HAEM5:Follicular lymphoma

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Follicular Lymphoma.

Other relevent pages include: HAEM4:Testicular Follicular Lymphoma

Note: autho needs to correlate with Testicular Follicular Lymphoma

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Primary Author(s)*

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

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

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	B-cell lymphoid proliferations and lymphomas
Family	Mature B-cell neoplasms
Type	N/A
Subtype(s)	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.
  • 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)
  • There is emerging evidence that FL may arise from in situ FL or as a primary
• 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.

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Clinical Features

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• 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.

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Sites of Involvement

Lymph Nodes / Lymphadenopathy; Spleen; Bone Marrow  

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Morphologic Features

Appearance of predominantly follicular pattern

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

Grade 1:   0-5 centroblasts/high power field (hpf)

Grade 2:  6-15 centroblasts/hpf

Grade III: >15 centroblasts/hpf

  Grade IIIa:  centrocytes present

Grade IIIb:  sheets of centroblasts

Immunophenotype

Typically, FL is 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)

Chromosomal Rearrangements (Gene Fusions)

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
t(14;18)(q32;q21)	5' IGH / 3' BCL2	der(18)	80%~90%	No	No	No	Rarely, BCL2 rearrangement may also be observed with IGK at 2p11.2 or IGL at 22q11.22. Additional info and example karyotypes can be found here.

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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%

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editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• 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

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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).

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

Characteristic Chromosomal Patterns

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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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Gene Mutations (SNV / INDEL)

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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.

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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

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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

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

HAEM5:Follicular lymphoma

HAEM5:In situ follicular B-cell neoplasm

HAEM5:Duodenal-type follicular lymphoma

References

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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 09/6/2024, https://ccga.io/index.php/HAEM5:Follicular_lymphoma.