How to understand lymphoplasmacytic lymphoma? This article is the best combing I've seen!

Lymphoplasmacytic lymphoma (LPL) is a rare mature B-cell lymphoma that often invades the bone marrow and, rarely, the spleen and/or lymph nodes
.
Waldenström macroglobulinemia (WM) is a clinicopathological disorder associated with IgM monoclonal gammopathy in the blood, which is almost common in LPL patients
.

The epidemiology, pathobiology, clinical manifestations, pathological features, diagnosis, and differential diagnosis
of LPL will be reviewed here.

LPL accounts for approximately 1% of hematologic malignancies in the United States and Western Europe, with an incidence of approximately 8.
3 per 1,000,000 per year, and in Asia it is about one-tenth
of that in the United States and Western Europe.
The vast majority of patients are Caucasian, with other ethnic groups accounting for about 5%
of all cases.
The median age at diagnosis was 65 years, and 50% to 60% of patients were male
.

Most patients with LPL have circulating monoclonal IgM, which often leads to a hyperviscosity syndrome called WM.

Although WM appears to present as a sporadic disease in most cases, some cases present with familial susceptibility to LPL and the epidemiology of WM, which are not discussed
in more detail here.

Cases classified as LPL occasionally are associated
with mixed (type II) cryoglobulinemia with hepatitis C virus (HCV) infection.
However, many of these cases may actually fall under the diagnostic category of marginal zone lymphoma (MZL), as MZL is also associated with HCV infection and may be associated with abnormal proteinemia
.

Malignant cells in LPL are presumed to be derived from peripheral B lymphocytes (which differentiate into plasma cells when stimulated), and may be B cells that do not enter the germinal center after the primary immune response to antigens, or B cells
that have undergone somatic mutations at the germinal center without antibody class (heavy chain) switching.
A gene expression profiling study comparing the transcription profile of WM with that of multiple myeloma and chronic lymphocytic leukemia (CLL) showed that the phenotype of WM was more similar to CLL
.

The pathogenesis of LPL is not fully understood, but as with other lymphomas, both acquired and epigenetic alterations appear to play a role
.

A study of 14 patients with LPL found that 13 of them had high-frequency somatic mutations in the immunoglobulin heavy chain (IgH) gene without intraclonal variation, suggesting that LPL cells originated from B cells
that underwent affinity maturation in germinal centers.
Several other studies have found that chromosomal rearrangements of IgH sites in LPL are uncommon
.
However, deletion of 6q21-q25 is identified in 40% to 60% of WM patients, which is also a common chromosomal loss site in a variety of B-cell
lymphomas.
The pathogenic target gene in the 6q21-q25 region has not been identified, but it is clear that genes encoding regulators of NF-κ-B, BCL2, apoptosis, and plasma cell differentiation are included in the region that is often missing
.

The new generation of LPL gene sequencing technology has identified common frequent mutations in the following genes: MYD88 (95%-97%), CXCR4 (30%-40%), ARID1A (17%), and CD79B (8%-15%)
.
Mutations in the CXCR4 gene are similar to those in WHIM syndrome, which are: warts, hypogammaglobulinemia, infection, and myelokathexis
.
Several studies have shown that somatic mutation status can divide tumors into groups with varying clinical manifestations and survival
.
Compared with MYD88 mutant tumors, MYD88 wild-type tumors have a more aggressive course of disease, shorter overall survival, and less effective treatment with irutinib
.
Tumors with both MYD88 and CXCR4 mutations were more likely to present with hyperviscosity and bone marrow involvement, and compared with CXCR4 wild-type tumors, they took longer to achieve significant efficacy, achieved shallower depths, and had lower
progression-free survival.

Another report combined mutation data with genome-wide DNA methylation and transcriptome analysis to identify 2 subclasses of LPL with different DNA methylation patterns, one similar to memory B cells and the other similar to plasma cells
.
Memory cell-like tumors are associated with CXCR4 mutations, 13q deletion, splenomegaly, and thrombocytopenia, while plasma celloid tumors are associated
with 6q deletion, use of IGHV3 variable region genes, CD38, and expression of other plasma cell markers.

MYD88 mutation

MYD88 is a molecule that plays a role in toll-like receptor and IL-1 receptor signaling, which enhances the survival
of B cells.
The pathogenesis of LPL involves an activating point mutation (MYD88 L265P)
of MYD88.
In LPL cells with the MYD88 L265P mutation, the complex of MYD88 with Bruton tyrosine kinase (BTK) promotes tumor survival
.

A study performed genome-wide large-parallel sequencing of bone marrow LPL cells and matching normal cells in the same patient found MYD88 L265P mutations
in bone marrow LPL cells in 10 LPL patients.
Sequencing of the gene in other patients found that 49 of the 54 WM patients had MYD88 L265P mutations, and 3 non-IgM secretory LPL patients all had MYD88 L265P mutations
.
The mutation
was not present in normal tissue samples from LPL patients and B cells in 10 healthy and 10 patients with multiple myeloma.
The MYD88 L265P mutation is also very rare in monoclonal gammopathy of undetermined significance (MGUS) of MZL and IgM types, with only 7% of MZL patients and 10% of MGUS patients
.

A subsequent study found that 18 of 27 patients with WM/LPL (67%), 2 of 28 patients with extranodal MZL (7%), 2 of 53 patients with splenic MZL (4%) had MYD88 L265P mutations, and none of the 11 patients with intranodal MZL had MYD88 L265P mutations
.

The third study found that 97 of 104 WM patients and 13 of 24 IgM MGUS patients (54%) had MYD88 L265P mutations
.
In contrast, only 2 of 20 patients with splenic MZL and only 1 of 26 patients with chronic lymphocytic lymphoma had the mutation, and the mutation
was not present in patients with multiple myeloma, IgG MGUS patients, and healthy people.

Another study included 64 patients with MYD88 wild-type B-cell tumors with macroglobulinemia and systematically reviewed their clinicopathological features
.
Results showed that up to 30% of cases had a diagnosis other than LPL, including IgM multiple myeloma and diffuse large B-cell lymphoma
.
The 10-year survival rate for wild-type WM cases of MYD88 was lower than that of MYD88 L265P mutant cases (73% versus 90%)
.

Together, these findings suggest that MYD88 mutations play a central role
in the pathogenesis of LPL.
MYD88 enhances signaling of toll-like receptors, thereby activating transcription factors of the NF-kB family, which are associated
with the growth and survival of normal B cells or tumor B cells.

As mentioned above, MYD88 also appears to enhance signaling through the BTK pathway, an important component of the B cell receptor signaling pathway that promotes B cell survival and growth
.
MYD88 mutations, although highly correlated with LPL, are not completely specific; This mutation has also been reported in a subtype of diffuse large B-cell lymphoma and, as described above, in a subtype of other plasma cell disorders (eg, IgM MGUS), as well as in low-grade B-lymphoproliferative disorders
.

Clinical features Patients with LPL vary clinically and may present with symptoms associated with tumor invasion (lymphadenopathy, organ enlargement, and cytopenias) or symptoms associated with monoclonal protein production (hyperviscosity and neuropathy).

About one-third of patients are asymptomatic at diagnosis
.
The most common onset features include weakness and fatigue, often due to
anaemia.
Up to one quarter of patients present with systemic B symptoms (i.
e.
, fever, night sweats, and weight loss).

Lymphadenopathy, hepatomegaly, and splenomegaly occur in about 20% of patients
.
More than 70% of patients have stage IV lymphoma at diagnosis because the bone marrow is already involved
.

Gamma globulinopathy

Monoclonal Ig (gammaglobulinopathy) is detectable in serum in most patients after protein electrophoresis or immunofixation electrophoresis, but the presence of gammopathy is not necessary to
diagnose LPL.
Blood list cloned IgM is the most common subtype and can diagnose clinical syndromes of WM
.
Rarely, tumors may produce other Ig, Ig combinations (i.
e.
, IgM and IgG), mixed cryoglobulins, or γ heavy chains
.
As mentioned earlier, most cases of mixed cryoglobulinaemia can be associated with
coexisting HCV infection.

A small proportion of patients have tumor cells that secrete IgG and/or express IgG on the surface of the cell membrane, otherwise consistent with typical LPL
.
In one case series, the median age of these patients was 70 years, there was significant lymphocytosis and splenomegaly, CD79b was strongly positive, the incidence of trisomy 12 was 60%, and the clinical course was non-aggressive
.

As in other cases of paraproteinaemia, serum total protein levels and erythrocyte sedimentation rate are usually elevated, and laboratory tests may also have pseudo-differences
.

other

Up to 40%
of patients have mild anaemia at diagnosis.
Severe anaemia, neutropenia, and thrombocytopenia are rare
.
β2-microglobulin may be elevated
.
Serum lactate dehydrogenase is usually normal
.

Monoclonal proteins in circulation may interfere with laboratory testing, resulting in pseudo-aberrations
.
This part will not be discussed
in depth.

The infiltrating cells of LPL typically contain small B cells, plasmacyte-like lymphocytes, and plasma cells, which can involve the bone marrow and, rarelymph nodes, and/or spleen
.
In peripheral blood, circulating tumor cells
are rare.

histology

1.
Bone marrow

Bone marrow infiltrates may be diffuse, nodular, or interstitial with or without paratrabecular aggregation
.
Infiltrating cells include small lymphocytes, plasma cells, and plasma celloid cells with variable cell numbers, often mixed with reactive mast cells, and may also be mixed with variable numbers of immunoblasts
.

The cytosolic Ig (IgM) of some cells accumulates to form PAS-stained (Periodic Acid-Schiff stain)-positive inclusion bodies, called Russell bodies (within the cytoplasm) or Dutcher bodies (within the pseudonucleus)
depending on their localization within the cell.

Extracellular Ig deposition may appear as amorphous or crystalline, sometimes with foreign body giant cell reactions
.
Such deposits are usually incidental and have no clinical significance
.
Amyloid deposition may occur in patients with LPL, but is less common
than in patients with myeloma and other plasma cell tumors.

2.
Lymph nodes

Lymph node structure is often preserved but may be absent
by diffuse, interstitial infiltrates of small lymphocytes, plasma cells, and plasma cells.
Some cases may also contain larger immunoblast-like cells
.
The lymphatic sinuses are usually open, and the sinus cavity may contain specialized histiocytes that react
with secreted Ig stained positive for PAS.
Typical features include Dutcher and Russell bodies, mast cells, and hemosiderins
.
Rarely, a large number of noncaseating granulomas
of unknown etiology are seen.
In some cases, such noncaseating granulomas may be so numerous that the underlying lymphoma is not obvious or even ignored
.

Importantly, there are no proliferative centers [chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) markers] in the lymph nodes, nor is there gray-white edge differentiation (seen in MZL).

3.
Spleen

Both the red and white pith of the spleen can be infiltrate
.
Its pattern of infiltration is usually diffuse, with no distinct marginal or nodular
areas in the red pulp.

4.
Peripheral blood

Circulating malignant cells usually have a plasmacytic-like appearance (i.
e.
, similar to plasma cells).

These cells are usually oval in shape and rich in basophilic cytoplasm
.
The nucleus is round, eccentric in position, and has a perinuclear depression or hyaline cytoplasm
.
The nucleus contains "clock face" or "wheel spoke" chromatin, but no nucleoli
.

Immunophenotyping

LPL cells express high levels of surface immunoglobulin (sIg), which are usually IgM type and often lack surface IgD
.
Cases
expressing IgG and IgA have been reported.

Infiltrated lymphocytes in these tumors express pan-B cell antigens (CD19, CD20, CD22, CD79a), while infiltrated plasma cells typically downregulate CD20 and upregulate CD138
.
Most express lymphocyte function-associated antigen 1 (LFA-1).

About half of the tumors express the adhesion molecules L-selectin, ICAM-1, CD44, and CD11c
.
CD43 expression varied in these cells; In some cases, CD25 or CD11c may be weakly positive
.
CD5
can be expressed in a few cases.
CD10, CD103, and CD23
are not usually expressed.

Genetic characteristics

As mentioned earlier, the most common genetic aberration is the MYD88 point mutation
.
LPL has no specific chromosomal abnormalities
.
The Ig heavy and light chain genes of tumor cells were rearranged, and somatic mutations occurred in the variable region (V region) genes, suggesting that these cells came from a B cell population
that had undergone antigen-driven selection.

Deletion of chromosomes 6q21 to q25 is the most common chromosome copy number abnormality, occurring in more than half of cases involving the bone marrow, but less common in cases involving lymph nodes
.
Less common chromosomal changes include trisomy 3, trisomy 8, and trisomy
4.
Chromosomal translocation t(9; 14)(p13; q32) was initially reported in some cases, but it was subsequently found that this translocation was rare and non-specific
in LPL.

diagnosis

Diagnosis is based on pathologic evaluation of the affected tissue, usually bone marrow or lymph nodes
.
Combined histologic and immunophenotypic findings exclude other small B-cell lymphoid tissue tumors with plasma cell differentiation:

≥10% of biopsy specimens must show infiltration of small lymphocytes, plasmacytooid lymphocytes, and plasma cells, mixed with variable numbers of immunoblasts
.
Mast cells in the bone marrow exhibit characteristic (but not diagnostic) hyperplasia with neoplastic infiltrates
.
Proliferative centers (diagnostic features of CLL/SLL and gray-white marginal differentiation (seen in MZL)
are absent.

This infiltration should express a typical immunophenotype (eg, surface IgM+, CD5-/+, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138-).

Plasma cellular components should be CD138+, CD38+, and CD45-/dim
.

Typical immunophenotypic changes may be present, but the purpose of this consideration is to reasonably exclude other lymphoproliferative disorders
.
Detection of the MYD88 L265P mutation is helpful in the diagnosis
of difficult cases.
The MYD88 mutation is LPL-compliant but not specific
.
Conversely, cases without MYD88 mutations are unlikely to be LPL
.

Further evaluation of patients with LPL includes serum protein electrophoresis (SPEP) to determine the presence of monoclonal Ig "peaks," a phenomenon associated
with WM clinicopathology.

Differential diagnosis The differential diagnosis of LPL includes other small B-cell lymphoid tissue tumors
with plasma cell differentiation.

1.
Chronic lymphocytic leukemia

Both LPL and CLL/SLL are small lymphoproliferative disorders with a slow
progression.
Features that help distinguish CLL from LPL include:

Peripheral blood involvement is generally more pronounced in CLL, but rarely, LPL can present with a "leukemia-like" manifestation
.
Circulating tumor cells in patients with LPL usually have a plasmacytic-like appearance, whereas circulating tumor cells in patients with CLL usually resemble mature lymphocytes mixed with a variable number of young lymphocytes (larger cells with a single distinct nucleoli).

Bone marrow infiltrates in patients with LPL are generally less extensive than in CLL, and unlike CLL, infiltrating cells in patients with LPL include small lymphocytes, plasma cells, and plasma cells, but lack proliferative lymphocytes and proliferative centers
.
Frequent appearance of reactive mast cells is also characteristic of LPL, but is sometimes seen in CLL
.

The affected lymph nodes in LPL lack the diagnostic features of CLL/SLL – proliferative centers
.

LPL has the following immunophenotypic characteristics: CD23 negative, surface IgM and CD20 strong positive, cytosolic Ig positive
.
Most cases of LPL lack expression of CD5, which can be expressed
in CLL.

2.
Multiple myeloma

Multiple myeloma is a plasma cell tumor characterized by the presence of malignant plasma cells in the bone marrow and monoclonal proteins
in serum or urine.
Symptoms associated with hyperviscosity are rare
.
Unlike LPL, the presence of IgM paraprotein in typical multiple myeloma is extremely rare, accounting for less than 1%
of all patients.

In general, LPL lacks CD56 and has a large number of small lymphocytes expressing clonal surface Ig, which distinguishes it from multiple myeloma
.
In difficult cases, it may be necessary to exclude multiple myeloma
based on differences in clinical presentation.
For example, if osteolytic lesions (with or without hypercalcaemia) are present, IgM multiple myeloma should be preferred over LPL
.
If symptoms of hyperviscosity are present and lymphadenopathy and/or splenomegaly are present, priority is given to LPL
.

3.
Mantle cell lymphoma

Mantle cell lymphoma (MCL) is usually made up of small to medium-sized monomorphic B lymphocytes with an irregular
nucleus shape.
MCL tumor cells are usually CD5+ and CD23-; The vast majority overexpression of cyclin D1 can be determined
by immunohistochemistry.
By traditional cytogenetic testing, chromosomal translocations involving cyclin D1 gene (CCDN1) can be detected in slightly more than half of MCL patientst(11; 14), but the proportion of patients detected using FISH technology was much
higher.
This translocation can occur in some patients with multiple myeloma, but not in patients with
LPL.

4.
Marginal lymphoma

Both LPL and MZL are tumors with small cell pleomorphic invasion.

Its immunophenotype is also similar to MZL cells, that is, it expresses the B cell markers CD19, CD20 and CD22, but does not express CD5, CD10 and CD23
.
Most cases present with chromosomal abnormalities, usually trisomy 3 or T (11; 18)
。

Unlike LPL, MZL usually has a population of lightly stained cytoplasm-rich cells (so-called monocytes-like B cells), which suggests marginal differentiation
.
In addition, patients with MZL are more likely to have mixed cryoglobulinemia and HCV infection
.
However, due to the similarity of the histological and immunophenotypes of LPL and MZL, it may still be difficult to distinguish
between the two.
Although IgM paraprotein may be present in MZL, IgM levels are typically below 0.
5 g/dL, while most LPL patients can have IgM paraprotein levels above 0.
5 g/dL
.
Testing for MYD88 mutations is being carried out at some centers, which may also be useful, but as mentioned earlier, this is not an absolute point of differentiation because a small percentage of MZLs also have MYD88 mutations
.
For some difficult cases, it is classified as "small B-cell lymphoma with plasma cell differentiation" first, and then LPL and MZL are included for differential diagnosis, which may be the most accurate classification method
.

5.
Follicular lymphoma

Rarely, follicular lymphoma (FL) may exhibit diffuse growth patterns and some degree of plasmacyte-like differentiation
.
Unlike FL, LPL is CD10 negative and does not have the chromosomal translocation
involved in BCL-2 in most FL cases.

Prognosis The clinical course of LPL is progressing slowly, and some case series in Europe have reported that LPL is more aggressive than typical CLL/SLL with a median survival of 5 to 7 years
.
However, in the REAL clinical study, 5-year overall survival (58%) and failure-free survival (25%) for LPL patients were the same
as those for CLL/SLL patients.
Initial studies have shown that the absence of MYD88 mutations is associated with lymphadenopathy and poorer prognosis, but this association requires further research
.

Most patients with LPL have circulating monoclonal IgM, consistent with the diagnosis
of WM.

Lymphoplasmacytic lymphoma (LPL) is an uncommon mature B-cell lymphoma that usually affects the bone marrow and, less commonly, the spleen and/or lymph nodes
.
Waldenstrom macroglobulinemia (WM) is a disease with unique clinicopathological features with bone marrow manifestations of LPL and blood manifestations of IgM monoclonal gammopathy
.

The clinical manifestations of LPL vary and include symptoms associated with tumor invasion (lymphadenopathy, organ enlargement, and cytopenias) or symptoms associated with monoclonal protein production (hyperviscosity, neuropathy).

About one-third of patients are asymptomatic
.

Monoclonal gammopathy is confirmed in most patients, but gammopathy is not necessary to
diagnose LPL.
The most common subtype is monoclonal IgM, from which WM is diagnosed
.
Rarely, tumors may produce other Ig, Ig combinations, mixed cryoglobulins, or γ heavy chains
.

Diagnosis of LPL is based on pathologic evaluation of the affected tissue, usually bone marrow or lymph nodes
.
Combined histologic and immunophenotypic findings can exclude other small B-cell lymphoid tissue tumors with plasma cell differentiation:

1.
≥10% of biopsy samples must confirm the presence of infiltration of small lymphocytes, plasma cell-like lymphocytes and plasma cells, mixed with an unvariable number of immunoblasts
.
In bone marrow, mast cell hyperplasia is characteristic (but not diagnostic) with neoplastic infiltrates
.
Proliferative centers [diagnostic features of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)] and lightly chromatic cytoplasm-rich cells showing marginal differentiation (so-called monocytes-like B cells, seen in marginal zone lymphoma (MZL)) are absent
in LPL.

2.
This infiltration should express a typical immunophenotype (eg, surface IgM+, CD5-/+, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138-).

Plasma cellular components should be CD138+, CD38+, and CD45-/dim
.

Typical histologic and immunophenotypic changes may be present, but the goal of this consideration is to reasonably exclude other lymphoproliferative disorders
.

Detection of MYD88 L265P mutation is diagnostic
in difficult cases.

Further evaluation in patients with lymphoplasmacytic lymphoma (LPL) includes serum protein electrophoresis (SPEP) to assess for the presence of monoclonal Ig "peaks"
associated with WM.

The clinical course of LPL progresses slowly, similar to typical chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL).

References:

Arnold S Freedman, MD，Jon C Aster, MD, PhD，Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma