Follicular Lymphoma

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Primary Author(s)*

Ruthann Pfau, PhD, FACMG, Nationwide Children's Hospital

Cancer Category/Type

Mature B Cell Neoplasm

Cancer Sub-Classification / Subtype

Follicular Lymphoma

Definition / Description of Disease

  • Follicular Lymphoma (FL) arises from germinal center B cells of the secondary lymphatic system (lymph nodes, spleen)
  • Four variants of FL are commonly recognized:  in situ FL, duodenal-type FL, testicular FL, and diffuse FL [1].
  • For most patients, FL is a chronic, incurable disease with survival often measured in decades.
  • Histologic transformation to more aggressive disease with potentially fatal outcome may occur

Synonyms / Terminology

Follicular Center Lymphoma; Follicle-related B-cell Lymphoma

Epidemiology / Prevalence

Slight male predominance (male-to-female ratio of 1.2:1)

Median age at diagnosis is 60-65 years;

Progressive increase in incidence between ages 35-70

FL is extremely rare in children; considered a separate entity from adult FL

~5% of all hematological neoplasms are FL

~20% of all non-Hodgkin lymphomas are FL

Highest incidence in developed/high income countries

Second most common lymphoma in the USA and western Europe

Most common lymphoma among non-Hispanic white population [2]

Environmental exposures to pesticides and herbicides as risk factors are disputed; Hair dye use prior to 1980 is associated with increased risk (meta RR = 1.66) [3, 4].

Genetic risk factors may include SNPs within HLA class I or II genes [8] or homozygosity of HLA class II genes [9]; these features have been identified within a few familial cases of FL.

Clinical Features [1, 2, 3, 4]

  • FL commonly presents as painless lymphadenopathy
  • May wax and wane over years before diagnosis
  • Majority of cases have widespread involvement at diagnosis
  • Bone marrow involvement in 40-70% of cases at diagnosis
  • May not require treatment depending staging and other parameters.

Sites of Involvement [1, 2, 3, 4]

Lymph Nodes / Lymphadenopathy; Spleen; Bone Marrow  

Morphologic Features [1, 2, 3, 4]

Appearance of predominantly follicular pattern

Consists of both centrocytes and centroblasts, with the relative proportions of these cells informing grading

Grade I:   0-5 centroblasts/high power field (hpf)

Grade II:  6-15 centroblasts/hpf

Grade III: >15 centroblasts/hpf

  Grade IIIa:  centrocytes present

Grade IIIb:  sheets of centroblasts

Immunophenotype [1, 9, 10]

Typical FL has CD10+, BL2+. Atypical FL subgroups CD10- and/or BCL2 - all FL are STMN+ - useful differentiator between atypical FL and MZL [9]

Finding Marker
Positive (universal) BCL2, CD10, CD19, CD20, CD79a, STMN+
Positive (subset) atypical FL [CD10+/- and/or BCL2 +/-]
Negative (universal) CD5-, CD23-, CD43-
Negative (subset)

Chromosomal Rearrangements (Gene Fusions) [1, 2, 5, 7, 9, 11]

BCL2 and BCL6 rearrangements appear mutually exclusive [9]

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
t(14;18)(q32;q21) IGH-BCL2 der(14) 85-90%
t(3;14)(q27;q32) BCL6-IGH der(3) 10-15%

Characteristic Chromosomal Aberrations / Patterns [11]

Put your text here

Genomic Gain/Loss/LOH

deletions in 1p36, 6q, 10q, 13p, 17p; gains of 1q, 2p, 7, 8, 12q, 18q

Gene Mutations (SNV/INDEL)

Put your text here and/or fill in the tables

Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
KMT2D epigenetic modification EXAMPLE LOF 70-80%
CREBBP epigenetic modification 70%
EP300 epigenetic modification 15%
TNFRSF14 epigenetic modification 40%
Histone H1, H2B families epigenetic modification

Other Mutations

Type Gene/Region/Other
Concomitant Mutations EXAMPLE IDH1 R123H
Secondary Mutations EXAMPLE Trisomy 7
Mutually Exclusive BCL2, BCL6 rearrangement

Epigenomics (Methylation)

KMT2D, H3K4 methyltransferase, CREBBP Histone acetyltransferase (HAT) enzyme, and EZH2 SET domain histone methyltransferase mutations

Genes and Main Pathways Involved

BCR-NFκB, JAK/STAT; mTORC signaling

Diagnostic Testing Methods

Surgical excision preferred; FISH or PCR for BCL2 rearrangement; preserve frozen tissue for further molecular testing

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Most common: Risk stratification using Follicular Lymphoma International Prognostic Index (FLIPI) is based on clinical indicators.

(m7-FLIPI adds performance status plus mutational status of EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11 - utility not confirmed [7])

Familial Forms

SNPs within HLA class I or II genes [8] or homozygosity of HLA class II genes [9]

Other Information Follicular Lymphoma CNV plot:


Testicular Follicular Lymphoma

In Situ Follicular Neoplasia

Duodenal-Type Follicular Lymphoma Follicular Lymphoma CNV plot your links here (use "Link" icon at top of page)


(use "Cite" icon at top of page) [1][2][3][4][5][6][7][8][9]


Precursor B cells typically mature in the marrow, where they may become mature naïve B cells or may apoptose.  Following antigen exposure, mature B cells may become short lived plasma cells, or may enter the germinal center and undergo somatic hypermutation and heavy chain class switching.

  1. Swerdlow, Steven H.; et al. (2016-05-19). "The 2016 revision of the World Health Organization classification of lymphoid neoplasms". Blood. 127 (20): 2375–2390. doi:10.1182/blood-2016-01-643569. ISSN 0006-4971.
  2. Cerhan, James R. (08 2020). "Epidemiology of Follicular Lymphoma". Hematology/Oncology Clinics of North America. 34 (4): 631–646. doi:10.1016/j.hoc.2020.02.001. ISSN 1558-1977. PMC 7323888 Check |pmc= value (help). PMID 32586570 Check |pmid= value (help). Check date values in: |date= (help)
  3. Odutola, Michael K.; et al. (2020-11). "Lifestyle and risk of follicular lymphoma: a systematic review and meta-analysis of observational studies". Cancer causes & control: CCC. 31 (11): 979–1000. doi:10.1007/s10552-020-01342-9. ISSN 1573-7225. PMID 32851495 Check |pmid= value (help). Check date values in: |date= (help)
  4. Pickard, Lucy; et al. (10 2020). "Follicular lymphoma genomics". Leukemia & Lymphoma. 61 (10): 2313–2323. doi:10.1080/10428194.2020.1762883. ISSN 1029-2403. PMID 32427008 Check |pmid= value (help). Check date values in: |date= (help)
  5. Krysiak, Kilannin; et al. (01 26, 2017). "Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma". Blood. 129 (4): 473–483. doi:10.1182/blood-2016-07-729954. ISSN 1528-0020. PMC 5270390. PMID 28064239. Check date values in: |date= (help)
  6. Dreyling, M.; et al. (12 01, 2017). "Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Annals of Oncology: Official Journal of the European Society for Medical Oncology. 28 (12): 3109. doi:10.1093/annonc/mdx020. ISSN 1569-8041. PMID 28327933. Check date values in: |date= (help)
  7. McAulay, K. A.; et al. (2015-08). "Human leukocyte antigens and genetic susceptibility to lymphoma". Tissue Antigens. 86 (2): 98–113. doi:10.1111/tan.12604. ISSN 1399-0039. PMID 26189878. Check date values in: |date= (help)
  8. Wang, Sophia S.; et al. (07 15, 2018). "HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes". Cancer Research. 78 (14): 4086–4096. doi:10.1158/0008-5472.CAN-17-2900. ISSN 1538-7445. PMC 6065509. PMID 29735552. Check date values in: |date= (help)
  9. Marafioti, Teresa; et al. (2013-05). "Another look at follicular lymphoma: immunophenotypic and molecular analyses identify distinct follicular lymphoma subgroups". Histopathology. 62 (6): 860–875. doi:10.1111/his.12076. ISSN 1365-2559. PMID 23509938. Check date values in: |date= (help)