Follicular lymphoma

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Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes
This page was converted to the new template on 2023-11-30. The original page can be found at HAEM4:Follicular Lymphoma.

Other relevent pages include: Testicular Follicular Lymphoma

Note: autho needs to correlate with Testicular Follicular Lymphoma

Primary Author(s)*

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

Rachel D. Burnside, PhD, MBA, FACMG, University of Florida

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)
  • WHO 5th edition classifies FL into four variants:  in situ FL, duodenal-type FL, pediatric FL, and Follicular Lymphoma[1].
    • FL is further classified as Classic FL (cFL), characterized by t(14;18), follicular large B-cell lymphoma (FLBL), and FL with uncommon features (uFL)[1]
    • There is emerging evidence that FL may arise from in situ FL or as a primary [2]
  • 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[3]

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

Put your text here and fill in the table (Instruction: Can include references in the table)

Signs and Symptoms EXAMPLE Asymptomatic (incidental finding on complete blood counts)

EXAMPLE B-symptoms (weight loss, fever, night sweats)

EXAMPLE Fatigue

EXAMPLE Lymphadenopathy (uncommon)

Laboratory Findings EXAMPLE Cytopenias

EXAMPLE Lymphocytosis (low level)


editv4:Clinical Features
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  • FL commonly presents as painless lymphadenopathy[3]
  • May wax and wane over years before diagnosis
  • Majority of cases have widespread involvement at diagnosis[3]
  • Bone marrow involvement in 40-70% of cases at diagnosis
  • May not require treatment depending staging and other parameters.


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[1, 2, 3, 4]

Sites of Involvement

Lymph Nodes / Lymphadenopathy; Spleen; Bone Marrow  


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[1, 2, 3, 4]

Morphologic Features

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


editUnassigned References
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[1, 2, 3, 4]

Immunophenotype

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


editUnassigned References
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[1, 9, 10]

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE t(9;22)(q34;q11.2) EXAMPLE 3'ABL1 / 5'BCR EXAMPLE der(22) EXAMPLE 20% (COSMIC)

EXAMPLE 30% (add reference)

Yes No Yes EXAMPLE

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).


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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%


editUnassigned References
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[1, 2, 5, 7, 9, 11]


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)

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])

Individual Region Genomic Gain / Loss / LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.)

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE

7

EXAMPLE Loss EXAMPLE

chr7:1- 159,335,973 [hg38]

EXAMPLE

chr7

Yes Yes No EXAMPLE

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

EXAMPLE

8

EXAMPLE Gain EXAMPLE

chr8:1-145,138,636 [hg38]

EXAMPLE

chr8

No No No EXAMPLE

Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH
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deletions in 1p36, 6q, 10q, 13p, 17p; gains of 1q, 2p, 7, 8, 12q, 18q

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE

Co-deletion of 1p and 18q

Yes No No EXAMPLE:

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns
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Put your text here


editUnassigned References
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[11]

Gene Mutations (SNV / INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.)

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE: TP53; Variable LOF mutations

EXAMPLE:

EGFR; Exon 20 mutations

EXAMPLE: BRAF; Activating mutations

EXAMPLE: TSG EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add Reference)

EXAMPLE: IDH1 R123H EXAMPLE: EGFR amplification EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).


Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


editv4:Gene Mutations (SNV/INDEL)
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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

Epigenomic Alterations

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

Genes and Main Pathways Involved

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Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations EXAMPLE:  Histone modification, chromatin remodeling EXAMPLE:  Abnormal gene expression program
editv4:Genes and Main Pathways Involved
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BCR-NFκB, JAK/STAT; mTORC signaling

Genetic Diagnostic Testing Methods

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

Familial Forms

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

Additional Information

Progenetix.org Follicular Lymphoma CNV plot: https://progenetix.org/subsets/list?filters=NCIT:C3209&datasetIds=progenetix

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.

Links

Testicular Follicular Lymphoma

In Situ Follicular Neoplasia

Duodenal-Type Follicular Lymphoma

Progenetix.org Follicular Lymphoma CNV plot your links here (use "Link" icon at top of page)

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference.)

  1. 1.0 1.1 Alaggio, Rita; et al. (2022). "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms". Leukemia. 36 (7): 1720–1748. doi:10.1038/s41375-022-01620-2. ISSN 0887-6924. PMC 9214472 Check |pmc= value (help). PMID 35732829 Check |pmid= value (help).
  2. Carbone, Antonino; et al. (2012-03). "In situ follicular lymphoma: pathologic characteristics and diagnostic features: In situ follicular lymphoma". Hematological Oncology. 30 (1): 1–7. doi:10.1002/hon.993. Check date values in: |date= (help)
  3. 3.0 3.1 3.2 Ferry, Judith A. (2010-12-01). "Recent Advances in Follicular Lymphoma: Pediatric, Extranodal, and Follicular Lymphoma in Situ". Surgical Pathology Clinics. Current Concepts in Hematopathology. 3 (4): 877–906. doi:10.1016/j.path.2010.08.002. ISSN 1875-9181.

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

*Citation of this Page: “Follicular lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 11/30/2023, https://ccga.io/index.php/HAEM5:Follicular_lymphoma.