Splenic Marginal Zone Lymphoma

Splenic Marginal Zone Lymphoma

Roberto N. Miranda, MD

Gross photograph shows SMZL involving the white pulp of the spleen resulting in numerous, miliary micronodules image.

SMZL with nodular expansion of white pulp image with a biphasic pattern: Dark center and pale marginal zone. There is also secondary red pulp image involvement.



  • Splenic marginal zone lymphoma (SMZL)


  • Splenic B-cell marginal zone lymphoma, splenic lymphoma with circulating villous lymphocytes (SLVL)


  • B-cell neoplasm composed of small lymphocytes

  • Neoplastic lymphocytes replace white pulp germinal centers and mantle zones, merge with peripheral (marginal) zone of larger cells, and infiltrate red pulp

  • Splenic hilar lymph nodes and bone marrow often involved; leukemic involvement can occur (SLVL)


Postulated Normal Counterpart

  • B cell of unknown differentiation stage

  • In approximately 50% of cases, precursor cells have differentiation stage compatible with antigen exposure



  • Incidence

    • < 2% of lymphoid neoplasms

  • Age

    • Most patients over 50 years old

  • Gender

    • No sex predilection


  • Splenomegaly

  • Enlarged splenic hilar lymph nodes but not usually peripheral lymph nodes

  • Bone marrow involvement

  • Peripheral blood lymphocytosis (so-called villous lymphocytes) in subset of patients; total white blood cell count can be high

  • Occasional autoimmune thrombocytopenia or anemia

  • Monoclonal serum protein in 1/3 of patients

  • Hyperviscosity and hypergammaglobulinemia are rare

  • Association with hepatitis C infection in 20% of cases in Southern Europe


  • Response to chemotherapy used for chronic lymphocytic leukemia is often suboptimal

  • Splenectomy results in hematologic response and long-term survival

  • Patients with concomitant HCV(+) may respond to interferon-γ or ribavirin


  • Clinical course is indolent

  • Transformation to large cell lymphoma may occur in about 10% of cases

  • Adverse clinical prognostic factors include large tumor mass or poor general health status

  • P53 mutations, 7q deletion, and unmutated IgH variable region genes may show unfavorable outcome


General Features

  • Micronodular miliary-like pattern of white pulp upon serial sections


Histologic Features

  • Low-power magnification shows dark inner zone surrounded by light outer marginal zone (“biphasic pattern”)

    • Both components are considered part of neoplastic process

    • Germinal centers and mantle zones are usually effaced

  • Small lymphocytes replace white pulp and infiltrate red pulp

    • Predominance of small, round to slightly irregular lymphocytes with minimal cytoplasm

    • Mixture of small, medium, and larger lymphocytes with relatively abundant pale cytoplasm in peripheral (marginal) zones that merge with red pulp

    • Scattered large centroblasts are present

    • Mitotic figures are usually rare

    • Plasmacytoid differentiation is common in subset of cells and can be marked in some cases

    • Cords and sinuses of red pulp contain small aggregates of neoplastic cells; these can be associated with epithelioid histiocytes

  • Splenic hilar lymph nodes are typically partially replaced by SMZL and show dilated sinuses

  • Peripheral blood lymphocytes are small and often characterized by unipolar cytoplasmic projections (villous lymphocytes)

  • Bone marrow involvement can have nodular, paratrabecular, diffuse, or mixed pattern and has a sinusoidal component in a subset of cases

  • Immunohistochemistry of bone marrow commonly shows follicular dendritic cells (e.g., CD21[+], CD23[+]) within aggregates

Predominant Pattern/Injury Type

  • Lymphoid, marginal zone

Predominant Cell/Compartment Type

  • Hematopoietic, lymphoid



  • B-cell neoplasm positive for pan-B-cell antigens (CD20, CD79a, pax-5) and negative for pan-T-cell antigens

  • CD72 is positive in ˜ 75% of cases; similar to hairy cell leukemia (HCL)

  • Negative for cyclin-D1, CD10, Bcl-6, and annexin-A1; usually negative for CD5 and CD23

Flow Cytometry

  • Positive for monotypic surface immunoglobulin light chain, CD19, CD20, CD22, and CD79b

  • Positive for IgM and usually positive for IgD

  • Negative for CD10, CD43, and usually CD103

  • Neoplastic cells can dimly express CD5 or CD23 in ˜ 20% of cases


  • Allelic loss of 7q31-32 in 40% of cases

  • Specific chromosomal translocations (including those identified in MALT lymphoma) have not been consistently identified in SMZL

  • Chromosomal translocations involving the CDK6 gene at 7q21 have been identified

  • Gene expression profiling studies have suggested activation of AKT1 and B-cell receptor signaling pathways


  • Immunoglobulin heavy and light chain genes are clonally rearranged

  • 1/2 of cases show somatic hypermutation of immunoglobulin genes; no relationship to prognosis


Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

  • Expansion of white pulp forming uniform nodules without marginal zone; extensive involvement of red pulp

  • Lymphocytes are round to oval with clumped chromatin and scant cytoplasm

  • Proliferation centers are unusual in spleen (compared with lymph nodes) but are helpful when identified

  • Lymphocytes are positive for CD5 and CD23 by immunohistochemistry or flow cytometry immunophenotyping

  • In bone marrow, paratrabecular pattern is rare in CLL/SLL; in blood, CLL/SLL cells do not have villous features

Follicular Lymphoma (FL)

  • Miliary pattern growing along preexisting follicles

  • Follicles can enlarge and coalesce to form large, grossly visible masses

  • Neoplastic lymphocytes are centrocytes and centroblasts

  • Neoplastic follicles similar to nodal follicular lymphoma; may have marginal zone appearance at periphery of nodules

  • Neoplastic lymphocytes are positive for CD10 and Bcl-6 by immunohistochemistry &/or flow cytometry immunophenotyping

  • In bone marrow, paratrabecular pattern is very common and a sinusoidal pattern is rare in FL

  • In peripheral blood, lymphocytes are cleaved with minimal cytoplasm

Hairy Cell Leukemia (HCL)

  • Patients present with splenomegaly and usually pancytopenia; monocytopenia is very common

  • Red pulp involvement with effacement of nodularity of white pulp

  • Red cell “lakes” and “pseudosinuses” represent areas of disruption of sheets of tumor cells

  • Indented nuclei with abundant clear cytoplasm

  • Lymphocytes are positive for CD11c (bright), CD22 (bright), CD25, CD103, and FMC7 by flow cytometry

  • Lymphocytes are positive for annexin-A1 by immunohistochemistry (but must be distinguished from granulocytes that are also positive)

  • Immunohistochemistry for tartrate-resistant acid phosphatase and CD72 supports diagnosis of HCL in absence of cell suspensions for flow cytometry immunophenotype

  • Currently rare to obtain spleen specimens with HCL because diagnosis can be made confidently based on peripheral blood, bone marrow, and immunophenotypic features

Hairy Cell Leukemia Variant (HCL-v)

  • Resembles HCL morphologically, but patients often have lymphocytosis and circulating monocytes; neoplastic lymphocytes often have small nucleolus

  • Negative for CD25 and annexin-A1; positive for CD103 in ˜ 70% of cases

Lymphoplasmacytic Lymphoma (LPL)

  • SMZL can be difficult to distinguish from LPL in patients with serum paraprotein and bone marrow involvement; usually spleen in LPL patients is not very large

  • Periarteriolar aggregates of small lymphocytes, plasmacytoid lymphocytes, plasma cells

  • Absence of marginal zone differentiation

  • del 6q favors LPL; del 7q and gains of 3q favor SMZL

Mantle Cell Lymphoma (MCL)

  • Splenic involvement by MCL is usually associated with splenomegaly

  • Enlarged white pulp nodules with frequent coalescence of nodules; residual germinal centers are occasionally detected

  • Lymphocytes are intermediate in size with irregular nuclear contours

  • Red pulp involvement shows small nodules or aggregates

  • Touch imprints or peripheral blood may show nucleolated lymphocytes

  • Lymphocytes are positive for CD5 and negative for CD23 by flow cytometry or immunohistochemistry

  • Translocation t(11;14) by classical cytogenetics, FISH, or RT-PCR

  • Cyclin-D1 positive by immunohistochemistry

Marginal Zone Lymphoma, Extranodal (MALT) or Nodal

  • Splenomegaly and lymphocytosis are usually not features of patients with MALT lymphoma

    • By definition, splenic involvement excludes diagnosis of nodal marginal zone lymphoma

  • Monocytoid cells surrounding germinal centers rarely occur in SMZL

Splenic Follicular or Marginal Zone Hyperplasia (SMZH)

  • Usually associated with autoimmune processes or idiopathic thrombocytopenic purpura

  • Spleen may be normal size but can also weigh up to 1,000 g

  • White pulp displays distinct germinal centers, mantle zones, and marginal zones (‘triphasic” pattern as compared with “biphasic” pattern of SMZL)

  • Red pulp is well preserved with only rare lymphocytes in sinuses or in splenic cords

  • Immunohistochemistry does not reveal abnormal distribution of Bcl-6 or CD10(+) lymphocytes, nor disruption of germinal centers by infiltrating marginal zone lymphocytes

  • Flow cytometry does not reveal evidence of immunoglobulin light chain restriction or aberrant B-cell immunophenotype

Splenic Diffuse Red Pulp Small B-cell Lymphoma

Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Splenic Marginal Zone Lymphoma

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