Lymphoplasmacytic lymphoma: Difference between revisions

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===Physical Examination===
===Physical Examination===


===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:<ref name="pmid11736938">{{cite journal| author=García-Sanz R, Montoto S, Torrequebrada A, de Coca AG, Petit J, Sureda A et al.| title=Waldenström macroglobulinaemia: presenting features and outcome in a series with 217 cases. | journal=Br J Haematol | year= 2001 | volume= 115 | issue= 3 | pages= 575-82 | pmid=11736938 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11736938  }} </ref>
* '''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 anemia|Normocytic normochromic red blood cells]].
**[[Rouleaux]] formation.
* '''Chemistry Lab tests:'''<ref name="pmid19520758">{{cite journal| author=Katzmann JA, Kyle RA, Benson J, Larson DR, Snyder MR, Lust JA et al.| title=Screening panels for detection of monoclonal gammopathies. | journal=Clin Chem | year= 2009 | volume= 55 | issue= 8 | pages= 1517-22 | pmid=19520758 | doi=10.1373/clinchem.2009.126664 | pmc=3773468 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19520758  }} </ref>
**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.<ref name="pmid4924493">{{cite journal| author=Penny R, Castaldi PA, Whitsed HM| title=Inflammation and haemostasis in paraproteinaemias. | journal=Br J Haematol | year= 1971 | volume= 20 | issue= 1 | pages= 35-44 | pmid=4924493 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4924493  }} </ref>
*** Possibly due to interaction between [[platelet]] membrane [[Glycoprotein|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.<ref name="pmid23321251">{{cite journal| author=Xu L, Hunter ZR, Yang G, Zhou Y, Cao Y, Liu X et al.| title=MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. | journal=Blood | year= 2013 | volume= 121 | issue= 11 | pages= 2051-8 | pmid=23321251 | doi=10.1182/blood-2012-09-454355 | pmc=3596964 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23321251  }} </ref>
*'''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===
===Bone Marrow Aspirate===
A [[Bone marrow aspiration|bone marrow aspirate]] is essential in the diagnosis of Waldenström macroglobulinemia.  
A [[Bone marrow aspiration|bone marrow aspirate]] is essential in the diagnosis of Waldenström macroglobulinemia.  

Revision as of 16:44, 12 February 2019

Lymphoplasmacytic lymphoma Microchapters

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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

Overview

Differentiating Lymphoplasmacytic Lymphoma from Other B cell lymphoid neoplasms

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

  • Always express CD5
  • Usually CD23 positive[1]
  • Express CD10, HLA-DR, pan B-cell antigens (CD19, CD20, CD79a), CD21, and surface IgM, IgG, or IgA
  • Rearrangement of Bcl-2[4][5]
  • 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)[6]
  • 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[7][8]
  • 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% )[9][10]

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications, and Prognosis

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.

Physical Examination

Bone Marrow Aspirate

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

Findings suggestive of Waldenström macroglobulinemia include:[11]

  • 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. [11]

Findings on the biopsy suggestive of Waldenström macroglobulinemia include:[11]

  • 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:[12]

  • 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.[12]

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:[13]
    • 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.[14]
  • Waldenström's macroglobulinemia shows evidence of lymphadenopathy, and hepatosplenomegaly.[14]
  • 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:[15]
  • Fundoscopy, which demonstrates:[16]
  • Plasma viscosity, which demonstrates:[17]
    • 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[18]

Treatment

There are several different options for treating Waldenström macroglobulinemia depending on stage of the disease:[19]

Asymptomatic/Smoldering Waldenström's Macroglobulinemia

There is no treatment for asymptomatic Waldenström macroglobulinemia. Asymptomatic waldenström's macroglobulinemia can be monitored every 3-6 months.[20] 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.[21]

  • Initial stage of waldenström's macroglobulinemia associated with:
  • Late stage of Waldenström's macroglobulinemia associated with:
Treatment Regimen[21]

Drugs Side effects

CHOP-R regimen

Ibrutinib

Rituximab

  • Infusion related reaction
  • Hepatitis B reaction
  • Progressive multi-focal leukoencephaloptahy

FR regimen

BDR regimen

DRC regimen

CR regimen

IR regimen

Hyperviscosity syndrome

  • Waldenström macroglobulinemia complicated with hyperviscosity syndrome is a medical emergency and requires prompt treatment with plasmapheresis.[21]
  • 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.[22]

Primary Prevention

Primary prevention of Waldenström macroglobulinemia depends on the type of risk factor causing the disease.[23]

Modifiable risk factors

Non-modifiable risk factors

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

References

  1. ↑ Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ (2008). "Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines". Blood. 111 (12): 5446–56. doi:10.1182/blood-2007-06-093906. PMC 2972576. PMID 18216293.
  2. ↑ Del Giudice I, Davis Z, Matutes E, Osuji N, Parry-Jones N, Morilla A, Brito-Babapulle V, Oscier D, Catovsky D (2006). "IgVH genes mutation and usage, ZAP-70 and CD38 expression provide new insights on B-cell prolymphocytic leukemia (B-PLL)". Leukemia. 20 (7): 1231–7. doi:10.1038/sj.leu.2404238. PMID 16642047.
  3. ↑ Ravandi F, O'Brien S (2005). "Chronic lymphoid leukemias other than chronic lymphocytic leukemia: diagnosis and treatment". Mayo Clin. Proc. 80 (12): 1660–74. doi:10.4065/80.12.1660. PMID 16342661.
  4. ↑ Karube K, Guo Y, Suzumiya J, Sugita Y, Nomura Y, Yamamoto K, Shimizu K, Yoshida S, Komatani H, Takeshita M, Kikuchi M, Nakamura N, Takasu O, Arakawa F, Tagawa H, Seto M, Ohshima K (2007). "CD10-MUM1+ follicular lymphoma lacks BCL2 gene translocation and shows characteristic biologic and clinical features". Blood. 109 (7): 3076–9. doi:10.1182/blood-2006-09-045989. PMID 17138820.
  5. ↑ Anderson KC, Bates MP, Slaughenhoupt BL, Pinkus GS, Schlossman SF, Nadler LM (1984). "Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation". Blood. 63 (6): 1424–33. PMID 6609729.
    • Bone marrow infiltration of small, cleaved cells that are usually paratrabecular
  6. ↑ Pangalis GA, Kyrtsonis MC, Kontopidou FN, Vassilakopoulos TP, Siakantaris MP, Dimopoulou MN, Kittas C, Angelopoulou MK (2003). "Differential diagnosis of Waldenstrom's macroglobulinemia from other low-grade B-cell lymphoproliferative disorders". Semin. Oncol. 30 (2): 201–5. doi:10.1053/sonc.2003.50046. PMID 12720136.
  7. ↑ Dorfman DM, Pinkus GS (1994). "Distinction between small lymphocytic and mantle cell lymphoma by immunoreactivity for CD23". Mod. Pathol. 7 (3): 326–31. PMID 8058704.
  8. ↑ DiRaimondo F, Albitar M, Huh Y, O'Brien S, Montillo M, Tedeschi A, Kantarjian H, Lerner S, Giustolisi R, Keating M (2002). "The clinical and diagnostic relevance of CD23 expression in the chronic lymphoproliferative disease". Cancer. 94 (6): 1721–30. PMID 11920534.
  9. ↑ Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD (1999). "World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997". J. Clin. Oncol. 17 (12): 3835–49. PMID 10577857.
  10. ↑ Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC (1994). "A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group". Blood. 84 (5): 1361–92. PMID 8068936.
  11. ↑ 11.0 11.1 11.2 Leleu X, Roccaro AM, Moreau AS, Dupire S, Robu D, Gay J; et al. (2008). "Waldenstrom macroglobulinemia". Cancer Lett. 270 (1): 95–107. doi:10.1016/j.canlet.2008.04.040. PMC 3133633. PMID 18555588.
  12. ↑ 12.0 12.1 Riches PG, Sheldon J, Smith AM, Hobbs JR (1991). "Overestimation of monoclonal immunoglobulin by immunochemical methods". Ann Clin Biochem. 28 ( Pt 3): 253–9. doi:10.1177/000456329102800310. PMID 1872571.
  13. ↑ Rausch PG, Herion JC (1980). "Pulmonary manifestations of Waldenstrom macroglobulinemia". Am. J. Hematol. 9 (2): 201–9. PMID 6776807.
  14. ↑ 14.0 14.1 Banwait R, O'Regan K, Campigotto F, Harris B, Yarar D, Bagshaw M, Leleu X, Leduc R, Ramaiya N, Weller E, Ghobrial IM (2011). "The role of 18F-FDG PET/CT imaging in Waldenstrom macroglobulinemia". Am. J. Hematol. 86 (7): 567–72. doi:10.1002/ajh.22044. PMID 21681781.
  15. ↑ Nobile-Orazio E, Marmiroli P, Baldini L, Spagnol G, Barbieri S, Moggio M, Polli N, Polli E, Scarlato G (1987). "Peripheral neuropathy in macroglobulinemia: incidence and antigen-specificity of M proteins". Neurology. 37 (9): 1506–14. PMID 2442666.
  16. ↑ Castillo JJ, Garcia-Sanz R, Hatjiharissi E, Kyle RA, Leleu X, McMaster M; et al. (2016). "Recommendations for the diagnosis and initial evaluation of patients with Waldenström Macroglobulinaemia: A Task Force from the 8th International Workshop on Waldenström Macroglobulinaemia". Br J Haematol. 175 (1): 77–86. doi:10.1111/bjh.14196. PMC 5154335. PMID 27378193.
  17. ↑ Crawford J, Cox EB, Cohen HJ (1985). "Evaluation of hyperviscosity in monoclonal gammopathies". Am J Med. 79 (1): 13–22. PMID 4014299.
  18. ↑ Xu L, Hunter ZR, Yang G, Zhou Y, Cao Y, Liu X; et al. (2013). "MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction". Blood. 121 (11): 2051–8. doi:10.1182/blood-2012-09-454355. PMC 3596964. PMID 23321251.
  19. ↑ Lymphoplasmacytic lymphoma. Canadian Cancer Society 2015. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/lymphoplasmacytic-lymphoma/?region=ab Accessed on November 6 2015
  20. ↑ Waldenström's macroglobulinemia. Patient (2015)http://patient.info/doctor/waldenstroms-macroglobulinaemia-pro Accessed on November 10, 2015
  21. ↑ 21.0 21.1 21.2 Waldenström's macroglobulinemia: prognosis and management. Blood Cancer Journal (2015)http://www.nature.com/bcj/journal/v5/n3/full/bcj201528a.html Accessed on November 13, 2015
  22. ↑ Waldenström's macroglobulinemia: prognosis and management. Blood Cancer Journal (2015) http://www.nature.com/bcj/journal/v5/n3/full/bcj201528a.html Accessed on November 13, 2015
  23. ↑ Waldenström's macroglobulinemia. American Cancer Society. (2015)http://www.cancer.org/cancer/waldenstrommacroglobulinemia/detailedguide/waldenstrom-macroglobulinemia-prevention Accessed on November 11, 2015
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