterised by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes. We report the case of a 67-year-old patient with RA who developed numbness and tingling in both legs due to polyneuropathy. CT showed a massive right pleural effusion and a sclerotic lesion in the right ninth rib. Histopathological examination of the rib revealed IgA lambda-type plasmacytoma. Serum vascular endothelial growth factor was extremely high at 5530 pg/mL. We made a diagnosis of POEMS syndrome. A literature search of the PubMed database identified only two documented cases of POEMS syndrome in patients with RA. Neuropathies are reportedly more frequent in patients with RA than in the general population. Rheumatologists should consider POEMS syndrome in patients with RA and neurological symptoms.

POEMS syndrome: 2017 Update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. DIAGNOSIS: The diagnosis of POEMS syndrome is made with 3 of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. RISK STRATIFICATION: Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the plasma cell disorder is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy RISK-ADAPTED THERAPY: For those patients with a dominant sclerotic plasmacytoma, first-line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3-6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low-dose conventional therapy or high dose with stem cell transplantation. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. The benefit of anti-VEGF antibodies is conflicting. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

POEMS Syndrome: an Enigma.

POEMS syndrome is a paraneoplastic disorder secondary to an underlying plasma cell dyscrasia. By definition, all patients with POEMS syndrome must display polyneuropathy and monoclonal plasma cell disorder. In addition, at least one major criterion (Castleman's disease, sclerotic bone lesions, or vascular endothelial growth factor elevation) and one minor criterion (organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, thrombocytosis, or polycythemia) are required for diagnosis. Treatment is based on extent of the disease. Radiotherapy is used for localized disease. Systemic therapy is required for disseminated disease, with bone marrow involvement by clonal plasma cells, or in patients who progress shortly after radiation. Upfront autologous stem cell transplantation is the treatment of choice for transplant-eligible patients. Outcomes are typically superior to that of standard myeloma. Herein, using a case vignette, we outline the latest evidence regarding the prognostication and management of POEMS syndrome, with a focus on its relapsing-remitting course.

Glomeruloid hemangioma and POEMS syndrome. / Hemangiomas glomeruloides y síndrome POEMS.

POEMS syndrome is a paraneoplastic manifestation associated with hematopoietic disorders such as multiple myeloma and Castleman disease. POEMS is an acronym for the main clinical features of the syndrome, namely, Polyneuropathy, Organomegaly, Endocrinopathy, M protein, and Skin abnormalities. Glomeruloid hemangiomas are considered to be a specific clinical marker of POEMS syndrome. However, while they are not pathognomonic, their presence should raise suspicion of this syndrome or alert clinicians to its possible future development, as these lesions can appear years before the onset of the syndrome. We report the cases of 2 women with plasma cell dyscrasias and sudden onset of lesions with a vascular appearance and histologic findings consistent with glomeruloid hemangioma. Recognition of this vascular tumor is important for the early diagnosis of POEMS syndrome.

TAFRO syndrome with primary Sjogren's syndrome.

A 25-year-old woman diagnosed 1 year earlier with Primary Sjogren's syndrome was admitted to a nearby hospital with fever of unknown origin. Examination revealed anasarca, systemic lymphadenopathy, hepatosplenomegaly and high C-reactive protein level. The patient's symptoms were initially suspected to be caused by severe bacterial infection with Sjogren's syndrome flare. She was given antibiotics and prednisolone (PSL) at 50 mg/day. However, the patient developed anemia and thrombocytopenia and was transferred to our hospital for further care. Histological examination of the right inguinal lymph node showed neutrophilic infiltration. Bone marrow aspiration revealed a normocellular marrow with increased megakaryocytes and mild reticulin fiber hyperplasia. After initiation of minocycline hydrochloride, the patient's symptoms improved. However, as PSL was tapered, her symptoms worsened. The patient's clinical symptoms and laboratory data improved again with initiation of intravenous steroid pulse therapy and cyclosporine. TAFRO syndrome is characterized by a constellation of symptoms: Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis and Organomegaly. Although histological findings of the lymph node in this case differed from previous reports, the patient's other symptoms and clinical course were similar to TAFRO syndrome. TAFRO syndrome can occur with several diseases, including infection, rheumatic disease and malignancies. We report a case in which infection might have triggered TAFRO syndrome.

Skin manifestations of POEMS and AESOP syndrome in the same patient revealing plasma cell dyscrasia.

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin signs) and AESOP (adenopathy and extensive skin patch overlying a plasmacytoma) syndromes are rare paraneoplastic conditions due to an underlying plasma cell dyscrasia. We report a 70-year-old patient with the rare coexistence of POEMS and AESOP syndromes and in whom skin signs, that differ both clinically and histologically, were the clues to the diagnosis of a plasma cell disorder. Vascular endothelial growth factor-A overexpression seems to be the common pathogenetic link of the different clinicopathological presentations of the skin lesions.

POEMS Syndrome with IgG-λ/IgA-κ Biclonal Gammopathy and Abnormal Serum Free Light Chain Ratio: a Case Report.

BACKGROUND: POEMS syndrome is a rare paraneoplastic disorder with atypical plasma cell proliferation. Cases of POEMS syndrome presented with either biclonal gammopathy or an abnormal serum free light chain ratio are considered uncommon. The present authors encountered a case of POEMS syndrome with IgG-λ/IgA-κ biclonal gammopathy with dominant κ free light chain and abnormal serum free light chain ratio. CASE: A 56-year-old man with a history of Castleman disease was suspected with POEMS syndrome and admitted for further evaluation for B-cell proliferative disease to rule out multiple myeloma. He also had a sustained tingling sensation on both feet and gait disturbance, which were compatible with diffuse peripheral sensorimotor polyneuropathy with demyelinating features. His laboratory findings revealed hyperlipidemia and hypothyroidism, and he had hypertrichosis. The results of the serum and urine protein electrophoresis seemed normal, except a very weak band at the end of the serum gamma region. Serum immunofixation electrophoresis confirmed IgG-λ and IgA-κ biclonal gammopathy, with an increased serum IgA concentration and normal levels of IgG, IgM, and IgD. Both serum free light chain κ and λ values were increased, and the κ/λ ratio was higher than normal. CONCLUSIONS: The finding of IgG-λ/IgA-κ biclonal gammopathy and abnormal serum free light chain ratio with dominant κ clonality in our case was definitely rare. However, a primary pathogenic role of the different paraproteinemia in POEMS syndrome remains unclear. Further studies to identify better management modalities for POEMS syndrome is needed.

[Male aged 31 years with polyneuropathy, prostration, and hypogonadism]. / Hombre de 31 años con polineuropatía, postración e hipogonadismo.

We present the case of a 31 year-old male patient, who presented polyneuropathy, symmetrical, ascending, and progressive, that led to prostration of eight months duration, accompanied by hypogonadism, hypothyroidism, hyperprolactinemia, and the presence of multiple erythematous nodules on the skin. The MRI showed hypointense lesions in the vertebrae T-6 and L-4 with sclerotic appearance. The bone marrow biopsy reported the presence of 12% plasma cells with A. restriction, supporting monoclonal gammopathy (plasmocytoma).