MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction

Abstract

Key Points• MYD88 L265P is expressed in WM and IgM MGUS patients using AS-PCR assays with potential use in diagnostic discrimination and response assessment.By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor kB activity and is present in >90% of Waldenström macroglobulinemia (WM) patients. MYD88 L265P was absent in 90% of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) patients. We therefore developed conventional and real-time allele-specific polymerase chain reaction (AS-PCR) assays for more sensitive detection and quantification of MYD88 L265P. Using either assay, MYD88 L265P was detected in 97 of 104 (93%) WM and 13 of 24 (54%) IgM MGUS patients and was either absent or rarely expressed in samples from splenic marginal zone lymphoma (2/20; 10%), CLL (1/26; 4%), multiple myeloma (including IgM cases, 0/14), and immunoglobulin G MGUS (0/9) patients as well as healthy donors (0/40; P < 1.5 3 10 25 for WM vs other cohorts). Real-time AS-PCR identified IgM MGUS patients progressing to WM and showed a high rate of concordance between MYD88 L265P DC T and BM disease involvement (r 5 0.89, P 5 .008) in WM patients undergoing treatment. These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. The finding of this mutation in many IgM MGUS patients suggests that MYD88 L265P may be an early

MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma

“…12,15,22,23 In contrast, this abnormality has been found much less frequently in other small B-cell neoplasms, including 4-21% of cases diagnosed as splenic marginal zone lymphoma and 1-10% of chronic lymphocytic leukemia. 11,12,15,[23][24][25][26] The current study was designed to examine the morphologic correlates of MYD88 L265P in nodal and splenic small B-cell neoplasms with plasmacytic differentiation, and determine whether molecular studies for this mutation may assist in the diagnosis of lymphoplasmacytic lymphoma in routine practice. Figure 3 Four cases with MYD88 mutation (two originally classified as nodal marginal zone lymphoma with plasmacytic differentiation and two as small B-cell neoplasm with plasmacytic differentiation, not otherwise specified) showed similar features.…”

“…19,20 Subsequent studies from multiple institutions have confirmed MYD88 L265P to be present in the majority of lymphoplasmacytic lymphoma/ Waldenstrom's macroglobulinemia, with reported incidence from 67 to 93%. 12,15,21 The mutation has also been found in 44-87% of IgM monoclonal gammopathy of undetermined significance. 12,15,22,23 In contrast, this abnormality has been found much less frequently in other small B-cell neoplasms, including 4-21% of cases diagnosed as splenic marginal zone lymphoma and 1-10% of chronic lymphocytic leukemia.…”

“…12,15,21 The mutation has also been found in 44-87% of IgM monoclonal gammopathy of undetermined significance. 12,15,22,23 In contrast, this abnormality has been found much less frequently in other small B-cell neoplasms, including 4-21% of cases diagnosed as splenic marginal zone lymphoma and 1-10% of chronic lymphocytic leukemia. 11,12,15,[23][24][25][26] The current study was designed to examine the morphologic correlates of MYD88 L265P in nodal and splenic small B-cell neoplasms with plasmacytic differentiation, and determine whether molecular studies for this mutation may assist in the diagnosis of lymphoplasmacytic lymphoma in routine practice.…”

“…This case displayed a prominently nodular growth pattern and cytology that appeared much more consistent with a diagnosis of nodal marginal zone lymphoma with plasmacytic differentiation. MYD88 L265P has also been described in a small percentage of chronic lymphocytic leukemia/small lymphocytic lymphoma, 15,21,25,26,40,41 emphasizing that MYD88 mutation status alone clearly cannot be used to define lymphoplasmacytic lymphoma. The MYD88 L265P abnormality has also been reported in a small percentage of cases diagnosed as extranodal marginal zone lymphoma, 19,20 although distinction between extranodal marginal zone lymphoma with plasmacytic differentiation and an extranodal lymphoplasmacytic lymphoma may be somewhat arbitrary, and the prior studies included insufficient clinical or histologic information to completely exclude extranodal lymphoplasmacytic lymphoma.…”

“…Recently, next generation sequencing studies have identified a highly recurrent point mutation, MYD88 L265P, in 490% of cases of bone-marrow-based lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia, [11][12][13][14][15][16] suggesting that this mutation may serve as a sensitive diagnostic marker for lymphoplasmacytic lymphoma. A previous study has suggested that detection of the MYD88 L265P abnormality can assist in classifying challenging bonemarrow-based B-cell neoplasms with plasmacytic differentiation.…”