Paediatric-type follicular lymphoma

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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
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Primary Author(s)*

  • Kathleen M. Schieffer, PhD
  • Ruthann Pfau, PhD, FACMG

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category B-cell lymphoid proliferations and lymphomas
Family Mature B-cell neoplasms
Type Follicular lymphoma
Subtype(s) Paediatric-type follicular lymphoma

Definition / Description of Disease

  • Paediatric-type follicular lymphoma (PTFL) is an uncommon variant of nodal follicular B-cell lymphoma presenting in children and young adults
    • Does not include tumors with areas of diffuse large B-cell lymphoma or lymphomas of follicle centre derivation
    • Does not include testicular follicular lymphoma or large B-cell lymphoma with IRF4 rearrangement
  • Characterized by high histological grade (Grade 3) and high proliferation rate, but indolent localized disease (commonly Stage I/II disease)
  • Genetically distinct from its adult counterpart
  • Presents as asymptomatic, localized lymphadenopathy
  • Prognosis is excellent
    • Event-free survival: ~95%
    • Overall survival: 100%
  • Most individuals with localized disease have complete remission following surgical resection
  • Many do not require adjuvant chemotherapy or radiation


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[1][2][3][4][5][6][7]

Synonyms / Terminology

  • Not applicable

Epidemiology / Prevalence

  • Male predominance (male-to-female ratio ≥ 10:1)
  • Median age of onset: 15-18 years old


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[1][2][3][8][9][10][11][12]

Clinical Features

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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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  • Most frequently presents as a singular site of lymph node enlargement
  • Additional symptoms, such as fever, weight loss (i.e. B symptoms) are not typically present


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[3]

Sites of Involvement

  • Primary site: head and neck region, including the cervical, postaurical, periparotid, submandibular, and submental lymph nodes
  • Other sites: inguinal or femoral lymph nodes
  • Bone marrow or bone involvement is exceedingly rare


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[1][2][3][8][9][10][11][12]

Morphologic Features

  • Large, expansile atypical lymphoid follicles with attenuated mantle zones
  • Effaced lymph node architecture
  • Germinal centers composed of monotonous intermediate sized blastoid cells with round/oval nuclei lacking prominent nucleoli, scant cytoplasm, and finely dispersed chromatin
  • Tingible body macrophages
  • Starry-sky appearance
  • Apparent mitotic figures
  • Lacks marked increase of interfollicular B-cells, distinguishing from pediatric nodal marginal zone lymphoma
  • Effaced lymph node architecture distinguishes PTFL from reactive follicular hyperplasia with clonal B cells


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[3][6][13]

Immunophenotype

  • PTFL cells demonstrate positivity of the mature B cell markers CD20, CD79a, and PAX5
  • Germinal cell-associated markers BCL6, CD10, LLT1, and STMN1 are also strongly expressed in these cells
  • Nuclear FOXP1 transcription factor staining in >80% of PTFL cells
  • Although weak staining may be seen in few cases, BCL2 is typically negative, consistent with the absence of BCL2 rearrangement which distinguishes PTFL from other follicular lymphomas
  • IRF4/MUM1 is negative, distinguishing PTFL from large B-cell lymphoma with IRF4 rearrangement
  • The Ki67 proliferation index is moderate to high (>30% of PTFL cells)
Finding Marker
Positive (universal) CD20, CD79a, PAX5, BCL6, CD10, LLT1, STMN1, FOXP1
Negative BCL2, IRF4/MUM1


editUnassigned References
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[2][3][8][9][10][11]

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).


editv4:Chromosomal Rearrangements (Gene Fusions)
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  • Negative for BCL2, BCL6, IGF4, IG@, and MYC rearrangement[8][9][10][12]


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)
  • No genomic findings currently assist in diagnosis.
  • No differences in overall survival between patients with and without genomic alterations[12]
  • Activating alterations within the MAPK pathway alterations are frequently reported in PTFL which demonstrate constitutive activation of MEK/ERK signaling. Currently, the utility of MEK inhibitors, such as trametinib, in PTFL is not established.[9]

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. Do not delete table.)

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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  • Copy number alterations are uncommon (~0.5% of the genome)[9]
  • Copy neutral loss of heterozygosity (cnLOH) of 1p36 is most frequently reported, commonly overlapping the TNFRSF14 gene and frequently in patients with concomitant TNFRSF14 non-synonymous variation[9][10][12][14]
Chromosome Number Gain/Loss/Amp/LOH Region Reference
1p36 cnLOH overlapping TNFRSF14 gene [9][10][12][14]
1p36 Loss overlapping TNFRSF14 gene [10][12][14]

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. Do not delete table.)

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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  • No characteristic chromosomal aberrations or patterns are described

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.


editv4:Gene Mutations (SNV/INDEL)
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  • Although alterations in chromatin-modifying genes, such as KMT2D, CREBBP, EP300, EZH2, are frequently described in adult follicular lymphoma[15][16], these genes are not recurrently altered in PTFL
  • PTFL frequently presents with somatic activating alterations in the MAPK signaling pathway[9][14]
  • Although IRF8 alterations in the C-terminal domain are described in adult follicular lymphoma and diffuse large B-cell lymphoma, the hotspot alteration p.K88R is specific to PTFL[9][11][14]
Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other) Reference(s)
MAP2K1 Exon 2 (p.F53Y, p.Q56P, p.K77E, p.K57R)

Exon 3 (p.C121S)

Oncogene Gain-of-function; Driver 43-49% [9][11][14]
TNFRSF14 Exons 1-3 inactivating mutations Tumor suppressor Loss-of-function; Driver 33-54% [9][10][12][14]
IRF8 p.K88R Other Loss-of-function; Driver 15-50% [9][11][14]
MAPK1 p.N297D, p.D321G Oncogene Gain-of-function; Driver 10% [9]
GNA13 Identified throughout the gene Tumor suppressor Loss-of-function 9-11% [10][14]

Other Mutations

Type Gene/Region/Other Reference(s)
Concomitant Mutations TNFRSF14 missense mutation and cnLOH [9][10][12][14]
Mutually Exclusive Oncogenic driver mutations (MAP2K1, MAPK1, RRAS) [9][14]

Epigenomic Alterations

  • Not applicable

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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  • MAP2K1 encodes mitogen-activated protein kinase kinase 1 (also known as MEK1) involved in the MAPK signaling pathway. Oncogenic MAP2K1 alterations are predicted to constitutively activate the MAPK signaling pathway through ERK1/2 phosphorylation.[17]
  • TNFRSF14 encodes the tumor necrosis factor (TNF) superfamily member herpesvirus entry mediator (HVEM) involved in activating both inflammatory and inhibitory T-cell responses. TNFRSF14 alterations disrupt the interaction of TNFRSF14 and the immunoglobulin superfamily proteins B and T lymphocyte attenuator (BTLA) receptor, thereby abrogating B-cell receptor activation.[18][19]
  • IRF8 encodes interferon regulatory factor 8 primarily expressed in immune cells. In B cells, IRF8, in tandem with IRF4, plays a critical role in pre-B cell development.[20]
  • GNA13 encodes G protein subunit alpha 13 involved in signal transduction. GNA13 is expressed in germinal center B cells and is involved in sphingosine-1-phosphate signaling and germinal center confinement.[21][22]

Genetic Diagnostic Testing Methods

  • Histopathology and immunophenotyping

Familial Forms

  • Not applicable

Additional Information

  • Not applicable

Links

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References

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  1. ↑ 1.0 1.1 1.2 Q, Liu; et al. (2013). "Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma". doi:10.1097/PAS.0b013e31826b9b57. PMC 3566339. PMID 23108024.CS1 maint: PMC format (link)
  2. ↑ 2.0 2.1 2.2 2.3 A, Louissaint; et al. (2012). "Pediatric-type nodal follicular lymphoma: an indolent clonal proliferation in children and adults with high proliferation index and no BCL2 rearrangement". PMID 22855608.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Jaffe ES, Harris NL, Siebert R et al (2017) Paediatric-type follicular lymphoma. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, pp 278–279
  4. ↑ A, Attarbaschi; et al. (2013). "Children and adolescents with follicular lymphoma have an excellent prognosis with either limited chemotherapy or with a "Watch and wait" strategy after complete resection". PMID 23665980.
  5. ↑ W, Woessmann; et al. (2019). "Rare mature B-cell lymphomas in children and adolescents". PMID 31187530.
  6. ↑ 6.0 6.1 I, Oschlies; et al. (2010). "Pediatric follicular lymphoma--a clinico-pathological study of a population-based series of patients treated within the Non-Hodgkin's Lymphoma--Berlin-Frankfurt-Munster (NHL-BFM) multicenter trials". doi:10.3324/haematol.2009.013177. PMC 2817028. PMID 19679882.CS1 maint: PMC format (link)
  7. ↑ C, O'Suoji; et al. (2016). "Rare Pediatric Non-Hodgkin Lymphomas: A Report From Children's Oncology Group Study ANHL 04B1". PMID 26728447.
  8. ↑ 8.0 8.1 8.2 8.3 C, Agostinelli; et al. (2019). "Novel markers in pediatric-type follicular lymphoma". doi:10.1007/s00428-019-02681-y. PMC 6881426. PMID 31686194.CS1 maint: PMC format (link)
  9. ↑ 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 9.12 9.13 9.14 9.15 A, Louissaint; et al. (2016). "Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations". doi:10.1182/blood-2015-12-682591. PMC 5000844. PMID 27325104.CS1 maint: PMC format (link)
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 J, Schmidt; et al. (2016). "Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene". doi:10.1182/blood-2016-03-703819. PMC 5000845. PMID 27257180.CS1 maint: PMC format (link)
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 Mg, Ozawa; et al. (2016). "A study of the mutational landscape of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma". doi:10.1038/modpathol.2016.102. PMC 5047957. PMID 27338637.CS1 maint: PMC format (link)
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8 I, Martin-Guerrero; et al. (2013). "Recurrent loss of heterozygosity in 1p36 associated with TNFRSF14 mutations in IRF4 translocation negative pediatric follicular lymphomas". doi:10.3324/haematol.2012.073916. PMC 3729904. PMID 23445872.CS1 maint: PMC format (link)
  13. ↑ Q, Liu; et al. (2013). "Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma". doi:10.1097/PAS.0b013e31826b9b57. PMC 3566339. PMID 23108024.CS1 maint: PMC format (link)
  14. ↑ 14.00 14.01 14.02 14.03 14.04 14.05 14.06 14.07 14.08 14.09 14.10 J, Schmidt; et al. (2017). "Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation". doi:10.1182/blood-2017-03-776278. PMC 5520474. PMID 28533310.CS1 maint: PMC format (link)
  15. ↑ J, Okosun; et al. (2014). "Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma". doi:10.1038/ng.2856. PMC 3907271. PMID 24362818.CS1 maint: PMC format (link)
  16. ↑ Mr, Green; et al. (2015). "Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation". doi:10.1073/pnas.1501199112. PMC 4364211. PMID 25713363.CS1 maint: PMC format (link)
  17. ↑ Yaeger, Rona; et al. (2019). "Targeting Alterations in the RAF–MEK Pathway". Cancer Discovery. 9 (3): 329–341. doi:10.1158/2159-8290.CD-18-1321. ISSN 2159-8274. PMC 6397699. PMID 30770389.CS1 maint: PMC format (link)
  18. ↑ S, Ma; et al. (2008). "Interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to down-regulate pre-B-cell receptor and promote cell-cycle withdrawal in pre-B-cell development". doi:10.1182/blood-2007-08-110106. PMC 2214771. PMID 17971486.CS1 maint: PMC format (link)
  19. ↑ S, Ma; et al. (2006). "IFN regulatory factor 4 and 8 promote Ig light chain kappa locus activation in pre-B cell development". PMID 17114461.
  20. ↑ Mw, Steinberg; et al. (2011). "The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation". doi:10.1111/j.1600-065X.2011.01064.x. PMC 3381650. PMID 22017438.CS1 maint: PMC format (link)
  21. ↑ Ja, Green; et al. (2012). "S1PR2 links germinal center confinement and growth regulation". doi:10.1111/j.1600-065X.2012.01114.x. PMC 3335345. PMID 22500830.CS1 maint: PMC format (link)
  22. ↑ J, Shimono; et al. (2018). "Analysis of GNA13 Protein in Follicular Lymphoma and its Association With Poor Prognosis". doi:10.1097/PAS.0000000000000969. PMC 6266301. PMID 30307409.CS1 maint: PMC format (link)

Notes

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