Compendium of Cancer Genome Aberrations

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

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


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


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|}
|}


==Definition / Description of Disease==
==Related Terminology==
 
''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 name=":1">{{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-
|}


==WHO Essential and Desirable Genetic Diagnostic Criteria==
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
{| class="wikitable"
|+
|WHO Essential Criteria (Genetics)*
|
|-
|WHO Desirable Criteria (Genetics)*
|
|-
|Other Classification
|
|}
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
==Related Terminology==
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
{| class="wikitable"
{| class="wikitable"
|+
|+
|Acceptable
|Acceptable
|
|In situ follicular neoplasia
|-
|-
|Not Recommended
|Not Recommended
|
|Follicular lymphoma in situ
|}
|}


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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 name=":1" /><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>
|}
|}


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{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
!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'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
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!Chromosomal Pattern
!Chromosomal Pattern
!Molecular Pathogenesis
!Molecular Pathogenesis
!'''Prevalence -'''
!Prevalence -  
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
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{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|<span class="blue-text">EXAMPLE:</span>''EGFR''
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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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==Additional Information==
==Additional Information==


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


==Links==
==Links==
Retrieved from "https://test.ccga.io/index.php/HAEM5:In_situ_follicular_B-cell_neoplasm"