Follicular Lymphoma

Follicular Lymphoma

Roberto N. Miranda, MD

Follicular lymphoma involving the spleen. The lymphoma has a diffuse micronodular pattern enhancing white pulp. This is the most common pattern of follicular lymphoma involving the spleen.

Follicular lymphoma of spleen displays multiple tumor masses effacing the splenic architecture. This is the 2nd most common pattern of follicular lymphoma involving spleen.



  • Follicular lymphoma (FL)


  • Follicular center cell lymphoma, grades 1-3 (REAL classification)

  • Follicular lymphoma, predominantly small cleaved cell, mixed small cleaved and large cell, or large cell (Working Formulation)

  • Centroblastic/centrocytic lymphoma (Kiel classification)

  • Nodular lymphoma, poorly differentiated, mixed, or histiocytic (Rappaport classification)


  • Mature B-cell neoplasm composed of germinal (follicle) lymphocytes (centrocytes and centroblasts) in variable mixture

  • Histopathology usually shows follicular growth pattern; less frequently is purely diffuse



  • Bcl-2 overexpression as result of t(14;18)(q32;q21)/IgH-BCL2 gene rearrangement

    • Bcl-2 inhibits programmed cell death, giving Bcl-2(+) lymphoma cells a survival advantage

    • Many other anti-apoptotic molecules (e.g., Bcl-x, Mcl-1, etc.)

  • IgH-BCL2 by itself is insufficient for lymphomagenesis

    • Other mechanisms are involved and needed for FL to develop



  • Incidence

    • FL is 2nd most common lymphoma in Western hemisphere

    • FL rarely arises in spleen

      • Splenic involvement is usually manifestation of systemic disease

  • Age

    • Range: 30-83 years (median: 59 years)

  • Gender

    • M:F = 1:1.4


  • Most cases of FL involving spleen are diagnosed by splenectomy

    • FL primarily affects lymph nodes, but also bone marrow, peripheral blood, and Waldeyer ring

    • FL involving extranodal sites usually reflects widespread nodal disease

  • Primary FL of spleen is rare


  • Splenomegaly, abdominal pain, anemia, or thrombocytopenia

    • Usually associated with peripheral or abdominal lymphadenopathy with widespread disease

    • B-type symptoms in subset of patients

Laboratory Tests

  • ˜ 30% peripheral blood lymphocytosis

Natural History

  • Splenectomy is not curative

    • May alleviate symptoms or cytopenias


  • Surgical approaches

    • Splenectomy performed usually for cytopenias, pain, or less usually, for diagnostic purposes

  • Adjuvant therapy

    • Rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)

    • Watchful waiting or rituximab alone are also alternatives depending on staging


  • Usually considered an indolent lymphoma, but with frequent relapses

  • International Prognostic Index for Follicular Lymphoma (FLIPI) is predictor of outcome

  • 5-year overall survival is 55-70%

  • Transformation to large B-cell lymphoma occurs

    • ˜ 20% of patients with prolonged clinical follow-up


General Features

  • Variable gross appearance

    • Diffuse/miliary growth pattern, predominantly involving preexisting white pulp

    • Single or multiple tumor masses of variable size also can be observed

  • Median weight: 1.1 kg (range: 0.5-2.7 kg)


Histologic Features

  • Miliary pattern growing along preexisting follicles is most common pattern

    • Usually associated with marginal zone pattern and less red pulp involvement

    • Some researchers have suggested that this pattern is a form of in situ follicular lymphoma

      • Associated with or without disseminated disease

  • Effacement of architecture is 2nd most common pattern

    • Follicles are packed and coalescent

    • Correlates with grossly visible tumor mass

    • Can display diffuse areas

  • Neoplastic follicles are composed of centrocytes and centroblasts

    • Variable cytologic predominance according to grade of tumor

      • Low grade (grades 1 and 2): Up to 15 centroblasts per high-power field on average

      • Grade 3: More than 15 centroblasts or immunoblasts per high-power field on average

      • Some high-grade cases have sparse centrocytes

  • Marginal zone pattern in ˜ 50% of cases

    • Lymphocytes acquire abundant, pale (monocytoid) cytoplasm

      • Typically present at periphery of neoplastic follicles

    • Splenic hilar lymph nodes also may show marginal zone pattern

  • Red pulp infiltration as satellite aggregates

    • ˜ 30% with diffuse red pulp involvement; mainly small FL lymphocytes

    • FL cells often appear smaller and less irregular than those in white pulp

  • Bone marrow biopsy specimen is involved by paratrabecular aggregates

    • Other patterns are often present, but rare without paratrabecular pattern

Cytologic Features

  • Fine needle aspiration performed uncommonly on spleen

    • Centrocytes and centroblasts are present in smears

Lymph Nodes

  • Hilar or peripheral lymph nodes usually show features similar to those in spleen

    • Usually follicular pattern is present

    • Marginal zone pattern in ˜ 10% cases



  • Positive for B-cell markers: CD19(+), CD20(+), CD79a(+), pax-5(+)

  • CD10(+) and Bcl-6(+) in most cases

    • Stronger in white pulp; weaker in red pulp or in interfollicular areas

  • Bcl-2 (variable [+]) in white and red pulp

    • Bcl-2 more frequently (+) in low-grade FL (65-90%) than in high-grade FL (50-80%)

  • Follicular dendritic meshworks usually present

    • CD21(+), CD23(+), CD35(+), &/or CNA.42(+)

  • T-cell antigens(−), Cyclin-D1(−)

  • Variable proliferation rate as determined with Ki-67

    • Low-grade FL usually has low proliferation rate (< 20%)

Flow Cytometry

  • Monotypic surface immunoglobulin(+)

  • Heavy chains: IgM(+) or IgG(+), and IgD(−)

    • IgD(+) in rim of occasional residual mantle zone lymphocytes

  • CD19(+), CD20(+), CD22(+), and CD79a(+)

  • Usually CD10(+)

    • Occasional downregulation of CD10 in peripheral blood and bone marrow

  • T-cell antigens(−)


  • t(14;18)(q32;q21) in ˜ 80-90%

  • Other cytogenetic abnormalities are found in ˜ 90% of FL and include

    • Losses of 1p, 6q, 10q, &/or 17p

    • Gains of 1, 6p, 7, 8, 12q, X, &/or 18q

In Situ Hybridization

  • BCL2-IgH gene rearrangements can be demonstrated in almost all cases using fusion probes and FISH

    • Probes used are quite large and cover relevant regions of chromosomes 14 and 18

  • BCL6 translocations in ˜ 10% of cases

Molecular Genetics

  • Monoclonal IgH gene rearrangements in 60-70% of cases

    • False-negative results are common

      • Result from presence of somatic hypermutation in IgH variable region genes

  • BCL2-IgH gene rearrangements can be demonstrated in ˜ 80% of cases

    • Most breakpoints in BCL2 on chromosome 18 occur on MBR (major breakpoint region)

      • Other minor breakpoints: Mcr (minor cluster region), icr (intermediate cluster region), etc.

      • PCR assays can sensitively detect most of these breakpoints

      • FISH assays, unlike PCR, can assess all breakpoints but are less sensitive

  • It is important to remember that

    • PCR can detect BCL2-IgH fusions sequences in people without evidence of FL

    • Frequency of (+) result correlates with increasing age

    • This finding suggests that other molecular mechanisms are required for lymphomagenesis

  • P53 gene mutations associated with transformation to high-grade lymphoma


Splenic Marginal Zone Lymphoma (SMZL)

  • Micronodular infiltrate of white pulp centered on preexisting follicles

  • Low-power magnification shows darker inner zone surrounded by paler marginal zone (biphasic pattern)

    • Residual germinal centers or mantle zones (−/+); usually not present

  • Red pulp involvement usually as small aggregates

  • Neoplastic cells are predominantly small with abundant pale cytoplasm, round nuclei, and small nucleoli

    • Scattered large cells always present

    • Plasmacytic differentiation is common; can be marked

      • Subset of cases associated with serum paraprotein; can be high level

  • Proposed variant of SMZL diffusely involves red pulp of spleen

  • Splenic hilar lymph nodes often show

    • Incomplete effacement with preservation of some sinuses

    • Marginal zone pattern that can colonize follicles and mimic FL

  • Peripheral blood lymphocytes characterized by unipolar cytoplasmic projections (villous lymphocytes)

    • Subset of patients can present with marked lymphocytosis (˜ 100 K)

  • Bone marrow shows intertrabecular and sometimes paratrabecular lymphoid aggregates

    • Sinusoidal pattern of involvement in ˜ 33-50% of patients

  • Immunophenotype

    • IgM(+), IgD(+/−), CD19(+), CD20(bright [+]), CD22(bright [+])

    • CD11c(+), FMC7(+), CD5(−/+), CD10(−), Bcl-6(−)

Mantle Cell Lymphoma (MCL)

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

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