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Background
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.
OUTLINE
\EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Lymphoplasmacytoid lymphoma
Lymphoplasmacytic lymphomaINCIDENCE About 16% of monoclonal gammopathies are IgM
60% are MGUS
23% are associated with malignant lymphoproliferative disorders
17% are Waldenstrom'sAGE-RANGE AND MEDIAN Median 60 years
30-90 years rangeSEX (MALE:FEMALE) Males 2/3 of patients GEOGRAPHIC DISTRIBUTION Worldwide
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION Serum protein electrophoresis Monoclonal IgM varying from 3- 8 g/dL
Light chain kappa in 75% of casesBleeding 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
CLINICAL VARIANTS/GROSS DISEASE CHARACTERIZATION GENERAL
- 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.EXTRAMEDULLARY
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.SKIN 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 ColumbiaJ 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.
HISTOLOGICAL TYPES CHARACTERIZATION 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, PhDAm 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 casesBone 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
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SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION PAS Intranuclear and cytoplasmic inclusions strongly positive B cell phenotype The neoplastic B cells exhibit the usual characteristics of B cells
DIFFERENTIAL DIAGNOSIS CHARACTERIZATION MARGINAL ZONE LYMPHOMA
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Death usually from complications of disease such as hyperviscosity, infection, or hemorrhage
May progress to refractory lymphoproliferative disorderWaldenström 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, PhDAm 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, PhDAm 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 GENERAL
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.RANDOMIZED TRIALS 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.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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