Lymphoplasmacytic lymphoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

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.The term “macroglobulinemia” refers to the production of excess IgM monoclonal protein that occurs in certain clonal lymphoproliferative disorders and plasma cell dyscrasias. This broad definition includes patients with monoclonal gammopathy of undetermined significance of the IgM type (IgM MGUS), smoldering Waldenström macroglobulinemia, Waldenström macroglobulinemia (WM), and a number of related disorders in which an IgM monoclonal protein is detected, such as chronic lymphocytic leukemia (CLL), a number of lymphoma variants, and primary (AL) amyloidosis. According to new 2016 WHO classification, when hyperviscosity occurs in LPL patients due to excess IgM paraprotein, it is termed as Waldenström macroglobulinemia (WM). Hence, now WM is considered as a rare distinct subtype/clinicopathologic entity demonstrating lymphoplasmacytic lymphoma (LPL), with symptoms associated with presence of a serum IgM paraprotein due to infiltration of the hematopoietic tissues and the effects of monoclonal IgM in the blood. Waldenström macroglobulinemia is a type of lymphoproliferative disease involving lymphocytes with IgM as the main attributing antibody and shares clinical characteristics with the indolent non-Hodgkin lymphomas. Waldenström’s macroglobulinemia was first discovered by Jan G. Waldenström and represents 1% of all hematological cancers. Common causes of LPL include genetic, environmental, and autoimmune factors. While common risk factors include monoclonal gammopathy of undetermined significance, age >50 year old, white ethnicity, heredity, hepatitis C, and immune disorders. Genes involved in the pathogenesis of lymphoplasmacytic lymphoma include: MYD88-L265P, CXCR4 and chromosomes 6q, 13q, 3q, 6p and 18q. The hallmark of Waldenström’s macroglobulinemia is hyper-viscosity syndrome. If left untreated, patients with asymptomatic Waldenström’s macroglobulinemia may progress to develop a symptomatic disease. Common complications of Waldenström’s macroglobulinemia include: hyperviscosity syndrome, cold haemagglutinin disease, cryoglobulinemia, peripheral neuropathy, venous thromboembolism, primary amyloidosis, malabsorptive diarrhea, and bleeding manifestations. Less common but more severe complications include Schnitzler syndrome, Richter syndrome, and Bing-Neel syndrome. Prognosis varies depending on the multiple factors involved. Five year survival rate is 87% for low-risk disease and 36% for high-risk disease. Signs and symptoms of patients with lymphoplasmacytic lymphoma depend on the degree of tissue infiltration by malignant tumor cells, hyperviscosity syndrome, and accumulation of paraprotein. The diagnosis of lymphoplasmacytic lymphoma is based on bone marrow biopsy and serum protein analysis. Risk stratification determines the protocol of management used for lymphoplasmacytic lymphoma patients. Watchful waiting is recommended for asymptomatic Waldenström’s macroglobulinemia. Symptomatic Waldenström’s macroglobulinemia is treated with Rituximab +/- Chemotherapy. Ibrutinib with or without concurrent rituximab, is considered as a drug of choice for treatment of Bing-Neel syndrome.

Waldenström macroglobulinemia was first discovered by Jan G. Waldenström, a Swedish physician in 1944. Bing-Neel syndrome, a late and rare complication of lymphoplasmacytic lymphoma, was first discovered in 1936 by Jens Bing and Axel Valdemar Neel. First report on familial aggregation of Waldenstrom macroglobulinemia was published in 1962. In 1944, Revised European-American classification of lymphoid neoplasms (REAL) and WHO in 2001, placed Waldenstrom macroglobulinemia in the category of lymphoplasmacytic lymphoma. A diagnostic criteria for Waldenstrom macroglobulinemia was proposed by a consensus group at the Second International Workshop in Athens, Greece in 2002. A report published in 2013 showed that a patient of Bing-Neel syndrome who discontinued the treatment in 2009 remained asymptomatic.

There is no established system for the classification of lymphoplasmacytic lymphoma. However, according to a devised criteria based upon patient’s symptoms, Waldenström’s macroglobulinemia can be further classified into smoldering/asymptomatic and symptomatic WM.

Lymphoplasmacytic lymphoma (LPL) is an uncontrolled clonal proliferation of terminally differentiated B lymphocytes, which are normally involved in humoral immunity. Two main factors mediating this disease include IgM paraprotein secretion and tissue infiltration with neoplastic lymphoplasmacytic cells. Genes involved in the pathogenesis of LPL include MYD88-L265P, and CXCR4 along with various other cytogenetic and epigenetic abnormalities. In patients of lymphoplasmacytic lymphoma, there is an increased incidence of diffuse large B-cell lymphoma, myelodysplastic syndrome (acute myeloid leukemia), brain tumor, and renal MALT lymphoma. Two histologic subtypes include lymphoplasmacytoid and lymphoplasmacytic which invade the lymphoid organs such as spleen, lymph nodes and bone marrow. Bone marrow is infiltrated by small lymphocytes, well-formed plasma cells, and plasmacytoid lymphocytes in diffuse, interstitial, nodular, paratrabecular, nodular–interstitial and mixed paratrabecular-nodular patterns. Lymph nodes infiltration shows Dutcher and Russell bodies, mast cells, and hemosiderin-laden macrophages. Peripheral smear shows circulating malignant cells with a plasmacytoid appearance, having basophilic cytoplasm, perinuclear halo, and nucleus with “clock-face” chromatin without nucleoli. Immunohistochemistry shows pan B-cell surface antigens such as Ig+CD19+, CD20+, CD22+, CD79A+ and variable expression of some other antigens.

The exact cause of lymphoplasmacytic lymphoma has not been identified; however, the disease has been highly-associated with somatic mutations in MYD88 and CXR4 genes. In addition, less possible common cause of the disease includes chromosomal abnormalities.

Lymphoplasmacytic lymphoma must be differentiated from multiple myeloma, chronic lymphocytic leukemia/small lymphocytic lymphoma, b-cell prolymphocytic leukemia, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

The prevalence of lymphoplasmacytic lymphoma is estimated to be 1000-1500 cases in United States annually. Lymphoplasmacytic lymphoma represents 1-2% of all hematological cancers. Overall age-adjusted incidence of lymphoplasmacytic lymphoma is 0.38 cases per 100,000 persons annually, increasing with age to 2.85 in patients above 80 years. Incidence of lymphoplasmacytic lymphoma increases after 50 years of age with median age at diagnosis to be 65 years. Men are twice more likely than women to develop LPL and there is higher incidence of LPL in whites than blacks.

Common risk factors for the development of lymphoplasmacytic lymphoma are monoclonal gammopathy of undetermined significance, inherited immune disorders,heredity, hepatitis C and other autoimmune disorders, age >50 years, male gender, white race, allergic conditions like hay fever, multiple environmental factors, Human T-lymphotropic virus type I or Epstein-Barr virus, history of Helicobacter pylori infection, history of immunosuppressant drug therapy after an organ transplant, diet rich in meat and fat and history of past treatment for Hodgkin lymphoma.

According to the the United States Preventive Services Task Force (USPSTF), there is insufficient evidence to recommend routine screening for lymphoplasmacytic lymphoma.

If left untreated, patients with asymptomatic disease may progress to develop fatigue, weight loss, peripheral neuropathy, shortness of breath, purpura, raynaud’s phenomenon, and vision problems. Common complications of lymphoplasmacytic lymphoma include: hyperviscosity syndrome, cold haemagglutinin disease, cryoglobulinemia, peripheral neuropathy, primary amyloidosis, renal insufficiency, malabsorptive diarrhea, visual abnormalities, congestive heart failure, and schnitzler syndrome. Late and rare severe complications include richter syndrome, and bing-Neel syndrome. Prognosis varies depending on the various factors involved. Five year survival rate is 87% for low-risk disease and 36% for high-risk disease. A standardized scoring system known as the International PrognosticStaging System for Waldenström’s Macroglobulinemia (IPSSWM) risk stratifies the patients with Waldenstrom’s macroglobulinemia.

The diagnosis of lymphoplasmacytic lymphoma is based on bone marrow aspiration and biopsy and serum protein analysis studies such as immunohistochemistry,flow cytometry and cytogenetics to distinguish LPL from other types of B-cell lymphomas. CSF flow cytometry, protein electrophoresis and immunofixation is donefor the diagnosis of Bing-Neel syndrome (a late, but severe, rare complication).

Many patients with lymphoplasmacytic lymphoma are asymptomatic. The disease is subtle and symptoms are nonspecific and are caused by tumor infiltration, circulating monoclonal IgM, IgM deposition into tissues, amyloidogenic properties of IgM, and autoantibody activity of IgM. The most common symptoms of lymphoplasmacytic lymphoma include weakness, anorexia, unexplained weight loss, fever, heavy sweating, blurry vision, peripheral neuropathy, and abdominal pain. Less common symptoms of the disease include enlarged lymph nodes, abdominal distension, headache, painless lumps, raynaud phenomenon, altered mental status, mucosal bleeding, vision problems, kidney issues, heart problems, infections, GIT problems, and other symptoms due to cryoglobulinemia, cold agglutinin disease, hyperviscosity syndrome, and bing-neel syndrome.

Patients with lymphoplasmacytic lymphoma usually appear oriented to time, place, and person. Physical examination of patients with lymphoplasmacytic lymphomais usually remarkable for various findings depending on the degree of tissue infiltration by malignant tumor cells, hyperviscosity syndrome, and accumulation of paraprotein. Common physical exam findings include maculopapular lesions, purpura, petechiae, raynaud’s phenomenon, skin ulcers, skin necrosis, cold urticaria, macroglobulinemia cutis, pallor, papilledema, retinopathy, lymphadenopathy, jugular venous distension, pleural effusion, lung rales, pulmonary infiltrates, displaced apical impulse, S3 gallop, hepatosplenomegaly causing abdominal distension, peripheral edema due to congestive heart failure, and distal, symmetric, sensorimotor peripheral neuropathy.

Laboratory findings consistent with the diagnosis of lymphoplasmacytic lymphoma include any cytopenia, lymphocytosis, monocytosis, elevated levels of LDH, Beta-2 microglobulin, uric acid, and urea & creatinine, elevated ESR, hypercalcemia, hyponatremia, positive rheumatoid factor, positive cryoglobulins, positive direct antiglobulin test, positive cold agglutinin titre, proteinuria, prolonged bleeding time, prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time and peripheral smear shows plasmacytoid lymphocytes, normocytic normochromic red blood cells and rouleaux formation.

There are no ECG findings associated with lymphoplasmacytic lymphoma.

On chest x-ray, lymphoplasmacytic lymphoma may be characterized by enlarged lymph nodes, pulmonary infiltrates, nodules, effusion, and cardiomegaly due to congestive heart failure.

There are no specific echocardiography and ultrasound findings associated with lymphoplasmacytic lymphoma. However, ultrasound can be used to look at enlarged spleen, liver, kidneys, lymph nodes and to help guide a biopsy needle into an enlarged lymph node.

In lymphoplasmacytic lymphoma, CT scan imaging of chest, abdomen, and pelvis may show evidences of lymphadenopathy and hepatomegaly. CT of the lungs or abdomen can also be diagnostic for infection, which is particularly relevant to immunocompromised patients.

There are no specific MRI findings associated with lymphoplasmacytic lymphoma. However, MRI of the brain, spinal cord and orbits is especially important while assessing hyperviscosity and for diagnosing Bing-Neel syndrome.

A PET scan can be helpful in spotting small collections of cancer cells, to detect whether an enlarged lymph node has lymphoma or not, to see the response of treatment, and to help decide whether an enlarged lymph node still contains lymphoma or is merely scar tissue after treatment.

Other diagnostic studies for lymphoplasmacytic lymphoma include nerve conduction study, electromyography, funduscopy, plasma viscosity, and mutational analysis.

Risk stratification determines the protocol of management used for lymphoplasmacytic lymphoma. There is no treatment for asymptomatic lymphoplasmacytic lymphoma. The mainstay of treatment for symptomatic lymphoplasmacytic lymphoma is Rituximab +/- Chemotherapy. Hyperviscosity syndrome is a medical emergency and requires prompt treatment with plasmapheresis. Drug of choice for the treatment of bing-neel syndrome is Ibrutinib with or without concurrent rituximab. Other treatment options include targeted therapy, immunotherapy and radiation therapy.

Surgery is not the first-line treatment option for patients with lymphoplasmacytic lymphoma. Stem cell transplant is usually reserved for patients with either relapseor refractory lymphoplasmacytic lymphoma. In very rare cases, laparotomy or laparoscopy might be required.

Primary prevention of lymphoplasmacytic lymphoma depends on avoiding the type of modifiable risk factor causing the disease such as hepatitis C, HIV, rickettsiosis, hay fever, human T-lymphotropic virus type 1 infection, epstein-Barr virus infection, environmental factors, history of helicobacter pylori infection, history of immunosuppressant drug therapy after an organ transplant, diet rich in meat and fat and history of past treatment for hodgkin lymphoma.

There are no established measures for the secondary prevention of lymphoplasmacytic lymphoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

Waldenström macroglobulinemia was first discovered by Jan G. Waldenström, a Swedish physician in 1944. Bing-Neel syndrome, a late and rare complication of lymphoplasmacytic lymphoma, was first discovered in 1936 by Jens Bing and Axel Valdemar Neel. First report on familial aggregation of Waldenstrom macroglobulinemia was published in 1962. In 1944, Revised European-American classification of lymphoid neoplasms (REAL) and WHO in 2001, placed Waldenstrom macroglobulinemia in the category of lymphoplasmacytic lymphoma. A diagnostic criteria for Waldenstrom macroglobulinemia was proposed by a consensus group at the Second International Workshop in Athens, Greece in 2002. A report published in 2013 showed that a patient of Bing-Neel syndrome who discontinued the treatment in 2009 remained asymptomatic.

• In 1936, Jens Bing and Axel Valdemar Neel, discovered a late and rare complication of lymphoplasmacytic lymphoma known as Bing-Neel syndrome (BNS), who observed a case of 2 women, 56 and 39 years old, presenting with rapid neurodegeneration in the setting of hyperglobulinemia.
• In 1944, Jan G. (Gosta) Waldenstrom, a Swedish doctor of internal medicine, first discovered Waldenstrom macroglobulinemia (WM) who reported an unusual presentation of fatigue, lymphadenopathy, bleeding from nose and mouth, worsening anemia, elevated sedimentation rate, low serum fibrinogen levels (hypofibrinogenemia), hyperviscosity, and hypergammaglobulinemia in two patients due to increased levels of a class of an abnormal high molecular weight serum protein called macroglobulins.^[1][2]
• In 1962, the first report on familial inheritance in WM was published, and since then many cohort studies as well as small case-control studies have been published showing familial aggregation of WM.^{[3][4][5][6][7][8][9][10][11] [12][13][14][15]}
• In 1994, a Revised European-American classification of lymphoid neoplasms (REAL) was published by International Lymphoma Study Group which placed WM in the category of lymphoplasmacytic lymphoma (an indolent subtype of Non Hodgkin’s lymphoma and it is based on the morphology, immunophenotype, genetic and clinical features.^[16][17]
• In 2001, WHO also classified the pathology of WM as lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia based on REAL classification.^[2]
• In September 26-30, 2002, a consensus group at the Second International Workshop on WM in Athens, Greece, defined WM as a distinct clinicopathologic entity with characteristics of bone marrow infiltration associated with IgM monoclonal gammopathy by WM and proposed a diagnostic criteria for WM.^[2][18]
• In 2009, in Arkansas, a patient of Bing-Neel syndrome discontinued the treatment for BNS which included, intrathecal chemotherapy with several cycles of systemic chemotherapy followed by autologous BEAM transplant. In 2013, the patient was still asymptomatic when a follow-up report was published.^[19]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

There is no established system for the classification of lymphoplasmacytic lymphoma. However, according to a devised criteria based upon patient’s symptoms, Waldenström’s macroglobulinemia can be further classified into smoldering/asymptomatic and symptomatic Waldenstrom macroglobulinemia(WM).

There is no established system for the classification of lymphoplasmacytic lymphoma. However, according to a devised criteria based upon patient’s symptoms, Waldenström’s macroglobulinemia can be further classified into:^[1]

• Symptomatic Waldenstrom macroglobulinemia
• Asymptomatic/Smoldering Waldenstrom macroglobulinemia (SWM)^[2]

Classification of Waldenstrom macroglobulinemia (WM) and Related Disorders

Criteria	Symptomatic WM	Asymptomatic WM	IgM-Related Disorders	MGUS
IgM monoclonal protein	+	+	+	+
Bone marrow infiltration	+	+	–	–
Symptoms attributable to IgM	+	–	+	–
Symptoms attributable to tumor infiltration	+	–	–	–

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

Lymphoplasmacytic lymphoma (LPL) is an uncontrolled clonal proliferation of terminally differentiated B lymphocytes, which are normally involved in humoral immunity. Two main factors mediating this disease include IgM paraprotein secretion and tissue infiltration with neoplastic lymphoplasmacytic cells. Genes involved in the pathogenesis of LPL include MYD88-L265P, and CXCR4 along with various other cytogenetic and epigenetic abnormalities. In patients of lymphoplasmacytic lymphoma, there is an increased incidence of diffuse large B-cell lymphoma, myelodysplastic syndrome (acute myeloid leukemia), brain tumor, and renal MALT lymphoma. Two histologic subtypes include lymphoplasmacytoid and lymphoplasmacytic which invade the lymphoid organs such as spleen, lymph nodes and bone marrow. Bone marrow is infiltrated by small lymphocytes, well-formed plasma cells, and plasmacytoid lymphocytes in diffuse, interstitial, nodular, paratrabecular, nodular–interstitial and mixed paratrabecular-nodular patterns. Lymph nodes infiltration shows Dutcher and Russell bodies, mast cells, and hemosiderin-laden macrophages. Peripheral smear shows circulating malignant cells with a plasmacytoid appearance, having basophilic cytoplasm, perinuclear halo, and nucleus with “clock-face” chromatin without nucleoli. Immunohistochemistry shows pan B-cell surface antigens such as Ig+CD19+, CD20+, CD22+, CD79A+ and variable expression of some other antigens.

• Lymphoplasmacytic lymphoma arises from terminally differentiated B lymphocytes. Which are normally involved in humoral immunity.

• B cells develop from hematopoietic stem cells (HSCs) in bone marrow^[1]
• Then undergo 2 types of selection in bone marrow:
  • The positive selection by antigen–independent signaling involving both the pre-BCR and the BCR^[2][3]
  • Negative selection leads to a state of central tolerance, by binding of self-antigen with the BCR which if binds strongly to self-antigen, leads to four fates of B-cell:
    • Clonal deletion
    • Receptor editing
    • Anergy
    • Ignorance (B cell ignores signal and continues development)
• Immature B cells then migrate from bone marrow to secondary lymphoid organs (SLOs) such as spleen and lymph nodes
• B cell activation begins when the B cell binds to an antigen via its BCR in SLOs

B cells are:^[4]

• Lymphocyte subtype of white blood cells
• Function as a part of humoral immunity which is a component of adaptive immune system
• Secrete antibodies
• Secrete cytokines
• Classified as professional antigen-presenting cells (APCs)

• It is understood that LPL is mediated by 2 major factors:
  1. The secretion of IgM paraprotein:
     • Causes symptoms of hyperviscosity syndrome
  2. The infiltration of tissues with neoplastic lymphoplasmacytic cells:
     • Mainly the bone marrow, spleen,and lymph nodes
     • Sometimes the liver, gastrointestinal tract, lungs, kidneys, skin, eyes, and central nervous system

• The exact pathogenesis of lymphoplasmacytic lymphoma is not completely understood; however, its familial pattern of involvement supports the role played by genetic factors in the pathogenesis of this disease^[5][6]
• Development of LPL is the result of multiple genetic mutations^[7]
• Somatic hypermutations of immunoglobulin heavy chain gene, without any intraclonal variation, suggests that the cell of origin is a post-germinal center B cell that has undergone affinity maturation as well as chromosomal abnormalities play a part in the pathogenesis of this disease:
  • A mutation of the MYD88 gene (L265P) has been found in more than 90% of patients with lymphoplasmacytic lymphoma, while it has rarely presented in patients with other types of mature B-cell tumors^{[8][9][10][11][12][13][14][15]}
    • MYD88: The activating point mutation of MYD88 augments signaling by Toll-like receptor and Bruton tyrosine kinase (BTK), which leads to activation of transcription factors of the NF-kB family which are involved in growth and survival of both normal and neoplastic B cells by preventing apoptosis. Point mutation of MYD88 leads to leucine to proline substitution in codon 265 (L265P) of MYD88 and produces constantly overactive protein causing proliferation of malignant cells that should normally undergo apoptosis.The opening <ref> tag is malformed or has a bad name
    • Monoclonal gammopathy of undetermined significance patients found to have MYD88 L265P mutation have significantly higher risk of progression to Waldenström macroglobulinemia or to other lymphoproliferative disordersThe opening <ref> tag is malformed or has a bad name
  • Less commonly (30-35%), nonsense or frameshift mutations in the C-X-C chemokine receptor type 4 (CXCR4) 5338X gene have also been reported in patients with lymphoplasmacytic lymphoma. Mutations in CXCR4 are similar to those seen in patients with the warts, hypogammaglobulinemia, infection, and myelokathexis (WHIM) syndrome:^[16]
    • Patients with lymphoplasmacytic lymphoma with co-existing mutation of MYD88 & CXCR4 are more likely to have hyper-viscosity syndrome and bone marrow involvement^[7]
    • Somatic hypermutation in IGHV/IG gene rearrangement^[17]
    • AT-rich interactive domain-containing protein 1A gene (ARIDA) mutations (17%)

• Many cytogenetic abnormalities were reported in lymphoplasmacytic lymphoma’s patients including:
  • Deletion of the long arm of chromosome 6q21-22.1 (most common, 50%)^[18]
  • t(9;14) (p13;q32) (50% of patients)^[17]
  • Trisomy 4 (20%)^[17]
  • Deletion of long arm of chromosome 10, 12 or 20
  • Trisomy 3
  • Trisomy 5
  • Monosomy 8^[19]
  • Deletions of regions of 13q14 that include MIRN15A and MIRN16-1^[20]
  • t(11;18) (q21;q21) involving API-malt1^[20]
  • t(8;14)
  • t(14;18)

• Three most common epigenetic causes are:
  • DNA methylation, histone acetylation, and non-coding RNAs such as miRNAs^[21]
  • Upregulation of miRNAs 155, 184, 206, 363, 494, and 542-3p occurs in Waldenström macroglobulinemia; among which miRNA-155 has a crucial role in tumor cell growth and proliferation in Waldenström macroglobulinemia
• Gene transcription through histone acetylation occurs following increased expression of miRNA-206 and reduced expression of miRNA-9

Several studies showed an increased incidence of following second cancers in patients with lymphoplasmacytic lymphoma:^[22]

• Diffuse large B-cell lymphoma
• Myelodysplastic syndrome/Acute myeloid leukemia
• Brain tumor
• Renal MALT lymphoma ^[23]

• LPL is a form of an indolent (slowly growing) non-hodgkin’s lymphoma. LPL is called so because the lymphoma cells have the characteristics of both lymphocytes and plasma cells.
• Following lymphoid organs are involved in LPL:
  • Bone marrow
  • Lymph nodes (nodal involvement is characterized by paracortical and hilar infiltration with frequent sparing of the subscapular and marginal sinuses)
  • Spleen
• After a detailed clinicopathological assessment and review of the published literature, the following diagnostic criteria was proposed for LPL:^[24]
• IgM monoclonal gammopathy of any concentration
• Bone marrow infiltration by:^[25][26][27]
  • Small lymphocytes with clumped chromatin, inconspicuous nucleoli, and sparse cytoplasm
  • Well-formed plasma cells
  • Plasmacytoid lymphocytes (have cytologic features intermediate between above 2 extremes), in following patterns:^[28][29]
    • Diffuse
    • Interstitial
    • Nodular
    • Paratrabecular
    • Nodular–interstitial
    • Mixed paratrabecular-nodular
• WM has two histologic subtypes:^[29]
  • Lymphoplasmacytoid (73%)
  • Lymphoplasmacytic (27%)
• The cytologic composition and the degree of plasmacytic differentiation varies from case to case
• The bone marrow contains variable numbers of pleomorphic lymphoid cells
• Russell bodies (cytoplasmic) or Dutcher bodies (pseudonuclear) which are positive for periodic acid Schiff, can be seen due to accumulation of cytoplasmic IgM in some bone marrow cells
• Mast cell hyperplasia is common and may stimulate tumor cell proliferation and monoclonal IgM secretion
• Gene expression profiling has indicated that lymphoid cells of WM more closely resemble those of chronic lymphocytic leukemia than those of myeloma^[30]
• Lymph nodes involvement has following characteristics:
  • Dutcher and Russell bodies, mast cells, and hemosiderin-laden macrophages comprise the typical characteristic lymph node involvement
  • Numerous non-caseating granulomas are rarely observed
  • Lymph node architecture is frequently preserved
  • Diffuse and interstitial infiltration pattern is observed containing small lymphocytes, plasma cells, and plasmacytoid cells
  • Sometimes, large, immunoblast-like cells may be present
  • Often, sinuses remain open, and may contain histiocytes reacting to secreted periodic acid Schiff (PAS) positive immunoglobulin
  • Proliferation centers, which are 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
• Spleen involvement comprises of:
  • Both red and white pulp
  • Infiltration in a diffuse pattern
  • No distinct marginal zone or nodularity in the red pulp
• Peripheral blood contains:
  • Circulating malignant cells with a plasmacytoid appearance (i.e, resembling a plasma cell)
  • These cells are typically oval–shaped with abundant basophilic cytoplasm
  • Round and eccentrically located nucleus with a perinuclear halo, or cytoplasmic clearing
  • Nucleus has “clock-face” or “spoke wheel” chromatin without nucleoli

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Malignant cells in lymphoplasmacytic lymphoma have following immunophenotypic characteristics:^[27][7]

• Express pan B-cell surface antigens with following immunophenotype:^[31][32][33]
  • Ig+CD19+
  • CD20+
  • CD22+
  • CD79A+
• Variable expression of:
  • CD11c+
  • CD43+
  • CD38+
  • CD45+
  • CD138+
  • CD25+
  • CD27+
  • FMC7+
  • PAX5+
  • CD38+
  • Bcl2+
• Following aren’t expressed:
  • CD5–
  • CD10–
  • CD23–
  • CD103–
  • Bcl6–
  • CD75–
• IgM positive (mostly)
• IgG positive (few)
• IgA (rare)
• IgD negative (lack)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

The exact cause of lymphoplasmacytic lymphoma has not been identified; however, the disease has been highly-associated with somatic mutations in MYD88 and CXR4 genes. In addition, less possible common cause of the disease includes chromosomal abnormalities.

• Lymphoplasmacytic lymphoma is most probably caused by a somatic mutation in the MYD88 gene (seen in 90% of cases) or CXR4 gene (seen in 30% of cases)^[1][2]

Less common causes of lymphoplasmacytic lymphoma may include:^[3][4]

• Chromosomal abnormalities: to see the list of all cytogenetic abnormalities, click here
  • Deletions of 6q23 and 13q14
  • Gains of 3q13-q28, 6p and 18q

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

Lymphoplasmacytic lymphoma must be differentiated from multiple myeloma, chronic lymphocytic leukemia/small lymphocytic lymphoma, b-cell prolymphocytic leukemia, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

Lymphoplasmacytic lymphoma must be differentiated from following other B cell lymphoid neoplasms:

Disease		Etiology (Genetic or other)	Clinical manifestations						Paraclinical findings		Associated findings
									Lab findings
			Symptoms				Signs		Immunochemistry	Histopathology
			Constitutional symptoms	Rash	Abdominal pain	Diarrhea	Mass	Other
Lymphoplasmacytic lymphoma (Waldenstrom’s macroglobulinemia) [1][2][3][4][5]		Mature B-cell Lymphoma Mutation of the MYD88 gene (L265P) Nonsense or frameshift mutations in the CXR4 gene	Weakness Anorexia Weight loss Fever	–	–	+	Generalized and local lymphadenopathy	Retinal hemorrhage with blurring of vision Vertigo Dizziness Headache Nystagmus Tinnitus Ataxia Bleeding	Expresses pan B-cell antigens: CD19 CD20 CD22 CD79a CD5 Variable expression of: CD11c CD43 CD25 Majority express: IgM surface immunoglobulin Fewer express: IgG or IgA Lack IgD Lack expression of: CD10 Cyclin D1	≥10 percent infiltration by small lymphocytes, plasmacytoid lymphocytes, and plasma cells Variable numbers of admixed immunoblasts Hyperplasia of mast cells in marrow (characteristic but not pathognomonic) Diffusely effaced lymph nodes Absence of proliferation centers and marginal zone type differentiation Russell bodies (intracytoplasmic inclusions) Dutcher bodies (intranuclear inclusions) Prominent epithelioid histiocytes	Diffuse large B-cell lymphoma Myelodysplastic syndrome/Acute myeloid leukemia Brain tumor Renal MALT lymphoma
B cell chronic lymphocytic leukemia/small lymphocytic lymphoma [6]		Mature B-cell Lymphoma Chromosome 13 abnormalities Del13q Del11q Del17p Trisomy 12	33% of patients present with: Fever Weight loss Night sweats	–	–	–	Painless lymphadenopathy	May be asymptomatic Fatigue Recurrent infections Hepatosplenomegaly	Always expresses: CD5 CD38 Usually expresses: CD23 Dim expression of: CD20 Surface Ig	Monoclonal small well differentiated lymphocytes with a dense nucleus, partially aggregated chromatin, no discernible nucleoli, and a narrow border of clear to slightly basophilic cytoplasm Significant number of smudge cells or basket cells	Autoimmune hemolytic anemia Red cell aplasia Autoimmune thrombocytopenia
Follicular lymphoma [7][8][9][10][11]		Mature B-cell Lymphoma Reciprocal translocation t(14;18) Overexpression of BCL2	20% of patients present with: Fever Weight loss Night sweats	+	+	±	Painless peripheral adenopathy in the cervical, axillary, inguinal, and/or femoral regions Asymptomatic large abdominal mass	Seizures Chest pain Bone pain Cough Dyspnea	Expresses: CD21 CD23 CD10 HLA-DR CD19 CD20 CD79a Expresses Surface: IgM IgG IgA	Nodular growth pattern	Most common clinically indolent NHL Peripheral nerve compression
Mantle cell lymphoma [12][13][14][15][16]		Mature B-cell Lymphoma CD5 positive antigen in pre germinal center of B-cell Monomorphous small to medium sized B lymphocytes with irregular nuclei Chromosomal translocation at t(11:14)	Fatigue Night sweats Weight Loss	–	Abdominal distention	+	Palpable masses in skin, breast, and salivary glands Generalized lymphadenopathy	Extranodal involvement of GI tract, lungs, and CNS Mental Retardation	Positive for: CD5 B-cell antigen Cyclin D (overexpression) Co-express surface: IgM IgD Negative for: CD23–	Germinal centers filled by small-to-medium atypical lymphocytes Nodular appearance	_
Marginal zone lymphoma	Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type [17][18][19][20][21][22][23][24][25][26]	Mature B-cell Lymphoma Recurrent translocations such as: t(1;14)(p22;q32) t(11;18)(q21;q21) t(14;18)(q32;q21) t(3;14)(p14.1;q32)	B symptoms may or may not be present	±	+	+	Painless or painfullymphadenopathy which can be gastric or non-gastric Lump in the superior lateral quadrant of the orbit, breast, neck, or salivary gland	Symptoms depend on the location of the tumor and may include: Fatigue Heartburn Fever Cough with blood in sputum Shortness of breath	B-cell associated antigens that co-express: BCL-2 CD19 CD20 CD22 CD79a Negative for: CD5 CD10 CD43 Cyclin D1	Presence of dense diffuse lymphoid infiltrate of marginal‐zone cells in lamina propria Prominent lymphoepithelial lesions and consisting of small atypical cells with monocytoid features	H. pylori infection Hashimoto’s thyroiditis Sjogren’s syndrome Celiac disease
	Splenic marginal zone lymphoma [27][28][29][30][31][32][33]	Mature B-cell Lymphoma Clonal rearrangements of the immunoglobulin genes (heavy and light chains) Deletion 7q21-32 Translocations of the CDK6 gene located on 7q21	Fever Weight loss Night sweats	+	+	–	Painless swelling in the neck, axilla, groin, thorax, and abdomen.	Chest pain Bone pain	CD20 CD79a	Small lymphocytes Transformed blasts Epithelial histocytes Plasmacytic differentiation of neoplastic cells	Hepatitis C infection
	Nodal marginal zone B-cell lymphoma [34][35]	Mature B-cell Lymphoma Stimulation of antigen receptor by autoantigen and co-stimulatory molecule CD40 Mutations in KMT2D, PTTPRD, NOTCH2, KLF2	Fever Weight loss Night sweats	+	–	–	Painless swelling in the neck, axilla, groin, thorax, and abdomen Generalized and local lymphadenopathy	Hemorrhage Dyspepsia	_	Follicular cells in reactive zone Centrocyte like cells in marginal zone lymphoma Centroblasts Plasma cells Immunoblasts	Hepatitis C infection Chronic infectious conditions or autoimmune processes, such as: H pylori gastritis Hashimoto thyroiditis Sjögren syndrome
Multiple Myeloma[36][37][38][39][40][41]		Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells Clonal plasma cell proliferation	Constitutional symptoms may or may not be present Diffuse bone pain and tenderness with osteolytic lesions Worsens with activity Usually involves spine and ribs (axial skeleton) Hypercalcemia symptoms: Polyuria Polydipsia Constipation Loss of appetite Nausea and vomiting Lethary due to anemia Neurological symptoms: Numbness due to plasma cell infiltration of nerves or anti-neuronal glycoprotein antibodies Muscle weakness Confusion Dizziness Headache Paralysis Visual changes	–	Abdominal pain due to mesenteric venous thrombosis	No diarrhea Constipation due to hypercalcemia	Lymphadenopathy Hepatomegaly Splenomegaly Abdominal tenderness (if hypercalcemia is present)	Bone marrow failure–related symptoms, due to crowding out of normal bone marrow precursors by malignant plasma cells: Easy bruising, nosebleeds, bleeding gums due to thrombocytopenia Fatigue, weakness, shortness of breath, dizziness and paleness due to anemia Recurrent infections due to leukopenia Thrombotic symptoms, due to cancer–associated thrombosis and due to lenalidomide, which increases thrombotic risk: Shortness of breath due to pulmonary embolism Lower extremity edema due to deep vein thrombosis and renal involvement Abdominal pain due to mesenteric venous thrombosis Transient ischemic attack Retinal hemorrhage Pallor Ecchymoses Purpura Conjuctival pallor Visual defects Exudative retinal detachment Increased adipose deposition around the neck (if dexamethasone is used for therapy) Cotton-wool spots may be present Bony tenderness along cervical, thoracic, lumbar spine and in long bones Tinel’s sign may be present Phalen sign may be present Dermatomal sensory loss Altered sensation Neuropathy Mood alterations (if hypercalcemia is present)	Expresses: CD138 CD38 CD79a VS38c Infrequently expresses CD19 CD56 (expressed by 70% of myeloma cells) Absent surface Ig	Infiltration of plasma cells in the bone marrow	Relevant history includes: Review of past medical history for other plasma cell diseases, hematologic malignancies, underlying renal disease, and underlying bone disease Review of family history for members with positive history of hematologic malignancies Review of occupational history related to farming, oil industry, or Agent Orange exposure
B-cell prolymphocytic leukemia[42][43][44][45][46][47]		Deletion of chromosome 11 Chromosome 13	Anemia Weight loss Loss of appetite Fever	–	–	–	Massive splenomegaly Peripheral lymphadenopathy Hepatomegaly	Rapidly rising lymphocyte count Thrombocytopenia Pallor Petechiae Bruising Tachycardia Tachypnea	Expresses: Bright surface IgM IgD +/- CD20 CD19 CD22 CD79a FMC7 CD5 CD45 HLA-DR CD23+/- CD38 FMC7[45] Doesn’t express: CD10	Prolymphocytes comprise >55% of the neoplastic cells Bone marrow has interstitial pattern of infiltration Lymph nodes may show vague nodularity, but proliferation centers are absent	t(11;14) must be excluded No associated paraproteinemia More common in white race and Ashkenazi jewish male

]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

The prevalence of lymphoplasmacytic lymphoma is estimated to be 1000-1500 cases in United States annually. Lymphoplasmacytic lymphoma represents 1-2% of all hematological cancers. Overall age-adjusted incidence of lymphoplasmacytic lymphoma is 0.38 cases per 100,000 persons annually, increasing with age to 2.85 in patients above 80 years. Incidence of lymphoplasmacytic lymphoma increases after 50 years of age with median age at diagnosis to be 65 years. Men are twice more likely than women to develop LPL and there is higher incidence of LPL in whites than blacks.

• Lymphoplasmacytic lymphoma is one of the rare subtypes of NHL accounting just 1-2% of it

• The prevalence of lymphoplasmacytic lymphoma is estimated to be 1000-1,500 cases in United States annually^[1][2]

• LPL accounts for approximately 1% to 2% of hematologic cancers in United States and Western Europe^[3][2]
• Worldwide, the overall age-adjusted incidence of lymphoplasmacytic lymphoma is 0.38 cases per 100,000 persons annually, increasing with age to 2.85 in patients above 80 years (or 5 cases per 1 million persons per year)^[4]
• Incidence of LPL is approximately 8.3 cases per million persons per year^[5]
• LPL incidence is approximately 10-fold lower in Asia^[6]
• Majority of LPL patients are Caucasians, with other ethnic groups accounting for only 5 percent of cases^[2]
• The age-adjusted incidence rate for males is 0.92 per 100,000 person–years^[7]
• The age-adjusted incidence rate for females is 0.30 per 100,000 person–years^[7]
• Combined age and sex-adjusted incidence is 0.57 per 100,000 person–years^[7]

• The incidence of lymphoplasmacytic lymphoma increases after 50 years of age^[8]

• The median age at diagnosis is 65 years^[1][9][3]

• Men are twice more likely than women to develop LPL (5.4 vs. 2.7 per million, respectively) ^{[1][9][10][3]}

• Higher incidence in whites (4.1 per million per year) comparative to blacks (1.8 per million per year) and in past 20 years, incidence in whites has elevated^[1][9][5][3]

According to a recent study done in 2017, the following data was found out regarding epidemiology and demographics of smoldering Waldenstrom macroglobulinemia:^[11]

Epidemiology and demographics of Smoldering Waldenstrom macroglobulinemia according to Sex, Race and Age

Risk factors	Proportion of Smoldering Waldenstrom Macroglobulinemia
Sex	Males: 27.72% Females: 28.31%
Race	White, non-hispanic: 28.97% White, Hispanic: 24.79% Black: 21.01% Asian: 20.41% Other: 26.08%
Age in years	18-49: 18.32% 50-64: 25.91% 65-79: 30.8% ≥80 : 27.26%

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

Common risk factors for the development of lymphoplasmacytic lymphoma are monoclonal gammopathy of undetermined significance, inherited immune disorders, heredity, hepatitis C and other autoimmune disorders, age >50 years, male gender, white race, allergic conditions like hay fever, multiple environmental factors, Human T-lymphotrophic virus type I or Epstein-Barr virus, history of Helicobacter pylori infection, history of immunosuppressant drug therapy after an organ transplant, diet rich in meat and fat and history of past treatment for Hodgkin lymphoma.

Following are the common risk factors for the development of lymphoplasmacytic lymphoma:^{[1][2][3][4][5][6][7][8][9][10][11]}

Risk factors for the development of lymphoplasmacytic lymphoma
Pre-existing Monoclonal gammopathy of undetermined significance (MGUS) is the most common risk factor, associated with 40 times more likelihood of developing lymphoplasmacytic lymphoma[1]		Non-modifiable factors
Inherited immune disorders	Hypogammaglobulinemia Wiskott-Aldrich syndrome
Heredity[2][3][4]	Patients with lymphoplasmacytic lymphoma usually have a close/first-degree relative with the disease or with a related B-cell disease, such as MGUS or certain types of lymphoma or leukemia
Age >50 years
Gender–Male
Race–White
Autoimmune Diseases[4][5][6][7][8][9]	Personal and family history of autoimmune diseases with autoantibodies and chronic immune stimulation leads to 2-3 fold higher risk of developing LPL, especially elevated risks are associated with following: Sjogren syndrome Autoimmune hemolytic anemia Sarcoidosis SLE Rheumatoid arthritis Psoriasis
	Chronic hepatitis C infection leads to an overall 20-30% increased risk for developing non-Hodgkin lymohoma and 3-fold increased risk for lymphoplasmacytic lymphoma	Modifiable factors
	HIV
	Rickettsiosis
Allergic conditions	Hay fever is also known to be associated with increased risk of lymphoplasmacytic lymphoma
Human T-lymphotrophic virus type I or Epstein-Barr virus infection
Environmental factors[10][11]	According to some recent studies, exposure to following environmental factors seems to have an association with the development of LPL: Occupational (Farming) Pesticides Paint Rubber dyes Benzene Coal dust Leather manufacturing Wood dust Organic solvents
History of Helicobacter pylori infection
History of immunosuppressant drug therapy after an organ transplant
Diet rich in meat and fat
History of past treatment for Hodgkin lymphoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

According to the the United States Preventive Services Task Force (USPSTF), there is insufficient evidence to recommend routine screening for lymphoplasmacytic lymphoma.

According to the the United States Preventive Services Task Force (USPSTF), there is insufficient evidence to recommend routine screening for lymphoplasmacytic lymphoma.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

If left untreated, patients with asymptomatic disease may progress to develop fatigue, weight loss, peripheral neuropathy, shortness of breath, purpura, raynaud’s phenomenon, and vision problems. Common complications of lymphoplasmacytic lymphoma include: hyperviscosity syndrome, cold haemagglutinin disease, cryoglobulinemia, peripheral neuropathy, primary amyloidosis, renal insufficiency, malabsorptive diarrhea, visual abnormalities, congestive heart failure, and schnitzler syndrome. Late and rare severe complications include richter syndrome, and bing-Neel syndrome. Prognosis varies depending on the various factors involved. Five year survival rate is 87% for low-risk disease and 36% for high-risk disease. A standardized scoring system known as the International Prognostic Staging System for Waldenström’s Macroglobulinemia (IPSSWM) risk stratifies the patients with Waldenstrom’s macroglobulinemia.

• Symptoms of lymphoplasmacytic lymphoma usually develop in the seventh and eighth decade of life
• It will typically start with symptoms such as:
  • Fatigue
  • Unexplained weight loss
  • Numbness and tingling associated with peripheral neuropathy
  • Shortness of breath
  • Purpura
  • Raynaud’s phenomenon
  • Vision problems such as blurred vision, vision loss or blind spots^[1]

• As the disease progresses, the following complications can commonly occur in patients with lymphoplasmacytic lymphoma:
  • Hyperviscosity syndrome^[2]
  • Cryoglobulinemia^[3]
  • Peripheral neuropathy(15%)^[4]
  • Amyloidosis of the heart, kidney, liver, lungs, and joints^[5]
  • Cold haemagglutinin disease/Autoimmune hemolytic anemia(<10%)^[6]
  • Gastrointestinal malabsorption^[7]
  • Renal insufficiency^[8]
  • Fundoscopic abnormalities^[2]
  • Congestive heart failure
  • Schnitzler syndrome which is an autoimmune complication associated with elevated IgM levels, that leads to fever, itchy skin lesions, and joint aches

• Large cell transformation (Richter syndrome):
  • Dr. Richter of the University of Minnesota first recognized the blockage in maturity of the lymphoma cells at a point when they can’t mature beyond the large cell stage thus, leading to large cell transformation
• Central nervous system Lymphoma (Bing-Neel syndrome):^[9]
  • The development of Waldenström macroglobulinemia cells in the central nervous system was first described by Drs. Bing and Neel and carries their names as the Bing-Neel syndrome. WM involves CNS in following two forms:
    • Actual tumor developing in the brain substance causing seizures and paralysis
    • Tumor cells invading meninges and cranial nerves without causing the actual tumors and with or without CSF cryoglobulinemia,^[10] leading to the following symptoms:^[11]
      • Headache
      • Confusion
      • Neck stiffness
      • Sporadic loss of motor function
      • Facial paralysis
      • Drooping eyelid
      • Double vision
      • Difficult swallowing
      • Visual loss
      • Hearing loss

		Initial symptoms Fatigue Unexplained weight loss Numbness and tingling associated with peripheral neuropathy Shortness of breath Purpura Raynaud’s phenomenon Vision problems such as blurred vision, vision loss or blind spots
		Common complications Hyperviscosity syndrome Cryoglobulinemia Peripheral neuropathy (15%) Amyloidosis of the heart, kidney, liver, lungs, and joints Cold haemagglutinin disease/Autoimmune hemolytic anemia (<10%) Gastrointestinal malabsorption Renal insufficiency Fundoscopic abnormalities Congestive heart failure Schnitzler syndrome which is associated with: Elevated IgM levels Fever Itchy skin lesions Joint aches
		Late and rare severe complications Large cell transformation (Richter syndrome) Central nervous system Lymphoma (Bing-Neel syndrome)

• Prognosis is generally poor
• The median survival from the time of diagnosis is 6.4 years^[12]
• The median disease–specific survival is 11.2 years^[12]
• Approximately 10% patients still live uptil 15 years^[13][14]
• 5-year survival rate is 78%
• In the last decade (2001-2010), the median overall survival for all LPL groups has improved to just over 8 years compared to 6 years in the previous decade (1991-2000)
• Cases without MYD88 mutations are associated with adenopathy and a worse outcome^[15]
• After 2000, a 2-fold increased mortality is reported in patients diagnosed with LPL when compared with expected population mortality^[16]
• The presence of symptoms is associated with a particularly poor prognosis among patients with the disease
• Prognosis of asymptomatic patients is similar to that of the general population with a 10-year survival rate of 70-75%^[17][18]

• Some of the pretreatment factors associated with shorter survival in LPL patients are:^[19][12]
  • Clinical parameters:
    • Age >/=65 years
    • Hyperviscosity symptoms
    • Bulky organomegaly (Hepatosplenomegaly)
    • Bulky lymphadenopathy
    • B symptoms (weight loss, fever or night sweats)
    • Presence of symptomatic or unresponsive neuropathy
    • Hemolytic anemia
  • Laboratory parameters:^[20][21]
    • Hemoglobin < 10.0 g/dl)
    • Platelets <100 x 10(6)/dl
    • Albumin <3.5 g/dl
    • Bone marrow lymphoplasmacytic infiltrate >/=50%
    • Elevated β2 microglobulin (associated with 3-fold increase in death)
    • Leucopenia (<4.0 x 10(9)/l)
    • Thrombocytopenia (<150 x 10(9)/l)
    • Quantitative IgM < 0.4 g/l
    • Serum free light chain^[22]
    • Serum lactate dehydrogenase^[23]
    • Serum soluble CD27^[24]
• Most of the prognostic factors have defined the outcome of lymphoplasmacytic lymphoma in patients requiring treatment, however, very few studies have evaluated the prognostic factors in patients who don’t initially need the treatment

All the above prognostic data has been combined to risk stratify the WM patients and to formulate a standardized scoring system known as the International Prognostic Staging System for Waldenström’s Macroglobulinemia (IPSSWM):^[25]

Risk factors	Score
Age > 65	1
Hemoglobin ≤ 11.5g/dl	1
Platelet ≤ 100,000μl	1
β-microglobulin > 3mg/l	1
IgM > 70g/l	1

International prognostic scoring system for Waldenström macroglobulinemia

Risk group	Score	5-year survival	Median survival
Low	0-1 (except age)	87%	12 years
Intermediate	2 or age>65	68%	8 years
High	≥3	36%	3.5 years

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