Osteosclerotic Bone Lesions Research Articles

Cardiovascular manifestations of Erdheim-Chester disease: A narrative review with two cases.

Erdheim-Chester disease (ECD) is a rare 'L' (Langerhans) group histiocytic neoplasm that affects a multitude of organ systems, causing osteosclerotic bone lesions, periaortic encasement ('coated' aorta), retroperitoneal fibrosis involving kidneys and ureters ('hairy kidney'), and infiltration of the central nervous system. Cardiovascular involvement can occur in up to 70% of patients and is usually found during computed tomography/magnetic resonance imaging evaluation. When present, cardiovascular symptoms can have wide variability in presentation from asymptomatic to pericarditis, fatal cardiac tamponade, myocardial infarction, conduction abnormalities, heart failure, renal artery stenosis, and claudication. Cardiac involvement found on imaging includes right atrial pseudotumor, right atrioventricular groove infiltration, and pericardial effusions. ECD can involve the large- and medium-sized arteries, often seen as periarterial thickening (commonly coating the aorta) with stenosis/occlusion. Although more cardiovascular ECD cases have begun to be published in the literature, more data are needed on the outcomes of these patients, as well as how cardiovascular manifestations respond to treatment of ECD.

Dutcher bodies as a diagnostic key to POEMS syndrome.

A 55-year-old Japanese man was presented to our hospital for examination of edema in the lower legs, followed by numbness in the lower legs and penis, and erectile dysfunction for the past 4 months. Physical examination showed hypoesthesia of the bilateral feet, indicating peripheral polyneuropathy. Imaging studies showed pleural and pericardial effusions. Blood tests revealed high levels in leukocyte (108.2 × 102 /µl) and platelet (63.7 × 104 /µl) counts, C-reactive protein (1.27 mg/dl), potassium (7.2 mmol/L), blood urea nitrogen (82 mg/dl), and creatinine (2.22 mg/dl). Acute kidney injury was suggested. Computerized tomography of the sagittal section of the body showed multiple osteosclerotic lesions in the vertebrae (Figure 1A, arrowheads). A metastatic bone tumor was suspected, although tumor markers and history presented no evidence of the primary tumor. A biopsy of the osteosclerotic lesions was performed. Hematoxylin-eosin image of the bone biopsy showed a few areas of tiny cellular nests among sclerotic bones at low magnification (Figure 1B, circles; bar: 200 µm). A careful examination of the cells in the nests at high power revealed the presence of nuclear pseudoinclusion called Dutcher bodies (Figure 1C, circles; bar: 20.0 µm), suggesting their plasma cell origin. Immunohistochemistry showed that the lesion was positive for CD138 and negative for cytokeratin AE1/AE3. In situ hybridization for immunoglobulin (Ig) κ and Ig λ confirmed that the tumor was an Ig λ-positive plasma cell neoplasm. Taken together, the diagnosis was established as POEMS syndrome, characterized by polyneuropathy (“P”), organomegaly (“O”), endocrine abnormality (“E”), monoclonal proliferation of plasma cells (“M”), and skin lesion (“S”). [1] The present case meets its one major criteria (osteosclerotic bone lesions) and two minor criteria (extravascular volume overload and thrombocytosis) in addition to “P” and “M”. The patient underwent Rd (lenalidomide and dexamethasone) therapy, followed by high-dose melphalan administration and autologous peripheral blood stem cell transplantation. Four and a half years later, a bone marrow aspiration sample was negative for minimal residual disease by 8-color flow cytometry. In the present case, a plethora of clinical findings hampered a unified interpretation, and hence, an early diagnosis. A pathologist's eye integrated a histological clue (Dutcher bodies) and all clinical findings, leading to a definite diagnosis. We have no funding resources to declare for this work. The authors declare no conflict of interest. This work was approved by the Ethics Review Board of Hyogo Medical University (No.0231). Informed consent was obtained from the patient for the publication of this article. The data that support the findings of this study are available at reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Recent Advances in the Treatment and Supportive Care of POEMS Syndrome

POEMS is a rare clonal plasma cell disorder characterized by multi-systemic features that include demyelinating peripheral neuropathy, organomegaly, endocrinopathy, presence of monoclonal proteins (M-protein), and skin changes. Even though the pathophysiology is poorly understood, recent studies suggest that both clonal and polyclonal plasmacytosis leading to the production of pro-inflammatory cytokines and angiogenic mediators play the central role. These mediators including vascular endothelial growth factor (VEGF) are the driving forces of the syndrome. The diagnosis of POEMS is not always straight forward and often the diagnosis is delayed. It is based on fulfilling mandatory criteria of polyradiculoneuropathy and monoclonal protein and the presence of one major criterion (Castleman disease, sclerotic bone lesions, or elevated VEGF), and at least one minor criterion. Due to the presence of neuropathy, it can be confused with chronic inflammatory demyelinating polyradiculopathy (CIDP), and if thrombocytosis and splenomegaly are present, it can be confused with myeloproliferative neoplasms. Due to the rarity of the syndrome, clear guidelines for treatment are still lacking. Immediate treatment targeting the underlying plasma cell proliferation results in a dramatic response in most patients. The key is early diagnosis and immediate anti-plasma cell directed therapy for the best clinical outcomes. For patients with disseminated disease as defined by bone marrow involvement or more than three osteosclerotic bone lesions, high-dose chemotherapy with autologous hematopoietic stem cell transplant (ASCT) yields durable responses and is the preferred treatment in eligible patients. For patients with localized bony disease, radiotherapy has proven to be very effective. Lenalidomide and dexamethasone is a proven therapy in patients ineligible for ASCT. In this review article, we tackle the diagnostic approach and discuss the latest treatment modalities of this rare debilitating disease.

Occupational engagement, fatigue, and upper and lower extremity abilities in persons with melorheostosis.

Melorheostosis is a rare bone disorder with limited literature that describes the effect of this disease on functional and motor abilities. As part of a natural history study, four outcome measures were administered to better understand the burden this disease has on a person's ability to engage in basic and instrumental activities of daily living. To investigate the relationship between functional engagement, fatigue, and motor ability in patients with melorheostosis. Cross-sectional data gathered from a longitudinal natural history observational study. Rehabilitation department within a single institution. Forty-seven adult volunteers with melorheostosis were enrolled. Two participants were removed for failure to meet diagnosis eligibility. Thirty patients had lower extremity (LE) osteosclerotic bone lesions, 14 had upper extremity (UE) lesions, and one had lesions in both UEs and LEs. Not applicable. Activity Card Sort, Second Edition (ACS); Multi-Dimensional Fatigue Inventory; Lower Extremity Functional Scale; Upper Extremity Functional Index. On the ACS, high-demand leisure (HDL) activities were the least retained (p < .001). Of the activities rated most important, HDL activities were the most likely to have been given up (27%). General fatigue (μ=11.8) and physical fatigue (μ=11.0) were the two most limiting fatigue constructs. There were moderate negative correlations with HDL activities compared to physical fatigue (r=-0.524, p < .001) and reduced activity fatigue (r=-0.58, p=.001). LE lesions had a large effect on completing LE tasks (d=0.95) and UE lesions had a medium effect on completing tasks involving the UE (d=0.69). Patients with melorheostosis experience fatigue and low engagement in HDL activities. The results of this study underscore the importance of acknowledging activity domain, fatigue constructs, and lesion location to support and provide targeted evidence-based rehabilitative therapy. NCT02504879.

Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice.

Prostate cancer (PCa) is the most frequent malignancy in older men with a high propensity for bone metastases. Characteristically, PCa causes osteosclerotic lesions as a result of disrupted bone remodeling. Extracellular vesicles (EVs) participate in PCa progression by conditioning the pre-metastatic niche. However, how EVs mediate the cross-talk between PCa cells and osteoprogenitors in the bone microenvironment remains poorly understood. We found that EVs derived from murine PCa cell line RM1-BM increased metabolic activity, vitality, and cell proliferation of osteoblast precursors by >60%, while significantly impairing mineral deposition (−37%). The latter was further confirmed in two complementary in vivo models of ossification. Accordingly, gene and protein set enrichments of osteoprogenitors exposed to EVs displayed significant downregulation of osteogenic markers and upregulation of proinflammatory factors. Additionally, transcriptomic profiling of PCa-EVs revealed the abundance of three microRNAs, miR-26a-5p, miR-27a-3p, and miR-30e-5p involved in the suppression of BMP-2-induced osteogenesis in vivo, suggesting the critical role of these EV-derived miRNAs in PCa-mediated suppression of osteoblast activity. Taken together, our results indicate the importance of EV cargo in cancer-bone cross-talk in vitro and in vivo and suggest that exosomal miRNAs may contribute to the onset of osteosclerotic bone lesions in PCa.

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.

Erdheim chester disease: A case report and review of the literature

Erdheim Chester disease is a rare form of non-Langerhans histiocytosis with frequent BRAF V600E mutations. It is mainly characterized by multifocal osteosclerotic bone lesions with or without systemic involvement. The histologic image is consistent with a histiocytic proliferation of foamy cells in a polymorphic background. The main difference from the Langerhans histiocytosis is the immune profile with mainly S100, CD1a, and langerin negative. The overall prognosis is dependent on extraskeletal involvement. Herein, we present a typical presentation of Erdheim Chester disease with a review of the literature.

MON-511 Erdheim-Chester Disease: A Challenging Diagnosis in a Patient with Ataxia, Osteosclerotic Bone Lesions, and a Long-Standing History of Central Diabetes Insipidus

Background: Erdheim- Chester Disease (ECD) is a rare hematopoietic neoplasm characterized by multi-organ infiltration with CD-68 -positive, CD1a-/S100-negative foamy histiocytes causing xantho-granulomatous inflammation. ECD most commonly involves the skeleton. CNS, pulmonary and CV involvement are also reported. Clinical Case: A 47-year-old male with a prior history of central Diabetes Insipidus (DI) presented with bone pain and ataxia. He was initially referred in 1993 for evaluation of DI. It was concluded that he had lymphocytic infundibulitis (LI), based on the finding of a thickened pituitary stalk on MRI while CSF revealed no evidence of infection or neoplasm. His DI was controlled with DDAVP. He had no other anterior pituitary hormone deficiencies. Although subsequent MRI showed resolution of the pituitary stalk thickening, his DI persisted. In 2012, he developed progressive gait instability, slurred speech and impaired motor coordination. On exam, he exhibited horizontal nystagmus, dysarthria, and truncal ataxia greater than limb ataxia. A brain MRI revealed absence of the posterior pituitary bright spot, enhancement along the proximal 7th and 8th nerve complex, disproportionate cerebellar atrophy and enhancement along the bilateral cerebellar folia. He complained of progressive, chronic leg pain since 2005. In 2018, he underwent tibial bone biopsy for an osteosclerotic lesion with diagnosis of Paget’s disease (PD). His Ca, Phos, 25OH- D, PTH, and Alk Phos were normal. Subsequent X-rays noted lesions of the pedicle of the left shoulder and pelvis, medullary sclerosis in the humeral diaphysis, and symmetrical lesions in the distal femur and tibia, bilaterally. Bone scan and FDG-Pet scan showed increased activity in the lesions. A repeat tibial biopsy revealed the marrow was infiltrated with histiocytes, fibrosis and sclerosis of trabecular bone. The histiocytes were highlighted by CD163, CD68, CD14, factor XIIIa and fascin A few scattered histiocytes were BRAF V600E immuno-stain positive, consistent with a diagnosis of ECD. His symptoms improved on Vemurafenib. Conclusion: We report a male with ECD who initially presented with isolated DI and a clinical course that mimicked LI. DI is a feature that occurs early in the disease process in 25% of patients. More than 10 years later, he developed ataxia and multifocal osteosclerotic bone lesions. His bone lesions were misdiagnosed as PD, but a repeat bone biopsy led to the correct diagnosis. In contrast to PD, the bone lesions in ECD are bilateral and symmetric and affect the diaphysis of long bones, specifically. As in our case, some patients with ECD can be asymptomatic for decades. For symptomatic patients who are BRAFV600E +, the B-Raf enzyme inhibitor, Vemurafenib, is recommended. His diagnosis was challenging, because ECD is rare (500 cases) and has features that overlap with other more common medical conditions.

Long-Term Durable Responses after Autologous Stem Cell Transplantation in POEMS Syndrome

Abstract:Background:POEMS syndrome is a constellation of symptoms of polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Other features often present in this syndrome include papilledema, extravascular volume overload, sclerotic bone lesions, Castleman disease, high vascular endothelial growth factor (VEGF) levels and thrombocytosis/polycythemia. The standard of care has not been established in the management of the disease. We had previously reported on the role of auto-HCT in a smaller cohort of POEMS patients at our institution1. Here, we present an updated analysis in a larger cohort of POEMS patients who underwent auto-HCT.Methods:We retrospectively reviewed the outcomes of POEMS patients who underwent auto-HCT at our institution from the period of January, 1999, through June, 2018. The Kaplan-Meier method was used to caculate progression-free survival (PFS) and overall survival (OS). Hematologic response was defined as per the International Myeloma Working Group (IMWG) criteria. OS was defined as the duration from the date of transplant to death or last date of follow-up in alive patients. PFS was defined as the duration from the date of transplant to either progressive disease or death, whichever occurred first.Results:16 patients (13 males, 3 females) with POEMS syndrome received a total of 17 auto-HCTs. One patient underwent auto-HCT two times for multiple relapses. The median age at auto-HCT was 48 years (range: 18-75). The median time from diagnosis to auto-HCT was 15 months (2-141 months). All 16 (100%) patients had peripheral neuropathy and monoclonal gammopathy: IgG lambda in 7, IgA lambda in 6, IgG kappa in 2 and light chain in 1 patient. Other features were: osteosclerotic bone lesions in 13 (81%), endocrinopathy in 10 (69%), skin involvement in 8 (50%) and extravascular fluid overload in 7 (44%). Three (18%) patients had biopsy-proven co-existent Castleman disease. Among patients with available data (n=7), the mean serum VEGF level pre-transplant was 389 pg/ml (268-1622). The median HCT-CI (comorbidity index) score available for 15 patients was 2 (range 0-7). The median number of chemotherapies received before the transplant was 1 (range 1-3). Table 1 summarizes the prior systemic chemotherapies received before auto-HCT. Two patients also received plasmapheresis, and eight patients received radiation therapy for bone disease. The mobilization regimens used for collecting peripheral blood stem cells were granulocyte colony-stimulating factor (G-CSF) alone, cyclophosphamide+G-CSF and G-CSf+plerixafor in 16, 2 and one patient, respectively. The median number of CD34+ stem cells collected was 3.43 X 106 cells/kg (range 1.73 - 6.5).The overall response rate, as per the IMWG criteria, for the entire cohort was 94% (16/17): 5 (29.4%) CR, 4 (23.5%) nCR, 1 (5.8%) VGPR, and 6 (35.2%) PR. The mean serum VEGF levels improved from 389 pg/ml before transplant to a level of 35 pg/ml (31-86) post-transplant. Engraftment syndrome was seen only in 1 patient who required corticosteroid use. One-year transplant-related mortality was 0%. Median follow-up among surviving patients is 52 months (5-120 months). The median PFS and OS have not been reached yet. All 16 patients had a complete or partial resolution of their clinical symptoms after auto-HCT. 4-year PFS and OS rate for the entire cohort is 80.2% and 100% respectively. At ten years, PFS and OS rate is 59.4% and 80% respectively. Fourteen out of 16 patients were alive at the time of the last follow-up. One patient died six years after his auto-HCT secondary to gastrointestinal bleeding unrelated to his underlying disease, and the second patient died after 11 years post auto-HCT of unknown cause.Conclusions:Upfront Auto-HCT provides durable chemotherapy free remission and significant clinical improvement in patients with POEMS syndrome.

Abstract 637: Establishment of a realistic patient-derived xenograft (PDX) model for prostate cancer bone metastasis

Abstract Bone metastases are frequent and fatal outcome of advanced prostate cancer. Many of the currently used preclinical models lack typical characteristics of the heterogenic human disease. We improved existing methodology by using fresh patient-derived material in a xenograft model of bone metastasis. Clinical prostate tumor specimens were collected from robotic-assisted laparoscopic radical prostatectomy operations in Turku University Hospital (Turku, Finland). Patient-derived tumor tissue of Gleason grade 8-10 tumors (n = 5) were cut into small pieces, digested overnight, and then cell suspension was intratibially inoculated into the bone marrow cavity of nude mice (n = 8-10/patient). X-ray pictures were taken and blood samples were collected once a month. Mice were sacrificed 6 months after tumor cell inoculation, and hind limbs and lungs were collected for histological and immunohistochemical analysis. PSA was measured from serum using commercial kit. X-rays demonstrated osteosclerotic bone lesions. Immunohistochemical analysis showed that 80% of tumors in bone expressed similar characteristics compared with original tumor (androgen receptor AR, prostate specific antigen PSA, proliferation marker Ki67). However, no changes were seen in serum PSA. Lung metastases were detected in 50% of tumor-bearing mice. Interestingly, the most of lung metastases were negative for AR and PSA, which indicates that the cell population that forms metastases may be undifferentiated clone of heterogenic tumor and therefore the most aggressive. Our platform provides new tools for prostate cancer research. Citation Format: Yvonne Konkol, Maija Valta, Jenni Bernoulli, Pekka Taimen, Peter Boström, Pirkko Härkönen, Jussi Halleen, Johanna M. Tuomela. Establishment of a realistic patient-derived xenograft (PDX) model for prostate cancer bone metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 637.

Durable responses with autologous hematopoietic SCT in patients with POEMS syndrome

Durable responses with autologous hematopoietic SCT in patients with POEMS syndrome

Complete Remission and Long-term Survival in a Child With Relapsed Medulloblastoma With Extensive Osteosclerotic Bony Metastasis With a Novel Metronomic Chemobiological Approach

Extraneural metastases in medulloblastoma are rare. We report a boy with medulloblastoma who was initially treated with gross total excision of primary tumor followed by radiotherapy. Six years later, he developed disseminated osteosclerotic bony relapse associated with bone marrow involvement. He was successfully salvaged with metronomic low-dose cyclophosphamide, etoposide, and zoledronic acid. In patients with medulloblastoma and bone pain, metastases to bone should be excluded, and medulloblastoma should be considered while investigating osteosclerotic bone lesions. Furthermore, metronomic chemotherapy should be considered in this setting until better therapeutic modalities emerge.

Patients with POEMS Syndrome Have High Bone Turnover and Increased Circulating Angiogenic Cytokines; Should Angiopoietin-2 and Bone-Specific Alkaline Phosphatase Be Used As Minor Criteria for the Diagnosis of the Disease?

Abstract 806▪FN2▪This icon denotes a clinically relevant abstractPOEMS syndrome is defined by the presence of peripheral neuropathy (P), monoclonal plasma cell disorder (M), organomegaly (O), endocrinopathy (E) and skin changes (S). The majority of patients have sclerotic bone lesions, although the underlying mechanisms are still unclear. Increased circulating vascular endothelial growth factor (VEGF) is another feature of the disease. However, there is almost no information on the role of other angiogenic molecules in POEMS biology. The aim of the study was to evaluate bone metabolism and angiogenic cytokines in POEMS and compare the results with multiple myeloma (MM) and osteosclerotic patients of other etiology.We retrospectively studied 61 POEMS patients (40M/21F, median age 52 years) who were diagnosed between 1996 and 2010 and were treated and followed in Mayo Clinic Rochester (MN, USA), Hôpital Saint-Louis, Paris (France) and in Alexandra Hospital, Athens (Greece). We evaluated the following indices of bone remodeling and angiogenesis in all patients at diagnosis and in 22 of them one month after front-line treatment: i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)]; ii) osteoblast inhibitor dickkopf-1 (Dkk-1); iii) bone resorption marker CTX; iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin]; and v) angiogenic cytokines [VEGF, angiogenin (ang), angiopoietin (angp)-1 and -2]. These molecules were also measured in 60 newly diagnosed, untreated MM patients (34M/26F, median age: 54 years) and 44 healthy controls. Bone markers were also evaluated in 24 patients with HbS/beta-thalassemia (10M/14F, median age: 43 years) who presented with osteosclerosis, defined as osteosclerotic bone lesions in plain radiography and high T-score of lumbar spine DXA (median: +3.6, range: +2 to +7.9).All POEMS patients presented with P and M, while 90% had E, 83% had S, 61% had O and 32% had papilloedema. One or more documented sclerotic bone lesions in plain X-rays were observed in 78% of patients (diffuse lesions in 44%), while 43% of patients had also an osteolytic component. Seven patients had Castleman disease.At diagnosis, compared to controls, POEMS patients had increased levels of bALP (mean ± SD: 48.3 ± 22.9 IU/L vs. 21.6 ± 8.2 IU/L; p<0.001), CTX (0.97 ± 0.94 ng/ml vs. 0.33 ± 0.24 ng/ml; p<0.001), Dkk-1 (p<0.001), sRANKL (p<0.001) and sRANKL/OPG ratio (p<0.001). Patients with diffuse osteosclerosis had increased levels of Dkk-1 compared to others (p = 0.05), suggesting a balance effect to increased formation activity. Patients with POEMS had increased levels of bALP and decreased levels of CTX compared to MM patients (p<0.001 and p = 0.03, respectively), while they had increased levels of CTX and sRANKL/OPG ratio compared to HbS/beta-thal patients (p = 0.001 for both comparisons). There were no other differences regarding bone markers among studied groups.Regarding angiogenic cytokines, at diagnosis, POEMS patients had elevated VEGF (1232 ± 565 pg/ml vs. 195 ± 211 pg/ml; p<0.001), ang (266 ± 82 ng/ml vs. 190 ± 45; p<0.001) and angp-2 (3.5 ± 2.2 ng/ml vs. 1.2 ± 0.6 ng/ml; p<0.001) and decreased angp-1 (p =0.05) and angp-1/angp-2 ratio (reflects increased angiogenic capacity; 9.1 ± 8.8 vs. 44.8 ± 76.1; p<0.001) compared to normal controls. We found no strong correlations between the levels of VEGF, ang and angps. When compared to MM patients, POEMS patients had increased circulating VEGF (p = 0.001) without any difference regarding the other angiogenic cytokines. Response to therapy was accompanied by a dramatic reduction of VEGF only (551 ± 541 pg/ml compared to baseline 1800 ± 1510 pg/ml; p = 0.003).Receiver-operating characteristic (ROC) curve analysis showed that high levels of angiopoietin-2 (≥ 2.3 ng/ml) and high bALP (≥ 38 IU/l) each have a 95% specificity for patients with POEMS syndrome.These results suggest that patients with POEMS syndrome have high bone turnover with increased bone formation as compared to healthy subjects, to MM patients, who have reduced bone formation, and to osteosclerotic HbS/beta-thal patients, who have diminished bone resorption. Importantly, our analysis supports the use of angp-2, bALP along with VEGF as minor criteria for the diagnosis of POEMS. Successful treatment reduced VEGF, which seems to be a suitable marker for the follow-up of POEMS patients. Furthermore the imbalance of angp-1/angp-2 pathway may indicate possible targets for the development of novel agents against POEMS. Disclosures:No relevant conflicts of interest to declare.

Durable Responses with Autologous Hematopoietic Stem Cell Transplantation in Patients with POEMS Syndrome

Abstract 4522 Introduction:POEMS syndrome (polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) is a rare plasma cell disorder often associated with papilledema, extravascular volume overload, sclerotic bone lesions, Castleman disease, and high vascular endothelial growth factor (VEGF) levels. High-dose chemotherapy and autologous hematopoietic stem cell transplant (auto-HCT) can be used with good clinical response, but has significant post-transplant morbidity. Here we present our experience in 5 patients with POEMS syndrome who underwent auto-HCT at the MD Anderson Cancer Center (MDACC). Method:Between January 1999 and October 2010, 5 patients (4 males, 1 female) with POEMS syndrome received auto-HCT at MDACC. Diagnosis of POEMS was based on criteria of Dispenzieri et. al.1 All 5 patients had received systemic therapy prior to auto-HCT as follows: bortezomib+dexamethasone (dex) in 2, lenalidomide+dex in 1, cyclophosphamide+dex in 1, and pulse dex in 1. Two patients also received localized radiation for bone disease. Peripheral blood stem cells were collected with granulocyte colony-stimulating factor (G-CSF) in 4 patients and with cyclophosphamide+G-CSF in 1. The preparative regimen was melphalan 200 mg/m2 in 4 patients, while 1 patient received 180 mg/m2 due to renal insufficiency. We evaluated the response rate, toxicity, transplant-related mortality, progression-free survival (PFS) and overall survival (OS). Hematologic response was defined by the International Myeloma Working Group (IMWG) criteria2. Result:Median age at auto-HCT was 48 years (range: 39–58) and median time from diagnosis to auto-HCT was 16.6 months (6.4 – 89 months). All 5 patients had osteosclerotic bone lesions and monoclonal gammopathy: IgA lambda in 3, IgG lambda in 1, and IgG kappa in 1. Two patients had biopsy proven Castleman disease. Four patients had debilitating polyneuropathy. Other features were: skin involvement in 3, endocrinopathy in 2, ascites in 1, anasarca in 2, pulmonary hypertension in 1, and papilledema in 1. Median follow up after auto-HCT was 11.6 months (8.6 – 83.5 months). Median Karnofsky performance status was 80% (70–100) at the time of transplant and 90% (80–100) by the one year follow up visit. Two patients (40%) had complete response, 2 (40%) had a very good partial response, and 1 (20%) had a partial response by IMWG criteria. Engraftment syndrome was not seen in any of the 5 patients. Significant post auto-HCT complications were fungal pneumonia in 2 patients and pulmonary embolism in one. Patients fully recovered from these complications. One-year transplant-related mortality was 0%. All 5 patients had complete or significant resolution of their clinical symptoms after auto-HCT. Median PFS and OS have not yet been reached. With a median follow up of 11.6 months, 1-year PFS and OS were 100%. Four patients are alive and in remission, while one patient died 6 years after his auto-HCT secondary to gastrointestinal bleeding unrelated to his underlying disease. Conclusion:High-dose therapy followed by auto-HCT is safe and effective in selected patients with POEMS syndrome and is associated with durable responses and survival. Disclosures:No relevant conflicts of interest to declare.

Improvement of recurrent urticaria in a patient with Schnitzler syndrome associated with B-cell lymphoma with combination rituximab and radiotherapy

Schnitzler syndrome is a rare condition defined by chronic urticaria, osteosclerotic bone lesions, and monoclonal IgM gammopathy. Schnitzler syndrome can precede the onset of a true lymphoproliferative disorder including Waldenström macroglobulinemia and rarely systemic marginal zone B-cell lymphoma. We describe a case of intractable chronic urticaria accompanied by a retroperitoneal neoplasm. IgM monoclonal gammopathy, lumber pain, intermittent fever, and elevation of C-reactive protein were the clues for the diagnosis of Schnitzler syndrome. An evaluation for malignancy using systemic computed tomography scan and fluorodeoxyglucose positron emission tomography revealed the retroperitoneal tumor, and a subsequent bone-marrow aspirate confirmed the diagnosis of B-cell lymphoma. Combined rituximab and radiotherapy ameliorated the skin symptoms. This case indicates that a detailed search for malignant neoplasms might be required for the long-term management of Schnitzler syndrome, and that B-cell lymphomas may contribute to the pathogenesis of this condition.

A Case of Multiple Myeloma Associated with Multifocal Osteosclerosis (Multiple Myeloma with Osteosclerosis)

Osteosclerotic myeloma is a rare entity, characterized by single or multiple osteosclerotic bone lesions and usually accompanied by a polyneuropathy syndrome (POEMS). Multiple myeloma with osteosclerotic lesions without polyneuropathy is exceedingly rare. We report a case of multiple myeloma associated with multifocal osteosclerotic lesions without any evidence of POEMS. A 48-year-old woman presented with incidentally found osteosclerosis of 8th thoracic vertebra on a plain chest film. Bone survey, CT scan, MR scan, and radioisotope scintigraphy revealed multiple localized osteoclerosis; serum protein immunofixation showed IgG, lambda monoclonal gammopathy. A biopsy of T8 vertebral body disclosed plasma cell myeloma. Given that there was no organ or tissue damage other than multifocal osteosclerosis, the patient was placed on close observation with regular examination. This case indicates that although rare, multiple myeloma should be included in the differential diagnosis of sclerotic bone lesions.

High Bone Turnover and Increased Angiogenesis Cytokines in Patients with POEMS Syndrome.

POEMS syndrome is defined by the presence of peripheral neuropathy (P), monoclonal plasma cell disorder (M), organomegaly (O), endocrinopathy (E), and skin changes (S). Virtually all patients will have sclerotic bone lesions, although the mechanisms of their development have not been clarified to-date. Increased plasma level of VEGF is another characteristic of the disease. However, there is very little information for the role of other angiogenic molecules in POEMS pathogenesis. The aim of this study was to evaluate bone metabolism and angiogenic cytokines in POEMS and compare the results with multiple myeloma (MM) and osteosclerotic patients of other etiology. Seven patients with POEMS at diagnosis (6M/1F; median age: 49 years) were evaluated. A series of bone remodeling indices were measured: i) bone resorption markers [C- and N- telopeptide of type-I collagen (CTX and NTX), TRACP-5b], ii) bone formation markers [bone-alkaline phosphatase, osteocalcin (OC), and C-terminal propeptide of type-I collagen (CICP)], and iii) osteoclast regulators [soluble RANKL, osteoprotegerin (OPG), MIP-1α, and TNF-α]. Furthermore, the following angiogenic cytokines were measured in the plasma of POEMS patients: VEGF, VEGF-A, angiogenin, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and bFGF. All above molecules were also measured in 25 newly diagnosed, untreated MM patients (14M/11F, median age: 64 years) and 20 healthy controls. Bone markers were also evaluated in 24 patients with HbS/beta-thalassemia (10M/14F, median age: 43 years) who presented with osteosclerosis, i.e. osteosclerotic bone lesions in plain radiography and a median T-score of lumbar spine Bone Mineral Density of +3.6 (range: +2 to +7.9). All POEMS patients had P, O, E, S, edema and thombocytosis; 6 had E and 2 Castleman's disease. Six patients had sclerotic bone lesions, while 4 had also a lytic component in their bone lesions. POEMS patients had increased levels of sRANKL (p=0.003), OPG (p=0.008), TNF-α (p=0.001), NTX (p<0.001), CTX (p=0.001) and CICP (p=0.001) compared with controls. Interestingly, NTX levels were even higher in POEMS than in MM patients (p<0.01). NTX and CTX were elevated in POEMS compared with osteosclerotic HbS/β-thal patients (p<0.01), who had reduced bone resorption compared with controls. POEMS patients had increased levels of OC and CICP compared with MM (p=0.02 and p=0.003, respectively), and increased levels of OC compared with osteosclerotic HbS/β-thal patients (p<0.01). In terms of angiogenic cytokines, POEMS patients had increased levels of all studied cytokines compared with controls (p<0.01). All POEMS patients had at least 1.8-fold higher value of VEGF-A (the major angiogenic component of VEGF) compared with the higher value observed in controls. Furthermore, VEGF (p=0.03), VEGF-A (p<0.001), angiogenin (p<0.001), and bFGF (p=0.01) were higher in POEMS than in MM. The ratio of Ang-1/Ang-2 was very low in POEMS compared with both controls and MM. These results suggest that POEMS patients have increased bone turnover in contrast to MM patients who have reduced bone formation and osteosclerotic HbS/β-thal patients who have diminished bone resorption. Furthermore the imbalance of Ang-1/Ang-2 pathway and the increased levels of angiogenic cytokines, even compared with MM, may indicate possible targets for the development of novel agents against POEMS.

Glomeruloid haemangioma with cerebriform morphology in a patient with POEMS syndrome

A 40-year-old Chinese man presented with sensorimotor polyneuropathy, IgAlambda paraprotein, osteosclerotic bone lesions, hypertrichosis, and impotence with decreased testosterone and raised prolactin level. POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome was diagnosed and he was treated with melphalan and prednisolone. After chemotherapy, other manifestations of POEMS syndrome developed, such as multiple haemangiomas over the chest and neck region, splenomegaly and generalized oedema. One haemangioma had a peculiar clinical morphology, similar to the appearance of cerebral gyri. Skin biopsy confirmed the diagnosis of glomeruloid haemangioma. Chemotherapy was then switched to cyclophosphamide and prednisolone, resulting in further improvement in muscle power and hypertrichosis. To our knowledge, this is the first report on a clinically distinctive morphology of glomeruloid haemangioma, and its recognition may increase the index of suspicion for early skin biopsy.

Angiogenetic Factors and Biochemical Markers of Bone Metabolism in POEMS Syndrome Treated with High-Dose Therapy and Autologous Stem Cell Support

The cause of the polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes (POEMS) syndrome is currently unknown, but increased levels of vascular endothelial growth factor (VEGF) appear to play a pathogenetic role. Osteosclerotic bone lesions are a characteristic finding in POEMS, but there are no data about the specific role of various molecules that control bone remodeling in patients with POEMS. Serum levels of angiogenic cytokines (VEGF, angiogenin, angiopoietin-2, and basic fibroblast growth factor) along with a series of bone remodeling indices (C-telopeptide of type I collagen, bone-alkaline phosphatase [bALP], osteocalcin [OC], soluble receptor activator of nuclear factor–κB ligand [RANKL], osteoprotegerin [OPG], and macrophage inflammatory protein-1α) were measured in 2 patients with POEMS before and after high-dose therapy (HDT) with autologous stem cell transplantation and in age- and sex-matched controls. Increased VEGF levels before HDT were reduced significantly after treatment, although levels of the other angiogenetic factors did not differ from that of controls and were less influenced by HDT. Serum RANKL levels were increased before HDT, whereas OPG levels were within the levels of healthy controls, resulting in an abnormal soluble RANKL to OPG ratio. Levels of bone resorption markers (C-telopeptide of type I collagen) were very low or undetectable before HDT, although bALP and OC levels were similar to that of controls. After HDT, soluble RANKL levels decreased, OPG remained rather stable, bone resorption markers increased to levels of normal individuals, bALP levels were rather unchanged, and OC levels increased. Decreasing VEGF levels parallel clinical improvement, and the restoration of normal bone metabolism follows HDT.

Polyneuropathy in Osteosclerotic Myeloma Coexisting With Hyaline Vascular Castleman's Disease

Peripheral neuropathy is usually the presenting feature of POEMS syndrome. Approximately 50% of patients with POEMS syndrome are associated with osteosclerotic myeloma, a rare variant of multiple myeloma, and some with Castleman's disease, an unusual lymphoproliferative disorder. The multicentric plasma cell variant of Castleman's disease is usually associated with systemic disorders rather than its localized form of mediastinal lymphoid hyperplasia characterized by hyalinization of follicles and interfollicular vascular proliferation. We report a 48-year-old woman who presented with progressive sensorimotor demyelinating polyradiculoneuropathy, bilateral optic disc edema, hepatosplenomegaly, generalized lymphadenopathy, and skin changes. There was associated thrombocytosis, hypothyroidism, hypoparathyroidism, mixed osteolytic and osteosclerotic bone lesions, monoclonal gammopathy of IgG lambda type, and hyaline vascular type of Castleman's disease. This combination of POEMS syndrome, osteosclerotic myeloma with a hyaline vascular type of Castleman's disease is uncommon.