Bailey.Glen at 21:42, 4 December 2023

2023-12-04T21:42:25Z

← Older revision		Revision as of 16:42, 4 December 2023
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	==Cancer Category/Type==		==Cancer Category/Type==

	[[Classic Hodgkin Lymphoma]]		[[HAEM4:Classic Hodgkin Lymphoma]]

	==Cancer Sub-Classification / Subtype==		==Cancer Sub-Classification / Subtype==
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	==Definition / Description of Disease==		==Definition / Description of Disease==

	Hodgkin lymphomas (HL) are a group of B-cell neoplasms that arise in lymph nodes, categorized mainly into nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and classic Hodgkin lymphoma (CHL). CHL accounts for approximately 90% of HL and is subdivided into four histologic types, [[~~Nodular Sclerosis~~ Classic Hodgkin ~~Lymphoma~~\|nodular sclerosis CHL (NSCHL)]], [[~~Lymphocyte-Rich~~ Classic Hodgkin ~~Lymphoma~~\|lymphocyte-rich CHL]], [[~~Mixed Cellularity~~ Classic Hodgkin ~~Lymphoma~~\|mixed cellularity CHL]], and [[~~Lymphocyte-Depleted~~ Classic Hodgkin ~~Lymphoma~~\|lymphocyte-depleted CHL]]. NSCHL is the most common type of CHL and is characterized by the appearance of nodular growth surrounded by prominent collagen bands and the presence of lacunar type Hodgkin/Reed-Sternberg cells (HRS).		Hodgkin lymphomas (HL) are a group of B-cell neoplasms that arise in lymph nodes, categorized mainly into nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and classic Hodgkin lymphoma (CHL). CHL accounts for approximately 90% of HL and is subdivided into four histologic types, [[HAEM5:Classic Hodgkin lymphoma\|nodular sclerosis CHL (NSCHL)]], [[HAEM5:Classic Hodgkin lymphoma\|lymphocyte-rich CHL]], [[HAEM5:Classic Hodgkin lymphoma\|mixed cellularity CHL]], and [[HAEM5:Classic Hodgkin lymphoma\|lymphocyte-depleted CHL]]. NSCHL is the most common type of CHL and is characterized by the appearance of nodular growth surrounded by prominent collagen bands and the presence of lacunar type Hodgkin/Reed-Sternberg cells (HRS).

	==Synonyms / Terminology==		==Synonyms / Terminology==
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	==Links==		==Links==

	[[Hodgkin Lymphomas\|Hodgkin Lymphoma]]		[[HAEM4:Hodgkin Lymphomas\|Hodgkin Lymphoma]]

	[[Classic Hodgkin Lymphoma]]		[[HAEM4:Classic Hodgkin Lymphoma]]

	[[~~Nodular Sclerosis~~ Classic Hodgkin ~~Lymphoma~~\|Nodular sclerosis CHL]]		[[HAEM5:Classic Hodgkin lymphoma\|Nodular sclerosis CHL]]

	[[~~Lymphocyte-Rich~~ Classic Hodgkin ~~Lymphoma~~\|Lymphocyte-rich CHL]]		[[HAEM5:Classic Hodgkin lymphoma\|Lymphocyte-rich CHL]]

	[[~~Mixed Cellularity~~ Classic Hodgkin ~~Lymphoma~~\|Mixed cellularity CHL]]		[[HAEM5:Classic Hodgkin lymphoma\|Mixed cellularity CHL]]

	[[~~Lymphocyte-Depleted~~ Classic Hodgkin ~~Lymphoma~~\|Lymphocyte-depleted CHL]]		[[HAEM5:Classic Hodgkin lymphoma\|Lymphocyte-depleted CHL]]

	<br />		<br />

Bailey.Glen at 18:58, 3 November 2023

2023-11-03T18:58:04Z

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 ==Primary Author(s)*==
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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.

Bailey.Glen: Created page with "==Primary Author(s)*== Xiaolin Hu, PhD, Sema4 OpCo Inc. TOC ==Cancer Category/Type== Classic Hodgkin Lymphoma ==Cancer Sub-Classification / Subtype== Nodular scl..."

2023-11-03T18:23:44Z

Created page with "==Primary Author(s)*== Xiaolin Hu, PhD, Sema4 OpCo Inc. __TOC__ ==Cancer Category/Type== Classic Hodgkin Lymphoma ==Cancer Sub-Classification / Subtype== Nodular scl..."

New page

==Primary Author(s)*==

Xiaolin Hu, PhD, Sema4 OpCo Inc.

__TOC__

==Cancer Category/Type==

[[Classic Hodgkin Lymphoma]]

==Cancer Sub-Classification / Subtype==

Nodular sclerosis classic Hodgkin lymphoma

==Definition / Description of Disease==

Hodgkin lymphomas (HL) are a group of B-cell neoplasms that arise in lymph nodes, categorized mainly into nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and classic Hodgkin lymphoma (CHL). CHL accounts for approximately 90% of HL and is subdivided into four histologic types, [[Nodular Sclerosis Classic Hodgkin Lymphoma|nodular sclerosis CHL (NSCHL)]], [[Lymphocyte-Rich Classic Hodgkin Lymphoma|lymphocyte-rich CHL]], [[Mixed Cellularity Classic Hodgkin Lymphoma|mixed cellularity CHL]], and [[Lymphocyte-Depleted Classic Hodgkin Lymphoma|lymphocyte-depleted CHL]]. NSCHL is the most common type of CHL and is characterized by the appearance of nodular growth surrounded by prominent collagen bands and the presence of lacunar type Hodgkin/Reed-Sternberg cells (HRS).

==Synonyms / Terminology==

Hodgkin disease, nodular sclerosis, NOS

Hodgkin lymphoma, nodular sclerosis, grade 1

Hodgkin lymphoma, nodular sclerosis, grade 2

Hodgkin lymphoma, nodular sclerosis, cellular phase

==Epidemiology / Prevalence==

CHL has an incidence of 2-3 cases per 100000 people every year in developed country <ref>{{Cite journal|last=Yung|first=Lynny|last2=Linch|first2=David|date=2003-03-15|title=Hodgkin's lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/12648984|journal=Lancet (London, England)|volume=361|issue=9361|pages=943–951|doi=10.1016/S0140-6736(03)12777-8|issn=0140-6736|pmid=12648984}}</ref>. NSCHL is the most common type of CHL in developed countries, accounting for 70% of diagnosed cases. It is seen most in individuals between 15 and 35 years old, affecting both males and females at similar frequency. Concurrent Epstein-Barr virus infection is found in approximately 25%-40% CHL but the percentages vary in different subtypes <ref>{{Cite journal|last=Brice|first=Pauline|last2=de Kerviler|first2=Eric|last3=Friedberg|first3=Jonathan W.|date=2021-10-23|title=Classical Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/33493434|journal=Lancet (London, England)|volume=398|issue=10310|pages=1518–1527|doi=10.1016/S0140-6736(20)32207-8|issn=1474-547X|pmid=33493434}}</ref>. EBV-positivity is not as common in the context of NSCHL as it is in mixed cellularity and lymphocyte-depleted subtypes of CHL. Reported frequencies of EBV positive NSCHL range from 10-40% <ref>{{Cite journal|last=Zanelli|first=Magda|last2=Sanguedolce|first2=Francesca|last3=Palicelli|first3=Andrea|last4=Zizzo|first4=Maurizio|last5=Martino|first5=Giovanni|last6=Caprera|first6=Cecilia|last7=Fragliasso|first7=Valentina|last8=Soriano|first8=Alessandra|last9=Valle|first9=Luca|date=2021-09-12|title=EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 1)|url=https://pubmed.ncbi.nlm.nih.gov/34572803|journal=Cancers|volume=13|issue=18|pages=4578|doi=10.3390/cancers13184578|issn=2072-6694|pmc=8465149|pmid=34572803}}</ref> <ref>{{Cite journal|last=Campos|first=Antonio Hugo Jose Froes Marques|last2=Moreira|first2=Adriana|last3=Ribeiro|first3=Karina Braga|last4=Paes|first4=Roberto Pinto|last5=Zerbini|first5=Maria Claudia|last6=Aldred|first6=Vera|last7=de Souza|first7=Carmino Antonio|last8=Neto|first8=Cristovam Scapulatempo|last9=Soares|first9=Fernando Augusto|date=2018-01-30|title=Frequency of EBV associated classical Hodgkin lymphoma decreases over a 54-year period in a Brazilian population|url=https://pubmed.ncbi.nlm.nih.gov/29382865|journal=Scientific Reports|volume=8|issue=1|pages=1849|doi=10.1038/s41598-018-20133-6|issn=2045-2322|pmc=5789833|pmid=29382865}}</ref>, some of this variation may be accounted for by differences in detection techniques used.

==Clinical Features==

Clinical staging is based on the revised Ann Arbor system (stage I to IV), with incorporation of clinical signs/symptoms and CT/PET scan data <ref>{{Cite journal|last=Cheson|first=Bruce D.|last2=Fisher|first2=Richard I.|last3=Barrington|first3=Sally F.|last4=Cavalli|first4=Franco|last5=Schwartz|first5=Lawrence H.|last6=Zucca|first6=Emanuele|last7=Lister|first7=T. Andrew|last8=Alliance, Australasian Leukaemia and Lymphoma Group|last9=Eastern Cooperative Oncology Group|date=2014-09-20|title=Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification|url=https://pubmed.ncbi.nlm.nih.gov/25113753|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=32|issue=27|pages=3059–3068|doi=10.1200/JCO.2013.54.8800|issn=1527-7755|pmc=4979083|pmid=25113753}}</ref>. 40% of patients at diagnosis are at stage II (lymphoma involves two or more lymph nodes on the same side of the diaphragm) with B symptoms. Patients may present with a mediastinal mass, including bulky disease where the mediastinal mass exceeds 1/3 of the width of the thoracic cavity, or any mass ≥ 10 cm in any dimension when measured via CT scan.
{| class="wikitable"
|'''B Symptoms'''
|
*weight loss, fever, night sweats, fatigue
*pruritus
*chest pain, cough, dyspnea
|}

==Sites of Involvement==

Mediastinum - 80%

Spleen/lung - 5%

Bone marrow - 3%

Liver - 2 %

==Morphologic Features==
The lymph node capsule is thickened with prominent collagen bands dividing the lymph node into variable nodules, which are composed of highly variable mixture of neoplastic and inflammatory cells, including small lymphocytes, eosinophils, histiocytes and neutrophils.

The neoplastic cells do not have the classical binucleate appearance of Reed-Sternberg cells seen in other types of HL. Instead they tend to have multilobated nuclei, smaller nucleoli than classical Reed Sternberg cells, coarse chromatin, and when formalin-fixed the cells have the appearance of being surrounded by an empty space (lacuna) due to the retraction and condensation of the cytoplasm. These lacunar cells can form large clusters attracting aggregation of inflammatory cells especially eosinophils and histiocytes, resembling necrotizing granulomas. This is called syncytial variant of NSCHL.

Nodular necrosis can be seen in higher grade lymphoma and cystic degeneration is commonly seen with thymic involvement.

==Immunophenotype==

R-S cells, including lacunar cells, have a typical immunophenotype as CD30+, CD15+/−, CD20−/+, CD19−, CD45−, EBV/EBER−/+, PAX5+, EMA−, and MUM1.

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||CD30, PAX5,
|-
|Positive (subset)||CD15, CD20, CD79a, CD4, CD2, EBV
|-
|Negative (universal)||CD19, CD45, EMA
|-
|Negative (subset)||CD15, CD20, EBV
|}

==Chromosomal Rearrangements (Gene Fusions)==

Translocation breakpoints involving immunoglobin loci have been reported in approximately 20% of CHL. Some translocations may involve known oncogenes such as ''BCL1,'' ''BCL2'', ''BCL3'', ''BCL6'', ''REL'' and ''MYC'', but most of partners are unknown <ref>{{Cite journal|last=Martín-Subero|first=José I.|last2=Klapper|first2=Wolfram|last3=Sotnikova|first3=Anna|last4=Callet-Bauchu|first4=Evelyne|last5=Harder|first5=Lana|last6=Bastard|first6=Christian|last7=Schmitz|first7=Roland|last8=Grohmann|first8=Susanne|last9=Höppner|first9=Jorge|date=2006-11-01|title=Chromosomal breakpoints affecting immunoglobulin loci are recurrent in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/17079453|journal=Cancer Research|volume=66|issue=21|pages=10332–10338|doi=10.1158/0008-5472.CAN-06-1992|issn=0008-5472|pmid=17079453}}</ref><ref>{{Cite journal|last=Szymanowska|first=Natalia|last2=Klapper|first2=Wolfram|last3=Gesk|first3=Stefan|last4=Küppers|first4=Ralf|last5=Martín-Subero|first5=José I.|last6=Siebert|first6=Reiner|date=2008-10-15|title=BCL2 and BCL3 are recurrent translocation partners of the IGH locus|url=https://pubmed.ncbi.nlm.nih.gov/18940474|journal=Cancer Genetics and Cytogenetics|volume=186|issue=2|pages=110–114|doi=10.1016/j.cancergencyto.2008.06.007|issn=1873-4456|pmid=18940474}}</ref>. Disease-specific translocations have not been characterized in NSCHL. t(14;18) is common in certain types of non-Hodgkin lymphoma but is a rare event in HL. ''CIITA'' rearrangements have been detected in 15% of CHL by fluorescence in situ hybridization (FISH) <ref>{{Cite journal|last=Steidl|first=Christian|last2=Shah|first2=Sohrab P.|last3=Woolcock|first3=Bruce W.|last4=Rui|first4=Lixin|last5=Kawahara|first5=Masahiro|last6=Farinha|first6=Pedro|last7=Johnson|first7=Nathalie A.|last8=Zhao|first8=Yongjun|last9=Telenius|first9=Adele|date=2011-03-17|title=MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers|url=https://pubmed.ncbi.nlm.nih.gov/21368758|journal=Nature|volume=471|issue=7338|pages=377–381|doi=10.1038/nature09754|issn=1476-4687|pmc=3902849|pmid=21368758}}</ref>.
==Individual Region Genomic Gain/Loss/LOH==

Chromosome analysis usually renders a normal karyotype, due to the paucity of neoplastic cells. Studies have shown that HRS cells may exhibit complex karyotypes including triploidy, tetraploidy, multiple aneuploidies and copy number variations (CNV) <ref>{{Cite journal|last=Weber-Matthiesen|first=K.|last2=Deerberg|first2=J.|last3=Poetsch|first3=M.|last4=Grote|first4=W.|last5=Schlegelberger|first5=B.|date=1995-08-15|title=Numerical chromosome aberrations are present within the CD30+ Hodgkin and Reed-Sternberg cells in 100% of analyzed cases of Hodgkin's disease|url=https://pubmed.ncbi.nlm.nih.gov/7632954|journal=Blood|volume=86|issue=4|pages=1464–1468|issn=0006-4971|pmid=7632954}}</ref>. Recurrent CNVs have been reported in 5-20% of CHL, involving chromosome 1p, 2p, 6q, 7q, 8q, 9p, 11q, 12q, 13q, 14q, 16p, 17q, 19 and 20q <ref>{{Cite journal|last=Falzetti|first=D.|last2=Crescenzi|first2=B.|last3=Matteuci|first3=C.|last4=Falini|first4=B.|last5=Martelli|first5=M. F.|last6=Van Den Berghe|first6=H.|last7=Mecucci|first7=C.|date=1999-04|title=Genomic instability and recurrent breakpoints are main cytogenetic findings in Hodgkin's disease|url=https://pubmed.ncbi.nlm.nih.gov/10190942|journal=Haematologica|volume=84|issue=4|pages=298–305|issn=0390-6078|pmid=10190942}}</ref><ref>{{Cite journal|last=Steidl|first=Christian|last2=Telenius|first2=Adele|last3=Shah|first3=Sohrab P.|last4=Farinha|first4=Pedro|last5=Barclay|first5=Lorena|last6=Boyle|first6=Merrill|last7=Connors|first7=Joseph M.|last8=Horsman|first8=Douglas E.|last9=Gascoyne|first9=Randy D.|date=2010-07-22|title=Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome|url=https://pubmed.ncbi.nlm.nih.gov/20339089|journal=Blood|volume=116|issue=3|pages=418–427|doi=10.1182/blood-2009-12-257345|issn=1528-0020|pmid=20339089}}</ref>. Among these, deletions are associated with loss of function in 6q (''TNFAIP3)'' <ref name=":0">{{Cite journal|last=Schmitz|first=Roland|last2=Hansmann|first2=Martin-Leo|last3=Bohle|first3=Verena|last4=Martin-Subero|first4=Jose Ignacio|last5=Hartmann|first5=Sylvia|last6=Mechtersheimer|first6=Gunhild|last7=Klapper|first7=Wolfram|last8=Vater|first8=Inga|last9=Giefing|first9=Maciej|date=2009-05-11|title=TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19380639|journal=The Journal of Experimental Medicine|volume=206|issue=5|pages=981–989|doi=10.1084/jem.20090528|issn=1540-9538|pmc=2715030|pmid=19380639}}</ref>, 14q (''IKBA'') and 16p (''SOCS1''), duplications are associated with gain of function in 2p (''REL'') <ref>{{Cite journal|last=Barth|first=Thomas F. E.|last2=Martin-Subero|first2=Josée I.|last3=Joos|first3=Stefan|last4=Menz|first4=Christiane K.|last5=Hasel|first5=Cornelia|last6=Mechtersheimer|first6=Gunhild|last7=Parwaresch|first7=Reza M.|last8=Lichter|first8=Peter|last9=Siebert|first9=Reiner|date=2003-05-01|title=Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/12511414|journal=Blood|volume=101|issue=9|pages=3681–3686|doi=10.1182/blood-2002-08-2577|issn=0006-4971|pmid=12511414}}</ref> and 9p (''JAK2, PDL1'' and ''PDL2'') <ref>{{Cite journal|last=Green|first=Michael R.|last2=Monti|first2=Stefano|last3=Rodig|first3=Scott J.|last4=Juszczynski|first4=Przemyslaw|last5=Currie|first5=Treeve|last6=O'Donnell|first6=Evan|last7=Chapuy|first7=Bjoern|last8=Takeyama|first8=Kunihiko|last9=Neuberg|first9=Donna|date=2010-10-28|title=Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/20628145|journal=Blood|volume=116|issue=17|pages=3268–3277|doi=10.1182/blood-2010-05-282780|issn=1528-0020|pmc=2995356|pmid=20628145}}</ref>.
==Characteristic Chromosomal Patterns==

Not reported.
==Gene Mutations (SNV/INDEL)==

Recurrent sequencing mutations have been detected in genes involved in several cell signaling pathways that promote proliferation and growth in CHL. ''STAT6'' and ''SOCS1'' are the most commonly involved genes, and are associated with the JAK-STAT signalling pathway <ref name=":1">{{Cite journal|last=Tiacci|first=Enrico|last2=Ladewig|first2=Erik|last3=Schiavoni|first3=Gianluca|last4=Penson|first4=Alex|last5=Fortini|first5=Elisabetta|last6=Pettirossi|first6=Valentina|last7=Wang|first7=Yuchun|last8=Rosseto|first8=Ariele|last9=Venanzi|first9=Alessandra|date=2018-05-31|title=Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/29650799|journal=Blood|volume=131|issue=22|pages=2454–2465|doi=10.1182/blood-2017-11-814913|issn=1528-0020|pmc=6634958|pmid=29650799}}</ref><ref>{{Cite journal|last=Spina|first=Valeria|last2=Bruscaggin|first2=Alessio|last3=Cuccaro|first3=Annarosa|last4=Martini|first4=Maurizio|last5=Di Trani|first5=Martina|last6=Forestieri|first6=Gabriela|last7=Manzoni|first7=Martina|last8=Condoluci|first8=Adalgisa|last9=Arribas|first9=Alberto|date=2018-05-31|title=Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/29449275|journal=Blood|volume=131|issue=22|pages=2413–2425|doi=10.1182/blood-2017-11-812073|issn=1528-0020|pmid=29449275}}</ref>. ''TNFAIP3'', ''NFKBIA'' variants are associated with dysregulation of the NF-kB pathway. ''ITPKB'' and ''GNA13'' variants are associated with disruption of the PI3K/AKT pathway <ref name=":1" />. Other reported common variants in HL include ''XPO1'', ''B2M'' and ''TP53'' <ref name=":2">{{Cite journal|last=Liang|first=Winnie S.|last2=Vergilio|first2=Jo-Anne|last3=Salhia|first3=Bodour|last4=Huang|first4=Helen J.|last5=Oki|first5=Yasuhiro|last6=Garrido-Laguna|first6=Ignacio|last7=Park|first7=Haeseong|last8=Westin|first8=Jason R.|last9=Meric-Bernstam|first9=Funda|date=2019-02|title=Comprehensive Genomic Profiling of Hodgkin Lymphoma Reveals Recurrently Mutated Genes and Increased Mutation Burden|url=https://pubmed.ncbi.nlm.nih.gov/30108156|journal=The Oncologist|volume=24|issue=2|pages=219–228|doi=10.1634/theoncologist.2018-0058|issn=1549-490X|pmc=6369943|pmid=30108156}}</ref>. Studies using genomic profiling report that HL has an overall increased mutational burden <ref name=":2" />.

{| 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
|-
|''TNFAIP3''
|TSG
|20% (COSMIC) in HL
|NA
|NA
|Unknown
|
|
|
|-
|''SOCS1''
|TSG
|47% (COSMIC) in HL
|NA
|NA
|Unknown
|
|
|
|-
|''GNA13''
|G protein
|24% <ref name=":1" /> in CHL
|NA
|NA
|Unknown
|
|
|
|-
|''ITPKB''
|Kinase
|16% <ref name=":1" /> in CHL
|NA
|NA
|Unknown
|
|
|
|-
|''STAT6''
|Oncogene
|32% <ref name=":1" /> in CHL
|NA
|NA
|Unknown
|
|
|
|-
|''XPO1''
|protein transporter
|18% <ref name=":1" /> in CHL
|NA
|NA
|Unknown
|
|
|
|-
|''B2M''
|MHC class I molecule
|26% <ref name=":1" /> in CHL
|NA
|NA
|Unknown
|
|
|
|}
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==

Promoter hypermethylation may play a role in silencing B-cell specific genes such as ''SYK, PU.1, CD19,'' and ''CD79B'' <ref>{{Cite journal|last=Ushmorov|first=Alexey|last2=Leithäuser|first2=Frank|last3=Sakk|first3=Olena|last4=Weinhaüsel|first4=Andreas|last5=Popov|first5=Sergey W.|last6=Möller|first6=Peter|last7=Wirth|first7=Thomas|date=2006-03-15|title=Epigenetic processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/16304050|journal=Blood|volume=107|issue=6|pages=2493–2500|doi=10.1182/blood-2005-09-3765|issn=0006-4971|pmid=16304050}}</ref> as well as genes involved in a variety of biological functions <ref>{{Cite journal|last=Dhiab|first=Myriam Ben|last2=Ziadi|first2=Sonia|last3=Mestiri|first3=Sarra|last4=Gacem|first4=Riadh Ben|last5=Ksiaa|first5=Feryel|last6=Trimeche|first6=Mounir|date=2015-12|title=DNA methylation patterns in EBV-positive and EBV-negative Hodgkin lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/26350502|journal=Cellular Oncology (Dordrecht)|volume=38|issue=6|pages=453–462|doi=10.1007/s13402-015-0242-8|issn=2211-3436|pmid=26350502}}</ref>''.'' Some isoforms of histone deacetylases (HDAC) are highly expressed in HL <ref>{{Cite journal|last=Adams|first=Heiner|last2=Fritzsche|first2=Florian R.|last3=Dirnhofer|first3=Stephan|last4=Kristiansen|first4=Glen|last5=Tzankov|first5=Alexandar|date=2010-06|title=Class I histone deacetylases 1, 2 and 3 are highly expressed in classical Hodgkin's lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/20415600|journal=Expert Opinion on Therapeutic Targets|volume=14|issue=6|pages=577–584|doi=10.1517/14728221003796609|issn=1744-7631|pmid=20415600}}</ref>.

==Genes and Main Pathways Involved==

Both canonical and non-canonical NF-kB pathways have been reported to be constitutively activated, resulting in HRS cell proliferation and survival. The deregulation of NF-kB signaling may be influenced by the tumor microenvironment but can also be caused by genetic alterations in components of the B-cell receptor (BCR), Toll-like receptor signaling (TLR), and the NF-kB pathway itself <ref>{{Cite journal|last=Weniger|first=Marc A.|last2=Küppers|first2=Ralf|date=2016-08|title=NF-κB deregulation in Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/27221964|journal=Seminars in Cancer Biology|volume=39|pages=32–39|doi=10.1016/j.semcancer.2016.05.001|issn=1096-3650|pmid=27221964}}</ref>. ''TNFAIP3'', a NF-kB inhibitor, is commonly mutated in HL not associated with concurrent EBV infection, suggesting NF-kB activation and EBV are two different mechanisms to transform HRS cells <ref name=":0" />.

The JAK/STAT signaling pathway is constitutively activated in CHL, which is likely an aberration caused by both deregulated cytokines/chemokines, and/or genetic lesions in the JAK/STAT pathway. The cytokine and chemokines produced by the HRS cells could further stimulate the proinflammatory environment to promote tumor growth and proliferation <ref>{{Cite journal|last=Steidl|first=Christian|last2=Connors|first2=Joseph M.|last3=Gascoyne|first3=Randy D.|date=2011-05-10|title=Molecular pathogenesis of Hodgkin's lymphoma: increasing evidence of the importance of the microenvironment|url=https://pubmed.ncbi.nlm.nih.gov/21483001|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=29|issue=14|pages=1812–1826|doi=10.1200/JCO.2010.32.8401|issn=1527-7755|pmid=21483001}}</ref>. Other signaling pathways that may play a role in the pathogenesis include Notch1 signaling, PI2K/AKT pathway and MAPK/ERK pathway <ref>{{Cite journal|last=Jundt|first=F.|last2=Acikgöz|first2=O.|last3=Kwon|first3=S.-H.|last4=Schwarzer|first4=R.|last5=Anagnostopoulos|first5=I.|last6=Wiesner|first6=B.|last7=Mathas|first7=S.|last8=Hummel|first8=M.|last9=Stein|first9=H.|date=2008-08|title=Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/18449208|journal=Leukemia|volume=22|issue=8|pages=1587–1594|doi=10.1038/leu.2008.101|issn=1476-5551|pmid=18449208}}</ref><ref>{{Cite journal|last=Dutton|first=Amanda|last2=Reynolds|first2=Gary M.|last3=Dawson|first3=Christopher W.|last4=Young|first4=Lawrence S.|last5=Murray|first5=Paul G.|date=2005-03|title=Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR|url=https://pubmed.ncbi.nlm.nih.gov/15714459|journal=The Journal of Pathology|volume=205|issue=4|pages=498–506|doi=10.1002/path.1725|issn=0022-3417|pmid=15714459}}</ref><ref>{{Cite journal|last=Zheng|first=Bei|last2=Fiumara|first2=Paolo|last3=Li|first3=Yang V.|last4=Georgakis|first4=Georgios|last5=Snell|first5=Virginia|last6=Younes|first6=Mamoun|last7=Vauthey|first7=Jean Nicolas|last8=Carbone|first8=Antonino|last9=Younes|first9=Anas|date=2003-08-01|title=MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival|url=https://pubmed.ncbi.nlm.nih.gov/12689928|journal=Blood|volume=102|issue=3|pages=1019–1027|doi=10.1182/blood-2002-11-3507|issn=0006-4971|pmid=12689928}}</ref>.
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|''TNFAIP3'' inactivating mutations
''REL'' amplification

''NFKBIA, NFKBIE'' inactivating mutations
|NF-kB signalling
|Promotes HRS cell survival<br />
|-
|''JAK2'', chromosome gain, translocation
''SOCS1'', inactivating mutation

''STAT6, STAT3, STAT5b,'' activating mutations
|JAK/STAT signalling
|Promotes HRS cell growth and survival
|-
|''PD1, PDL1,'' chromosome gain
|immune checkpoint
|Creates an immunosuppressive microenvironment
|}
==Genetic Diagnostic Testing Methods==

There is no definitive genetic diagnostic testing for NSCHL. The diagnosis is mainly based on clinical symptoms and histopathological findings.

==Familial Forms==

Familial Hodgkin Lymphoma Predisposing Genes are under investigation.

==Additional Information==

Overall, NSCHL has good prognosis when compared to other subtypes of CHL, with a 5-year survival rate over 80% <ref>{{Cite journal|last=Allemani|first=Claudia|last2=Sant|first2=Milena|last3=De Angelis|first3=Roberta|last4=Marcos-Gragera|first4=Rafael|last5=Coebergh|first5=Jan Willem|last6=EUROCARE Working Group|date=2006-07-15|title=Hodgkin disease survival in Europe and the U.S.: prognostic significance of morphologic groups|url=https://pubmed.ncbi.nlm.nih.gov/16770772|journal=Cancer|volume=107|issue=2|pages=352–360|doi=10.1002/cncr.21995|issn=0008-543X|pmid=16770772}}</ref>. Bulky disease at diagnosis is an adverse prognostic indicator.

==Links==

[[Hodgkin Lymphomas|Hodgkin Lymphoma]]

[[Classic Hodgkin Lymphoma]]

[[Nodular Sclerosis Classic Hodgkin Lymphoma|Nodular sclerosis CHL]]

[[Lymphocyte-Rich Classic Hodgkin Lymphoma|Lymphocyte-rich CHL]]

[[Mixed Cellularity Classic Hodgkin Lymphoma|Mixed cellularity CHL]]

[[Lymphocyte-Depleted Classic Hodgkin Lymphoma|Lymphocyte-depleted CHL]]

<br />

==References==
<references />

==Notes==
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HAEM4:Nodular Sclerosis Classic Hodgkin Lymphoma - Revision history

Bailey.Glen at 21:42, 4 December 2023

Bailey.Glen at 18:58, 3 November 2023

Bailey.Glen: Created page with "==Primary Author(s)*== Xiaolin Hu, PhD, Sema4 OpCo Inc. __TOC__ ==Cancer Category/Type== Classic Hodgkin Lymphoma ==Cancer Sub-Classification / Subtype== Nodular scl..."

Bailey.Glen: Created page with "==Primary Author(s)*== Xiaolin Hu, PhD, Sema4 OpCo Inc. TOC ==Cancer Category/Type== Classic Hodgkin Lymphoma ==Cancer Sub-Classification / Subtype== Nodular scl..."