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Lymphoplasmacytic Lymphoma (LPL) is a rare type of non-Hodgkin lymphoma that is characterized by infiltration of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells. The condition most commonly affects the bone marrow, followed by lymph nodes and spleen, and, to a lesser extent, the lung or gastrointestinal (GI) system. Typically, LPL is associated with monoclonal IgM paraprotein section of >3 g/dL [rx].
Lymphoplasmacytic lymphoma (LPL) with non-immunoglobulin M (IgM) paraproteinemia is a rare subtype of LPL [rx]. Furthermore, the clinicopathological features and appropriate treatment regimen for non-IgM LPL have not been clarified. Non-IgM LPL reportedly has a higher rate of extramedullary involvement and poorer overall survival than IgM LPL-Waldenström macroglobulinemia (WM) [rx].
Lymphoplasmacytic lymphoma, or Waldenstrom macroglobulinemia, is a low-grade B cell lymphoproliferative neoplasm characterized by small lymphocytes and monoclonal IgM monoclonal gammopathy. The disorder presents with symptoms related to bone marrow infiltration and IgM monoclonal gammopathy. Lymphoplasmacytic lymphoma is a diagnosis of exclusion; a diagnosis should only be rendered after the exclusion of all other small B cell lymphomas. Waldenstrom macroglobulinemia was described in 1944 by Jan G. Waldenstrom, who reported an unusual presentation of lymphadenopathy bleeding, anemia, elevated sedimentation rate, hyperviscosity, and hypergammaglobulinemia in two patients [rx][rx][rx].
Types of Lymphoplasmacytic Lymphoma
According to the latest World Health Organization (WHO) classification revised in 2016, lymphoplasmacytic lymphoma (LPL) is a monoclonal expansion of B-lymphocytes with varying degrees of B-cell differentiation from small lymphocytes to plasma cells [rx,rx]. Waldenström’s macroglobulinemia (WM) is a subset of LPL with bone marrow involvement and the presence of circulating immunoglobulin M (IgM) paraprotein [rx]. LPL presenting with serum monoclonal IgM, referred to as LPL/WM in clinical practice, is frequent, whereas non-IgM LPL presenting with IgG or IgA is rare and accounts for <5% of all LPL cases [rx].
The incidence of LPL is approximately 0.3–0.4 cases per million persons per year in Asia, which is 10-fold lower than in Western countries [rx]. Possible reasons for this difference in incidence likely include race-dependent genetic predisposition to LPL, lifestyle differences, and environmental factors [rx].
Recently, a mutation in MYD88 (MYD88 L265P) has been recognized in most patients with IgM LPL/WM, accounting for >90% of tumor samples from patients with LPL [rx]. This mutation plays a crucial role in the pathogenesis of LPL/WM and can help to differentiate B-cell lymphomas and plasma cell myeloma, both of which warrant further research [rx]. A previous study reported that fewer patients with non-IgM LPL harbor this mutation than those with classic LPL/WM; consequently, these 2 diseases may have different disease entities [rx].
Pathophysiology
The malignant cells in lymphoplasmacytic lymphoma are believed to originate from cells at a late stage of B-cell differentiation. These cells derive from a B-cell arrest after somatic hypermutation in the germinal center and before terminal differentiation to a plasma cell. The pathological findings in lymphoplasmacytic lymphoma are due to the infiltration of the bone marrow with small lymphocytes and IgM monoclonal gammopathy. Visual and neurological symptoms are related to the hyperviscosity and sluggishness of blood flow. Bleeding encountered in Waldenstrom macroglobulinemia is due to IgM binding to the clotting factors. Cryoglobulinemia in Waldenstrom macroglobulinemia patients leads to Raynaud phenomena and cold urticaria [rx][rx]
Causes of Lymphoplasmacytic Lymphoma
The etiology of lymphoplasmacytic lymphoma is poorly understood. However, the association of the disease with the hepatitis C virus and autoimmune disorders has been documented. Treatment of patients with hepatitis C and lymphoplasmacytic lymphoma with antivirals is an effective management strategy. Up to 20% of lymphoplasmacytic lymphoma cases also report familial predisposition; these patients usually present at an earlier age and show a greater degree of bone marrow involvement. Several research groups are interested in the prognostic implications of the genetic susceptibility in lymphoplasmacytic lymphoma [rx][rx][rx].
Symptoms of Lymphoplasmacytic Lymphoma
WM usually develops slowly over many months or years. You might have no symptoms at all to start with. Some people with WM are diagnosed by chance, during a routine blood test or an investigation for another condition.
The symptoms of WM can be very variable, even in people who have the same level of IgM paraprotein. The symptoms can relate to the LPL cells themselves, but they can also can be due to the high level of IgM paraprotein in the blood, or complications related to the IgM paraprotein. The symptoms are often quite different from the symptoms of other types of lymphoma.
Symptoms related to LPL
Most people with WM (and other types of LPL) have abnormal B cells and plasma cells in their bone marrow (the spongy tissue in the centre of bones where blood cells are made). The bone marrow may then not able to make as many normal blood cells as usual. This can cause:
- anemia (shortage of red blood cells), leading to tiredness, weakness, and breathlessness
- bacterial infection. সহজ বাংলা: ব্যাকটেরিয়ার বিরুদ্ধে লড়াই করা শ্বেত রক্তকণিকা।" data-rx-term="neutrophil" data-rx-definition="Neutrophil is a white blood cell important for fighting bacterial infection. সহজ বাংলা: ব্যাকটেরিয়ার বিরুদ্ধে লড়াই করা শ্বেত রক্তকণিকা।">neutrophil count, which may increase infection risk. সহজ বাংলা: নিউট্রোফিল কম থাকা, সংক্রমণের ঝুঁকি বাড়তে পারে।" data-rx-term="neutropenia" data-rx-definition="Neutropenia means low neutrophil count, which may increase infection risk. সহজ বাংলা: নিউট্রোফিল কম থাকা, সংক্রমণের ঝুঁকি বাড়তে পারে।">neutropenia (shortage of neutrophils, a type of white blood cell), leading to an increased risk of infections
- platelet count, which can increase bleeding risk. সহজ বাংলা: প্লাটিলেট কম।" data-rx-term="thrombocytopenia" data-rx-definition="Thrombocytopenia means low platelet count, which can increase bleeding risk. সহজ বাংলা: প্লাটিলেট কম।">thrombocytopenia (shortage of platelets, which help your blood clot), leading to a tendency to bruise and bleed easily (for example, nosebleeds).
- weakness and fatigue (often caused by anemia)
- fever, night sweats, and weight loss (generally associated with B-cell lymphomas)
- blurred vision
- dizziness
- nose bleeds
- bleeding gums
- bruises
- elevated beta-2-microglobulin, a blood marker for tumors
- swollen lymph nodes (lymphadenopathy)
- liver enlargement (hepatomegaly)
- spleen enlargement (splenomegaly)
Swollen lymph nodes are less common in people with WM than in other types of lymphoma. However, around 1 in 5 people with WM have swollen lymph nodes or a swollen spleen. A swollen spleen can cause discomfort or pain in your abdomen (tummy).
People with WM can also experience fevers, night sweats and weight loss, which are symptoms of many types of lymphoma. Doctors sometimes call these ‘B symptoms’.
In about 1 in 100 cases of WM, abnormal lymphocytes and plasma cells can build up in your central nervous system (brain and spinal cord). This is called ‘Bing-Neel syndrome’. It is very rare. It may cause headaches, seizures (fits), changes in your thinking processes or abnormal movements.
Rarely, lymphoma cells build up in other parts of the body and form masses or tumours. These are usually slow-growing and cause few symptoms. However, they can press on surrounding organs, nerves or blood vessels. This can cause pain or other symptoms in the affected area.
Symptoms related to abnormal antibodies
Many people with WM have symptoms caused by high levels of abnormal IgM antibody in their blood. This can make blood thicker than usual. This is called ‘hyperviscosity’. Hyperviscosity can cause symptoms such as:
- nosebleeds
- blurring or loss of vision
- dizziness or headaches
- ringing in the ears (tinnitus)
- drowsiness, poor concentration or confusion
- shortness of breath.
If you have hyperviscosity that causes symptoms, it is known as ‘hyperviscosity syndrome’ (HVS).
About 1 in 4 people with WM develop peripheral neuropathy (nerve damage). This might be caused by abnormal proteins or by the effects of the lymphoma cells on the nerves. Peripheral pain, numbness, tingling, or weakness. সহজ বাংলা: স্নায়ুর ক্ষতি/সমস্যা।" data-rx-term="neuropathy" data-rx-definition="Neuropathy means nerve damage or irritation causing pain, numbness, tingling, or weakness. সহজ বাংলা: স্নায়ুর ক্ষতি/সমস্যা।">neuropathy can cause tingling or numbness, usually in the fingers or toes on both sides of your body. If it isn’t treated, it slowly gets worse. You might find it harder than usual to write or handle small objects.
Diagnosis of Lymphoplasmacytic Lymphoma
History and Physical
The diagnosis of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia is usually challenging due to the lack of specific morphologic, immunophenotypic, or chromosomal changes. This lack makes the differentiation of this disease entity from other small B cell lymphomas based on exclusion. Symptoms can be classified into two categories: neoplasmic organ involvement and IgM paraprotein related symptoms. Patients may present with B related symptoms such as fever, night sweats, weight loss. Because of the frequent involvement of bone marrow, most lymphoplasmacytic lymphoma patients present with weakness and/or fatigue related to anemia. Some patients may present with the involvement of spleen, liver, and other extranodal sites, including skin, stomach, and bowel. As a rule, the diagnosis of lymphoplasmacytic lymphoma should be considered in elderly individuals with unexplained weakness, bleeding, neurological deficits, neuropathies, and visual difficulties [rx][rx][rx][rx][rx].
The 2017 World Health Organization classification of tumors of hematopoietic and lymphoid tissues have established four diagnostic criteria for Waldenstrom macroglobulinemia, including[rx]:
-
Presence of IgM monoclonal gammopathy
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Infiltration of bone marrow by small lymphocytes showing plasmacytoid or plasma cell differentiation
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Bone marrow infiltration showing an intertrabecular pattern
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Immunophenotype supportive of Waldenstrom macroglobulinemia that including surface IgM+, CD19+, CD20+, CD22+, CD25+, CD27+, FMC7+, CD5 variable, CD10-, CD23-, CD103-, and CD108-
Most Waldenstrom macroglobulinemia patients have monoclonal IgM. A minority can have both IgM and IgG. Waldenstrom macroglobulinemia patients can present with hyperviscosity symptoms (30%), autoimmune hemolysis (20%), coagulopathy, and/or diarrhea. Symptoms related to hyperviscosity include visual impairment, neurologic symptoms (neuropathy), bleeding, new-onset headaches, blurred vision, and cryoglobulinemia leading to Raynaud phenomena and cold urticaria. The neuropathy is sensory and affects more the feet than hands in a bilaterally symmetric pattern. The autoimmune hemolysis is due to cold agglutinins (IgM antibodies that bind at less than 37 C) [rx][rx][rx].
Evaluation
Lymphoplasmacytic lymphoma is diagnosed by identifying small malignant lymphocytes in the bone marrow that are usually admixed with plasma cells, plasmacytoid lymphocytes, and/or mast cells. The small malignant lymphocytes can be monocytoid, centroblasts, or immunoblastic. The bone marrow infiltration in those patients can be diffuse, interstitial, paratrabecular, or focal non-paratrabecular. Lymphoplasmacytic lymphoma involvement of the lymph nodes is associated with the retained overall architecture, paracortical expansion with small lymphocytes, and dilated sinuses with periodic acid Schiff positive material. Other characteristics such as Dutcher bodies (periodic acid Schiff positive intranuclear pseudo inclusions), increased mast cells, and hemosiderin deposition may be helpful in making the diagnosis. Some cases may show amyloid or other immunoglobin deposition. The presence of large prominent cells should raise the suspicion of a diagnosis other than lymphoplasmacytic lymphoma. Overall, lymphoplasmacytic lymphoma evaluation in the bone marrow and lymph node is a diagnostic challenge due to the variability of presentation and the wide differential diagnosis related to plasmacytoid differentiation. These include marginal zone lymphoma, follicular lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, and mantle cell lymphoma [rx][rx][rx].
Complete blood count in lymphoplasmacytic lymphoma usually shows variable degrees of cytopenias, with anemia and thrombocytopenia being common. Examination of the peripheral blood smear in lymphoplasmacytic lymphoma patients can show normochromic anemia and rouleau formation. On flow cytometry, lymphoplasmacytic lymphoma cells are surface IgM+, CD19+, CD20+, CD22+, CD25+, CD27+, FMC7+, CD5 variable, CD10-, CD23-, CD103-, and CD108-. Plasma cells are typically CD138-. Protein electrophoresis and immunofixation are usually required to assess the paraprotein in lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia serum. Assessment of serum viscosity can be helpful in making a diagnosis in some patients; levels commonly range between 4 to 8 cP [rx][rx].
Lymphoplasmacytic lymphoma usually shows immunoglobulin gene rearrangement and somatic hypermutation. Although no specific chromosomal abnormality has been reported in lymphoplasmacytic lymphoma, the presence of an MYD88 L265P mutation can favor diagnosis. However, this mutation is nonspecific and not necessary for identification of the disease. This mutation has also been reported in nongerminal center subtype diffuse large B cell lymphoma (DLBCL), primary cutaneous DLBCL, leg type DLBCL, primary central nervous system DLBCL, and testicular DLBCL. Other genetic mutations that have been reported include ARID1A, TP53, CD79B, KMT2D, and MYBBP1A. The 2017 World Health Organization classification of tumors of hematopoietic and lymphoid tissues stressed that the presence of IgM paraprotein only is not diagnostic for either lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia because paraproteins may be present in other lymphoproliferative disorders and even some benign conditions [rx][rx][rx][rx].
- Diagnostic criteria for Waldenström recommended by Second International Workshop (Semin Oncol 2003;30:110)
- IgM monoclonal gammopathy of any concentration
- Bone marrow infiltration by small lymphocytes showing plasmacytoid or plasma cell differentiation
- Intertrabecular pattern of bone marrow infiltration
- IgM monoclonal gammopathy of any concentration
- Immunophenotype
- Positive: IgM, CD19, CD20, CD22, CD79a, CD25 and CD38 frequent expression
- Negative: CD5, CD10, CD103, CD23; however, CD23 expression not uncommon in some cases
- CD5 and CD10 positive but BCL6 negative seen in a minority of cases
- Plasma cells in lymphoplasmacytic lymphoma:
- Positive: CD138, CD19, CD45 and sometimes MUM1 but can be negative
- Can be PAX5 positive
- IgM monoclonal paraprotein commonly present in serum, rarely IgG or IgA
- Lymphoplasmacytic lymphoma
- IgM paraprotein not required for diagnosis
- IgA or IgG paraprotein alone or coexists with IgM in serum (rare)
- Waldenström macroglobulinemia
- IgM paraprotein required for diagnosis
- No cutoff level for IgM in serum
- Lymphoplasmacytic lymphoma
- Other abnormal tests with Waldenström macroglobulinemia
- Elevated erythrocyte sedimentation rate (ESR), cytopenia / anemia
- Elevated serum levels of lactate dehydrogenase (LDH) and beta 2 microglobulin
In patients with suspected extramedullary disease (hepatosplenomegaly, lymphadenopathy), it is essential the use of CT scans with contrast. If it is confirmed, CT scans need to be used during and after treatment. [rx]
Treatment of Lymphoplasmacytic Lymphoma
Lymphoplasmacytic lymphoma management is similar to other indolent small B cell lymphomas. Asymptomatic patients are usually managed by close observation, and symptomatic patients are managed by single-agent rituximab therapy without maintenance. Treatment of Waldenstrom macroglobulinemia depends on the extent of end-organ involvement and symptoms. Asymptomatic patients are managed by close follow-up every 1 to 2 months including serial IgM measurements and assessment of serum viscosity.
Common regimens (combinations of drugs) that may be used include:
- DRC: dexamethasone, rituximab and cyclophosphamide
- Benda-R: bendamustine and rituximab.
Other chemotherapy combinations have been used in the past, including regimens containing fludarabine, chlorambucil or cladribine. These are used less frequently nowadays, but may still be used in certain circumstances. Gentler chemotherapy drugs such as chlorambucil might be used if you are not well enough for stronger chemotherapy. These drugs can be very effective.
Other treatments may also be used – your medical team should discuss these with you if they are relevant to you.
- Proteasome inhibitors (for example, bortezomib, carfilzomib, and ixazomib) are highly active in WM. They are not yet approved for use on the NHS. The regimen with the longest follow-up data is botezomib, rituximab and dexamethasone.
- Clinical trials of ibrutinib have had promising results in people who have not had any previous treatment for WM but long-term follow-up data isn’t yet available. Ibrutinib is currently licensed for people with WM that has come back (relapsed) or has not responded to initial treatment (refractory lymphoma) but it is not approved for first-line treatment. However, it may be used in certain circumstances.
You might be given:
- plasmapheresis (plasma exchange) if your blood is too thick because of high levels of IgM (hyperviscosity)
- blood transfusions or platelet transfusions (blood or platelets given through a drip into your vein) if you develop a low red blood cell count (anemia) or low platelet count (thrombocytopenia); you might need plasmapheresis first to stop your blood getting even thicker during the transfusion
- immunoglobulin replacement therapy (a drip containing antibodies) if your antibody levels are low and you have had severe or repeated injections
- antibiotics or antiviral drugs to prevent infections if you have low antibody levels or a low white blood cell count (for example neutropenia).
Symptomatic patients are managed by chemotherapy, immunotherapy, and/or an autologous bone marrow stem cell transplant. Chemotherapeutic agents that are effective in managing Waldenstrom macroglobulinemia include dexamethasone, fludarabine, bortezomib, and cyclophosphamide. A bone marrow transplant is usually reserved for younger patients with more extensive bone marrow involvement. Treatment algorithms for Waldenstrom macroglobulinemia recommend rituximab and bendamustine as a first line treatment. In cases of failure or relapse less than 36 months, bortezomib and cyclophosphamide or ibrutinib should be considered. Third-line treatment for Waldenstrom macroglobulinemia can be either fludarabine, everolimus, or lenalidomide. Plasmapheresis is useful in managing hyperviscosity [rx][rx][rx][rx][rx].
Watch and wait
LBL is slow-growing cancer. You and your doctor may decide to wait and monitor your blood regularly before starting treatment. According to the American Cancer Society (ACS), people who delay treatment until their symptoms are problematic have the same longevity as people who start treatment as soon as they’re diagnosed.
Chemotherapy
Several drugs that work in different ways, or combinations of drugs, may be used to kill the cancer cells. These include:
- chlorambucil (Leukeran)
- fludarabine (Fludara)
- bendamustine (Treanda)
- cyclophosphamide (Cytoxan, Procytox)
- dexamethasone (Decadron, Dexasone), rituximab (Rituxan), and cyclophosphamide
- bortezomib (Velcade) and rituximab, with or without dexamethasone
- cyclophosphamide, vincristine (Oncovin), and prednisone
- cyclophosphamide, vincristine (Oncovin), prednisone, and rituximab
- thalidomide (Thalomid) and rituximab
The particular regimen of drugs will vary, depending on your general health, your symptoms, and possible future treatments.
Biological therapy
Biological therapy drugs are manmade substances that act like your own immune system to kill the lymphoma cells. These drugs may be combined with other treatments.
Some of these manmade antibodies, called monoclonal antibodies, are:
- rituximab (Rituxan)
- ofatumumab (Arzerra)
- alemtuzumab (campath)
Other biological drugs are immunomodulating drugs (IMiDs) and cytokines.
Targeted therapy
Targeted therapy drugs aim to block particular cell changes that cause cancer. Some of these drugs have been used to combat other cancers and are now being researched for LBL. In general, these drugs block proteins that allow the lymphoma cells to keep growing.
Stem cell transplants
This is a newer treatment that the ACS says may be an option for younger people with LBL.
In general, blood-forming stem cells are removed from the bloodstream and stored frozen. Then a high dose of chemotherapy or radiation is used to kill all the bone marrow cells (normal and cancerous), and the original blood-forming cells are returned to the bloodstream. The stem cells may come from the person being treated (autologous), or they may be donated by someone who is a close match to the person (allogenic).
Be aware that stem cell transplants are still in an experimental stage. Also, there are short-term and long-term side effects from these transplants.
References
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664001/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394558/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779941/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894394/
- https://www.ncbi.nlm.nih.gov/books/NBK513356/
- https://www.ncbi.nlm.nih.gov/books/NBK536985/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170298/
