Differential Diagnosis of Suspected MYD88 Wild-Type Waldenstrom's Macroglobulinemia Includes Other Malignant and Non-Malignant IgM Secreting Entities, Including Frequent Cases of IgM Myeloma

MYD88 mutations are present in 95% of patients with Waldenstrom's Macroglobulinemia (WM), and permit diagnostic discrimination from other overlapping IgM-secreting B-cell malignancies. However, such diagnostic discrimination can often be difficult among suspected WM patients with wild-type MYD88 (MYD88^WT), and can result in either diagnostic misclassification or mistreatment. We therefore examined a relatively large cohort of patients with suspected MYD88^WT WM, and performed a systematic review of their clinical, pathologic and laboratory studies. Sixty-four patients with suspected MYD88 wild-type WM were identified. All had a monoclonal IgM protein, and bone marrow (BM) disease involvement. AS-PCR testing for MYD88 L265P mutation, and exclusion of non-L265P mutations by Sanger sequencing was performed to confirm MYD88^WT status utilizing CD19-selected and unselected BM mononuclear cells (Xu et al, Blood 2013). WHO and WM consensus guidelines were used to establish clinicopathological diagnosis.

Forty-six (71.8%) patients fulfilled WHO and WM consensus criteria for WM. Their median BM involvement was 37.5% (range 5-95%), serum IgM was 2,980 (range 160-9,000 mg/dL), and hemoglobin was 11 (range 4-15.5 g/dL). Sixteen (35%) and 13 (28%) had adenopathy and splenomegaly, respectively. Principal reasons for diagnosis included anemia (50%), and/or other cytopenias (13%), peripheral neuropathy (13%), adenopathy (8%), symptomatic hyperviscosity (5%), and renal failure (5%). At a median follow-up of 5.4 years, 31 (67%) patients required therapy. Notably, 7 (15.2%) MYD88^WT patients were diagnosed with diffuse large B-cell lymphoma (DLBCL) during the follow-up period. Eleven (24%) patients died, 4 due to DLBCL transformation. Among the other MYD88^WT patients, 7 (10.9%) had IgM multiple myeloma (IgM MM). Their median BM disease involvement was 60% (range 10%-80%), with a predominant plasma cell infiltrate. In 3(43%) patients, both clonal B-cells and plasma cells were detected, while clonal plasma cells alone were observed in the other 4 patients. FISH testing of BM mononuclear cells showed t(11;14) in 5 patients; t(14;16) in one patient; and normal cytogenetics in one patient. The median serum IgM level was significantly higher at 8,375 (range 2,530-12,000 mg/dL) versus MYD88^WT WM patients (p=0.016). One (14%) patient had both adenopathy and splenomegaly. Principal reasons for diagnosis included anemia (100%), and symptomatic hyperviscosity (43%). With a median follow-up of 2.4 years, all patients required treatment and one died of myeloma. Findings consistent with marginal zone lymphoma (MZL) were observed in 6 (9%) patients. Their median BM involvement was 10% (range 5-25%), and three (50%) had detectable clonal B-cells by BM flow cytometry. Their median serum IgM level was 1,642 (95-2,800 mg/dL), and was not significantly different versus MYD88^WT WM patients. Adenopathy and splenomegaly were present in 4 (67%) and 2 (33%) patients. With a median follow-up of 3.8 years, 4 (67%) required therapy, and all remain alive. For 3 (4.6%) patients, the findings favored a diagnosis of IgM MGUS with plasma cell infiltration. The median BM involvement for these patients was 5% (range 5-8%) with flow cytometry demonstrating clonal plasma cells. The median serum IgM level for these patients was 1,846 (range 1,262-2,390 mg/dL), and did not differ versus MYD88^WT WM patients. With a median follow-up of 2.5 years, none progressed or received treatment, and are alive. In one patient, the findings favored the diagnosis of CLL while another patient had intravascular DLBCL. The serum IgM level was 1,822 and 355 mg/dL respectively. The BM disease burden was 5% in both patients. The CLL patient remains alive without treatment, while the patient with DLBCL required therapy and remains alive. No DLBCL transformation was observed among non-WM cases. Our findings show that up to 30% of suspected MYD88^WT WM cases have an alternative clinicopathological diagnosis that includes both malignant and non-malignant entities. IgM MM was frequently present among suspected MYD88^WT WM cases, and presented with very high serum IgM levels, symptomatic hyperviscosity and chr. 14 translocations. Patients with MYD88^WT WM disease had a high incidence of DLBCL transformation that contributed to a third of deaths. The findings highlight the importance of diagnostic discrimination among suspected MYD88^WT WM cases.