Chapter 70: Macroglobulinemia

DEFINITION

• Waldenström macroglobulinemia (WM) is an indolent B-cell neoplasm resulting from the accumulation, predominantly in the marrow, of a clonal population of lymphocytes, lymphoplasmacytic cells, and plasma cells, which secrete a monoclonal immunoglobulin (Ig) M.

• WM corresponds to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization (WHO) classification.

• Most cases of LPL are WM. Less than 5% of cases are IgA-secreting, IgG-secreting, or nonsecreting LPL.

EPIDEMIOLOGY

• The age-adjusted incidence rate of WM in the United States is 3.4 per 1 million among males and 1.7 per 1 million among females.

• The incidence rate is higher among Americans of European descent. Americans of African descent represent approximately 5% of all patients.

• Approximately 20% of patients are of Eastern European descent, specifically of Ashkenazi-Jewish ethnic background.

• Approximately 20% of 257 sequential patients with WM presenting to a tertiary referral center had a first-degree relative with either WM or another B-cell disorder.

PATHOGENESIS

Immunophenotypic Profile

• The characteristic immunophenotypic profile of WM lymphoplasmacytic cells includes the expression of the pan–B-cell markers CD19, CD20 (including FMC7), CD22, and CD79. Expression of CD5, CD10, and CD23 can be present in 10% to 20% of cases, and their presence does not exclude the diagnosis of WM. Multiparameter flow cytometric analysis has also identified CD25 and CD27 as being characteristic of the WM clone.

Somatic Mutations

• MYD88^L265P and CXCR4^WHIM mutations are highly prevalent and trigger transcriptional factors that support the growth and survival of lymphoplasmacytic cells.

Cytogenetic Findings

• Loss of all or part of chromosomes 17, 18, 19, 20, 21, 22, X, and Y is commonly observed, and gains in chromosomes 3, 4, and 12 also occur.

• Chromosome 6q deletions encompassing 6q21–25 have been observed in up to half of WM patients.

CLINICAL FEATURES

• Presenting symptoms most commonly are fatigue, weakness, weight loss, episodic bleeding, and manifestations of the hyperviscosity syndrome.

• Physical findings include:

  — Lymphadenopathy

  — Hepatosplenomegaly

  — Dependent purpura and mucosal bleeding

  — Dilated tortuous retinal veins

  — Multiple flesh-colored papules on extensor surfaces (deposits of IgM reacting to epidermal basement membrane antigens)

  — Peripheral sensory neuropathy

  — Raynaud phenomenon, especially on exposure to cold

  — Splenomegaly and lymphadenopathy (uncommon)

Morbidity Mediated by the Effects of IgM

• Table 70–1 lists the physiochemical and immunologic properties of the monoclonal IgM protein.