Plasma Cell Dyscrasia in Human Immunodefficiency Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3858-3858
Author(s):  
Ahmad Jajeh ◽  
Suresh Nukala
Keyword(s):  
Bone Marrow ◽  
Hiv Infection ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Plasma Cell Dyscrasia ◽  
Durable Response ◽  
Bone Marrow Biopsies ◽  
Hiv Therapy ◽  
Dexamethasone Therapy ◽  
One Year

Abstract Plasmacytosis is commonly seen in the bone marrow biopsies of patients with acquired immunodefficiency disease AIDS and human HIV virus infection. Polyclonal increase of immunoglobulin is very common. However few cases of plasma cell dyscrasia are reported. The purpose of this abstract is to show our institution experience with plasma cell dyscrasia and HIV infection. For the last ten years ten patients were identified based on bone marrow biopsy, immunoelectophoresis and immunofixation, twenty four hours urine collection and urine electrophoresis and immunofixation. Immuno staining for kappa and lambda light chain to check for clonality were done on four cases. Mean age of patients is 49 years (range 33 to 59 years). Seven were black, two hispanic and one white. Nine were males and one female. All patients had plasmacytosis on bone marrow more than 30% and protiurea of more than one gram. five patients had nephrotic range protien urea. one patient had IgA lambda, one patient had Ig G kappa All patients had low CD4 counts except two patients with CD4 above 200 and have long standing HIV infection. One patient presented with hepatosplenomegally and increased IgM level and waldnestrome looking plasmacytoid lymphocytes. One patient had plasmablast and plasma cells syncitia who had rapidly fatal disease. one patient expired of respiratory failure before treatment. One patient, a female presented with plasma cell leukemia and did respond to Doxil, vincristine and dexamethasone therapy. She is alife. Two other patients with long standing HIV infection and CD4 count above 200 are still alife both patients were treated initially with Thalidomide and dexamethasone with excellent response. one of them failed Thalidomide after more than one year response and currently on his fourth cycle of velcaid (proteosome inhibitor). All patients were not on HIV therapy at time of diagnosis. In conclusion plasma cell dyscrasia with HIV infection do respond to treatment with durable response. Repetetive antigenic stimulation with HIV-1 p24 antigen are the proposed mechnism of oncogenesis.

scholarly journals Quantitation of Monoclonal Plasma Cells in Bone Marrow Biopsies in Plasma Cell Dyscrasia

2003 ◽  
Vol 25 (4) ◽  
pp. 167-171 ◽  
Author(s):  
G. M. Markey ◽  
P. Kettle ◽  
T. C. M. Morris ◽  
N. Connolly ◽  
H. Foster
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Cell Mass ◽  
Observation Time ◽  
Plasma Cell Dyscrasia ◽  
Bone Marrow Biopsies ◽  
Colour Figure ◽  
Light Chain Immunoglobulin ◽  
Monoclonal Proteins

Direct measurement of monoclonal plasma cell mass in bone marrow biopsies may be a useful parameter to establish in plasma cell dyscrasia. In this study monoclonal plasma cells/mm2in light chain immunoglobulin immunostained archival bone marrow sections from 22 patients in whom a diagnosis of multiple myeloma (MM) had been excluded but who had monoclonal proteins were counted by two observers at light microscopic level. There was good correlation between the counts of the two observers. The levels of monoclonal plasma cells/mm2in biopsies were not related to the % counts in the aspirates taken at the same time as the biopsies. Three of seven patients with biopsy levels in excess of the polyclonal levels in patients without plasma cell dyscrasia developed progressive MM within the observation time. Monoclonal plasma cell levels/mm2of bone marrow biopsies can be measured and they provide a useful parameter for the assessment of patients with low volume plasma cell dyscrasia. Colour figure can be viewed onhttp://www.esacp.org/acp/2003/25‐4/markey.htm.

Do patients with MGUS require a bone marrow biopsy?

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8117-8117
Author(s):  
J. Singh ◽  
A. K. Malani ◽  
C. H. Huang ◽  
M. Hashmi ◽  
S. C. Mathur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Regression Analysis ◽  
Bone Marrow Biopsy ◽  
Plasma Cell ◽  
Linear Correlation ◽  
Plasma Cells ◽  
Bone Marrow Biopsies ◽  
Cell Percentage ◽  
Serum Igg ◽  
Immunoglobulin Levels

8117 Monoclonal gammopathy of undetermined significance (MGUS) increase in prevalence with age and it is associated with risk of progression to plasma cell disorder. According to ASH guidelines, patients (pts) should have a complete blood count (CBC), creatinine, calcium, and a complete bone survey and periodic follow up. There has been no clear-cut guideline regarding the role of bone marrow biopsy in these patients. There is suggestion in the literature that bone marrow aspiration and biopsy is indicated if the M protein is 1.5 g/dL. Hypothesis We hypothesize that the increase in serum immunoglobulin is correlated with an increase in plasma cell in the bone marrow biopsy. Methods: We performed a retrospective chart review of 327 MGUS veteran patients seen from 2002 to 2005. Diagnostic criteria for MGUS were defined as <3 g/dL serum monoclonal protein, <10 % plasma cells in the bone marrow and absence of radiographic or laboratory abnormality related to the plasma cell proliferative process. Patients with smoldering myeloma were excluded. Bone marrow biopsies were available on 97/327 patients. Bone marrow biopsy with plasma cell percentage, serum protein electrophoresis (SPEP) and immunofixation (SFE), and immunoglobulin levels of these patients were retrieved and statistical analysis was performed by using Pearson correlation coefficient and linear regression analysis to detect the correlation between plasma cell percentage and immunoglobulin levels. Results: Of the 97 patients whom the bone marrow biopsy was available, 66 patients had IgG, 15 had IgA and 16 had IgM monoclonal paraprotein. There was linear correlation between serum IgG and IgA levels with the percentage of plasma cells in the bone marrow. (p< 0.001 and < 0.02 respectively. By regression analysis, using a cut off value of 10% plasma cells in the bone marrow, the predicted level of IgG and IgA immunoglobulin was 2124 mg /dl and 1564 mg/dl respectively. There was no correlation between IgM immunoglobulin and plasma cell percentage in the marrow. Conclusion: There is a linear correlation between serum IgG and IgA immunoglobulin with plasma cell percentage in the bone marrow. Bone marrow biopsy with plasma cell percentage of 10% or higher may be predicted in patients with MGUS with IgG or IGA above 2g/dl and 1.5g/dl respectively. No significant financial relationships to disclose.

scholarly journals Significance of Bone Marrow Plasma Cell Percentage in Patients with Monoclonal Gammopathy of Unknown Significance Developing Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5688-5688
Author(s):  
Mona L Vekaria ◽  
Bharat Rao ◽  
Philip Kuriakose
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Plasma Cell ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Time To Progression ◽  
Bone Marrow Biopsies ◽  
Monoclonal Protein ◽  
Cell Percentage

Abstract Introduction: Monoclonal gammopathies are characterized by the detection of a monoclonal immunoglobulin in the serum or urine and underlying proliferation of a plasma cell/B lymphoid clone. (1) Patients with monoclonal gammopathy of undetermined significance (MGUS) have a clonal plasma cell population in the marrow (<10%) and secrete a monoclonal protein in the serum (<3g/dL) and/or urine. However, they lack clinical features of overt Multiple Myeloma (MM) (lytic bone lesions, anemia, renal impairment and hypercalcemia). In a study from the Mayo Clinic, 59 of 241 patients with MGUS (24%) developed MM over a period of 22 years. (2) The interval from recognition of monoclonal protein to diagnosis of MM ranged from 2-29 years, indicating that patients with MGUS need to be followed indefinitely. Many risk factors have been looked at to identify those with MGUS who are at the highest risk to progress into MM. We hypothesize that a higher number of plasma cells would correlate with a greater risk of progression to MM and sought to find out if this could be documented by arbitrarily dividing patients between < or ≥5% plasma cells seen on initial bone marrow biopsy. Methods: We retrospectively reviewed patients diagnosed with MGUS at Henry Ford Hospital between 1999-2013 who underwent a bone marrow biopsy for documenting plasma cell percentage. In addition to this, we also recorded serum hemoglobin, calcium, creatinine, monoclonal protein type and amount, serum free light chains, beta-2 microglobulin and urine for monoclonal protein at the time of diagnosis of MGUS as well as last completed values. For patients that had skeletal surveys we noted if lytic lesions were present at diagnosis, as well as cytogenetics and karyotype evaluations on bone marrow biopsy samples, if completed. Results: 120 patients with bone marrow biopsies were reviewed. Out of this 17 patients were noted from initial bone marrow biopsy to have ≥10% plasma cells. The remaining 103 patients were categorized as having MGUS. While we were not able to complete full statistical analyses, we did note that 14 of these 103 (13.6%) patients went on to develop overt MM. Further evaluation of these patients revealed that 8 of 14 (57%) had bone marrow biopsies showing ≥5% plasma cells. Interestingly the average time to progression into MM in this subgroup was 1,879 days whereas in the 6 of 14 (43%) with bone marrow biopsy showing <5% plasma cells had average time to progression into MM of 1,965 days. Abnormal cytogenetics and karyotypes of the bone marrow biopsy were also seen in 37.5% of the subgroup of patients with ≥5% plasma cells whereas it was only seen in 16.7% of the subgroup of patients with <5% plasma cells. With statistical data analyses we hope to prove significance in the above collected data as well as make further correlations in regards to risk factors in patients with MGUS. Conclusion: While we have not been able to complete full statistical analyses of the collected data yet, basic review of the above patients with MGUS and ≥5% plasma cells in the bone marrow biopsy showed a trend to develop MM faster by an average of 86 days than those that had <5% plasma cells. These same patients also were more likely to have abnormal cytogenetics and karyotypes of their bone marrow biopsies. There is a need for further investigations to be done in patients with MGUS and higher risk features. It is important that hematologists be able to recognize a high risk MGUS patient as this would lead to closer monitoring and consideration for earlier aggressive treatment to potentially delay progression into overt MM. Disclosures No relevant conflicts of interest to declare.

AL Amyloidosis and Concomitant Myeloma: Time to Reconsider Assumptions

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4044-4044
Author(s):  
Wesley Witteles ◽  
Ronald Witteles ◽  
Michaela Liedtke ◽  
Sally Arai ◽  
Richard Lafayette ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Renal Involvement ◽  
World Health ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Bone Marrow Biopsies

Abstract Abstract 4044 Background: Conventionally, multiple myeloma is believed to coexist in approximately 10% of AL amyloidosis patients. However, it is unclear whether this figure is too low based on current World Health Organization criteria. These criteria, mainly created to differentiate myeloma from monoclonal gammopathy of undetermined significance, include the presence of ≥ 10% plasma cells on a bone marrow biopsy or aspirate as being diagnostic of myeloma. Aims: To define the frequency and relevance of a concomitant diagnosis of myeloma in patients with AL amyloidosis. Methods: Records from consecutive patients with biopsy-proven AL amyloidosis treated at the Stanford University Amyloid Center were reviewed. Plasma cell percentages were determined by manual counts from bone marrow aspirate smears and by CD138 immunohistochemistry (IHC) performed on bone marrow core biopsies. Results: A total of 41 patients (median age 61 years, 32% female) were evaluated. The median number of organs involved with amyloidosis was 2 (range 1–4), with 28 patients (68%) having cardiac involvement, 22 patients (54%) having renal involvement, 15 patients (37%) having gastrointestinal involvement, 12 patients (29%) having soft tissue involvement, and 10 patients (24%) having nervous system involvement. All patients had bone marrow biopsies and aspirates performed at the time of amyloid diagnosis, with most undergoing both manual counts of plasma cells from aspirates and IHC from core biopsies. Based on conventional criteria, manual aspirate counts defined 15/28 (54%) patients as having myeloma, and IHC defined 26/31 (84%) patients as having myeloma (p=0.01). Only nine patients had a detectable serum paraprotein on immunofixation (median 1.1 g/dl, range 0.4–2.6). 81% of patients had an elevated serum free light chain (85% lambda), with a median level of 37.3 mg/dl (range 8.6–256 mg/dl). Compared to the frequency of elevated plasma cells, the prevalence of anemia (29%), hypercalcemia (14%), impaired kidney function (21%), and lytic lesions (7%) was low. After a median follow-up of 13 months (range 1–127 months), the one-year overall survival (74% vs. 58%) and three-year overall survival (50% vs. 50%) was not significantly different between patients with ≥10% plasma cells and patients with <10% plasma cells (p=NS). Discussion: As defined by bone marrow plasma cell involvement, a strikingly high percentage (84%) of AL amyloidosis patients would be considered to have concurrent myeloma. This figure is much higher than has been traditionally quoted in the literature, likely due to the utilization of newer methods of counting plasma cells. There was a low prevalence of myeloma-associated end-organ effects (hypercalcemia, anemia, renal insufficiency, lytic bone lesions), and a myeloma diagnosis had no impact on survival. Conclusion: In this cohort of AL amyloid patients, concomitant myeloma was present in the vast majority of patients using modern diagnostic techniques. The significance of this diagnosis appears to be minimal – calling into question whether the diagnostic criteria for myeloma should be redefined in this population. Disclosures: Witteles: Celgene: Research Funding. Liedtke:Celgene: Lecture fee, Research Funding. Schrier:Celgene: Research Funding.

Observations On Eosinophil Ifiltrates in The Bone Marrow Of Patients With Multiple Myeloma. Clinicopathological Correlates

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5338-5338
Author(s):  
Finella MC Brito-Babapulle ◽  
Tanya Cranfield ◽  
Robert B Corser ◽  
Helen Dignum ◽  
Christopher James ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Osteolytic Lesion ◽  
Inverse Correlation ◽  
Eosinophil Infiltration ◽  
Bone Marrow Biopsies ◽  
Lytic Lesions

Abstract Mouse eosinophils have been shown in 2011 to be required for the maintenance of long lasting plasma cells in the bone marrow and in maintaining the bone marrow plasma cell microenvironment. Human eosinophils have been shown by Wong et al to support multiple myeloma cell proliferation via a mechanism independent of IL6. We looked at bone marrow biopsies taken from patients who had a paraprotein and in whom a diagnosis of multiple myeloma was suspected. These samples were taken solely for the purposes of diagnosisng multiple myeloma and were retrospectively reviewed from the point of view of degree of eosinophil infiltration and its correlation with tumour load, bone lytic lesions, plasma cell morphology, whether blastic, crystalline inclusions, Mott cells, flame cells and or lymphoplasmacytoid. There were no cases of IGD or E myeloma or osteosclerotic myeloma.Nonsecretory myeloma and cases of light chain myeloma with or without amyloid were included in the series. Biopsies were not performed from osteolytic lesion unless biopsy was necessary to make a diagnosis of myeloma. Myeloma was diagnosed when plasma cell infiltrate was greater than 10% on bone marrow aspirate with a paraprotein and or lytic lesions. Eosinophil infiltration did not correlate with any of the tumour clinicopathological markers but showed an inverse correlation with degree of plasmacytosis. Eosinophils were hardly ever found in marrow aspirates that had over 70% plasma cells. They were usually found in trephine sections of bone marrow in areas where there was Grade I/II fibrosis and were often found in close proximity to focal areas of plasma cell infiltration. Whether eosinophils play a role in preventing or maintaining malignant plasma cell recurrence is currently being studied. Disclosures: No relevant conflicts of interest to declare.

CD81: A Novel, Specific and Highly Sensitive Marker in Flow Cytometric Diagnosis of Plasma Cell Dyscrasia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2880-2880
Author(s):  
Prashant Ramesh Tembhare ◽  
Constance Yuan ◽  
Neha Korde ◽  
Irina Maric ◽  
Katherine Calvo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Antigen Expression ◽  
Plasma Cell Dyscrasia ◽  
Fluorescent Intensity ◽  
Reliable Marker ◽  
Sensitive Marker

Abstract Abstract 2880 Background: The percent abnormal plasma cells (aPC) as determined by flow cytometry (FC) has been shown to be an independent risk factor for progression from myeloma precursor disease (monoclonal gammopathy of uncertain significance, MGUS; smoldering multiple myeloma, SMM) to multiple myeloma (MM). However, differentiation of aPCs from normal PCs (nPCs) in these patients is challenging. MM cell lines are know to underexpress the tetraspanin proteins (e.g. CD81, CD82) in comparison to nPCs. Although CD81, a nonglycosylated tetraspanin, is robustly expressed on the surface of nPCs, little information is available regarding its expression in the aPCs of MM, SMM and MGUS. In this study we evaluate the expression of CD81 in conjunction with CD19, CD45 and CD56 in bone marrow aPCs and nPCs from patients with MM, SMM and MGUS. Methods: Bone marrow aspirates from 41 patients (9 MGUS, 22 SMM, 7 MM, 3 non-neoplastic with clinical suspicion of MGUS) were analyzed with 8-color multiparametric FC using a panel of antibodies (CD138, CD38, CD19, CD20, CD27, CD28, CD45, CD56, CD81, CD13, CD14, CD16, CD3, CD34 and intracellular kappa & lambda light chains). The pattern of surface antigen and intracellular light chain expression was utilized to determine the percent aPC (defined as monoclonal with aberrant antigen expression) and percent nPC (defined as polyclonal with normal antigen expression). In all cases the pattern of antigen expression was evaluated in the aPCs; additionally, in cases with greater than 5% nPCs (19/41 patients: 8 MGUS, 8 SMM and 3 non-neoplastic) the pattern of antigen expression was evaluated in the nPCs. The ability to detect clonal aPC by evaluation of FC pattern of antigen expression was determined and compared for CD19, CD45, CD56 and CD81. We also examined the sensitivity and specificity of the CD19 and CD81 combination verses the conventional combination of CD19, CD56 and CD45 (Perez-Persona et al, Blood 2007) for the detection of clonal aPC. Results: CD81 was strongly expressed by nPC (average mean fluorescent intensity (MFI): 11500, standard deviation (SD): 5061, range: 5347–21657) in contrast to aPC with abnormally weak expression (average MFI: 1487, SD: 887, range: 647–4311). CD81 was a highly reliable marker for the detection of clonal PC; with 90% sensitivity and 100% specificity. It was the most specific and second most sensitive marker in our study (Table 1). CD81 was equally sensitive in detection of aPCs in MGUS, SMM and MM. Evaluation of the combined pattern of expression of CD19 and CD81 resulted in 100% sensitivity and 100% specificity for detection of aPC, which is greater than the conventional combination of CD19, CD56 and CD45, yielding 100% sensitivity but 90% specificity, for diagnostic evaluation of aPC. Conclusions: CD81 is a highly reliable marker in the detection of abnormal plasma cells in MM, SMM and MGUS. The combined approach of CD19 and CD81 is superior to other conventional marker combinations (i.e. CD19, CD45, and CD56) in terms of detection of clonal plasma cells and may replace their use in the clinical evaluation of bone marrow aspirates for plasma cell processes. Furthermore, it should help widening the applicability of minimal residual disease testing in MM. Disclosures: No relevant conflicts of interest to declare.

Automated digital enumeration of plasma cells in bone marrow trephine biopsies of multiple myeloma

2020 ◽  
pp. jclinpath-2020-207066
Author(s):  
Jacques A J Malherbe ◽  
Kathryn A Fuller ◽  
Bob Mirzai ◽  
Bradley M Augustson ◽  
Wendy N Erber
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Intraclass Correlation ◽  
Antigen Expression ◽  
Bone Marrow Biopsies ◽  
Bone Marrow Trephine ◽  
Bone Marrow Trephine Biopsy ◽  
Plasma Cell Neoplasms

AimsDetermination of the number of plasma cells in bone marrow biopsies is required for the diagnosis and ongoing evaluation of plasma cell neoplasms. We developed an automated digital enumeration platform to assess plasma cells identified by antigen expression in whole bone marrow sections in multiple myeloma, and compared it with manual assessments.MethodsBone marrow trephine biopsy specimens from 91 patients with multiple myeloma at diagnosis, remission and relapse were stained for CD138 and multiple myeloma oncogene 1 (MUM1). Manual assessment and digital quantification were performed for plasma cells in the entire trephine section. Concordance rates between manual and digital methods were evaluated for each antigen by intraclass correlation analyses (ICC) with associated Spearman’s correlations.ResultsThe digital platform counted 16 484–1 118 868 cells and the per cent CD138 and MUM1-positive plasma cells ranged from 0.05% to 93.5%. Overall concordance between digital and manual methods was 0.63 for CD138 and 0.89 for MUM1. Concordance was highest with diffuse plasma cell infiltrates (MUM1: ICC=0.90) and lowest when in microaggregates (CD138: ICC=0.13). Manual counts exceeded digital quantifications for both antigens (CD138: mean=26.4%; MUM1: mean=9.7%). Diagnostic or relapse threshold counts, as determined by CD138 manual assessments, were not reached with digital counting for 16 cases (18%).ConclusionsAutomated digital enumeration of the entire, immunohistochemically stained bone marrow biopsy section can accurately determine plasma cell burden, irrespective of pattern and extent of disease (as low as 0.05%). This increases precision over manual visual assessments which tend to overestimate plasma burden, especially for CD138, and when plasma cells are in clusters.

scholarly journals Characterization of a monoclonal antibody having selective reactivity with normal and neoplastic plasma cells

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 238-245 ◽  
Author(s):  
AW Tong ◽  
JC Lee ◽  
MJ Stone
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Pokeweed Mitogen ◽  
Enzyme Linked Immunosorbent Assay ◽  
Immunoperoxidase Technique ◽  
Binding Studies ◽  
Bone Marrow Biopsies

A myeloma cell-reactive monoclonal antibody (MoAb), MM4, was generated from BALB/c mice immunized with alternate injections of cells from two human multiple myeloma (MM) cell lines. Screening by the enzyme-linked immunosorbent assay (ELISA) technique showed that MM4 reacted with human MM cell lines (7 of 7 positive), as well as bone marrow aspirates from MM patients (4 of 4 cases positive). MM4 did not react with marrow aspirates from control patients (3 cases), or with peripheral blood mononuclear (PBM) cells from normal subjects, lymphocytic (12 cases) and myelogenous (8 cases) leukemia patients. In addition, MM4 was negative with polymorphonuclear leukocytes and RBCs from normal donors. By means of the immunoperoxidase technique, the MM4-reactive antigen was detected in paraffin-embedded, Zenker formalin-fixed bone marrow biopsies of MM (12 of 12 cases positive), Waldenstrom's macroglobulinemia (2 of 2 cases positive), asymptomatic plasma cell dyscrasia (4 of 4 cases positive), and certain lymphomas (2 of 5 cases positive). Marrow biopsies from lymphocytic (5 cases) and myelogenous (5 cases) leukemias were uniformly negative. The MM4-reactive antigen also was expressed on plasma cells generated from pokeweed mitogen (PWM)-stimulated normal PBM cultures. The pattern of reactivity of MM4 with lymphocytes of B origin was similar to that of the plasma cell MoAb PCA-1. Competitive binding studies showed, however, that these two MoAbs recognized distinct antigenic determinants. These observations suggest that MM4 may be useful for the study of human plasma cell dyscrasias.

Macroglossia – Not Always AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5007-5007 ◽  
Author(s):  
Andrew J Cowan ◽  
Martha Skinner ◽  
J. Mark Sloan ◽  
John L Berk ◽  
Carl J O'Hara ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Light Chain ◽  
Plasma Cells ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis ◽  
Amyloid Deposits ◽  
Immuno Electron Microscopy ◽  
Congo Red Staining

Abstract Abstract 5007 Introduction: Amyloidosis is characterized by extracellular deposition of abnormal insoluble fibrillar proteins. The two most frequent systemic amyloidoses are the light-chain (AL amyloidosis) and familial transthyretin (ATTR) forms. Clinical presentations often vary between the two types. Macroglossia is viewed as pathognomic of AL amyloidosis, and has not previously been described in patients with hereditary TTR amyloidosis. Here, we describe two cases of systemic amyloidosis with macroglossia in which immuno-electron microscopy diagnosed ATTR in one and AL in the other. Case Presentations: A 61 year old woman presented initially to her general internist with weight loss, difficulty swallowing, and tongue numbness. Her clinical exam revealed macroglossia and peripheral neuropathy. Tongue and axillary lymph node biopsies demonstrated amyloid deposits by Congo red staining. There was no evidence of renal, cardiac or other vital organ involvement. She had no evidence of a plasma cell dyscrasia with negative serum and urine immunofixation electrophoresis, normal serum free light chain concentration and ratio as well as polytypic plasma cells in the bone marrow. Immuno-electron microscopy using gold-labeled antibodies was performed on the tongue biopsy. The fibrils were immunoreactive with anti-TTR but not anti-kappa, anti-lambda, or anti-AA antibodies. DNA sequencing identified a known amyloidogenic T60A TTR mutation in exon 3 of chromosome 18, confirming the diagnosis of ATTR with amyloidotic polyneuropathy and macroglossia. The second case involved a 59 year old man with renal insufficiency. He complained of fatigue, weight loss, and tongue swelling. Physical examination was significant for macroglossia and submandibular gland enlargement. Tongue biopsy demonstrated amyloid deposits by Congo red staining. As in the previous case, markers of plasma cell dyscrasia with clonal plasma cells in the bone marrow, blood, and urine were absent. Immuno-electron microscopy of the tongue biopsy documented antibody reactivity to lambda light chain and not TTR, kappa light chain or AA proteins, confirming the diagnosis of AL amyloidosis. He subsequently underwent treatment with high dose intravenous melphalan followed by stem cell transplantation achieving a good clinical response sustained for 2 years to date. Discussion: While macroglossia is thought to be pathognomonic of AL amyloidosis, we report a case of macroglossia with fibrillar ATTR amyloid deposits diagnosed by immuno-electron microscopy. This is contrasted with a clinical presentation consistent with AL in which routine laboratory testing failed to identify evidence of a plasma cell dyscrasia. In both cases, electron microscopy demonstrated immunoreactivity for the fibrils of a single pathogenic protein. The first case was confirmed by DNA sequencing, and the second had a typical response to anti-plasma cell chemotherapy, in spite of the lack of identifiable markers of disease. Disclosures: No relevant conflicts of interest to declare.

A Paracrine Circuit Regulates Vascular Endothelial Growth Factor Production By Bone Marrow Plasma Cells in Patients with POEMS Syndrome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1757-1757
Author(s):  
Chen Wang ◽  
Qian-qian Cai ◽  
Xin-xin Cao ◽  
Dao-bin Zhou ◽  
Jian Li
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Serum Levels ◽  
Poems Syndrome ◽  
Newly Diagnosed ◽  
Bone Marrow Biopsies ◽  
Fluorescent Intensity ◽  
Bone Marrow Plasma ◽  
Endothelial Growth Factor

Abstract Background : POEMS syndrome is a rare paraneoplastic disorder, characterized by polyneuropathy, organomegaly, osteosclerosis and extravascular volume overload, due to an underlying plasma cell dyscrasia. Vascular endothelial growth factor (VEGF), a potent angiogenic cytokine that can increase vascular permeability, plays a critical role in its pathogenesis. Despite extensive VEGF studies concerning its role in disease diagnosis, monitoring and response assessment, little is known about its cellular source and mechanisms governing the production of VEGF in POEMS patients. Methods and Materials : Patients with POEMS syndrome, 62 newly diagnosed and 46 of them after lenalidomide-dexamethasone (LenDex) treatment, admitted to Peking Union Medical College Hospital between February 2014 and April 2015, were included in the current study. Clinical information, serum and bone marrow samples were collected with the Institutional approval. Serum levels of VEGF were measured by ELISA. VEGF levels in bone marrow plasma cells were quantified via real-time quantitative PCR and multiparameter flow cytometry, respectively. In addition, the phenotype, clonality and intracellular interleukin-6 (IL-6) expression of bone marrow plasma cells were also analyzed by flow cytometry. Furthermore, immunohistochemical staining was performed to study the plasma cell distribution, clonality and expression of VEGF, IL-6 and hypoxia-inducible factor-1α (HIF-1α) in bone marrow biopsies. Statistical analyses were conducted using SPSS 22, and a p < 0.05 was considered as significant. Results : Serum levels of VEGF were dramatically elevated in patients with newly diagnosed POEMS syndrome (median 5958 pg/mL), significantly higher than both disease and healthy controls (p < 0.001), and can be used as a diagnostic marker (area under curve 0.988, p < 0.001). A cut-off value of 2000 pg/mL had a specificity of 97.7% with a sensitivity of 91.9% in support of the diagnosis. After treatment, VEGF levels decreased gradually (6-cycle after LenDex, median 1184 pg/mL, p < 0.001; 12-cycle after LenDex, median 832 pg/mL, p < 0.001). Bone marrow plasma cells showed remarkable VEGF expression, validated in both mRNA and protein levels, which also decreased in response to LenDex therapy. More importantly, a statistically linear correlation was observed between serum and bone marrow plasma cell VEGF levels (newly diagnosed patients, rho = 0.33, p = 0.01; post-therapeutic patients, rho = 0.53, p < 0.001), supporting that bone marrow plasma cells were the source of circulating VEGF. Intriguingly, immunophenotying revealed that bone marrow plasma cells were polyclonal in most newly diagnosed cases. Monoclonal population, co-existing with polyclonal plasma cells, was observed only in 11 patients (18%). Further analyses showed that the relative amounts of these two populations were similar (41% vs. 59%) and they also had comparable intracellular VEGF expression (mean fluorescent intensity, 2009 vs. 2367, p = 0.594). However, monoclonal plasma cells had significantly higher intracellular IL-6 expression (mean fluorescent intensity, 1635 vs. 865, p = 0.006). In 46 newly diagnosed cases with bone marrow biopsies available, immunohistochemical staining was performed, and plasma cells were typically distributed in a scattered manner, with focal aggregates observed in 21 cases (46%). Intracellular κ and λ light chain staining demonstrated that the background scattered plasma cells were polyclonal, while both monoclonal and polyclonal fractions were observed in the focal area, which showed similar nuclear and intracellular staining of HIF-1α and VEGF, respectively. In contrast, IL-6 was mainly expressed in λ-restricted plasma cells. Conclusion : Bone marrow plasma cells are the potential source of VEGF production in patients with POEMS syndrome. Monoclonal plasma cells, aggregates focally in the bone marrow, may secret IL-6 to stimulate polyclonal plasma cells proliferation, and consequent VEGF production in a paracrine circuit. Disclosures Off Label Use: Lenalidomide for POEMS syndrome.

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