Advertisement

A practical guide to laboratory investigations at diagnosis and follow up in Waldenström macroglobulinaemia: recommendations from the Medical and Scientific Advisory Group, Myeloma Australia, the Pathology Sub-committee of the Lymphoma and Related Diseases Registry and the Australasian Association of Clinical Biochemists Monoclonal Gammopathy Working Group

  • M. Gohar Maqbool
    Affiliations
    Department of Haematology, ACT Pathology, Canberra Hospital, ACT, Australia

    ANU Medical School, College of Medicine and Health, Australian National University, Canberra, ACT, Australia
    Search for articles by this author
  • Constantine S. Tam
    Affiliations
    Peter MacCallum Cancer Center, St Vincent's Hospital and University of Melbourne, Melbourne, Vic, Australia
    Search for articles by this author
  • Ian M. Morison
    Affiliations
    Southern Community Laboratories, Dunedin, New Zealand

    Australasian Association of Clinical Biochemists (AACB) Monoclonal Gammopathy Working Group (MGWG), Australia
    Search for articles by this author
  • David Simpson
    Affiliations
    Department of Haematology, Waitemata District Health Board, Auckland, New Zealand

    Medical and Scientific Advisory Group, Myeloma Australia
    Search for articles by this author
  • Peter Mollee
    Affiliations
    Australasian Association of Clinical Biochemists (AACB) Monoclonal Gammopathy Working Group (MGWG), Australia

    Medical and Scientific Advisory Group, Myeloma Australia

    Department of Haematology, Princess Alexandra Hospital and University of Queensland Medical School, Brisbane, Qld, Australia
    Search for articles by this author
  • Hans Schneider
    Affiliations
    Australasian Association of Clinical Biochemists (AACB) Monoclonal Gammopathy Working Group (MGWG), Australia

    Alfred Pathology Service and Monash University, Melbourne, Vic, Australia
    Search for articles by this author
  • Henry Chan
    Affiliations
    Department of Haematology, Waitemata District Health Board, Auckland, New Zealand

    Medical and Scientific Advisory Group, Myeloma Australia
    Search for articles by this author
  • Surender Juneja
    Affiliations
    Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, Vic, Australia

    Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia
    Search for articles by this author
  • Yasmin Harvey
    Affiliations
    Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia

    Sullivan Nicolaides Pathology, Brisbane, Qld, Australia
    Search for articles by this author
  • Lakshmi Nath
    Affiliations
    Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia

    Department of Haematology and Transfusion Medicine, Clinpath Pathology, Adelaide, SA, Australia
    Search for articles by this author
  • Pravin Hissaria
    Affiliations
    Australasian Association of Clinical Biochemists (AACB) Monoclonal Gammopathy Working Group (MGWG), Australia

    Royal Adelaide Hospital, University of Adelaide and SA Pathology, Adelaide, SA, Australia
    Search for articles by this author
  • H. Miles Prince
    Affiliations
    Medical and Scientific Advisory Group, Myeloma Australia

    Epworth Healthcare, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Vic, Australia
    Search for articles by this author
  • Helen Wordsworth
    Affiliations
    Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia

    Sullivan Nicolaides Pathology, Brisbane, Qld, Australia
    Search for articles by this author
  • Stephen Opat
    Affiliations
    Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia

    Department of Haematology, Monash Health, Melbourne, Vic, Australia
    Search for articles by this author
  • Dipti Talaulikar
    Correspondence
    Address for correspondence: Dr Dipti Talaulikar, ACT Pathology, Canberra Hospital and ANU Medical School, Canberra, ACT, 2605, Australia.
    Affiliations
    Department of Haematology, ACT Pathology, Canberra Hospital, ACT, Australia

    ANU Medical School, College of Medicine and Health, Australian National University, Canberra, ACT, Australia

    Medical and Scientific Advisory Group, Myeloma Australia

    Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia
    Search for articles by this author
Published:January 02, 2020DOI:https://doi.org/10.1016/j.pathol.2019.11.002

      Summary

      Waldenström macroglobulinaemia (WM) is an indolent non-Hodgkin lymphoma which usually presents with symptoms related to infiltration of bone marrow or other tissues like lymph nodes, liver or spleen and has certain unusual clinical manifestations, e.g., renal and central nervous system (CNS) involvement. It also has an array of laboratory features including hypersecretion of IgM, cryoglobulinaemia, increased plasma viscosity and identification of mutated MYD88L265P in more than 90% of cases. In this review, we aim to provide a guide to the laboratory investigations recommended for WM at initial diagnosis and at follow-up. A discussion on the nuances of diagnosis and differential diagnoses is followed by bone marrow (BM) assessment, measurement of paraprotein and other ancillary investigations. Recommendations are provided on laboratory work-up at diagnosis, in the asymptomatic follow-up phase, and during and post-treatment. Finally, we briefly discuss the implications of laboratory diagnosis in regard to recruitment and monitoring on clinical trials.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Pathology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Sekhar J.
        • Sanfilippo K.
        • Zhang Q.
        • Trinkaus K.
        • Vij R.
        • Morgensztern D.
        Waldenstrom macroglobulinemia: a surveillance, epidemiology, and end results database review from 1988 to 2005.
        Leuk Lymphoma. 2012; 53: 1625-1626
        • Varettoni M.
        • Zibellini S.
        • Defrancesco I.
        • et al.
        Pattern of somatic mutations in patients with Waldenstrom macroglobulinemia or IgM monoclonal gammopathy of undetermined significance.
        Haematologica. 2017; 102: 2077-2085
        • Kapoor P.
        • Ansell S.M.
        • Fonseca R.
        • et al.
        Diagnosis and management of Waldenstrom macroglobulinemia: mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines 2016.
        JAMA Oncol. 2017; 3: 1257-1265
        • Paiva B.
        • Corchete L.A.
        • Vidriales M.B.
        • et al.
        The cellular origin and malignant transformation of Waldenstrom macroglobulinemia.
        Blood. 2015; 125: 2370-2380
      1. Swerdlow S.H. Harris N.L. Jaffe E.S. Plieri S.A. Stein H. Thiele J. WHO Classification of Tumours of Haemopoietic and Lymphoid Tissues. IARC, Lyon2017
        • Kyle R.A.
        • San-Miguel J.F.
        • Mateos M.V.
        • Rajkumar S.V.
        Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma.
        Hematol Oncol Clin North Am. 2014; 28: 775-790
        • Kyle R.A.
        • Therneau T.M.
        • Rajkumar S.V.
        • et al.
        Long-term follow-up of IgM monoclonal gammopathy of undetermined significance.
        Blood. 2003; 102: 3759-3764
        • Tsai H.T.
        • Caporaso N.E.
        • Kyle R.A.
        • et al.
        Evidence of serum immunoglobulin abnormalities up to 9.8 years before diagnosis of chronic lymphocytic leukemia: a prospective study.
        Blood. 2009; 114: 4928-4932
        • Dimopoulos M.A.
        • Panayiotidis P.
        • Moulopoulos L.A.
        • Sfikakis P.
        • Dalakas M.
        Waldenstrom's macroglobulinemia: clinical features, complications, and management.
        J Clin Oncol. 2000; 18: 214-226
        • Baehring J.M.
        • Hochberg E.P.
        • Raje N.
        • Ulrickson M.
        • Hochberg F.H.
        Neurological manifestations of Waldenstrom macroglobulinemia.
        Nat Clin Pract Neurol. 2008; 4: 547-556
        • Lee S.H.
        • Erber W.N.
        • Porwit A.
        • Tomonaga M.
        • Peterson L.C.
        ICSH guidelines for the standardization of bone marrow specimens and reports.
        Int J Lab Hematol. 2008; 30: 349-364
        • Owen R.G.
        • Treon S.P.
        • Al-Katib A.
        • et al.
        Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.
        Semin Oncol. 2003; 30: 110-115
        • Tournilhac O.
        • Santos D.D.
        • Xu L.
        • et al.
        Mast cells in Waldenstrom's macroglobulinemia support lymphoplasmacytic cell growth through CD154/CD40 signaling.
        Ann Oncol. 2006; 17: 1275-1282
        • Naderi N.
        • Yang D.T.
        Lymphoplasmacytic lymphoma and Waldenstrom macroglobulinemia.
        Arch Pathol Lab Med. 2013; 137: 580-585
        • Sargent R.L.
        • Cook J.R.
        • Aguilera N.I.
        • et al.
        Fluorescence immunophenotypic and interphase cytogenetic characterization of nodal lymphoplasmacytic lymphoma.
        Am J Surg Pathol. 2008; 32: 1643-1653
        • Garcia-Sanz R.
        • Jimenez C.
        • Puig N.
        • et al.
        Origin of Waldenstrom's macroglobulinaemia.
        Best Pract Res Clin Haematol. 2016; 29: 136-147
        • de Tute R.M.
        • Rawstron A.C.
        • Owen R.G.
        Immunoglobulin M concentration in Waldenstrom macroglobulinemia: correlation with bone marrow B cells and plasma cells.
        Clin Lymphoma Myeloma Leuk. 2013; 13: 211-213
        • Pasricha S.R.
        • Juneja S.K.
        • Westerman D.A.
        • Came N.A.
        Bone-marrow plasma cell burden correlates with IgM paraprotein concentration in Waldenstrom macroglobulinaemia.
        J Clin Pathol. 2011; 64: 520-523
        • Sun T.
        Flow Cytometry, Immunohistochemistry, and Molecular Genetics for Hematologic Neoplasms.
        Lippincott Williams & Wilkins, Philadelphia2011
        • Ocio E.M.
        • Schop R.F.
        • Gonzalez B.
        • et al.
        6q deletion in Waldenstrom macroglobulinemia is associated with features of adverse prognosis.
        Br J Haematol. 2007; 136: 80-86
        • Nguyen-Khac F.
        • Lambert J.
        • Chapiro E.
        • et al.
        Chromosomal aberrations and their prognostic value in a series of 174 untreated patients with Waldenstrom's macroglobulinemia.
        Haematologica. 2013; 98: 649-654
        • Treon S.P.
        • Xu L.
        • Yang G.
        • et al.
        MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia.
        N Engl J Med. 2012; 367: 826-833
        • Varettoni M.
        • Arcaini L.
        • Zibellini S.
        • et al.
        Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms.
        Blood. 2013; 121: 2522-2528
        • Treon S.P.
        • Gustine J.
        • Xu L.
        • et al.
        MYD88 wild-type Waldenstrom Macroglobulinaemia: differential diagnosis, risk of histological transformation, and overall survival.
        Br J Haematol. 2018; 180: 374-380
        • Abeykoon J.P.
        • Paludo J.
        • King R.L.
        • et al.
        MYD88 mutation status does not impact overall survival in Waldenstrom macroglobulinemia.
        Am J Hematol. 2018; 93: 187-194
        • Hunter Z.R.
        • Xu L.
        • Tsakmaklis N.
        • et al.
        Insights into the genomic landscape of MYD88 wild-type Waldenstrom macroglobulinemia.
        Blood Adv. 2018; 2: 2937-2946
        • Xu L.
        • Hunter Z.R.
        • Yang G.
        • et al.
        MYD88 L265P in Waldenstrom macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction.
        Blood. 2013; 121: 2051-2058
        • Poulain S.
        • Roumier C.
        • Galiegue-Zouitina S.
        • et al.
        Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia.
        Am J Hematol. 2013; 88: 948-954
        • Hunter Z.R.
        • Xu L.
        • Yang G.
        • et al.
        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.
        Blood. 2014; 123: 1637-1646
        • Poulain S.
        • Roumier C.
        • Venet-Caillault A.
        • et al.
        Genomic landscape of CXCR4 mutations in Waldenström macroglobulinemia.
        Clin Cancer Res. 2016; 22: 1480-1488
        • Treon S.P.
        • Xu L.
        • Hunter Z.
        MYD88 Mutations and response to ibrutinib in Waldenström's macroglobulinemia.
        N Engl J Med. 2015; 373: 584-586
        • Treon S.P.
        • Tsakmaklis N.
        • Meid K.
        • et al.
        Mutated MYD88 zygosity and CXCR4 mutation status are important determinants of ibrutinib response and progression free survival in Waldenstrom's macroglobulinemia.
        Blood. 2016; 128: 2984
        • Castillo J.J.
        • Xu L.
        • Gustine J.N.
        • et al.
        CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenström macroglobulinaemia treated with ibrutinib.
        Br J Haematol. 2019; 187: 356-363
        • Poulain S.
        • Boyle E.M.
        • Roumier C.
        • et al.
        MYD88 L265P mutation contributes to the diagnosis of Bing Neel syndrome.
        Br J Haematol. 2014; 167: 506-513
        • Bagratuni T.
        • Ntanasis-Stathopoulos I.
        • Gavriatopoulou M.
        • et al.
        Detection of MYD88 and CXCR4 mutations in cell-free DNA of patients with IgM monoclonal gammopathies.
        Leukemia. 2018; 32: 2617-2625
        • Yeh P.
        • Hunter T.
        • Sinha D.
        • et al.
        Circulating tumour DNA reflects treatment response and clonal evolution in chronic lymphocytic leukaemia.
        Nat Commun. 2017; 8: 14756
        • Murray D.L.
        • Ryu E.
        • Snyder M.R.
        • Katzmann J.A.
        Quantitation of serum monoclonal proteins: relationship between agarose gel electrophoresis and immunonephelometry.
        Clin Chem. 2009; 55: 1523-1529
        • Boyle E.
        • Manier S.
        • Lejeune J.
        • et al.
        IgMkappa and IgMlambda measurements for the assessment of patients with Waldenstrom's macroglobulinaemia.
        Clin Cancer Res. 2016; 22: 5152-5158
        • Gustine J.N.
        • Meid K.
        • Dubeau T.
        • et al.
        Serum IgM level as predictor of symptomatic hyperviscosity in patients with Waldenstrom macroglobulinaemia.
        Br J Haematol. 2017; 177: 717-725
        • Owen R.G.
        • Pratt G.
        • Auer R.L.
        • et al.
        Guidelines on the diagnosis and management of Waldenstrom macroglobulinaemia.
        Br J Haematol. 2014; 165: 316-333
        • Morel P.
        • Duhamel A.
        • Gobbi P.
        • et al.
        International prognostic scoring system for Waldenstrom macroglobulinemia.
        Blood. 2009; 113: 4163-4170
        • Treon S.P.
        • Tripsas C.K.
        • Ciccarelli B.T.
        • et al.
        Patients with Waldenstrom macroglobulinemia commonly present with iron deficiency and those with severely depressed transferrin saturation levels show response to parenteral iron administration.
        Clin Lymphoma Myeloma Leuk. 2013; 13: 241-243
        • Hivert B.
        • Caron C.
        • Petit S.
        • et al.
        Clinical and prognostic implications of low or high level of von Willebrand factor in patients with Waldenstrom macroglobulinemia.
        Blood. 2012; 120: 3214-3221
        • D'Sa S.
        • Kersten M.J.
        • Castillo J.J.
        • et al.
        Investigation and management of IgM and Waldenstrom-associated peripheral neuropathies: recommendations from the IWWM-8 consensus panel.
        Br J Haematol. 2017; 176: 728-742
        • Nobile-Orazio E.
        • Manfredini E.
        • Carpo M.
        • et al.
        Frequency and clinical correlates of anti-neural IgM antibodies in neuropathy associated with IgM monoclonal gammopathy.
        Ann Neurol. 1994; 36: 416-424
        • Hiemcke-Jiwa L.S.
        • Minnema M.C.
        • Radersma-van Loon J.H.
        • et al.
        The use of droplet digital PCR in liquid biopsies: a highly sensitive technique for MYD88 p.(L265P) detection in cerebrospinal fluid.
        Hematol Oncol. 2018; 36: 429-435
        • Giampaolo Merlini M.
        Amyloidosis associated with Waldenström disease or IgM MGUS.
        IWMF Torch. 2013; 14: 1-4
        • Sachchithanantham S.
        • Roussel M.
        • Palladini G.
        • et al.
        European collaborative study defining clinical profile outcomes and novel prognostic criteria in monoclonal immunoglobulin M-related light chain amyloidosis.
        J Clin Oncol. 2016; 34: 2037-2045
        • Fernandez de Larrea C.
        • Verga L.
        • Morbini P.
        • et al.
        A practical approach to the diagnosis of systemic amyloidoses.
        Blood. 2015; 125: 2239-2244
        • Gibbs S.
        • Mollee P.
        • on behalf of The Medical Scientific Advisory Group (MSAG) to the Myeloma Foundation Australia (MFA)
        Clinical practice guideline: systemic AL amyloidosis.
        Sep 2019 (cited Oct 2019)
        • Ghobrial I.M.
        Are you sure this is Waldenstrom macroglobulinemia?.
        Hematol Am Soc Hematol Educ Program. 2012; 2012: 586-594
        • Sun T.
        • Nordberg M.L.
        • Cotelingam J.D.
        • Veillon D.M.
        • Ryder J.
        Fluorescence in situ hybridization: method of choice for a definitive diagnosis of mantle cell lymphoma.
        Am J Hematol. 2003; 74: 78-84
        • García-Sanz R.
        • Montoto S.
        • Torrequebrada A.
        • et al.
        Waldenström macroglobulinaemia: presenting features and outcome in a series with 217 cases.
        Br J Haematol. 2001; 115: 575-582
        • Kyle R.A.
        • Treon S.P.
        • Alexanian R.
        • et al.
        Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.
        Semin Oncol. 2003; 30: 116-120
        • Owen R.G.
        • Kyle R.A.
        • Stone M.J.
        • et al.
        Response assessment in Waldenstrom macroglobulinaemia: update from the VIth international Workshop.
        Br J Haematol. 2013; 160: 171-176
        • Minnema M.C.
        • Kimby E.
        • D'Sa S.
        • et al.
        Guideline for the diagnosis, treatment and response criteria for Bing-Neel syndrome.
        Haematologica. 2017; 102: 43-51
        • Treon S.P.
        • Branagan A.R.
        • Hunter Z.
        • Santos D.
        • Tournhilac O.
        • Anderson K.C.
        Paradoxical increases in serum IgM and viscosity levels following rituximab in Waldenstrom's macroglobulinemia.
        Ann Oncol. 2004; 15: 1481-1483
        • Ghobrial I.M.
        • Fonseca R.
        • Greipp P.R.
        • et al.
        Initial immunoglobulin M 'flare' after rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia: an eastern cooperative oncology group study.
        Cancer. 2004; 101: 2593-2598
        • Gustine J.N.
        • Meid K.
        • Dubeau T.
        • et al.
        Ibrutinib discontinuation in Waldenstrom macroglobulinemia: etiologies, outcomes, and IgM rebound.
        Am J Hematol. 2018; 93: 511-517
        • Durot E.
        • Tomowiak C.
        • Michallet A.S.
        • et al.
        Transformed Waldenstrom macroglobulinaemia: clinical presentation and outcome. A multi-institutional retrospective study of 77 cases from the French Innovative Leukemia Organization (FILO).
        Br J Haematol. 2017; 179: 439-448
        • Durot E.
        • Tomowiak C.
        • Michallet A.-S.
        • et al.
        Retrospective analysis of 56 cases of transformed Waldenström macroglobulinemia. A study on behalf of the French Innovative Leukemia Organization (FILO).
        Blood. 2016; 128: 2982
        • Jimenez C.
        • Alonso-Alvarez S.
        • Alcoceba M.
        • et al.
        From Waldenstrom's macroglobulinemia to aggressive diffuse large B-cell lymphoma: a whole-exome analysis of abnormalities leading to transformation.
        Blood Cancer J. 2017; 7e591
        • Talaulikar D.
        • Biscoe A.
        • Lim J.H.
        • et al.
        Genetic analysis of diffuse large b-cell lymphoma occurring in cases with antecedent Waldenstrom macroglobulinaemia reveals different patterns of clonal evolution.
        Br J Haematol. 2019; 185: 767-770
        • Talaulikar D.
        • Tam C.S.
        • Joshua D.
        • et al.
        Treatment of patients with Waldenström macroglobulinaemia: clinical practice guidelines from the Myeloma Foundation of Australia Medical and Scientific Advisory Group.
        Intern Med J. 2017; 47: 35-49