ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma

Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma
Authors:
Arnold S Freedman, MD
Jon C Aster, MD, PhD
Section Editor:
Andrew Lister, MD, FRCP, FRCPath, FRCR
Deputy Editor:
Rebecca F Connor, MD
Literature review current through: Jan 2024.
This topic last updated: Apr 28, 2022.

INTRODUCTION — Lymphoplasmacytic lymphoma (LPL, previously termed lymphoplasmacytoid lymphoma) is an uncommon mature B cell lymphoma usually involving the bone marrow and, less commonly, the spleen and/or lymph nodes [1,2]. Waldenström macroglobulinemia is a clinicopathologic entity associated with an immunoglobulin M (IgM) monoclonal gammopathy in the blood that is virtually always a manifestation of LPL. (See "Classification of hematopoietic neoplasms".)

The epidemiology, pathobiology, clinical presentation, pathologic features, diagnosis, and differential diagnosis of LPL will be reviewed here. The diagnosis, treatment, and prognosis of Waldenström macroglobulinemia are discussed separately. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia" and "Treatment and prognosis of Waldenström macroglobulinemia".)

EPIDEMIOLOGY — LPL accounts for roughly 1 percent of hematologic malignancies in the United States and Western Europe with an incidence of approximately 8.3 cases per million persons per year [3-6]. The incidence is approximately 10-fold lower in Asia [7]. The vast majority of patients are White people with other groups accounting for approximately 5 percent of cases [8]. The median age is 65 years and 50 to 60 percent of patients are male.

The majority of patients with LPL have a circulating monoclonal IgM that can lead to a hyperviscosity syndrome known as Waldenström macroglobulinemia (WM). Although LPL appears to be a sporadic disease in the majority of cases, a familial predisposition is present in some cases. The epidemiology of LPL and WM is discussed in more detail separately. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Epidemiology'.)

Occasional cases classified as LPL are associated with mixed (type II) cryoglobulinemia and concurrent hepatitis C virus (HCV) infection [9-11]. However, many such cases may in fact fall into the diagnostic category of splenic marginal zone lymphoma, which has also been associated with hepatitis C infection and may be accompanied by paraproteinemia. (See 'Marginal zone lymphoma' below.)

PATHOGENESIS — The postulated normal counterpart to the malignant cell in LPL is a peripheral B lymphocyte stimulated to differentiate to a plasma cell, possibly corresponding to the primary immune response to antigen, or to a post germinal center cell that has undergone somatic mutation but not heavy chain class switch [12]. Gene expression profiling studies reveal a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma [13].

The pathogenesis of LPL is incompletely understood, but as in other lymphomas, both acquired genetic and epigenetic alterations appear to contribute. One report found that 13 of 14 tumors studied had evidence of somatic hypermutation of the immunoglobulin heavy chain gene, without intraclonal variation, suggesting that the cell of origin is a post-germinal center B cell that has undergone affinity maturation [14]. Several other studies have found that chromosomal rearrangements involving the IgH locus are uncommon in LPL. However, deletions of 6q21-q25, a common site of chromosome loss in many different B cell lymphomas [15], have been identified in 40 to 60 percent of patients with Waldenström macroglobulinemia [16]. The pathogenic target gene(s) in the 6q21-q25 region have not yet been identified, but notably genes in the commonly deleted region include modulators of NF-kappa-B, BCL2, apoptosis, and plasma cell differentiation.

Next-generation sequencing of LPL has identified common recurrent mutations in the following genes: MYD88 (95 to 97 percent), CXCR4 (30 to 40 percent), ARID1A (17 percent), and CD79B (8 to 15 percent) [17]. Mutations in CXCR4 are similar to those seen in patients with the warts, hypogammaglobulinemia, infection, and myelokathexis (WHIM) syndrome. Multiple studies have shown that the somatic mutation status defines groups of tumors with different clinical presentations and survival rates [18]:

●MYD88MutCXCR4WT – Tumors with MYD88 mutation without CXCR4 mutation are the most common subtype. These tumors generally respond well to BTK inhibition.

●MYD88MutCXCR4Mut – Tumors with both MYD88 and CXCR4 mutations are more likely to present with hyperviscosity and bone marrow involvement, and relative to CXCR4 wild type tumors show an increased time to major response, decreased depth of response, and decreased progression-free survival [19,20]. Details regarding MYD88 are presented in the following section.

●MYD88WT – As compared with tumors with MYD88 mutations, tumors with wild type MYD88 pursue a more aggressive course and are associated with a decreased overall survival [21-23] and poor response to Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib [19,24].

Another report integrating mutational data with genome-wide DNA methylation and transcriptomic analyses identified two subclasses of LPL with distinct DNA methylation patterns, one resembling memory B cells and the second plasma cells [25]. Memory cell-like tumors were associated with CXCR4 mutations, deletion of 13q, splenomegaly, and thrombocytopenia, while the plasma cell-like tumors were associated with del(6q), use of IGHV3 variable region genes, and expression of CD38 and other plasmacytic markers.

MYD88 mutations — MYD88 is a molecule that plays a part in Toll-like receptor and interleukin-1 receptor signaling leading to enhanced B cell survival. An activating point mutation of MYD88 (MYD88 L265P) is the most common pathogenic mutation in LPL [17,21,26-29]. In LPL cells with the MYD88 L265P mutation, MYD88 complexes with Bruton tyrosine kinase (BTK) to promote tumor survival [30].

●In one study, genome-wide massively parallel sequencing of bone marrow LPL cells and paired normal cells from the same patient identified MYD88 L265P mutations in 10 of 10 patients with LPL [26]. Sequencing of this gene in additional patients revealed the MYD88 L265P mutation in 49 of 54 patients with WM and three of three patients with non-IgM-secreting LPL. This mutation was absent in the paired normal tissue samples and in B cells from 10 healthy donors and 10 patients with multiple myeloma. The MYD88 L265P mutation was also significantly less common in patients with marginal zone lymphoma (7 percent), or IgM monoclonal gammopathy of undetermined significance (10 percent).

●A subsequent study reported the MYD88 L265P mutation in 18 of 27 cases of WM/LPL (67 percent), 2 of 28 cases of extranodal marginal zone lymphoma (7 percent), 2 of 53 cases of splenic marginal zone lymphoma (4 percent), and none of 11 cases of nodal marginal zone lymphoma [27].

●A third study identified the MYD88 L265P mutation in 97 of 104 cases of WM (93 percent) and in 13 of 24 cases of IgM MGUS (54 percent) [28]. In contrast, this mutation was only found in 2 of 20 cases of splenic marginal zone lymphoma, 1 of 26 cases of chronic lymphocytic lymphoma, and none of the cases of multiple myeloma, IgG MGUS, or healthy donors.

●Another study systematically reviewed the clinicopathologic features of 64 patients with B cell tumors with macroglobulinemia and wild-type MYD88 [31]. On review, up to 30 percent of these cases were found to have diagnoses other than LPL, including IgM multiple myeloma and diffuse large B cell lymphoma. In comparison with MYD88 L265P-mutated WM cases, MYD88 wild type cases had less favorable 10-year survival (73 versus 90 percent).

Together, these findings indicate that MYD88 mutations have a central role in the pathogenesis of LPL. MYD88 augments Toll-like receptor signaling, thereby leading to the activation of transcription factors of the NF-kB family, which have been linked to the growth and survival of both normal and neoplastic B cells. As already noted, MYD88 also appears to augment signaling by BTK, an important component of the B cell receptor signaling pathway that also promotes B cell survival and growth. Although highly associated with LPL, MYD88 mutations are not entirely specific; they have also been reported in a subset of diffuse large B cell lymphomas [32] and, as noted above, also occur in a subset of other plasma cell dyscrasias (eg, IgM MGUS) [28,33] and low-grade B cell lymphoproliferative disorders [34,35].

CLINICAL FEATURES — The clinical presentation of patients with LPL is varied and can include symptoms related to tumor infiltration (lymphadenopathy, organomegaly, cytopenias) or monoclonal protein production (hyperviscosity, neuropathy). Approximately one-third of patients are asymptomatic at the time of diagnosis [36]. The most common presenting features include weakness and fatigue, often due to anemia. Up to one-quarter of patients display systemic B symptoms (ie, fever, night sweats, weight loss) [36]. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Systemic "B" symptoms'.)

Lymphadenopathy, hepatomegaly, and splenomegaly are each seen in approximately 20 percent of patients [37]. More than 70 percent of patients have stage IV disease by virtue of bone marrow involvement at the time of diagnosis (table 1).

The clinical syndrome of Waldenström macroglobulinemia (WM) describes cases of LPL associated with an IgM monoclonal gammopathy. In addition to the features described above, patients with WM may present with a clinically important bleeding diathesis, neuropathy, symptoms secondary to hyperviscosity, and funduscopic abnormalities. These are described in more detail separately. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Clinical presentation'.)

LABORATORY FINDINGS

Gammopathy — The majority of patients demonstrate a monoclonal immunoglobulin protein (gammopathy) on serum protein electrophoresis or immunofixation, but the presence of a gammopathy is not necessary for the diagnosis of LPL. A monoclonal serum IgM (figure 1) is the most common subtype and confers a diagnosis of the clinical syndrome Waldenström macroglobulinemia (WM) [38]. Less commonly, the tumor produces other immunoglobulins, a combination of immunoglobulins (ie, IgM and IgG), mixed cryoglobulins, or gamma heavy chains [39]. As mentioned earlier, most cases with mixed cryoglobulinemia are related to concurrent hepatitis C virus (HCV) infection [9-11]. (See "Laboratory methods for analyzing monoclonal proteins".)

The tumor cells of a small percent of otherwise typical LPL secrete IgG and/or express it on their surface membrane. In one series, these patients had a median age of 70 years, with significant lymphocytosis and splenomegaly, strong positivity for CD79b, a 60 percent incidence of trisomy 12, and a non-aggressive clinical course [40].

As in other cases of paraproteinemia, the serum total protein level and erythrocyte sedimentation rate are commonly elevated and laboratory artifacts may occur. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Laboratory findings'.)

Other — Up to 40 percent of patients have mild anemia at the time of diagnosis [36]. Severe anemia, neutropenia, and thrombocytopenia are much less common. Beta-2-microglobulin can be elevated. The serum lactate dehydrogenase is typically normal.

Circulating monoclonal protein may interfere with laboratory tests resulting in spurious results. This is discussed in more detail separately. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Laboratory artifacts'.)

PATHOLOGY — LPL is typically composed of small B cells, plasmacytoid lymphocytes, and plasma cells, involving the bone marrow. Less commonly, it can involve the lymph nodes and/or spleen. Circulating tumor cells are infrequently seen in the peripheral blood.

Histology

Bone marrow — The bone marrow infiltrate may be diffuse, nodular, or interstitial with or without paratrabecular aggregates. The infiltrate contains small lymphocytes, plasma cells and plasmacytoid cells in variable numbers admixed with frequent reactive mast cells. Variable numbers of immunoblasts may be admixed (picture 1).

Accumulation of cytoplasmic immunoglobulin (IgM) in some cells results in inclusions with periodic acid Schiff (PAS) staining known as Russell bodies (cytoplasmic) or Dutcher bodies (pseudonuclear) depending on their intracellular location (picture 2 and picture 3).

Extracellular deposits of immunoglobulin can take the form of amorphous masses or crystals, sometimes associated with a foreign-body giant cell reaction. Such deposits are usually discovered incidentally and of no clinical importance. Amyloid deposition may occur, but is less common in LPL than in myeloma and other plasma cell neoplasms.

Lymph node — Lymph node architecture is frequently preserved, but can be effaced by a diffuse, interstitial infiltrate comprised of small lymphocytes, plasma cells, and plasmacytoid cells. Some cases may also contain large, immunoblast-like cells. Sinuses are often open, and may contain histiocytes reacting to secreted periodic acid Schiff (PAS) positive immunoglobulin (picture 4). Typical characteristics include Dutcher and Russell bodies, mast cells, and hemosiderin-laden macrophages. Rarely, numerous non-caseating granulomas of uncertain etiology may be seen. In some instances, they may be so numerous that the underlying lymphoma is inconspicuous and overlooked. (See 'Bone marrow' above.)

Of importance, proliferation centers, the hallmark of chronic lymphocytic leukemia/small lymphocytic leukemia, are absent, as is paler-appearing marginal zone differentiation, which is seen in marginal zone lymphoma. (See 'Chronic lymphocytic leukemia' below and 'Marginal zone lymphoma' below.)

Spleen — Both the red and white pulp of the spleen may be infiltrated. The pattern is usually diffuse, without a distinct marginal zone or nodularity in the red pulp.

Peripheral blood — Circulating malignant cells often have a plasmacytoid appearance (ie, resembling a plasma cell). Such cells are typically oval with abundant basophilic cytoplasm (picture 5). The nucleus is round and eccentrically located with a perinuclear hof, or cytoplasmic clearing. The nucleus contains "clock-face" or "spoke wheel" chromatin without nucleoli.

Immunophenotype — LPL cells express high levels of surface immunoglobulin (sIg), usually of IgM type; surface IgD is usually lacking. Cases in which IgG and IgA are expressed have been described.

The lymphocytic component of these tumors expresses pan B cell antigens (CD19, CD20, CD22, CD79a), while the plasma cell component usually downregulates CD20 and upregulates expression of CD138 (table 2). The majority express lymphocyte function associated antigen 1 (LFA-1). Adhesion molecules expressed on approximately half of these tumors include L-selectin, ICAM-1, CD44 and CD11c. The cells are variable in their expression of CD43; CD25 or CD11c may be faintly positive in some cases [41-44]. A minority of cases expresses CD5 [45]. CD10, CD103, and CD23 are usually not expressed.

Genetic features — As already mentioned, the most frequent genetic aberration is point mutation of MYD88. There are no chromosomal abnormalities that are specific for LPL. Immunoglobulin heavy and light chain genes are rearranged, and variable (V) region genes show somatic mutations, suggesting that these cells arise from a population of B cells that have undergone antigen–driven selection [46-50]. (See 'MYD88 mutations' above.)

Deletion of chromosome 6q21-q25 is the most common chromosomal copy number abnormality and is found in more than half of cases based in the bone marrow, but less frequently in lymph node-based disease [51]. In patients with LPL, del6q is associated with symptomatic disease, adverse prognostic features, and shorter overall survival [52]. Less common chromosomal changes include trisomy 3, trisomy 8, and trisomy 4 [1]. The translocation t(9;14)(p13;q32) originally reported in a number of cases [53-57], was subsequently found to be rare in LPL and is not specific for this entity [58-60].

DIAGNOSIS — The diagnosis of LPL is made by pathologic evaluation of involved tissue, usually bone marrow or lymph node. A combination of histology and immunophenotypic findings is used to exclude other small B cell lymphoid neoplasms with plasmacytic differentiation:

●Ten percent or more of the biopsy sample must demonstrate infiltration by small lymphocytes, plasmacytoid lymphocytes, and plasma cells, with variable numbers of admixed immunoblasts. In the marrow there is a characteristic (but not pathognomonic) hyperplasia of mast cells that accompanies the neoplastic infiltrate. Proliferation centers (pathognomonic of CLL/SLL) and paler-appearing marginal zone type differentiation (seen in marginal zone lymphoma) are absent.

●This infiltrate should express a typical immunophenotype (eg, surface IgM+, CD5-/+, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138-). The plasmacytic component will be CD138+, CD38+ and CD45- or dim.

Variations from the typical immunophenotype may occur, but the goal is to satisfactorily exclude other lymphoproliferative disorders. Testing for the MYD88 mutation L265P may be helpful in difficult cases. Identification of a MYD88 mutation is consistent with but not specific for LPL. In contrast, cases without MYD88 mutation are less likely to be LPL. (See 'MYD88 mutations' above.)

Further evaluation of a patient with LPL includes a serum protein electrophoresis (SPEP) to look for the presence of a monoclonal immunoglobulin (Ig) "spike" associated with the clinicopathologic entity Waldenström macroglobulinemia. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for LPL includes other small B cell lymphoid neoplasms with plasmacytic differentiation (table 3).

Chronic lymphocytic leukemia — Both LPL and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) are lymphoproliferative disorders of small cells, which have an indolent course. Characteristics useful in distinguishing LPL from CLL include:

●Peripheral blood involvement in LPL is usually less prominent than in CLL, but on rare occasions "leukemic" presentations are seen. Circulating malignant cells in LPL often have a plasmacytoid appearance whereas those in CLL resemble mature lymphocytes mixed with variable numbers of so-called prolymphocytes, larger cells with single distinct nucleoli.

●The bone marrow infiltrate of LPL is usually less extensive than that of CLL, and, unlike CLL, contains a mixture of small lymphocytes, plasma cells, and plasmacytoid cells, and lacks prolymphocytes and proliferation centers. Frequent reactive mast cells are also characteristic of LPL, but are sometimes seen in CLL as well.

●Lymph node involvement in LPL lacks proliferation centers that are pathognomonic of CLL/SLL.

●The immunophenotype of LPL is notable for the lack of CD23, the presence of strong staining for surface IgM and CD20, and the presence of cytoplasmic Ig (table 2). Most cases of LPL lack expression of CD5, which is expressed in CLL. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Multiple myeloma — Multiple myeloma is a plasma cell neoplasm characterized by malignant plasma cells in the bone marrow and the presence of a monoclonal protein in the serum or urine. Symptoms related to hyperviscosity are uncommon. In contrast to LPL, classical multiple myeloma with an IgM paraprotein is rare, comprising less than 1 percent of patients.

Often, LPL can be distinguished from multiple myeloma by the absence of CD56 and the presence of a substantial small lymphocytic component that expresses a clonal surface immunoglobulin. In difficult cases, one may have to rely on the differences in clinical presentation to exclude multiple myeloma. For example, a diagnosis of IgM multiple myeloma is preferred over a diagnosis of LPL if lytic bone lesions are present with or without hypercalcemia. Symptoms of hyperviscosity, and the presence of lymphadenopathy and/or splenomegaly favor a diagnosis of LPL. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis" and "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

Mantle cell lymphoma — Mantle cell lymphoma (MCL) is usually comprised of monomorphous small to medium-sized B lymphocytes with irregular nuclei. MCL tumor cells are typically CD5+ and CD23-; the vast majority overexpress cyclin D1 protein, which can be identified by immunohistochemistry (table 2). The t(11;14) translocation involving the cyclin D1 gene (CCDN1) is seen in a little over half of MCL by conventional cytogenetics, but in a much higher percentage of cases tested with FISH. This translocation also is seen in some cases of multiple myeloma, but not in LPL. (See "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis".)

Marginal zone lymphoma — Both LPL and marginal zone lymphoma (MZL) are tumors that contain a polymorphous infiltrate of small cells. The immunophenotype is also similar with MZL cells expressing B cell markers CD19, CD20, and CD22, and not CD5, CD10, and CD23 (table 2). Chromosomal abnormalities, usually trisomy 3 or t(11;18), are found in most cases. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Unlike LPL, MZL often has a population of cells with abundant pale cytoplasm (so-called monocytoid B cells) that is indicative of marginal zone-type differentiation. In addition, patients with MZL are more likely to demonstrate mixed cryoglobulinemia and hepatitis C infection. However, given the similar histology and immunophenotype, it can be difficult to differentiate between LPL and MZL. While MZL may be associated with an IgM paraprotein, the level of IgM is typically less than 0.5 g/dL, whereas most cases of LPL have IgM paraprotein levels that exceed 0.5 g/dL. Testing for MYD88 mutation is being done at some centers and can also be useful, although as already discussed it is not an absolute discriminator, as a small minority of MZL has MYD88 mutations. In some difficult cases, "small B cell lymphoma with plasmacytic differentiation" followed by a differential diagnosis including LPL and MZL may be the most accurate classification.

Follicular lymphoma — On rare occasions, follicular lymphoma (FL) can demonstrate a diffuse growth pattern and exhibit some degree of plasmacytic differentiation. In contrast to FL, LPL is CD10 negative and is not associated with translocations involving BCL-2, which are seen in most follicular lymphomas (table 2). (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma".)

PROGNOSIS — The clinical course of LPL is indolent; in some European series it has been reported to be more aggressive than typical chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), with median survival in the range of five to seven years [61,62]. However, in the REAL clinical study, five-year overall survival (58 percent) and failure-free survival (25 percent) were identical to that of CLL/SLL [5]. Initial studies suggest that cases without MYD88 mutations are associated with adenopathy and a worse outcome [18], but this association requires further study. (See 'MYD88 mutations' above.)

The majority of patients with LPL have a circulating monoclonal IgM consistent with the diagnosis of Waldenström macroglobulinemia (WM). Prognostic factors for WM are discussed in more detail separately. (See "Treatment and prognosis of Waldenström macroglobulinemia".)

SUMMARY

●Definitions – Lymphoplasmacytic lymphoma (LPL) is an uncommon mature B cell lymphoma usually involving the bone marrow and, less commonly, the spleen and/or lymph nodes. Waldenström macroglobulinemia (WM) is a distinct clinicopathologic entity demonstrating LPL in the bone marrow with an IgM monoclonal gammopathy in the blood. (See 'Epidemiology' above and "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

●Clinical presentation – The clinical presentation of LPL is varied and can include symptoms related to tumor infiltration (lymphadenopathy, organomegaly, cytopenias) or monoclonal protein production (hyperviscosity, neuropathy). Approximately one-third of patients are asymptomatic. (See 'Clinical features' above.)

Most patients demonstrate a monoclonal gammopathy, but a gammopathy is not necessary for the diagnosis. The most common subtype is monoclonal IgM (figure 1), which confers a diagnosis of WM. Less commonly the tumor produces other immunoglobulins, a combination of immunoglobulins, mixed cryoglobulins, or gamma heavy chains. (See 'Laboratory findings' above.)

●Diagnostic evaluation – The diagnosis of LPL is made by pathologic evaluation of involved tissue, usually bone marrow or lymph node. A combination of histology and immunophenotypic findings is used to exclude other small B cell lymphoid neoplasms with plasmacytic differentiation (see 'Diagnosis' above):

•Biopsy sample demonstrates at least 10 percent infiltration by small lymphocytes, plasmacytoid lymphocytes, and plasma cells, with variable numbers of admixed immunoblasts. In the marrow there is a characteristic (but not pathognomonic) hyperplasia of mast cells that accompanies the neoplastic infiltrate. Proliferation centers (pathognomonic of CLL/SLL) and cells with abundant pale cytoplasm showing marginal zone type differentiation (so-called monocytoid B cells, seen in marginal zone lymphoma) are absent. (See 'Histology' above.)

•The infiltrate should express a typical immunophenotype (eg, surface IgM+, CD5+/-, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138-). The plasmacytic component will be CD138+, CD38+ and CD45- or dim. (See 'Immunophenotype' above.)

Variations from the typical histology and immunophenotype may occur, but the goal is to satisfactorily exclude other lymphoproliferative disorders (table 3). (See 'Differential diagnosis' above.)

Testing for the MYD88 mutation L265P is of diagnostic value in difficult cases. Identification of a MYD88 mutation is consistent with but not specific for LPL. In contrast, cases without MYD88 mutation are less likely to be LPL.

Further evaluation of a patient with LPL includes a serum protein electrophoresis (SPEP) to evaluate for the presence of a monoclonal immunoglobulin (Ig) "spike" associated with WM. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

●Prognosis – The clinical course of LPL is indolent and similar to that typical chronic lymphocytic leukemia/small lymphocytic leukemia. (See 'Prognosis' above.)

  1. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IARC Press, Lyon 2008.
  2. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127:2375.
  3. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006; 107:265.
  4. Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 1998; 16:2780.
  5. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997; 89:3909.
  6. Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010; 116:3724.
  7. Iwanaga M, Chiang CJ, Soda M, et al. Incidence of lymphoplasmacytic lymphoma/Waldenström's macroglobulinaemia in Japan and Taiwan population-based cancer registries, 1996-2003. Int J Cancer 2014; 134:174.
  8. Groves FD, Travis LB, Devesa SS, et al. Waldenström's macroglobulinemia: incidence patterns in the United States, 1988-1994. Cancer 1998; 82:1078.
  9. Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992; 327:1490.
  10. Pozzato G, Mazzaro C, Crovatto M, et al. Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia. Blood 1994; 84:3047.
  11. Krishnan C, Cupp JS, Arber DA, Faix JD. Lymphoplasmacytic lymphoma arising in the setting of hepatitis C and mixed cryoglobulinemia. J Clin Oncol 2007; 25:4312.
  12. Sahota SS, Forconi F, Ottensmeier CH, et al. Typical Waldenstrom macroglobulinemia is derived from a B-cell arrested after cessation of somatic mutation but prior to isotype switch events. Blood 2002; 100:1505.
  13. Chng WJ, Schop RF, Price-Troska T, et al. Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma. Blood 2006; 108:2755.
  14. Walsh SH, Laurell A, Sundström G, et al. Lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia derives from an extensively hypermutated B cell that lacks ongoing somatic hypermutation. Leuk Res 2005; 29:729.
  15. Offit K, Wong G, Filippa DA, et al. Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: clinical correlations. Blood 1991; 77:1508.
  16. Schop RF, Kuehl WM, Van Wier SA, et al. Waldenström macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions. Blood 2002; 100:2996.
  17. Treon SP, Xu L, Guerrera ML, et al. Genomic Landscape of Waldenström Macroglobulinemia and Its Impact on Treatment Strategies. J Clin Oncol 2020; 38:1198.
  18. Treon SP, Cao Y, Xu L, et al. Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood 2014; 123:2791.
  19. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med 2015; 372:1430.
  20. Treon SP, Gustine J, Meid K, et al. Ibrutinib Monotherapy in Symptomatic, Treatment-Naïve Patients With Waldenström Macroglobulinemia. J Clin Oncol 2018; 36:2755.
  21. Poulain S, Roumier C, Decambron A, et al. MYD88 L265P mutation in Waldenstrom macroglobulinemia. Blood 2013; 121:4504.
  22. Bustoros M, Sklavenitis-Pistofidis R, Kapoor P, et al. Progression Risk Stratification of Asymptomatic Waldenström Macroglobulinemia. J Clin Oncol 2019; 37:1403.
  23. Abeykoon JP, Paludo J, King RL, et al. MYD88 mutation status does not impact overall survival in Waldenström macroglobulinemia. Am J Hematol 2018; 93:187.
  24. Dimopoulos MA, Trotman J, Tedeschi A, et al. Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol 2017; 18:241.
  25. Roos-Weil D, Giacopelli B, Armand M, et al. Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features. Blood 2020; 136:585.
  26. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. N Engl J Med 2012; 367:826.
  27. Gachard N, Parrens M, Soubeyran I, et al. IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas. Leukemia 2013; 27:183.
  28. Xu L, Hunter ZR, Yang G, et al. MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. Blood 2013; 121:2051.
  29. Varettoni M, Arcaini L, Zibellini S, et al. Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms. Blood 2013; 121:2522.
  30. Yang G, Zhou Y, Liu X, et al. A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood 2013; 122:1222.
  31. Treon SP, Gustine J, Xu L, et al. MYD88 wild-type Waldenstrom Macroglobulinaemia: differential diagnosis, risk of histological transformation, and overall survival. Br J Haematol 2018; 180:374.
  32. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011; 470:115.
  33. Landgren O, Staudt L. MYD88 L265P somatic mutation in IgM MGUS. N Engl J Med 2012; 367:2255.
  34. Jiménez C, Sebastián E, Chillón MC, et al. MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström's macroglobulinemia. Leukemia 2013; 27:1722.
  35. Martínez-Trillos A, Pinyol M, Navarro A, et al. Mutations in TLR/MYD88 pathway identify a subset of young chronic lymphocytic leukemia patients with favorable outcome. Blood 2014; 123:3790.
  36. García-Sanz R, Montoto S, Torrequebrada A, et al. Waldenström macroglobulinaemia: presenting features and outcome in a series with 217 cases. Br J Haematol 2001; 115:575.
  37. Vitolo U, Ferreri AJ, Montoto S. Lymphoplasmacytic lymphoma-Waldenstrom's macroglobulinemia. Crit Rev Oncol Hematol 2008; 67:172.
  38. Dimopoulos MA, Alexanian R. Waldenstrom's macroglobulinemia. Blood 1994; 83:1452.
  39. Varettoni M, Boveri E, Zibellini S, et al. Clinical and molecular characteristics of lymphoplasmacytic lymphoma not associated with an IgM monoclonal protein: A multicentric study of the Rete Ematologica Lombarda (REL) network. Am J Hematol 2019; 94:1193.
  40. Garand R, Sahota SS, Avet-Loiseau H, et al. IgG-secreting lymphoplasmacytoid leukaemia: a B-cell disorder with extensively mutated VH genes undergoing Ig isotype-switching frequently associated with trisomy 12. Br J Haematol 2000; 109:71.
  41. Zukerberg LR, Medeiros LJ, Ferry JA, Harris NL. Diffuse low-grade B-cell lymphomas. Four clinically distinct subtypes defined by a combination of morphologic and immunophenotypic features. Am J Clin Pathol 1993; 100:373.
  42. Stein H, Lennert K, Feller AC, Mason DY. Immunohistological analysis of human lymphoma: correlation of histological and immunological categories. Adv Cancer Res 1984; 42:67.
  43. Harris NL, Bhan AK. B-cell neoplasms of the lymphocytic, lymphoplasmacytoid, and plasma cell types: immunohistologic analysis and clinical correlation. Hum Pathol 1985; 16:829.
  44. Lennert K, Tamm I, Wacker HH, et al. Histopathology and immunocytochemistry of lymph node biopsies in chronic lymphocytic leukemia and immunocytoma. Leuk Lymphoma 1991; (Suppl):157.
  45. Konoplev S, Medeiros LJ, Bueso-Ramos CE, et al. Immunophenotypic profile of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Am J Clin Pathol 2005; 124:414.
  46. Aoki H, Takishita M, Kosaka M, Saito S. Frequent somatic mutations in D and/or JH segments of Ig gene in Waldenström's macroglobulinemia and chronic lymphocytic leukemia (CLL) with Richter's syndrome but not in common CLL. Blood 1995; 85:1913.
  47. Crouzier R, Martin T, Pasquali JL. Monoclonal IgM rheumatoid factor secreted by CD5-negative B cells during mixed cryoglobulinemia. Evidence for somatic mutations and intraclonal diversity of the expressed VH region gene. J Immunol 1995; 154:413.
  48. Sahota SS, Garand R, Bataille R, et al. VH gene analysis of clonally related IgM and IgG from human lymphoplasmacytoid B-cell tumors with chronic lymphocytic leukemia features and high serum monoclonal IgG. Blood 1998; 91:238.
  49. Wagner SD, Martinelli V, Luzzatto L. Similar patterns of V kappa gene usage but different degrees of somatic mutation in hairy cell leukemia, prolymphocytic leukemia, Waldenstrom's macroglobulinemia, and myeloma. Blood 1994; 83:3647.
  50. Kriangkum J, Taylor BJ, Treon SP, et al. Molecular characterization of Waldenstrom's macroglobulinemia reveals frequent occurrence of two B-cell clones having distinct IgH VDJ sequences. Clin Cancer Res 2007; 13:2005.
  51. Mansoor A, Medeiros LJ, Weber DM, et al. Cytogenetic findings in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Chromosomal abnormalities are associated with the polymorphous subtype and an aggressive clinical course. Am J Clin Pathol 2001; 116:543.
  52. García-Sanz R, Dogliotti I, Zaccaria GM, et al. 6q deletion in Waldenström macroglobulinaemia negatively affects time to transformation and survival. Br J Haematol 2021; 192:843.
  53. Offit K, Parsa NZ, Jhanwar SC, et al. Clusters of chromosome 9 aberrations are associated with clinico-pathologic subsets of non-Hodgkin's lymphoma. Genes Chromosomes Cancer 1993; 7:1.
  54. Hamada T, Yonetani N, Ueda C, et al. Expression of the PAX5/BSAP transcription factor in haematological tumour cells and further molecular characterization of the t(9;14)(p13;q32) translocation in B-cell non-Hodgkin's lymphoma. Br J Haematol 1998; 102:691.
  55. Morrison AM, Jäger U, Chott A, et al. Deregulated PAX-5 transcription from a translocated IgH promoter in marginal zone lymphoma. Blood 1998; 92:3865.
  56. Iida S, Rao PH, Ueda R, et al. Chromosomal rearrangement of the PAX-5 locus in lymphoplasmacytic lymphoma with t(9;14)(p13;q32). Leuk Lymphoma 1999; 34:25.
  57. Krenacs L, Himmelmann AW, Quintanilla-Martinez L, et al. Transcription factor B-cell-specific activator protein (BSAP) is differentially expressed in B cells and in subsets of B-cell lymphomas. Blood 1998; 92:1308.
  58. Cook JR, Aguilera NI, Reshmi-Skarja S, et al. Lack of PAX5 rearrangements in lymphoplasmacytic lymphomas: reassessing the reported association with t(9;14). Hum Pathol 2004; 35:447.
  59. Lin P, Medeiros LJ. Lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia: an evolving concept. Adv Anat Pathol 2005; 12:246.
  60. Andrieux J, Fert-Ferrer S, Copin MC, et al. Three new cases of non-Hodgkin lymphoma with t(9;14)(p13;q32). Cancer Genet Cytogenet 2003; 145:65.
  61. Brittinger G, Bartels H, Common H, et al. Clinical and prognostic relevance of the Kiel classification of non-Hodgkin lymphomas results of a prospective multicenter study by the Kiel Lymphoma Study Group. Hematol Oncol 1984; 2:269.
  62. Engelhard M, Brittinger G, Heinz R, et al. Chronic lymphocytic leukemia (B-CLL) and immunocytoma (LP-IC): Clinical and prognostic relevance of this distinction. Leuk Lymphoma 1991; Suppl:161.
Topic 4768 Version 30.0

References

1 : World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IARC Press, Lyon 2008.

2 : The 2016 revision of the World Health Organization classification of lymphoid neoplasms.

3 : Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001.

4 : New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project.

5 : A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project.

6 : Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project.

7 : Incidence of lymphoplasmacytic lymphoma/Waldenström's macroglobulinaemia in Japan and Taiwan population-based cancer registries, 1996-2003.

8 : Waldenström's macroglobulinemia: incidence patterns in the United States, 1988-1994.

9 : A role for hepatitis C virus infection in type II cryoglobulinemia.

10 : Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia.

11 : Lymphoplasmacytic lymphoma arising in the setting of hepatitis C and mixed cryoglobulinemia.

12 : Typical Waldenstrom macroglobulinemia is derived from a B-cell arrested after cessation of somatic mutation but prior to isotype switch events.

13 : Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma.

14 : Lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia derives from an extensively hypermutated B cell that lacks ongoing somatic hypermutation.

15 : Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: clinical correlations.

16 : Waldenström macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions.

17 : Genomic Landscape of Waldenström Macroglobulinemia and Its Impact on Treatment Strategies.

18 : Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia.

19 : Ibrutinib in previously treated Waldenström's macroglobulinemia.

20 : Ibrutinib Monotherapy in Symptomatic, Treatment-Naïve Patients With Waldenström Macroglobulinemia.

21 : MYD88 L265P mutation in Waldenstrom macroglobulinemia.

22 : Progression Risk Stratification of Asymptomatic Waldenström Macroglobulinemia.

23 : MYD88 mutation status does not impact overall survival in Waldenström macroglobulinemia.

24 : Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial.

25 : Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features.

26 : MYD88 L265P somatic mutation in Waldenström's macroglobulinemia.

27 : IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas.

28 : MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction.

29 : Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms.

30 : A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia.

31 : MYD88 wild-type Waldenstrom Macroglobulinaemia: differential diagnosis, risk of histological transformation, and overall survival.

32 : Oncogenically active MYD88 mutations in human lymphoma.

33 : MYD88 L265P somatic mutation in IgM MGUS.

34 : MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström's macroglobulinemia.

35 : Mutations in TLR/MYD88 pathway identify a subset of young chronic lymphocytic leukemia patients with favorable outcome.

36 : Waldenström macroglobulinaemia: presenting features and outcome in a series with 217 cases.

37 : Lymphoplasmacytic lymphoma-Waldenstrom's macroglobulinemia.

38 : Waldenstrom's macroglobulinemia.

39 : Clinical and molecular characteristics of lymphoplasmacytic lymphoma not associated with an IgM monoclonal protein: A multicentric study of the Rete Ematologica Lombarda (REL) network.

40 : IgG-secreting lymphoplasmacytoid leukaemia: a B-cell disorder with extensively mutated VH genes undergoing Ig isotype-switching frequently associated with trisomy 12.

41 : Diffuse low-grade B-cell lymphomas. Four clinically distinct subtypes defined by a combination of morphologic and immunophenotypic features.

42 : Immunohistological analysis of human lymphoma: correlation of histological and immunological categories.

43 : B-cell neoplasms of the lymphocytic, lymphoplasmacytoid, and plasma cell types: immunohistologic analysis and clinical correlation.

44 : Histopathology and immunocytochemistry of lymph node biopsies in chronic lymphocytic leukemia and immunocytoma

45 : Immunophenotypic profile of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.

46 : Frequent somatic mutations in D and/or JH segments of Ig gene in Waldenström's macroglobulinemia and chronic lymphocytic leukemia (CLL) with Richter's syndrome but not in common CLL.

47 : Monoclonal IgM rheumatoid factor secreted by CD5-negative B cells during mixed cryoglobulinemia. Evidence for somatic mutations and intraclonal diversity of the expressed VH region gene.

48 : VH gene analysis of clonally related IgM and IgG from human lymphoplasmacytoid B-cell tumors with chronic lymphocytic leukemia features and high serum monoclonal IgG.

49 : Similar patterns of V kappa gene usage but different degrees of somatic mutation in hairy cell leukemia, prolymphocytic leukemia, Waldenstrom's macroglobulinemia, and myeloma.

50 : Molecular characterization of Waldenstrom's macroglobulinemia reveals frequent occurrence of two B-cell clones having distinct IgH VDJ sequences.

51 : Cytogenetic findings in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Chromosomal abnormalities are associated with the polymorphous subtype and an aggressive clinical course.

52 : 6q deletion in Waldenström macroglobulinaemia negatively affects time to transformation and survival.

53 : Clusters of chromosome 9 aberrations are associated with clinico-pathologic subsets of non-Hodgkin's lymphoma.

54 : Expression of the PAX5/BSAP transcription factor in haematological tumour cells and further molecular characterization of the t(9;14)(p13;q32) translocation in B-cell non-Hodgkin's lymphoma.

55 : Deregulated PAX-5 transcription from a translocated IgH promoter in marginal zone lymphoma.

56 : Chromosomal rearrangement of the PAX-5 locus in lymphoplasmacytic lymphoma with t(9;14)(p13;q32).

57 : Transcription factor B-cell-specific activator protein (BSAP) is differentially expressed in B cells and in subsets of B-cell lymphomas.

58 : Lack of PAX5 rearrangements in lymphoplasmacytic lymphomas: reassessing the reported association with t(9;14).

59 : Lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia: an evolving concept.

60 : Three new cases of non-Hodgkin lymphoma with t(9;14)(p13;q32).

61 : Clinical and prognostic relevance of the Kiel classification of non-Hodgkin lymphomas results of a prospective multicenter study by the Kiel Lymphoma Study Group.

62 : Chronic lymphocytic leukemia (B-CLL) and immunocytoma (LP-IC): Clinical and prognostic relevance of this distinction

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟