• Neoplasm composed primarily of small round B lymphocytes with prominent plasmacytoid differentiation, lacking defining features of other types of small B cell lymphomas

Alternate/Historical Names

• Gamma heavy chain disease (variant)
• Immunocytoma
• Lymphoplasmacytoid lymphoma
• Small lymphocytic lymphoma with plasmacytoid features
• Waldenstrom macroglobulinemia

Diagnostic Criteria

• Monomorphic lymphoplasmacytoid population with interfollicular, sinusoidal or diffuse pattern
  • Residual germinal centers may be atretic or hyperplastic
  • Epithelioid histiocytes may be numerous, may form granulomas
  • Hemosiderosis frequently associated with autoimmune hemolytic anemia
  • Amyloid may be present
  • Three clusters of patterns described by Andriko et al.
    • Atretic germinal centers, dlated sinuses, hemosiderosis, no histiocytes
    • Interfollicular with normal or hyperplastic germinal centers and epithelioid histoctyes
    • Complete effacement of architecture with clusters of epithelioid histocytes
• Nuclear features are those of small round lymphocytes
  • Similar to cells of primary follicles
  • Clumped chromatin with small or inconspicuous nucleoli
• Cytoplasm shows plasmacytoid features
  • Amphophilic staining
  • Russell bodies (cytoplasmic inclusions)
  • Dutcher bodies (intranuclear inclusions)
  • Crystals may be seen in lymphocytes or histocytes
• Most cases secrete IgM with resultant hyperviscosity (Waldenstrom hypergammaglobulinemia)
  • Variant secreting truncated gamma heavy chain without light chains termed "gamma heavy chain disease"
• Must lack specific features of other small lymphocytic lymphomas:
  • Proliferation centers, mantle pattern, marginal zone pattern, follcular pattern
  • CD5 (5%), CD10 (3%), bcl1
  • CD23 0-30% in immunohistochemistry
    • Up to 60% positive by flow, but weak
• Polymorphous type with 10-40% large transformed cells, immunoblasts and small cleaved cells
  • No monomorphous sheets of large cells
  • Increased mitotic figures (30/10 hpf vs. 4/10 hpf)
  • Occasional Reed-Sternberg like cells
  • Reported in 25% of cases
  • Worse survival than typical cases

Yasodha Natkunam MD PhD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting:: May 1, 2006

Supplemental studies

Immunohistology and Flow Cytometry

• B lineage 100%
• Light chain monotypia and heavy chains reliably detectable in plasmacytoid cells
  • IgM 67%
  • IgG 33%
  • IgA very rare
• Immunoglobulin light and heavy chains variably detectable in small cells
• bcl2 >50%
• CD43 10-30%
• Lacks specific markers of other lymphoma types
  • CD5 5%
  • bcl1 negative
  • CD10 3%
• CD23
  • 0-30% by immunohistology
  • Flow results reported up to 60% but weak
• CD138 100%
• FMC7 38%

Clinical Laboratory

• IgM monoclonal spike (>3 gm/dl) in 100%

Differential Diagnosis

• Immunologic differences of small B cell lymphomas
• SLL/CLL
• Mantle cell lymphoma
• Marginal zone lymphoma
• Plasmacytoma / myeloma
• Castleman disease
• Reactive plasmacytosis

• CD23 staining refers to lymphoid staining
  • Follicular dendritic cells stain in many processes
• bcl1
  • Blastic mantle cell lymphoma 100%
  • Hairy cell leukemia 41%
• CD43 stains only 2% of splenic marginal zone lymphoma

• No useful distinguishing immunologic markers
• Marginal zone lymphomas are frequently plasmacytoid; this combined with the lack of a definitive marker can make this distinction difficult
• The distinction is sometimes suggested by the propensity to involve mucosal sites by extranodal marginal zone lymphoma

Clinical

• Mean age 60 years, rare before 30
• 100% have monoclonal serum or urine IgM
  • Typically exhibit findings of Waldenstrom macroglobulinemia
    • Hyperviscosity
    • Autoimmune hemolytic anemia and thrombocytopenia
    • Cryoglobulinemia
    • Neuropathy
  • Rare cases make a defective, non-secreted IgM
  • Rare gamma heavy chain variant
  • Very rare alpha heavy chain production
• More frequent extranodal disease than SLL/CLL
• Increased circulating lymphocytes variably reported from 0-30%
• 50% 4 year survival
• May be associated with Hepatitis C
  • 30% incidence of Hepatitis C reported
  • So far, only reported from Italy

Grading / Staging / Report

• While staging is linked to prognosis, it does not generally determine therapy
  • Therapy generally determined by clinical signs and symptoms
• Pathologic staging is usually limited to bone marrow biopsy and biopsies of other sites to confirm clinical evidence of involvement

Ann Arbor Staging System

• Stage I
  • I if involvement of a single lymph node region
  • IE if involvement of a single extralymphatic organ or site
• Stage II
  • II if two or more lymph node regions on same side of diaphragm
  • IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm
• Stage III
  • III if Involvement of lymph node regions on both sides of the diphragm
  • IIIS if spleen involved
  • IIIE if extralymphatic site involved
• Stage IV
  • Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement
• Systemic Symptoms in 6 months preceding admission
  • Fever, night sweats, 10% weight loss
  • A = absent
  • B = present
• Extranodal sites are also designated
  • M+ = marrow
  • L+ = lung
  • H+ = liver
  • P+ = pleura
  • O+ = bone
  • D+ = skin and subcutaneous tissue
• Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas.

The pathology report should contain the following information:

• Diagnosis in the World Health Organization (WHO) classification
  • Equivalent diagnosis in other classifications used by relevant clinicians
• Results of supplementary studies if performed
• Relationship to other specimens from the same patient
• Information relevant to staging if available

Lists

Types of small B cell lymphoma

• Follicular lymphoma grade 1
• Lymphoplasmacytic lymphoma / Immunocytoma
• Mantle cell lymphoma
• Marginal zone B cell lymphoma, extranodal
• Marginal zone B cell lymphoma, nodal
• Marginal zone B cell lymphoma, splenic
• Small cell lymphoma / chronic lymphocytic leukemia

Bibliography

• Warnke RA, Weiss LM, Chan JKC, Cleary ML, Dorfman RF . Tumors of the Lymph Nodes and Spleen, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 14, 1995
• Jaffe ES, Harris NL Stein H, Vardiman JW . Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2001
• Andriko JA, Swerdlow SH, Aguilera NI, Abbondanzo SL. Is lymphoplasmacytic lymphoma/immunocytoma a distinct entity? A clinicopathologic study of 20 cases. Am J Surg Pathol. 2001 Jun;25(6):742-51.
• Berger F, Felman P, Sonet A, Salles G, Bastion Y, Bryon PA, Coiffier B. Nonfollicular small B-cell lymphomas: a heterogeneous group of patients with distinct clinical features and outcome. Blood. 1994 May 15;83(10):2829-35.
• Silvestri F, Sperotto A, Fanin R. Hepatitis C and lymphoma. Curr Oncol Rep. 2000 Mar;2(2):172-5.
• Konoplev S, Medeiros LJ, Bueso-Ramos CE, Jorgensen JL, Lin P. Immunophenotypic profile of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. Am J Clin Pathol. 2005 Sep;124(3):414-20.
• Owen RG, Barrans SL, Richards SJ, O'Connor SJ, Child JA, Parapia LA, Morgan GJ, Jack AS. Waldenstrom macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors. Am J Clin Pathol. 2001 Sep;116(3):420-8.