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This is a type of lymphoma characterized by a proliferation of small lymphocytes producing a monoclonal IgM gammopathy. It is a clinical-pathologic syndrome often associated with a hyperviscosity syndrome. Patients usually present with fatigue, weight loss and bleeding problems. Lymphadenopathy and organomegaly are commonly present. Currently, this disease is best viewed as a lymphoplasmacytic lymphoma involving the bone marrow and associated with serum IgM paraprotein.


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SYNONYMS Lymphoplasmacytoid lymphoma
Lymphoplasmacytic lymphoma

About 16% of monoclonal gammopathies are IgM
60% are MGUS
23% are associated with malignant lymphoproliferative disorders
17% are Waldenstrom's

AGE-RANGE AND MEDIAN Median 60 years
30-90 years range
SEX (MALE:FEMALE) Males 2/3 of patients



Increased serum proteins leads to a variety of symptoms:
Focal and centralized nervous system impairment
Congestive heart failure

May progress to coma and death

CRYOGLOBULINS Raynaud's syndrome

Waldenström Macroglobulinemia Caused by Extranodal Marginal Zone B-cell Lymphoma A Report of Six Cases

Riccardo Valdez, MD
William G. Finn, MD
Charles W. Ross, MD
Timothy P. Singleton, MD
Joseph A. Tworek, MD
Bertram Schnitzer, MD

Am J Clin Pathol 2001;116:683-690 Abstract quote

Waldenström macroglobulinemia (WM) and its associated hyperviscosity syndrome (HVS) are generally caused by lymphoplasmacytoid lymphoma or other small B-cell lymphoproliferative disorders. WM associated with extranodal marginal zone B-cell–mucosa-associated lymphoid tissue lymphoma (EMZL/MALT-type) has not been emphasized.

We describe 4 men and 2 women (age, 40-79 years) with clinical and laboratory manifestations of WM and EMZL/MALT-type involving one or more sites: lung, pericardium/pleura, ocular adnexa, nasopharynx, minor salivary gland, glossopharyngeal fold, skin, and stomach. The following immunophenotypic patterns were observed: CD20+, 6; CD43+, 3; kappa light chain restriction, 5; and lambda light chain restriction, 1. All were negative for CD5, CD10, and cyclin D1 expression. A clonal paraproteinemia was present in each (IgM kappa, 4; IgM lambda, 1; biclonal IgM kappa/IgA kappa, 1). All 4 patients tested had elevated plasma viscosity; clinical HVS occurred in 3, and 2 required emergency plasmapheresis.

These findings suggest that EMZL/MALT-type can cause WM and that the laboratory evaluation of EMZL/MALT-type should include serum protein electrophoresis/immunofixation, and plasma viscosity measurements and urine immunofixation in select cases. EMZL/MALT-type should be considered in the differential diagnosis in patients with clinicopathologic features of WM.

Diffuse Large B-Cell Lymphoma Occurring in Patients With Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia
Clinicopathologic Features of 12 Cases

Pei Lin, MD, Adnan Mansoor, MD,* Carlos Bueso-Ramos, MD, PhD, Suyang Hao, MD, Raymond Lai, MD, PhD, and L. Jeffrey Medeiros, MD


Am J Clin Pathol 2003;120:246-253 Abstract quote

Of 92 patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) treated at our institution, diffuse large B-cell lymphoma (DLBCL) also developed in 12 (13%). In 10 patients, DLBCL developed 12 to 128 months (median, 44 months) after the diagnosis of LPL/WM. Two patients had LPL/WM and DLBCL simultaneously.

Clinicopathologic features at diagnosis of LPL/WM did not predict the risk of DLBCL. Onset of DLBCL was characterized by worsening constitutional symptoms, profound cytopenias, extramedullary disease, and organomegaly. Immunoglobulin light chain expression was identical in both LPL/WM and DLBCL. In situ hybridization for Epstein-Barr virus (EBV) in 8 cases of DLBCL was negative.

Of 11 patients with clinical follow-up information available, 8 (73%) died within 10 months of diagnosis of DLBCL. DLBCL, most likely as a result of histologic transformation, occurs in a subset of patients with LPL/WM and is associated with aggressive clinical course and poor outcome. EBV is unlikely to be involved in transformation.


Cytogenetics 50% of cases have abnormalities
Trisomy 12
t(1;14) and t(11;18) in the differential diagnosis of Waldenstrom's macroglobulinemia.

Ye H, Chuang SS, Dogan A, Isaacson PG, Du MQ.

Department of Pathology, University of Cambridge, UK.

Mod Pathol. 2004 Sep;17(9):1150-4. Abstract quote  

Waldenstrom's macroglobulinemia is caused by several B-cell proliferative disorders including lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, B-cell chronic lymphocytic leukemia and multiple myeloma. Differential diagnosis between lymphoplasmacytic lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is particularly difficult as there is a considerable overlap in histological presentation.

We report a case of Waldenstrom's macroglobulinemia with involvement of the peripheral blood, bone marrow and stomach. Serum chemistry revealed an IgM of 5.4 g/dl, but Bence-Jones protein in urine was negative. Abnormal lymphoid cells were detected in both blood and the bone marrow. Flow cytometry of the bone marrow aspirate showed that majority of cells were CD20(+), CD38(+), expressing immunoglobulin lambda light chain, but CD5(-) and CD10(-). Gastric biopsies revealed infiltration of the gastric mucosa by small lymphoid cells showing plasmacytoid differentiation and occasional Dutcher bodies. Lymphoepithelial lesions and Helicobacter pylori were not seen. Thus, the differential diagnosis between lymphoplasmacytic lymphoma and mucosa-associated lymphoid tissue lymphoma was raised. To resolve this, we performed BCL10 immunohistochemistry and reverse transcriptional polymerase chain reaction (RT-PCR) for the API2-MALT1 fusion transcript of t(11;18)(q21;q21). Both bone marrow and gastric biopsies showed strong BCL10 nuclear staining, similar to that seen in t(1;14)(p22;q32) positive mucosa-associated lymphoid tissue lymphoma, but absence of the API2-MALT1 fusion transcript.

To further ascertain whether the detection of t(1;14)(p22;q32) and t(11;18)(q21;q21) can be reliably used for the differential diagnosis between lymphoplasmacytic lymphoma and mucosa-associated lymphoid tissue lymphoma, we screened for these translocations by BCL10 immunohistochemistry in 58 lymphoplasmacytic lymphomas and RT-PCR for t(11;18)(q21;q21) in 40 lymphoplasmacytic lymphomas, respectively. None of the lymphoplasmacytic lymphomas studied harbored these translocations.

Thus, detection of t(1;14)(p22;q32) and t(11;18)(q21;q21) is useful in the differential diagnosis between lymphoplasmacytic lymphoma and mucosa-associated lymphoid tissue lymphoma.


Serum protein electrophoresis Monoclonal IgM varying from 3- 8 g/dL
Light chain kappa in 75% of cases
Bleeding time Prolonged
Serum viscosity Increased in 90% of patients
Cryoglobulins Rarely present
Light chains in urine 80% of cases
Serum creatinine Elevated in 1/3 of cases


Lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia: an evolving concept.

Lin P, Medeiros LJ.

From the Department of Hematopathology, U. T. M. D. Anderson Cancer Center, Houston, Texas.

Adv Anat Pathol. 2005 Sep;12(5):246-55. Abstract quote  

The concept of Waldenstrom macroglobulinemia has evolved from the original description of a clinical syndrome to its more recent designation as a distinct clinicopathologic entity, that is, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM), in the World Health Organization (WHO) classification and by the participants of consensus meetings on WM.

The diagnosis of LPL/WM, however, remains a challenge in daily practice. Distinguishing LPL/WM from other B-cell lymphomas, especially marginal zone B-cell lymphomas, which share overlapping morphologic features, is difficult.

The traditional practice of separating LPL/WM from other lymphomas by an arbitrary level of serum IgM is no longer considered valid. The characteristic immunophenotype described for LPL/WM by the WHO classification, that is, CD5CD10CD23, is observed in 60-80% of neoplasms, but variations from this pattern of antigen expression are common, with CD23 being detected in up to 40% of cases.

Lack of a distinct molecular genetic hallmark complicates the distinction of LPL/WM from other B-cell lymphomas. Although the t(9;14) is stated to be present in 50% of cases in the WHO classification, translocations involving the Ig heavy chain including the t(9;14) are actually rare in LPL/WM. Deletion of 6q21-q23, a nonspecific finding, is the most common aberration reported in 40-70% of patients. At the molecular level, the neoplastic clone in most cases has undergone Ig variable gene mutation, but not isotype switching, and the clone retains the capability of plasmacytic differentiation.

Currently, the diagnosis of LPL/WM can only be established by incorporating clinical and pathologic findings and excluding alternative diagnoses. In some cases, in our opinion, distinguishing LPL/WM from marginal zone B-cell lymphomas seems arbitrary using currently recommended criteria.

Waldenstrom macroglobulinemia involving extramedullary sites: morphologic and immunophenotypic findings in 44 patients.

Lin P, Bueso-Ramos C, Wilson CS, Mansoor A, Medeiros LJ.


Am J Surg Pathol. 2003 Aug;27(8):1104-13. Abstract quote

Waldenstrom macroglobulinemia (WM) is a clinicopathologic syndrome in which a B-cell neoplasm involving the bone marrow, usually lymphoplasmacytic lymphoma (LPL), is associated with immunoglobulin M paraprotein in the serum. Extramedullary involvement occurs in a subset of patients and is infrequently examined histologically. The files of M.D. Anderson Cancer Center were searched for patients with WM who underwent biopsy of one or more extramedullary sites during the course of disease. Each biopsy specimen was classified using the criteria of the World Health Organization classification.

The study group consisted of 44 patients (26 men and 18 women), with a total of 51 specimens obtained from lymph nodes (n = 36), soft tissue (n = 4), spleen (n = 3), skin (n = 2), lung (n = 2), tonsils (n = 1), colon (n = 1), liver (n = 1), and gallbladder (n = 1). Lymphoplasmacytic lymphoma was the most common histologic type, in 40 (78%) samples.

This category was morphologically heterogeneous and was further subclassified as lymphoplasmacytic (n = 21), lymphoplasmacytoid (n = 18), and polymorphous (n = 1). Four of these LPL cases morphologically resembled marginal zone B-cell lymphoma. Four additional samples were involved by diffuse large B-cell lymphoma, probably transformed from LPL. Three more samples were involved by LPL with unusual features: two were CD5-positive and one was a composite tumor with classical Hodgkin's disease. Other categories of lymphoma in this group of patients with WM included small lymphocytic lymphoma/chronic lymphocytic leukemia (n = 2), mantle cell lymphoma (n = 1), and follicular lymphoma (n = 1).

Waldenstrom macroglobulinemia is most commonly associated with LPL but can rarely occur with other types of B-cell lymphoma. Lymphoplasmacytic lymphoma in patients with WM is morphologically heterogeneous and can be indistinguishable from marginal zone B-cell lymphoma. CD5+ B-cell lymphomas with features otherwise typical of LPL are rare, and we think these tumors are part of the spectrum of LPL.


Cutaneous Waldenström's macroglobulinemia: Report of a case and overview of the spectrum of cutaneous disease

COL Lester F. Libow, MD
MAJ Jeffrey P. Mawhinney, DO
CPT Glenn T. Bessinger, MD, PhD

San Antonio, Texas, and Washington, District of Columbia

J Am Acad Dermatol 2001;45:S202-6 Abstract quote

Specific infiltration of the skin is a rare complication of Waldenström's macroglobulinemia. Cutaneous disease may also develop as a direct result of paraproteinemia and paraprotein specific antiepidermal autoimmune disease.

We report a patient with Waldenström's macroglobulinemia in whom cutaneous infiltration developed with a clonal population of lymphoplasmacytoid B cells, summarize previously reported cases, and review the spectrum of cutaneous disease associated with this hematologic malignancy.



Waldenström Macroglobulinemia Development of Diagnostic Criteria and Identification of Prognostic Factors

Roger G. Owen, MD
Sharon L. Barrans
Stephen J. Richards, PhD
Sheila J.M. O'Connor, MSc
J. Anthony Child, MD
Liakat A. Parapia, MD
Gareth J. Morgan, PhD
Andrew S. Jack, PhD

Am J Clin Pathol 2001;116:420-428 Abstract quote

To establish whether a combination of morphologic and immunophenotypic criteria could be developed to more precisely define Waldenström macroglobulinemia (WM) and prognostic factors, we retrospectively assessed the clinical and laboratory features of 111 cases of WM.

Bone marrow infiltration by small lymphocytes was documented in each case; and diffuse, interstitial, nodular, and paratrabecular patterns of infiltration were documented in 58%, 32%, 6%, and 4% of cases, respectively. Ninety percent were characterized by a surface immunoglobulin–positive, CD19+CD20+CD5–CD10–CD23– immunophenotype.

The median overall survival from diagnosis was 60 months; univariate analysis revealed the following adverse prognostic factors: older than 60 years, performance status more than 1, platelet count less than 100 × 103/µL (<100 × 109/L), pancytopenia, and diffuse bone marrow infiltration. Associated median survival was 40, 38, 46, 28, and 59 months, respectively. Multivariate analysis revealed age, performance status, and platelet count as prognostically significant, but stratification of patients according to the International Prognostic Index had limited value.

We suggest defining WM by the following criteria: IgM monoclonal gammopathy; bone marrow infiltration by small lymphocytes, plasmacytoid cells, and plasma cells in a diffuse, interstitial, or nodular pattern; and a surface immunoglobulin–positive, CD19+CD20+CD5–CD10–CD23– immunophenotype.

Peripheral blood Anemia, leukopenia, and thrombocytopenia
Rouleaux may be present
Leukemic blood picture in 30$ of cases
Bone marrow aspiration and biopsy 85% of cases are involved
Percentage of lymphocytes involved varies from normal to 90%
Cytologically, these are well differentiated lymphocytes with plasmacytoid features
Intranuclear inclusions (Dutcher bodies) are present in some of the lymphocytes


PAS Intranuclear and cytoplasmic inclusions strongly positive
B cell phenotype The neoplastic B cells exhibit the usual characteristics of B cells

PROGNOSIS Death usually from complications of disease such as hyperviscosity, infection, or hemorrhage
May progress to refractory lymphoproliferative disorder

Waldenström Macroglobulinemia Development of Diagnostic Criteria and Identification of Prognostic Factors

Roger G. Owen, MD
Sharon L. Barrans
Stephen J. Richards, PhD
Sheila J.M. O'Connor, MSc
J. Anthony Child, MD
Liakat A. Parapia, MD
Gareth J. Morgan, PhD
Andrew S. Jack, PhD

Am J Clin Pathol 2001;116:420-428 Partial abstract quote

The median overall survival from diagnosis was 60 months; univariate analysis revealed the following adverse prognostic factors: older than 60 years, performance status more than 1, platelet count less than 100 × 103/µL (<100 × 109/L), pancytopenia, and diffuse bone marrow infiltration. Associated median survival was 40, 38, 46, 28, and 59 months, respectively. Multivariate analysis revealed age, performance status, and platelet count as prognostically significant, but stratification of patients according to the International Prognostic Index had limited value.

Cytogenetic Findings in Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia Chromosomal Abnormalities Are Associated With the Polymorphous Subtype and an Aggressive Clinical Course

Adnan Mansoor, MD
L. Jeffrey Medeiros, MD
Donna M. Weber, MD
Raymond Alexanian, MD
Kimberly Hayes
Dan Jones, MD, PhD
Raymond Lai, MD, PhD
Armand Glassman, MD
Carlos E. Bueso-Ramos, MD, PhD

Am J Clin Pathol 2001;116:543-549 Abstract quote

We correlated bone marrow cytogenetic findings with morphologic and immunophenotypic data in 37 patients with lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM).

Each LPL/WM case was classified as lymphoplasmacytoid (n = 18), lymphoplasmacytic (n = 10), or polymorphous (n = 9) using the Kiel criteria. Of 12 cases with chromosomal abnormalities, a single numeric abnormality was present in 4 and a complex karyotype in 8. The most common numeric abnormalities were +5 and –8 in 3 cases each; the most common structural abnormality was del(6q) in 6 cases. Cytogenetic abnormalities were significantly less common in the lymphoplasmacytic and lymphoplasmacytoid groups (5/28 [18%]) compared with the polymorphous group (7/9 [78%]). Clinical follow-up was available for 28 patients for a median of 36 months. Six (67%) of 9 patients with aneuploid tumors, including 4 with polymorphous subtype, subsequently had clinical progression or developed high-grade lymphoma. In contrast, 4 (21%) of 19 patients with diploid tumors, including 1 of polymorphous type, developed clinical progression or high-grade lymphoma.

We conclude that abnormal cytogenetic findings in LPL/WM correlate with the polymorphous subtype and poor prognosis.

5 Year Survival Median survival of 5 years after diagnosis
TREATMENT Chemotherapy with alkylating agent
Hyperviscosity May be treated with plasmapheresis

Lymphoplasmacytic lymphoma/immunocytoma: towards a disease-targeted treatment?

Clavio M, Quintino S, Venturino C, Ballerini F, Varaldo R, Gatto S, Galbusera V, Garrone A, Grasso R, Canepa L, Miglino M, Pierri I, Gobbi M.

Dept. of Internal Medicine, University of Genoa, Genova, Italy.


J Exp Clin Cancer Res. 2001 Sep;20(3):351-8. Abstract quote

Lymphoplasmacytic-lymphoplasmacytoid lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) or immunocytoma (IMC) consists of diffuse proliferation of small mature B lymphocytes, plasmacytoid lymphocytes, and plasma-cells. The nosographic definition includes the lack of histological, immunophenotypic, cytogenetic, and molecular markers considered specific of other types of lymphoma. The cells show surface Ig (usually IgM), B-cell-associated antigens and display the CD5-, CD23- and CD10- phenotype, which allows for differential diagnosis from B-CLL and mantle cell lymphoma. t(9;14)(p13;q32) chromosomal translocation has been found in 50% of all LPL cases. The cytogenetic rearrangement juxtaposes the PAX-5 gene, which encodes for an essential transcription factor for B-cell proliferation and differention, to the Ig heavy chain gene.

The combination of chlorambucil and prednisone holds as the standard treatment and seems to guarantee good control of the disease in most patients. Similar therapeutic results have been described with the combination of cyclophosphamide, vincristine, prednisone with (CHOP) or without doxorubicin (CVP), or with a combination of other alkylating agents and prednisone. Nucleoside analogues, alone or in combination with alkylating agents and anthracyclines, provide good salvage therapy for IMC and being increasingly employed as first line therapy.

In a multicentric European trial Foran et al. administered the chimeric anti-CD20-monoclonal antibody (Rituximab) to 28 patients with previously treated IMC. Seven out of 25 evaluable patients (28%) achieved a partial response. Byrd et al. examined the outcome of 7 previously treated WM patients who received weekly infusions of rituximab (375 mg/m2). Therapy was well tolerated by all patients, and there was no decrease in cellular immune function, or significant infectious morbidity. Partial responses were noted in three of these patients, including two with fludarabine-refractory disease. These data suggest that rituximab exerts clinical activity on heavily pre-treated patients with WM. Furthermore, Weide et al. first reported that WM-associated polyneuropathy can be treated effectively with a combination of chemotherapy and the anti-CD20 monoclonal antibody rituximab.

Most published trials exploring the efficacy of high dose treatment as salvage therapy for relapsed or refractory low grade non Hodgkin's lymphoma have included prevalently follicular or lymphocytic lymphomas. In selected high risk patients radioimmunotherapy with autologous stem-cell rescue, and myeloablative therapy followed either by autologous stem cell transplantation (SCT) or allogeneic SCT might represent an alternative strategy.


Multicenter, randomized comparative trial of fludarabine and the combination of cyclophosphamide-doxorubicin-prednisone in 92 patients with Waldenstrom macroglobulinemia in first relapse or with primary refractory disease.

Leblond V, Levy V, Maloisel F, Cazin B, Fermand JP, Harousseau JL, Remenieras L, Porcher R, Gardembas M, Marit G, Deconinck E, Desablens B, Guilhot F, Philippe G, Stamatoullas A, Guibon O;

The French Cooperative Group on Chronic Lymphocytic Leukemia and Macroglobulinemia. Departement d'hematologie, Hopital Pitie-Salpetriere, AP-HP, Paris, France.

Blood 2001 Nov 1;98(9):2640-4 Abstract quote

Few reports are available on the treatment of patients with Waldenstrom macroglobulinemia (WM) and primary or secondary resistance to alkylating-agent-based regimens.

From December 1993 through December 1997, 92 patients with WM resistant to first-line therapy (42) or with first relapse (50) after alkylating-agent therapy were randomly assigned to receive fludarabine (25 mg/m(2) of body-surface area on days 1-5) or cyclophosphamide, doxorubicin (Adriamycin), and prednisone (CAP; 750 mg/m(2) cyclophosphamide and 25 mg/m(2) doxorubicin on day 1 and 40 mg/m(2) prednisone on days 1-5).

The first end point evaluated was the response rate after 6 treatment courses. Forty-five patients received CAP and 45 received fludarabine. Two patients died before the first course of chemotherapy. No statistical differences were observed between the 2 treatment arms with respect to hematologic toxicity or infections. Mucositis and alopecia occurred significantly more often in patients treated with CAP. Partial responses were obtained in 14 patients (30%) treated with fludarabine and 5 patients (11%) treated with CAP (P =.019). Responses were more durable in patients treated with fludarabine (19 months versus 3 months), and the event-free survival rate was significantly higher in this group (P <.01). Forty-four patients died, 22 in the fludarabine group and 22 in the CAP group.

There was no statistical difference in the median overall survival time in the 2 study arms. Fludarabine was thus more active than CAP in salvage therapy of WM and should be tested as first-line therapy in a randomized comparison with alkylating agents.

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