Nodal Follicular Lymphoma

Nodal Follicular Lymphoma

C. Cameron Yin, MD, PhD

Gross photograph shows matted mesenteric lymph nodes involved by low-grade follicular lymphoma (FL). This specimen was obtained at time of autopsy.

FL involving lymph node shows numerous follicles throughout the cortex and medulla. The large number and random distribution of follicles supports lymphoma.



  • Follicular lymphoma (FL)


  • Follicle (germinal) center cell lymphoma

  • Centroblastic/centrocytic lymphoma


  • B-cell neoplasm composed of germinal center B cells (centrocytes and centroblasts)

    • Follicular, follicular and diffuse, and diffuse growth patterns


t(14;18)(q32;q21) Resulting in Overexpression of Bcl-2

  • Bcl-2 is antiapoptotic and confers survival advantage

  • t(14;18) is considered initiating molecular event of FL

    • Insufficient to induce lymphomagenesis by itself

    • Other molecular changes necessary for development of lymphoma

Imbalance of Other Proteins Involved in Apoptosis

  • Overexpression of cell death suppressor proteins BCL-xL and MCL1

  • Decreased expression of cell death promoting proteins BAX and BAD

  • Overexpression of inhibitors of apoptosis proteins (IAP)

Germline Susceptibility Factors

  • Genotypic analysis has identified novel susceptibility locus at 6p21.3

    • Contains single gene, chromosome 6 open reading frame 15 (C6orf15)

  • 4-fold increased lymphoma risk in 1st-degree relatives of patients with FL

  • Association of single nucleotide polymorphisms of estrogen receptor gene with reduced risk of FL

Immunologic Microenvironment

  • CD40L(+) T cells in secondary follicles inhibit FL cell death

  • Follicular dendritic cells contribute to preventing apoptosis of FL cells



  • Incidence

    • ˜ 20% of NHL; 2nd most common NHL in USA and Europe

    • Uncommon in Asia and underdeveloped countries

  • Age

    • Median = 59 years

  • Gender

    • M:F = 1:1.7


  • Cervical and inguinal lymph nodes are more frequently affected

  • Commonly affected extranodal sites

    • Bone marrow, spleen, liver, and peripheral blood

  • FL uncommonly arises at extranodal sites

    • Skin, gastrointestinal tract, thyroid gland, testis


  • Insidious onset

  • Often asymptomatic at time of initial diagnosis

  • Almost always disseminated (stages III-IV)

Natural History

  • Indolent clinical course but frequent relapses

  • Some cases progress to diffuse large B-cell lymphoma (DLBCL)


  • In the past, “watch and wait” strategy was usually employed for asymptomatic patients

  • Chemotherapy is currently used upfront more often for patients with stage III-IV disease

    • Rituximab, cyclophosphamide, adriamycin (doxorubicin), vincristine, and prednisone (R-CHOP)

    • Bulky disease or signs of progression necessitate chemotherapy

  • Radiation has value for subset of patients with stage I and II disease


  • Overall 10-year survival is up to ˜ 80%

  • Adverse prognostic factors summarized in FL International Prognostic Index 2 (FLIPI 2)

    • High serum β2-microglobulin

    • Bulky lymph nodes > 6 cm

    • Bone marrow involvement

    • Hemoglobin < 12 g/dL

    • Age > 60 years

  • FLIPI 2 prognostic model stratifies patients into different prognostic risk groups

    • Model developed in post rituximab era using prospective analysis

  • Pathologic adverse prognostic factors include

    • High histologic grade and diffuse areas > 25% with predominance of large cells

      • These areas are designated as DLBCL

    • High proliferation index

    • Complex karyotype

    • Del6q23-26; del17p and mutation of TP53


General Features

  • Widespread lymphadenopathy; often small lymph nodes


General Features

  • Replacement of nodal parenchyma by “fish-flesh” tumor; ± nodularity


Histologic Features

  • Lymph node

    • Partial or complete effacement of architecture

    • Closely packed neoplastic follicles, fairly uniform in size and shape

    • Follicles usually poorly circumscribed with faint or absent mantle zones

    • “Cracking” artifact may surround neoplastic follicles

    • Neoplastic follicles are composed of centrocytes and centroblasts

      • Cells randomly distributed throughout individual follicles, without polarity

      • Infrequent mitoses and absent or scanty tingible body macrophages

      • Centrocytes: Small to large with angulated, elongated, or twisted nuclei, with dark chromatin and scant cytoplasm

      • Centroblasts: Large cells with oval or multilobated nuclei, vesicular chromatin, 1-3 nucleoli, and moderate cytoplasm

    • Diffuse areas with or without sclerosis

      • More frequent in mesenteric and retroperitoneal lymph nodes

      • Scattered interfollicular neoplastic lymphocytes are not considered as diffuse growth pattern

      • Follicular dendritic cell meshworks are absent in diffuse areas

  • Bone marrow

    • Paratrabecular aggregates of centrocytes and, less frequently, centroblasts in bone marrow

      • Aspirate smears may have scant lymphoma cells or are negative

    • Interstitial &/or diffuse patterns in advanced disease

  • Peripheral blood

    • Marked leukemic involvement in 5-10% of patients

    • Neoplastic cells have highly cleaved nuclei and are known as “buttock cells”

    • Low-level involvement is detected by molecular methods in ˜ 90% of patients

  • Liver

    • Portal tracts are preferentially involved

    • Large mass lesions usually indicate transformation to DLBCL

  • Spleen

    • Preferential involvement of white pulp

  • Unusual morphologic variants of FL

    • Floral variant

      • Mantle zone lymphocytes penetrate into neoplastic follicles, imparting irregular shapes

      • Better highlighted with follicular dendritic cell markers, e.g., CD21

      • Often grade 3

    • Plasmacytic differentiation

      • Focal plasmacytic differentiation can occur rarely in FL, intrafollicular or interfollicular

      • Extreme degrees with intracytoplasmic inclusions appear as “signet ring cells”

    • Marginal zone differentiation

      • Monocytoid cells with clear cytoplasm at periphery of neoplastic follicles

      • Has been correlated with poorer prognosis

Cytologic Features

  • Diagnosis of FL can be established by FNA with ancillary support

    • In smears, aggregates of cells bound by follicular dendritic cells

    • Variable mixture of centrocytes and centroblasts

    • Usually, absence of tingible body macrophages

Grading of FL

  • Grading has prognostic and therapeutic significance

  • Most reliably performed on lymph node biopsy specimen

  • System is based on mean number of centroblasts per high power field (HPF)

    • Count 10 HPFs and divide by 10

  • Grade 1: 0-5 centroblasts/HPF

  • Grade 2: 6-15 centroblasts/HPF

  • Grade 3: > 15 centroblasts/HPF

    • Grade 3A: Centrocytes admixed with centroblasts

    • Grade 3B: Sheets of centroblasts with rare or no centrocytes

  • Remember: Cutoff values are based on 40x objective and 18 mm field-of-view ocular

    • Many microscopes have larger field-of-view ocular

      • 20 mm field-of-view ocular: Divide 10 HPF count by 12

      • 22 mm field-of-view ocular: Divide 10 HPF count by 15

  • 2008 WHO classification recommends lumping cases of FL 1-2 together as low grade

    • Minimal differences in outcome between patients with FL grade 1 vs. 2

    • Diffuse areas > 25% of grade 3 FL should be diagnosed as DLBCL

Histologic Discordance (Discrepant Histology) in Patients with FL

  • FL involving different lymph node groups may show different grades

    • Occurs in up to 1/3 of patients who undergo staging laparotomy

  • Lymph node can be involved by grade 3 FL or DLBCL with bone marrow showing grade 1 FL

    • Occurs in ˜ 10-20% of patients with grade 3 FL or DLBCL

    • Low-grade bone marrow involvement does not affect prognosis

Reporting Pattern in FL

  • Most reliably performed on lymph node biopsy specimen

  • Follicular: > 75% follicular

  • Follicular and diffuse: 25-75% follicular

  • Focally follicular: 1-25% follicular

  • Diffuse: 0% follicular

Diffuse Follicular Lymphoma

  • Diffuse growth of small centrocytes with few or absent centroblasts

    • Immunophenotype: CD10(+), Bcl-6(+), Bcl-2(+)

    • IgH-BCL2 fusion gene or t(14;18)(q32;q21) present

  • Rare diagnosis; more common in core needle biopsy specimens

    • Extensive sampling may reveal focal follicular pattern

Intrafollicular Neoplasia/In Situ Follicular Lymphoma

  • Lymph node with widely spaced follicles of which a subset have Bcl-2(+) germinal centers

    • Bcl-2 expression by germinal centers is characteristically bright

    • Bcl-2(+) follicles have immunophenotype of FL and t(14;18)

    • Using histologic criteria alone, diagnosis of FL can be difficult or not possible

  • Patients with intrafollicular neoplasia may

    • Have FL elsewhere simultaneously or develop FL subsequently

    • Have other types of non-Hodgkin lymphoma or Hodgkin lymphoma simultaneously or subsequently

    • Not develop lymphoma on clinical follow-up

Clinically Aggressive B-cell Lymphoma

  • FL transformation to more clinically aggressive B-cell lymphomas occurs in ˜ 30% of FL patients

  • Usually transforms into DLBCL

    • Accounts for most disease-related deaths

  • Transformed tumor less often resembles Burkitt lymphoma (BL) or tumor with features intermediate between BL and DLBCL

  • Transformation is commonly associated with

    • Resistance to therapy and median survival ˜ 1 year

    • Inactivation of P53 or P16; activation of MYC

Pediatric FL

  • Localized disease, usually involves neck lymph nodes

  • Extranodal sites also affected: testis, Waldeyer ring

  • High histological grade; usually with large follicles

  • Usually Bcl-2(-) and lacks t(14;18)(q32;q21) or IgH-BCL2

  • Most patients have good prognosis without disease progression



  • Monotypic surface Ig(+); pan-B-cell markers(+)

  • CD10(+), Bcl-6(+)

    • CD10 and Bcl-6 more brightly expressed within follicles than in interfollicular regions

  • HGAL(+), LMO2(+)

  • Bcl-2(+) in 85-90% of FL grade 1 and grade 2; 50% in FL grade 3

    • Bcl-2(+) is useful to distinguish FL from reactive follicles that are Bcl-2(-)

  • Follicular dendritic cell meshworks are present in follicles

    • Variable expression of CD21, CD23, or CD35

  • CD23(+/-), IRF-4/MUM1(-)

  • FLs are usually CD5(-), CD43(-)

    • Small subset (< 5%) can be CD5(+) or CD43(+)

  • CD2(-), CD3(-), CD4(-), CD7(-), CD8(-)

  • Proliferation rate of FLs assessed by Ki-67

    • Percentage of Ki-67(+) cells correlates with grade

      • Most low-grade FLs show low proliferation rate (< 20%)

      • High-grade FLs show moderate to high proliferation rate (> 40%)

    • Approximately 20% of low-grade FLs have moderate/high proliferation rate

      • These FLs appear to behave more aggressively, similar to grade 3A FL

  • Grade 3 FLs

    • Can be CD10(-), Bcl-2(-), IRF-4/MUM1(+)


  • 80-90% of cases have t(14;18)(q32;q21)

    • Juxtaposes BCL2 at 18q21 adjacent to IgH on derivative chromosome 14

    • Is rarely (10%) the only karyotypic abnormality

  • Other common chromosomal aberrations in FL include

    • Deletions of 1p, 6q, 10q, 17p

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

  • Complex karyotype correlates with poorer prognosis

In Situ Hybridization

  • FISH can detect t(14;18)(q32;q21) in up to 90% of FL cases

    • Large probes can detect multiple breakpoints


  • Monoclonal IgH and Ig light chain gene rearrangements

    • Variable regions of Ig genes undergo extensive and ongoing mutations

    • Mutations can cause false-negative result when using PCR to assess for Ig gene rearrangements

      • Multiple primer sets are therefore required for analysis

  • There are multiple breakpoints in Bcl-2 that must be individually assessed by PCR

    • Major breakpoint cluster region (MBR): ˜ 50-60% of FLs with t(14;18)

    • Minor breakpoint cluster region (MCR): ˜ 5-10% of FLs

    • Intermediate cluster region (ICR): ˜ 10-15% of FLs

    • 5′ breakpoint region: ˜ 5% of FLs

Array CGH

  • ˜ 90% of FLs have abnormalities detected by CGH or array CGH

    • Gains: 2p15, 7p, 7q, 8q, 12q, 18p, 18q

    • Losses: 1p36, 3q, 6q, 9p, 11q, 13q, 17p

  • Abnormalities associated with worse prognosis

    • Loss of 6q or 9p21

    • Gain of chromosome X

  • Abnormalities associated with transformation to DLBCL

    • Gains of 2, 3q, and 5

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

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