Lymphoplasmacytic lymphoma: Difference between revisions

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{{CMG}}; {{AE}} {{S.M.}}
{{CMG}}; {{AE}} {{S.M.}}


{{SK}} Waldenstrom's macroglobulinemia; Waldenstrom's disease; Primary macroglobulinemia; Hyperviscosity syndrome  
{{SK}} Plasmacytoid lymphocytic [[lymphoma]]; Familial Waldenström's macroglobulinemia; Primary macroglobulinemia; Hyperviscosity syndrome; Lymphoplasmacytoid [[lymphoma]]


==Overview==
==[[Lymphoplasmacytic lymphoma overview|Overview]]==


==Historical Perspective==
==[[Lymphoplasmacytic lymphoma historical perspective|Historical Perspective]]==
*In 1936, Jens Bing and Axel Valdemar Neel, discovered a late and rare complication of WM 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. Waldenstrom]], a Swedish doctor of internal medicine, first discovered Waldenstrom macroglobulinemia(WM). He reported an unusal 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.<ref name="Waldenström2009">{{cite journal|last1=Waldenström|first1=Jan|title=Incipient myelomatosis or «essential« hyperglobulinemia with fibrinogenopenia - a new syndrome?|journal=Acta Medica Scandinavica|volume=117|issue=3-4|year=2009|pages=216–247|issn=00016101|doi=10.1111/j.0954-6820.1944.tb03955.x}}</ref><ref name="KonoplevMedeiros2005">{{cite journal|last1=Konoplev|first1=Sergej|last2=Medeiros|first2=L. Jeffrey|last3=Bueso-Ramos|first3=Carlos E.|last4=Jorgensen|first4=Jeffrey L.|last5=Lin|first5=Pei|title=Immunophenotypic Profile of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia|journal=American Journal of Clinical Pathology|volume=124|issue=3|year=2005|pages=414–420|issn=0002-9173|doi=10.1309/3G1XDX0DVHBNVKB4}}</ref>
*In 1962, the first report on familiality 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.<ref name="pmid13933388">{{cite journal| author=MASSARI R, FINE JM, METAIS R| title=Waldenstrom's macroglobulinaemia observed in two brothers. | journal=Nature | year= 1962 | volume= 196 | issue=  | pages= 176-8 | pmid=13933388 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13933388  }} </ref><ref name="pmid16224483">{{cite journal| author=Altieri A, Bermejo JL, Hemminki K| title=Familial aggregation of lymphoplasmacytic lymphoma with non-Hodgkin lymphoma and other neoplasms. | journal=Leukemia | year= 2005 | volume= 19 | issue= 12 | pages= 2342-3 | pmid=16224483 | doi=10.1038/sj.leu.2403991 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16224483  }} </ref><ref name="pmid6778280">{{cite journal| author=Blattner WA, Garber JE, Mann DL, McKeen EA, Henson R, McGuire DB et al.| title=Waldenström's macroglobulinemia and autoimmune disease in a family. | journal=Ann Intern Med | year= 1980 | volume= 93 | issue= 6 | pages= 830-2 | pmid=6778280 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6778280  }} </ref><ref name="pmid6805257">{{cite journal| author=Fine JM, Lambin P, Massari M, Leroux P| title=Malignant evolution of asymptomatic monoclonal IgM after seven and fifteen years in two siblings of a patient with Waldenström's macroglobulinemia. | journal=Acta Med Scand | year= 1982 | volume= 211 | issue= 3 | pages= 237-9 | pmid=6805257 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6805257  }} </ref><ref name="pmid3099545">{{cite journal| author=Fine JM, Muller JY, Rochu D, Marneux M, Gorin NC, Fine A et al.| title=Waldenström's macroglobulinemia in monozygotic twins. | journal=Acta Med Scand | year= 1986 | volume= 220 | issue= 4 | pages= 369-73 | pmid=3099545 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3099545  }} </ref><ref name="pmid408931">{{cite journal| author=Gétaz EP, Staples WG| title=Familial Waldenström's macroglobulinaemia: a case report. | journal=S Afr Med J | year= 1977 | volume= 51 | issue= 24 | pages= 891-2 | pmid=408931 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=408931  }} </ref><ref name="pmid8371587">{{cite journal| author=Linet MS, Humphrey RL, Mehl ES, Brown LM, Pottern LM, Bias WB et al.| title=A case-control and family study of Waldenstrom's macroglobulinemia. | journal=Leukemia | year= 1993 | volume= 7 | issue= 9 | pages= 1363-9 | pmid=8371587 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8371587  }} </ref><ref name="pmid8047841">{{cite journal| author=Ogmundsdóttir HM, Jóhannesson GM, Sveinsdóttir S, Einarsdóttir S, Hegeman A, Jensson O et al.| title=Familial macroglobulinaemia: hyperactive B-cells but normal natural killer function. | journal=Scand J Immunol | year= 1994 | volume= 40 | issue= 2 | pages= 195-200 | pmid=8047841 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8047841  }} </ref><ref name="pmid4143650">{{cite journal| author=Seligmann M, Danon F, Mihaesco C, Fudenberg HH| title=Immunoglobulin abnormalities in families of patients with Waldenström's macroglobulinemia. | journal=Am J Med | year= 1967 | volume= 43 | issue= 1 | pages= 66-83 | pmid=4143650 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4143650  }} </ref> <ref name="pmid1958390">{{cite journal| author=Taleb N, Tohme A, Abi Jirgiss D, Kattan J, Salloum E| title=Familial macroglobulinemia in a Lebanese family with two sisters presenting Waldenström's disease. | journal=Acta Oncol | year= 1991 | volume= 30 | issue= 6 | pages= 703-5 | pmid=1958390 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1958390  }} </ref><ref name="pmid16357024">{{cite journal| author=Treon SP, Hunter ZR, Aggarwal A, Ewen EP, Masota S, Lee C et al.| title=Characterization of familial Waldenstrom's macroglobulinemia. | journal=Ann Oncol | year= 2006 | volume= 17 | issue= 3 | pages= 488-94 | pmid=16357024 | doi=10.1093/annonc/mdj111 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357024  }} </ref><ref name="pmid104746">{{cite journal| author=Youinou P, le Goff P, Saleun JP, Rivat L, Morin JF, Fauchier C et al.| title=Familial occurrence of monoclonal gammapathies. | journal=Biomedicine | year= 1978 | volume= 28 | issue= 4 | pages= 226-32 | pmid=104746 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=104746  }} </ref><ref name="pmid2505923">{{cite journal| author=Renier G, Ifrah N, Chevailler A, Saint-Andre JP, Boasson M, Hurez D| title=Four brothers with Waldenstrom's macroglobulinemia. | journal=Cancer | year= 1989 | volume= 64 | issue= 7 | pages= 1554-9 | pmid=2505923 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2505923  }} </ref>
*In 1994, a Revised European-American classification of lymphoid neaoplasms (REAL) was published by International Lymphoma Study Group which placed WM in the category of lymphoplasmacytic lymphoma (an indolent subtype of non-hodgkins lymphoma). The REAL classification is based on the morphology, immunophenotype, genetic features, and clinical features.<ref name="pmid10577857">{{cite journal| author=Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J et al.| title=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. | journal=J Clin Oncol | year= 1999 | volume= 17 | issue= 12 | pages= 3835-49 | pmid=10577857 | doi=10.1200/JCO.1999.17.12.3835 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10577857  }} </ref><ref name="pmid8068936">{{cite journal| author=Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML et al.| title=A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. | journal=Blood | year= 1994 | volume= 84 | issue= 5 | pages= 1361-92 | pmid=8068936 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8068936  }} </ref>
*In 2001, WHO also classified the pathology of WM as lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia based on REAL classification.<ref name="KonoplevMedeiros2005">{{cite journal|last1=Konoplev|first1=Sergej|last2=Medeiros|first2=L. Jeffrey|last3=Bueso-Ramos|first3=Carlos E.|last4=Jorgensen|first4=Jeffrey L.|last5=Lin|first5=Pei|title=Immunophenotypic Profile of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia|journal=American Journal of Clinical Pathology|volume=124|issue=3|year=2005|pages=414–420|issn=0002-9173|doi=10.1309/3G1XDX0DVHBNVKB4}}</ref>
*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 forn WM.<ref name="KonoplevMedeiros2005">{{cite journal|last1=Konoplev|first1=Sergej|last2=Medeiros|first2=L. Jeffrey|last3=Bueso-Ramos|first3=Carlos E.|last4=Jorgensen|first4=Jeffrey L.|last5=Lin|first5=Pei|title=Immunophenotypic Profile of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia|journal=American Journal of Clinical Pathology|volume=124|issue=3|year=2005|pages=414–420|issn=0002-9173|doi=10.1309/3G1XDX0DVHBNVKB4}}</ref><ref name="pmid15735132">{{cite journal| author=Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP| title=Diagnosis and management of Waldenstrom's macroglobulinemia. | journal=J Clin Oncol | year= 2005 | volume= 23 | issue= 7 | pages= 1564-77 | pmid=15735132 | doi=10.1200/JCO.2005.03.144 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15735132  }} </ref>
*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 stem cell-supported High-dose chemotherapy and bone marrow transplant|high-dose therapy transplant", and in 2013, was still asymptomatic when a follow-up report was published.<ref name="pmid23747080">{{cite journal| author=Abdallah AO, Atrash S, Muzaffar J, Abdallah M, Kumar M, Van Rhee F et al.| title=Successful treatment of Bing-Neel syndrome using intrathecal chemotherapy and systemic combination chemotherapy followed by BEAM auto-transplant: a case report and review of literature. | journal=Clin Lymphoma Myeloma Leuk | year= 2013 | volume= 13 | issue= 4 | pages= 502-6 | pmid=23747080 | doi=10.1016/j.clml.2013.03.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23747080  }} </ref>


==Classification==
==[[Lymphoplasmacytic lymphoma classification|Classification]]==
There is no established system for the classification of Waldenström's macroglobulinemia. However, according to a devised criteria based upon patient's symptoms, it can be classified into:<ref name="pmid15735132">{{cite journal| author=Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP| title=Diagnosis and management of Waldenstrom's macroglobulinemia. | journal=J Clin Oncol | year= 2005 | volume= 23 | issue= 7 | pages= 1564-77 | pmid=15735132 | doi=10.1200/JCO.2005.03.144 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15735132  }} </ref>
*Symptomatic Waldenstrom macroglobulinemia.
*Asymptomatic/Smoldering Waldenstrom macroglobulinemia (SWM).<ref name="pmid12720119">{{cite journal| author=Kyle RA, Treon SP, Alexanian R, Barlogie B, Björkholm M, Dhodapkar M et al.| title=Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. | journal=Semin Oncol | year= 2003 | volume= 30 | issue= 2 | pages= 116-20 | pmid=12720119 | doi=10.1053/sonc.2003.50038 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12720119  }} </ref>
{| class="wikitable"
|+ '''Classification of WM and Related Disorders'''
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Criteria
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Symptomatic WM
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Asymptomatic WM
! style="background:#4479BA; color: #FFFFFF;" align="center" + |IgM-Related Disorders
! style="background:#4479BA; color: #FFFFFF;" align="center" + |MGUS
|-
| style="background:#DCDCDC;" align="center" + |IgM monoclonal protein
| style="background:#F5F5F5;" align="center" + |+
| style="background:#F5F5F5;" align="center" + |+
| style="background:#F5F5F5;" align="center" + |+
| style="background:#F5F5F5;" align="center" + |+
|-
| style="background:#DCDCDC;" align="center" + |Bone marrow infiltration
| style="background:#F5F5F5;" align="center" + |+
| style="background:#F5F5F5;" align="center" + |+
| style="background:#F5F5F5;" align="center" + |-
| style="background:#F5F5F5;" align="center" + |-
|-
| style="background:#DCDCDC;" align="center" + |Symptoms attributable to IgM
| style="background:#F5F5F5;" align="center" + |+
| style="background:#F5F5F5;" align="center" + |-
| style="background:#F5F5F5;" align="center" + |+
| style="background:#F5F5F5;" align="center" + |-
|-
| style="background:#DCDCDC;" align="center" + |Symptoms attributable to tumor infiltration
| style="background:#F5F5F5;" align="center" + |+
| style="background:#F5F5F5;" align="center" + |-
| style="background:#F5F5F5;" align="center" + |-
| style="background:#F5F5F5;" align="center" + |-
|}


==Pathophysiology==
==[[Lymphoplasmacytic lymphoma pathophysiology|Pathophysiology]]==
*Waldenström macroglobulinemia arises from terminally differentiated B [[Lymphocyte|lymphocytes]], which are normally involved in [[humoral immunity]].


* It is understood that Waldenström macroglobulinemia is mediated by 2 major factors:
==[[Lymphoplasmacytic lymphoma causes|Causes]]==
*#The secretion of [[IgM]] [[paraprotein]]
*#*Causes symptoms of [[hyperviscosity syndrome]]
*#The infiltration of tissues with [[neoplastic]] lymphoplasmacytic cells
*#*Mainly the [[bone marrow]], [[spleen]],and [[Lymph node|lymph nodes]]
*#*Sometimes the [[liver]], [[gastrointestinal tract]], [[Lung|lungs]], [[kidneys]], [[skin]], [[eyes]], and [[central nervous system]]
===Genetics===
*The exact pathogenesis of Waldenström macroglobulinemia is not completely understood; however, its [[Heredity|familial pattern]] of involvement supports the role played by [[Genetics|genetic factors]] in the pathogenesis of this disease.<ref name="pmid20308603">{{cite journal| author=Royer RH, Koshiol J, Giambarresi TR, Vasquez LG, Pfeiffer RM, McMaster ML| title=Differential characteristics of Waldenström macroglobulinemia according to patterns of familial aggregation. | journal=Blood | year= 2010 | volume= 115 | issue= 22 | pages= 4464-71 | pmid=20308603 | doi=10.1182/blood-2009-10-247973 | pmc=2881498 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20308603  }} </ref><ref name="pmid16357024">{{cite journal| author=Treon SP, Hunter ZR, Aggarwal A, Ewen EP, Masota S, Lee C et al.| title=Characterization of familial Waldenstrom's macroglobulinemia. | journal=Ann Oncol | year= 2006 | volume= 17 | issue= 3 | pages= 488-94 | pmid=16357024 | doi=10.1093/annonc/mdj111 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357024  }} </ref>
*Development of Waldenström macroglobulinemia is the result of multiple [[genetic mutations]].<ref name="UTDR">{{cite journal |vauthors=Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Staudt LM |title=Oncogenically active MYD88 mutations in human lymphoma |journal=Nature |volume=470 |issue=7332 |pages=115–9 |year=2011 |pmid=21179087 |doi=10.1038/nature09671 |url=}}</ref>
*Somatic mutations as well as [[Chromosome abnormality|chromosomal abnormalities]] play a part in the pathogenesis of this disease:
**A mutation of the [[MYD88|MYD88 gene]] (L265P) has been found in more than 90% of patients with Waldenström macroglobulinemia, while it has rarely presented in patients with other types of mature B-cell tumors.<ref name="TreonXu2012">{{cite journal|last1=Treon|first1=Steven P.|last2=Xu|first2=Lian|last3=Yang|first3=Guang|last4=Zhou|first4=Yangsheng|last5=Liu|first5=Xia|last6=Cao|first6=Yang|last7=Sheehy|first7=Patricia|last8=Manning|first8=Robert J.|last9=Patterson|first9=Christopher J.|last10=Tripsas|first10=Christina|last11=Arcaini|first11=Luca|last12=Pinkus|first12=Geraldine S.|last13=Rodig|first13=Scott J.|last14=Sohani|first14=Aliyah R.|last15=Harris|first15=Nancy Lee|last16=Laramie|first16=Jason M.|last17=Skifter|first17=Donald A.|last18=Lincoln|first18=Stephen E.|last19=Hunter|first19=Zachary R.|title=MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia|journal=New England Journal of Medicine|volume=367|issue=9|year=2012|pages=826–833|issn=0028-4793|doi=10.1056/NEJMoa1200710}}</ref><ref name="pmid23355535">{{cite journal| author=Varettoni M, Arcaini L, Zibellini S, Boveri E, Rattotti S, Riboni R et al.| title=Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms. | journal=Blood | year= 2013 | volume= 121 | issue= 13 | pages= 2522-8 | pmid=23355535 | doi=10.1182/blood-2012-09-457101 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23355535  }} </ref><ref name="pmid26231802">{{cite journal| author=Shi M, Spurgeon S, Press R, Olson S, Fan G| title=MYD88 mutation analysis of a rare composite chronic lymphocyte leukemia and lymphoplasmacytic lymphoma by flow cytometry cell sorting. | journal=Ann Hematol | year= 2015 | volume= 94 | issue= 11 | pages= 1941-4 | pmid=26231802 | doi=10.1007/s00277-015-2460-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26231802  }} </ref><ref name="pmid23836557">{{cite journal| author=Yang G, Zhou Y, Liu X, Xu L, Cao Y, Manning RJ et al.| title=A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. | journal=Blood | year= 2013 | volume= 122 | issue= 7 | pages= 1222-32 | pmid=23836557 | doi=10.1182/blood-2012-12-475111 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23836557  }} </ref><ref name="pmid21179087">{{cite journal| author=Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH et al.| title=Oncogenically active MYD88 mutations in human lymphoma. | journal=Nature | year= 2011 | volume= 470 | issue= 7332 | pages= 115-9 | pmid=21179087 | doi=10.1038/nature09671 | pmc=5024568 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21179087  }} </ref><ref name="pmid24224040">{{cite journal| author=Mori N, Ohwashi M, Yoshinaga K, Mitsuhashi K, Tanaka N, Teramura M et al.| title=L265P mutation of the MYD88 gene is frequent in Waldenström's macroglobulinemia and its absence in myeloma. | journal=PLoS One | year= 2013 | volume= 8 | issue= 11 | pages= e80088 | pmid=24224040 | doi=10.1371/journal.pone.0080088 | pmc=3818242 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24224040  }} </ref><ref name="pmid29080258">{{cite journal| author=Abeykoon JP, Paludo J, King RL, Ansell SM, Gertz MA, LaPlant BR et al.| title=MYD88 mutation status does not impact overall survival in Waldenström macroglobulinemia. | journal=Am J Hematol | year= 2018 | volume= 93 | issue= 2 | pages= 187-194 | pmid=29080258 | doi=10.1002/ajh.24955 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29080258  }} </ref><ref>{{Cite journal
| author = [[Steven P. Treon]], [[Lian Xu]], [[Guang Yang]], [[Yangsheng Zhou]], [[Xia Liu]], [[Yang Cao]], [[Patricia Sheehy]], [[Robert J. Manning]], [[Christopher J. Patterson]], [[Christina Tripsas]], [[Luca Arcaini]], [[Geraldine S. Pinkus]], [[Scott J. Rodig]], [[Aliyah R. Sohani]], [[Nancy Lee Harris]], [[Jason M. Laramie]], [[Donald A. Skifter]], [[Stephen E. Lincoln]] & [[Zachary R. Hunter]]
| title = MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia
| journal = [[The New England journal of medicine]]
| volume = 367
| issue = 9
| pages = 826–833
| year = 2012
| month = August
| doi = 10.1056/NEJMoa1200710
| pmid = 22931316
}}</ref>
***MYD88: The activating [[point mutation]] of MYD88 augments 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.<ref /><ref />
***[[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 disorders]].<ref />
**Less commonly (30-35%), [[Nonsense mutation|nonsense]] or [[Frameshift mutation|frameshift mutations]] in the C-X-C chemokine receptor type 4 (CXCR4) 5338X gene have also been reported in patients with Waldenström macroglobulinemia.<ref>{{Cite journal
| author = [[Zachary R. Hunter]], [[Lian Xu]], [[Guang Yang]], [[Yangsheng Zhou]], [[Xia Liu]], [[Yang Cao]], [[Robert J. Manning]], [[Christina Tripsas]], [[Christopher J. Patterson]], [[Patricia Sheehy]] & [[Steven P. Treon]]
| title = The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis
| journal = [[Blood]]
| volume = 123
| issue = 11
| pages = 1637–1646
| year = 2014
| month = March
| doi = 10.1182/blood-2013-09-525808
| pmid = 24366360
}}</ref>
***Patients with Waldenström's macroglobulinemia with co-existing mutation of MYD88 & CXCR4 are more likely to have [[hyperviscosity syndrome|hyper-viscosity syndrome]] and [[bone marrow]] involvement.<ref name="UTDR" />
***Somatic hypermutation in [[IGHV]]/IG gene rearrangement.<ref name="pmid28366781">{{cite journal| author=Yun S, Johnson AC, Okolo ON, Arnold SJ, McBride A, Zhang L et al.| title=Waldenström Macroglobulinemia: Review of Pathogenesis and Management. | journal=Clin Lymphoma Myeloma Leuk | year= 2017 | volume= 17 | issue= 5 | pages= 252-262 | pmid=28366781 | doi=10.1016/j.clml.2017.02.028 | pmc=5413391 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28366781  }} </ref>
***ARIDA mutations.
====Cytogenetics====
*Many [[Cytogenetics|cytogenetic]] abnormalities were reported in Waldenström macroglobulinemia patients including:
**[[Deletion (genetics)]] of the long arm of [[Chromosome 6 (human)|chromosome 6]]q21-22.1 (most common,50%).<ref name="TreonHunter2006">{{cite journal|last1=Treon|first1=S. P.|last2=Hunter|first2=Z. R.|last3=Aggarwal|first3=A.|last4=Ewen|first4=E. P.|last5=Masota|first5=S.|last6=Lee|first6=C.|last7=Santos|first7=D. Ditzel|last8=Hatjiharissi|first8=E.|last9=Xu|first9=L.|last10=Leleu|first10=X.|last11=Tournilhac|first11=O.|last12=Patterson|first12=C. J.|last13=Manning|first13=R.|last14=Branagan|first14=A. R.|last15=Morton|first15=C. C.|title=Characterization of familial Waldenström's macroglobulinemia|journal=Annals of Oncology|volume=17|issue=3|year=2006|pages=488–494|issn=1569-8041|doi=10.1093/annonc/mdj111}}</ref>
**Deletion of long arm of [[Chromosome 10 (human)|chromosome 10]], 12 0r 20.
**t(9;14)(p13;q32)(50%).<ref name="pmid28366781">{{cite journal| author=Yun S, Johnson AC, Okolo ON, Arnold SJ, McBride A, Zhang L et al.| title=Waldenström Macroglobulinemia: Review of Pathogenesis and Management. | journal=Clin Lymphoma Myeloma Leuk | year= 2017 | volume= 17 | issue= 5 | pages= 252-262 | pmid=28366781 | doi=10.1016/j.clml.2017.02.028 | pmc=5413391 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28366781  }} </ref>
**[[Trisomy]] 4(20%).<ref name="pmid28366781">{{cite journal| author=Yun S, Johnson AC, Okolo ON, Arnold SJ, McBride A, Zhang L et al.| title=Waldenström Macroglobulinemia: Review of Pathogenesis and Management. | journal=Clin Lymphoma Myeloma Leuk | year= 2017 | volume= 17 | issue= 5 | pages= 252-262 | pmid=28366781 | doi=10.1016/j.clml.2017.02.028 | pmc=5413391 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28366781  }} </ref>
**Trisomy 5.
**[[Monosomy]] 8.<ref>{{Cite journal
| author = [[Roelandt F. J. Schop]], [[W. Michael Kuehl]], [[Scott A. Van Wier]], [[Gregory J. Ahmann]], [[Tammy Price-Troska]], [[Richard J. Bailey]], [[Syed M. Jalal]], [[Ying Qi]], [[Robert A. Kyle]], [[Philip R. Greipp]] & [[Rafael Fonseca]]
| title = Waldenstrom macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions
| journal = [[Blood]]
| volume = 100
| issue = 8
| pages = 2996–3001
| year = 2002
| month = October
| doi = 10.1182/blood.V100.8.2996
| pmid = 12351413
}}</ref>
**Deletions of regions of 13q14 that include MIRN15A and MIRN16-1.<ref name="pmid19351844">{{cite journal| author=Braggio E, Keats JJ, Leleu X, Van Wier S, Jimenez-Zepeda VH, Valdez R et al.| title=Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom's macroglobulinemia. | journal=Cancer Res | year= 2009 | volume= 69 | issue= 8 | pages= 3579-88 | pmid=19351844 | doi=10.1158/0008-5472.CAN-08-3701 | pmc=2782932 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19351844  }} </ref>
**t(11;18)(q21;q21) involving API-malt1.<ref name="pmid19351844">{{cite journal| author=Braggio E, Keats JJ, Leleu X, Van Wier S, Jimenez-Zepeda VH, Valdez R et al.| title=Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom's macroglobulinemia. | journal=Cancer Res | year= 2009 | volume= 69 | issue= 8 | pages= 3579-88 | pmid=19351844 | doi=10.1158/0008-5472.CAN-08-3701 | pmc=2782932 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19351844  }} </ref>
**t(8;14).
**t(14;18).


====Epigenetics====
==[[Lymphoplasmacytic lymphoma differential diagnosis|Differentiating Lymphoplasmacytic lymphoma from other Diseases]]==
*Three most common [[epigenetic]] causes are [[DNA methylation]], [[histone acetylation]], and [[non-coding RNA]]<nowiki/>s such as miRNAs.<ref name="aa">Waldenström macroglobulinemia. International Waldenström Macroglobulinemia foundation (2015)http://www.iwmf.com/sites/default/files/docs/WM_Review_Ghobrial_Jan2014.pdf Accessed on November 12, 2015</ref>
*Up-regulation 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 [[Gene expression|expression]] of miRNA-206 and reduced expression of miRNA-9.
===Associated Conditions===
Several studies showed an increased incidence of following second cancers in patients with Waldenström macroglobulinemia:<ref name="Acs">{{cite journal |vauthors=Morra E, Varettoni M, Tedeschi A, Arcaini L, Ricci F, Pascutto C, Rattotti S, Vismara E, Paris L, Cazzola M |title=Associated cancers in Waldenström macroglobulinemia: clues for common genetic predisposition |journal=Clin Lymphoma Myeloma Leuk |volume=13 |issue=6 |pages=700–3 |year=2013 |pmid=24070824 |doi=10.1016/j.clml.2013.05.008 |url=}}</ref>
*[[Diffuse large B-cell lymphoma]]
*[[Myelodysplastic syndrome]]/[[Acute myeloid leukemia]]
*[[Brain tumor]]
*[[MALT lymphoma|Renal MALT lymphoma]] <ref name="AC">{{cite journal |vauthors=Chi PJ, Pei SN, Huang TL, Huang SC, Ng HY, Lee CT |title=Renal MALT lymphoma associated with Waldenström macroglobulinemia |journal=J. Formos. Med. Assoc. |volume=113 |issue=4 |pages=255–7 |year=2014 |pmid=24685302 |doi=10.1016/j.jfma.2011.02.007 |url=}}</ref>
===Microscopic Pathology===
WM/LPL is a form of an indolent (slowly growing) non-hodgkin lymphoma. LPL is called so because the lymphoma cells have the characteristics of both lymphocytes and plasma cells. After a detailed clinicopathological assessment and review of the published literature, the following diagnostic criteria was proposed for WM:<ref name="pmid12720135">{{cite journal| author=Owen RG| title=Developing diagnostic criteria in Waldenstrom's macroglobulinemia. | journal=Semin Oncol | year= 2003 | volume= 30 | issue= 2 | pages= 196-200 | pmid=12720135 | doi=10.1053/sonc.2003.50069 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12720135  }} </ref>
*IgM monoclonal gammopathy of any concentration.
*Bone marrow infiltration by:<ref name="pmid19287458">{{cite journal| author=Morice WG, Chen D, Kurtin PJ, Hanson CA, McPhail ED| title=Novel immunophenotypic features of marrow lymphoplasmacytic lymphoma and correlation with Waldenström's macroglobulinemia. | journal=Mod Pathol | year= 2009 | volume= 22 | issue= 6 | pages= 807-16 | pmid=19287458 | doi=10.1038/modpathol.2009.34 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19287458  }} </ref><ref name="pmid12720118">{{cite journal| author=Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML et al.| title=Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. | journal=Semin Oncol | year= 2003 | volume= 30 | issue= 2 | pages= 110-5 | pmid=12720118 | doi=10.1053/sonc.2003.50082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12720118  }} </ref><ref name="AnsellKyle2010">{{cite journal|last1=Ansell|first1=Stephen M.|last2=Kyle|first2=Robert A.|last3=Reeder|first3=Craig B.|last4=Fonseca|first4=Rafael|last5=Mikhael|first5=Joseph R.|last6=Morice|first6=William G.|last7=Bergsagel|first7=P. Leif|last8=Buadi|first8=Francis K.|last9=Colgan|first9=Joseph P.|last10=Dingli|first10=David|last11=Dispenzieri|first11=Angela|last12=Greipp|first12=Philip R.|last13=Habermann|first13=Thomas M.|last14=Hayman|first14=Suzanne R.|last15=Inwards|first15=David J.|last16=Johnston|first16=Patrick B.|last17=Kumar|first17=Shaji K.|last18=Lacy|first18=Martha Q.|last19=Lust|first19=John A.|last20=Markovic|first20=Svetomir N.|last21=Micallef|first21=Ivana N.M.|last22=Nowakowski|first22=Grzegorz S.|last23=Porrata|first23=Luis F.|last24=Roy|first24=Vivek|last25=Russell|first25=Stephen J.|last26=Short|first26=Kristen E. Detweiler|last27=Stewart|first27=A. Keith|last28=Thompson|first28=Carrie A.|last29=Witzig|first29=Thomas E.|last30=Zeldenrust|first30=Steven R.|last31=Dalton|first31=Robert J.|last32=Rajkumar|first32=S. Vincent|last33=Gertz|first33=Morie A.|title=Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines|journal=Mayo Clinic Proceedings|volume=85|issue=9|year=2010|pages=824–833|issn=00256196|doi=10.4065/mcp.2010.0304}}</ref>
**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:<ref name="pmid11554171">{{cite journal| author=Owen RG, Barrans SL, Richards SJ, O'Connor SJ, Child JA, Parapia LA et al.| title=Waldenström macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors. | journal=Am J Clin Pathol | year= 2001 | volume= 116 | issue= 3 | pages= 420-8 | pmid=11554171 | doi=10.1309/4LCN-JMPG-5U71-UWQB | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11554171  }} </ref><ref name="pmid9366295">{{cite journal| author=Andriko JA, Aguilera NS, Chu WS, Nandedkar MA, Cotelingam JD| title=Waldenström's macroglobulinemia: a clinicopathologic study of 22 cases. | journal=Cancer | year= 1997 | volume= 80 | issue= 10 | pages= 1926-35 | pmid=9366295 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9366295  }} </ref>
***Diffuse.
***Interstitial.
***Nodular.
***Paratrabecular.
***Nodular-interstitial.
***Mixed paratrabacular-nodular.
*Following lymphoid organs are involved in WM:
**Bone marrow.
**Lymph nodes(nodal involvement is characterized by paracortical and hilar infiltration with frequent sparing of the subscapular and marginal sinuses).
**Spleen.
*WM has two histologic subtypes:<ref name="pmid9366295">{{cite journal| author=Andriko JA, Aguilera NS, Chu WS, Nandedkar MA, Cotelingam JD| title=Waldenström's macroglobulinemia: a clinicopathologic study of 22 cases. | journal=Cancer | year= 1997 | volume= 80 | issue= 10 | pages= 1926-35 | pmid=9366295 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9366295  }} </ref>
**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.
*Dutcher bodies may be seen in plasma cells, as intracytoplasmic inclusions positive for periodic acid Schiff.
*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.<ref name="pmid16804116">{{cite journal| author=Chng WJ, Schop RF, Price-Troska T, Ghobrial I, Kay N, Jelinek DF et al.| title=Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma. | journal=Blood | year= 2006 | volume= 108 | issue= 8 | pages= 2755-63 | pmid=16804116 | doi=10.1182/blood-2006-02-005488 | pmc=1895596 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16804116  }} </ref>
===Immunohistochemistry===
Malignant cells in Waldenström macroglobulinemia have following immunophenotypic characteristics:<ref name="AnsellKyle2010">{{cite journal|last1=Ansell|first1=Stephen M.|last2=Kyle|first2=Robert A.|last3=Reeder|first3=Craig B.|last4=Fonseca|first4=Rafael|last5=Mikhael|first5=Joseph R.|last6=Morice|first6=William G.|last7=Bergsagel|first7=P. Leif|last8=Buadi|first8=Francis K.|last9=Colgan|first9=Joseph P.|last10=Dingli|first10=David|last11=Dispenzieri|first11=Angela|last12=Greipp|first12=Philip R.|last13=Habermann|first13=Thomas M.|last14=Hayman|first14=Suzanne R.|last15=Inwards|first15=David J.|last16=Johnston|first16=Patrick B.|last17=Kumar|first17=Shaji K.|last18=Lacy|first18=Martha Q.|last19=Lust|first19=John A.|last20=Markovic|first20=Svetomir N.|last21=Micallef|first21=Ivana N.M.|last22=Nowakowski|first22=Grzegorz S.|last23=Porrata|first23=Luis F.|last24=Roy|first24=Vivek|last25=Russell|first25=Stephen J.|last26=Short|first26=Kristen E. Detweiler|last27=Stewart|first27=A. Keith|last28=Thompson|first28=Carrie A.|last29=Witzig|first29=Thomas E.|last30=Zeldenrust|first30=Steven R.|last31=Dalton|first31=Robert J.|last32=Rajkumar|first32=S. Vincent|last33=Gertz|first33=Morie A.|title=Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines|journal=Mayo Clinic Proceedings|volume=85|issue=9|year=2010|pages=824–833|issn=00256196|doi=10.4065/mcp.2010.0304}}</ref>
<ref name="UTDR" />
*Express pan B-cell antigens surface with following immunophenotype:<ref name="pmid19047284">{{cite journal| author=Dimopoulos MA, Gertz MA, Kastritis E, Garcia-Sanz R, Kimby EK, Leblond V et al.| title=Update on treatment recommendations from the Fourth International Workshop on Waldenstrom's Macroglobulinemia. | journal=J Clin Oncol | year= 2009 | volume= 27 | issue= 1 | pages= 120-6 | pmid=19047284 | doi=10.1200/JCO.2008.17.7865 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19047284  }} </ref><ref name="pmid17303694">{{cite journal| author=Vijay A, Gertz MA| title=Waldenström macroglobulinemia. | journal=Blood | year= 2007 | volume= 109 | issue= 12 | pages= 5096-103 | pmid=17303694 | doi=10.1182/blood-2006-11-055012 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17303694  }} </ref><ref name="pmid12720135">{{cite journal| author=Owen RG| title=Developing diagnostic criteria in Waldenstrom's macroglobulinemia. | journal=Semin Oncol | year= 2003 | volume= 30 | issue= 2 | pages= 196-200 | pmid=12720135 | doi=10.1053/sonc.2003.50069 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12720135  }} </ref>
**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).
*[[Immunoglobulin A|IgA]] (rare).
*[[Immunoglobulin D|IgD]] negative (lack).


==Causes==
==[[Lymphoplasmacytic lymphoma epidemiology and demographics|Epidemiology and Demographics]]==
=== Genetic Causes ===
*Waldenström Macroglobulinemia 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).<ref name=":0">{{Cite journal
| author = [[Steven P. Treon]], [[Lian Xu]], [[Guang Yang]], [[Yangsheng Zhou]], [[Xia Liu]], [[Yang Cao]], [[Patricia Sheehy]], [[Robert J. Manning]], [[Christopher J. Patterson]], [[Christina Tripsas]], [[Luca Arcaini]], [[Geraldine S. Pinkus]], [[Scott J. Rodig]], [[Aliyah R. Sohani]], [[Nancy Lee Harris]], [[Jason M. Laramie]], [[Donald A. Skifter]], [[Stephen E. Lincoln]] & [[Zachary R. Hunter]]
| title = MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia
| journal = [[The New England journal of medicine]]
| volume = 367
| issue = 9
| pages = 826–833
| year = 2012
| month = August
| doi = 10.1056/NEJMoa1200710
| pmid = 22931316
}}</ref><ref>{{Cite journal
| author = [[Zachary R. Hunter]], [[Lian Xu]], [[Guang Yang]], [[Yangsheng Zhou]], [[Xia Liu]], [[Yang Cao]], [[Robert J. Manning]], [[Christina Tripsas]], [[Christopher J. Patterson]], [[Patricia Sheehy]] & [[Steven P. Treon]]
| title = The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis
| journal = [[Blood]]
| volume = 123
| issue = 11
| pages = 1637–1646
| year = 2014
| month = March
| doi = 10.1182/blood-2013-09-525808
| pmid = 24366360
}}</ref>


=== Less Common Causes ===
==[[Lymphoplasmacytic lymphoma risk factors|Risk Factors]]==
Less common causes of Waldenström macroglobulinemia may include:<ref name="UTDR">{{cite journal |vauthors=Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Staudt LM |title=Oncogenically active MYD88 mutations in human lymphoma |journal=Nature |volume=470 |issue=7332 |pages=115–9 |year=2011 |pmid=21179087 |doi=10.1038/nature09671 |url=}}</ref><ref>{{Cite journal
| author = [[Roelandt F. J. Schop]], [[W. Michael Kuehl]], [[Scott A. Van Wier]], [[Gregory J. Ahmann]], [[Tammy Price-Troska]], [[Richard J. Bailey]], [[Syed M. Jalal]], [[Ying Qi]], [[Robert A. Kyle]], [[Philip R. Greipp]] & [[Rafael Fonseca]]
| title = Waldenstrom macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions
| journal = [[Blood]]
| volume = 100
| issue = 8
| pages = 2996–3001
| year = 2002
| month = October
| doi = 10.1182/blood.V100.8.2996
| pmid = 12351413
}}</ref>
*[[Chromosomal abnormalities]]: deletions of 6q23 and 13q14, and gains of 3q13-q28, 6p and 18q.
*Personal and family history of [[autoimmune diseases]] with autoantibodies and chronic immune stimulation leads to 2-3 fold higher risk of developing WM, especially elevated risks are associated with following:
**Hepatitis C virus infection (overall 20-30% increased risk for non-Hodgkin lymohoma and 3-fold increased risk for WM).<ref name="pmid18703425">{{cite journal| author=Kristinsson SY, Björkholm M, Goldin LR, McMaster ML, Turesson I, Landgren O| title=Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden. | journal=Blood | year= 2008 | volume= 112 | issue= 8 | pages= 3052-6 | pmid=18703425 | doi=10.1182/blood-2008-06-162768 | pmc=2569164 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18703425  }} </ref><ref name="pmid18809818">{{cite journal| author=Koshiol J, Gridley G, Engels EA, McMaster ML, Landgren O| title=Chronic immune stimulation and subsequent Waldenström macroglobulinemia. | journal=Arch Intern Med | year= 2008 | volume= 168 | issue= 17 | pages= 1903-9 | pmid=18809818 | doi=10.1001/archinternmed.2008.4 | pmc=2670401 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18809818  }} </ref><ref name="pmid18387498">{{cite journal| author=de Sanjose S, Benavente Y, Vajdic CM, Engels EA, Morton LM, Bracci PM et al.| title=Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium. | journal=Clin Gastroenterol Hepatol | year= 2008 | volume= 6 | issue= 4 | pages= 451-8 | pmid=18387498 | doi=10.1016/j.cgh.2008.02.011 | pmc=3962672 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18387498  }} </ref>
**HIV.<ref name="pmid18809818">{{cite journal| author=Koshiol J, Gridley G, Engels EA, McMaster ML, Landgren O| title=Chronic immune stimulation and subsequent Waldenström macroglobulinemia. | journal=Arch Intern Med | year= 2008 | volume= 168 | issue= 17 | pages= 1903-9 | pmid=18809818 | doi=10.1001/archinternmed.2008.4 | pmc=2670401 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18809818  }} </ref>
**Rickettsiosis.<ref name="pmid18809818">{{cite journal| author=Koshiol J, Gridley G, Engels EA, McMaster ML, Landgren O| title=Chronic immune stimulation and subsequent Waldenström macroglobulinemia. | journal=Arch Intern Med | year= 2008 | volume= 168 | issue= 17 | pages= 1903-9 | pmid=18809818 | doi=10.1001/archinternmed.2008.4 | pmc=2670401 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18809818  }} </ref>
**Sjogren syndrome.<ref name="pmid20181958">{{cite journal| author=Kristinsson SY, Koshiol J, Björkholm M, Goldin LR, McMaster ML, Turesson I et al.| title=Immune-related and inflammatory conditions and risk of lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia. | journal=J Natl Cancer Inst | year= 2010 | volume= 102 | issue= 8 | pages= 557-67 | pmid=20181958 | doi=10.1093/jnci/djq043 | pmc=2857799 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20181958  }} </ref><ref name="pmid18263783">{{cite journal| author=Ekström Smedby K, Vajdic CM, Falster M, Engels EA, Martínez-Maza O, Turner J et al.| title=Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. | journal=Blood | year= 2008 | volume= 111 | issue= 8 | pages= 4029-38 | pmid=18263783 | doi=10.1182/blood-2007-10-119974 | pmc=2288717 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18263783  }} </ref>
**Autoimmune hemolytic anemia.<ref name="pmid20181958">{{cite journal| author=Kristinsson SY, Koshiol J, Björkholm M, Goldin LR, McMaster ML, Turesson I et al.| title=Immune-related and inflammatory conditions and risk of lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia. | journal=J Natl Cancer Inst | year= 2010 | volume= 102 | issue= 8 | pages= 557-67 | pmid=20181958 | doi=10.1093/jnci/djq043 | pmc=2857799 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20181958  }} </ref><ref name="pmid18263783">{{cite journal| author=Ekström Smedby K, Vajdic CM, Falster M, Engels EA, Martínez-Maza O, Turner J et al.| title=Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. | journal=Blood | year= 2008 | volume= 111 | issue= 8 | pages= 4029-38 | pmid=18263783 | doi=10.1182/blood-2007-10-119974 | pmc=2288717 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18263783  }} </ref>
**Sarcoidosis.<ref name="pmid16985251">{{cite journal| author=Landgren O, Engels EA, Pfeiffer RM, Gridley G, Mellemkjaer L, Olsen JH et al.| title=Autoimmunity and susceptibility to Hodgkin lymphoma: a population-based case-control study in Scandinavia. | journal=J Natl Cancer Inst | year= 2006 | volume= 98 | issue= 18 | pages= 1321-30 | pmid=16985251 | doi=10.1093/jnci/djj361 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16985251  }} </ref>
**SLE.<ref name="pmid18263783">{{cite journal| author=Ekström Smedby K, Vajdic CM, Falster M, Engels EA, Martínez-Maza O, Turner J et al.| title=Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. | journal=Blood | year= 2008 | volume= 111 | issue= 8 | pages= 4029-38 | pmid=18263783 | doi=10.1182/blood-2007-10-119974 | pmc=2288717 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18263783  }} </ref>
*Hay fever.
*[[Environmental factor|Environmental factors]]:
**According to some recent studies, exposure to following environmental factors seems to have association with the development of WM:<ref name="pmid20308603">{{cite journal| author=Royer RH, Koshiol J, Giambarresi TR, Vasquez LG, Pfeiffer RM, McMaster ML| title=Differential characteristics of Waldenström macroglobulinemia according to patterns of familial aggregation. | journal=Blood | year= 2010 | volume= 115 | issue= 22 | pages= 4464-71 | pmid=20308603 | doi=10.1182/blood-2009-10-247973 | pmc=2881498 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20308603  }} </ref><ref name="pmid25174029">{{cite journal| author=Vajdic CM, Landgren O, McMaster ML, Slager SL, Brooks-Wilson A, Smith A et al.| title=Medical history, lifestyle, family history, and occupational risk factors for lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. | journal=J Natl Cancer Inst Monogr | year= 2014 | volume= 2014 | issue= 48 | pages= 87-97 | pmid=25174029 | doi=10.1093/jncimonographs/lgu002 | pmc=4155457 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25174029  }} </ref>
***Occupational (Farming).
***[[Pesticides]].
***Paint.
***Rubber dyes.
***Benzene.
***Coal dust.
***Leather manufacturing.
***Wood dust.
***Organic solvents.


==Differentiating Lymphoplasmacytic Lymphoma from Other B cell lymphoid neoplasms==
==[[Lymphoplasmacytic lymphoma screening|Screening]]==
Waldenström macroglobulinemia must be differentiated from other B cell lymphoid neoplasms including:


*[[Chronic lymphocytic leukemia]]/[[small lymphocytic lymphoma]]:
==[[Lymphoplasmacytic lymphoma natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
:*Always express CD5
:*Usually CD23 positive<ref name="CLL">{{cite journal |vauthors=Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ |title=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 |journal=Blood |volume=111 |issue=12 |pages=5446–56 |year=2008 |pmid=18216293 |pmc=2972576 |doi=10.1182/blood-2007-06-093906 |url=}}</ref>
 
*[[B-cell prolymphocytic leukemia]]:
:*Express bright surface [[Immunoglobulin M|IgM]], [[CD20]] and other B-cell antigens ([[CD19]], [[CD22]], [[CD79a]], [[FMC7]])<ref name=",m">{{cite journal |vauthors=Del Giudice I, Davis Z, Matutes E, Osuji N, Parry-Jones N, Morilla A, Brito-Babapulle V, Oscier D, Catovsky D |title=IgVH genes mutation and usage, ZAP-70 and CD38 expression provide new insights on B-cell prolymphocytic leukemia (B-PLL) |journal=Leukemia |volume=20 |issue=7 |pages=1231–7 |year=2006 |pmid=16642047 |doi=10.1038/sj.leu.2404238 |url=}}</ref><ref name="njl">{{cite journal |vauthors=Ravandi F, O'Brien S |title=Chronic lymphoid leukemias other than chronic lymphocytic leukemia: diagnosis and treatment |journal=Mayo Clin. Proc. |volume=80 |issue=12 |pages=1660–74 |year=2005 |pmid=16342661 |doi=10.4065/80.12.1660 |url=}}</ref>
 
*[[Follicular lymphoma]]:
:*Express [[CD10]], [[HLA-DR]], pan B-cell antigens (CD19, CD20, CD79a), CD21, and surface IgM, [[Immunoglobulin G|IgG]], or [[IgA]]
:*Rearrangement of Bcl-2<ref name="FL">{{cite journal |vauthors=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 |title=CD10-MUM1+ follicular lymphoma lacks BCL2 gene translocation and shows characteristic biologic and clinical features |journal=Blood |volume=109 |issue=7 |pages=3076–9 |year=2007 |pmid=17138820 |doi=10.1182/blood-2006-09-045989 |url=}}</ref><ref name="FL1">{{cite journal |vauthors=Anderson KC, Bates MP, Slaughenhoupt BL, Pinkus GS, Schlossman SF, Nadler LM |title=Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation |journal=Blood |volume=63 |issue=6 |pages=1424–33 |year=1984 |pmid=6609729 |doi= |url=}}
:*Bone marrow infiltration of small, cleaved cells that are usually paratrabecular
</ref>
 
*[[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)<ref name="UTD">{{cite journal |vauthors=Pangalis GA, Kyrtsonis MC, Kontopidou FN, Vassilakopoulos TP, Siakantaris MP, Dimopoulou MN, Kittas C, Angelopoulou MK |title=Differential diagnosis of Waldenstrom's macroglobulinemia from other low-grade B-cell lymphoproliferative disorders |journal=Semin. Oncol. |volume=30 |issue=2 |pages=201–5 |year=2003 |pmid=12720136 |doi=10.1053/sonc.2003.50046 |url=}}</ref>
 
*[[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<ref name="MCL">{{cite journal |vauthors=Dorfman DM, Pinkus GS |title=Distinction between small lymphocytic and mantle cell lymphoma by immunoreactivity for CD23 |journal=Mod. Pathol. |volume=7 |issue=3 |pages=326–31 |year=1994 |pmid=8058704 |doi= |url=}}</ref><ref name="MCL1">{{cite journal |vauthors=DiRaimondo F, Albitar M, Huh Y, O'Brien S, Montillo M, Tedeschi A, Kantarjian H, Lerner S, Giustolisi R, Keating M |title=The clinical and diagnostic relevance of CD23 expression in the chronic lymphoproliferative disease |journal=Cancer |volume=94 |issue=6 |pages=1721–30 |year=2002 |pmid=11920534 |doi= |url=}}</ref>
 
*[[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% )<ref name="add">{{cite journal |vauthors=Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD |title=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 |journal=J. Clin. Oncol. |volume=17 |issue=12 |pages=3835–49 |year=1999 |pmid=10577857 |doi= |url=}}</ref><ref name="asdf">{{cite journal |vauthors=Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC |title=A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group |journal=Blood |volume=84 |issue=5 |pages=1361–92 |year=1994 |pmid=8068936 |doi= |url=}}</ref>
 
==Epidemiology and Demographics==
*Lymphoplasmacytic lymphoma is one of the rare subtypes of NHL accounting just 1-2% of it.
===Prevalence===
* The prevalence of Waldenström macroglobulinemia is estimated to be 1000-1,500 cases in United States annually.<ref name="pmid22139816">{{cite journal| author=Wang H, Chen Y, Li F, Delasalle K, Wang J, Alexanian R et al.| title=Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study. | journal=Cancer | year= 2012 | volume= 118 | issue= 15 | pages= 3793-800 | pmid=22139816 | doi=10.1002/cncr.26627 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22139816  }} </ref><ref name="pmid9506352">{{cite journal| author=Groves FD, Travis LB, Devesa SS, Ries LA, Fraumeni JF| title=Waldenström's macroglobulinemia: incidence patterns in the United States, 1988-1994. | journal=Cancer | year= 1998 | volume= 82 | issue= 6 | pages= 1078-81 | pmid=9506352 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9506352  }} </ref>
 
===Incidence===
*WM accounts for approximately 1% to 2% of hematologic cancers.<ref name="pmid8219203">{{cite journal| author=Herrinton LJ, Weiss NS| title=Incidence of Waldenström's macroglobulinemia. | journal=Blood | year= 1993 | volume= 82 | issue= 10 | pages= 3148-50 | pmid=8219203 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8219203  }} </ref><ref name="pmid9506352">{{cite journal| author=Groves FD, Travis LB, Devesa SS, Ries LA, Fraumeni JF| title=Waldenström's macroglobulinemia: incidence patterns in the United States, 1988-1994. | journal=Cancer | year= 1998 | volume= 82 | issue= 6 | pages= 1078-81 | pmid=9506352 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9506352  }} </ref>
*World-wide, the overall age-adjusted incidence of Waldenström macroglobulinemia 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).<ref name="pmid23901022">{{cite journal| author=Monge J, Braggio E, Ansell SM| title=Genetic factors and pathogenesis of Waldenström's macroglobulinemia. | journal=Curr Oncol Rep | year= 2013 | volume= 15 | issue= 5 | pages= 450-6 | pmid=23901022 | doi=10.1007/s11912-013-0331-7 | pmc=PMC3807757 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23901022  }} </ref>
*The age-adjusted incidence rate for males is 0.92 per 100,000 person-years.<ref name="KyleLarson2018">{{cite journal|last1=Kyle|first1=Robert A.|last2=Larson|first2=Dirk R.|last3=McPhail|first3=Ellen D.|last4=Therneau|first4=Terry M.|last5=Dispenzieri|first5=Angela|last6=Kumar|first6=Shaji|last7=Kapoor|first7=Prashant|last8=Cerhan|first8=James R.|last9=Rajkumar|first9=S. Vincent|title=Fifty-Year Incidence of Waldenström Macroglobulinemia in Olmsted County, Minnesota, From 1961 Through 2010: A Population-Based Study With Complete Case Capture and Hematopathologic Review|journal=Mayo Clinic Proceedings|volume=93|issue=6|year=2018|pages=739–746|issn=00256196|doi=10.1016/j.mayocp.2018.02.011}}</ref>
*The age-adjusted incidence rate for females is 0.30 per 100,000 person-years.<ref name="KyleLarson2018">{{cite journal|last1=Kyle|first1=Robert A.|last2=Larson|first2=Dirk R.|last3=McPhail|first3=Ellen D.|last4=Therneau|first4=Terry M.|last5=Dispenzieri|first5=Angela|last6=Kumar|first6=Shaji|last7=Kapoor|first7=Prashant|last8=Cerhan|first8=James R.|last9=Rajkumar|first9=S. Vincent|title=Fifty-Year Incidence of Waldenström Macroglobulinemia in Olmsted County, Minnesota, From 1961 Through 2010: A Population-Based Study With Complete Case Capture and Hematopathologic Review|journal=Mayo Clinic Proceedings|volume=93|issue=6|year=2018|pages=739–746|issn=00256196|doi=10.1016/j.mayocp.2018.02.011}}</ref>
*Combined age and sex-adjusted incidence is 0.57 per 100,000 person-years.<ref name="KyleLarson2018">{{cite journal|last1=Kyle|first1=Robert A.|last2=Larson|first2=Dirk R.|last3=McPhail|first3=Ellen D.|last4=Therneau|first4=Terry M.|last5=Dispenzieri|first5=Angela|last6=Kumar|first6=Shaji|last7=Kapoor|first7=Prashant|last8=Cerhan|first8=James R.|last9=Rajkumar|first9=S. Vincent|title=Fifty-Year Incidence of Waldenström Macroglobulinemia in Olmsted County, Minnesota, From 1961 Through 2010: A Population-Based Study With Complete Case Capture and Hematopathologic Review|journal=Mayo Clinic Proceedings|volume=93|issue=6|year=2018|pages=739–746|issn=00256196|doi=10.1016/j.mayocp.2018.02.011}}</ref>
 
===Age===
* The incidence of Waldenström's macroglobulinemia increases after 50 years of age.<ref name="RF">Waldenström's macroglobulinemia. American Cancer Society (2015)http://www.cancer.org/cancer/waldenstrommacroglobulinemia/detailedguide/waldenstrom-macroglobulinemia-risk-factors Accessed on November 6, 2015</ref>
 
* The median age at diagnosis is 65 years.<ref name="pmid22139816">{{cite journal| author=Wang H, Chen Y, Li F, Delasalle K, Wang J, Alexanian R et al.| title=Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study. | journal=Cancer | year= 2012 | volume= 118 | issue= 15 | pages= 3793-800 | pmid=22139816 | doi=10.1002/cncr.26627 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22139816  }} </ref><ref name="pmid28366781">{{cite journal| author=Yun S, Johnson AC, Okolo ON, Arnold SJ, McBride A, Zhang L et al.| title=Waldenström Macroglobulinemia: Review of Pathogenesis and Management. | journal=Clin Lymphoma Myeloma Leuk | year= 2017 | volume= 17 | issue= 5 | pages= 252-262 | pmid=28366781 | doi=10.1016/j.clml.2017.02.028 | pmc=5413391 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28366781  }} </ref><ref name="pmid8219203">{{cite journal| author=Herrinton LJ, Weiss NS| title=Incidence of Waldenström's macroglobulinemia. | journal=Blood | year= 1993 | volume= 82 | issue= 10 | pages= 3148-50 | pmid=8219203 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8219203  }} </ref>
 
===Gender===
* Men are twice more likely than women to develop WM(5.4 vs. 2.7 per million, respectively). <ref name="pmid22139816">{{cite journal| author=Wang H, Chen Y, Li F, Delasalle K, Wang J, Alexanian R et al.| title=Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study. | journal=Cancer | year= 2012 | volume= 118 | issue= 15 | pages= 3793-800 | pmid=22139816 | doi=10.1002/cncr.26627 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22139816  }} </ref><ref name="pmid28366781">{{cite journal| author=Yun S, Johnson AC, Okolo ON, Arnold SJ, McBride A, Zhang L et al.| title=Waldenström Macroglobulinemia: Review of Pathogenesis and Management. | journal=Clin Lymphoma Myeloma Leuk | year= 2017 | volume= 17 | issue= 5 | pages= 252-262 | pmid=28366781 | doi=10.1016/j.clml.2017.02.028 | pmc=5413391 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28366781  }} </ref><ref name="pmid17488966">{{cite journal| author=Giordano TP, Henderson L, Landgren O, Chiao EY, Kramer JR, El-Serag H et al.| title=Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. | journal=JAMA | year= 2007 | volume= 297 | issue= 18 | pages= 2010-7 | pmid=17488966 | doi=10.1001/jama.297.18.2010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17488966  }} </ref><ref name="pmid8219203">{{cite journal| author=Herrinton LJ, Weiss NS| title=Incidence of Waldenström's macroglobulinemia. | journal=Blood | year= 1993 | volume= 82 | issue= 10 | pages= 3148-50 | pmid=8219203 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8219203  }} </ref>
 
===Race===
*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.<ref name="pmid22139816">{{cite journal| author=Wang H, Chen Y, Li F, Delasalle K, Wang J, Alexanian R et al.| title=Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study. | journal=Cancer | year= 2012 | volume= 118 | issue= 15 | pages= 3793-800 | pmid=22139816 | doi=10.1002/cncr.26627 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22139816  }} </ref><ref name="pmid28366781">{{cite journal| author=Yun S, Johnson AC, Okolo ON, Arnold SJ, McBride A, Zhang L et al.| title=Waldenström Macroglobulinemia: Review of Pathogenesis and Management. | journal=Clin Lymphoma Myeloma Leuk | year= 2017 | volume= 17 | issue= 5 | pages= 252-262 | pmid=28366781 | doi=10.1016/j.clml.2017.02.028 | pmc=5413391 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28366781  }} </ref><ref name="pmid16150940">{{cite journal| author=Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS| title=Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. | journal=Blood | year= 2006 | volume= 107 | issue= 1 | pages= 265-76 | pmid=16150940 | doi=10.1182/blood-2005-06-2508 | pmc=1895348 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16150940  }} </ref><ref name="pmid8219203">{{cite journal| author=Herrinton LJ, Weiss NS| title=Incidence of Waldenström's macroglobulinemia. | journal=Blood | year= 1993 | volume= 82 | issue= 10 | pages= 3148-50 | pmid=8219203 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8219203  }} </ref>
 
=== Epidemiology and demographics of Smoldering Waldenstrom macroglobulinemia ===
According to a recent study done in 2017, the following data was found out regarding epidemiology and demographics of SWM.<ref name="PophaliBartley2017">{{cite journal|last1=Pophali|first1=Priyanka Avinash|last2=Bartley|first2=Adam C.|last3=Kapoor|first3=Prashant|last4=Gonsalves|first4=Wilson I.|last5=Ashrani|first5=Aneel A.|last6=Marshall|first6=Ariela L.|last7=Siddiqui|first7=Mustaqeem Ahmad|last8=Go|first8=Ronald S.|title=Smoldering Waldenström’s macroglobulinemia (SWM): Analysis from the National Cancer Database (NCDB).|journal=Journal of Clinical Oncology|volume=35|issue=15_suppl|year=2017|pages=1573–1573|issn=0732-183X|doi=10.1200/JCO.2017.35.15_suppl.1573}}</ref>
 
{| class="wikitable"
|+ ''' Epidemiology and demographics of Smoldering Waldenstrom macroglobulinemia according to Sex, Race and Age'''
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Risk factors
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Proportion of SWM
|-
| style="background:#DCDCDC;" align="center" + |Sex
| style="background:#F5F5F5;" align="center" + |Males:27.72%, Females:28.31%
|-
| style="background:#DCDCDC;" align="center" + |Race
| style="background:#F5F5F5;" align="center" + |White, non-hispanic:28.97%, White, Hispanic:24.79%, Black:21.01%, Asian:20.41%, Other:26.08%.
|-
| style="background:#DCDCDC;" align="center" + |Age in years
| style="background:#F5F5F5;" align="center" + |18-49:18.32%, 50-64:25.91%, 65-79:30.8%, ≥80 : 27.26%
|-
|}
 
==Risk Factors==
Common risk factors in the development of Waldenström macroglobulinemia include:<ref name="RF">Waldenström's macroglobulinemia. American Cancer Society (2015)http://www.cancer.org/cancer/waldenstrommacroglobulinemia/detailedguide/waldenstrom-macroglobulinemia-risk-factors Accessed on November 6, 2015</ref>
* [[Monoclonal gammopathy of undetermined significance]] (MGUS):
** Pre-existing [[monoclonal gammopathy of undetermined significance]] is the most common [[Risk factors|risk factor]], associated with 40 times more likelihood of developing Waldenström's macroglobulinemia.
 
* [[Heredity]]:
** Patients with Waldenström's macroglobulinemia usually have a close/first-degree relative with the disease or with a related [[B-cell leukemia|B-cell disease]], such as [[MGUS]] or certain types of [[lymphoma]] or [[leukemia]].<ref name="pmid16357024">{{cite journal| author=Treon SP, Hunter ZR, Aggarwal A, Ewen EP, Masota S, Lee C et al.| title=Characterization of familial Waldenstrom's macroglobulinemia. | journal=Ann Oncol | year= 2006 | volume= 17 | issue= 3 | pages= 488-94 | pmid=16357024 | doi=10.1093/annonc/mdj111 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357024  }} </ref><ref name="pmid17785558">{{cite journal| author=McMaster ML, Csako G, Giambarresi TR, Vasquez L, Berg M, Saddlemire S et al.| title=Long-term evaluation of three multiple-case Waldenstrom macroglobulinemia families. | journal=Clin Cancer Res | year= 2007 | volume= 13 | issue= 17 | pages= 5063-9 | pmid=17785558 | doi=10.1158/1078-0432.CCR-07-0299 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17785558  }} </ref><ref name="pmid18703425">{{cite journal| author=Kristinsson SY, Björkholm M, Goldin LR, McMaster ML, Turesson I, Landgren O| title=Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden. | journal=Blood | year= 2008 | volume= 112 | issue= 8 | pages= 3052-6 | pmid=18703425 | doi=10.1182/blood-2008-06-162768 | pmc=2569164 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18703425  }} </ref>
 
* [[Hepatitis C]]:
** Patients with chronic [[hepatitis C]] infection have an overall 20-30% increased risk for developing non-Hodgkin lymohoma and 3-fold increased risk for WM.<ref name="pmid18703425">{{cite journal| author=Kristinsson SY, Björkholm M, Goldin LR, McMaster ML, Turesson I, Landgren O| title=Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden. | journal=Blood | year= 2008 | volume= 112 | issue= 8 | pages= 3052-6 | pmid=18703425 | doi=10.1182/blood-2008-06-162768 | pmc=2569164 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18703425  }} </ref><ref name="pmid18809818">{{cite journal| author=Koshiol J, Gridley G, Engels EA, McMaster ML, Landgren O| title=Chronic immune stimulation and subsequent Waldenström macroglobulinemia. | journal=Arch Intern Med | year= 2008 | volume= 168 | issue= 17 | pages= 1903-9 | pmid=18809818 | doi=10.1001/archinternmed.2008.4 | pmc=2670401 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18809818  }} </ref><ref name="pmid18387498">{{cite journal| author=de Sanjose S, Benavente Y, Vajdic CM, Engels EA, Morton LM, Bracci PM et al.| title=Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium. | journal=Clin Gastroenterol Hepatol | year= 2008 | volume= 6 | issue= 4 | pages= 451-8 | pmid=18387498 | doi=10.1016/j.cgh.2008.02.011 | pmc=3962672 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18387498  }} </ref>
 
* [[Autoimmune Disease|Autoimmune Diseases]]:
**Personal and family history of autoimmune diseases with autoantibodies leads to 2-3 fold higher risk of developing WM, especially elevated risks are associated with following:
***HIV.<ref name="pmid18809818">{{cite journal| author=Koshiol J, Gridley G, Engels EA, McMaster ML, Landgren O| title=Chronic immune stimulation and subsequent Waldenström macroglobulinemia. | journal=Arch Intern Med | year= 2008 | volume= 168 | issue= 17 | pages= 1903-9 | pmid=18809818 | doi=10.1001/archinternmed.2008.4 | pmc=2670401 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18809818  }} </ref>
***Rickettsiosis.<ref name="pmid18809818">{{cite journal| author=Koshiol J, Gridley G, Engels EA, McMaster ML, Landgren O| title=Chronic immune stimulation and subsequent Waldenström macroglobulinemia. | journal=Arch Intern Med | year= 2008 | volume= 168 | issue= 17 | pages= 1903-9 | pmid=18809818 | doi=10.1001/archinternmed.2008.4 | pmc=2670401 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18809818  }} </ref>
***[[Sjögren syndrome]].<ref name="pmid20181958">{{cite journal| author=Kristinsson SY, Koshiol J, Björkholm M, Goldin LR, McMaster ML, Turesson I et al.| title=Immune-related and inflammatory conditions and risk of lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia. | journal=J Natl Cancer Inst | year= 2010 | volume= 102 | issue= 8 | pages= 557-67 | pmid=20181958 | doi=10.1093/jnci/djq043 | pmc=2857799 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20181958  }} </ref><ref name="pmid18263783">{{cite journal| author=Ekström Smedby K, Vajdic CM, Falster M, Engels EA, Martínez-Maza O, Turner J et al.| title=Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. | journal=Blood | year= 2008 | volume= 111 | issue= 8 | pages= 4029-38 | pmid=18263783 | doi=10.1182/blood-2007-10-119974 | pmc=2288717 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18263783  }} </ref>
***Autoimmune hemolytic anemia.<ref name="pmid20181958">{{cite journal| author=Kristinsson SY, Koshiol J, Björkholm M, Goldin LR, McMaster ML, Turesson I et al.| title=Immune-related and inflammatory conditions and risk of lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia. | journal=J Natl Cancer Inst | year= 2010 | volume= 102 | issue= 8 | pages= 557-67 | pmid=20181958 | doi=10.1093/jnci/djq043 | pmc=2857799 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20181958  }} </ref><ref name="pmid18263783">{{cite journal| author=Ekström Smedby K, Vajdic CM, Falster M, Engels EA, Martínez-Maza O, Turner J et al.| title=Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. | journal=Blood | year= 2008 | volume= 111 | issue= 8 | pages= 4029-38 | pmid=18263783 | doi=10.1182/blood-2007-10-119974 | pmc=2288717 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18263783  }} </ref>
***Sarcoidosis.<ref name="pmid16985251">{{cite journal| author=Landgren O, Engels EA, Pfeiffer RM, Gridley G, Mellemkjaer L, Olsen JH et al.| title=Autoimmunity and susceptibility to Hodgkin lymphoma: a population-based case-control study in Scandinavia. | journal=J Natl Cancer Inst | year= 2006 | volume= 98 | issue= 18 | pages= 1321-30 | pmid=16985251 | doi=10.1093/jnci/djj361 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16985251  }} </ref>
***SLE.<ref name="pmid18263783">{{cite journal| author=Ekström Smedby K, Vajdic CM, Falster M, Engels EA, Martínez-Maza O, Turner J et al.| title=Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. | journal=Blood | year= 2008 | volume= 111 | issue= 8 | pages= 4029-38 | pmid=18263783 | doi=10.1182/blood-2007-10-119974 | pmc=2288717 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18263783  }} </ref>
* [[Allergic]] conditions:
**[[Hay fever]] is also known to be associated with increased risk of WM.
 
==Screening==
According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for Waldenström macroglobulinemia.<ref name="US">Recommendations. US preventive services task force(2015) http://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=waldenstrom+macroglobulinemia Accessed on November 10, 2015</ref>
 
==Natural History, Complications, and Prognosis==
=== Natural History ===
*The symptoms of Waldenström macroglobulinemia usually develop in the seventh and eighth decade of life, and it will typically start with symptoms such as [[fatigue]], unexplained weight loss, [[peripheral neuropathy]], [[Dyspnea|shortness of breath]], [[purpura]], [[raynaud's phenomenon]], and [[Blurred vision|vision problems]].<ref name="pmid22139816">{{cite journal| author=Wang H, Chen Y, Li F, Delasalle K, Wang J, Alexanian R et al.| title=Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study. | journal=Cancer | year= 2012 | volume= 118 | issue= 15 | pages= 3793-800 | pmid=22139816 | doi=10.1002/cncr.26627 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22139816  }} </ref>
 
=== Complications ===
* Common complications of Waldenström macroglobulinemia include:
** [[Hyperviscosity syndrome]]<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>
** [[Cryoglobulinemia]]<ref name="pmid14871241">{{cite journal| author=Michael AB, Lawes M, Kamalarajan M, Huissoon A, Pratt G| title=Cryoglobulinaemia as an acute presentation of Waldenstrom's macroglobulinaemia. | journal=Br J Haematol | year= 2004 | volume= 124 | issue= 5 | pages= 565 | pmid=14871241 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14871241  }} </ref>
** [[Peripheral neuropathy]](15%).<ref name="pmid16421127">{{cite journal| author=Levine T, Pestronk A, Florence J, Al-Lozi MT, Lopate G, Miller T et al.| title=Peripheral neuropathies in Waldenström's macroglobulinaemia. | journal=J Neurol Neurosurg Psychiatry | year= 2006 | volume= 77 | issue= 2 | pages= 224-8 | pmid=16421127 | doi=10.1136/jnnp.2005.071175 | pmc=2077569 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16421127  }} </ref>
** [[Amyloidosis]] of the heart, kidney, liver, lungs, and joints<ref name="pa">{{cite journal |vauthors=Zimmermann I, Gloor HJ, Rüttimann S |title=[General AL-amyloidosis: a rare complication in Waldenstrom macroglobulinemia] |language=German |journal=Praxis (Bern 1994) |volume=90 |issue=47 |pages=2050–5 |year=2001 |pmid=11763619 |doi= |url=}}</ref>
** [[Cold agglutinin disease|Cold haemagglutinin disease]]/Autoimmune hemolytic anemia(<10%).<ref name="pmid24528152">{{cite journal| author=Owen RG, Pratt G, Auer RL, Flatley R, Kyriakou C, Lunn MP et al.| title=Guidelines on the diagnosis and management of Waldenström macroglobulinaemia. | journal=Br J Haematol | year= 2014 | volume= 165 | issue= 3 | pages= 316-33 | pmid=24528152 | doi=10.1111/bjh.12760 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24528152  }} </ref>
** [[Malabsorption|Gastrointestinal malabsorption]]<ref name="pmid3141496">{{cite journal| author=Veloso FT, Fraga J, Saleiro JV| title=Macroglobulinemia and small intestinal disease. A case report with review of the literature. | journal=J Clin Gastroenterol | year= 1988 | volume= 10 | issue= 5 | pages= 546-50 | pmid=3141496 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3141496  }} </ref>
** [[Renal insufficiency]]<ref name="pmid27468978">{{cite journal| author=Vos JM, Gustine J, Rennke HG, Hunter Z, Manning RJ, Dubeau TE et al.| title=Renal disease related to Waldenström macroglobulinaemia: incidence, pathology and clinical outcomes. | journal=Br J Haematol | year= 2016 | volume= 175 | issue= 4 | pages= 623-630 | pmid=27468978 | doi=10.1111/bjh.14279 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27468978  }} </ref>
** [[Fundoscopy|Fundoscopic]] abnormalities<ref name="pmid11736938" />
**[[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.
===Late and rare complications===
*[[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]]).<ref name="pmid9686227">{{cite journal| author=Civit T, Coulbois S, Baylac F, Taillandier L, Auque J| title=[Waldenström's macroglobulinemia and cerebral lymphoplasmocytic proliferation: Bing and Neel syndrome. Apropos of a new case]. | journal=Neurochirurgie | year= 1997 | volume= 43 | issue= 4 | pages= 245-9 | pmid=9686227 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9686227  }} </ref>
**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,<ref name="pmid19362988">{{cite journal| author=Fintelmann F, Forghani R, Schaefer PW, Hochberg EP, Hochberg FH| title=Bing-Neel Syndrome revisited. | journal=Clin Lymphoma Myeloma | year= 2009 | volume= 9 | issue= 1 | pages= 104-6 | pmid=19362988 | doi=10.3816/CLM.2009.n.028 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19362988  }} </ref> leading to following symptoms:<ref name="pmid19951888">{{cite journal| author=Grewal JS, Brar PK, Sahijdak WM, Tworek JA, Chottiner EG| title=Bing-Neel syndrome: a case report and systematic review of clinical manifestations, diagnosis, and treatment options. | journal=Clin Lymphoma Myeloma | year= 2009 | volume= 9 | issue= 6 | pages= 462-6 | pmid=19951888 | doi=10.3816/CLM.2009.n.091 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19951888  }} </ref>
****Headache.
****Confusion.
****Neck stiffness.
****Sporadic loss of motor function.
****Facial paralysis.
****Drooping eyelid.
****Double vision.
****Difficult swallowing.
****Visual loss.
****Hearing loss.
 
=== Prognosis ===
*Prognosis is generally poor.
*The median survival from the time of diagnosis is 6.4 years.<ref name="pmid16611306">{{cite journal| author=Ghobrial IM, Fonseca R, Gertz MA, Plevak MF, Larson DR, Therneau TM et al.| title=Prognostic model for disease-specific and overall mortality in newly diagnosed symptomatic patients with Waldenstrom macroglobulinaemia. | journal=Br J Haematol | year= 2006 | volume= 133 | issue= 2 | pages= 158-64 | pmid=16611306 | doi=10.1111/j.1365-2141.2006.06003.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16611306  }} </ref>
*The median disease-specific survival is 11.2 years.<ref name="pmid16611306">{{cite journal| author=Ghobrial IM, Fonseca R, Gertz MA, Plevak MF, Larson DR, Therneau TM et al.| title=Prognostic model for disease-specific and overall mortality in newly diagnosed symptomatic patients with Waldenstrom macroglobulinaemia. | journal=Br J Haematol | year= 2006 | volume= 133 | issue= 2 | pages= 158-64 | pmid=16611306 | doi=10.1111/j.1365-2141.2006.06003.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16611306  }} </ref>
*Approximately 10% patients still live at 15 years.<ref name="MorelDuhamel2009">{{cite journal|last1=Morel|first1=P.|last2=Duhamel|first2=A.|last3=Gobbi|first3=P.|last4=Dimopoulos|first4=M. A.|last5=Dhodapkar|first5=M. V.|last6=McCoy|first6=J.|last7=Crowley|first7=J.|last8=Ocio|first8=E. M.|last9=Garcia-Sanz|first9=R.|last10=Treon|first10=S. P.|last11=Leblond|first11=V.|last12=Kyle|first12=R. A.|last13=Barlogie|first13=B.|last14=Merlini|first14=G.|title=International prognostic scoring system for Waldenstrom macroglobulinemia|journal=Blood|volume=113|issue=18|year=2009|pages=4163–4170|issn=0006-4971|doi=10.1182/blood-2008-08-174961}}</ref><ref name="pmid10792277">{{cite journal| author=Kyle RA, Greipp PR, Gertz MA, Witzig TE, Lust JA, Lacy MQ et al.| title=Waldenström's macroglobulinaemia: a prospective study comparing daily with intermittent oral chlorambucil. | journal=Br J Haematol | year= 2000 | volume= 108 | issue= 4 | pages= 737-42 | pmid=10792277 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10792277  }} </ref>
*5-year survival rate is 78%.
*In the last decade (2001-2010), the median overall survival for all WM groups has improved to just over 8 years compared to 6 years in the previous decade (1991-2000).
*After 2000, a 2-fold increased mortality is reported in patients diagnosed with WM when compared with expected population mortality.<ref name="KyleLarson2018">{{cite journal|last1=Kyle|first1=Robert A.|last2=Larson|first2=Dirk R.|last3=McPhail|first3=Ellen D.|last4=Therneau|first4=Terry M.|last5=Dispenzieri|first5=Angela|last6=Kumar|first6=Shaji|last7=Kapoor|first7=Prashant|last8=Cerhan|first8=James R.|last9=Rajkumar|first9=S. Vincent|title=Fifty-Year Incidence of Waldenström Macroglobulinemia in Olmsted County, Minnesota, From 1961 Through 2010: A Population-Based Study With Complete Case Capture and Hematopathologic Review|journal=Mayo Clinic Proceedings|volume=93|issue=6|year=2018|pages=739–746|issn=00256196|doi=10.1016/j.mayocp.2018.02.011}}</ref>
*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.<ref name="pmid15756000">{{cite journal| author=Gobbi PG, Baldini L, Broglia C, Goldaniga M, Comelli M, Morel P et al.| title=Prognostic validation of the international classification of immunoglobulin M gammopathies: a survival advantage for patients with immunoglobulin M monoclonal gammopathy of undetermined significance? | journal=Clin Cancer Res | year= 2005 | volume= 11 | issue= 5 | pages= 1786-90 | pmid=15756000 | doi=10.1158/1078-0432.CCR-04-1899 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15756000  }} </ref>
 
===Adverse prognostic factors===
*Some of the pretreatment factors associated with shorter survival in WM patients are:<ref name="pmid12881396">{{cite journal| author=Dimopoulos MA, Hamilos G, Zervas K, Symeonidis A, Kouvatseas G, Roussou P et al.| title=Survival and prognostic factors after initiation of treatment in Waldenstrom's macroglobulinemia. | journal=Ann Oncol | year= 2003 | volume= 14 | issue= 8 | pages= 1299-305 | pmid=12881396 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12881396  }} </ref><ref name="pmid16611306">{{cite journal| author=Ghobrial IM, Fonseca R, Gertz MA, Plevak MF, Larson DR, Therneau TM et al.| title=Prognostic model for disease-specific and overall mortality in newly diagnosed symptomatic patients with Waldenstrom macroglobulinaemia. | journal=Br J Haematol | year= 2006 | volume= 133 | issue= 2 | pages= 158-64 | pmid=16611306 | doi=10.1111/j.1365-2141.2006.06003.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16611306  }} </ref>
**Age >/=65 years.
**Organomegaly (Hepatosplenomegaly).
**B-symptoms (weight loss, fever or night sweats).
**Anaemia (Hb < 10.0 g/dl).
**Platelets <100 x 10(6)/dl.
**Albumin <3.5 g/dl.
**Bone marrow lymphoplasmacytic infiltrate >/=50%.
**Elevated beta2-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.
**Hyperviscosity.
*Other prognostic factors recently studied are:
**Serum free light chain.<ref name="pmid18452095">{{cite journal| author=Leleu X, Moreau AS, Weller E, Roccaro AM, Coiteux V, Manning R et al.| title=Serum immunoglobulin free light chain correlates with tumor burden markers in Waldenstrom macroglobulinemia. | journal=Leuk Lymphoma | year= 2008 | volume= 49 | issue= 6 | pages= 1104-7 | pmid=18452095 | doi=10.1080/10428190802074619 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18452095  }} </ref>
**Serum lactate dehydrogenase.<ref name="pmid19362972">{{cite journal| author=Kastritis E, Zervas K, Repoussis P, Michali E, Katodrytou E, Zomas A et al.| title=Prognostication in young and old patients with Waldenström's macroglobulinemia: importance of the International Prognostic Scoring System and of serum lactate dehydrogenase. | journal=Clin Lymphoma Myeloma | year= 2009 | volume= 9 | issue= 1 | pages= 50-2 | pmid=19362972 | doi=10.3816/CLM.2009.n.012 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19362972  }} </ref>
**Serum soluble CD27.<ref name="pmid18216294">{{cite journal| author=Ho AW, Hatjiharissi E, Ciccarelli BT, Branagan AR, Hunter ZR, Leleu X et al.| title=CD27-CD70 interactions in the pathogenesis of Waldenstrom macroglobulinemia. | journal=Blood | year= 2008 | volume= 112 | issue= 12 | pages= 4683-9 | pmid=18216294 | doi=10.1182/blood-2007-04-084525 | pmc=2597134 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18216294  }} </ref>
*Most of the prognostic factors have defined the outcome of Waldenström macroglobulinemia in patients requiring treatment. However, very few studies have evaluated the prognostic factors in patients who don't initially need the treatment.
 
===Risk Stratification Criteria===
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):<ref name="pmid19196866">{{cite journal| author=Morel P, Duhamel A, Gobbi P, Dimopoulos MA, Dhodapkar MV, McCoy J et al.| title=International prognostic scoring system for Waldenstrom macroglobulinemia. | journal=Blood | year= 2009 | volume= 113 | issue= 18 | pages= 4163-70 | pmid=19196866 | doi=10.1182/blood-2008-08-174961 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19196866  }} </ref>
 
{| class="wikitable"
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Risk factors
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Score
|-
| style="background:#DCDCDC;" align="center" + |Age > 65
| style="background:#F5F5F5;" align="center" + |1
|-
| style="background:#DCDCDC;" align="center" + |Hemoglobin ≤ 11.5g/dl
| style="background:#F5F5F5;" align="center" + |1
|-
| style="background:#DCDCDC;" align="center" + |Platelet ≤ 100,000μl
| style="background:#F5F5F5;" align="center" + |1
|-
| style="background:#DCDCDC;" align="center" + |β-microglobulin > 3mg/l
| style="background:#F5F5F5;" align="center" + |1
|-
| style="background:#DCDCDC;" align="center" + |IgM > 70g/l
| style="background:#F5F5F5;" align="center" + |1
|}
{| class="wikitable"
|+ '''International prognostic scoring system for Waldenström macroglobulinemia'''
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Risk group
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Score
! style="background:#4479BA; color: #FFFFFF;" align="center" + |5-year survival
|-
| style="background:#DCDCDC;" align="center" + |Low
| style="background:#F5F5F5;" align="center" + |0-1 (except age)
| style="background:#F5F5F5;" align="center" + |87%
|-
| style="background:#DCDCDC;" align="center" + |Intermediate
| style="background:#F5F5F5;" align="center" + |2 or age>65
| style="background:#F5F5F5;" align="center" + |68%
|-
| style="background:#DCDCDC;" align="center" + |High
| style="background:#F5F5F5;" align="center" + |≥3
| style="background:#F5F5F5;" align="center" + |36%
|}
{| class="wikitable"
|+ '''International prognostic scoring system for Waldenström macroglobulinemia'''
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Risk group
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Score
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Median survival
|-
| style="background:#DCDCDC;" align="center" + |Low
| style="background:#F5F5F5;" align="center" + |0-1 (except age)
| style="background:#F5F5F5;" align="center" + |12 years
|-
| style="background:#DCDCDC;" align="center" + |Intermediate
| style="background:#F5F5F5;" align="center" + |2 or age>65
| style="background:#F5F5F5;" align="center" + |8 years
|-
| style="background:#DCDCDC;" align="center" + |High
| style="background:#F5F5F5;" align="center" + |≥3
| style="background:#F5F5F5;" align="center" + |3.5 years
|}


==Diagnosis==
==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.
===Diagnostic Study of Choice===
There is no single diagnostic study of choice for the diagnosis of Waldenström macroglobulinemia (WM), but '''bone marrow aspiration and biopsy''' is considered to be mandatory for assessment of patients with WM and further supported by monoclonal protein/immunophenotypic studies like [[immunohistochemistry]], [[flow cytometry]] and [[cytogenetics]] to distinguish WM from other types of B-cell lymphomas.<ref name="pmid15735132">{{cite journal| author=Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP| title=Diagnosis and management of Waldenstrom's macroglobulinemia. | journal=J Clin Oncol | year= 2005 | volume= 23 | issue= 7 | pages= 1564-77 | pmid=15735132 | doi=10.1200/JCO.2005.03.144 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15735132  }} </ref><ref name="pmid26980727">{{cite journal| author=Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R et al.| title=The 2016 revision of the World Health Organization classification of lymphoid neoplasms. | journal=Blood | year= 2016 | volume= 127 | issue= 20 | pages= 2375-90 | pmid=26980727 | doi=10.1182/blood-2016-01-643569 | pmc=4874220 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26980727  }} </ref>


====Diagnostic Criteria====
[[Lymphoplasmacytic lymphoma diagnostic study of choice|Diagnostic study of choice]] | [[Lymphoplasmacytic lymphoma history and symptoms|History and Symptoms]] | [[Lymphoplasmacytic lymphoma physical examination|Physical Examination]] | [[Lymphoplasmacytic lymphoma laboratory findings|Laboratory Findings]] | [[Lymphoplasmacytic lymphoma electrocardiogram|Electrocardiogram]] | [[Lymphoplasmacytic lymphoma x ray|X-Ray Findings]] | [[Lymphoplasmacytic lymphoma echocardiography and ultrasound|Echocardiography and Ultrasound]] | [[Lymphoplasmacytic lymphoma CT scan|CT-Scan Findings]] | [[Lymphoplasmacytic lymphoma MRI|MRI Findings]] | [[Lymphoplasmacytic lymphoma other imaging findings|Other Imaging Findings]] | [[Lymphoplasmacytic lymphoma other diagnostic studies|Other Diagnostic Studies]]
In September 26-30, 2002, in Athens, Greece,the Second International Workshop was held in which a diagnostic criteria for Waldenstrom's Macroglobulinemia was proposed. According to this criteria, the following findings on performing [[Bone marrow examination|bone marrow biopsy]] and '''serum protein analysis''' are confirmatory of Waldenström macroglobulinemia:<ref name="pmid15735132" />
#Presence of [[IgM]] monoclonal [[gammopathy]] of any concentration on serum protein analysis.
#A bone marrow biopsy demonstrating more than 10% infiltration by small [[lymphocytes]] showing plasmacytoid/plasma-cell differentiation.with an intertrabecular pattern consistent with lymphoplasmacytic lymphoma.
#*IgM concentration widely varies in WM, and it is not possible to define a concentration that reliably distinguishes WM from other lymphoproliferative disorders. Hence, a diagnosis of WM can be made irrespective of IgM concentration if there is evidence of bone marrow infiltration by lymphoplasmacytoid lymphoma as defined by the Revised European-American Lymphoma classification and WHO criteria.<ref name="pmid8068936">{{cite journal| author=Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML et al.| title=A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. | journal=Blood | year= 1994 | volume= 84 | issue= 5 | pages= 1361-92 | pmid=8068936 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8068936  }} </ref> This is a tumor of small lymphocytes showing evidence of plasmacytoid or plasma-cell differentiation.
#*A recent study found that, in 39% of patients, the bone marrow aspirate contained a spectrum of small lymphocytes, plasmacytoid lymphocytes, and plasma cells; in 39% of patients, there was a predominance of small lymphocytes with fewer plasmacytoid lymphocytes or plasma cells, and 22% of patients contained a mixture of small lymphocytes and plasma cells, with rare plasmacytoid cells. Mast cells were increased in 26% of patients.<ref name="pmid12720133">{{cite journal| author=Remstein ED, Hanson CA, Kyle RA, Hodnefield JM, Kurtin PJ| title=Despite apparent morphologic and immunophenotypic heterogeneity, Waldenstrom's macroglobulinemia is consistently composed of cells along a morphologic continuum of small lymphocytes, plasmacytoid lymphocytes, and plasma cells. | journal=Semin Oncol | year= 2003 | volume= 30 | issue= 2 | pages= 182-6 | pmid=12720133 | doi=10.1053/sonc.2003.50073 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12720133  }} </ref>
#Intertrabecular pattern of bone marrow infiltration.
#[[Immunophenotype]] of the lymphoplasmacytic infiltrate consistent with Waldenstrom's macroglobulinemia. This includes: IgM+, CD5-, CD10-, CD11c-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103- and CD138+.<ref name="pmid12720134">{{cite journal| author=San Miguel JF, Vidriales MB, Ocio E, Mateo G, Sánchez-Guijo F, Sánchez ML et al.| title=Immunophenotypic analysis of Waldenstrom's macroglobulinemia. | journal=Semin Oncol | year= 2003 | volume= 30 | issue= 2 | pages= 187-95 | pmid=12720134 | doi=10.1053/sonc.2003.50074 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12720134  }} </ref><ref name="pmid11554171">{{cite journal| author=Owen RG, Barrans SL, Richards SJ, O'Connor SJ, Child JA, Parapia LA et al.| title=Waldenström macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors. | journal=Am J Clin Pathol | year= 2001 | volume= 116 | issue= 3 | pages= 420-8 | pmid=11554171 | doi=10.1309/4LCN-JMPG-5U71-UWQB | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11554171  }} </ref><ref name="pmid16191510">{{cite journal| author=Konoplev S, Medeiros LJ, Bueso-Ramos CE, Jorgensen JL, Lin P| title=Immunophenotypic profile of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. | journal=Am J Clin Pathol | year= 2005 | volume= 124 | issue= 3 | pages= 414-20 | pmid=16191510 | doi=10.1309/3G1X-DX0D-VHBN-VKB4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16191510  }} </ref>
(3,4 are supportive of but not necessary for WM diagnosis).
*Another diagnostic Criteria for Waldenström Macroglobulinemia and Associated Disorders is as follow:<ref name="AnsellKyle2010">{{cite journal|last1=Ansell|first1=Stephen M.|last2=Kyle|first2=Robert A.|last3=Reeder|first3=Craig B.|last4=Fonseca|first4=Rafael|last5=Mikhael|first5=Joseph R.|last6=Morice|first6=William G.|last7=Bergsagel|first7=P. Leif|last8=Buadi|first8=Francis K.|last9=Colgan|first9=Joseph P.|last10=Dingli|first10=David|last11=Dispenzieri|first11=Angela|last12=Greipp|first12=Philip R.|last13=Habermann|first13=Thomas M.|last14=Hayman|first14=Suzanne R.|last15=Inwards|first15=David J.|last16=Johnston|first16=Patrick B.|last17=Kumar|first17=Shaji K.|last18=Lacy|first18=Martha Q.|last19=Lust|first19=John A.|last20=Markovic|first20=Svetomir N.|last21=Micallef|first21=Ivana N.M.|last22=Nowakowski|first22=Grzegorz S.|last23=Porrata|first23=Luis F.|last24=Roy|first24=Vivek|last25=Russell|first25=Stephen J.|last26=Short|first26=Kristen E. Detweiler|last27=Stewart|first27=A. Keith|last28=Thompson|first28=Carrie A.|last29=Witzig|first29=Thomas E.|last30=Zeldenrust|first30=Steven R.|last31=Dalton|first31=Robert J.|last32=Rajkumar|first32=S. Vincent|last33=Gertz|first33=Morie A.|title=Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines|journal=Mayo Clinic Proceedings|volume=85|issue=9|year=2010|pages=824–833|issn=00256196|doi=10.4065/mcp.2010.0304}}</ref>
#[[Waldenström macroglobulinemia]]:
#*IgM monoclonal gammopathy (regardless of the size of the M protein) with >10% bone marrow lymphoplasmacytic infiltration (usually intertrabecular) by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation and a typical immunophenotype (surface IgM+, CD5–, CD10–, CD19+, CD20+, CD23–) that satisfactorily excludes other lymphoproliferative disorders, including chronic lymphocytic leukemia and mantle cell lymphoma.
#[[IgM MGUS]]:
#*Serum IgM monoclonal protein level <3 g/dL, bone marrow lymphoplasmacytic infiltration <10%, and no evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly.
#Smoldering Waldenström macroglobulinemia (also referred to as indolent or asymptomatic Waldenström macroglobulinemia):
#*Serum IgM monoclonal protein level ≥3 g/dL and/or bone marrow lymphoplasmacytic infiltration ≥10% and no evidence of end-organ damage, such as anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly, that can be attributed to a lymphoplasmacytic proliferative disorder.
 
====Definitive Diagnostic Tests====
*Genetic Testing.
**ARIDA.
**IG gene rearrangement.
**CXCR4 5338X.
**MYD88 L265P.
*Immunophenotyping.
*Serum paraprotein.
 
===History and Symptoms===
=== History ===
* The onset of Waldenström macroglobulinemia is insidious and non-specific.
* Approximately 25% of patients with WM are asymptomatic upon presentation; their diagnosis is often made [[Incidental finding|incidentally]] from routine blood tests done for some other reason. WM found this way is sometimes called asymptomatic or Smoldering WM (SWM).<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>
* Symptoms develop depending on the tissues involved in the malignant cell infiltration or [[IgM]] deposition.<ref name="pmid10623712">{{cite journal| author=Dimopoulos MA, Panayiotidis P, Moulopoulos LA, Sfikakis P, Dalakas M| title=Waldenström's macroglobulinemia: clinical features, complications, and management. | journal=J Clin Oncol | year= 2000 | volume= 18 | issue= 1 | pages= 214-26 | pmid=10623712 | doi=10.1200/JCO.2000.18.1.214 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10623712  }} </ref>
 
=== Manifestations of WM ===
Following is a list of WM manifestations with attributable causes:<ref name="pmid15735132">{{cite journal| author=Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP| title=Diagnosis and management of Waldenstrom's macroglobulinemia. | journal=J Clin Oncol | year= 2005 | volume= 23 | issue= 7 | pages= 1564-77 | pmid=15735132 | doi=10.1200/JCO.2005.03.144 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15735132  }} </ref><ref name="DimopoulosPanayiotidis2000">{{cite journal|last1=Dimopoulos|first1=Meletios A.|last2=Panayiotidis|first2=Panayiotis|last3=Moulopoulos|first3=Lia A.|last4=Sfikakis|first4=Petros|last5=Dalakas|first5=Marinos|title=Waldenström’s Macroglobulinemia: Clinical Features, Complications, and Management|journal=Journal of Clinical Oncology|volume=18|issue=1|year=2000|pages=214–214|issn=0732-183X|doi=10.1200/JCO.2000.18.1.214}}</ref><ref name="pmid3110508">{{cite journal| author=Kyle RA, Garton JP| title=The spectrum of IgM monoclonal gammopathy in 430 cases. | journal=Mayo Clin Proc | year= 1987 | volume= 62 | issue= 8 | pages= 719-31 | pmid=3110508 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3110508  }} </ref><ref name="pmid12883242">{{cite journal| author=Lin P, Bueso-Ramos C, Wilson CS, Mansoor A, Medeiros LJ| title=Waldenstrom macroglobulinemia involving extramedullary sites: morphologic and immunophenotypic findings in 44 patients. | journal=Am J Surg Pathol | year= 2003 | volume= 27 | issue= 8 | pages= 1104-13 | pmid=12883242 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12883242  }} </ref><ref name="pmid8123836">{{cite journal| author=Dimopoulos MA, Alexanian R| title=Waldenstrom's macroglobulinemia. | journal=Blood | year= 1994 | volume= 83 | issue= 6 | pages= 1452-9 | pmid=8123836 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8123836  }} </ref><ref name="pmid6767276">{{cite journal| author=Fudenberg HH, Virella G| title=Multiple myeloma and Waldenström macroglobulinemia: unusual presentations. | journal=Semin Hematol | year= 1980 | volume= 17 | issue= 1 | pages= 63-79 | pmid=6767276 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6767276  }} </ref><ref name="pmid9671845">{{cite journal| author=Fadil A, Taylor DE| title=The lung and Waldenström's macroglobulinemia. | journal=South Med J | year= 1998 | volume= 91 | issue= 7 | pages= 681-5 | pmid=9671845 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9671845  }} </ref><ref name="pmid9198063">{{cite journal| author=Veltman GA, van Veen S, Kluin-Nelemans JC, Bruijn JA, van Es LA| title=Renal disease in Waldenström's macroglobulinaemia. | journal=Nephrol Dial Transplant | year= 1997 | volume= 12 | issue= 6 | pages= 1256-9 | pmid=9198063 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9198063  }} </ref><ref name="pmid10188670">{{cite journal| author=Daoud MS, Lust JA, Kyle RA, Pittelkow MR| title=Monoclonal gammopathies and associated skin disorders. | journal=J Am Acad Dermatol | year= 1999 | volume= 40 | issue= 4 | pages= 507-35; quiz 536-8 | pmid=10188670 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10188670  }} </ref><ref name="pmid6801795">{{cite journal| author=Orellana J, Friedman AH| title=Ocular manifestations of multiple myeloma, Waldenström's macroglobulinemia and benign monoclonal gammopathy. | journal=Surv Ophthalmol | year= 1981 | volume= 26 | issue= 3 | pages= 157-69 | pmid=6801795 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6801795  }} </ref><ref name="pmid9686227">{{cite journal| author=Civit T, Coulbois S, Baylac F, Taillandier L, Auque J| title=[Waldenström's macroglobulinemia and cerebral lymphoplasmocytic proliferation: Bing and Neel syndrome. Apropos of a new case]. | journal=Neurochirurgie | year= 1997 | volume= 43 | issue= 4 | pages= 245-9 | pmid=9686227 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9686227  }} </ref><ref name="pmid10357087">{{cite journal| author=Kwaan HC, Bongu A| title=The hyperviscosity syndromes. | journal=Semin Thromb Hemost | year= 1999 | volume= 25 | issue= 2 | pages= 199-208 | pmid=10357087 | doi=10.1055/s-2007-994921 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10357087  }} </ref><ref name="pmid3094151">{{cite journal| author=Farhangi M, Merlini G| title=The clinical implications of monoclonal immunoglobulins. | journal=Semin Oncol | year= 1986 | volume= 13 | issue= 3 | pages= 366-79 | pmid=3094151 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3094151  }} </ref><ref name="pmid2104668">{{cite journal| author=| title=Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 3-1990. A 66-year-old woman with Waldenström's macroglobulinemia, diarrhea, anemia, and persistent gastrointestinal bleeding. | journal=N Engl J Med | year= 1990 | volume= 322 | issue= 3 | pages= 183-92 | pmid=2104668 | doi=10.1056/NEJM199001183220308 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2104668  }} </ref><ref name="GertzKyle1993">{{cite journal|last1=Gertz|first1=M A|last2=Kyle|first2=R A|last3=Noel|first3=P|title=Primary systemic amyloidosis: a rare complication of immunoglobulin M monoclonal gammopathies and Waldenström's macroglobulinemia.|journal=Journal of Clinical Oncology|volume=11|issue=5|year=1993|pages=914–920|issn=0732-183X|doi=10.1200/JCO.1993.11.5.914}}</ref><ref name="pmid12720162">{{cite journal| author=Gertz MA, Kyle RA| title=Amyloidosis with IgM monoclonal gammopathies. | journal=Semin Oncol | year= 2003 | volume= 30 | issue= 2 | pages= 325-8 | pmid=12720162 | doi=10.1053/sonc.2003.50060 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12720162  }} </ref><ref name="pmid11530809">{{cite journal| author=Gardyn J, Schwartz A, Gal R, Lewinski U, Kristt D, Cohen AM| title=Waldenström's macroglobulinemia associated with AA amyloidosis. | journal=Int J Hematol | year= 2001 | volume= 74 | issue= 1 | pages= 76-8 | pmid=11530809 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11530809  }} </ref><ref name="pmid9603799">{{cite journal| author=Ropper AH, Gorson KC| title=Neuropathies associated with paraproteinemia. | journal=N Engl J Med | year= 1998 | volume= 338 | issue= 22 | pages= 1601-7 | pmid=9603799 | doi=10.1056/NEJM199805283382207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9603799  }} </ref><ref name="pmid11556684">{{cite journal| author=Vital A| title=Paraproteinemic neuropathies. | journal=Brain Pathol | year= 2001 | volume= 11 | issue= 4 | pages= 399-407 | pmid=11556684 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11556684  }} </ref><ref name="pmid6807086">{{cite journal| author=Crisp D, Pruzanski W| title=B-cell neoplasms with homogeneous cold-reacting antibodies (cold agglutinins). | journal=Am J Med | year= 1982 | volume= 72 | issue= 6 | pages= 915-22 | pmid=6807086 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6807086  }} </ref><ref name="pmid6777101">{{cite journal| author=Lindström FD, Hed J, Eneström S| title=Renal pathology of Waldenström's macroglobulinaemia with monoclonal antiglomerular antibodies and nephrotic syndrome. | journal=Clin Exp Immunol | year= 1980 | volume= 41 | issue= 2 | pages= 196-204 | pmid=6777101 | doi= | pmc=1537007 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6777101  }} </ref><ref name="pmid15019332">{{cite journal| author=Sen HN, Chan CC, Caruso RC, Fariss RN, Nussenblatt RB, Buggage RR| title=Waldenström's macroglobulinemia-associated retinopathy. | journal=Ophthalmology | year= 2004 | volume= 111 | issue= 3 | pages= 535-9 | pmid=15019332 | doi=10.1016/j.ophtha.2003.05.036 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15019332  }} </ref>
 
{| class="wikitable"
|+ '''Manifestations of WM'''
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Cause
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Manifestations
|-
| style="background:#DCDCDC;" align="center" + |Tumor infiltration
| style="background:#F5F5F5;" align="center" + |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.
|-
| style="background:#DCDCDC;" align="center" + |Circulating monoclonal IgM
| style="background:#F5F5F5;" align="center" + |Hyperviscosity syndrome, Type 1 Cryoglobulinemia (consists of Raynaud's phenomenon, skin ulcers & necrosis and cold urticaria), frequent bruising, prolonged bleeding and clotting times.
|-
| style="background:#DCDCDC;" align="center" + |IgM deposition into tissues
| style="background:#F5F5F5;" align="center" + |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.
|-
| style="background:#DCDCDC;" align="center" + |Amyloidogenic properties of IgM
| style="background:#F5F5F5;" align="center" + |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.
|-
| style="background:#DCDCDC;" align="center" + |Autoantibody activity of IgM
| style="background:#F5F5F5;" align="center" + |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:<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><ref name="pmid12720138">{{cite journal| author=Merlini G, Baldini L, Broglia C, Comelli M, Goldaniga M, Palladini G et al.| title=Prognostic factors in symptomatic Waldenstrom's macroglobulinemia. | journal=Semin Oncol | year= 2003 | volume= 30 | issue= 2 | pages= 211-5 | pmid=12720138 | doi=10.1053/sonc.2003.50064 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12720138  }} </ref>
* [[B symptoms|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).
*[[Blurred vision|Blurry vision]] or blind spots.
*Abdominal pain.
 
==== Less Common Symptoms ====
Less common symptoms 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><ref name="pmid12720138">{{cite journal| author=Merlini G, Baldini L, Broglia C, Comelli M, Goldaniga M, Palladini G et al.| title=Prognostic factors in symptomatic Waldenstrom's macroglobulinemia. | journal=Semin Oncol | year= 2003 | volume= 30 | issue= 2 | pages= 211-5 | pmid=12720138 | doi=10.1053/sonc.2003.50064 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12720138  }} </ref>
*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|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:<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>
*Symptoms resembling those of [[stroke]].
* Retinal [[hemorrhage]] with [[Blurred vision|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.<ref name="aa">Waldenström's macroglobulinemia. MedlinePlus (2015) https://www.nlm.nih.gov/medlineplus/ency/article/000588.htm Accessed on November 15th, 2015</ref>
 
====Skin====
*Maculopapular lesions, plaques, or nodules.<ref name="pmid12883242">{{cite journal| author=Lin P, Bueso-Ramos C, Wilson CS, Mansoor A, Medeiros LJ| title=Waldenstrom macroglobulinemia involving extramedullary sites: morphologic and immunophenotypic findings in 44 patients. | journal=Am J Surg Pathol | year= 2003 | volume= 27 | issue= 8 | pages= 1104-13 | pmid=12883242 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12883242  }} </ref><ref name="pmid10188670">{{cite journal| author=Daoud MS, Lust JA, Kyle RA, Pittelkow MR| title=Monoclonal gammopathies and associated skin disorders. | journal=J Am Acad Dermatol | year= 1999 | volume= 40 | issue= 4 | pages= 507-35; quiz 536-8 | pmid=10188670 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10188670  }} </ref><ref name="pmid9198063">{{cite journal| author=Veltman GA, van Veen S, Kluin-Nelemans JC, Bruijn JA, van Es LA| title=Renal disease in Waldenström's macroglobulinaemia. | journal=Nephrol Dial Transplant | year= 1997 | volume= 12 | issue= 6 | pages= 1256-9 | pmid=9198063 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9198063  }} </ref>
*[[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.<ref name="pmid10188670">{{cite journal| author=Daoud MS, Lust JA, Kyle RA, Pittelkow MR| title=Monoclonal gammopathies and associated skin disorders. | journal=J Am Acad Dermatol | year= 1999 | volume= 40 | issue= 4 | pages= 507-35; quiz 536-8 | pmid=10188670 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10188670  }} </ref>
 
====HEENT====
*[[Pallor]].
*[[Papilledema]].
*Malignant vitreitis.<ref name="pmid6801795">{{cite journal| author=Orellana J, Friedman AH| title=Ocular manifestations of multiple myeloma, Waldenström's macroglobulinemia and benign monoclonal gammopathy. | journal=Surv Ophthalmol | year= 1981 | volume= 26 | issue= 3 | pages= 157-69 | pmid=6801795 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6801795  }} </ref>
*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.<ref name="pmid16044069">{{cite journal| author=Pilon AF, Rhee PS, Messner LV| title=Bilateral, persistent serous macular detachments with Waldenström's macroglobulinemia. | journal=Optom Vis Sci | year= 2005 | volume= 82 | issue= 7 | pages= 573-8 | pmid=16044069 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16044069  }} </ref><ref name="pmid2507620">{{cite journal| author=Avashia JH, Fath DF| title=Bilateral central retinal vein occlusion in Waldenström's macroglobulinemia. | journal=J Am Optom Assoc | year= 1989 | volume= 60 | issue= 9 | pages= 657-8 | pmid=2507620 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2507620  }} </ref><ref name="pmid3081619">{{cite journal| author=Goen TM, Terry JE| title=Mid-peripheral hemorrhages secondary to Waldenström's macroglobulinemia. | journal=J Am Optom Assoc | year= 1986 | volume= 57 | issue= 2 | pages= 109-12 | pmid=3081619 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3081619  }} </ref>
 
====Neck====
*[[Lymphadenopathy]].<ref name="DimopoulosPanayiotidis2000">{{cite journal|last1=Dimopoulos|first1=Meletios A.|last2=Panayiotidis|first2=Panayiotis|last3=Moulopoulos|first3=Lia A.|last4=Sfikakis|first4=Petros|last5=Dalakas|first5=Marinos|title=Waldenström’s Macroglobulinemia: Clinical Features, Complications, and Management|journal=Journal of Clinical Oncology|volume=18|issue=1|year=2000|pages=214–214|issn=0732-183X|doi=10.1200/JCO.2000.18.1.214}}</ref>
*[[Jugular venous distension]].
 
====Respiratory====
*[[Pleural effusion]] - in 3-5% of patients.<ref name="pmid9671845">{{cite journal| author=Fadil A, Taylor DE| title=The lung and Waldenström's macroglobulinemia. | journal=South Med J | year= 1998 | volume= 91 | issue= 7 | pages= 681-5 | pmid=9671845 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9671845  }} </ref>
*[[Rales]] on auscultation.
*Pulmonary infiltrates, nodules, masses.<ref name="pmid9671845">{{cite journal| author=Fadil A, Taylor DE| title=The lung and Waldenström's macroglobulinemia. | journal=South Med J | year= 1998 | volume= 91 | issue= 7 | pages= 681-5 | pmid=9671845 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9671845  }} </ref>
 
====Cardiovascular system====
*[[Apical impulse|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.<ref name="cns">{{cite journal |vauthors=Coimbra J, Costa AP, Pita F, Rosado P, de Almeida LB |title=[Neuropathy in Waldenstrom's macroglobulinemia] |language=Portuguese |journal=Acta Med Port |volume=8 |issue=4 |pages=253–7 |year=1995 |pmid=7625222 |doi= |url=}}</ref>
 
===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===
A [[Bone marrow aspiration|bone marrow aspirate]] is essential in the diagnosis of Waldenström macroglobulinemia.
 
Findings suggestive of Waldenström macroglobulinemia include:<ref name="pmid18555588">{{cite journal| author=Leleu X, Roccaro AM, Moreau AS, Dupire S, Robu D, Gay J et al.| title=Waldenstrom macroglobulinemia. | journal=Cancer Lett | year= 2008 | volume= 270 | issue= 1 | pages= 95-107 | pmid=18555588 | doi=10.1016/j.canlet.2008.04.040 | pmc=3133633 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18555588  }} </ref>
* 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. <ref name="pmid18555588">{{cite journal| author=Leleu X, Roccaro AM, Moreau AS, Dupire S, Robu D, Gay J et al.| title=Waldenstrom macroglobulinemia. | journal=Cancer Lett | year= 2008 | volume= 270 | issue= 1 | pages= 95-107 | pmid=18555588 | doi=10.1016/j.canlet.2008.04.040 | pmc=3133633 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18555588  }} </ref>
 
Findings on the biopsy suggestive of Waldenström macroglobulinemia include:<ref name="pmid18555588">{{cite journal| author=Leleu X, Roccaro AM, Moreau AS, Dupire S, Robu D, Gay J et al.| title=Waldenstrom macroglobulinemia. | journal=Cancer Lett | year= 2008 | volume= 270 | issue= 1 | pages= 95-107 | pmid=18555588 | doi=10.1016/j.canlet.2008.04.040 | pmc=3133633 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18555588  }} </ref>
* Hypercellular and [[Infiltration (medical)|infiltrated]] with [[lymphoid]] and [[Plasmacytoid|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:<ref name="pmid1872571">{{cite journal| author=Riches PG, Sheldon J, Smith AM, Hobbs JR| title=Overestimation of monoclonal immunoglobulin by immunochemical methods. | journal=Ann Clin Biochem | year= 1991 | volume= 28 ( Pt 3) | issue=  | pages= 253-9 | pmid=1872571 | doi=10.1177/000456329102800310 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1872571  }} </ref>
*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|monoclonal protein]], in addition to determining its type.<ref name="pmid1872571">{{cite journal| author=Riches PG, Sheldon J, Smith AM, Hobbs JR| title=Overestimation of monoclonal immunoglobulin by immunochemical methods. | journal=Ann Clin Biochem | year= 1991 | volume= 28 ( Pt 3) | issue=  | pages= 253-9 | pmid=1872571 | doi=10.1177/000456329102800310 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1872571  }} </ref>
 
===Electrocardiogram===
There are no ECG findings associated with Waldenström macroglobulinemia.
 
===X-ray===
Key Chest X-Ray Findings in Waldenström's Macroglobulinemia:
*[[Chest X-ray|Chest x-ray]] may be used to evaluate the following:<ref name="X-ray">{{cite journal |vauthors=Rausch PG, Herion JC |title=Pulmonary manifestations of Waldenstrom macroglobulinemia |journal=Am. J. Hematol. |volume=9 |issue=2 |pages=201–9 |year=1980 |pmid=6776807 |doi= |url=}}</ref>
**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.<ref name="ct">{{cite journal |vauthors=Banwait R, O'Regan K, Campigotto F, Harris B, Yarar D, Bagshaw M, Leleu X, Leduc R, Ramaiya N, Weller E, Ghobrial IM |title=The role of 18F-FDG PET/CT imaging in Waldenstrom macroglobulinemia |journal=Am. J. Hematol. |volume=86 |issue=7 |pages=567–72 |year=2011 |pmid=21681781 |doi=10.1002/ajh.22044 |url=}}</ref>
*Waldenström's macroglobulinemia shows evidence of [[lymphadenopathy]], and [[hepatosplenomegaly]].<ref name="ct" />
*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|Nerve conduction]] study''' and '''[[electromyography]]''', which demonstrates:<ref name="ser">{{cite journal |vauthors=Nobile-Orazio E, Marmiroli P, Baldini L, Spagnol G, Barbieri S, Moggio M, Polli N, Polli E, Scarlato G |title=Peripheral neuropathy in macroglobulinemia: incidence and antigen-specificity of M proteins |journal=Neurology |volume=37 |issue=9 |pages=1506–14 |year=1987 |pmid=2442666 |doi= |url=}}</ref>
**[[Demyelination]] with sensory involvement more than motor
*'''[[Fundoscopy]]''', which demonstrates:<ref name="pmid27378193">{{cite journal| author=Castillo JJ, Garcia-Sanz R, Hatjiharissi E, Kyle RA, Leleu X, McMaster M et al.| title=Recommendations for the diagnosis and initial evaluation of patients with Waldenström Macroglobulinaemia: A Task Force from the 8th International Workshop on Waldenström Macroglobulinaemia. | journal=Br J Haematol | year= 2016 | volume= 175 | issue= 1 | pages= 77-86 | pmid=27378193 | doi=10.1111/bjh.14196 | pmc=5154335 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27378193  }} </ref>
**Dilated, segmented, and tortuous [[retinal veins]] giving a "sausage link" appearance
***Useful in patients with suspected [[hyperviscosity syndrome]]
* '''Plasma viscosity''', which demonstrates:<ref name="pmid4014299">{{cite journal| author=Crawford J, Cox EB, Cohen HJ| title=Evaluation of hyperviscosity in monoclonal gammopathies. | journal=Am J Med | year= 1985 | volume= 79 | issue= 1 | pages= 13-22 | pmid=4014299 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4014299  }} </ref>
**Values > 1.5 centipoise
***Should be measured in patients presenting with signs and symptoms suggestive of hyperviscosity syndrome or whenever the monoclonal [[Immunoglobulin M|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<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>


==Treatment==
==Treatment==
There are several different options for treating Waldenström macroglobulinemia depending on stage of the disease:<ref name="Tx">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 </ref>
[[Lymphoplasmacytic lymphoma medical therapy|Medical Therapy]] | [[Lymphoplasmacytic lymphoma surgery|Surgery]] | [[Lymphoplasmacytic lymphoma primary prevention|Primary Prevention]] | [[Lymphoplasmacytic lymphoma secondary prevention|Secondary Prevention]] | [[Lymphoplasmacytic lymphoma cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Lymphoplasmacytic lymphoma future or investigational therapies|Future or Investigational Therapies]]
 
====Asymptomatic/Smoldering Waldenström's Macroglobulinemia====
There is no treatment for asymptomatic Waldenström macroglobulinemia. Asymptomatic waldenström's macroglobulinemia can be monitored every 3-6 months.<ref name="BM">Waldenström's macroglobulinemia. Patient (2015)http://patient.info/doctor/waldenstroms-macroglobulinaemia-pro Accessed on November 10, 2015</ref> Active surveillance includes monitoring of the following laboratory parameters:
*Complete blood count ([[Complete blood count|CBC]]) with differential
*Complete metabolic panel ([[CMP-N-acetylneuraminate monooxygenase|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.<ref name="ADR">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</ref>
 
*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]]
:*[[Cytopenia|Cytopenias]]
:*[[Hyperviscosity syndrome]]
:*[[Neuropathy]]
:*Constitutional symptoms
 
{| style="border: 0px; font-size: 90%; margin: 3px; width: 800px"
| valign="top" |
|+
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Treatment Regimen<ref name="ADR">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</ref>
}}
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Drugs}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|Side effects}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
'''[[CHOP-R regimen]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Cyclophosphamide]]
*[[Doxorubicin]]
*[[Vincristine]]
*[[Prednisone]]
*[[Rituximab]]
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Nausea]]
*[[Alopecia]]
*[[Granulocytopenia]]
*[[Cardiotoxicity]]
*[[Mucositis]]
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
'''[[Ibrutinib]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Ibrutinib]]
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Fatigue]]
*[[Cytopenia]]
*[[Bleeding]]
*[[Atrial fibrillation]]
*[[Opportunistic infection]]
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
'''[[Rituximab]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Rituximab]]
| style="padding: 5px 5px; background: #F5F5F5;" |
*Infusion related reaction
*[[Hepatitis B]] reaction
*Progressive multi-focal leukoencephaloptahy
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
'''FR regimen'''
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Fludarabine]]
*[[Rituximab]]
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Neutropenia]] (63%)
*[[Thrombocytopenia]]
*[[Pneumonia]]
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
'''BDR regimen'''
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Bortezomib]]
*[[Dexamethasone]]
*[[Rituximab]]
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Peripheral neuropathy]] - reversible in 61% of patients
*[[Infections]]
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
'''DRC regimen'''
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Dexamethasone]]
*[[Rituximab]]
*[[Cyclophosphamide]]
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Neutropenia]]
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
'''CR regimen'''
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Cladribine]]
*[[Rituximab]]
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Anemia]]
*Neurological symptoms
*Symptomatic [[cryoglobulinemia]]
*[[Thrombocytopenia]]
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
'''IR regimen'''
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[Ibrutinib]]
*[[Rituximab]]
| style="padding: 5px 5px; background: #F5F5F5;" |
*[[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.<ref name="ADR">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</ref>
*[[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.<ref name="sure">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</ref>
===Primary Prevention===
Primary prevention of Waldenström macroglobulinemia depends on the type of risk factor causing the disease.<ref name="PP">Waldenström's macroglobulinemia. American Cancer Society. (2015)http://www.cancer.org/cancer/waldenstrommacroglobulinemia/detailedguide/waldenstrom-macroglobulinemia-prevention Accessed on November 11, 2015</ref>
===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.


==Case Studies==
[[Lymphoplasmacytic lymphoma case study one|Case #1]]


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
[[Category: (name of the system)]]
==References==
{{reflist|2}}

Latest revision as of 20:45, 19 August 2020

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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: Plasmacytoid lymphocytic lymphoma; Familial Waldenström's macroglobulinemia; Primary macroglobulinemia; Hyperviscosity syndrome; Lymphoplasmacytoid lymphoma

Overview

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