Clinicopathologic characterization of diffuse-large-B-cell lymphoma with an associated serum monoclonal IgM component

Abstract

Recently, diffuse-large-B-cell lymphoma (DLBCL) associated with serum IgM monoclonal component (MC) has been shown to be a very poor prognostic subset although, detailed pathological and molecular data are still lacking. In the present study, the clinicopathological features and survival of IgM-secreting DLBCL were analyzed and compared to non-secreting cases in a series of 151 conventional DLBCL treated with R-CHOP. IgM MC was detected in 19 (12.5%) out of 151 patients at disease onset. In 17 of these cases secretion was likely due to the neoplastic clone, as suggested by the expression of heavy chain IgM protein in the cytoplasm of tumor cells. In IgM-secreting cases immunoblastic features (p<.0001), non-GCB-type (p = .002) stage III-IV(p = .003), ≥ 2 extra nodal sites (p<.0001), bone-marrow (p = .002), central-nervous-system (CNS) involvement at disease onset or relapse (p<.0001), IPI-score 3-5 (p = .009) and failure to achieve complete remission (p = .005), were significantly more frequent. FISH analyses for BCL2, BCL6 and MYC gene rearrangements detected only two cases harboring BCL2 gene translocation and in one case a concomitant BCL6 gene translocation was also observed. None of the IgM-secreting DLBCL was found to have L265P mutation of MYD88 gene. Thirty-six month event-free (11.8% vs 66.4% p<.0001), progression-free (23.5% vs 75.7%, p<.0001) and overall (47.1% vs 74.8%, p<.0001) survivals were significantly worse in the IgM-secreting group. In multivariate analysis IgM-secreting (p = .005, expB = 0.339, CI = 0.160-0.716) and IPI-score 3-5 (p = .010, expB = 0.274, CI = 0.102-0.737) were the only significant factors for progression-free-survival. Notably, four relapsed patients, who were treated with salvage immunochemotherapy combined with bortezomib or lenalidomide, achieved lasting remission. Our data suggests that IgM-secreting cases are a distinct subset of DLBCL, originating from activated-B-cells with terminally differentiated features, prevalent extra nodal dissemination and at high risk of CNS involvement.

Figure 1. The cross table diagram shows in the colored rectangles the type of analysis that was carried out or the subgroup of DLBCL (non-secreting and IgM-secreting).

The white rectangles show the number of cases that match the crossing of horizontal and vertical rows.

Figure 2. Kaplan-Meier estimates of progression free survival (PFS) in IgM-secreting and in non-secreting DLBCL patients.

a) PFS of IgM-secreting and non-secreting DLBCL patients; b) PFS of IgM-secreting and non-GCB-type DLBCL patients.

Figure 3

a) Kaplan-Meier estimates of progression free survival (PFS) in patients who are positive for heavy chain IgM (IgM+) by Immunohistochemistry (IHC) and in patients who are negative for heavy chain IgM (IgM-negative) by IHC. b) Kaplan-Meier estimates of PFS in patients negative for heavy chain IgM expression by IHC (IgM-negative), in patients positive for heavy chain IgM expression by IHC but non-secreting (IgM+/non-secreting) and in patients positive for heavy chain IgM expression by IHC and IgM-secreting (IgM-secreting).