Figure 1 - uploaded by Francesca Gulli
Content may be subject to copyright.
Source publication
We analyzed the prognostic impact of levels of free light chains (FLC) in 106 patients with DLBCL, selecting 61 patients with a monoclonal (M) protein in serum, and 45 patients without a M protein as an IPI-matched control group. Patients with a M protein had higher levels of FLC, but these were not of prognostic significance in this group. The pre...
Contexts in source publication
Context 1
... identified patients from our patient registry that included 677 patients diagnosed with DLBCL at our center between 2006 and 2017. (Figure 1) Data on serum electrophoresis was available for 505 patients. A monoclonal Ig component (MC) was characterized in 82 patients by immune electrophoresis. ...
Similar publications
Bone marrow (BM) involvement is associated with prognosis in diffuse large B-cell lymphoma (DLBCL), the most prevalent disease subtype of malignant lymphoma. We conducted this multi-institutional retrospective study to investigate the functional association and prognostic values of four BM tests (BM biopsy, BM clot, flow cytometry (FCM), and BM sme...
Citations
... Similar to other types of B-cell lymphoma, DLBCL can be associated with a monoclonal immunoglobulin. The most common type in Western Europe, IgM gammopathy, has been associated with poor outcome [7][8][9][10]. It is detected with comparable sensitivity by immunofixation or the Hevylite TM assay that allows distinction between μ heavy chains linked to κ as opposed to λ light chains [11]. ...
... Most clinical associations have also been reported before. These include old age, poor performance status, advanced stage, extensive extranodal involvement, elevated lactate dehydrogenase levels, high IPI risk, low remission rates, and poor long-term outcome [7][8][9][10]. In addition, we found a highly significant increase in ctDNA and a trend for increased baseline TMTV, markers that are related to IPI and tumor burden [3,26]. ...
... Immunohistochemistry revealed IgM expression in four, concordant light chain restriction in tumor and monoclonal serum protein in one, and discordant restriction in two of seven samples studied. In two earlier studies, concordant light chain restriction, always associated with IgM expression, was found in 17 of 19 (89%) and 6 of 6 samples (100%; all derived from bone marrow), respectively [8,9]. In two other studies, immunohistochemistry was restricted to IgM expression that was found in 56 of 63 (89%) and 23 of 41 cases (56%), respectively [7,10]. ...
In diffuse large B-cell lymphoma (DLBCL), a positive interim positron emission tomography (PET) scan predicts treatment failure, but the proportion of high-risk patients thus identified is small. To improve prediction, we combined the interim PET result with the presence or absence of an associated IgM gammopathy. Of 108 DLBCL patients participating in a prospective trial, nine (8%) were interim PET positive and 19 (18%) had an IgM gammopathy. The monoclonal protein was not associated with distinguishing genetic features, and its light chain restriction was not always concordant with the light chain restriction of the lymphoma. The information provided by interim PET and IgM gammopathy was combined to dichotomize the population into sizeable high-risk (1–2 adverse factors) and low-risk groups (no adverse factor) with widely different outcomes (population size, 25% vs. 75%; 3-year risk of progression, 51% vs. 10%; 3-year overall survival, 64% vs. 95%). Multivariable analyses including established risk factors revealed the interim PET result and the IgM gammopathy status to be the only factors significantly associated with outcome. Information about interim PET response and IgM gammopathy may be useful in studies testing risk-adapted treatment strategies.
... Most of IgMs-DLBCL and OP were DLBCL-NOS (89% and 93%, respectively; Table 3s). Of these, 30 cases were already described [1,8]. The rate of DLBCL transformed from low-grade-NHL or with a previously recorded monoclonal gammopathy of undermined significance (MGUS), were slightly higher among IgMs-DLBCL compared to the other subsets (p = 0.018, Table 1 and 3s). ...
IgM-secreting diffuse large b-cell lymphoma: results of a multicentre clinicopathological study.
Running title IgMs-DLBCL
Key-words: Diffuse-large-b-cell-lymphoma, DLBCL, paraprotein, IgM, Prognosis, elderly, CNS, TP53, MYD88, CD79b
Abstract word count=210
Main text word count=3535
Tables= 4
Figures= 3
Corresponding Authors:
-Maria Christina Cox, chrisscox@gmail.com
-Arianna Di Napoli, arianna.dinapoli@uniroma1.it
Fundings:
-Sant’Andrea, University Hospital , Rome Italy
-Department of Clinical and Molecular Medicine , Sapienza University, Rome, Italy
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
ABSTRACT
A subgroup of diffuse large b-cell lymphoma (DLBCL) is characterised by the secretion of an IgM paraprotein (IgMs-DLBCL). This is an under-diagnosed subset, recently reported to have a poor outcome. Therefore, in 2015 we started the IgMs-DLBCL study, aiming at the clinicopathological characterization of this subset in a large multicentre series. Overall, 650 DLBCL were enrolled: 102 had an associated IgM (IgMs-DLBCL), 56 other paraprotein (OP) and the remaining 492 cases were the reference group (REF) respectively. IgMs-DLBCL was characterized by: 1) frequent mutation of the MYD88, CD79b and TP53 genes; 2) prevalence of non-GCB/ABC-type and preferential IGVH4-34 gene usage; 3) frequent overexpression of BCL2. In multivariate analysis, IgMs qualified as an independent prognostic factor for both PFS and OS (p<.001). Remarkably, the incidence of CNS involvement (17%), at diagnosis and progression, was significantly higher in this subgroup (p<.001). Also, IgMs-DLBCL patients, had higher IPI, NCCN-IPI and CNS-IPI scores (p<.001). Conversely, the OP subset had no poor outcome. This study shows IgMs-DLBCL is a sizeable subgroup (≈8%) which harbours a molecular subset of non-GCB type with worse outcome. The detection of IgM paraprotein, by immunofixation, should become part of DLBCL workup. Also IgMs should be considered as a risk factor for CNS spreading.
... When studying survival according to the Ig isotypes, we could not identify significant differences in outcome between IgG and IgM cases, in contrast to the unfavourable impact of an IgM sMC on PFS found by Maiolo and colleagues in DLBCL. 23 However, cases with a biclonal serum Ig did have a poorer OS compared with IgG cases. Although the biological explanation of these findings remains elusive and no previous study has addressed this point, it is reasonable to hypothesize that the immunological processes that promote tumour development in B cells, as well as the interactions with the tumour microenvironment (TME), 24 might induce a state of immune deregulation, which could explain the presence of more than one single Ig isotype at diagnosis (biclonal cases), the discordant lightchain restriction between the serum and the lymph node, and the emergence of a different Ig isotype during follow-up. ...
... Preceding studies reported a trend towards a better survival for indolent lymphoma patients with a sMC, 13 whereas we identified an impact in the opposite direction concerning the fraction of POD24 patients, PFS, and OS, which is in line with recent studies recognizing the +sIFE as an adverse prognostic factor in DLBCL. [15][16][17]23 This apparent discrepancy with the findings by Economopoulos and colleagues might be explained by the low number of patients with indolent lymphoma included in that study, the histological heterogeneity within the indolent lymphoma group, and the absence of rituximab treatment for historical reasons. ...
The presence of a serum monoclonal component has been associated with poor outcomes in some lymphomas. However, data in follicular lymphoma (FL) are scarce. We studied 311 FL patients diagnosed at a single institution, for whom information on serum immunofixation electrophoresis (sIFE) at diagnosis was available. Baseline characteristics and outcomes were compared between patients with a positive (+sIFE) and a negative sIFE (−sIFE). sIFE was positive in 82 patients (26%). Baseline features were comparable between both groups, except for an older age and higher proportion of elevated β2‐microglobulin levels in the +sIFE group. With a median follow‐up of 4.6 years, a +sIFE was associated with a higher risk of early relapse (POD24, 27% vs. 15%, P = 0·02), shorter progression‐free survival (PFS; 42% vs. 52% at 5 years, P = 0·008), and shorter overall survival (OS; 59% vs. 77% at 10 years, P = 0·046). In patients >60 years, a +sIFE was an independent predictor of OS [hazard ratio (HR) = 2·4, 95% confidence interval (CI): 1·2–5·0; P = 0·02]. Approximately one quarter of patients with FL has a +sIFE at diagnosis, which is a predictor of poor outcome. These findings encourage further investigation of its relationship with B‐cell biology and the tumour microenvironment.
... In samples with increased levels of IgMκ, a typical trend to suppress the uninvolved IgMλ isotype emerged that never occurred in cases of uninvolved IgMκ [91]. Abnormal IgMκ/IgMλ ratios have been reported to be associated with poor outcomes in patients with B-cell non-Hodgkin lymphoma [92,93]. Because of the increased risk of B-NHL in patients with HCV-related MC, it is mandatory to determine sensitive and specific biomarkers for prediction. ...
Cryoglobulins consist of serum immunoglobulins that precipitate below 37°C and resolubilize upon warming. The clinical triad of cryoglobulinemia usually includes purpura, weakness, and arthralgia. Cryoglobulinemic syndrome, clinically defined as a systemic vasculitis, is associated with chronic infection with hepatitis C virus (HCV) and autoimmune disorders and can evolve into B-cell malignancies. While the current literature about HCV-associated cryoglobulinemia is not very limited, little is known about the immunologic and serologic profiles of affected patients. Therefore, comprehension of the pathogenetic mechanisms underlying cryoprecipitation could be very helpful. Due to the persistence of viral antigenic stimulation, biomarkers to use after the worsening progression of HCV infection to lymphoproliferative and/or autoimmune diseases are widely needed. Laboratory methods used to detect and characterize low concentrations of cryoprecipitates and immunotyping patterns could improve patient management. The most critical factor affecting cryoglobulin testing is that the pre-analytical phase is not fully completed at 37°C.
... Accurate measurement of k/λ ratios provides a quantitative biomarker of clonality 23 . Although most cases of B-NHL are light chain restricted, only a minority of patients display sFLC abnormalities; moreover, in patients without a monoclonal component, the FLC assay proved to be of prognostic relevance 24 . The mechanism underlying this association is not clear but correlated with laboratory parameters indicating an immune system/ B cell dysregulation; this might simply reflect an environment of cytokines or other immune system interactions that may trigger a malignant B cell growth 24 . ...
... Although most cases of B-NHL are light chain restricted, only a minority of patients display sFLC abnormalities; moreover, in patients without a monoclonal component, the FLC assay proved to be of prognostic relevance 24 . The mechanism underlying this association is not clear but correlated with laboratory parameters indicating an immune system/ B cell dysregulation; this might simply reflect an environment of cytokines or other immune system interactions that may trigger a malignant B cell growth 24 . ...
... The mechanism underlying this association is not still clear. Elevated FLC correlates with laboratory testing that indicate the immune system or B cell activation, reflecting an environment of cytokines or other immune system interactions favorable for malignant B cell growth 24 . ...
Objective:
Chronic Hepatitis C virus (HCV) infection can cause severe extrahepatic manifestations, such as mixed cryoglobulins (MC), up to the development of B cell nonHodgkin's lymphoma (B-NHL). Mechanisms transforming of HCV infection into lymphoproliferative and/or autoimmune disorders are still poorly understood. In course of HCV infection, the sustained virus-driven antigenic stimulation may probably induce a B-cell clonal expansion. Measurements of serum free light chains (FLCs) levels, considered as a direct marker of B cell activity, are analyzed with increasing interest in clinical practice, for diagnosis, monitoring and follow-up of plasma cell dyscrasia. Syndecan-1 (CD138) is a transmembrane heparan sulfate proteoglycan expressed and actively shed by most myeloma cells. Membrane CD138 represents the major receptor protein for HCV attachment to the hepatocyte surface and high levels of circulating sCD138 levels are detected in patients at early stage of B-cell chronic lymphocytic leukemia. This study is aimed to evaluate sCD138 and FLC levels as diagnostic biomarkers of HCV-related MC with B-NHL.
Patients and methods:
We enrolled 35 HCV-MC-NHL patients, characterized for the specific type of cryoglobulins, and 25 healthy blood donors (HBD) as negative control. Serum sCD138 levels were determined using ELISA kits specific for human sCD138. Serum FLCs were assessed by means of the turbidimetric assay.
Results:
We found that serum levels of sCD138, as well as FLCs, were significantly higher in patients than in HBD (p<0.001).
Conclusions:
In agreement with the definition of HCV-driven lymphoproliferative disorders as the consequence of a multifactorial and multistep pathogenetic process, we suggest that sCD138 and FLCs could be considered putative independent markers of worsening progression of the disease.
The presence of serum monoclonal components has been associated with poor outcomes in various hematological malignancies. The current study focused on exploring its prognostic role in B-cell non-Hodgkin lymphoma. Our study represented 314 patients with information on serum immunofixation electrophoresis at diagnosis that were available with B-cell non-Hodgkin lymphoma. IFE was positive in 61 patients (19%). Baseline features were comparable between pairs of groups, poor ECOG PS, B symptoms, advanced stage, and high-risk IPI score were significantly more frequent in the + IFE group. Shorter PFS and OS of B-NHL patients were observed in patients who presented at diagnosis with a + IFE, and IFE was the independent predictor of PFS and OS in multivariate analysis. Moreover, integrating IFE into the IPI-M1, IPI-M2, and IPI-M3 models improved the area under the curve for more accurate survival prediction and prognosis. Serum monoclonal proteins are significant prognostic indicators for newly diagnosed B-cell non-Hodgkin lymphoma that can early identify patients with poor prognosis and guide clinical treatment decisions.
Simple Summary
This systematic review encompasses the clinical impact of serum paraprotein (PP), in low- and high-grade mature B-cell malignancies (except for myeloma and Waldenstrom Macroglobulinemia). In fact, reports on this topic are sparse and heterogeneous, and an overall view is lacking. Literature analysis shows that, across different entities, PP is consistently associated with high-risk biological and clinical features, as well as with poor outcome. Indeed, screening for serum PP should be included in the diagnostic work-up of all mature B-cell malignancies.
Abstract
The presence of a serum paraprotein (PP) is usually associated with plasma-cell dyscrasias, Waldenstrom Macroglobulinemia/lymphoplasmacytic lymphoma, and cryoglobulinemia. However, PP is also often reported in other high- and low-grade B-cell malignancies. As these reports are sparse and heterogeneous, an overall view on this topic is lacking, Therefore, we carried out a complete literature review to detail the characteristics, and highlight differences and similarities among lymphoma entities associated with PP. In these settings, IgM and IgG are the prevalent PP subtypes, and their serum concentration is often low or even undetectable without immunofixation. The relevance of paraproteinemia and its prevalence, as well as the impact of IgG vs. IgM PP, seems to differ within B-NHL subtypes and CLL. Nonetheless, paraproteinemia is almost always associated with advanced disease, as well as with immunophenotypic, genetic, and clinical features, impacting prognosis. In fact, PP is reported as an independent prognostic marker of poor outcome. All the above call for implementing clinical practice, with the assessment of paraproteinemia, in patients’ work-up. Indeed, more studies are needed to shed light on the biological mechanism causing more aggressive disease. Furthermore, the significance of paraproteinemia, in the era of targeted therapies, should be assessed in prospective trials.
