Paediatric-Type Follicular Lymphoma

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This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

Primary Author(s)*

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

Cancer Category/Type

Cancer Sub-Classification / Subtype

  • Paediatric-type follicular lymphoma

Definition / Description of Disease[1][2][3][4][5][6][7]

  • 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

Synonyms / Terminology

  • Not applicable

Epidemiology / Prevalence[1][2][3][8][9][10][11][12]

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

Clinical Features[3]

  • 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

Sites of Involvement[1][2][3][8][9][10][11][12]

  • 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

Morphologic Features[3][6][13]

  • 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

Immunophenotype[2][3][8][9][10][11]

  • 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

Chromosomal Rearrangements (Gene Fusions)

  • Negative for BCL2, BCL6, IGF4, IG@, and MYC rearrangement[8][9][10][12]

Characteristic Chromosomal Aberrations / Patterns

  • No characteristic chromosomal aberrations or patterns are described

Genomic Gain/Loss/LOH

  • 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]

Gene Mutations (SNV/INDEL)

  • 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]

Epigenomics (Methylation)

  • Not applicable

Genes and Main Pathways Involved

  • 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]

Diagnostic Testing Methods

  • Histopathology and immunophenotyping

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • 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]

Familial Forms

  • Not applicable

Other Information

  • Not applicable

Links

  • Put your links here (use "Link" icon at top of page)

References

  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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