HAEM4Backup: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.
  • 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 [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)	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) [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

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 "Cite" icon at top of page)

Notes

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