MYD88L265P mutated IgA lymphoplasmacytic lymphoma

Here we report two new cases of IgA-Lymphoplasmacytic Lymphoma (LPL) with diverse clinical presentation and performed a review of the three cohorts of patients with non-IgM LPL published in the literature. IgA LPL is rare and affects patients with a mean age at diagnosis of 67-year-old, with male predominance. Hyper viscosity related symptoms are extremely uncommon in comparison with LPL/WM and reported in unique cases. Extramedullary involvement includes lymph node disease (6/14, 42%) and rarely splenomegaly (3 cases, 21%). Associated amyloid deposition has been found in 21% of the cases. Histopathological features in the bone marrow if IgA-LPL are equivalent to IgM-LPL/WM. IgA LPL are positive for MYD88L265P mutation in 83% of the cases (10/12 cases). 6 q deletion is rarely found. In conclusion, the available evidence about the biological features of IgA-LPL supports the inclusion of these cases in the lymphoplasmacytic lymphoma spectrum. This is relevant for therapeutic reasons, mainly due to the availability of novel highly effective regimens for the treatment of LPL/WM. This article is protected by copyright. All rights reserved.

extremely uncommon in comparison with LPL/WM and reported in unique cases.
Extramedullary involvement includes lymph node disease (6/14, 42%) and rarely splenomegaly (3 cases, 21%). Associated amyloid deposition has been found in 21% of the cases. Histopathological features in the bone marrow if IgA-LPL are equivalent to IgM-LPL/WM. IgA LPL are positive for MYD88L265P mutation in 83% of the cases (10/12 cases). 6 q deletion is rarely found. In conclusion, the available evidence about the biological features of IgA-LPL supports the inclusion of these cases in the lymphoplasmacytic lymphoma spectrum. This is relevant for therapeutic reasons, mainly due to the availability of novel highly effective regimens for the treatment of LPL/WM. Lymphoplasmacytic Lymphoma (LPL)/ Waldestrom Macroglobulinemia is a neoplasm of small B lymphocytes, plasmacytoid lymphocytes and plasma cells, usually involving the bone marrow and sometimes lymph node and spleen 1 with an associated IgM monoclonal component 2 . MYD88L265P somatic mutation is the driver mutation in most cases 3-6 . Patients with IgG or IgA monoclonal proteins and those with non-secretory LPL exist and show clinical and pathological heterogeneity 7,8 .
Here we describe two cases of IgA LPL diagnosed and treated in our institution. These two cases accounted for 7% of all LPL patients managed in our center in a 5 years period.

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Case number 1 was treated with immunochemotherapy with Rituximab, Bortezomib and Dexamethasone. After 6 cycles the patient achieved partial response. The second patient was treated with Rituximab, cyclophosphamide and dexamethasone. After 2 cycles the patient developed a cutaneous rash and hyper viscosity related symptoms. A second line treatment with Ibrutinib is now ongoing.
We reviewed the clinical, morphological, phenotypical and molecular features in comparison with the cases described in the three larger cohorts of patients with non-IgM LPL so far published 7,8,10 (Table). Including the two cases here reported IgA-LPL affects patients with a mean age at diagnosis of 67-year-old (range 51-80) and male predominance (9 out

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Molecular features of IgA-LPL include the frequent detection of MYD88L265P mutation.
Including our two cases, IgA LPL are reported to be positive in 83% of the cases (10/12 cases 7,8,10 ). The identification of MYD88L265P mutation in IgA-LPL aids in the differential diagnosis with multiple myeloma and marginal zone lymphoma, since it is never found in multiple myeloma and appears only in roughly 15% of marginal zone lymphoma cases (mostly splenic type) [11][12][13] .
The prevalence of other genetic features found in WM such as 6q deletion is poorly defined in the non-IgM LPL group of cases 9 . 6q deletion in WM has been found to be associated with features of poor prognosis 14,15 and upregulation of BCR pathway 16 . The clinical significance of this alteration in IgA-LPL is however not well stablished.
In conclusion here we report two cases of IgA-LPL with diverse clinical presentation. Bone marrow histopathological findings and demonstration of MYD88L265P mutation were essential for the diagnosis. The available evidence about the biological features of IgA-LPL supports the inclusion of these cases in the lymphoplasmacytic lymphoma spectrum. This is critical for therapeutic reasons, mainly due to the availability of novel highly effective regimens for the treatment of LPL/WM 17 .

Table. Clinicopathological features of patients with IgA Lymphoplasmacytic Lymphoma.
A summary of the clinical and pathologic features of the IgA LPL cases described in the three larger cohorts of patients so far published is shown, together with the results of the two cases here reported 7,8,10 . ccepted Article This article is protected by copyright. All rights reserved. Cao