Castleman Disease: A Rare Lymphoproliferative Disorder With Diverse Clinical Presentation, Diagnosis, and Treatment Approach.

Castleman disease (CD) includes rare and intricate lymphoproliferative disorders characterized by the abnormal growth of lymph nodes and immune system disturbances. It primarily presents in two forms: unicentric Castleman disease (UCD), which affects a single lymph node area, and multicentric Castleman disease (MCD), which involves multiple lymph nodes and systemic manifestations. The disease's underlying mechanisms are often linked to immune system irregularities, especially involving interleukin-6 (IL-6). The condition was first documented by Dr. Benjamin Castleman in 1954, laying the groundwork for understanding this complex disorder. MCD can be further divided into idiopathic MCD (iMCD), which includes thrombocytopenia, ascites, fibrosis, renal impairment, and organ enlargement (TAFRO) syndrome, and human herpesvirus-8 (HHV-8)-associated MCD, which can occur in individuals with or without HIV. The prevalence of CD shows a higher occurrence of UCD, with the disease typically presenting in individuals in their fifth to seventh decades of life and being more common in areas with high HIV prevalence. The clinical presentation of CD can include symptoms such as swollen lymph nodes, fever, anemia, and systemic inflammation. Diagnostic challenges arise due to the disease's rarity, and its symptoms overlap with other conditions. Treatment approaches differ based on the subtype. UCD generally responds favorably to the surgical removal of the affected lymph nodes, while MCD often requires antiviral treatments, interleukin-6 (IL-6) inhibitors, and new biologic therapies. Recent advances in treatment, including innovative biologic agents and combination therapies, offer promising prospects for improving patient outcomes. Accurate diagnosis and customized treatment strategies are essential for the effective management of this complex disease.

[Diagnosis and management of POEMS syndrome].

POEMS syndrome is a plasma cell neoplasm that presents with peripheral neuropathy, organomegaly, fluid retention, skin manifestations, osteosclerotic lesions, and λ-type M-proteinemia. The pathogenesis of POEMS syndrome is poorly understood, as the genetic profile of plasma cells in POEMS syndrome differs from that of myeloma. In most cases, POEMS syndrome is difficult to distinguish from chronic inflammatory demyelinating polyneuropathy (CIDP). Consequently, it is essential not to miss characteristic signs of POEMS syndrome such as M-protein, VEGF, pleural effusion, and osteosclerotic lesions. Novel agents for myeloma, such as thalidomide, lenalidomide, and bortezomib, are effective. For younger patients, these agents followed by autologous transplantation with high-dose melphalan is the standard of care. More relapses are now being reported in results of long-term observation, and treatment strategies for relapsed disease must be established.

Intersecting Pathologies: A Case Report on the Co-presentation of Quasi-Moyamoya Disease and Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Plasma Cell Disorder, and Skin Changes (POEMS) Syndrome.

Moyamoya disease (MMD) is a rare chronic vasculopathy characterized by progressive stenosis of the internal carotid arteries and the formation of fragile collateral vessels in the brain. Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome is a rare paraneoplastic syndrome with a complex presentation that includes polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. Here, we report a unique case of a 54-year-old male with MMD presenting with recurrent speech loss and mumbling, later diagnosed with POEMS syndrome. Initial imaging revealed Moyamoya vasculopathy, confirmed by computed tomographic angiography (CTA) and magnetic resonance imaging (MRI). Further examination revealed polyneuropathy, organomegaly, and elevated vascular endothelial growth factor (VEGF), meeting the diagnostic criteria for POEMS syndrome. The patient was treated with a cyclophosphamide-bortezomib-dexamethasone regimen, followed by the addition of daratumumab, resulting in clinical improvement. This case highlights the importance of thorough diagnostics and a multidisciplinary treatment approach for patients with complex comorbidities, emphasizing the need for early detection and targeted therapy in managing dual pathologies of MMD and POEMS syndrome.

Atypical POEMS syndrome: Report of a patient.

BACKGROUND: The order of clinical symptoms of POEMS syndrome is different, and the first diagnosis department is different accordingly, which is easy to cause misdiagnosis by clinicians. METHODS: A retrospective study was conducted between 2019 and 2023 in West China Hospital. Demographic, clinical and laboratory test indicators data were collected. RESULTS: Out of a total of 48 patients, 32 patients were from outpatient clinics and 16 were inpatients. The median age was 51 years old, and 30 were male. The most prevalent initial symptom is polyneuropathy (77.1%). 22 out of the 48 patients had an elevated VEGF. The most prevalent serum M protein was lgA λ(54.2%), and one patient had no M protein which could be regarded as the atypical POEMS syndrome. CONCLUSIONS: At present, the diagnosis of POEMS syndrome is based on the combination of clinical manifestations and laboratory tests. Emphasizing pluralism is of great significance for the diagnosis of this disease.

Case report: POEMS syndrome with portal hypertension.

This patient was an elderly patient with abdominal distension and shortness of breath. According to relevant examinations, his condition was initially considered to be related to cirrhosis, but pathological biopsy confirmed the diagnosis of noncirrhotic portal hypertension of unknown etiology. The portal vein pressure was significantly reduced after transjugular intrahepatic portosystemic shunt (TIPS). Nevertheless, the relief of the hydrothorax and ascites was not significant, and the numbness in both lower limbs gradually worsened. POEMS syndrome was ultimately diagnosed following a comprehensive examination. After two courses of bortezomib combined with dexamethasone, the patient died due to a systemic infection. The clinical symptoms of the patient were atypical, as was the presence of portal hypertension, which hindered the diagnosis of POEMS. Due to the patient's advanced age, the diagnosis was delayed, and the prognosis was poor. This case reminds clinicians that POEMS patients can also have portal hypertension as the main manifestation.

Case report: DKRd regimen in the treatment of newly diagnosed POEMS syndrome and literature review.

POEMS syndrome, characterized as a rare multisystem paraneoplastic syndrome, arises from plasma cell abnormalities. Coined by Bardwick in 1980, the acronym POEMS delineates the distinctive features of the syndrome: Peripheral nerve Lesions, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes. The prevalence of POEMS syndrome stands at approximately 0.3 per 100,000 individuals. Owing to its low prevalence and the paucity of prospective studies, current treatment approaches largely hinge on retrospective studies and revolve around the use of plasma cell-directed therapy typically used in multiple myeloma treatments. This article presents the pioneering case of utilizing a four-drug combination regimen of DKRd (daratumumab, carfilzomib, lenalidomide, and dexamethasone) as a first-line treatment. This is succeeded by induction therapy and subsequently, autologous hematopoietic stem cell transplantation. A comprehensive review of related literature is conducted.

Requirement of Repeated Serum VEGF Measurements in POEMS Syndrome.

POEMS syndrome is often associated with a poor prognosis. Elevated serum vascular endothelial growth factor (sVEGF) is a useful diagnostic marker with high sensitivity and specificity. However, the relationship between sVEGF elevation and polyneuropathy in POEMS syndrome remains controversial. We herein report a case of polyneuropathy without sVEGF elevation at the first admission. However, at 21 months after the onset, the patient tested positive for sVEGF and was diagnosed with POEMS syndrome. Therefore, it is important to repeatedly measure sVEGF levels in patients with polyneuropathy with an atypical course when POEMS syndrome is suspected, even if the initial sVEGF level is normal.

An open-label, prospective trial to evaluate the efficacy and safety of ixazomib in combination with cyclophosphamide and dexamethasone in patients with newly diagnosed POEMS syndrome.

This open-label, prospective trial evaluated the combination of ixazomib, cyclophosphamide and dexamethasone (ICD) in 12 newly diagnosed POEMS syndrome patients. The study is registered with the Chinese Clinical Trials Registry (ChiCTR2000030072). The treatment protocol consisted of 12 cycles of the ICD regimen compromising ixazomib (4 mg on Days 1, 8 and 15), oral cyclophosphamide (300 mg on Days 1, 8 and 15) and dexamethasone (20 mg weekly). A total of 12 patients received a median of 10 (range: 3-23) cycles of the ICD regimen. The haematological response could be evaluated in 10 patients. The overall haematological response rate was 80% (8/10), with 30% (3/10) achieving complete haematological response, and the overall serum VEGF response rate and neurological response were 100% and 83.3% respectively. Two patients experienced grade 3/4 AEs, including diarrhoea (n = 1) and leukopenia (n = 1). The combination of ixazomib, cyclophosphamide and dexamethasone demonstrated both efficacy and safety in newly diagnosed POEMS syndrome, making it a viable treatment option.

Monoclonal gammopathy of clinical signifi cance with osteosclerotic lesions - a case report and a literature review.

INTRODUCTION: Multiple myeloma is a common plasma cell neoplasia usually accompanied by the formation of osteolytic foci, whereas osteosclerotic myeloma is a very rare form of plasma cell dyscrasia. When osteosclerotic myeloma is detected, osteosclerotic foci are usually part of the POEMS syndrome. Osteosclerotic myeloma without other manifestations of the POEMS syndrome is an unusual finding. CASE DESCRIPTION: In a 46-year-old woman, osteosclerotic changes of the temporoparietal region caused soft tissue induration over this lesion, which initiated further investigation. Imaging studies subsequently showed multiple osteosclerotic foci in the skull. Examination of blood proteins revealed 8 g/L of IgG-lambda monoclonal immunoglobulin, subclass IgG1. In search of the cause of the osteosclerotic changes, FDG-PET/CT was performed, which revealed no FDG accumulation, i.e., no other tumor (breast or stomach cancer). Low-dose CT showed irregular bone structure, but not significant osteolytic or osteosclerotic foci. To map the extent of osteosclerotic changes, NaF-PET/CT imagination followed, which revealed multiple spots with high fluoride accumulation. A parietal bone biopsy showed osteosclerosis with minor clonal plasma cell infiltration. Trepanobioptic bone marrow sampling revealed an infiltration of bone marrow with atypical plasma cells in 8%. Flow-cytometric examination of bone marrow showed 0,37% of plasma cells, however predominantly (91%) clonal with lambda expression. MRI of the brain identified asymptomatic meningeal thickening. There was no evidence of POEMS syndrome in the patient; thus, we concluded the diagnosis as monoclonal gammopathy of clinical significance with osteosclerosis which was previously termed osteosclerotic multiple myeloma. CONCLUSION: Monoclonal gammopathy of clinical significance (MGCS) with osteosclerotic skeletal changes, documented on CT and multiple foci with intensive osteoneogenesis, documented on NaF-PET/CT without evidence of POEMS syndrome, is an extremely rare form of plasma cell dyscrasia. This publication documents the unique clinical manifestations of IgG-lambda type plasma cell proliferation without signs of POEMS syndrome and the role of NaF-PET/CT imaging. Classification of this disease as MGSC with osteosclerotic manifestations is more consistent with the indolent nature of the disease with a significantly better prognosis, compared with multiple myeloma.

[A race against time: POEMS syndrome]. / "Verseny az idovel": a POEMS szindróma.

Background - POEMS syndrome is a potentially well manageable disease with an ascendant therapeutic arsenal nowadays. The early recognition of the syndrome is key to prevent serious multiorgan damage, and that is still a big challenge for physicians. With the following two case reports the authors aimed to highlight the consequences of late recognition of the disease and summarize the potential therapeutic options for POEMS syndrome.

Results - We have presented two patients’ cases with a long history of examination and treatment because of uncleared polyneuropathy. Through these cases we could see how serious could be the consequences of late diagnosis and despite multiorgan impairment there are still therapeutic options which could improve the patient’s condition. Although the diagnosis of POEMS syndrome is not easy, it must raise our mind the thought and be prudent when we start a treatment in polyneuropathy.

Unusual Types of Plasma Cell Dyscrasias Associated With HIV: Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, and Skin Changes (POEMS) Syndrome.

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a multisystem paraneoplastic disorder due to an underlying plasma cell neoplasm, and its occurrence among HIV patients is extremely rare. The diagnosis of POEMS syndrome can be challenging in this context, particularly if its disabling polyneuropathy is misdiagnosed as neuropathy related to HIV. Herein, we report the case of a female patient with treated HIV who later developed POEMS syndrome. After a misdiagnosis of chronic inflammatory demyelinating polyneuropathy related to HIV and unsuccessful corticosteroids and cyclophosphamide therapies, the correct diagnosis of POEMS syndrome was made. The patient achieved significant hematological and neurological improvement after six cycles of lenalidomide. Autologous stem cell transplantation was then scheduled to prevent eventual relapses.

POEMS syndrome with undetectable M-protein: a case report and literature review.

BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell (PC) neoplasm with associated paraneoplastic syndrome. According to the current diagnostic criteria, peripheral polyneuropathy and monoclonal PC proliferative disorder represent two mandatory criteria. CASE PRESENTATION: We report a 54-year-old male with peripheral neuropathy of bilateral lower limbs, sclerotic bone lesions, elevated vascular endothelial growth factor (VEGF) levels, splenomegaly, extravascular volume overload, endocrinopathy, and skin hemangiomas. Of note, serum and urine protein electrophoresis (PEP) and immunofixation electrophoresis (IFE) of this patient indicated undetectable M-protein and the normal ratio of free light chains κ and λ (FLC-R (κ/λ)). No monoclonal PCs were found in bone marrow examinations or biopsy of diseased bones. However, his clinical manifestations matched most of the diagnostic criteria. After excluding other diseases that are easily confused with POEMS syndrome, the diagnosis of variant POEMS syndrome with undetectable M-protein was proposed. The patient obtained clinically significant improvement and elevated VEGF returned to normal after 6 months of treatment with lenalidomide plus dexamethasone. CONCLUSIONS: Monoclonal PC dyscrasia (M-protein) while being a mandatory criterion for POEMS syndrome is undetectable in a considerable amount of patients that otherwise demonstrate typical symptoms. Here, we reported a case of variant POEMS syndrome with featured clinical manifestations, elevated VEGF levels, and good response to therapies targeting PCs but no evidence of M-protein. Therefore, negative results in M-protein and monoclonal PCs aren't enough to reject the diagnosis of POEMS syndrome. It is imperative to recognize the variant form of POEMS syndrome.

Detection of clonal plasma cells in POEMS syndrome using multiparameter flow cytometry.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein], and skin changes) is a rare systemic disorder characterized by various symptoms caused by underlying plasma cell (PC) dyscrasia. Detection of monoclonal PCs is mandatory for the diagnosis of POEMS syndrome; however, the usefulness of EuroFlow-based next-generation flow cytometry (EuroFlow-NGF) in POEMS syndrome for detecting monoclonal PCs in bone marrow (BM) and the gating strategy suitable for flow cytometry study of POEMS syndrome remain unknown. We employed EuroFlow-NGF-based single-tube eight-color multiparameter flow cytometry (MM-flow) and established a new gating strategy (POEMS-flow) to detect the monoclonal PCs in POEMS syndrome, gating CD38 broadly from dim to bright and CD45 narrowly from negative to dim compared to MM-flow. MM-flow detected monoclonal PCs in 9/25 (36.0%) cases, including 2/2 immunofixation electrophoresis (IFE)-negative cases (100%). However, POEMS-flow detected monoclonal PCs in 18/25 cases (72.0%), including 2/2 IFE-negative cases (100%). POEMS-flow detected monoclonal PCs with immunophenotypes of CD19- in 17/18 (94.4%). In six cases where post-treatment samples were available, the size of the clones was significantly reduced after the treatment (P = 0.031). POEMS-flow can enhance the identification rate of monoclonal PCs in POEMS syndrome and become a valuable tool for the diagnosis of POEMS syndrome.

Paraproteinemic neuropathies.

The diagnostic evaluation of a peripheral neuropathy includes testing for the presence of monoclonal gammopathy, which can be found in about 10% of patients with peripheral neuropathy. Our role, as physicians, is to determine whether the neuropathy is directly related to the gammopathy or whether the co-occurrence of these two disorders is purely coincidental. The evaluating physician needs to be familiar with the different types of neuropathies associated with monoclonal gammopathies, their clinical and electrodiagnostic characteristics, and their appropriate diagnostic evaluation and management. Testing for monoclonal protein disorders includes serum protein electrophoresis (SPEP) and immunofixation of blood, and in some cases of urine, as well as measurement of free light chains and quantitative immunoglobulins. Specific antibody testing is directed by paraprotein type and neuropathy phenotype. Patients with abnormal free light chains in association with sensory and autonomic neuropathy should be evaluated for AL amyloidosis. When a lambda monoclonal protein is identified together with a clinical phenotype of chronic inflammatory demyelinating neuropathy (CIDP), a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome should be considered. Patients with IgM paraprotein associated neuropathy should be assessed for distal acquired demyelinating sensorimotor (DADS) neuropathy, with or without anti myelin associated glycoprotein (MAG) antibody or CANOMAD syndrome. In many cases, a monoclonal gammopathy of uncertain significance (MGUS) is incidental and unrelated to the neuropathy. Collaboration with oncology is critical in evaluating patients with monoclonal proteins to assess for underlying plasma cell neoplasms or B cell lymphomas.

Non-POEMS osteosclerotic multiple myeloma: Clinical characteristics and differential diagnosis.

Osteosclerosis in multiple myeloma (MM) is typically associated with rare POEMS syndrome, characterized by polyneuropathy (P), organomegaly (O), endocrinopathy (E), M-protein (M), and skin changes (S). However, osteosclerosis in multiple myeloma (MM) without POEMS syndrome, defined as non-POEMS Osteosclerotic MM, is exceedingly rare. We report a 70-year-old man with rib pain, remarkably high bone mineral density and diffuse osteosclerosis. The diagnosis of non-POEMS osteosclerotic MM was confirmed by biopsy and aspiration of bone marrow through surgery. A literature review spanning from 1990 identified 12 cases of similar non-POEMS osteosclerotic MM, including 5 males and 7 females with a mean age of 59.7 ± 10.6 years. The non-POEMS osteosclerotic MM can be divided into two subtypes, the osteosclerotic lesion subtype and the diffuse osteosclerosis subtype. Absence of polyneuropathy and organomegaly are the main factors that differentiate non-POEMS osteosclerotic MM from POEMS. A hyperactive osteoblastic process might be the etiology of diffuse osteosclerosis. Further research is needed to understand its etiology and pathophysiology.

Hematologic malignancies and hematopoietic stem cell transplantation.

Paraneoplastic neurologic syndromes are rarely associated with hematologic malignancies. In their rarity, lymphomas are the diseases with more frequent paraneoplastic neurologic syndrome. High-risk antibodies are absent in most lymphoma-associated paraneoplastic neurologic syndromes, with the exception of antibodies to Tr/DNER in paraneoplastic cerebellar degeneration, mGluR5 in limbic encephalitis, and mGluR1 in some cerebellar ataxias. Peripheral nervous system paraneoplastic neurologic syndromes are rare and heterogeneous, with a prevalence of demyelinating polyradiculoneuropathy in non-Hodgkin lymphoma. Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) is a rare, paraneoplastic syndrome due to an underlying plasma cell disorder. The diagnosis is based on defined criteria, and vascular endothelial growth factor (VEGF), not an antibody, is considered a reliable diagnostic marker that also mirrors therapy response. As with the paraneoplastic neurologic syndromes in solid tumors, therapies rely on cancer treatment associated with immunomodulatory treatment with better response in PNS with antibodies to surface antigens. The best outcome is generally present in Ophelia syndrome/limbic encephalitis with anti-mGluR5 antibodies, with frequent complete recovery. Besides patients with isolated osteosclerotic lesions (where radiotherapy is indicated), hematopoietic stem-cell transplantation is the therapy of choice in patients with POEMS syndrome. In the paraneoplastic neurologic syndromes secondary to immune checkpoint inhibitors, discontinuation of the drug together with immunomodulatory treatment is recommended.

Low serum total cholesterol levels predict inferior prognosis of patients with POEMS syndrome.

Low serum cholesterol levels are associated with increased tumor morbidity and mortality. However, the relationship between serum lipid profile and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) is still unclear. The aim of our study was to clarify the importance of the serum lipid profile in predicting the severity and prognosis of patients with POEMS syndrome. Forty-three patients with newly diagnosed POEMS syndrome admitted to the Department of Hematology of Jiangsu Provincial People's Hospital between August 2013 and February 2023 were selected. They had explicit serum lipid profiles. There were 27 males and 16 females with a median age of 54 years (range, 28-77 years). Survival curves were plotted using the Kaplan-Meier method, and comparisons between the two groups were performed using the log-rank test. The Cox proportional-hazards model examined risk factors associated with the prognosis of POEMS syndrome. Receiver-operator characteristic (ROC) curves assessed the predictive accuracy. 23 (53.5%) patients had low total cholesterol (TC) levels. Low levels of TC were concerned with unfavorable progression-free survival (PFS) (p = 0.007) and overall survival (OS) (p = 0.004), and at the same time, the low circulating TC concentration was an independent risk factor for PFS (p = 0.020) and OS (p = 0.011). Low TC values could improve the risk stratification, especially in high-risk patients. In conclusion, low serum TC levels may predict inferior prognosis in patients with POEMS syndrome; in future clinical application, low TC may be a reliable indicator of prognosis.

A Multicenter Analysis of Clinical Features and Long-Term Outcomes of POEMS Syndrome in Korea.

BACKGROUND: POEMS syndrome is a rare form of plasma cell dyscrasia characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins, and skin changes. Owing to its low incidence, there are few reports regarding this syndrome. This multicenter study included 84 patients diagnosed with POEMS syndrome in South Korea. METHODS: We retrospectively evaluated 84 patients diagnosed with POEMS syndrome at 8 hospitals in South Korea between January 2000 and October 2022. The clinical characteristics and treatment outcomes were analyzed. RESULTS: The median patient age was 53 years (range, 26-77 years), and 63.1% of the patients were male. All patients had peripheral neuropathy, and 81 (96.4%) had monoclonal plasma cell proliferation. Plasma vascular endothelial growth factor levels were available for 32 patients with a median of 821 pg/mL (range, 26-12,900 pg/mL). Other common features included skin changes (54.2%), volume overload (71.4%), and organomegaly (72.6%). Of the 84 patients, 75 received initial treatment (local radiotherapy, 6 [8.0%]; chemotherapy, 17 [22.7%]; both chemotherapy and local radiotherapy, 9 [12.0%]), upfront autologous stem cell transplantation (ASCT), 43 (57.3%; with induction chemotherapy, n = 12, 16.0%; without induction chemotherapy, n = 31, 41.3%). The median follow-up duration was 40.7 months. The 5-year overall survival (OS) was 78%, and the 5-year progression-free survival (PFS) was 55%. Patients who underwent upfront ASCT and were diagnosed after 2014 had a longer OS and PFS. CONCLUSION: The demographics of Korean patients with POEMS syndrome were similar to those reported previously. Because of the introduction of new treatment agents and the reduced rate of transplant-related mortality related to ASCT, the treatment outcomes of Korean patients with POEMS syndrome have improved in recent years.