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)

B cell of unknown differentiation stage

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

Incidence

Age

Gender

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

Micronodular miliary-like pattern of white pulp upon serial sections

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

Small lymphocytes replace white pulp and infiltrate red pulp

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

Lymphoid, marginal zone

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

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

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

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

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

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

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

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

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

Monocytoid cells surrounding germinal centers rarely occur in SMZL

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

Spleen cut surface is homogeneously brown-red, without miliary-like nodularity