• B cell neoplasm composed of small and medium sized cells that involves the mantle and marginal zones of splenic follicles and the splenic red pulp

Alternate/Historical Names

• Monocytoid lymphoma
• Splenic lymphoma with circulating villous lymphocytes
• Splenic lymphoma with villous lymphocytes

Diagnostic Criteria

• Polymorphous population with mantle and marginal zone distribution
  • Small round lymphocytes surround and replace follicles (follicular colonization)
    • Results in micronodular pattern
  • Medium sized cells with clear cytoplasm in surrounding marginal zone
    • Scattered large blasts may be intermixed
  • Occasional features
    • Plasmacytoid differentiation
    • Epithelioid histiocytes
• Red pulp infiltrated by small nodules of mixed sized cells
  • Small cells invade sinuses
• Marginal zone type lymphocytes may be numerous
  • Small cells with clear cytoplasm
• Peripheral blood may show villous lymphocytes
  • Lymphoid cells with short polar villi
  • Plasmacytoid differentiation may be seen
  • Not all cases or cells show villi
  • 65% of cases have some kind of circulating lymphocytes
• Marrow involved in 95% of cases
• Splenic hilar nodes frequently involved
  • May not show distinct marginal zone distribution
  • More mixing of small and medium sized cells
• Lacks specific markers of other small cell lymphomas
  • Negative to infrequent for CD23, bcl1, CD5, CD10
  • Positive for B lineage markers and bcl2
  • No specific positive immunologic marker
    • Immunologically, a diagnosis of exclusion
• Lacks features of nodal or extranodal marginal zone lymphomas
  • No peripheral node involvement
  • No extranodal tissue involvement
• Transformation reported in 13% of cases
  • Large B cell lymphoma

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%
• Immunoglobulin light and heavy chains variably detectable
  • More frequently detectable in plasmacytoid cases
  • IgM and IgD positive
• CD23 8%
• CD5 negative
• CD43 2%
• bcl1 negative
• CD10 2%
• bcl2 65-90%
• bcl6 negative
• Cases with transformation to diffuse large cell lymphoma maintain CD5 and CD10 negativity
• CD138 can be extensive if plasmacytoid differentiation is prominent

Genetic Study

• Microarray analysis supports a single molecular entity
• 7q31-32 allelic loss is found in 45% of cases
  • Associated with aggressive disease
  • Not specific as may be found in other B cell lymphomas

Clinical Laboratory

• 30-50% have small monoclonal protein spike

Differential Diagnosis

• Extranodal vs. Nodal vs. Splenic marginal zone lymphomas
• Immunologic differences of small B cell lymphomas
• SLL / CLL
• Lymphoplasmacytoid lymphoma / Immunocytoma
• Mantle cell Lymphoma
• Follicular lymphoma
• Mast cell disease
• Marginal zone hyperplasia
• Diffuse large B cell lymphoma vs.marginal zone lymphoma with transformation
• Plasmacytoma
• Hairy cell leukemia

Extranodal vs. Nodal vs. Splenic Marginal Zone Lymphomas

• Extranodal involvement takes precedence in separation of the three types
  • Mixed types are designated as extranodal with nodal or splenic involvement
• Nodal type must lack extranodal involvement
• Splenic type must lack both extranodal and peripheral nodal involvement
  • Splenic hilar nodes may be involved
• Genetic abnormalities are incompletely studied but support the above separation

• 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

• Both may involve the GI tract and other mucosal sites in extranodal cases.
• Enlarged marginal and mantle zones may be hard to distinguish

• Both usually express bcl2 in the neoplastic cells
• Both may have prominent marginal zones
• Cases with combined features are occasionally seen

Splenic Marginal Zone Lymphoma	Hairy Cell Leukemia
DBA44 negative	DBA44 positive
Tartrate resistant acid phosphatase negative	Tartrate resistant acid phosphatase positive
Biphasic cell sizes	Uniform cells with small nuclei and abundant cytoplasm
Villi if present are polar	Hairy projections circumferential
Nodular pattern of white pulp involvement	White pulp atrophic
Peripheral nodes only rarely involved	Peripheral nodes may be involved

Both typically involve the spleen and may have circulating cells with cytoplasmic processes/villi

Clinical

• Mean age 60's, rare before 30
• Involves spleen, splenic hilar nodes, bone marrow
  • May involve peripheral blood
  • May involve liver
  • Peripheral node involvement rare
• Autoimmune associations
  • Hemolytic anemia
  • Thrombocytopenia
• Frequent Hepatitis C reported in Italian cases
• 70% 5 year survival
  • No worsening of prognosis with marrow involvement
  • Splenectomy may relieve hematologic abnormalities
  • Worse prognosis following transformation
• Incidence
  • Approximately 1-3% of lymphomas

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
• If present, comment on transformation
• Comment on the possiblity or presence of peripheral blood involvement

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 eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2001
• Ruiz-Ballesteros E, Mollejo M, Rodriguez A, Camacho FI, Algara P, Martinez N, Pollan M, Sanchez-Aguilera A, Menarguez J, Campo E, Martinez P, Mateo M, Piris MA. Splenic marginal zone lymphoma. Proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis. Blood. 2005 May 24;
• Iannitto E, Ambrosetti A, Ammatuna E, Colosio M, Florena AM, Tripodo C, Minardi V, Calvaruso G, Mitra ME, Pizzolo G, Menestrina F, Franco V. Splenic marginal zone lymphoma with or without villous lymphocytes. Hematologic findings and outcomes in a series of 57 patients. Cancer. 2004 Nov 1;101(9):2050-7.
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• Kansal R, Ross CW, Singleton TP, Finn WG, Schnitzer B. Histopathologic features of splenic small B-cell lymphomas. A study of 42 cases with a definitive diagnosis by the World Health Organization classification. Am J Clin Pathol. 2003 Sep;120(3):335-47.
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• Thieblemont C, Felman P, Callet-Bauchu E, Traverse-Glehen A, Salles G, Berger F, Coiffier B. Splenic marginal-zone lymphoma: a distinct clinical and pathological entity. Lancet Oncol. 2003 Feb;4(2):95-103.
• Chacon JI, Mollejo M, Munoz E, Algara P, Mateo M, Lopez L, Andrade J, Carbonero IG, Martinez B, Piris MA, Cruz MA. Splenic marginal zone lymphoma: clinical characteristics and prognostic factors in a series of 60 patients. Blood. 2002 Sep 1;100(5):1648-54.
• Camacho FI, Mollejo M, Mateo MS, Algara P, Navas C, Hernandez JM, Santoja C, Sole F, Sanchez-Beato M, Piris MA. Progression to large B-cell lymphoma in splenic marginal zone lymphoma: a description of a series of 12 cases. Am J Surg Pathol. 2001 Oct;25(10):1268-76.
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