AA amyloidosis complicating monoclonal gammopathies, an unusual feature validating the concept of “monoclonal gammopathy of inflammatory significance”?

Author(s):  
Alexandre Terré ◽  
Magali Colombat ◽  
Alexandre Cez ◽  
Claire Martin ◽  
Carine Diet ◽  
...  
Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 380-388
Author(s):  
Angela Dispenzieri

Abstract “Monoclonal gammopathy of clinical significance” (MGCS) is the term used to describe nonmalignant monoclonal gammopathies causing important disease. MGCS is the differential diagnosis for any patient presenting with what appears to be a monoclonal gammopathy of undetermined significance but is also experiencing other unexplained symptoms. Broadly, these conditions can be separated into symptoms and signs referable to the nerves, the kidneys, and the skin. The first step in making these diagnoses is to consider them. With a particular condition in mind, the next step is to order those tests that can help confirm or dismiss a particular diagnosis. Nearly all of the renal and dermatologic conditions are diagnosed by renal and skin biopsies, respectively. The importance of a highly competent renal pathologist and dermatopathologist cannot be underestimated. Biopsy is less specific for the neuropathic conditions. Because several of the MGCSs are syndromes, recognizing other manifestations is also key. Treatment recommendations for many of these conditions are anecdotal because of their rarity, but for several of the conditions, IV immunoglobulin, rituximab, and plasma cell–directed therapy are the best options.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1449-1449
Author(s):  
Nicola J Camp ◽  
Rosalie G Waller ◽  
Cassandra Garner ◽  
Guido J Tricot ◽  
Michael Tomasson ◽  
...  

Abstract High-risk pedigrees can be a powerful design for disease gene discovery. Understanding tumor spectrum in high-risk pedigrees optimizes power for discovery, allows meaningful assessment of segregation and determination of familial risk. Many studies have observed that different hematological malignancies co-aggregate in families. In particular, we previously performed genealogical cluster analysis in the Utah Population Database and identified significant co-aggregation between chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We have also determined that the frequency of the pre-clinical state, monoclonal B-cell lymphocytosis (MBL), is elevated in high-risk CLL pedigrees. Here, we explore evidence for monoclonal gammopathies in high-risk CLL pedigrees using serum immunoglobulin (Ig) biomarkers. Monoclonal gammopathies are characterized by a clonal expansion of plasma cells that secrete a monoclonal Ig. We used two serum biomarker tests to indicate the existence of clonal Ig proteins: Freelite™ and Hevylite™ immunoassays. These were performed on 498 frozen serum samples: 163 population controls; 97 MM/MGUS cases; 114 CLL cases (91 sporadic CLL and 23 from high-risk pedigrees); and 124 relatives in CLL pedigrees. Freelite detects and quantitates free light chains (κ and λ). Hevylite detects and quantitates specific immunoglobulins (IgA, IgG or IgM) bound to specific light chains. We determined monoclonality if either assay indicated an abnormal κ/λ ratio (specifically in conjunction with increased total Ig-type for Hevylite).The majority of monoclonality identified (92%) included restricted free lights chains. Those involving monoclonal Ig heavy chains only were all positively confirmed by standard serum protein and/or immunofixation electrophoresis. We observed a background of monoclonal gammopathy in our control samples (5/163, frequency =0.031), consistent with the advanced age of this comparison set (average 67y). As expected, monoclonal gammopathy was evident in the MM/MGUS cases (38/97, frequency=0.392, p=3.5×10-14), which increased to frequency=0.732, for abnormal κ/λ ratio considered without requiring increase of the specific Ig-type for Hevylite. The absence of complete identification is likely due to our samples being from prevalent cases at different treatment stages, in addition to non-secretory disease. The CLL cases (sporadic or pedigree) exhibited very similar rates of suggested monoclonal gammopathy (together 43/114, frequency=0.377, p=6.5×10-14). Pedigree relatives also exhibited evidence of clonal Ig proteins (9/124, frequency=0.073). The frequency across all relatives was not statistically different than the control set; however, the relatives were substantially younger than controls (minimum age 20y). When relatives were restricted to those over 49y (with average 67y), the frequency increased to 0.095 and became statistically increased compared to controls (p=0.028). The 9 relatives with monoclonality were: 1 non-Hodgkin lymphoma NOS, 1 MBL case, 2 solid cancer cases, and 5 relatives with no known cancer diagnoses. In conclusion, using sensitive Ig biomarkers we find that individuals in high-risk CLL pedigrees are at a greater risk of monoclonal gammopathy than the general population. This observation is consistent with previous clustering results indicating co-aggregation and a possible genetic etiologic overlap between CLL and MM. Furthermore, these Ig quantitative measures offer detailed phenotypes for all pedigree members, creating more informative pedigrees, increasing the power for gene identification. These measures offer an avenue for exploiting similarities across B-cell malignancies and have the potential to improve our ability to identify at-risk individuals. Disclosures No relevant conflicts of interest to declare.


2007 ◽  
Vol 26 (2) ◽  
pp. 165-172
Author(s):  
Marijana Dajak

Preporuke za Primenu Tumorskih Markera Kod Monoklonskih GamapatijaMonoklonske gamapatije čine grupu poremećaja koji se karakterišu klonskom proliferacijom plazma ćelija. M protein je tumorski marker specifičan za monoklonske gamapatije jer odražava klonsku produkciju imunoglobulina. Monoklonske gamapatije uključuju: multipli mijelom,Waldenström-ovu makroglobulinemiju (WM), nesekretorni mijelom, prikriveni (smoldering) multipli mijelom, monoklonsku gamapatiju od neodređenog značaja (MGUS,Monoclonal gammopathy of undetermined significance), primarnu sistemsku amiloidozu i bolest teških lanaca. Dijagnoza multiplog mijeloma je zasnovana na detekciji M proteina u serumu i/ili urinu, infiltraciji plazma ćelija u koštanoj srži i litičkim koštanim lezijama na radiografiji skeleta. Prema NACB (National Academy of Clinical Biochemistry) preporukama, tumorski markeri za dijagnozu,screening, identifikaciju klonaliteta, praćenje bolesti i prognostičku evaluaciju kod monoklonskih gamapatija su: elektroforeza proteina u serumu i/ili urinu, imunofiksacija u serumu i/ili urinu, slobodni laki lanci (SLL) u serumu i/ili urinu, viskoznost seruma i β2-mikroglobulin. Imunofiksacija se koristi za identifikaciju klonaliteta (tipa) M proteina primećenog na elektroforezi i kada postoji sumnja bez obzira na normalan proteinski elektroforetogram. Posebno je korisna za prepoznavanje i razlikovanje biklonskih ili triklonskih gamapatija. Viskoznost seruma trebalo bi određivati ako pacijent ima znake i simptome sindroma hiperviskoznosti. WM je najčeŠći uzrok hiperviskoznosti, ali se takođe može pojaviti i kod pacijenata sa velikim nivoima monoklonskog IgA ili IgG. Automatizovana imunoodređivanja SLL u serumu su osetljivija od tradicionalne elektroforetske metode i imunofiksacije za detekciju mijeloma monoklonskih lakih lanaca, nesekretornog mijeloma i AL amiloidoze. Osim toga, odnos SLL u serumu je nezavisan faktor rizika za nastanak maligne progresije kod pacijenata sa MGUS. Određivanje SLL u serumu i elektroforeze proteina seruma kao testova prve linije za razmatranje prisustva mogućih poremećaja B ćelija daje dodatnu dijagnostičku informaciju.


2020 ◽  
Author(s):  
Gaetano Alfano ◽  
Alice Delrio ◽  
Francesco Fontana ◽  
Annachiara Ferrari ◽  
Giacomo Mori ◽  
...  

AbstractMonoclonal gammopathies have been widely associated with renal lesions. Nephrotoxicity of the secreted monoclonal (M)-protein relies on a complex interplay between biological characteristics and serum concentration. Little is known about the prevalence and renal manifestations of the different types of monoclonal gammopathies in patients with kidney disease.We reviewed all renal biopsies in our Center during a 12-year period to characterize patients diagnosed with monoclonal gammopathy. Data about demographics, laboratory examinations, renal manifestations and histological lesions were collected retrospectively. Results were correlated with the different lymphoproliferative disorders to evaluate the relationship between renal involvement and monoclonal gammopathies.Monoclonal gammopathy was detected in 179 (13.4%) patients. The circulating M-protein was secreted by monoclonal gammopathy of undetermined significate (MGUS) (51.9%), myeloma multiple (MM) (25.7%), primary amyloidosis (AL) (8.9%), smoldering MM (5 %), non-Hodgkin lymphoma (NHL) (6.7%) and HL (1.7%). Documented renal involvement in benign disorders such as MGUS and SMM accounted for 7.5% and 11.1%, respectively. MM was associated with an increased risk of kidney involvement (adjusted odds ratio=36.4; P=<0.001) and manifested with higher serum creatinine compared to other disorders. AL amyloidosis was principally secondary to MGUS (75%) and presented with nephrotic proteinuria. NHL and HL patients had heterogeneous renal manifestations. MGRS manifested both with light chain deposition disease and membranoproliferative glomerulonephritis. Compared to the other lymphoproliferative disorders, MM and AL amyloidosis showed higher creatinine blood levels and proteinuria, respectively. MM was significantly associated with kidney disease in our cohort of patients.Monoclonal gammopathy is a frequent diagnosis in patients with kidney disease. An accurate diagnostic process including lab tests and kidney biopsy is necessary to identify if the secreted M-protein is associated with renal involvement.


2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Gaetano Alfano ◽  
Alice Delrio ◽  
Francesco Fontana ◽  
Giacomo Mori ◽  
Silvia Cazzato ◽  
...  

Monoclonal gammopathies are associated with acute and chronic kidney injury. Nephrotoxicity of the secreted monoclonal (M)-protein is related to its biological properties and blood concentration. Little is known about epidemiology, clinical manifestations, and outcome of monoclonal gammopathies in patients with kidney disease. We retrospectively collected data about demographics, clinical manifestations, and renal histological lesions of all patients (n = 1334) who underwent kidney biopsy between January 2000 and March 2017. Monoclonal gammopathy was detected in 174 (13%) patients with a mean age of 66.4 ± 13.1 years. The spectrum of monoclonal gammopathies comprised monoclonal gammopathy of undetermined significate (MGUS) (52.8%), multiple myeloma (MM) (25.2%), primary amyloidosis (AL) (9.1%), smoldering MM (SMM) (4%), non-Hodgkin lymphoma (NHL) (6.8%), and Hodgkin lymphoma (HL) (1.7%). Monoclonal gammopathy of renal significance (MGRS) accounted for 6.5% in patients with MGUS and 14.2% in patients with SMM. Evaluation of kidney biopsy revealed that M-protein was directly involved in causing kidney injury in MM (93.1%). MM was the only gammopathy significantly associated with an increased risk of kidney injury (odds ratio [OR] = 47.5, CI 95%, 13.7–164.9; P ≤ 0.001 ). While there were no significant differences in the progression toward end-stage renal disease or dialysis P = 0.776 , monoclonal gammopathies were associated with a different risk of death P = 0.047 at the end of the follow-up. In conclusion, monoclonal gammopathy was a frequent finding (13%) in patients who underwent kidney biopsy. M-protein was secreted by both premalignant (56.8%) and malignant (43.2%) lymphoproliferative clones. Kidney biopsy had a key role in identifying MGRS in patients with MGUS (6.5%) and SMM (14.2%). Among monoclonal gammopathies, only MM was significantly associated with biopsy-proven kidney injury. The rate of end-stage renal disease or dialysis was similar among monoclonal gammopathies, whereas NHL, MM, and SMM showed a higher rate of deaths.


Biomedicine ◽  
2021 ◽  
Vol 41 (1) ◽  
pp. 31-35
Author(s):  
Neelam M Pawar ◽  
Anupama Hegde

Introduction and Aim: The confirmatory step in diagnosis of monoclonal gammopathies is bone marrow biopsy and presence of M-protein in serum protein electrophoresis. These tests are relatively expensive & invasive for screening and unavailable in low resource settings. Increased levels of serum globulin are clue to the diagnosis of monoclonal gammopathy. The aim of this study was to assess the relevance of serum globulin levels in discriminating between patients with & without monoclonal gammopathies/ paraproteinemia. Materials and Methods: We retrospectively reviewed serum protein electrophoresis (SPE) and related investigations of patients suspected of monoclonal gammopathy. Reports with an M-band were considered as paraproteinemias, and those without as controls. ROC for sensitivities & specificities for serum globulin levels were computed. Results: For the case-control study, median serum globulin values in cases were 4.4 (3.5-6.3) g/dL in males and 3.65 (3.33-5.0) g/dL in females. They were significantly higher than those with normal SPE pattern, with a p <0.001. A cut-off value of 3.25 g/dL of globulin could distinguish between paraproteinemias and controls with a sensitivity of 82.1% and specificity of 85.4% in males; a sensitivity of 79.2%, a specificity of 76.7% for females. At a cut-off value of 3.4 g/dL, sensitivity was 77% and specificity 92.7% for males; sensitivity was 75% and specificity 83.7% for females. Alternatively, a cut-off value of 0.458 of globulin/total protein ratio could distinguish at a best sensitivity & specificity of 80% and 89% in males; 83.3% and 83.7% in females. Conclusion: Serum globulin values and globulin/total protein ratio can reliably differentiate patients with paraproteinemias.


2018 ◽  
Vol 56 (2) ◽  
pp. 256-263 ◽  
Author(s):  
Joel Smith ◽  
Geoffrey Raines ◽  
Hans-Gerhard Schneider

Abstract Background: There are a variety of initial laboratory tests or combinations of tests that can be performed when a monoclonal gammopathy is suspected including serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), serum immunofixation (IFE) and serum free light chain assays. Some groups have recently used simplified “screening” IFE methods for the detection of monoclonal gammopathies leveraging the greater sensitivity of IFE over SPEP alone to improve the detection of monoclonal gammopathies. These screening techniques have been predominantly evaluated against lower resolution agarose gel electrophoresis techniques. Methods: In this study we evaluated the diagnostic performance of the combined κ and λ light chain screening immunofixation (CLIF) in comparison to serum protein electrophoresis on a high-resolution (Sebia Hydragel 15 HR) agarose gel system. Each gel was interpreted by three adjudicators. A total of 156 patient samples were analysed. Adjudicated diagnoses based on the screening techniques were compared against the results of high resolution serum protein electrophoresis and high resolution standard immunofixation performed during routine laboratory operation. Where standard immunofixation was not performed a combination of a review of medical records, serum free light chains, UPEP and bone marrow aspirate and trephine and subsequent standard immunofixation and protein electrophoresis results where available were used to confirm the absence of a monoclonal gammopathy. Results: In this cohort a total of 65 (41%) patients had a paraprotein confirmed by standard immunofixation. HR SPEP had a sensitivity and specificity of 95% and 85%, respectively, while CLIF had a sensitivity and specificity of 88% and 97%, respectively. Conclusions: Overall we found that high-resolution gel serum protein electrophoresis using a Sebia Hydragel 15 HR system was more sensitive than a screening immunofixation method (CLIF) for the detection of paraproteins in patient serum in this patient cohort. The drawback of the greater sensitivity of HR SPEP was a higher false positive rate requiring an increased utilisation of follow up immunofixation electrophoresis.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5011-5011
Author(s):  
Jerry A. Katzmann ◽  
Angela Dispenzieri ◽  
Robert Kyle ◽  
Melissa R. Snyder ◽  
Mathew F. Plevak ◽  
...  

Abstract Due to the diagnostic sensitivity of serum free light chain quantitation for monoclonal light chain diseases, it has been suggested that urine assays no longer need be performed as part of the diagnostic algorithm for monoclonal proteins. We reviewed our experience to determine the relative diagnostic contribution of urine assays. Methods: Patients with a monoclonal gammopathy and monoclonal urinary protein at initial diagnosis who also had a serum immunofixation and serum free light chain quantitation within 30 days of diagnosis were identified (n = 428). The laboratory results for serum protein electrophoresis, serum immunofixation, serum free light chain, urine protein electrophoresis, and urine immunofixation were reviewed. Results: The patients in this cohort had diagnoses of multiple myeloma, primary amyloid, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, solitary plasmacytomas, and other less frequently detected monoclonal gammopathies. By definition of the cohort, all 428 had a monoclonal urine protein. 86% had an abnormal serum free light chain K/L ratio, 81% had an abnormal serum protein electrophoresis, and 94% had an abnormal serum immunofixation. In only 2 patients, however, were all 3 serum assays normal. Both of these were patients with monoclonal gammopathy of undetermined significance (idiopathic Bence Jones proteinuria). Conclusion: Discontinuation of urine studies and reliance on a diagnostic algorithm using solely serum studies (protein electrophoresis, immunofixation, and free light chain quantitation), missed 2 of the 428 monoclonal gammopathies (0.5 %) with urinary monoclonal proteins, and these 2 cases required no medical intervention.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3365-3365
Author(s):  
Rafael Ríos Tamayo ◽  
Juan Sáinz Pérez ◽  
Jose Manuel Puerta Puerta ◽  
Rosario Leyva Ferrer ◽  
Youssef Moatassim de la Torre ◽  
...  

Abstract Positron emission tomography (PET) with 18fluorine-fluoro-deoxyglucose (FDG) integrated with computed tomography (PET/CT) is a functional imaging technique helping us to assess bone marrow infiltration as well as unsuspected disease sites involving the bones and/or extramedullary sites. PET/TC has proved to be an independent prognostic factor for overall survival (OS) in symptomatic multiple myeloma (MM)(Zamagni,2011). However, its role in other monoclonal gammopathies (MG) is still a matter of debate. We have prospectively analyzed the contribution of baseline PET/TC in a unselected consecutive series of 158 patients with MG, including 88 MM, 7 MM smoldering (MMS), 11 Waldenstršm's macroglobulinemia (WM), 3 WM smoldering (WMS), 3 solitary bone plasmacytoma (SBP) and 46 monoclonal gammopathy of uncertain significance (MGUS). Patients with only palliative care were excluded. The pattern of bone marrow uptake on PET/TC was described as negative (NEG), diffuse involvement (DI) or focal lesions (FLs). Patients with more than 3 FLs as well as the presence of extramedullary disease (EMD) were analyzed separately. Overall survival (OS) was estimated by the Kaplan-Meier method. The main characteristics of PET/TC findings according to the type of MG are shown in Table 1. PET/TC was positive in 70 (79,5 %) of MM and 8 (72,7%) of WM. PET/TC was NEG in 100 % of MMS, WMS and SBP (except for the primary lesion). In MGUS, the findings reflect the clinical heterogeneity of this group: 19,6 % had bone disease (all but one case of probable inflammatory etiology), 17,4 % positive lymphadenopathy, 15,2 % lung disease (infection, fibrosis, pulmonary nodules), 6,5 % splenomegaly, 6,5 % liver disease, 6,5 % positive uptake in adrenal gland and other organs such as thyroid, stomach, colon or skin were affected less frequently. Median age of MM patients was 62 years (12-91), 51 men and 37 women (42%), the distribution according ISS was I (36,5 %), II (28,2 %) and III (35,3%). Among PET-positive MM, 39 (55,7 %) had >3 FLs, 17 (24,3 %) 3 or less FLs and 14 (24,3 %) DI. Median OS was 40 months, not reached (NR) and 85,7 months, respectively (p=ns). Mean bone marrow plasma cells in the >3 FLs group vs 3 or less FLs was 25 vs 12 (p=0,028). EMD was present in 13 (18,6 %) of PET-positive MM. Response with PET/CT was available in 32 patients: 18 achieved CR, 8 PR and 8 progressed. OS was NR for CR and PR vs 40 months (p <0,0001). In WM, patients with NEG or FL had NR OS vs 26 months in those with DI (p=0,16). PET/CT is positive in the majority of MM and WM patients, helping to separate patients with true indolent disease. At baseline, PET/TC is a useful tool to improve prognostic assessment in patients with MG. MM with >3 FLs or EMD at baseline had a trend towards lower OS. Negative serial PET/CT in MM is associated with favorable prognosis. Table SEQ Tabla \* ARABIC 1. Characteristics of main PET/TC findings according to the type of MG Type MM MMS WM WMS SBP MGUS n 88 7 11 3 3 46 Positive n /% 70/79,5 0 8/72,7 0 0 9/19,6 ->3 FLs 39/55,7 0 0 0 0 0 -3 or < FLs 17/24,3 0 1/12,5 0 0 1/2,2 -DI 14/20 0 5/62,5 0 0 1/2,2 -EMD 13/18,6 0 0 0 0 0 -Adenopathy 2/2,9 2/28,6 2/25 0 0 8/17,4 -Spleen 3/4,3 0 1/12,5 0 0 3/6,5 MG: Monoclonal gammopathy; MM: Multiple myeloma symptomatic; MMS: Smoldering myeloma; WM: Waldenstršm's macroglobulinemia; WMS: Smoldering Waldenstršm's macroglobulinemia; SBP: Solitary bone plasmocytoma; MGUS: Monoclonal gammopathy of uncertain significance; FL: Focal lesion; DI: Diffuse involvement; EMD: Extramedullary disease. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3524-3524
Author(s):  
Ross D. Brown ◽  
Larissa Belov ◽  
Cris dos Remedios ◽  
Daniel Sze ◽  
Simon Cooper ◽  
...  

Abstract The recent development of a standardised proteomic microarray technique, DotScan, has allowed an innovative approach to the investigation of haematological disorders. In this study, mononuclear cells from 49 peripheral blood samples were studied to determine whether the technology could identify a differential consensus pattern of antigen expression for patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). An automated reader simultaneously determined the expression of 82 different cell surface antigens by binding cells to antibodies on microscopic dots on the nitrocellulose-coated region of a microscope slide. The figure illustrates the image from a typical slide. A consensus pattern of antigen expression was analysed in duplicate by cross-validated discriminant analysis and a pilot database of disease groups was accumulated. Cross validated discriminant analysis successfully predicted patients with monoclonal gammopathy (98% success) and a discrete mosaic pattern could differentiate patients with MM who were treated with thalidomide (n=9). As expected, no single antigen could be used to discriminate between multiple myeloma (n=24), MGUS (n=14) and normal controls (n=11). Antigens with the highest ranking for differentiating the monoclonal gammopathies were CD25 (reduced after thalidomide), CD8 and CD57 (high in MM), CD28 (reduced in MM) and CD95 (reduced in MGUS) reinforcing the importance of immunomodulatory mechanisms in both MM and MGUS. Traditional flow cytometry was used to confirm these specific observations but also to demonstrate that the reduced CD28 expression was specific for CD8+ cells and the reduced CD95 expression was on CD8+ CD57+ cells. Three patients with MGUS were misclassified as MM but on review these 3 patients could have been classified as smoldering myeloma. There was no significant difference in the mosaic of 5 long term survivors of MM (> 10 years). This study has demonstrated the potential of using disease-specific databases to compare the mosaic of antigen expression for the diagnosis of monoclonal gammopathies. Long term studies will be required to accurately determine the prognostic significance at diagnosis and the ability of consensus patterns to identify which MGUS patients develop MM. Figure Figure Specificity and sensitivity of proteomic array for monoclonal gammopathies MGUS MM MM Thal Normal Sensitivity % Specificity % MGUS prediction 5 3 2 4 35 100 MM prediction 0 15 0 0 100 91 MM Thal prediction 0 0 9 0 100 95 Normal prediction 0 0 0 11 100 89


Sign in / Sign up

Export Citation Format

Share Document