In situ follicular B-cell neoplasm
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:In Situ Follicular Neoplasia.
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Primary Author(s)*
Rachel D. Burnside, PhD, MBA, FACMGG
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) | In situ follicular B-cell neoplasm |
Definition / Description of Disease
In situ FL is a proliferation of abnormal B-cells within the germinal center or follicles of secondary lymphoid tissues. The neoplastic cells do not infiltrate beyond the follicular dendritic cell barrier and remain confined to the follicles.
Synonyms / Terminology
Intrafollicular neoplasia, in situ follicular neoplasia (ISFN), FL in situ (FLIS), lymphoma-like B-cells of uncertain/undetermined significance, FL B-cells of undetermined significance, in situ localization of FL, incipient FL, FL of compartmentalized follicular center cells[1]
Epidemiology / Prevalence
The prevalence of in situ FL is unknown but is found in 2-3% of reactive lymph nodes. Fewer than 5% of cases progress to overt FL.[2]
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) |
Sites of Involvement
Abnormal B-cells are confined to the germinal centers in otherwise reactive lymph nodes and do not infiltrate the interfollucular regions.
Morphologic Features
Morphology is insufficient to diagnose in situ FL; immunhistochemistry and genetic testing for t(14;18) are necessary. GCs show monotonous morphology and lack tingible body macrophages. By IHC, cells show strong and uniform staining for BCL2 and CD10 and a low Ki67 index.[3]
The following description of ISFN is derived from Jegalian et al[4]:
- Unlike early-stage or partial involvement of FL, in situ FL retains follicular architecture with normal-sized follicles;
- Involved follicles are dispersed throughout the lymph node, as opposed to being clustered together;
- There is an intact cuff with distinct edges to the GC;
- Very strong and uniform expression of BCL2 and CD10 within the follicle;
- Atypical cells are confined to the GC and are almost completely centrocytes (B-cells which have undergone somatic hypermutation of the B-cell receptor but not yet undergone anitbody affinity maturation)
Immunophenotype
Low Ki67 index
| Finding | Marker |
|---|---|
| Positive (universal) | BCL2+ (strong) |
| Positive (universal) | CD10+ (strong) |
| Negative (universal) | IGD- |
| Negative (universal) | CD3- |
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 |
|---|---|---|---|---|---|---|---|
| t(14;18)(q32;q21) or rarely, t(2;18)(p11;q21) or t(18;22)(q21;q11.2) | 5' BCL2/3' IGH | der(18) | 80-90% of all FL | Yes, but not restricted to FL; may also be seen in DLBCL | No | No | The translocation results in the juxtaposition of the BCL2 major or minor breakpoint cluster with the VDJ region of IGH during erroneous VDJ recombination[5][6] |
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). |
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). |
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 |
|---|---|---|---|---|---|---|---|---|
| CREBBP inactivating missense variants (various); mutation hotspots in exons 24-28 and exon 30. | TSG | 32.6%[7] | Inactivating mutations prevent acetylation of the protein and creates an environment permissive for accumulation of mutations[8]. Mutations in CREBBP are thought to be early driver mutations and possibly necessary for transformation to FL, as they have been found in ISFN and paired FL samples[9].
| |||||
| EZH2
p.Y646, p.A682G, p.A692V Gain of function variants. Y646 may have multiple amino acid replacements |
8.7%[7] |
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.
Epigenomic Alterations
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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 |
Genetic Diagnostic Testing Methods
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Familial Forms
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Additional Information
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Links
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References
- ↑ Carbone, Antonino; et al. (2014-03). "Emerging issues after the recognition of in situ follicular lymphoma". Leukemia & Lymphoma. 55 (3): 482–490. doi:10.3109/10428194.2013.807926. ISSN 1042-8194. Check date values in:
|date=(help) - ↑ Tamber, Gurdip S; et al. (2021-12). "In‐situ follicular neoplasia: a clinicopathological spectrum". Histopathology. 79 (6): 1072–1086. doi:10.1111/his.14535. ISSN 0309-0167. Check date values in:
|date=(help) - ↑ Vogelsberg, Antonio; et al. (2021). "Genetic evolution of in situ follicular neoplasia to aggressive B-cell lymphoma of germinal center subtype". Haematologica. 106 (10): 2673–2681. doi:10.3324/haematol.2020.254854. ISSN 1592-8721. PMC PMC8485666 Check
|pmc=value (help). PMID 32855278 Check|pmid=value (help).CS1 maint: PMC format (link) - ↑ . doi:10.1182/blood-2011-05-355255. PMC 3175777. PMID 21768298 https://ashpublications.org/blood/article/118/11/2976/28482/Follicular-lymphoma-in-situ-clinical-implications. Missing or empty
|title=(help)CS1 maint: PMC format (link) - ↑ . doi:10.1182/blood-2011-05-355255. PMC 3175777. PMID 21768298 https://ashpublications.org/blood/article/118/11/2976/28482/Follicular-lymphoma-in-situ-clinical-implications. Missing or empty
|title=(help)CS1 maint: PMC format (link) - ↑ Sotomayor, Edgar A.; et al. (2007-10-01). "In situ follicular lymphoma with a 14;18 translocation diagnosed by a multimodal approach". Experimental and Molecular Pathology. 83 (2): 254–258. doi:10.1016/j.yexmp.2007.03.001. ISSN 0014-4800.
- ↑ 7.0 7.1 Pasqualucci, Laura; et al. (2011-03). "Inactivating mutations of acetyltransferase genes in B-cell lymphoma". Nature. 471 (7337): 189–195. doi:10.1038/nature09730. ISSN 1476-4687. Check date values in:
|date=(help) - ↑ Schmidt, Janine; et al. (2018-12-20). "CREBBP gene mutations are frequently detected in in situ follicular neoplasia". Blood. 132 (25): 2687–2690. doi:10.1182/blood-2018-03-837039. ISSN 0006-4971.
- ↑ Schmidt, Janine; et al. (2018-12-20). "CREBBP gene mutations are frequently detected in in situ follicular neoplasia". Blood. 132 (25): 2687–2690. doi:10.1182/blood-2018-03-837039. ISSN 0006-4971.
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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: “In situ follicular B-cell neoplasm”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:In_situ_follicular_B-cell_neoplasm.