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]

Synonyms and keywords: Waldenstrom's macroglobulinemia; Waldenstrom's disease; Primary macroglobulinemia; Hyperviscosity syndrome; Lymphoplasmacytoid lymphoma

Differentiating Lymphoplasmacytic Lymphoma from Other B cell lymphoid neoplasms

Waldenström macroglobulinemia must be differentiated from other B cell lymphoid neoplasms including:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma:

• Always express CD5
• Usually CD23 positive

• B-cell prolymphocytic leukemia:

• Express bright surface IgM, CD20 and other B-cell antigens (CD19, CD22, CD79a, FMC7)

• Follicular lymphoma:

• Express CD10, HLA-DR, pan B-cell antigens (CD19, CD20, CD79a), CD21, and surface IgM, IgG, or IgA
• Rearrangement of Bcl-2

• Multiple myeloma:

• Express CD138, CD38, CD79a, VS38c and CD56 (70%)
• Presence of plasmacytic cell infiltration of bone marrow, osteolytic lesions, and renal insufficiency
• Translocation involving chromosome 11 (t11;14)

• Mantle cell lymphoma:

• Expresses CD5+ and CD23+
• Expresses surface IgM, IgD, and cyclin D1 in majority of cases
• Infiltration of bone marrow by monomorphous small lymphoid cells with irregular nuclei

• Marginal zone lymphoma:

• Expresses B cell markers CD19, CD20, and CD22
• Infiltrates the bone marrow with a characteristic intertrabecular and intrasinusoidal pattern
• Most common cytogenetic abnormalities are loss of 7q (19%) along with +3q (19%) and +5q (10% )

Diagnosis

• Not all the diagnostic tests mentioned are performed in a WM patient. A doctor takes into account the following factors before choosing diagnostic tests in a particular patient:
  • Suspected type of cancer.
  • Signs and symptoms.
  • Age.
  • Medical condition of the patient.
  • Results of earlier medical tests.

Manifestations of WM

Following is a list of WM manifestations with attributable causes:

Manifestations of WM

Cause	Manifestations
Tumor infiltration	Cytopenia, fever, night sweats, weight loss, lymphadenopathy, hepatomegaly, spleenomegaly, pulmonary infiltrates, nodules or masses, pleural effusion, abdominal pain, swelling and blood in stools secondary to stomach and bowel infiltration, renal and perirenal masses, maculopapular lesions, plaques or nodules secondary to dermis infiltration, lesions involving retro-orbital lymphoid tissue and lacrimal glands, infiltration of the conjunctiva and malignant vitreitis, Bing-Neel syndrome consists of confusion, memory loss, disorientation, motor dysfunction, and eventually coma.
Circulating monoclonal IgM	Hyperviscosity syndrome, Type 1 Cryoglobulinemia (consists of Raynaud's phenomenon, skin ulcers & necrosis and cold urticaria), frequent bruising, prolonged bleeding and clotting times.
IgM deposition into tissues	Sub-endothelial deposits in glomerular loops leading to non-selective proteinuria, dehydration, and uremia, Firm, flesh-colored skin papules and nodules have been reported and are called macroglobulinemia cutis, Diarrhea, malabsorption, or gastrointestinal bleeding.
Amyloidogenic properties of IgM	Organs more commonly affected by amyloidosis were the heart (44%), the peripheral nerves (38%), the kidneys (32%), the soft tissues (18%), the liver (14%), and lungs (10%), nephrotic syndrome and gastrointestinal involvement.
Autoantibody activity of IgM	Distal, symmetric, chronic demyelinating peripheral neuropathy, Type 2 cryoglobulinemia characterized by vasculitis affecting small vessels of skin, kidneys, liver, and peripheral nerves, Extravascular chronic hemolytic anemia called cold agglutinin disease exacerbated by cold exposure, glomerulonephritis, paraneoplastic pemphigus, and retinitis/retinopathy.

Common Symptoms

Common symptoms of Waldenström macroglobulinemia include:

• Constitutional B symptoms as seen in other types of NHL:
  • Weakness (due to normocytic anemia associated with IgM binding to RBCs).
  • Anorexia.
  • Unexplained weight loss.
  • Unexplained fever.
  • Heavy sweating, especially at night causing drenching of one's cloths and bedsheet.
  • Severe/extensive skin itchiness.
• Fatigue.
• Sensorimotor peripheral neuropathy (mostly associated with numbness and tingling, i.e. painful pins and needle sensation, of the fingers or toes).
• Blurry vision or blind spots.
• Abdominal pain.

Less Common Symptoms

Less common symptoms of Waldenström macroglobulinemia include:

• Enlarged lymph nodes (appearing as 1-2 inches sized lumps under the skin in neck, groin or the armpits).
• Swollen belly/abdomen (due to hepatosplenomegaly).
• Pain or a feeling of fullness below the ribs on the left side.
• Painless lumps in the neck, underarm, stomach, or groin
• Headache.
• Raised pink/flesh-colored lesions on skin.
• Altered mental status due to decreased blood flow and infiltration of CNS leading to:
  • Bing-Neel syndrome which includes:
    • Confusion.
    • Dizziness.
    • Memory loss.
    • Motor disorders.
• Symptoms resembling stroke like slurred speech or weakness on one side of body (such patients are advised to consult from their doctor right away).
• Abnormal mucous membrane bleeding (epistaxis, bleeding gums).
• Vision problems (blurred vision, double vision or blind spots).
• Kidney problems (leading to weakness, trouble breathing and fluid buildup in body tissues associated with accumulation of excess salt, fluid and waste products in blood secondary to amyloidosis).
• Heart problems (Secondary to amyloidosis, build up of M protein in heart affects its pumping ability, and also the heart has to work harder to pump the thick blood ultimately leading to CHF with following symptoms).
  • Palpitations.
  • Feeling of tiredness and weakness.
  • Cough.
  • Shortness of breath.
  • Rapid weight gain.
  • Swelling of feet and legs.
• Infections (high levels of abnormal antibody in WM slows down the production of normal antibodies).
• Digestive problems due to deposition of IgM protein in the lamina propria of the intestinal wall include:
  • Diarrhea.
  • Poor absorption of vitamins.
  • GIT bleeding/steatorrhea (blood in stools/dark stools).
• Sensitivity to cold (Raynaud's phenomenon due to cryoglobulinemia in 5% WM patients), which is associated with reduced blood flow leading to pain, itching, bluish discoloration or sores in following body parts:
  • Tip of nose.
  • Ears.
  • Fingers.
  • Toes.
• Cryoglobulinemia also leads to:
  • Numbness and tingling in hands and feet.
  • Joint aches.
  • Small bruises.
  • Skin ulcers.

Symptoms Secondary to Hyperviscosity Syndrome

The lymphoma cells make varying amounts of a monoclonal protein called immunoglobulin M (IgM, or macroglobulin). Higher amounts of this protein than normal in blood tends to make it thick leading to hyperviscosity syndrome which occurs in approximately 15-20% patients of WM. When blood becomes thick, it is harder for blood to flow through small blood vessels, and when this occurs, the condition is termed as Waldenstrom macroglobulinemia. This excess amount of IgM antibodies can be ultimately associated with circulatory problems leading to less blood flow to the brain, the eyes or other organs.Clinical manifestations of hyperviscosity syndrome occur only if serum viscosity is >4 centipoises and include:

• Symptoms resembling those of stroke.
• Retinal hemorrhage with blurring of vision/loss of vision.
• Vertigo.
• Dizziness.
• Headache.
• Loss of coordination.
• Nystagmus.
• Tinnitus.
• Ataxia.
• Bleeding.
• Shortness of breath.
• Numbness and tingling of the fingers or toes (called peripheral neuropathy).
• Muscle weakness.
• Confusion.
• Not all people with WM develop hyperviscosity, cryoglobulins, or amyloidosis.

Physical Examination

General Appearance

Patients with Waldenström macroglobulinemia are generally well-appearing.

Skin

• Maculopapular lesions, plaques, or nodules.
• Purpura.
• Raynaud phenomenon.
• Petechiae (if platelet count is low).
• Skin ulcers.
• Skin necrosis.
• Cold urticaria.
• Firm, flesh-colored skin papules and nodules also called macroglobulinemia cutis.

HEENT

• Pallor.
• Papilledema.
• Malignant vitreitis.
• Congestion/sludging of blood in conjunctival vessels.
• Retinitis/retinopathy including dilation, segmentation and tortuosity of retinal vessels, mid-peripheral retinal hemorrhages, serous retinal/macular neurosensory detachment, blurred disc margins and fundal exudates on fundoscopic examination.

Neck

• Lymphadenopathy.
• Jugular venous distension.

Respiratory

• Pleural effusion - in 3-5% of patients.
• Rales on auscultation.
• Pulmonary infiltrates, nodules, masses.

Cardiovascular system

• Displaced apical impulse.
• S3 gallop.

Abdomen

• Swollen abdomen/belly.
• Splenomegaly.
• Hepatomegaly.

Extremity

• Raynaud phenomenon.
• Patients may have peripheral edema if disease is complicated by congestive heart failure.

Neuromuscular

• Peripheral neuropathy - distal, symmetric, and sensorimotor.

Laboratory Findings

WM is mostly suspected when a patient has low blood counts and/or high levels of unusual protein levels on blood tests. Then usually after that, a blood test called serum protein electrophoresis is ordered to find out what type of protein is there. And mostly, only after these tests are done that a biopsy of either the bone marrow or a lymph node is considered to confirm the WM diagnosis. Laboratory findings consistent with the diagnosis of Waldenström macroglobulinemia include:

• Complete blood count:
  • Anemia.
    • Seen in 40% of newly diagnosed patients and in 80% of symptomatic patients with Waldenström's macroglobulinemia.
    • Multi-factorial causes including: decreased RBC synthesis due to bone marrow infiltration, iron deficiency due to gastrointestinal bleeding, and chronic inflammation.
  • Thrombocytopenia.
    • Due to bone marrow infiltration.
  • Neutropenia.
    • Due to bone marrow infiltration.
  • Lymphocytosis.
  • Monocytosis.
• Peripheral smear:
  • Plasmacytoid lymphocytes.
  • Normocytic normochromic red blood cells.
  • Rouleaux formation.
• Chemistry Lab tests:
  • Elevated lactate dehydrogenase (LDH).
    • Level indicates the extent of the disease.
  • Elevated urea and creatinine.
    • Rarely
  • Electrolyte abnormalities:
    • Hypercalcemia.
    • Hyponatremia.
  • Elevated erythrocyte sedimentation rate (ESR) and uric acid.
  • Rheumatoid factor, cryoglobulins, direct anti-globulin test, and cold agglutinin titre results can be positive.
  • Elevated beta-2-microglobulin in proportion to tumor mass.
    • Needed to evaluate prognosis.
• Platelet function test and blood coagulation studies:
  • Prolonged bleeding time.
    • Possibly due to interaction between platelet membrane glycoproteins and IgM paraprotein.
  • Abnormalities in prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen.
• Mutational analysis: The MYD88 gene mutation has been found in more than 90% of patients with Waldenstrom's macroglobulinemia.
• Cryocrit:
  • This test measures the blood levels of cryoglobulins (proteins that clump together in cool temperatures and can block blood vessels).
• Cold agglutinins:
  • Cold agglutinins are antibodies that attack and kill red blood cells, especially at cooler temperatures. These dead cells can then build up and block blood vessels. A blood test can be used to detect these antibodies.
• Beta-2 microglobulin (β2M):
  • This test measures another protein made by the cancer cells in WM. This protein itself doesn’t cause any problems, but it’s a useful indicator of a patient’s prognosis (outlook). High levels of β2M are linked with a worse outlook.
• Urinanalysis:
  • Proteinuria.

Bone Marrow Aspirate

A bone marrow aspirate is essential in the diagnosis of Waldenström macroglobulinemia.

Findings suggestive of Waldenström macroglobulinemia include:

• A hypercellular bone marrow aspirate.
• Lymphoplasmacytic infiltrate with characteristic immunophenotype.

Bone Marrow Biopsy

A bone marrow biopsy may be helpful in the diagnosis of Waldenström macroglobulinemia.

Findings on the biopsy suggestive of Waldenström macroglobulinemia include:

• Hypercellular and infiltrated with lymphoid and plasmacytoid cells.

• Dutcher bodies (PAS positive intra-nuclear vacuoles containing IgM monoclonal protein).
  • Characteristic feature of Waldenström macroglobulinemia.

Three patterns of marrow involvement are described, as follows:

• Lymphoplasmacytoid cells (lymphoplasmacytic and small lymphocytes) in a nodular pattern.
• Lymphoplasmacytic cells (small lymphocytes, mature plasma cells, mast cells) in an interstitial/nodular pattern.
• A polymorphous infiltrate (small lymphocytes, plasma cells, plasmacytoid cells, immunoblasts with mitotic figures).

Electrophoresis and Immunofixation

Serum protein electrophoresis is important for the diagnosis of Waldenström's macroglobulinemia.

Findings on an electrophoresis diagnostic of Waldenström's macroglobulinemia include:

• Sharp, narrow spike of monoclonal IgM protein
• Dense band of monoclonal IgM protein
• The paraprotein can be of any size

Serum immunofixation is important for the diagnosis of Waldenström's macroglobulinemia. It helps in confirming the presence of a monoclonal protein, in addition to determining its type.

Electrocardiogram

There are no ECG findings associated with Waldenström macroglobulinemia.

X-ray

Key Chest X-Ray Findings in Waldenström's Macroglobulinemia:

• Chest x-ray may be used to evaluate the following:
  • Enlarged lymph nodes.
  • Pulmonary infiltrates: This is especially important in patients who are immunocompromised while receiving chemotherapy.
  • Nodules.
  • Effusion.
  • Cardiomegaly (due to Congestive heart failure).

Echocardiography or Ultrasound

There are no echocardiography and ultrasound findings associated with Waldenström's macroglobulinemia. However, ultrasound of the spleen is more accurate at quantitation compared to physical examination findings alone. Ultrasound can be used to look at lymph nodes near body surface or to look for enlarged abdominal lymph nodes or organs such as the liver, spleen, and kidneys. (It can’t be used to look at organs or lymph nodes in the chest because the ribs block the sound waves.) It is sometimes used to help guide a biopsy needle into an enlarged lymph node.

CT scan

• CT scan imaging of chest, abdomen, and pelvis can be done to measure the tumor load.
• Waldenström's macroglobulinemia shows evidence of lymphadenopathy, and hepatosplenomegaly.
• CT of the lungs or abdomen can also be diagnostic for infection, which is particularly relevant to immunocompromised patients.

MRI

There are no specific MRI findings associated with Waldenström macroglobulinemia. However, MRI of the brain, spinal cord and orbits is important when assessing for hyperviscosity in the presence of high IgM paraprotein in the blood.

PET scan

A PET scan can be helpful in spotting small collections of cancer cells. It is even more valuable when combined with a CT scan (PET/CT scan). PET scans also can help tell if an enlarged lymph node contains lymphoma or not. It can help spot small areas that might be lymphoma, even if the area looks normal on a CT scan. These tests can be used to tell if a lymphoma is responding to treatment. They can also be used after treatment to help decide whether an enlarged lymph node still contains lymphoma or is merely scar tissue.

Other Diagnostic Studies

Other diagnostic studies for Waldenström macroglobulinemia include:

• Nerve conduction study and electromyography, which demonstrates:
  • Demyelination with sensory involvement more than motor
• Fundoscopy, which demonstrates:
  • Dilated, segmented, and tortuous retinal veins giving a "sausage link" appearance
    • Useful in patients with suspected hyperviscosity syndrome
• Plasma viscosity, which demonstrates:
  • Values > 1.5 centipoise
    • Should be measured in patients presenting with signs and symptoms suggestive of hyperviscosity syndrome or whenever the monoclonal IgM protein spike is > 4 g/dL.
• Mutational analysis for the MYD88 gene, since the MYD88 L265P mutation is found in 90% of patients with Waldenstrom's macroglobulinemia

Treatment

There are several different options for treating Waldenström macroglobulinemia depending on stage of the disease:

Asymptomatic/Smoldering Waldenström's Macroglobulinemia

There is no treatment for asymptomatic Waldenström macroglobulinemia. Asymptomatic waldenström's macroglobulinemia can be monitored every 3-6 months. Active surveillance includes monitoring of the following laboratory parameters:

• Complete blood count (CBC) with differential
• Complete metabolic panel (CMP)
• Immunoglobulin levels in the serum (quantitative)
• Serum protein electrophoresis

Symptomatic Waldenström's Macroglobulinemia

Symptomatic patients with waldenström macroglobulinemia are started on chemotherapy depending on the stage.

• Initial stage of waldenström's macroglobulinemia associated with:

• Neuropathy
• Anemia or cytopenias
• Low-volume nodal involvement
• Asymptomatic splenomegaly

• Late stage of Waldenström's macroglobulinemia associated with:

• Adenopathy
• Symptomatic splenomegaly
• Cytopenias
• Hyperviscosity syndrome
• Neuropathy
• Constitutional symptoms

Treatment Regimen	Drugs	Side effects
CHOP-R regimen	Cyclophosphamide Doxorubicin Vincristine Prednisone Rituximab	Nausea Alopecia Granulocytopenia Cardiotoxicity Mucositis
Ibrutinib	Ibrutinib	Fatigue Cytopenia Bleeding Atrial fibrillation Opportunistic infection
Rituximab	Rituximab	Infusion related reaction Hepatitis B reaction Progressive multi-focal leukoencephaloptahy
FR regimen	Fludarabine Rituximab	Neutropenia (63%) Thrombocytopenia Pneumonia
BDR regimen	Bortezomib Dexamethasone Rituximab	Peripheral neuropathy - reversible in 61% of patients Infections
DRC regimen	Dexamethasone Rituximab Cyclophosphamide	Neutropenia
CR regimen	Cladribine Rituximab	Anemia Neurological symptoms Symptomatic cryoglobulinemia Thrombocytopenia
IR regimen	Ibrutinib Rituximab	Anemia Neurological symptoms Symptomatic cryoglobulinemia Thrombocytopenia Atrial fibrillation

Hyperviscosity syndrome

• Waldenström macroglobulinemia complicated with hyperviscosity syndrome is a medical emergency and requires prompt treatment with plasmapheresis.
• Plasmapheresis temporarily lowers IgM levels by removing some of the abnormal IgM from the blood, which makes blood thinner.
• Plasmapheresis is usually given until chemotherapy starts to work.
• Plasmapheresis is combined with chemotherapy to control the disease for a longer period of time.

Surgery

Stem cell transplant is usually reserved for patients with either relapse or refractory Waldenström's macroglobulinemia.

Primary Prevention

Primary prevention of Waldenström macroglobulinemia depends on the type of risk factor causing the disease.

Modifiable risk factors

• Hepatitis C

Non-modifiable risk factors

• Age > 50
• Male gender
• Race - White
• Hereditary- Monoclonal gammopathy of undetermined significance

Secondary Prevention

There are no established measures for the secondary prevention of Waldenström's macroglobulinemia.

One or more of the following treatments can be given for lymphoplasmacytic lymphoma.

Watchful waiting

Watchful waiting (also called active surveillance) may be offered for lymphoplasmacytic lymphoma because it develops slowly and may not need to be treated right away. The healthcare team will carefully monitor the person with lymphoplasmacytic lymphoma and start treatment when symptoms appear, such as hyperviscosity syndrome, or there are signs that the disease is progressing more quickly.

Chemotherapy

• People with lymphoplasmacytic lymphoma who have symptoms or hyperviscosity syndrome are usually given chemotherapy. Chemotherapy drugs that may be used with or without prednisone include:
  • Chlorambucil (Leukeran)
  • Fludarabine (Fludara)
  • Bendamustine (Treanda)
  • Cyclophosphamide (Cytoxan, Procytox)

• Combinations of chemotherapy drugs that may be used include:
  • DRC – dexamethasone (Decadron, Dexasone), rituximab (Rituxan) and cyclophosphamide
  • BRD – bortezomib (Velcade) and rituximab, with or without dexamethasone
  • CVP – cyclophosphamide, vincristine (Oncovin) and prednisone
  • R-CVP – CVP with rituximab
  • Thalidomide (Thalomid) and rituximab

Targeted therapy

• Targeted therapy uses drugs to target specific molecules (such as proteins) on the surface of cancer cells. These molecules help send signals that tell cells to grow or divide. By targeting these molecules, the drugs stop the growth and spread of cancer cells while limiting harm to normal cells.
• Targeted therapy drugs used alone or in combination to treat lymphoplasmacytic lymphoma include rituximab, bortezomib and ibrutinib (Imbruvica).

Immunotherapy

• Immunotherapy works by stimulating, boosting, restoring or acting like the body’s immune system to create a response against cancer cells. Immunomodulatory drugs are a type of immunotherapy that interferes with the growth and division of cancer cells.
• Thalidomide is a type of immunomodulatory drug that may be used to treat lymphoplasmacytic lymphoma.

Radiation therapy

External beam radiation therapy may be used to treat lymphoplasmacytic lymphoma that develops outside of the lymphatic system (called extralymphatic disease), but this is rare.

Stem cell transplant

• Some people with lymphoplasmacytic lymphoma may be offered a stem cell transplant.
• It may be used if the lymphoma comes back (recurs) after treatment or doesn’t respond to other treatments (called refractory disease).
• Many people with lymphoplasmacytic lymphoma are older or may not be in good health, so a stem cell transplant may not be a good treatment option for them.

Read more: http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/more-types-of-nhl/lymphoplasmacytic-lymphoma/?region=on#ixzz5eb6iT7G6