Compendium of Cancer Genome Aberrations

HAEM5:In situ follicular B-cell neoplasm: Difference between revisions

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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]].
<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]].
}}</blockquote>
}}</blockquote>


<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>
<span style="color:#0070C0">(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], 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 in a table, click nearby within the table and select the > symbol that appears. 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)*==
==Primary Author(s)*==


Rachel D. Burnside, PhD, MBA, FACMGG
Rachel D. Burnside, PhD, MBA, FACMGG
==WHO Classification of Disease==


__TOC__
{| 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
|}


==Cancer Category / Type==
==Related Terminology==


Mature B-cell neoplasm
==Cancer Sub-Classification / Subtype==
''In situ'' follicular B-cell neoplasm (ISFN)
==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"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)
|Acceptable
 
|In situ follicular neoplasia
<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'''
|Not Recommended
|<span class="blue-text">EXAMPLE:</span> Cytopenias
|Follicular lymphoma in situ
 
<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
|}
|}


==Sites of Involvement==
==Gene Rearrangements==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
|-
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|<span class="blue-text">EXAMPLE:</span>
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). BCR::ABL1 is generally favorable in CML (add reference).
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
|<span class="blue-text">EXAMPLE:</span> D
|
|<span class="blue-text">EXAMPLE:</span>


Abnormal B-cells are confined to the germinal centers in otherwise reactive lymph nodes and do not infiltrate the interfollucular regions.
''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''


==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>
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
 
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
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>:
|<span class="blue-text">EXAMPLE:</span> N/A
 
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
*Unlike early-stage or partial involvement of FL, ''in situ'' FL retains follicular architecture with normal-sized follicles;
|<span class="blue-text">EXAMPLE:</span> T
*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;
|<span class="blue-text">EXAMPLE:</span>
*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"
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|-
!Finding!!Marker
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|-
|-
|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
Put your text here and fill in the table
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|No
|No
|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>
|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 name=":1">{{Cite journal|last=Jegalian|first=Armin G.|last2=Eberle|first2=Franziska C.|last3=Pack|first3=Svetlana D.|last4=Mirvis|first4=Mariya|last5=Raffeld|first5=Mark|last6=Pittaluga|first6=Stefania|last7=Jaffe|first7=Elaine S.|date=2011-09-15|title=Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/21768298|journal=Blood|volume=118|issue=11|pages=2976–2984|doi=10.1182/blood-2011-05-355255|issn=1528-0020|pmc=3175777|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==
==Individual Region Genomic Gain/Loss/LOH==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
|-
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span>
7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>
chr7
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> 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 references).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|<span class="blue-text">EXAMPLE:</span>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|<span class="blue-text">EXAMPLE:</span>
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
|-
|
|
|
|
|
|
|
|}


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Common recurrent secondary finding for t(8;21) (add reference).
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>
==Characteristic Chromosomal or Other Global Mutational Patterns==


Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as 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; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Molecular Pathogenesis
!Prognostic Significance (Yes, No or Unknown)
!Prevalence -
!Therapeutic Significance (Yes, No or Unknown)
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Notes
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
Co-deletion of 1p and 18q
Co-deletion of 1p and 18q
|Yes
|<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).
|No
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|No
|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
Microsatellite instability - hypermutated
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|-
|
|
|
|
|
|
|}
==Gene Mutations (SNV/INDEL)==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
|-
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''


See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
<br />
|}
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
==Gene Mutations (SNV / INDEL)==
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|<span class="blue-text">EXAMPLE:</span> T
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|<span class="blue-text">EXAMPLE:</span> P
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|
|-
|
|
|
|
|
|
|
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


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{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!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)'''
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
!Notes
|-
|-
|'''''CREBBP''''' inactivating missense variants (various); mutation hotspots in exons 24-28 and exon 30.
|''CREBBP'' inactivating missense variants (various); mutation hotspots in exons 24-28 and exon 30.
|TSG
|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>
|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>
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|
|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>.
|Inactivating mutations prevent acetylation of the protein and creates an environment permissive for accumulation of mutations<ref name=":2">{{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://pubmed.ncbi.nlm.nih.gov/30401710|journal=Blood|volume=132|issue=25|pages=2687–2690|doi=10.1182/blood-2018-03-837039|issn=1528-0020|pmc=6302496|pmid=30401710}}</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 name=":2" />.
<br />
<br />
|-
|-
|'''''EZH2'''''
|''EZH2''
p.Y646, p.A682G, p.A692V
p.Y646, p.A682G, p.A692V
Gain of function variants. Y646 may have multiple amino acid replacements
Gain of function variants. Y646 may have multiple amino acid replacements
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==Epigenomic Alterations==
==Epigenomic Alterations==


Put your text here
Put your text here
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==


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==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


Put your text here


Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>
==Familial Forms==
==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>
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==
This disease is <u>defined/characterized</u> as detailed below:
* ''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.<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>
The <u>epidemiology/prevalence</u> of this disease is detailed below:
* 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>


==Additional Information==
The <u>sites of involvement</u> of this disease are detailed below:
 
* Abnormal B-cells are confined to the germinal centers in otherwise reactive lymph nodes and do not infiltrate the interfollucular regions.
 
The <u>morphologic features</u> of this disease are detailed below:
 
* 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 name=":1" />:
**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)
 
The <u>immunophenotype</u> of this disease is detailed below:
 
* Low Ki67 index
 
* Positive (universal) - BCL2+ (strong), CD10+ (strong)


Put your text here
* Negative (universal) - IGD-, CD3-


==Links==
==Links==


Put your text placeholder here (or anywhere appropriate on the page) and use the "Link" icon at the top of the page <span style="color:#0070C0">(''Instructions: Highlight text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>


Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>
==References==
==References==
<references />
<references />
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<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>.
<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]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases I]]
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