Which of the following are characteristic findings in Waldenstrom disease?

Clinical Features

Lymphoplasmacytic lymphoma is an uncommon neoplasm of older adults with a slight male predominance. Usually, LPL affects the bone marrow with less frequent involvement of spleen and lymph nodes. Most commonly, it is associated with mutations in the myeloid differentiation primary response gene 88 (MYD88), IgM paraproteinemia, and manifestations of hyperviscosity (Waldenström macroglobulinemia [WM]). Although WM is defined as LPL with an IgM paraproteinemia of any level, the two terms LPL and WM are not synonymous, and, rarely, LPL can present with non-IgM paraproteins. Some cases of LPL may arise in association with hepatitis C, although other lymphoproliferative disorders can also arise in this setting. Primary cold agglutinin-associated lymphoproliferative disease was previously thought to be a form of LPL. This is no longer the case because newer molecular markers, such as MYD88, are negative in most cold agglutinin-associated lymphoproliferations, suggesting they are a distinct entity.

Lymphoplasmacytic Lymphoma—Fact Sheet

Waldenström Macroglobulinemia

Waldenström macroglobulinemia is a rare clinicopathologic syndrome associated with an uncontrolled clonal proliferation of terminally differentiated B lymphocytes (lymphoplasmacytic lymphoma), IgM paraprotein, and increased blood viscosity. Renal lesions are related either to lymphoplasmacytic infiltration or to deposition of the paraprotein. Typically, there are amorphous, at times massive, PAS-positive subendothelial or intraluminal deposits that are positive for IgM-κ. Most of the capillary thrombi are electron dense and amorphous (Figure 17). Waldenström macroglobulinemia can be seen in patients with amyloidosis and types I and II cryoglobulinemia and there is a significant morphological overlap with cryoglobulinemic nephropathy. Waldenström macroglobulinemia is indolent in nature and, while it is incurable, it is treatable. It generally occurs in older patients (median age of 63–70 years). Although IgM paraprotein is found in 16% of all myeloma patients, only < 25% of these patients develop Waldenström macroglobulinemia; IgM monoclonal gammopathy may be diagnosed years before the syndrome develops.

Lymphoplasmacytic Lymphoma ( and Waldenström’s Macroglobulinemia) (LPL)

Lymphoplasmacytic lymphoma (LPL), a rare lymphoma occurring in older adults is a neoplasm of small lymphocytes, plasmacytoid, lymphocytes and plasma cells, usually involving the bone marrow and sometimes lymph nodes and spleen. A subset of cases occur in association with chronic HCV infection. The majority of LPL patients have Waldenström’s macroglobulinemia, (WM), which is defined as bone marrow involvement by LPL and presence of an IgM serum paraprotein of any concentration, with or without hyperviscosity syndrome. More than 90% of LPL have MYD88 L265P mutation, but this abnormality, which leads to NF-kappaB signaling, is not specific as it is also encountered in other small B-cell lymphomas and in a subset of DLBCLs. About 30% of the patients harbors somatic mutations in CXCR4 (most commonly the nonsense truncating S338X, or frameshift mutations in the C-terminal domain) in addition to the activating MYD88 L265P mutation, and this genotype tends to correlate with higher disease activity.

MACROGLOBULINEMIA

Macroglobulinemia is considered to be a manifestation of certain nonintestinal lymphoproliferative disorders akin to multiple myeloma but distinguished from it by a more benign course and lack of osteolytic lesions, renal lesions, or amyloidosis.186 A diffuse lymphoplasmacytic infiltrate of the small intestine resembling IPSID has also been associated with macroglobulinemia. The biopsy specimen appearance is characteristic, with large eosinophilic extracellular masses that test positive on PAS staining as well as occasional clumps of foamy macrophages in the lamina propria of the small intestine (Fig. 22-23). Depending on the size of the deposits, intestinal villi may be variably clubbed and distorted. The intestinal deposits have been shown to be composed of a monoclonal IgM macroglobulin. Macroglobulinemia should not be confused histologically with amyloidosis. Although tinctorially similar to amyloidosis, macroglobulinemia deposits do not stain with Congo red.

Lymphoplasmacytic Lymphoma

Lymphoplasmacytic lymphoma (LPL) is a disease of adult life (median age in the 60s), usually presenting with generalized lymphadenopathy, constitutional symptoms, and splenomegaly.

Histologically, there is a diffuse interfollicular proliferation of small lymphocytes (many with plasmacytoid features) and plasma cells, with or without immunoglobulin (Ig)–filled intranuclear inclusions (Dutcher bodies) and sparing of the sinuses. An increased number of mast cells and iron-laden macrophages can be seen. Although many B-cell neoplasms occasionally show maturation to plasmacytoid or plasma cells with cytoplasmic Ig, the term LPL should be restricted to tumors lacking features of other well-defined entities, such as chronic lymphocytic leukemia (CLL) or mantle-cell lymphoma (MCL), which occasionally can manifest plasmacytoid differentiation. Many but not all patients with LPL may have clinical evidence of Waldenström macroglobulinemia (WM), which is based on the detection of an IgM monoclonal gammopathy of any concentration and is associated with bone marrow involvement by LPL (Chapter 80).

In LPL, cells have surface and cytoplasmic Ig, usually IgM (and usually lacking IgD), and express B cell–associated antigens (CD19, CD20, CD22, CD79a). They are generally negative for CD5 and cyclinD1, distinguishing LPL from CLL and MCL, respectively. CD25, CD10, or CD11c may be weakly expressed in some cases. The postulated normal counterpart is thought to be a postfollicular medullary cord B cell, based, in part, on the presence of somatic mutations in the Ig heavy-chain and light-chain variable region genes.

The recent identification of MYD88 L265P mutation (found in approximately 90% of WM cases) has become a reliable marker supporting a diagnosis of LPL.5 This mutation is also found in a significant proportion of IgM, but not IgG or IgA, monoclonal gammopathy of undermined significance (MGUS) cases.

Lymphoplasmacytic Lymphoma

Lymphoplasmacytic lymphoma (LPL) typically involves both the splenic white and red pulp and often in a diffuse pattern, although the infiltrate may form distinct small nodules in the red pulp (see Chapter 7). Periarteriolar aggregates of plasmacytoid cells, small lymphocytes, plasma cells, and a variable number of immunoblasts are consistent with LPL, and Dutcher bodies, increased mast cells, and hemosiderin may also be features. Rarely, LPL has been associated with Hodgkin lymphoma or progression to DLBCL. Recently MYD88 mutations have been identified in more than 90% of cases of LPL and are rare to absent in other small B-cell lymphomas with plasmacytic differentiation allowing molecular distinction. However as MYD88 mutations can be seen in other B-cell lymphomas, LPL remains somewhat a diagnosis of exclusion; other lymphomas in the differential diagnosis to rule out are splenic marginal zone lymphoma with plasmacytoid differentiation, CLL/SLL, and mantle cell lymphoma. The most frequently overlapping entity is splenic marginal zone lymphoma; however, SMZL shows abiphasic pattern, with paler cells suggesting marginal zone differentiation.

Waldenström's Macroglobulinemia

Waldenström's macroglobulinemia, or primary macroglobulinemia, is a clinical syndrome of an IgM monoclonal gammopathy, usually of 3 g/dL or more, that is associated with splenomegaly or hepatomegaly in 40% of cases.303-305 These patients are usually elderly with a slight male predominance. In contrast to multiple myeloma, Waldenström's macroglobulinemia is extremely unusual in black male patients. Patients have an increased risk of hemorrhage as well as a high frequency of hyperviscosity syndrome and cryoglobulinemia. This syndrome is characteristically associated with bone marrow and organ involvement by malignant lymphoma with plasmacytoid features, particularly lymphoplasmacytic lymphoma (Fig. 43-20).306,307

Normocytic anemia is the most common peripheral blood finding in Waldenström's macroglobulinemia, and rouleaux formation with the characteristic blue background associated with an increase in paraprotein is also common. Peripheral blood involvement by the associated lymphoproliferative disorder is frequently present and may have the appearance of an increase in small lymphocytes, similar to chronic lymphocytic leukemia (CLL), or an increase in lymphoplasmacytic cells. Virtually any type of malignant lymphoma may involve the bone marrow in Waldenström's macroglobulinemia, although lymphoplasmacytic lymphoma is the most common type. The pattern may be nodular, interstitial, diffuse, or a mixture of more than one pattern. The lymphocytes are generally small on smears; some show eccentric, basophilic cytoplasm, similar to the cytoplasm of plasma cells, while often retaining the nuclear features of mature lymphocytes (plasmacytoid lymphocytes). Some cases, however, demonstrate a frank plasma cell component. Intranuclear inclusions in some of the lymphoid cells (Dutcher bodies) are usually present and mast cells are usually increased in number.

Because any type of malignant lymphoma may cause clinical symptoms of Waldenström's macroglobulinemia, the bone marrow in these cases should be diagnosed as involved by the specific type of lymphoma with a comment acknowledging that the findings are consistent with the clinical setting of Waldenström's macroglobulinemia.

What are the symptoms of Waldenstrom's disease?

What is Waldenstrom disease?

How is Waldenstrom's diagnosis?

Which antibody is commonly elevated in Waldenstrom macroglobulinemia?