IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas

Abstract

To clarify the relationships between marginal zone lymphomas (MZLs) and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (WM/LPLs), immunoglobulin heavy chain variable gene (IGHV) features were analyzed and the occurrence of MYD88 L265P mutations was identified in a series of 123 patients: 53 MZLs from the spleen (SMZLs), 11 from lymph nodes (NMZLs), 28 mucosa-associated lymphatic tissue (MALT) lymphomas and 31 WM/LPLs. SMZLs were characterized by overrepresentation of IGHV1-2 gene rearrangements with a canonical motif, without selection pressure and with long CDR3 segments. NMZLs had increased frequencies of IGHV3 genes. The IGHV gene was unmutated in most cases, often with long CDR3 segments. MALT lymphomas were usually associated with a mutated IGHV gene, but with the absence of selection pressure. WM/LPLs were associated with an IGHV3-23 overrepresentation and high IGHV mutation rate, with features of selection pressure and short CDR3 segments. MYD88 L265P mutations were almost restricted exclusively to WM/LPL patients. Taken all diagnoses together, all patients with MYD88 L265P mutations had an immunoglobulin M peak and almost all patients except one had bone marrow infiltration. These results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs. WM/LPL may thus be functionally associated with constitutive nuclear factor-κB activation.

MYD88L265P Mutations, But No Other Variants, Identify a Subpopulation of DLBCL Patients of Activated B-cell Origin, Extranodal Involvement, and Poor Outcome

“…MYD88 has also been recurrently found mutated at different frequencies in several lymphoid neoplasms, including the majority of Waldenstr€ om macroglobulinemias (90%), in 69% of primary cutaneous leg-type DLBCL, in 38% to 50% of central nervous system lymphomas, in 9% of MALT lymphomas, and in approximately 3% of patients with chronic lymphocytic leukemia (CLL; refs. 11,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. MYD88 L265P mutation is the most frequent and most oncogenic form in DLBCL, although a gain of function triggering an increased production of chemokines has also been demonstrated for other variants (11,34,36).…”

MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma

“…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.…”

“…Several prior studies have therefore examined the incidence of MYD88 L265P in splenic marginal zone lymphoma to determine the utility of this marker in differential diagnosis, with positive results reported from 4 to 21% of cases. 11,12,14,15,22 Most of the cases reported to date, however, have been diagnosed from peripheral blood and bone marrow alone. Moreover, it is unclear how many of these splenic marginal zone lymphomas may show evidence of plasmacytic differentiation such that the differential diagnosis would include lymphoplasmacytic lymphoma.…”

“…One prior study which was restricted to splenic marginal zone lymphoma confirmed by splenic histology reported MYD88 L265P in 2/53 (4%) cases. 22 In the current study, we included only splenectomy-defined splenic marginal zone lymphoma cases, and included cases with and without plasmacytic differentiation. Notably, none of the 44 cases of splenic marginal zone lymphoma showed evidence of MYD88 mutation.…”

Hyperviscosity Syndrome Provoking Heart Failure in a Patient with Waldenström macroglobinemia

“…Given these results, the patient underwent a bone marrow biopsy which revealed findings consistent with small B-cell lymphoma with plasmacytic differentiation, containing kappa-restricted plasma cell population that was CD38+, CD138+, kappa+, CD56-, CD19+, CD200-, and CD117-.In addition to fulfilling all three of the criteria described above, the patient harbored the PL 265 p mutation identified at exxon 5 of the MYD88 gene found in 91% of patients with lymphoplasmacytic lymphoma or Waldenstom'smacroglobinemia [16]. This gene leads to NF-κB activation leading to the promotion of LPL/WM cell growth and survival [17]. With the findings of lymphoplasmacytic lymphoma with an IgM paraprotein, the diagnosis of Waldenstrommacroglobulinemia was made…”