View source for HAEM5:In situ follicular B-cell neoplasm

{{DISPLAYTITLE:In situ follicular B-cell neoplasm}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

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<blockquote class='blockedit'>{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This 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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<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>

==Primary Author(s)*==

Rachel D. Burnside, PhD, MBA, FACMGG

__TOC__

==WHO Classification of Disease==

{| class="wikitable"
!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<ref>{{Cite journal|last=Carbone|first=Antonino|last2=Gloghini|first2=Annunziata|date=2014-03|title=Emerging issues after the recognition of in situ follicular lymphoma|url=http://www.tandfonline.com/doi/full/10.3109/10428194.2013.807926|journal=Leukemia & Lymphoma|language=en|volume=55|issue=3|pages=482–490|doi=10.3109/10428194.2013.807926|issn=1042-8194}}</ref>

==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.<ref>{{Cite journal|last=Tamber|first=Gurdip S|last2=Chévarie‐Davis|first2=Myriam|last3=Warner|first3=Margaret|last4=Séguin|first4=Chantal|last5=Caron|first5=Carole|last6=Michel|first6=René P|date=2021-12|title=In‐situ follicular neoplasia: a clinicopathological spectrum|url=https://onlinelibrary.wiley.com/doi/10.1111/his.14535|journal=Histopathology|language=en|volume=79|issue=6|pages=1072–1086|doi=10.1111/his.14535|issn=0309-0167}}</ref>

==Clinical Features==

Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
{| class="wikitable"
|'''Signs and Symptoms'''
|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)

<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)

<span class="blue-text">EXAMPLE:</span> Fatigue

<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
|-
|'''Laboratory Findings'''
|<span class="blue-text">EXAMPLE:</span> Cytopenias

<span class="blue-text">EXAMPLE:</span> 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.<ref>{{Cite journal|last=Vogelsberg|first=Antonio|last2=Steinhilber|first2=Julia|last3=Mankel|first3=Barbara|last4=Federmann|first4=Birgit|last5=Schmidt|first5=Janine|last6=Montes-Mojarro|first6=Ivonne A.|last7=Hüttl|first7=Katrin|last8=Rodriguez-Pinilla|first8=Maria|last9=Baskaran|first9=Praveen|date=2021|title=Genetic evolution of in situ follicular neoplasia to aggressive B-cell lymphoma of germinal center subtype|url=https://haematologica.org/article/view/9914|journal=Haematologica|language=en|volume=106|issue=10|pages=2673–2681|doi=10.3324/haematol.2020.254854|issn=1592-8721|pmc=PMC8485666|pmid=32855278}}</ref>

The following description of ISFN is derived from Jegalian et al<ref>{{Cite journal|url=https://ashpublications.org/blood/article/118/11/2976/28482/Follicular-lymphoma-in-situ-clinical-implications|doi=10.1182/blood-2011-05-355255|pmc=PMC3175777|pmid=21768298}}</ref>:

*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 [https://www.sciencedirect.com/topics/immunology-and-microbiology/centrocyte centrocytes] (B-cells which have undergone somatic hypermutation of the B-cell receptor but not yet undergone anitbody affinity maturation)

<br />

==Immunophenotype==

Low Ki67 index

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||BCL2+ (strong)
|-
|Positive (universal)||CD10+ (strong)
|-
|Negative (universal)||IGD-
|-
|Negative (universal)||CD3-
|}

==Chromosomal Rearrangements (Gene Fusions)==

Put your text here and fill in the table

{| class="wikitable sortable"
|-
!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<ref>{{Cite journal|url=https://ashpublications.org/blood/article/118/11/2976/28482/Follicular-lymphoma-in-situ-clinical-implications|doi=10.1182/blood-2011-05-355255|pmc=PMC3175777|pmid=21768298}}</ref><ref>{{Cite journal|last=Sotomayor|first=Edgar A.|last2=Shah|first2=Inangati M.|last3=Sanger|first3=Warren G.|last4=Mark|first4=Hon Fong L.|date=2007-10-01|title=In situ follicular lymphoma with a 14;18 translocation diagnosed by a multimodal approach|url=https://www.sciencedirect.com/science/article/pii/S001448000700038X|journal=Experimental and Molecular Pathology|volume=83|issue=2|pages=254–258|doi=10.1016/j.yexmp.2007.03.001|issn=0014-4800}}</ref>
|}		
			
==Individual Region Genomic Gain / Loss / LOH==

Put your text here and fill in the table

{| class="wikitable sortable"
|-
!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
|-
|<span class="blue-text">EXAMPLE:</span>

7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>

chr7:1- 159,335,973 [hg38]
|<span class="blue-text">EXAMPLE:</span>

chr7
|Yes
|Yes
|No
|<span class="blue-text">EXAMPLE:</span>

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).
|-
|<span class="blue-text">EXAMPLE:</span>

8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>

chr8:1-145,138,636 [hg38]
|<span class="blue-text">EXAMPLE:</span>

chr8
|No
|No
|No
|<span class="blue-text">EXAMPLE:</span>

Common recurrent secondary finding for t(8;21) (add reference).
|}
==Characteristic Chromosomal Patterns==

Put your text here <span style="color:#0070C0">(''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.'')</span>

{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|<span class="blue-text">EXAMPLE:</span>

Co-deletion of 1p and 18q
|Yes
|No
|No
|<span class="blue-text">EXAMPLE:</span>

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}
==Gene Mutations (SNV / INDEL)==

Put your text here and fill in the table

{| class="wikitable sortable"
|-
!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%<ref name=":0">{{Cite journal|last=Pasqualucci|first=Laura|last2=Dominguez-Sola|first2=David|last3=Chiarenza|first3=Annalisa|last4=Fabbri|first4=Giulia|last5=Grunn|first5=Adina|last6=Trifonov|first6=Vladimir|last7=Kasper|first7=Lawryn H.|last8=Lerach|first8=Stephanie|last9=Tang|first9=Hongyan|date=2011-03|title=Inactivating mutations of acetyltransferase genes in B-cell lymphoma|url=https://www.nature.com/articles/nature09730|journal=Nature|language=en|volume=471|issue=7337|pages=189–195|doi=10.1038/nature09730|issn=1476-4687}}</ref>
|
|
|
|
|
|Inactivating mutations prevent acetylation of the protein and creates an environment permissive for accumulation of mutations<ref>{{Cite journal|last=Schmidt|first=Janine|last2=Ramis-Zaldivar|first2=Joan Enric|last3=Bonzheim|first3=Irina|last4=Steinhilber|first4=Julia|last5=Müller|first5=Inga|last6=Haake|first6=Andrea|last7=Yu|first7=Shan Chi|last8=Raffeld|first8=Mark|last9=Fend|first9=Falko|date=2018-12-20|title=CREBBP gene mutations are frequently detected in in situ follicular neoplasia|url=https://www.sciencedirect.com/science/article/pii/S0006497120429210|journal=Blood|volume=132|issue=25|pages=2687–2690|doi=10.1182/blood-2018-03-837039|issn=0006-4971}}</ref>. 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<ref>{{Cite journal|last=Schmidt|first=Janine|last2=Ramis-Zaldivar|first2=Joan Enric|last3=Bonzheim|first3=Irina|last4=Steinhilber|first4=Julia|last5=Müller|first5=Inga|last6=Haake|first6=Andrea|last7=Yu|first7=Shan Chi|last8=Raffeld|first8=Mark|last9=Fend|first9=Falko|date=2018-12-20|title=CREBBP gene mutations are frequently detected in in situ follicular neoplasia|url=https://www.sciencedirect.com/science/article/pii/S0006497120429210|journal=Blood|volume=132|issue=25|pages=2687–2690|doi=10.1182/blood-2018-03-837039|issn=0006-4971}}</ref>.
<br />
|-
|'''''EZH2'''''
p.Y646, p.A682G, p.A692V
Gain of function variants. Y646 may have multiple amino acid replacements
|
|8.7%<ref name=":0" />
|
|
|
|
|
|
|}
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==

Put your text here

==Genes and Main Pathways Involved==

Put your text here and fill in the table
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|-
|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
|}
==Genetic Diagnostic Testing Methods==

Put your text here

==Familial Forms==

Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>

==Additional Information==

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==Links==

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==References==
<references />
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==Notes==
<nowiki>*</nowiki>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.


<nowiki>*</nowiki>''Citation of this Page'': “In situ follicular B-cell neoplasm”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:In_situ_follicular_B-cell_neoplasm</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases I]]