Lymphoplasmacytic lymphoma–Waldenstrom's macroglobulinemia

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Abstract

The presence of IgM paraproteinemia in low-grade lymphomas is usually considered a clinical syndrome known as Waldenstrom's macroglobulinemia (WM). In the WHO classification, WM is associated to lymphoplasmacytic lymphoma (LPL); it is a clinicopathologic entity characterized by a monoclonal expansion of predominantly small B-lymphocytes with variable plasmacytoid differentiation. LPL constitutes less than 5% of all NHL and it is associated with hepatitis C virus infection in 26% of cases. Cells of LPL/WM are B cells positive for monocytic Ig light chains, IgM, pan-B-cell markers, and negative for CD3 and CD103. The t(9;14)(p13;q32) is present in 50% of LPL, and determines PAX-5 over-expression. 6q21 deletion is observed in 42% of cases.

LPL occurs in older adults. Clinical presentation usually consists of disseminated disease, but extranodal involvement and leukemic phase are rare. Most WM patients have symptoms attributable to tumour infiltration and/or monoclonal protein. In fact, a monoclonal serum paraprotein of IgM type and hyperviscosity symptoms may occur in more than 20% of cases (WM). Hyperviscosity syndrome is usually manifested by bleeding, blurring or loss of vision, dizziness, headache, and neurologic symptoms. Malignant infiltration of the CNS (Bing–Neel syndrome) is uncommon.

LPL/WM is an indolent malignancy that is not usually curable with conventional treatments. The median survival of patients with LPL or WM is 50–60 months, transformation to large cell lymphoma may occur. Stage definition is irrelevant in WM considering that initiation of therapy is decided on the bases of prognostic factors and the development of disease-related symptoms and signs. The main adverse prognostic factors are older age, B symptoms, anemia, low albumin serum levels, raised SGOT, and high beta 2-microglobulin values.

Several therapeutic alternatives for newly diagnosed or relapsed LPL/WM are available; however, the best location for every strategy is a matter of investigation. Several new drugs are being assessed in prospective trials. As a significant progress in this field, response criteria and therapeutic recommendations were updated during the Third International Workshop on WM (7–10 October 2004, Paris, France).

Section snippets

Definition

Immunocytoma is an old-fashioned term used to describe a distinct entity with individual morphologic, immunophenotypic and clinical features that includes cases formerly recognized as immunocytoma, lymphoplasmacytic type in the Kiel classification [1], [2]. Immunocytoma was not included in the Working Formulation; it mostly corresponds to small lymphocytic lymphoma; plasmacytoid, diffuse mixed small and large cell according to that classification. The terms lymphoplasmacytoid lymphoma,

Incidence and risk factors

WM constitutes less than 5% of all NHLs and 1–2% of hematological malignancies, with an incidence of ≈3/1,000,000 cases/year [6], [7]. Caucasians are predominantly affected, and only 5% of WM are diagnosed in Blacks and other ethnic groups [6], [7], [8]. The cause of WM is unknown; no specific occupational or environmental exposures, tobacco or alcohol use have been linked to WM [9].

WM appears to be a sporadic disease, but multiple reports of familial clustering exist [10], [11], [12], [13],

Morphology

The tumour consists of a diffuse proliferation of small lymphocytes, plasmacytoid lymphocytes and plasma cells, with or without Dutcher bodies. Plasmacytoid lymphocytes are cells with abundant basophilic cytoplasm, but lymphocyte-like nuclei. By definition, this tumour lacks features of B-chronic lymphocytic leukemia, mantle-cell lymphoma, follicular or marginal-zone lymphomas. The growth pattern is often interfollicular with sparing of the sinuses. The bone marrow aspirate in WM is often

Presentation

LPL occurs in older adults, involving bone marrow, lymph nodes and spleen, while extranodal involvement and leukemic phase are rare. A monoclonal serum paraprotein of IgM type and hyperviscosity symptoms may occur in more than 20% of cases (WM) [46], [47]. Clinical presentation usually consists of disseminated disease, less than 10% of patients have localized lymphoma (stages I–IIE). WM is more common among males (62%) with a median age of 65 years (range 27–82), only 1% of patients are younger

Natural history

LPL/WM is an indolent malignancy that is not usually curable with conventional treatments. Patients treated with single alkylating agents show an overall response rate of 70%, with 12% achieving a complete response [46]. Response criteria and therapeutic outcomes were updated during the Third International Workshop on WM (Table 1) [72]. Patients with WM have an overall response rate of 75%. Response rates at first recurrence are 50%. The median survival of patients with LPL is 50–60 months,

Treatment of stages I–II LPL

Standard therapeutic option for patients with stages I–II LPL is matter of debate. In the majority of prospective trials, LPL cases have been treated and analyzed together with other indolent lymphomas, rendering unreliable any conclusion. However, there is sufficient evidence supporting involved-field irradiation is suitable for individual clinical use on a type 3 level of evidence [77], [78]. This strategy is associated with a very high response rate and a 12-year disease-free survival of

Conflict of interest statement

Authors have no conflict of interest to be disclosed.

Reviewers

Professor Meletios A. Dimopoulos, University of Athens School of Medicine, Department of Clinical Therapeutics, 227 Kifissias Avenue, GR-14561 Athens, Greece.

Dr. Eva Kimby, Associate Professor, Karolinska University Hospital Huddinge, Center of Hematology, SE-141 86 Stockholm, Sweden.

Umberto Vitolo is the Director of Chemoimmunotherapy Lymphoma Section, Department of Oncology, San Giovanni Battista Hospital, Turin and Italy and member of the scientific commitee of Intergruppo Italiano Linfomi.

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    • Cited by (0)

    Umberto Vitolo is the Director of Chemoimmunotherapy Lymphoma Section, Department of Oncology, San Giovanni Battista Hospital, Turin and Italy and member of the scientific commitee of Intergruppo Italiano Linfomi.

    Andrés J.M. Ferreri is Coordinator of the Unit of Lymphoid Malignancies and Vice Director of the Medical Oncology Unit, San Raffaele H Scientific Institute, Milan, Italy.

    Silvia Montoto trained as a Haematologist at the Haematology Department of Hospital Clinic in Barcelona, Spain, and is currently a Senior Lecturer in Medical Oncology at the Medical Oncology Department, St Bartholomew's Hospital, London.

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