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
Progenetix.org Follicular Lymphoma CNV plot: https://progenetix.org/subsets/list?filters=NCIT:C3209&datasetIds=progenetix
Links
Testicular Follicular Lymphoma
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) [1][2][3][4][5][6][7][8][9]
Notes
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.
- ↑ 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.
- ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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)